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Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Annals of the rheumatic diseases OBJECTIVE:Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on the cardiovascular impact of HCQ in patients with RA. METHODS:We systematically searched for studies evaluating the effects of HCQ on cardiovascular outcomes of known risk factors for CVD in patients with RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another. RESULTS:The literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were -9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis. CONCLUSION:Besides its limited efficacy for disease activity and progression, HCQ may benefit the metabolic profile and to a lesser extent cardiovascular events in patients with RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs. 10.1136/annrheumdis-2017-211836
Extrahepatic Manifestations of Hepatitis C: A Meta-analysis of Prevalence, Quality of Life, and Economic Burden. Younossi Zobair,Park Haesuk,Henry Linda,Adeyemi Ayoade,Stepanova Maria Gastroenterology BACKGROUND & AIMS:Hepatitis C virus (HCV) infection has hepatic and extrahepatic manifestations with various costs and impairments to health-related quality of life (HRQL). We performed a meta-analysis to determine the prevalence of extrahepatic manifestations in patients with HCV infection, how these impair HRQL, and their costs. METHODS:We performed systematic reviews of the literature using MEDLINE, CINAHL, and the Cochrane Systematic Review Database, from 1996 through December 2014, to identify studies of the following extrahepatic manifestations of HCV infection: mixed cryoglobulinemia, chronic kidney or end-stage renal disease, type 2 diabetes, B-cell lymphoma, lichen planus, Sjögren's syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, or depression. We performed a separate meta-analysis for each condition to determine prevalence rates of extrahepatic manifestations of HCV infection and their effects on HRQL. We determined the annual costs (inpatient, outpatient, and pharmacy) associated with extrahepatic manifestations of HCV infection. RESULTS:In an analysis of data from 102 studies, we found the most common extrahepatic manifestations to be diabetes (in 15% of patients) and depression (in 25% of patients). HRQL data showed that HCV infection had negative effects on overall physical and mental health. Total direct medical costs of extrahepatic manifestations of HCV infection, in 2014 US dollars, were estimated to be $1506 million (range, $922 million-$2208 million in sensitivity analysis). CONCLUSIONS:In a systematic review and meta-analysis we determined the prevalence, risks, and costs associated with extrahepatic manifestations of HCV infection. These estimates should be added to the liver-related burden of disease to obtain a more accurate assessment of the total burden of chronic HCV infection. Prospective, real-world studies are needed to increase our understanding of the total clinical and economic effects of HCV infection and treatment on patients and society. 10.1053/j.gastro.2016.02.039
The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Human reproduction update BACKGROUND:Endometriosis is a chronic gynaecological disorder that affects 2-10% of women of reproductive age. The aetiology of endometriosis is largely under-explored, yet abnormalities in the immune system have been suggested to explain the origin of ectopic endometrial tissues, and an association between endometriosis and autoimmune diseases has been proposed. Evaluation of current evidence investigating the association between endometriosis and autoimmune diseases from population-based studies will facilitate our understanding of the causes and consequences of endometriosis and provide a reference for better healthcare practices population-wide. OBJECTIVE AND RATIONALE:The aim of this study was to systematically review the literature on population-based studies investigating an association between endometriosis and autoimmune diseases and to conduct a meta-analysis of combinable results to investigate the extent and robustness of evidence. SEARCH METHODS:Four electronic databases were searched (MEDLINE, Embase, Web of Science, and CINAHL) from each database inception date until 7 April 2018. Search terms included a combination of database-specific controlled vocabulary terms and free-text terms relating to 'endometriosis' and 'autoimmune diseases'. Study inclusion criteria focused on peer-reviewed published articles that reported an association between endometriosis and autoimmune diseases, excluding case reports/series, review papers, meta-analyses, organizational guidelines, editorial letters, expert opinions, and conference abstracts. Quality assessment of included studies was performed based on GRADE criteria. Key information of eligible studies was abstracted into a standard form. Meta-analysis was performed for autoimmune diseases with combinable study results from at least three studies investigating an association with endometriosis. For cross-sectional studies and case-control studies, raw data from each study were documented to calculate a Mantel-Haenszel odds ratio with 95% CIs. For cohort studies, an inverse variance probability weighted model was used to pool study results to calculate a rate ratio (a hazard ratio or a standardized incidence rate) with 95% CIs. OUTCOMES:A total of 26 published population-based cross-sectional, case-control, and cohort studies that investigated the association between endometriosis and autoimmune diseases met all eligible criteria and were included in the review. The studies quantified an association between endometriosis and several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatoid arthritis (RA), autoimmune thyroid disorder, coeliac disease (CLD), multiple sclerosis (MS), inflammatory bowel disease (IBD), and Addison's disease. However, the quality of the evidence was generally poor due to the high risk of bias in the majority of the chosen study designs and statistical analyses. Only 5 of the 26 studies could provide high-quality evidence, and among these, 4 supported a statistically significant association between endometriosis and at least 1 autoimmune disease: SLE, SS, RA, CLD, MS, or IBD. WIDER IMPLICATIONS:The observed associations between endometriosis and autoimmune diseases suggest that clinicians need to be aware of the potential coexistence of endometriosis and autoimmune diseases when either is diagnosed. Scientists interested in research studies on endometriosis or autoimmune diseases should consider the likelihood of comorbidity when studying these two types of health conditions. Well-designed large prospective cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to generate further insights into whether endometriosis is a risk factor for, or a consequence of, autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms even if they arise independently. Such insights may offer opportunities for the development of novel non-hormonal medications such as immuno-modulators or repurposing of existing immunomodulatory therapies for endometriosis. 10.1093/humupd/dmz014
Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nature reviews. Rheumatology Synovial tissue macrophages (STMs) were principally recognized as having a pro-inflammatory role in rheumatoid arthritis (RA), serving as the main producers of pathogenic tumour necrosis factor (TNF). Recent advances in single-cell omics have facilitated the discovery of distinct STM populations, providing an atlas of discrete phenotypic clusters in the context of healthy and inflamed joints. Interrogation of the functions of distinct STM populations, via ex vivo and experimental mouse models, has re-defined our understanding of STM biology, opening up new opportunities to better understand the pathology of the arthritic joint. These works have identified STM subpopulations that form a protective lining barrier within the synovial membrane and actively participate in the remission of RA. We discuss how distinct functions of STM clusters shape the synovial tissue environment in health, during inflammation and in disease remission, as well as how an increased understanding of STM heterogeneity might aid the prediction of clinical outcomes and inform novel treatments for RA. 10.1038/s41584-022-00790-8
BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nature communications Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; however, the function of BCATs in macrophages is unknown. Here we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identify ERG240 as a leucine analogue that blocks BCAT1 activity. Selective inhibition of BCAT1 activity results in decreased oxygen consumption and glycolysis. This decrease is associated with reduced IRG1 levels and itaconate synthesis, suggesting involvement of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic acid cycle in activated macrophages. ERG240 suppresses production of IRG1 and itaconate in mice and contributes to a less proinflammatory transcriptome signature. Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice and crescentic glomerulonephritis in rats, in part by decreasing macrophage infiltration. These results establish a regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions. 10.1038/ncomms16040
The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression. 10.1016/j.immuni.2021.03.003
Brazilin Limits Inflammatory Responses through Induction of Prosurvival Autophagy in Rheumatoid Fibroblast-Like Synoviocytes. Lee Hyunji,Kang Seong Wook,Byun Hee Sun,Jeon Juhee,Park Kyeong Ah,Kang Kidong,Seo Wonhyoung,Won Minho,Seok Jeong Ho,Han Man-Deuk,Shen Han-Ming,Hur Gang Min PloS one Brazilin is an active compound of Caesalpinia sappan L. (Leguminosae), which possesses pro-apoptotic and anti-inflammation potentials depending on the specific cell type. However, it is largely unknown whether autophagy is implicated in the mechanism underlying its chemotherapeutic and anti-inflammatory effects in rheumatoid arthritis (RA). Here, we show that treatment of RA fibroblast-like synoviocytes (FLS) with brazilin results in enhanced level of autophagic flux, evidenced by accumulation of autophagosome and increased level of lipidated LC3 (LC3-II), which is mainly mediated by enhanced production of reactive oxygen species (ROS). Interestingly, long-term exposure of brazilin was able to restore cell survival against the cytotoxity, exclusively in RA FLS, but not in normal fibroblast. Importantly, such a restoration from brazilin-induced cytotoxity in RA FLS was completely abrogated after co-treatment with autophagy inhibitors including NH4Cl or chloroquine. Furthermore, we found that the pretreatment of RA FLS with brazilin reduced LPS- or TNF-induced NF-κB activation and the secretion of inflammatory cytokines in parallel with the enhanced autophagic flux. Such anti-NF-κB potentials of brazilin were drastically masked in RA FLS when autophagy was suppressed. These results suggest that brazilin is capable of activating autophagy exclusively in RA FLS, and such inducible autophagy promotes cell survival and limits inflammatory response. 10.1371/journal.pone.0136122
Silibinin alleviates inflammation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes and has a therapeutic effect on arthritis in rats. Tong W W,Zhang C,Hong T,Liu D H,Wang C,Li J,He X K,Xu W D Scientific reports Silibinin, a natural polyphenolic flavonoid, possesses anti-oxidant, anti-inflammation and anti-cancer properties. The present study was designed to investigate the effects of silibinin on rheumatoid arthritis (RA) pathogenesis-related cells and collagen-induced arthritis (CIA) and further explore the potential underlying mechanisms. Our results showed that silibinin suppressed cell viability and increased the percentage of apoptotic RA-fibroblast-like synoviocytes (FLS). Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model was effectively inhibited by silibinin. Silibinin also induced macrophage M2 polarization in RAW264.7 cells. We further demonstrated that silibinin inhibits Th17 cell differentiation in vitro. The nuclear factor kappa B (NF-κB) pathway was suppressed in RA-FLS. In addition, Sirtuin1 (SIRT1) was decreased after silibinin treatment, and RA-FLS transfection with a short hairpin RNA (shRNA) of SIRT1 enhanced silibinin-induced apoptosis. Autophagy was markedly decreased in a dose-dependent manner following silibinin treatment. These findings indicate that silibinin inhibited inflammation by inhibiting the NF-κB pathway, and SIRT1 may participate in silibinin-induced apoptosis. Silibinin also inhibited autophagy in RA-FLS. Thus, silibinin may be a potential therapeutic agent for the treatment of RA. 10.1038/s41598-018-21674-6
Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis. Yang Ru,Zhang Yingzi,Wang Lin,Hu Ji,Wen Jian,Xue Leixi,Tang Mei,Liu Zhichun,Fu Jinxiang Oncotarget The incidence of rheumatoid arthritis (RA) has been reported to be correlated with a disorder of immunregulation. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) play an important role in regulating the local immune microenvironment. However, the potential mechanism of RA-FLS in regulating the immnue response is not clearly understood. In this study, we demonstrated that the expression of HIF-1α was significantly up-regulated in rheumatoid arthritis tissue which indicated that the hypoxia condition in the microenvironment. We also observed that RA-FLSs demonstrated the potential to up-regulate immune activation. Meanwhile, the level of autophagy increased in RA-FLSs compared with control group. Besides that, the expression of IL-6 was up-regulated not only in RA-FLSs but also in the fibroblasts that treated with hypoxia condition. Accordingly, we found that autophagy inhibitiors could effectively inhibit the immune activation function of RA-FLSs medicated by IL-6. Taken together, the results we demonstrated above indicated that the hypoxia microenvironment could effectively induce the incidence of autophagy and then lead to the immune activation function of RA-FLSs medicated by IL-6. 10.18632/oncotarget.14331
Roles of autophagy in rheumatoid arthritis. Clinical and experimental rheumatology Autophagy, a vital mechanism restricted in tissues, exerts its cytoprotective role through the degradation mechanism of damaged or aging organelles, harmful protein aggregates and intracellular pathogens, followed by energy furnishment. However, dysfunctional autophagy is associated with the development of autoimmune diseases such as rheumatoid arthritis (RA). In pathological conditions, autophagy may be involved in the maturation, survival and proliferation of various immune and non-immune cells and plays a key role in the pathogenesis of RA. Furthermore, autophagy appears to be involved in the citrullination of T lymphocytes and the presentation of citrullinated peptides, which are presented to T lymphocytes via the major histocompatibility complex, causing immune responses and chronic inflammation, as well as bone and cartilage destruction associated with apoptosis resistance of RA fibroblast-like synoviocyte (RAFLS) and osteoclastogenesis. In this review, we have summarised the roles of autophagy in the pathogenesis of RA including citrullination, immune tolerance break, osteoclastogenesis, RA FLS cell dysplasia, apoptosis resistance, together with the therapeutic potentials of autophagy regulators. 10.55563/clinexprheumatol/exg1ic
Omics analyses of a somatic breast cancer model identify cooperating driver events activating PI3K/AKT/mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America Alterations of the tumor suppressor , one of the most common events in cancer, alone are insufficient for tumor development but serve as drivers of transformation. We sought to identify cooperating events through genomic analyses of a somatic mouse model (equivalent to the hot spot mutation in human cancers) that recapitulates metastatic breast-cancer development. We identified cooperating lesions similar to those found in human breast cancers. Moreover, we identified activation of the Pi3k/Akt/mTOR pathway in most tumors via mutations in , , , and/or a recurrent mutation that stabilizes the Pip5k1c protein and activates Pi3k/Akt/mTOR signaling. Another family member, , is coamplified with in 18% of human breast cancer patients; both encode kinases that are responsible for production of the PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, the mutation and PI3K/AKT/mTOR signaling are major cooperative events driving breast-cancer development. Additionally, a combination of two US Food and Drug Administration (FDA)-approved drugs, tigecycline and metformin, which target oxidative phosphorylation downstream of PI3K signaling, inhibited tumor cell growth and may be repurposed for breast-cancer treatment. These findings advance our understanding of how mutant p53 drives breast-tumor development and pinpoint the importance of PI3K/AKT/mTOR signaling, expanding combination therapies for breast-cancer treatment. 10.1073/pnas.2210618119
Potential therapeutic application of biophenols - plants secondary metabolites in rheumatoid arthritis. Critical reviews in food science and nutrition Rheumatoid arthritis (RA) is a chronic autoimmune disease showed that persistent inflammation in the joints, induces the cartilage destruction, bone erosion, and leukocyte infiltration in the synovium. RA mostly affects the joints of hands, feet, wrists, ankles, and knees. Each year, approximately 20-40 new cases are reported per lac population and the disease affects women more than men. The etiology of RA is still unknown, but many pathways have been identified as potential targets in its pathophysiology, including the PI3K/AKT signaling pathway, NF-κB signaling, Adenosine signaling, Wnt, SYK/BTK, and mTOR signaling pathways. Biophenol, plant secondary metabolite, is considered one of the most abundantly phytoconstituents to have potential anti-inflammatory effects associated with multiple pathways. These indicate that biophenols can be used for its protective effect on the development and symptoms of RA. The current review explores and discusses the role of different biophenols in the treatment of RA disease. 10.1080/10408398.2022.2062700
Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer. Donnella Hayley J,Webber James T,Levin Rebecca S,Camarda Roman,Momcilovic Olga,Bayani Nora,Shah Khyati N,Korkola James E,Shokat Kevan M,Goga Andrei,Gordan John D,Bandyopadhyay Sourav Nature chemical biology Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer. 10.1038/s41589-018-0081-9
TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism. Cheng Jie,Huang Yan,Zhang Xiaohui,Yu Yue,Wu Shumin,Jiao Jing,Tran Linh,Zhang Wanru,Liu Ran,Zhang Liuzhen,Wang Mei,Wang Mengyao,Yan Wenyu,Wu Yilin,Chi Fangtao,Jiang Peng,Zhang Xinxiang,Wu Hong Nature communications PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation. 10.1038/s41467-020-15819-3
Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Neri L M,Cani A,Martelli A M,Simioni C,Junghanss C,Tabellini G,Ricci F,Tazzari P L,Pagliaro P,McCubrey J A,Capitani S Leukemia B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL. 10.1038/leu.2013.226
Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism. Acta pharmaceutica Sinica. B The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of , decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes. 10.1016/j.apsb.2021.12.023
Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal transduction and targeted therapy Circular RNAs (circRNAs), covalently closed noncoding RNAs, are widely expressed in eukaryotes and viruses. They can function by regulating target gene expression, linear RNA transcription and protein generation. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays key roles in many biological and cellular processes, such as cell proliferation, growth, invasion, migration, and angiogenesis. It also plays a pivotal role in cancer progression. Emerging data suggest that the circRNA/PI3K/AKT axis modulates the expression of cancer-associated genes and thus regulates tumor progression. Aberrant regulation of the expression of circRNAs in the circRNA/PI3K/AKT axis is significantly associated with clinicopathological characteristics and plays an important role in the regulation of biological functions. In this review, we summarized the expression and biological functions of PI3K-AKT-related circRNAs in vitro and in vivo and assessed their associations with clinicopathological characteristics. We also further discussed the important role of circRNAs in the diagnosis, prognostication, and treatment of cancers. 10.1038/s41392-021-00788-w
Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Ediriweera Meran Keshawa,Tennekoon Kamani Hemamala,Samarakoon Sameera Ranganath Seminars in cancer biology Ovarian cancer (OC) is a lethal gynecological cancer. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the regulation of cell survival, growth, and proliferation. Irregularities in the major components of the PI3K/AKT/mTOR signaling pathway are common in human cancers. Despite the availability of strong pre-clinical and clinical data of PI3K/AKT/mTOR pathway inhibitors in OC, there is no FDA approved inhibitor available for the treatment of OC. Here, we outline the importance of PI3K/AKT/mTOR signaling pathway in OC tumorigenesis, proliferation and progression, and pre-clinical and clinical experience with several PI3K/AKT/mTOR pathway inhibitors in OC. 10.1016/j.semcancer.2019.05.012
Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Seminars in cancer biology Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling. 10.1016/j.semcancer.2021.06.019
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Molecular cancer The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed. 10.1186/s12943-023-01827-6
The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. European heart journal Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-β, tumour necrosis factor-α, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase Cε, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks. 10.1093/eurheartj/ehab447
The cholinergic anti-inflammatory pathway: towards innovative treatment of rheumatoid arthritis. van Maanen Marjolein A,Vervoordeldonk Margriet J,Tak Paul P Nature reviews. Rheumatology The efferent vagus nerve can regulate inflammation via its principal neurotransmitter acetylcholine (ACh), a concept referred to as the 'cholinergic anti-inflammatory pathway'. ACh interacts with members of the nicotinic acetylcholine receptor (nAChR) family, in particular with the alpha7 subunit (alpha7nAChR), which is expressed not only by neurons but also macrophages and other cells involved in the inflammatory response. In these inflammatory cells, the stimulation of alpha7nAChR by ACh and other alpha7nAChR-specific agonists suppresses the release of proinflammatory cytokines. Recent work has suggested that alpha7nAChR could represent a new target for the treatment of rheumatic diseases. In this Perspective, we describe the cholinergic anti-inflammatory pathway and the therapeutic potential of modulating this pathway in rheumatoid arthritis. 10.1038/nrrheum.2009.31
Expression and Metabolomic Profiling in Axial Spondyloarthritis. O'Rielly Darren D,Zhai Guangju,Rahman Proton Current rheumatology reports PURPOSE OF REVIEW:The purpose of this review is to highlight recent evidence with respect to expression and metabolomic profiling in axial spondyloarthritis (axSpA) that included ankylosing spondylitis (AS). RECENT FINDINGS:AxSpA is not only characterized by the strongest genetic contribution for any complex rheumatic disease but is also influenced by environmental and immunological factors. Large-scale association-based studies have identified over 100 genetic variants contributing to 30% of the genetic risk of ankylosing spondylitis. Recent studies in global expression and metabolomic profiling appear to highlight common themes despite differences in tissues, populations, techniques, and relative paucity of patients in many of these studies. Expression studies support a role for immunomodulation and bone remodeling in the pathogenesis and progression of axSpA/AS, while metabolomic studies implicate the importance of the intestinal microbial metabolism as well as fat and choline metabolic pathways in AS. 10.1007/s11926-018-0756-y
Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O. Frontiers in immunology Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins. Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE). Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies. An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE. Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease. In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition. We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease. 10.3389/fimmu.2021.649693
Metabolomics and its potential in diagnosis, prognosis and treatment of rheumatic diseases. Smoleńska Żaneta,Zdrojewski Zbigniew Reumatologia The main aim of metabolomics is to make a comprehensive study of metabolites, the intermediates of biochemical processes in living organisms. Any pathophysiological mechanism caused by disease will inevitably lead to related changes in the concentrations of specific metabolites. In line with this, metabolomics offers a promising laboratory tool for the analysis of potential diagnostic biomarkers that may be used to assess susceptibility to a disease and to evaluate the prognosis and therapeutic response to treatment. Recent data have shown that metabolomics analysis in rheumatoid arthritis has made possible more efficient diagnosis, discrimination between patients with regard to disease activity, prediction of the response to a particular treatment approach, differentiation between rheumatic disease subtypes and greater understanding of the pathophysiology of this disease. Here we characterize metabolomics as a comprehensive laboratory tool and review its potential in the diagnosis, prognosis and treatment of rheumatic diseases such as rheumatoid arthritis. 10.5114/reum.2015.53137
Genomics, proteomics and metabolomics: their emerging roles in the discovery and validation of rheumatoid arthritis biomarkers. Castro-Santos Patricia,Laborde Carlos M,Díaz-Peña Roberto Clinical and experimental rheumatology Rheumatoid arthritis (RA) is an autoimmune inflammatory rheumatic disease which affects several organs and tissues, predominantly the synovial joints. Despite major advances, the aetiology of this disease is not completely understood. Although several biomarkers are routinely used in RA management and some of them can be detected even prior to the onset of the clinical disease, there is a high demand for novel biomarkers to further improve the early diagnosis of RA. The '-omics' techniques that have emerged and have been developed in recent years have allowed researchers to improve their knowledge of the aetiopathology of RA. At the same time, advances in screening technologies offer an excellent opportunity to find new biomarkers potentially useful for early diagnosis, stratification of patients, and even prediction of a better response to a specific therapy. This review describes what is known about the methodologies used in the discovery of novel biomarkers in RA, along with the findings of these methodologies, with specific attention to recent advances in the fields of genomics, proteomics and metabolomics.
Application of metabolomics in autoimmune diseases: insight into biomarkers and pathology. Kang Jian,Zhu Ling,Lu Jingli,Zhang Xiaojian Journal of neuroimmunology Metabolomics has recently become a new technology using mass spectrometry (MS) and high-resolution proton nuclear magnetic resonance (NMR) to access metabolite profiles in biofluids or tissue extracts for the detection of biomarker molecules and biochemical effects induced by a disease or its therapeutic intervention. This review outlines recent advances in the use of metabolomic techniques to study autoimmune diseases (ADs), including multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), autoimmune diabetes et al. Many studies have demonstrated that AD patients including subtypes of some diseases, and healthy individuals can be distinguished using metabolic profiling accompanied with well-established data analysis tools including principal component analysis (PCA) and partial least squares (PLS). These metabolites not only affect glucose, amino acid and lipid metabolism, but also involve alteration of neurotransmitters, nucleotides, immune responses and anti-inflammatory responses. Knowledge of unique metabolomic fingerprint in ADs could be useful for diagnosis, treatment, and detection mechanisms of diseases. 10.1016/j.jneuroim.2015.01.001
Metabolomics and Its Application in the Development of Discovering Biomarkers for Osteoporosis Research. International journal of molecular sciences Osteoporosis is a progressive skeletal disorder characterized by low bone mass and increased risk of fracture in later life. The incidence and costs associated with treating osteoporosis cause heavy socio-economic burden. Currently, the diagnosis of osteoporosis mainly depends on bone mineral density and bone turnover markers. However, these indexes are not sensitive and accurate enough to reflect the osteoporosis progression. Metabolomics offers the potential for a holistic approach for clinical diagnoses and treatment, as well as understanding of the pathological mechanism of osteoporosis. In this review, we firstly describe the study subjects of osteoporosis and bio-sample preparation procedures for different analytic purposes, followed by illustrating the biomarkers with potentially predictive, diagnosis and pharmaceutical values when applied in osteoporosis research. Then, we summarize the published metabolic pathways related to osteoporosis. Furthermore, we discuss the importance of chronological data and combination of multi-omics in fully understanding osteoporosis. The application of metabolomics in osteoporosis could provide researchers the opportunity to gain new insight into the metabolic profiling and pathophysiological mechanisms. However, there is still much to be done to validate the potential biomarkers responsible for the progression of osteoporosis and there are still many details needed to be further elucidated. 10.3390/ijms17122018
A systematic review on the role of eicosanoid pathways in rheumatoid arthritis. Hoxha Malvina Advances in medical sciences BACKGROUND:Rheumatoid arthritis is characterized by the production of eicosanoids, cytokines, adhesion molecules, infiltration of T and B lymphocytes in the synovium and oxygen reduction accompanied by the cartilage degradation. Eicosanoids are responsible for the progressive destruction of cartilage and bone, however neither steroids, nor the non steroidal anti-inflammatory drugs (NSAIDs), cannot slow down cartilage and bone destruction providing only symptomatic improvement. The current rheumatoid arthritis treatment options include mainly the use of disease-modifying anti-rheumatic drugs, the corticosteroids, the NSAIDs and biological agents. METHODS:PubMed, Cochrane, and Embase electronic database were used as the main sources for extracting several articles, reviews, original papers in English for further review and analysis on the implication of arachidonic acid metabolites with rheumatoid arthritis and different strategies of targeting arachidonic acid metabolites, different enzymes or receptors for improving the treatment of rheumatoid arthritis patients. RESULTS:We first focused on the role of individual prostaglandins and leukotrienes, in the inflammatory process of arthritis, concluding with an outline of the current clinical situation of rheumatoid arthritis and novel treatment strategies targeting the arachidonic acid pathway. CONCLUSIONS:Extended research is necessary for the development of these novel compounds targeting the eicosanoid pathway, by increasing the levels of anti-inflammatory eicosanoids (PGD,15dPGJ), by inhibiting the production of pro-inflammatory eicosanoids (PGE, LTB, PGI) involved in rheumatoid arthritis or also by developing dual compounds displaying both the COX-2 inhibitor/TP antagonist activity within a single compound. 10.1016/j.advms.2017.06.004
Metabolomics of osteoarthritis: emerging novel markers and their potential clinical utility. Zhai Guangju,Randell Edward W,Rahman Proton Rheumatology (Oxford, England) OA is a multifactorial and progressive disease with no cure yet. Substantial efforts have been made and several biochemical and genetic markers have been reported, but neither alone nor in combination is adequate to identify early OA changes or determine disease progression with sufficient predictive values. Recent advances in metabolomics and its application to the study of OA have led to elucidation of involvement of several metabolic pathways and new specific metabolic markers for OA. Some of these metabolic pathways affect amino acid metabolism, including branched chain amino acids and arginine, and phospholipid metabolism involving conversion of phosphatidylcholine to lysophosphatidylcholine. These metabolic markers appear to be clinically actionable and may potentially improve the clinical management of OA patients. In this article, we review the recent studies of metabolomics of OA, discuss those novel metabolic markers and their potential clinical utility, and indicate future research directions in the field. 10.1093/rheumatology/kex497
Emerging role of metabolomics in rheumatology. Gupta Latika,Ahmed Sakir,Jain Avinash,Misra Ramnath International journal of rheumatic diseases The pursuit for understanding disease pathogenesis, in this age of rapid laboratory diagnostics and fast-paced research, has led scientists worldwide to take recourse in hypothesis-free approaches for molecular diagnosis. Metabolomics is one such powerful tool that explores comprehensibly the metabolic alternations in human diseases. It involves study of small molecules of less than 1 kD in size by either LSMS or nuclear magnetic resonance. Unlike genomics, which tells us what may have happened, metabolomics reflects what did happen. The NMR technique has an advantage of analyzing metabolites without sample preparation, thereby diminishing artifacts, is less cumbersome and with the latest database on Metabolome; about 30 000 metabolites can be identified. The study of metabolomics for several rheumatic diseases, including rheumatoid arthritis, lupus, osteoarthritis and vasculitis, has revealed distinctive metabolic signatures. Thus, metabolomics is a technique that promises precision medicine with better biomarkers, robust predictors of drug response and of disease outcome, discovery of newer metabolites and pathways in disease pathogenesis, and finally, targeted drug development. This review intends to decipher its relevance in common rheumatic diseases. 10.1111/1756-185X.13353
The Metabolome and Osteoarthritis: Possible Contributions to Symptoms and Pathology. Rockel Jason S,Kapoor Mohit Metabolites Osteoarthritis (OA) is a progressive, deteriorative disease of articular joints. Although traditionally viewed as a local pathology, biomarker exploration has shown that systemic changes can be observed. These include changes to cytokines, microRNAs, and more recently, metabolites. The metabolome is the set of metabolites within a biological sample and includes circulating amino acids, lipids, and sugar moieties. Recent studies suggest that metabolites in the synovial fluid and blood could be used as biomarkers for OA incidence, prognosis, and response to therapy. However, based on clinical, demographic, and anthropometric factors, the local synovial joint and circulating metabolomes may be patient specific, with select subsets of metabolites contributing to OA disease. This review explores the contribution of the local and systemic metabolite changes to OA, and their potential impact on OA symptoms and disease pathogenesis. 10.3390/metabo8040092
Multi-omics analysis of synovial fluid: a promising approach in the study of osteoarthritis. Vicenti G,Bizzoca D,Carrozzo M,Solarino G,Moretti B Journal of biological regulators and homeostatic agents Osteoarthritis (OA), affecting 250 million individuals worldwide, is a significant social health problem. Therefore, the search for synovial fluid (SF) biomarkers that could anticipate the diagnosis of OA is gaining increasing importance in orthopaedics. This review summarizes the recent progresses preformed in the multi-omics approach to OA, mainly focusing on proteome and metabolome analysis of SF. Proteomics of the SF has shown the up-regulation of several components of the classic complement pathway in OA samples, including C1, C2, C3, C4A, C4B, C5 and C4 C4BPA, thus depicting that complement is involved in the pathogenesis of OA. Moreover, proteomics has displayed that some pro-inflammatory cytokines, namely IL-6, IL-8 and IL-18, have a role in OA. The metabolomic profiling of the SF in OA has identified some metabolites as potential biomarkers of OA and has shown the existence of metabolically different OA subgroups. However, further studies with larger samples sizes and matched-control groups are needed to identify SF biomarkers that could be useful in the diagnosis, treatment and follow-up of OA.
Metabolism as a key regulator in the pathogenesis of systemic lupus erythematosus. Takeshima Yusuke,Iwasaki Yukiko,Fujio Keishi,Yamamoto Kazuhiko Seminars in arthritis and rheumatism In the middle of the 20th century, biologists focused on investigating the mechanism of gene regulation and signal transduction in cells, which led to the concept that metabolites were products of gene expression and signal transduction pathways. In the 1920s, the importance of cellular metabolism was shown in the Warburg effect, in which cancer cells are characterized by a mitochondrial defect that shifts towards aerobic glycolysis. Recently, it is accepted that each organ and cell subset needs specific metabolic conditions and metabolic regulatory systems. Immunometabolism is a relatively new field of metabolism studies. The immune system consists of various cell subsets that have unique requirements and functions. The metabolic reprogramming in each immune cell causes different effects on different cell subsets. For example, resting lymphocytes generate energy through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), whereas activated lymphocytes rapidly shift to the glycolytic pathway. A detailed understanding of metabolic regulation has progressed rapidly, especially in T cells during their differentiation from naïve to effector T cells. Metabolism is now considered to play a key role in autoimmune diseases. Metabolic changes in autoimmune diseases might be due to inflammation as well as being involved in autoimmune pathogenesis. Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogenous clinical presentations whose precise pathophysiological mechanism is largely unknown. In this report, we review the altered metabolism in SLE and discuss the potential of metabolomics for accelerating the discovery of novel cellular autoimmune therapies and novel disease biomarkers. 10.1016/j.semarthrit.2019.04.006
Application of Metabolomics to Osteoarthritis: from Basic Science to the Clinical Approach. Showiheen Salah Ali A,Sun Antonia RuJia,Wu Xiaoxin,Crawford Ross,Xiao Yin,Wellard R Mark,Prasadam Indira Current rheumatology reports PURPOSE OF THE REVIEW:Osteoarthritis (OA) is a multifactorial and progressive disease affecting whole synovial joint. The extract pathogenic mechanisms and diagnostic biomarkers of OA remain unclear. In this article, we review the studies related to metabolomics of OA, discuss the biomarkers as a tool for early OA diagnosis. Furthermore, we examine the major studies on the application of metabolomics methodology in the complex context of OA and create a bridge from findings in basic science to their clinical utility. RECENT FINDINGS:Recently, the tissue metabolomics signature permits a view into transitional phases between the healthy and OA joint. Both nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry-based metabolomics approaches have been used to interrogate the metabolic alterations that may indicate the complex progression of OA. Specifically, studies on alterations pertaining to lipids, glucose, and amino acid metabolism have aided in the understanding of the complex pathogenesis of OA. The discovery of identified metabolites could be important for diagnosis and staging of OA, as well as for the assessment of efficacy of new drugs. 10.1007/s11926-019-0827-8
Understanding osteoarthritis pathogenesis: a multiomics system-based approach. Ratneswaran Anusha,Rockel Jason S,Kapoor Mohit Current opinion in rheumatology PURPOSE OF REVIEW:Osteoarthritis is a heterogeneous, multifactorial condition regulated by complex biological interactions at multiple levels. Comprehensive understanding of these regulatory interactions is required to develop feasible advances to improve patient outcomes. Improvements in technology have made extensive genomic, transcriptomic, epigenomic, proteomic, and metabolomic profiling possible. This review summarizes findings over the past 20 months related to omics technologies in osteoarthritis and examines how using a multiomics approach is necessary for advancing our understanding of osteoarthritis as a disease to improve precision osteoarthritis treatments. RECENT FINDINGS:Using the search terms 'genomics' or 'transcriptomics' or 'epigenomics' or 'proteomics' or 'metabolomics' and 'osteoarthritis' from January 1, 2018 to August 31, 2019, we identified advances in omics approaches applied to osteoarthritis. Trends include untargeted whole genome, transcriptome, proteome, and metabolome analyses leading to identification of novel molecular signatures, cell subpopulations and multiomics validation approaches. SUMMARY:To address the complexity of osteoarthritis, integration of multitissue analyses by multiomics approaches with the inclusion of longitudinal clinical data is necessary for a comprehensive understanding of the disease process, and for appropriate development of efficacious diagnostics, prognostics, and biotherapeutics. 10.1097/BOR.0000000000000680
Pharmacological targets of metabolism in disease: Opportunities from macrophages. Castegna Alessandra,Gissi Rosanna,Menga Alessio,Montopoli Monica,Favia Maria,Viola Antonella,Canton Marcella Pharmacology & therapeutics From advances in the knowledge of the immune system, it is emerging that the specialized functions displayed by macrophages during the course of an immune response are supported by specific and dynamically-connected metabolic programs. The study of immunometabolism is demonstrating that metabolic adaptations play a critical role in modulating inflammation and, conversely, inflammation deeply influences the acquisition of specific metabolic settings.This strict connection has been proven to be crucial for the execution of defined immune functional programs and it is now under investigation with respect to several human disorders, such as diabetes, sepsis, cancer, and autoimmunity. The abnormal remodelling of the metabolic pathways in macrophages is now emerging as both marker of disease and potential target of therapeutic intervention. By focusing on key pathological conditions, namely obesity and diabetes, rheumatoid arthritis, atherosclerosis and cancer, we will review the metabolic targets suitable for therapeutic intervention in macrophages. In addition, we will discuss the major obstacles and challenges related to the development of therapeutic strategies for a pharmacological targeting of macrophage's metabolism. 10.1016/j.pharmthera.2020.107521
The Potential of OMICs Technologies for the Treatment of Immune-Mediated Inflammatory Diseases. Anchang Charles Gwellem,Xu Cong,Raimondo Maria Gabriella,Atreya Raja,Maier Andreas,Schett Georg,Zaburdaev Vasily,Rauber Simon,Ramming Andreas International journal of molecular sciences Immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis-associated neoplasia. Only 40-60% of patients respond to currently used standard-of-care immunotherapies. In addition to this limited long-term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is considered as "the great hope" for improving the treatment of IMIDs. This review sheds light on the progressive development and the numerous approaches from basic science that gradually lead to the transfer from "bench to bedside" and the implementation into general patient care procedures. 10.3390/ijms22147506
Metabolomics in Bone Research. Fan Jingzhi,Jahed Vahid,Klavins Kristaps Metabolites Identifying the changes in endogenous metabolites in response to intrinsic and extrinsic factors has excellent potential to obtain an understanding of cells, biofluids, tissues, or organisms' functions and interactions with the environment. The advantages provided by the metabolomics strategy have promoted studies in bone research fields, including an understanding of bone cell behaviors, diagnosis and prognosis of diseases, and the development of treatment methods such as implanted biomaterials. This review article summarizes the metabolism changes during osteogenesis, osteoclastogenesis, and immunoregulation in hard tissue. The second section of this review is dedicated to describing and discussing metabolite changes in the most relevant bone diseases: osteoporosis, bone injuries, rheumatoid arthritis, and osteosarcoma. We consolidated the most recent finding of the metabolites and metabolite pathways affected by various bone disorders. This collection can serve as a basis for future metabolomics-driven bone research studies to select the most relevant metabolites and metabolic pathways. Additionally, we summarize recent metabolic studies on metabolomics for the development of bone disease treatment including biomaterials for bone engineering. With this article, we aim to provide a comprehensive summary of metabolomics in bone research, which can be helpful for interdisciplinary researchers, including material engineers, biologists, and clinicians. 10.3390/metabo11070434
Unraveling the complexities of psoriatic arthritis by the use of -Omics and their relevance for clinical care. Grivas Alexandros,Fragoulis George,Garantziotis Panagiotis,Banos Aggelos,Nikiphorou Elena,Boumpas Dimitrios Autoimmunity reviews -Omic technologies represent a novel approach to unravel ill-defined aspects of psoriatic arthritis (PsA). Large-scale information can be acquired from analysis of affected tissues in PsA via high-throughput studies in the domains of genomics, transcriptomics, epigenetics, proteomics and metabolomics. This is a critical overview of the current knowledge of -omics in PsA, with emphasis on the pathophysiological insights of diagnostic and therapeutic relevance, the advent of novel biomarkers and their potential use for precision medicine in PsA. 10.1016/j.autrev.2021.102949
Metabolomics: An Emerging Approach to Understand Pathogenesis and to Assess Diagnosis and Response to Treatment in Spondyloarthritis. Cells Spondyloarthritis (SpA) is a group of rheumatic diseases whose pathogenesis relies on a complex interplay between genetic and environmental factors. Over the last several years, the importance of the alteration of the gut microbiota, known as dysbiosis, and the interaction of bacterial products with host immunity have been highlighted as intriguing key players in SpA development. The recent advent of the so called "-omics" sciences, that include metabolomics, opened the way to a new approach to SpA through a deeper characterisation of the pathogenetic mechanisms behind the disease. In addition, metabolomics can reveal potential new biomarkers to diagnose and monitor SpA patients. The aim of this review is to highlight the most recent advances concerning the application of metabolomics to SpA, in particular focusing attention on Ankylosing Spondylitis and Psoriatic Arthritis. 10.3390/cells11030549
Lipidomic Profiling in Synovial Tissue. Frontiers in medicine The analysis of synovial tissue offers the potential for the comprehensive characterization of cell types involved in arthritis pathogenesis. The studies performed to date in synovial tissue have made it possible to define synovial pathotypes, which relate to disease severity and response to treatment. Lipidomics is the branch of metabolomics that allows the quantification and identification of lipids in different biological samples. Studies in animal models of arthritis and in serum/plasma from patients with arthritis suggest the involvement of different types of lipids (glycerophospholipids, glycerolipids, sphingolipids, oxylipins, fatty acids) in the pathogenesis of arthritis. We reviewed studies that quantified lipids in different types of tissues and their relationship with inflammation. We propose that combining lipidomics with currently used "omics" techniques can improve the information obtained from the analysis of synovial tissue, for a better understanding of pathogenesis and the development of new therapeutic strategies. 10.3389/fmed.2022.857135
A Review of Metabolomic Profiling in Rheumatoid Arthritis: Bringing New Insights in Disease Pathogenesis, Treatment and Comorbidities. Metabolites Metabolomic analysis provides a wealth of information that can be predictive of distinctive phenotypes of pathogenic processes and has been applied to better understand disease development. Rheumatoid arthritis (RA) is an autoimmune disease with the establishment of chronic synovial inflammation that affects joints and peripheral tissues such as skeletal muscle and bone. There is a lack of useful disease biomarkers to track disease activity, drug response and follow-up in RA. In this review, we describe potential metabolic biomarkers that might be helpful in the study of RA pathogenesis, drug response and risk of comorbidities. TMAO (choline and trimethylamine oxide) and TCA (tricarboxylic acid) cycle products have been suggested to modulate metabolic profiles during the early stages of RA and are present systemically, which is a relevant characteristic for biomarkers. Moreover, the analysis of lipids such as cholesterol, FFAs and PUFAs may provide important information before disease onset to predict disease activity and treatment response. Regarding therapeutics, TNF inhibitors may increase the levels of tryptophan, valine, lysine, creatinine and alanine, whereas JAK/STAT inhibitors may modulate exclusively fatty acids. These observations indicate that different disease modifying antirheumatic drugs have specific metabolic profiles and can reveal differences between responders and non-responders. In terms of comorbidities, physical impairment represented by higher fatigue scores and muscle wasting has been associated with an increase in urea cycle, FFAs, tocopherols and BCAAs. In conclusion, synovial fluid, blood and urine samples from RA patients seem to provide critical information about the metabolic profile related to drug response, disease activity and comorbidities. 10.3390/metabo12050394
Metabolic Profiling in Rheumatoid Arthritis, Psoriatic Arthritis, and Psoriasis: Elucidating Pathogenesis, Improving Diagnosis, and Monitoring Disease Activity. Journal of personalized medicine Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and psoriasis (Ps), represent autoinflammatory and autoimmune disorders, as well as conditions that have an overlap of both categories. Understanding the underlying pathogeneses, making diagnoses, and choosing individualized treatments remain challenging due to heterogeneous disease phenotypes and the lack of reliable biomarkers that drive the treatment choice. In this review, we provide an overview of the low-molecular-weight metabolites that might be employed as biomarkers for various applications, e.g., early diagnosis, disease activity monitoring, and treatment-response prediction, in RA, PsA, and Ps. The literature was evaluated, and putative biomarkers in different matrices were identified, categorized, and summarized. While some of these candidate biomarkers appeared to be disease-specific, others were shared across multiple IMIDs, indicating common underlying disease mechanisms. However, there is still a long way to go for their application in a routine clinical setting. We propose that studies integrating omics analyses of large patient cohorts from different IMIDs should be performed to further elucidate their pathomechanisms and treatment options. This could lead to the identification and validation of biomarkers that might be applied in the context of precision medicine to improve the clinical outcomes of these IMID patients. 10.3390/jpm12060924
Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes. Frontiers in immunology Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption. Metabolic changes in fibroblast-like synoviocytes (FLS) likely contribute to FLS abnormal response and strongly contribute to joint destruction. These changes often involve increased expression of nutrient transporters to meet a high demand for energy or biomolecules. The solute carrier (SLC) transporter families are nutrient transporters and serve as 'metabolic gates' for cells by mediating the transport of several different nutrients such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. In RA FLS SLC-mediated transmembrane transport was one pathway associated with different epigenetic landscape between RA and osteoarthritis (OA) FLS. These highlight that transporters from the SLC family offer unique targets for further research and offer the promise of future therapeutic targets for RA. 10.3389/fimmu.2022.984408
The impact of omics research on our understanding of osteoarthritis and future treatments. Current opinion in rheumatology PURPOSE OF REVIEW:To review recent studies using 'Omics' approaches (genomics, proteomics, metabolomics, single cell analyses) in patient populations and animal models of osteoarthritis (OA), with the goal of identifying disease-modifying mechanisms that could serve as therapeutic and diagnostic targets. RECENT FINDINGS:The number of genes, pathways and molecules with potential roles in OA pathogenesis has grown substantially over the last 18 months. Studies have expanded from their traditional focus on cartilage and gene expression to other joint tissues, proteins and metabolites. Single cell approaches provide unprecedented resolution and exciting insights into the heterogeneity of cellular activities in OA. Functional validation and investigation of underlying mechanisms in animal models of OA, in particular genetically engineered mice, link Omics findings to pathophysiology and potential therapeutic applications. SUMMARY:Although great progress has been made in the use of Omics approaches to OA, in both animal models and patient samples, much work remains to be done. In addition to filling gaps in data sets not yet existing, integration of data from the various approaches, mechanistic investigations, and linkage of Omics data to patient stratification remain significant challenges. 10.1097/BOR.0000000000000919
The biomarkers discovery of hyperuricemia and gout: proteomics and metabolomics. PeerJ Background:Hyperuricemia and gout are a group of disorders of purine metabolism. In recent years, the incidence of hyperuricemia and gout has been increasing, which is a severe threat to people's health. Several studies on hyperuricemia and gout in proteomics and metabolomics have been conducted recently. Some literature has identified biomarkers that distinguish asymptomatic hyperuricemia from acute gout or remission of gout. We summarize the physiological processes in which these biomarkers may be involved and their role in disease progression. Methodology:We used professional databases including PubMed, Web of Science to conduct the literature review. This review addresses the current landscape of hyperuricemia and gout biomarkers with a focus on proteomics and metabolomics. Results:Proteomic methods are used to identify differentially expressed proteins to find specific biomarkers. These findings may be suggestive for the diagnosis and treatment of hyperuricemia and gout to explore the disease pathogenesis. The identified biomarkers may be mediators of the link between hyperuricemia, gout and kidney disease, metabolic syndrome, diabetes and hypertriglyceridemia. Metabolomics reveals the main influential pathways through small molecule metabolites, such as amino acid metabolism, lipid metabolism, or other characteristic metabolic pathways. These studies have contributed to the discovery of Chinese medicine. Some traditional Chinese medicine compounds can improve the metabolic disorders of the disease. Conclusions:We suggest some possible relationships of potential biomarkers with inflammatory episodes, complement activation, and metabolic pathways. These biomarkers are able to distinguish between different stages of disease development. However, there are relatively few proteomic as well as metabolomic studies on hyperuricemia and gout, and some experiments are only primary screening tests, which need further in-depth study. 10.7717/peerj.14554
Utilizing metabolomics to identify potential biomarkers and perturbed metabolic pathways in osteoarthritis: A systematic review. Seminars in arthritis and rheumatism PURPOSE:Osteoarthritis (OA) is a joint disease that is clinically diagnosed using components of history, physical exam, and characteristic radiographic findings, such as joint space narrowing. Currently, there are no laboratory findings that are specific to a diagnosis of OA. The purpose of this systematic review is to evaluate the state of current studies of metabolomic biomarkers that can aid in the diagnosis and treatment of OA. METHODS:Articles were gathered from PubMed and Web of Science using the search terms "osteoarthritis" and "biomarkers" and "metabolomics". Last search of databases took place December 3rd, 2022. Duplicates were manually screened, along with any other results that were not original journal articles. Only original reports involving populations with diagnosed primary or secondary OA (human participants) or surgically induced OA (animal participants) and a healthy control group for comparison were considered for inclusion. Metabolites and metabolic pathways reported in included articles were then manually extracted and evaluated for importance based on reported a priori p-values and/or area under the receiver-operator curve (AUC). RESULTS:Of the 161 results that were returned in the database searches, 43 unique articles met the inclusion criteria. Articles were categorized based on body fluid analyzed: 6 studies on urine samples, 13 studies on plasma samples, 11 studies on synovial fluid (SF) samples, 11 studies on serum samples, 1 study on both synovial fluid and serum, and 1 study that involved both plasma and synovial fluid. To synthesize results, individual metabolites, as well as metabolic pathways that involve frequently reported metabolites, are presented for each study. Indications as to whether metabolite levels were increased or decreased are also included if this data was included in the original articles. CONCLUSIONS:These studies clearly show that there are a wide range of metabolic pathways perturbed in OA. For this period, there was no consensus on a single metabolite, or panel of metabolites, that would be clinically useful in early diagnosis of OA or distinguishing OA from a healthy control. However, many common metabolic pathways were identified in the studies, including TCA cycle, fatty acid metabolism, amino acid metabolism (notably BCAA metabolism and tryptophan metabolism via kynurenine pathway), nucleotide metabolism, urea cycle, cartilage matrix components, and phospholipid metabolism. Future research is needed to define effective clinical biomarkers of osteoarthritis from metabolomic and other data. 10.1016/j.semarthrit.2023.152163
Analysis of Metabolites in Gout: A Systematic Review and Meta-Analysis. Nutrients (1) Background: Many studies have attempted to explore potential biomarkers for the early detection of gout, but consistent and high levels of evidence are lacking. In this study, metabolomics was used to summarize the changes of metabolites in the literature and explore the potential value of metabolites in predicting the occurrence and development of gout. (2) Methods: We searched the databases including the EMBASE, the Cochrane Library, PubMed, Web of Science, VIP Date, Wanfang Data, and CNKI, and the screening was fulfilled on 30 July 2022. The records were screened according to the inclusion criteria and the risk of bias was assessed. Qualitative analysis was performed for all metabolites, and meta-analysis was performed for metabolite concentrations using random effects to calculate the Std mean difference and 95% confidence interval. (3) Results: A total of 2738 records were identified, 33 studies with 3422 participants were included, and 701 metabolites were identified. The qualitative analysis results showed that compared with the healthy control group, the concentration of 56 metabolites increased, and 22 metabolites decreased. The results of the meta-analysis indicated that 17 metabolites were statistically significant. (4) Conclusions: Metabolites are associated with gout. Some specific metabolites such as uric acid, hypoxanthine, xanthine, KYNA, guanosine, adenosine, creatinine, LB4, and DL-2-Aminoadipic acid have been highlighted in the development of gout. 10.3390/nu15143143
Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy. Frontiers in molecular biosciences Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects. 10.3389/fmolb.2023.1201912
Osteoarthritis: pathogenic signaling pathways and therapeutic targets. Signal transduction and targeted therapy Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies. 10.1038/s41392-023-01330-w
Metabolic control of arthritis: Switch pathways to treat. Tsokos George C Science translational medicine A shunting of glucose metabolism to the pentose phosphate pathway in rheumatoid arthritis T cells causes exhaustion of oxidants, enhanced cell proliferation, and differentiation toward the T helper 1 (TH1) and TH17 programs (Yanget al, this issue). 10.1126/scitranslmed.aaf4953
Co-stimulatory and Co-inhibitory Pathways in Autoimmunity. Zhang Qianxia,Vignali Dario A A Immunity The immune system is guided by a series of checks and balances, a major component of which is a large array of co-stimulatory and co-inhibitory pathways that modulate the host response. Although co-stimulation is essential for boosting and shaping the initial response following signaling through the antigen receptor, inhibitory pathways are also critical for modulating the immune response. Excessive co-stimulation and/or insufficient co-inhibition can lead to a breakdown of self-tolerance and thus to autoimmunity. In this review, we will focus on the role of co-stimulatory and co-inhibitory pathways in two systemic (systemic lupus erythematosus and rheumatoid arthritis) and two organ-specific (multiple sclerosis and type 1 diabetes) emblematic autoimmune diseases. We will also discuss how mechanistic analysis of these pathways has led to the identification of potential therapeutic targets and initiation of clinical trials for autoimmune diseases, as well as outline some of the challenges that lie ahead. 10.1016/j.immuni.2016.04.017
How the microbiota shapes rheumatic diseases. Van de Wiele Tom,Van Praet Jens T,Marzorati Massimo,Drennan Michael B,Elewaut Dirk Nature reviews. Rheumatology The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease. 10.1038/nrrheum.2016.85
Autophagy: controlling cell fate in rheumatic diseases. Rockel Jason S,Kapoor Mohit Nature reviews. Rheumatology Autophagy, an endogenous process necessary for the turnover of organelles, maintains cellular homeostasis and directs cell fate. Alterations to the regulation of autophagy contribute to the progression of various rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA) and systemic sclerosis (SSc). Implicit in the progression of these diseases are cell-type-specific responses to surrounding factors that alter autophagy: chondrocytes within articular cartilage show decreased autophagy in OA, leading to rapid cell death and cartilage degeneration; fibroblasts from patients with SSc have restricted autophagy, similar to that seen in aged dermal fibroblasts; fibroblast-like synoviocytes from RA joints show altered autophagy, which contributes to synovial hyperplasia; and dysregulation of autophagy in haematopoietic lineage cells alters their function and maturation in SLE. Various upstream mechanisms also contribute to these diseases by regulating autophagy as part of their signalling cascades. In this Review, we discuss the links between autophagy, immune responses, fibrosis and cellular fates as they relate to pathologies associated with rheumatic diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in rheumatic diseases. 10.1038/nrrheum.2016.92
The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Cuda Carla M,Pope Richard M,Perlman Harris Nature reviews. Rheumatology Rheumatoid arthritis affects nearly 1% of the world's population and is a debilitating autoimmune condition that can result in joint destruction. During the past decade, inflammatory functions have been described for signalling molecules classically involved in apoptotic and non-apoptotic death pathways, including, but not limited to, Toll-like receptor signalling, inflammasome activation, cytokine production, macrophage polarization and antigen citrullination. In light of these remarkable advances in the understanding of inflammatory mechanisms of the death machinery, this Review provides a snapshot of the available evidence implicating death pathways, especially within the phagocyte populations of the innate immune system, in the perpetuation of rheumatoid arthritis and other rheumatic diseases. Elevated levels of signalling mediators of both extrinsic and intrinsic apoptosis, as well as the autophagy, are observed in the joints of patients with rheumatoid arthritis. Furthermore, risk polymorphisms are present in signalling molecules of the extrinsic apoptotic and autophagy death pathways. Although research into the mechanisms underlying these pathways has made considerable progress, this Review highlights areas where further investigation is particularly needed. This exploration is critical, as new discoveries in this field could lead to the development of novel therapies for rheumatoid arthritis and other rheumatic diseases. 10.1038/nrrheum.2016.132
Rheumatoid arthritis. Smolen Josef S,Aletaha Daniel,McInnes Iain B Lancet (London, England) Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis. 10.1016/S0140-6736(16)30173-8
Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Cronstein Bruce N,Sitkovsky Michail Nature reviews. Rheumatology Adenosine, a nucleoside derived primarily from the extracellular hydrolysis of adenine nucleotides, is a potent regulator of inflammation. Adenosine mediates its effects on inflammatory cells by engaging one or more cell-surface receptors. The expression and function of adenosine receptors on different cell types change during the course of rheumatic diseases, such as rheumatoid arthritis (RA). Targeting adenosine receptors directly for the treatment of rheumatic diseases is currently under study; however, indirect targeting of adenosine receptors by enhancing adenosine levels at inflamed sites accounts for most of the anti-inflammatory effects of methotrexate, the anchor drug for the treatment of RA. In this Review, we discuss the regulation of extracellular adenosine levels and the role of adenosine in regulating the inflammatory and immune responses in rheumatic diseases such as RA, psoriasis and other types of inflammatory arthritis. In addition, adenosine and its receptors are involved in promoting fibrous matrix production in the skin and other organs, and the role of adenosine in fibrosis and fibrosing diseases is also discussed. 10.1038/nrrheum.2016.178
Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nature reviews. Rheumatology All immune cells depend on specific and efficient metabolic pathways to mount an appropriate response. Over the past decade, the field of immunometabolism has expanded our understanding of the various means by which cells modulate metabolism to achieve the effector functions necessary to fight infection or maintain homeostasis. Harnessing these metabolic pathways to manipulate inappropriate immune responses as a therapeutic strategy in cancer and autoimmunity has received increasing scrutiny by the scientific community. Fine tuning immunometabolism to provide the desired response, or prevent a deleterious response, is an attractive alternative to chemotherapy or overt immunosuppression. The various metabolic pathways used by immune cells in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis offer numerous opportunities for selective targeting of specific immune cell subsets to manipulate cellular metabolism for therapeutic benefit in these rheumatologic diseases. 10.1038/nrrheum.2017.54
Novel treatment strategies in rheumatoid arthritis. Burmester Gerd R,Pope Janet E Lancet (London, England) New treatment strategies have substantially changed the course of rheumatoid arthritis. Many patients can achieve remission if the disease is recognised early and is treated promptly and continuously; however, some individuals do not respond adequately to treatment. Rapid diagnosis and a treat-to-target approach with tight monitoring and control, can increase the likelihood of remission in patients with rheumatoid arthritis. In this Series paper, we describe new insights into the management of rheumatoid arthritis with targeted therapy approaches using classic and novel medications, and outline the potential effects of precision medicine in this challenging disease. Articles are included that investigate the treat-to-target approach, which includes adding or de-escalating treatment. Rheumatoid arthritis treatment is impeded by delayed diagnosis, problematic access to specialists, and difficulties adhering to treat-to-target principles. Clinical management goals in rheumatoid arthritis include enabling rapid access to optimum diagnosis and care and the well informed use of multiple treatments approved for this disease. 10.1016/S0140-6736(17)31491-5
Pathogenetic insights from the treatment of rheumatoid arthritis. McInnes Iain B,Schett Georg Lancet (London, England) Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor α and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis. 10.1016/S0140-6736(17)31472-1
Rheumatoid arthritis. Nature reviews. Disease primers 10.1038/nrdp.2018.2
Rheumatoid Arthritis. Sparks Jeffrey A Annals of internal medicine Rheumatoid arthritis (RA) is a common systemic inflammatory autoimmune disease characterized by painful, swollen joints that can severely impair physical function and quality of life. The presenting symptoms of musculoskeletal pain, swelling, and stiffness are common in clinical practice, so familiarity with diagnosing and managing RA is crucial. Patients with RA are at greater risk for serious infection, respiratory disease, osteoporosis, cardiovascular disease, cancer, and mortality than the general population. In recent years, early diagnosis, aggressive treatment, and expanded therapeutic options of disease-modifying antirheumatic drugs have markedly improved both the management and long-term prognosis of RA. 10.7326/AITC201901010
Chemokines in rheumatic diseases: pathogenic role and therapeutic implications. Nature reviews. Rheumatology Chemokines, a family of small secreted chemotactic cytokines, and their G protein-coupled seven transmembrane spanning receptors control the migratory patterns, positioning and cellular interactions of immune cells. The levels of chemokines and their receptors are increased in the blood and within inflamed tissue of patients with rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis or idiopathic inflammatory myopathies. Chemokine ligand-receptor interactions control the recruitment of leukocytes into tissue, which are central to the pathogenesis of these rheumatic diseases. Although the blockade of various chemokines and chemokine receptors has yielded promising results in preclinical animal models of rheumatic diseases, human clinical trials have, in general, been disappointing. However, there have been glimmers of hope from several early-phase clinical trials that suggest that sufficiently blocking the relevant chemokine pathway might in fact have clinical benefits in rheumatic diseases. Hence, the chemokine system remains a promising therapeutic target for rheumatic diseases and requires further study. 10.1038/s41584-019-0323-6
Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nature reviews. Rheumatology In the past three decades, extraordinary advances have been made in the understanding of the pathogenesis of, and treatment options for, inflammatory arthritides, including rheumatoid arthritis and spondyloarthritis. The use of methotrexate and subsequently biologic therapies (such as TNF inhibitors, among others) and oral small molecules have substantially improved clinical outcomes for many patients with inflammatory arthritis; for others, however, these agents do not substantially improve their symptoms. The emerging field of pharmacomicrobiomics, which investigates the effect of variations within the human gut microbiome on drugs, has already provided important insights into these therapeutics. Pharmacomicrobiomic studies have demonstrated that human gut microorganisms and their enzymatic products can affect the bioavailability, clinical efficacy and toxicity of a wide array of drugs through direct and indirect mechanisms. This discipline promises to facilitate the advent of microbiome-based precision medicine approaches in inflammatory arthritis, including strategies for predicting response to treatment and for modulating the microbiome to improve response to therapy or reduce drug toxicity. 10.1038/s41584-020-0395-3
Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nygaard Gyrid,Firestein Gary S Nature reviews. Rheumatology Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets. 10.1038/s41584-020-0413-5
The immunology of rheumatoid arthritis. Nature immunology The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity. 10.1038/s41590-020-00816-x
Location, location, location: how the tissue microenvironment affects inflammation in RA. Nature reviews. Rheumatology Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, or at all in some individuals, and cannot cure or prevent this disease. One major obstacle to developing better drugs is a lack of complete understanding of how inflammatory joint disease arises and progresses. Emerging evidence indicates an important role for the tissue microenvironment in the pathogenesis of RA. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix (ECM). These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a main site of disease activity in RA, positional and disease stage-specific cellular diversity exist. Improved understanding of the architecture of the synovium from gross anatomy to the single-cell level, in parallel with evidence demonstrating how the synovial ECM is vital for synovial homeostasis and how dysregulated signals from the ECM promote chronic inflammation and tissue destruction in the RA joint, has opened up new ways of thinking about the pathogenesis of RA. These new ideas provide novel therapeutic approaches for patients with difficult-to-treat disease and could also be used in disease prevention. 10.1038/s41584-020-00570-2
The non-coding RNA interactome in joint health and disease. Nature reviews. Rheumatology Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that 'non-coding' does not mean 'non-essential' and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA. 10.1038/s41584-021-00687-y
Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. The Journal of clinical investigation Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed. 10.1172/JCI148552
Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications. Nature reviews. Rheumatology Activation of endothelium and immune cells is fundamental to the initiation of autoimmune diseases such as rheumatoid arthritis (RA), and it results in trans-endothelial cell migration and synovial fibroblast proliferation, leading to joint destruction. In RA, the synovial microvasculature is highly dysregulated, resulting in inefficient oxygen perfusion to the synovium, which, along with the high metabolic demands of activated immune and stromal cells, leads to a profoundly hypoxic microenvironment. In inflamed joints, infiltrating immune cells and synovial resident cells have great requirements for energy and nutrients, and they adapt their metabolic profiles to generate sufficient energy to support their highly activated inflammatory states. This shift in metabolic capacity of synovial cells enables them to produce the essential building blocks to support their proliferation, activation and invasiveness. Furthermore, it results in the accumulation of metabolic intermediates and alteration of redox-sensitive pathways, affecting signalling pathways that further potentiate the inflammatory response. Importantly, the inflamed synovium is a multicellular tissue, with cells differing in their metabolic requirements depending on complex cell-cell interactions, nutrient supply, metabolic intermediates and transcriptional regulation. Therefore, understanding the complex interplay between metabolic and inflammatory pathways in synovial cells in RA will provide insight into the underlying mechanisms of disease pathogenesis. 10.1038/s41584-022-00771-x
Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go? Annals of the rheumatic diseases Fibroblast-like synoviocytes or synovial fibroblasts (FLS) are important cellular components of the inner layer of the joint capsule, referred to as the synovial membrane. They can be found in both layers of this synovial membrane and contribute to normal joint function by producing extracellular matrix components and lubricants. However, under inflammatory conditions like in rheumatoid arthritis (RA), they may start to proliferate, undergo phenotypical changes and become central elements in the perpetuation of inflammation through their direct and indirect destructive functions. Their importance in autoimmune joint disorders makes them attractive cellular targets, and as mesenchymal-derived cells, their inhibition may be carried out without immunosuppressive consequences. Here, we aim to give an overview of our current understanding of the target potential of these cells in RA. 10.1136/annrheumdis-2021-222021
Glycobiology of rheumatic diseases. Nature reviews. Rheumatology Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect B cell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases. 10.1038/s41584-022-00867-4
Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal transduction and targeted therapy Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future. 10.1038/s41392-023-01331-9
Heat of the night: sleep disturbance activates inflammatory mechanisms and induces pain in rheumatoid arthritis. Nature reviews. Rheumatology Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep-wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA. 10.1038/s41584-023-00997-3
Rheumatoid arthritis prevention in arthralgia: fantasy or reality? Nature reviews. Rheumatology The concept of a 'window of opportunity' in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the 'arthralgia' phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease. This Review summarizes the results of these trials and reflects on the outcomes in relation to the patients' perspectives. Overall, the majority of symptomatic at-risk individuals could benefit from a fixed period treatment, even if RA does not develop. Various factors must be taken into consideration when translating these findings into clinical practice. More evidence is needed to target the individuals at highest risk, and additional tools are needed to monitor treatment and guide decisions about whether treatment can be discontinued. Without these tools, there is a paradoxical risk of seemingly increasing the incidence of the disease and prolonging disease duration, which is the opposite of what the concept of intervening in the window of opportunity entails. 10.1038/s41584-023-01035-y
MicroRNA-17-5p Reduces Inflammation and Bone Erosions in Mice With Collagen-Induced Arthritis and Directly Targets the JAK/STAT Pathway in Rheumatoid Arthritis Fibroblast-like Synoviocytes. Najm Aurélie,Masson François-Marie,Preuss Pauline,Georges Steven,Ory Benjamin,Quillard Thibaut,Sood Shatakshi,Goodyear Carl S,Veale Douglas J,Fearon Ursula,Le Goff Benoit,Blanchard Frédéric Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:We undertook this study to examine microRNA (miRNA) expression across rheumatoid arthritis (RA) phenotypes, along with the effects and mechanisms of action of miRNA-17-5p (miR-17). METHODS:A miRNA array was performed in synovial tissue biopsied from patients with naive erosive RA (n = 3) and patients with nonerosive RA (n = 3). MicroRNA-17 lipoplex was delivered intraarticularly in the murine collagen-induced arthritis model. Clinical, histologic, and structural effects were studied over the course of arthritis. In-depth studies of the mechanisms of action of miR-17 were performed in primary RA fibroblast-like synoviocytes (FLS) isolated from synovial tissue. RESULTS:Fifty-five miRNAs including miR-17 were reduced in erosive RA. The miR-17 transfection into arthritic paws reduced the clinical inflammation score between day 2 and day 7 (2.8 versus 1.9; P = 0.03). Synovial B cell, T cell, macrophage, and polynuclear neutrophil infiltration was significantly reduced. Structural damage was also decreased, as shown by a reduction in the number of osteoclasts detected using tartrate-resistant acid phosphatase staining (osteoclast surface/bone surface 32% versus 18%; P = 0.005) and erosion score by computed tomography analysis (2.9 versus 1.7; P = 0.023). Proinflammatory cytokines from the interleukin-6 (IL-6) family and IL-1β expression were also significantly reduced, but tumor necrosis factor was not. MicroRNA-17 directly targeted the 3'-untranslated regions of STAT3 and JAK1. STAT3 and JAK1 messenger RNA (mRNA) and protein expression were reduced in RA FLS following miR-17 transfection. STAT3 and JAK1 mRNA and activation of STAT3, as assessed by immunohistochemistry, were also reduced in injected paws (% stained area 93% versus 62%; P = 0.035). CONCLUSION:We demonstrate an antiinflammatory and antierosive role of miR-17 in vivo. This effect involves the suppression of the IL-6 family autocrine-amplifying loop through the direct targeting of JAK1 and STAT3. 10.1002/art.41441
Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study. Annals of the rheumatic diseases OBJECTIVE:This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy. METHODS:The primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission. RESULTS:ABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464. CONCLUSION:ABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA. TRIAL REGISTRATION NAME:Phase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27 TRIAL REGISTRATION NUMBER: NCT03813199. 10.1136/annrheumdis-2022-222228
Deregulation and therapeutic potential of microRNAs in arthritic diseases. Vicente Rita,Noël Danièle,Pers Yves-Marie,Apparailly Florence,Jorgensen Christian Nature reviews. Rheumatology Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties - parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) - are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA. 10.1038/nrrheum.2015.162
Bone protection by inhibition of microRNA-182. Inoue Kazuki,Deng Zhonghao,Chen Yufan,Giannopoulou Eugenia,Xu Ren,Gong Shiaoching,Greenblatt Matthew B,Mangala Lingegowda S,Lopez-Berestein Gabriel,Kirsch David G,Sood Anil K,Zhao Liang,Zhao Baohong Nature communications Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection. 10.1038/s41467-018-06446-0
Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Annals of the rheumatic diseases MicroRNAs (miRNAs) are recently discovered regulators of gene expression, and early studies have indicated that they have a role in the regulation of haematopoiesis, the immune response and inflammation. They bind the 3'UTR of target mRNAs and mainly prevent translation of the protein product. Dysregulation of these molecules has been shown to be a hallmark of cancer and now investigators are examining their role in the pathogenesis of inflammatory diseases. miR-146 and miR-155 have been a particular focus for investigators, and these two miRNAs have been shown to be induced by proinflammatory stimuli such as interleukin 1, tumour necrosis factor alpha (TNFalpha) and Toll-like receptors (TLRs). They have also been detected in synovial fibroblasts and rheumatoid synovial tissue. Both have multiple targets, with miR-146 inhibiting TLR signalling and miR-155 regulating Th1 cells and also, interestingly, positively regulating mRNA for TNFalpha. The potential of miRNAs for improving our understanding of the pathogenesis of diseases such as rheumatoid arthritis, and for developing potentially new treatments for these diseases, is substantial. 10.1136/ard.2008.100289
microRNAs in rheumatoid arthritis: midget RNAs with a giant impact. Annals of the rheumatic diseases MicroRNAs (miRNAs) are tiny, non-coding molecules that primarily modulate gene expression at the post-transcriptional level by predominantly hybridising to complementary sequences in the 3'-untranslated region of their corresponding mRNAs. Depending on the degree of Watson-Crick base pairing, a miRNA either accelerates the degradation of the corresponding transcript or restricts its translation. There is compelling evidence that miRNAs have crucial roles in controlling and modulating immunity, while dysregulation of miRNAs can lead to autoimmunity and promote tumourigenesis, making miRNA regulation a balancing act between immunity and tumourigenesis. Here, the focus is on the role of miRNAs during the establishment and sustainment of rheumatoid arthritis (RA), a systemic, inflammatory autoimmune disease with irreversible joint destruction. An overview of the known function of miRNAs in RA and what the future might hold for the use of these small RNA molecules in RA diagnosis and treatment is provided. 10.1136/ard.2010.140152
MicroRNA-146a in autoimmunity and innate immune responses. Annals of the rheumatic diseases MicroRNA (miRNA) are approximately 22 nucleotide single-stranded RNA that regulate the stability of target messenger RNA by selective binding to specific sites at the 3'-untranslated regions (UTR). This triggers repression in translation and mRNA degradation. It has been estimated that approximately 60% of all mRNA are under the control of miRNA. Among the known hundreds of miRNA, some are considered master regulators controlling either a single or multiple cellular pathways. Some miRNA are known to affect development and cell differentiation, while others are implicated in immunity and autoimmune diseases. A very interesting example is miR-146a, which has been reported to be downregulated in systemic lupus erythematosus and upregulated in rheumatoid arthritis (RA). Several groups have recently focused their attention on miRNA in the pathogenesis of RA. Interestingly, the expression of miR-146a is upregulated in different cell types and tissues in RA patients. miRNA in RA could also be considered as possible future targets for new therapeutic approaches. This discussion will focus on the current understanding in the function of miR-146a in endotoxin tolerance and cross-tolerance, and how it may contribute to modulate the overproduction of known pathogenic cytokines, such as tumour necrosis factor α. 10.1136/annrheumdis-2012-202203
Epigenetics in 2013. DNA methylation and miRNA: key roles in systemic autoimmunity. Richardson Bruce C,Patel Dipak R Nature reviews. Rheumatology Several advances in 2013 have improved our understanding of how epigenetic mechanisms affect autoimmune disorders. Many new insights were made into the regulation of gene expression by DNA methylation in systemic lupus erythematosus. For rheumatoid arthritis, complex interrelationships between DNA methylation and microRNAs in regulating gene expression were described. 10.1038/nrrheum.2013.211
Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Annals of the rheumatic diseases OBJECTIVES:MicroRNAs (miRNAs) have been implicated in the pathogenesis of autoimmune diseases, not least for their critical role in the regulation of regulatory T cell (Treg) function. Deregulated expression of miR-146a and miR-155 has been associated with rheumatoid arthritis (RA). We therefore investigated miR-146a and miR-155 expression in Tregs of patients with RA and their possible impact on Treg function and disease activity. METHODS:Expression of miR-146a and miR-155 was assessed in RA patients and controls. MiRNA expression was correlated with disease activity and expression of target genes. Interference with biological activity of miRNAs was evaluated in functional Treg assays. RESULTS:Diminished upregulation of miR-146a and miR-155 in response to T cell stimulation was found in Tregs of RA patients. Diminution of miR-146a expression was observed in particular in patients with active disease, and correlated with joint inflammation. In patients with active RA, Tregs demonstrated a pro-inflammatory phenotype characterised by inflammatory cytokine expression. This was due to an augmented expression and activation of signal transducer and activator transcription 1 (STAT1), a direct target of miR-146a. CONCLUSIONS:Our results suggest that in RA miR-146a facilitates a pro-inflammatory phenotype of Tregs via increased STAT1 activation, and contributes thereby to RA pathogenesis. 10.1136/annrheumdis-2013-204377
MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats. Annals of the rheumatic diseases OBJECTIVE:MicroRNAs (miRNAs) are small endogenous, non-coding RNAs that act as post-transcriptional regulators. We analysed the in vivo effect of miRNA-124 (miR-124, the rat analogue of human miR-124a) on adjuvant-induced arthritis (AIA) in rats. METHODS:AIA was induced in Lewis rats by injecting incomplete Freund's adjuvant with heat-killed Mycobacterium tuberculosis. Precursor (pre)-miR-124 was injected into the right hind ankle on day 9. Morphological changes in the ankle joint were assessed by micro-CT and histopathology. Cytokine expression was examined by western blotting and real-time RT-PCR. The effect of miR-124 on predicted target messenger RNAs (mRNAs) was examined by luciferase reporter assays. The effect of pre-miR-124 or pre-miR-124a on the differentiation of human osteoclasts was examined by tartrate-resistant acid phosphatase staining. RESULTS:We found that miR-124 suppressed AIA in rats, as demonstrated by decreased synoviocyte proliferation, leucocyte infiltration and cartilage or bone destruction. Osteoclast counts and expression level of receptor activator of the nuclear factor κB ligand (RANKL), integrin β1 (ITGB1) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were reduced in AIA rats treated with pre-miR-124. Luciferase analysis showed that miR-124 directly targeted the 3'UTR of the rat NFATc1, ITGB1, specificity protein 1 and CCAAT/enhancer-binding protein α mRNAs. Pre-miR-124 also suppressed NFATc1 expression in RAW264.7 cells. Both miR-124 and miR-124a directly targeted the 3'-UTR of human NFATc1 mRNA, and both pre-miR-124 and pre-miR-124a suppressed the differentiation of human osteoclasts. CONCLUSIONS:We found that miR-124 ameliorated AIA by suppressing critical prerequisites for arthritis development, such as RANKL and NFATc1. Thus, miR-124a is a candidate for therapeutic use for human rheumatoid arthritis. 10.1136/annrheumdis-2014-206417
MicroRNA regulation of lymphocyte tolerance and autoimmunity. Simpson Laura J,Ansel K Mark The Journal of clinical investigation Understanding the cell-intrinsic cues that permit self-reactivity in lymphocytes, and therefore autoimmunity, requires an understanding of the transcriptional and posttranscriptional regulation of gene expression in these cells. In this Review, we address seminal and recent research on microRNA (miRNA) regulation of central and peripheral tolerance. Human and mouse studies demonstrate that the PI3K pathway is a critical point of miRNA regulation of immune cell development and function that affects the development of autoimmunity. We also discuss how miRNA expression profiling in human autoimmune diseases has inspired mechanistic studies of miRNA function in the pathogenesis of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and asthma. 10.1172/JCI78090
Maresin 1 improves the Treg/Th17 imbalance in rheumatoid arthritis through miR-21. Annals of the rheumatic diseases OBJECTIVE:Treg/Th17 imbalance plays an important role in rheumatoid arthritis (RA). Maresin 1 (MaR1) prompts inflammation resolution and regulates immune responses. We explored the effect of MaR1 on RA progression and investigated the correlation between MaR1 and Treg/Th17 balance. METHODS:Both patients with RA and healthy controls were recruited into the study. Collagen-induced arthritis (CIA) model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. Purified naive CD4+ T-cells were used to study the effect of MaR1 on its differentiation process and microRNA microarray studies were performed to investigate MaR1 downstream microRNAs in this process. MicroRNA transfection experiments were conducted by lentivirus to verify the mechanism of MaR1 on Treg/Th17 balance. RESULTS:Compared with controls, the MaR1 concentration was higher in the patients with inactive RA and lower in the patients with active RA. Expression of the Treg transcription factor FoxP3 was the highest in inactive RA and the lowest in active RA, while the Th17 transcription factor RORc showed a reverse trend. An inverse correlation was observed between the FoxP3/RORc ratio and Disease Activity Score 28. Intervention of MaR1 in the CIA model reduced joint inflammation and damage, and improved the imbalanced Treg/Th17 ratio. MaR1 increased Treg cells proportion while reduced Th17 cells proportion under specific differentiation conditions. Furthermore, miR-21 was verified as MaR1 downstream microRNA, which was upregulated by MaR1, modulating the Treg/Th17 balance and thus ameliorating the RA progression. CONCLUSIONS:MaR1 is a therapeutic target for RA, likely operating through effects on the imbalanced Treg/Th17 ratio found in the disease. 10.1136/annrheumdis-2018-213511
The role of microRNAs in diseases and related signaling pathways. Molecular biology reports MicroRNAs (miRNAs) are epigenetic regulators of the gene expression and act through posttranslational modification. They bind to 3'-UTR of target mRNAs to inhibit translation or increase the degradation mRNA in many tissues. Any alteration in the level of miRNA expression in many human diseases indicates their involvement in the pathogenesis of many diseases. On the other hand, the regulation of the signaling pathways is necessary for the maintenance of natural and physiological characteristics of any cell. It is worth mentioning that dysfunction of the signaling pathways manifests itself as a disorder or disease. The significant evidence report that miRNAs regulate the several signaling pathways in many diseases. Base on previous studies, miRNAs can be used for therapeutic or diagnostic purposes. According to the important role of miRNAs on the cell signaling pathways, this article reviews miRNAs involvement in incidence of diseases by changing signaling pathways. 10.1007/s11033-021-06725-y
Role of miR-9-5p in preventing peripheral neuropathy in patients with rheumatoid arthritis by targeting REST/miR-132 pathway. Li Zunzhong,Li Yanshan,Li Qinghua,Zhang Zhenchun,Jiang Li,Li Xingfu In vitro cellular & developmental biology. Animal MicroRNAs (miRNAs) are found to play a key role in neural cell differentiation, peripheral nerve injury, and rheumatoid arthritis (RA). However, no study has yet been conducted highlighting their role in RA-induced peripheral neuropathy. Here, we investigated the role of miRNAs in RA-induced peripheral neuropathy. Levels of six miRNAs were detected in serum collected from 15 patients with RA and peripheral neuropathy and 16 patients with RA. In vitro, Schwann cells were treated with 0.1 ng/mL IL-6 and 20 ng/mL TNF-α. The expression level of miR-9-5p and its association with the repressor element-1 silencing transcription factor (REST) were investigated. The roles of miR-9-5p and REST in Schwann cell injury were examined after transfection of miR-9-5p mimics or REST siRNA. In patients with RA and peripheral neuropathy, serum miR-9-5p was significantly downregulated when compared with RA. In IL-6- and TNF-α-stimulated Schwann cells, apoptosis was induced, while the cell viability and level of miR-9-5p were inhibited. A significantly negative correlation was observed between miR-9-5p and REST. Transfection of miR-9-5p mimics and REST siRNA significantly reversed the inhibition of cell viability and induction of apoptosis caused by IL-6 and TNF-α. In addition, overexpression of miR-9-5p upregulated the expression of miR-132, miRNA targeting E1A binding protein EP300 (EEP300), phosphatase and tensin homolog (PTEN) and forkhead box O3 (FOXO3). These results showed that Schwann cells were protected by miR-9-5p from inflammatory damage by targeting REST/miR-132 pathway, which could provide new targets for treatment of RA-induced peripheral neuropathy. 10.1007/s11626-018-0310-2
MiR-9-5p Inhibits the MMP-Induced Neuron Apoptosis through Regulating SCRIB/-Catenin Signaling in Parkinson's Disease. Oxidative medicine and cellular longevity The pathogenesis of Parkinson's disease remains unclear that there is no cure for Parkinson's disease yet. The abnormal expressions of certain miRNA are closely related to the occurrence and progression of Parkinson's disease. Here, we demonstrate that miR-9-5p inhibits the dopaminergic neuron apoptosis via the regulation of -catenin signaling which directly targets SCRIB, a tumor suppressor gene. Besides, miR-9-5p improved the motor function of mice with Parkinson's disease. The results of this study suggest that miR-9-5p might be a potential therapeutic target against Parkinson's disease. 10.1155/2022/9173514
Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Chen Meng-Lu,Hong Chun-Gu,Yue Tao,Li Hong-Ming,Duan Ran,Hu Wen-Bao,Cao Jia,Wang Zhen-Xing,Chen Chun-Yuan,Hu Xiong-Ke,Wu Ben,Liu Hao-Ming,Tan Yi-Juan,Liu Jiang-Hua,Luo Zhong-Wei,Zhang Yan,Rao Shan-Shan,Luo Ming-Jie,Yin Hao,Wang Yi-Yi,Xia Kun,Tang Si-Yuan,Xie Hui,Liu Zheng-Zhao Theranostics Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ). The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2) and activated microglia (CD68IBA1) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes () were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined. MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 () and Optineurin (), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage. Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy. 10.7150/thno.47408
Rheumatoid Arthritis - Common Origins, Divergent Mechanisms. The New England journal of medicine 10.1056/NEJMra2103726
Metabolic syndrome meets osteoarthritis. Zhuo Qi,Yang Wei,Chen Jiying,Wang Yan Nature reviews. Rheumatology Metabolic osteoarthritis (OA) has now been characterized as a subtype of OA, and links have been discovered between this phenotype and metabolic syndrome (MetS)--both with individual MetS components and with MetS as a whole. Hypertension associates with OA through subchondral ischaemia, which can compromise nutrient exchange into articular cartilage and trigger bone remodelling. Ectopic lipid deposition in chondrocytes induced by dyslipidemia might initiate OA development, exacerbated by deregulated cellular lipid metabolism in joint tissues. Hyperglycaemia and OA interact at both local and systemic levels; local effects of oxidative stress and advanced glycation end-products are implicated in cartilage damage, whereas low-grade systemic inflammation results from glucose accumulation and contributes to a toxic internal environment that can exacerbate OA. Obesity-related metabolic factors, particularly altered levels of adipokines, contribute to OA development by inducing the expression of proinflammatory factors as well as degradative enzymes, leading to the inhibition of cartilage matrix synthesis and stimulation of subchondral bone remodelling. In this Review, we summarize the shared mechanisms of inflammation, oxidative stress, common metabolites and endothelial dysfunction that characterize the aetiologies of OA and MetS, and nominate metabolic OA as the fifth component of MetS. We also describe therapeutic opportunities that might arise from uniting these concepts. 10.1038/nrrheum.2012.135
Hypertension meets osteoarthritis - revisiting the vascular aetiology hypothesis. Nature reviews. Rheumatology Osteoarthritis (OA) is a whole-joint disease characterized by subchondral bone perfusion abnormalities and neovascular invasion into the synovium and articular cartilage. In addition to local vascular disturbance, mounting evidence suggests a pivotal role for systemic vascular pathology in the aetiology of OA. This Review outlines the current understanding of the close relationship between high blood pressure (hypertension) and OA at the crossroads of epidemiology and molecular biology. As one of the most common comorbidities in patients with OA, hypertension can disrupt joint homeostasis both biophysically and biochemically. High blood pressure can increase intraosseous pressure and cause hypoxia, which in turn triggers subchondral bone and osteochondral junction remodelling. Furthermore, systemic activation of the renin-angiotensin and endothelin systems can affect the Wnt-β-catenin signalling pathway locally to govern joint disease. The intimate relationship between hypertension and OA indicates that endothelium-targeted strategies, including re-purposed FDA-approved antihypertensive drugs, could be useful in the treatment of OA. 10.1038/s41584-021-00650-x
The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Sellam Jérémie,Berenbaum Francis Nature reviews. Rheumatology Osteoarthritis (OA), one of the most common rheumatic disorders, is characterized by cartilage breakdown and by synovial inflammation that is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. The gold-standard method for detecting synovitis is histological analysis of samples obtained by biopsy, but the noninvasive imaging techniques MRI and ultrasonography might also perform well. The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage that are similar to those seen in rheumatoid arthritis. Catabolic and proinflammatory mediators such as cytokines, nitric oxide, prostaglandin E(2) and neuropeptides are produced by the inflamed synovium and alter the balance of cartilage matrix degradation and repair, leading to excess production of the proteolytic enzymes responsible for cartilage breakdown. Cartilage alteration in turn amplifies synovial inflammation, creating a vicious circle. As synovitis is associated with clinical symptoms and also reflects joint degradation in OA, synovium-targeted therapy could help alleviate the symptoms of the disease and perhaps also prevent structural progression. 10.1038/nrrheum.2010.159
Modern-day environmental factors in the pathogenesis of osteoarthritis. Berenbaum Francis,Wallace Ian J,Lieberman Daniel E,Felson David T Nature reviews. Rheumatology The prevalence of osteoarthritis (OA) is rising for reasons that are not fully understood. In this Opinion article, we review the possibility that OA is an evolutionary mismatch disease, which is a disease more common today than in the past because genes inherited from previous generations are inadequately or imperfectly adapted to modern environmental conditions. We focus on four major environmental factors in OA pathogenesis that have become ubiquitous within the past half-century: obesity, metabolic syndrome, dietary changes and physical inactivity. Because a cure for OA does not yet exist, prevention strategies that target these modifiable environmental factors are needed to curb further increases in OA prevalence. 10.1038/s41584-018-0073-x
Synovial inflammation in osteoarthritis progression. Nature reviews. Rheumatology Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with radiographic and pain progression. Several OA risk factors, including ageing, obesity, trauma and mechanical loading, play a role in OA pathogenesis, likely by modifying synovial biology. In addition, other factors, such as mitochondrial dysfunction, damage-associated molecular patterns, cytokines, metabolites and crystals in the synovium, activate synovial cells and mediate synovial inflammation. An understanding of the activated pathways that are involved in OA-related synovial inflammation could form the basis for the stratification of patients and the development of novel therapeutics. This Review focuses on the biology of the OA synovium, how the cells residing in or recruited to the synovium interact with each other, how they become activated, how they contribute to OA progression and their interplay with other joint structures. 10.1038/s41584-022-00749-9
Macro view of microRNA function in osteoarthritis. Miyaki Shigeru,Asahara Hiroshi Nature reviews. Rheumatology Osteoarthritis (OA), the most common musculoskeletal disorder, is complex, multifaceted, and characterized by degradation of articular cartilage and alterations in other joint tissues. Although some pathogenic pathways have been characterized, current knowledge is incomplete and effective approaches to the prevention or treatment of OA are lacking. Understanding novel molecular mechanisms that are involved in the maintenance and destruction of articular cartilage, including extracellular regulators and intracellular signalling mechanisms in joint cells that control cartilage homeostasis, has the potential to identify new therapeutic targets in OA. MicroRNAs control tissue development and homeostasis by fine-tuning gene expression, with expression patterns specific to tissues and developmental stages, and are increasingly implicated in the pathogenesis of complex diseases such as cancer and cardiovascular disorders. The emergent roles of microRNAs in cartilage homeostasis and OA pathogenesis are summarized in this Review, alongside potential clinical applications. 10.1038/nrrheum.2012.128
Fibroblast growth factor signalling in osteoarthritis and cartilage repair. Xie Yangli,Zinkle Allen,Chen Lin,Mohammadi Moosa Nature reviews. Rheumatology Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis. 10.1038/s41584-020-0469-2
The role of metabolism in the pathogenesis of osteoarthritis. Mobasheri Ali,Rayman Margaret P,Gualillo Oreste,Sellam Jérémie,van der Kraan Peter,Fearon Ursula Nature reviews. Rheumatology Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically. 10.1038/nrrheum.2017.50
Upregulation of microRNA‑590 in rheumatoid arthritis promotes apoptosis of bone cells through transforming growth factor‑β1/phosphoinositide 3‑kinase/Akt signaling. Yang Jun,Zhuang Yunxiang,Liu Jianghua International journal of molecular medicine The aim of the present study was to further define the role of microRNA (miR)‑590 in osteoarthritis (OA) and to investigate the underlying mechanism. In brief, reverse transcription‑quantitative polymerase chain reaction was used to analyze miR‑590 expression in bone tissue samples from rats with OA. Results indicated the expression of miR‑590 was increased. miR‑590 upregulation induced apoptosis in bone cells, whereas miR‑590 downregulation reduced apoptosis of bone cells. Furthermore, miR‑590 upregulation suppressed the protein expression levels of transforming growth factor (TGF)‑β1, phosphoinositide 3‑kinase (PI3K) and phosphorylated (p)‑Akt in bone cells. However, downregulation of miR‑590 induced the protein expression levels of TGF‑β1, PI3K and p‑Akt in bone cells. In addition, TGF‑β1 attenuated the effects of miR‑590 upregulation on bone cell apoptosis and the inactivation of PI3K inhibited the effects of miR‑590 downregulation on bone cell apoptosis. Taken together, the present data suggested that miR‑590 promoted apoptosis in bone cells from rats with OA by regulating the TGF‑β1/PI3K signaling pathway. 10.3892/ijmm.2019.4116
Effect of moxibustion on autophagy and the inflammatory response of synovial cells in rheumatoid arthritis model rat. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan OBJECTIVE:To investigate the effect of moxibustion on synovitis and the autophagy of synoviocytes in rheumatoid arthritis (RA). METHODS:Forty Sprague-Dawley rats were randomly divided into a normal group, model group, moxibustion group, cigarette moxibustion group, and medicine group, with eight rats included in each group. The RA model was established by subcutaneous injection of complete Freund's adjuvant into the left posterior toe. Rats in the model group were not interfered with. In the moxibustion group, rats were treated by moxibustion, where a 1-cm diameter moxa stick was applied at the left Zusanli (ST 36) point. The distance of the moxa stick to the skin was 2 cm and moxibustion was completed for 20 min daily for 15 d total. In the cigarette moxibustion group, the moxa stick was replaced by a common cigarette. In the medicine group, rats were treated with a tripterygium glycoside suspension (8 mg/kg) once a day for 15 d total. In each group, the left hind limb toe volume was measured with a toe volume meter; the synovial cells were observed by hematoxylin and eosin staining; the interleukin (IL)-4, IL-6, IL-10, IL-1β, IL-23, IL-17, and tumor necrosis factor (TNF)-α levels in serum were measured by enzyme-linked immunosorbent assay; the erythrocyte sedimentation rate (ESR) were detected by Westergren sedimentation rate testing; the C-reactive protein (CRP) and rheumatoid factor (RF) levels in serum were detected by rate nephelometry; the expression levels of ULK1, autophagy-associated protein (Atg)3, Atg5, and Atg12 messenger RNA (mRNA) in synovium were detected by real time-quantitative polymerase chain reaction (RT-qPCR); and the protein expression levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), LC3-II, beclin-1, phosphorylated-PI3K (p-PI3K), p-Akt, p-mTOR in synovium were detected by Western blotting. RESULTS:Among the RA model rats, joint swelling, an inflammatory reaction, and the proliferation of synovial tissue were obvious and the signal of the PI3K/Akt/mTOR pathway was active, while autophagy was inhibited. Moxibustion at Zusanli (ST36) or intragastric administration of Tripterygium wilfordii glycosides could alleviate the inflammatory reaction of RA rats; relieve the swelling of the toes; downregulate the levels of ESR, CRF, RF; lower the levels of IL-6, IL-1β, TNF-α, and IL-17; and increase the IL-4 and IL-10. At the same time, the mRNA expression levels of ULK1, Atg3, Atg5, and Atg12 and those of LC3-Ⅱ and beclin-1 were increased, while the PI3K, Akt, mTOR, p-PI3K, p-Akt, p-mTOR were decreased. Cigarette moxibustion did not significantly reduce the swelling of the toe joint in RA rats, and was not as good as that of moxibustion or Tripterygium wilfordii polyglycosides in the effects of inflammation relief and the influences of the levels of ESR, CRF, RF. While cigarette moxibustion has a weak effect to affect the expression of corresponding molecules in autophages and the expression level of the autophagy biomaker in synovial tissue. Moxibustion and tripterygium glycosides can significantly reduce the joint swelling, relieve synovitis and synovial hyperplasia, and inhibit the PI3K/Akt/mTOR signaling pathway to increase autophagy in a manner superior to cigarette moxibustion. CONCLUSION:Moxibustion can limit the proliferation of synoviocytes in RA rats by inhibiting the PI3K/Akt/mTOR signaling pathway, promoting autophagy, effectively reducing synovitis, and alleviating joint swelling.
Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis. Journal of nanobiotechnology Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases. 10.1186/s12951-023-01865-8
Downregulated microRNA-135a ameliorates rheumatoid arthritis by inactivation of the phosphatidylinositol 3-kinase/AKT signaling pathway via phosphatidylinositol 3-kinase regulatory subunit 2. Qu Yuan,Zhang Yu-Ping,Wu Jing,Jie Li-Gang,Deng Jia-Xin,Zhao Dong-Bao,Yu Qing-Hong Journal of cellular physiology Synovial fibroblasts (SFs) of rheumatoid arthritis (RA) are phenotypically aggressive, typically progressing into arthritic cartilage degradation. Throughout our study, we made explorations into the effects of microRNA-135a (miR-135a) on the SFs involved in RA by mediating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway via regulation of phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2). The expression of PI3K was higher, the expression of PIK3R2 was lower, and AKT was phosphorylated in the RA synovial tissues, relative to the levels found in the normal synovial tissues. We predicted miR-135a to be a candidate miR targeting PIK3R2 using an online website, microRNA.org, which was verified with a dual-luciferase reporter gene assay. Subsequently, high miR-135a expression was observed in RA synovial tissues. To study the effect of the interaction between miR-135a and PIK3R2 in RA, the SFs isolated from RA samples were cultured and transfected with mimic, inhibitor, and small interfering RNA. The proliferation, invasion, and apoptosis of the SFs were detected after the transfection. The cells transfected with miR-135a inhibitor showed inhibited cell proliferation, migration, and invasion, while also displaying promoted cell apoptosis, G0/G1 cell ratio, and decreased S cell ratio, through upregulation of PIK3R2 and inactivation of the PI3K/AKT signaling pathway. These findings provided evidence that downregulation of miR-135a inhibits proliferation, migration, and invasion and promotes apoptosis of SFs in RA by upregulating the PIK3R2 coupled with inactivating the PI3K/AKT signaling pathway. The downregulation of miR-135a might be a potential target in the treatment of RA. 10.1002/jcp.28390
Euphorbium total triterpenes improve Freund's complete adjuvant-induced arthritis through PI3K/AKT/Bax and NF-κB/NLRP3 signaling pathways. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Euphorbium is the resinous secretion of Euphorbia resinifera Berg. According to the record, Euphorbium was first used by Roman doctors to treat the emperor's joint pain. In China, it is applied in folk medicine to treat damp-cold or mucous diseases, such as arthralgia and ascites, etc. This herb is used for rheumatoid arthritis and skin tumors in the folklore of northeastern Brazil. Triterpenes are mainly characteristic constituents of Euphorbium, and possibly possess anti-rheumatoid arthritis. AIM OF THE STUDY:To explore the preventive effect of Euphorbium total triterpenes (TTE) on Freund's complete adjuvant (FCA) induced arthritis in rats and its mechanism. MATERIAL AND METHODS:TTE was extracted and isolated from Euphorbium, and its components were analyzed by HPLC. The safety of TTE was evaluated by an acute toxicity test in mice. Arthritis was induced in rats by injecting 0.2 mL FCA into the right hind paw toe, except for the control group, which was given the same volume of physiological saline. Tripterygium Glycosides (TG, 7.5 mg/kg) and TTE (32, 64 and 128 mg/kg) were administered by gavage for 30 days. Body weights, paw swelling, and arthritic scores were measured during the experiment process. After 30 days, blood and joints were harvested to determine various indicators of arthritis. RESULTS:The contents of euphol and euphorbol in TTE were 47.03% and 18.77% respectively, and the maximal feasible dose of TTE in mice is 12 g/kg. The experimental results showed that arthritis indicators in rats deteriorated after FCA inducement compared with the control group. After treatment with TTE, the swelling degree and histopathological change of the hind paws in rats were significantly improved as well as arthritic score; the serum TNF-α, CRP, IL-1β, IL-6, IL-18 and RF levels in rats were significantly reduced; The expression of PI3K, AKT, P-AKT, Bcl-2, NF-κB, NLRP3 and Pro-caspase-1 protein in joint tissue were down-regulated, and the expression of Bax protein was up-regulated. CONCLUSION:The results suggested that TTE possessed anti-arthritis effects, and its mechanism may be related to its anti-inflammatory and immunomodulatory properties, as well as regulation of PI3K/AKT/Bax and NF-κB/NLRP3 signaling pathway. 10.1016/j.jep.2023.116146
Anti-rheumatoid arthritis effects of total saponins from Rhizoma Panacis Majoris on adjuvant-induced arthritis in rats and rheumatoid arthritis fibroblast-like synoviocytes. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Total saponins from Rhizoma Panacis Majoris (RPMTG) showed significant antitumour activity in our previous studies. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) with tumour-like characteristics have received attention as a therapeutic target for RA. However, the potential effect and mechanism of action of RPMTG against RA-FLS remain unclear. OBJECTIVE:The study investigated the therapeutic effect of RPMTG on adjuvant-induced arthritis (AIA) in rats, and the regulation effect and underlying mechanism on apoptosis, autophagy of RA-FLS. METHODS:The therapeutic effect of RPMTG was determined by the symptoms and signs of AIA rats. The production of inflammatory cytokines was detected by ELISA. Histopathological change of the ankle and synovial tissues were detected by HE staining. Flow cytometry, Hoechst 33342/PI staining, MDC staining, and TEM were used to determine the effects of RPMTG on apoptosis and autophagy. Western blotting was applied to detect the expression levels of proteins. RESULTS:In AIA rats, RPMTG treatment ameliorated paw swelling, and arthritis score, restored synovial histopathological changes, inhibited the expression of IL-6 and IL-1β, exhibiting its potent anti-arthritis effect. In vitro, RPMTG depressed the proliferation of RA-FLS, arrested cell cycle in G0/G1 phase, and induced mitochondria-mediated apoptosis. Moreover, RPMTG significantly inhibited the autophagy in vivo and in vitro, proved by decreasing the expression of autophagy-related indicators (LC3II/LC3I, Beclin-1). Mechanistically, the study demonstrated that the activation of p38 MAPK and PI3K/Akt/mTOR pathways was mainly involved in the therapeutic effects of RPMTG. Interestingly, the effect of RPMTG on apoptosis was reversed after Rapamycin treatment, which preliminarily demonstrated that the inhibitory effect of RPMTG on autophagy was beneficial to the effect on inducing apoptosis. The regulation effect of RPMTG concurrently on apoptosis and autophagy revealed its unique advantages in RA treatment. CONCLUSION:RPMTG showed potent therapeutic effects on AIA rats and induced apoptosis, inhibited autophagy mainly through activating the p38 MAPK and PI3K/Akt/mTOR pathways in RA-FLS. 10.1016/j.phymed.2023.155021
Curcumin alleviates rheumatoid arthritis progression through the phosphatidylinositol 3-kinase/protein kinase B pathway: an and study. Bioengineered Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by synovial inflammation and joint bone and cartilage destruction. Curcumin can improve joint inflammation in rats with arthritis and inhibit synovial revascularization and abnormal proliferation of fibroblasts. However, it is unclear whether curcumin affects the RA progression. The TNF-α-stimulated primary RA fibroblast-like synoviocytes (RA-FLS) and SV-40 transformed MH7A cells were used as the model of RA. A mouse model of collagen-induced arthritis (CIA) was used as the model. The effects of curcumin on cell proliferation, apoptosis, migration, invasion, and inflammatory response were assessed by colony formation, flow cytometry, wound scratch, Transwell assays, and western blotting analysis. Arthritis index scores and degree of paw swelling in mice were assessed to evaluate RA. Curcumin inhibited the TNF-α-induced proliferation, migration, invasion of MH7A and RA-FLS cells and promoted cell apoptosis. Administration with curcumin reversed the CIA-induced increase in arthritis scores, hind paw edema, and loss of appetite, while these effects were rescued by insulin-like growth factor 1, the upstream cytokine of PI3K/AKT. Moreover, curcumin suppressed the inflammatory response by reducing TNF-α, IL-6, and IL-17 secretion in CIA-stimulated mice. Curcumin has an excellent anti-RA effect and , which is exerted by inhibiting the expression of pro-inflammatory factors TNF-a, IL-6 and IL-17 and inhibiting the activation of PI3K/AKT signaling pathway. Thus, curcumin may be a promising candidate for anti-RA treatment. 10.1080/21655979.2022.2078942
E2F2 directly regulates the STAT1 and PI3K/AKT/NF-κB pathways to exacerbate the inflammatory phenotype in rheumatoid arthritis synovial fibroblasts and mouse embryonic fibroblasts. Wang Shiguan,Wang Lin,Wu Changshun,Sun Shui,Pan Ji-Hong Arthritis research & therapy BACKGROUND:Expression of E2F transcription factor 2 (E2F2), a transcription factor related to the cell cycle, is abnormally high in rheumatoid arthritis synovial fibroblasts (RASFs). Deregulated expression of E2F2 leads to abnormal production of proinflammatory cytokines, such as interleukin (IL)-1α, IL-1β, and tumor necrosis factor (TNF)-α in RASFs. However, the underlying mechanism by which E2F2 regulates expression of IL-1α, IL-1β, and TNF-α has not been fully elucidated. This study aimed to elucidate this mechanism and confirm the pathological roles of E2F2 in rheumatoid arthritis (RA). METHODS:E2f2 knockout (KO) and wild-type (WT) mice were injected with collagen to induce RA. Cytokine production was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Western blot and qRT-PCR were performed to evaluate the effect of E2F2 on signaling pathway activity. Chromatin immunoprecipitation (ChIP)-PCR and luciferase assays were used to detect the transcriptional activity of target genes of E2F2. Nuclear translocation of STAT1 and p65 were assayed by Western blot, co-immunoprecipitation (co-IP), and immunofluorescence experiments. RESULTS:The occurrence and severity of collagen-induced arthritis were decreased in E2f2-KO mice compared with WT mice. The expression of IL-1α, IL-1β, and TNF-α was also suppressed in mouse embryonic fibroblasts (MEFs) from E2f2-KO mice and RASFs with E2F2 knocked down. Mechanistically, we found that E2F2 can upregulate the expression of STAT1 and MyD88 through direct binding to their promoters, facilitate the formation of STAT1/MyD88 complexes, and consequently activate AKT. However, silencing STAT1/MyD88 or inactivating AKT significantly attenuated the induction of IL-1α, IL-1β, and TNF-α caused by the introduction of E2F2. CONCLUSIONS:This study confirms the pathological role of E2F2 in RA and found that the E2F2-STAT1/MyD88-Akt axis is closely related with the inflammatory phenotype in RASFs. 10.1186/s13075-018-1713-x
Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro. Yuan Hongxia,Yang Pingting,Zhou Dun,Gao Wei,Qiu Zhenyu,Fang Fang,Ding Shuang,Xiao Weiguo Molecular biology reports To investigate the potential regulation of sphingosine kinase 1 (SPHK1) on the migration, invasion, and matrix metalloproteinase (MMP) expression in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were transfected control siRNA or SPHK1 siRNA. The migration and invasion of unmanipulated control, control siRNA or SPHK1 siRNA- transfected RA-FLS in vitro were measured by the transwell system. The relative levels of SPHK1, PI3K, and AKT as well as AKT phosphorylation in RA-FLS were determined by Western blot. The levels of MMP-2/9 secreted by RA-FLS were detected by ELISA. Knockdown of SPHK1 significantly inhibited the spontaneous migration and invasion of RA-FLS, accompanied by significantly reduced levels of PI3K expression and AKT phosphorylation. Similarly, treatment with LY294002, an inhibitor of the PI3K/AKT pathway, inhibited the migration and invasion of RA-FLS. Knockdown of SPHK1 and treatment with the inhibitor synergistically inhibited the migration and invasion of RA-FLS, by further reducing the levels of PI3K expression and AKT phosphorylation. In addition, knockdown of SPHK1 or treatment with LY294002 inhibited the secretion of MMP-2 and MMP-9, and both synergistically reduced the production of MMP-2 and MMP-9 in RA-FLS in vitro. Knockdown of SPHK1 expression inhibits the PI3K/AKT activation, MMP-2 and MMP-9 expression, and human RA-FLS migration and invasion in vitro. Potentially, SPHK1 may be a novel therapeutic target for RA. 10.1007/s11033-014-3382-4
[Effect of moxibustion on PI3K/Akt/mTOR signaling pathway in foot-pad synovium in rats with rheumatoid arthritis]. Hao Feng,Wu Li-Bin,Hu Jun,Liu Lei,Wu Zi-Jian,Cai Rong-Lin,Hu Ling,Yang Xiao-Cun,Wang Jie,Yu Qing,He Lu Zhongguo zhen jiu = Chinese acupuncture & moxibustion OBJECTIVE:To observe the effect of moxibustion on phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin protein (PI3K/Akt/mTOR) signaling pathway in the foot-pad synovial tissue in rats with rheumatoid arthritis (RA), and to explore the mechanism of moxibustion for treating RA. METHODS:Forty healthy SD rats were randomly divided into a control group, a model group, a moxibustion group, a cigarette-moxibustion group and a medication group, 8 rats in each group. The RA model was established with subcutaneous injection of complete Freund's adjuvant (CFA) in the left hind foot-pad under wind, cold and wet environment in the model group, the moxibustion group, the cigarette-moxibustion group and the medication group. The rats in the moxibustion group were treated with moxibustion at "Zusanli" (ST 36) for 20 min; the rats in the cigarette-moxibustion group were treated with moxibustion of ordinary cigarette at "Zusanli" (ST 36) for 20 min; the rats in the medication group were treated with tripterygium glycosides suspension (0.8 mg/100 g) by gavage. All the intervention was given once a day for 15 days. The left hind foot-pad volume was measured before and after modeling and after 15-day intervention. After 15-day intervention, the serum levels of IL-17 and IL-23 were detected by ELISA method, and the expression levels of PI3K, Akt and mTOR in synovial tissue of left hind foot-pad were detected by Western blot method. RESULTS:The volume of left hind foot-pad, the serum levels of IL-23 and IL-17 and the expression of PI3K, Akt and mTOR in synovial tissue of left hind foot-pad in the model group were higher than those in the control group (<0.01). After intervention, the volume of left hind foot-pad and the expression of PI3K, Akt and mTOR protein in synovium tissue in the moxibustion group and medication group were lower than those in the model group (<0.01, <0.05), while the serum levels of IL-17 and IL-23 in the moxibustion group were lower than those in the model group (<0.01). The volume of left hind foot-pad, the serum levels of IL-23 and the expression of mTOR protein in synovial tissue in the moxibustion group were lower than those in the medication group (<0.01, <0.05), while the volume of left hind foot-pad, the serum levels of IL-23 and the expression of PI3K, Akt and mTOR protein in synovium tissue in the moxibustion group were lower than those in the cigarette-moxibustion group (<0.01). CONCLUSION:Moxibustion may play a therapeutic effect on RA by inhibiting the level of IL-23, IL-17 and the activity PI3K/Akt/mTOR, and regulating inflammatory response and autophagy. 10.13703/j.0255-2930.20200112-k0003
MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway. Qu Yuan,Wu Jing,Deng Jia-Xin,Zhang Yu-Ping,Liang Wan-Yi,Jiang Zhen-Lan,Yu Qing-Hong,Li Juan Oncotarget Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and destruction of the joints as well as an increased risk of cardiovascular disease. RA synovial fibroblasts (RASFs) are involved in the progression of RA and release pro-inflammatory cytokines. On the other hand, microRNAs (miRs) may help control the inflammatory response of immune and non-immune cells. Therefore, our study used lentiviral expression vectors to test the effects of miR-126 overexpression on RASF proliferation and apoptosis. Luciferase experiments verified the targeting relationship between miR-126 and PIK3R2 gene. The co-transfection of anti-miR-126 and PIK3R2 siRNA to RASFs were used to identify whether PIK3R2 was directly involved in proliferation and apoptosis of miR-126-induced RASFs. Real-time polymerase chain reaction (PCR) was used to detect miR-126 and PIK3R2 expressions. MTT assay was used to detect cell proliferation. Flow cytometry was used to detect cell apoptosis and cell cycle. Western blotting was used to detect PIK3R2, PI3K, AKT and p-AKT proteins. After Lv-miR-126 infected RASFs, the relative expression of miR-126 was significantly enhanced. MiR-126 promoted RASF proliferation and inhibited apoptosis. Levels of PIK3R2 decreased while total PI3K and p-AKT levels increased in RASFs overexpressing miR-126. Co-transfection of anti-miR-126 and PIK3R2 siRNA also increased PI3K and p-AKT levels as well as RASF proliferation and reduced apoptosis, as compared to anti-miR-126 treatment alone. Finally, luciferase reporter assays showed that miR-126 targeted PIK3R2. Our data indicate that miR-126 overexpression in RASFs inhibits PIK3R2 expression and promotes proliferation while inhibiting apoptosis. This suggests inhibiting miR-126 may yield therapeutic benefits in the treatment of RA. 10.18632/oncotarget.12487
Venlafaxine and carvedilol ameliorate testicular impairment and disrupted spermatogenesis in rheumatoid arthritis by targeting AMPK/ERK and PI3K/AKT/mTOR pathways. Eid Ahmed H,Gad Amany M,Fikry Ebtehal Mohammad,Arab Hany H Toxicology and applied pharmacology Testicular impairment has been commonly described in long-standing rheumatoid arthritis (RA) patients. Since depression and cardiovascular disorders are the most disturbing co-morbidities of RA, investigating the efficacy of the anti-depressant venlafaxine or the beta-blocker carvedilol in RA-associated testicular dysfunction may add to their clinical utility for RA patients. Previously, both agents have demonstrated significant in vivo anti-oxidant and anti-inflammatory actions. In the current study, venlafaxine (50 mg/kg/day) and carvedilol (10 mg/kg/day) were orally administered to adjuvant arthritic rats for 20 days. Interestingly, venlafaxine and carvedilol effectively suppressed paw edema and mitigated the testicular histopathological aberrations and the disrupted spermatogenesis. Both drugs enhanced testicular steroidogenesis through upregulation of 3β-HSD, 17β-HSD and StAR gene expression with concomitant augmentation of serum testosterone. They also blunted the inflammatory burden via attenuation of myeloperoxidase, TNF-α and the protein expression of NF-κBp65 along with elevation of IL-10. They attenuated testicular oxidative perturbations via lowering lipid peroxides and nitric oxide and boosting glutathione levels. With regard to apoptosis, the two agents lowered the protein expression of caspase-3, cleaved caspase-3, cleaved PARP, Bax and p53, promoting germ cell survival. They also modulated the AMPK/ERK signaling via lowering of p-AMPK and upregulation of p-ERK1/2 along with PI3K/AKT/mTOR transduction by enhancing the PI3Kp110α, p-AKT and p-mTOR protein expression. Together, the present work demonstrates the beneficial effects of venlafaxine and carvedilol in RA testicular dysfunction and impaired spermatogenesis via modulation of AMPK/ERK and PI3K/AKT/mTOR signaling and intervention with the testicular oxidative stress, inflammation and apoptosis. 10.1016/j.taap.2018.12.014
uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis. Liu Yan,Pan Yun Feng,Xue You-Qiu,Fang Lin-Kai,Guo Xing-Hua,Guo Xin,Liu Meng,Mo Bi-Yao,Yang Meng-Ru,Liu Fang,Wu Yun-Ting,Olsen Nancy,Zheng Song Guo Cellular & molecular immunology Urokinase-type plasminogen activator receptor (uPAR), is a multifunctional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. Here, our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes (FLSs) from RA than those from osteoarthritis or traumatic injury patients. uPAR gene silencing significantly inhibited RA-FLSs cell proliferation, restrained cell transformation from the G0/G1 phase to S phase, aggravated cell apoptosis, interfered with RA-FLSs cell migration and invasion, and reduced activation of the PI3K/Akt signaling pathway, which may be associated with β1-integrin. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs (a human endothelial cell line). Therefore, we demonstrate that uPAR changes the biological characteristics of RA-FLSs, and affects neoangiogenesis of synovial tissues in patients with RA. All of these may be associated with the β1-integrin/PI3K/Akt signaling pathway. These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA. 10.1038/cmi.2016.60
Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. Wu Xiaodan,Long Li,Liu Jian,Zhang Jin,Wu Tong,Chen Xixi,Zhou Bing,Lv Ting-Zhuo Molecular medicine reports Gamboge is the dried resin secreted by the Garcinia maingayi gambogic tree and is a substance that may be used to treat a variety of diseases, exhibits anti‑tumor and detoxification effects and prevents bleeding. The primary active constituent is gambogic acid. The present study aimed to investigate the anti‑inflammatory effects of gambogic acid in rheumatoid arthritis (RA) rats and to elucidate the mechanisms by which these effects occur. The swelling degree, the clinical arthritic scoring and pain threshold measurements were used to evaluate the effects of gambogic acid on RA. ELISA kits and western blot analysis were used to investigate inflammatory processes and the expression of RA‑associated proteins, respectively. The present results demonstrated that gambogic acid significantly inhibited the degree of right foot swelling, increased pain thresholds and reduced clinical arthritic scores of RA rats. Treatment with gambogic acid suppressed the activities of interleukin (IL)‑1β and IL‑6, promoted the protein expression of phosphorylated (p)‑Akt serine/threonine kinase (Akt), p‑mammalian target protein of rapamycin (mTOR) and inhibited hypoxia‑inducible factor‑1α and vascular endothelial growth factor expression in RA rats. The results of the present study therefore suggest that the anti‑inflammatory effects of gambogic acid in RA rats occur via regulation of the phosphoinositide 3‑kinase/Akt/mTOR signaling pathway. 10.3892/mmr.2017.7459
Galangin alleviates rheumatoid arthritis in rats by downregulating the phosphatidylinositol 3-kinase/protein kinase B signaling pathway. Bioengineered Rheumatoid arthritis (RA) is a chronic autoimmune disease that greatly affect patients' quality of life. Galangin extract is renowned for its anti-proliferative and anti-oxidative characteristics. However, galangin cytotoxicity studies are presently inadequate. We aimed to investigate the therapeutic potential of galangin on RA by investigating the PI3K/AKT signaling pathway.Fibroblast-like synovial cells (FLSs) were exposed to lipopolysaccharide (LPS) to establish an RA model . An ELISA assay was used to detect the levels of IL-1β, TNF-α, and IL-6. Cell viability and apoptosis were determined by CCK8/EdU and flow cytometry assays. A western blot assay was used to analyze the protein expression levels. An RA rat model was established to evaluate the function of galangin through histopathological examination. Our results found that galangin induced apoptosis, inhibited cell proliferation, and increased cell invasion of rheumatoid arthritis fibroblast-like synovial cells (RAFLSs). Galangin inactivated the PI3K/AKT signaling pathway and the inflammatory response. An agonist of PI3K signaling, 740Y-P, restored the cellular functions of RAFLSs. Moreover, galangin suppressed the development of RA . Galangin effected its anti-arthritic influence through the PI3K/AKT signaling pathway. Galangin has potential as an alternative treatment for RA. 10.1080/21655979.2022.2062969
Effects of MiR-21 on proliferation and apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis through PTEN/PI3K/AKT signaling pathway. Panminerva medica 10.23736/S0031-0808.19.03713-3
MiR-26a-5p enhances cells proliferation, invasion, and apoptosis resistance of fibroblast-like synoviocytes in rheumatoid arthritis by regulating PTEN/PI3K/AKT pathway. Huang Zhengping,Xing Shan,Liu Meng,Deng Weiming,Wang Yunqing,Huang Zhixiang,Huang Yukai,Huang Xuechan,Wu Chiwei,Guo Xin,Pan Xia,Jiang Jiawei,Feng Fan,Li Tianwang Bioscience reports Behavior alterations in fibroblast-like synoviocytes (FLS) contribute to a pivotal role in pathogenesis of rheumatoid arthritis (RA). MiRNAs are closely involved in a variety of pathologic conditions. In the present study, we aimed to screen for the aberrant expression of miRNAs in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to further identify the altered expression of miR-26a-5p in RA-FLS and to investigate the role of miR-26a-5p in RA. The altered expression of miR-26a-5p in RA-FLS was screened by microarray analysis and confirmed by quantitative real time PCR. The effect of miR-26a-5p on proliferation, cell cycle, apoptosis, and invasion in RA-FLS were studied. The verification of miR-26a-5p target mRNA and downstream signaling pathway was elucidated by bioinformatics analysis, dual luciferase reporter assay, and western blot. Expression of miR-26a-5p was higher in RA-FLS than in fibroblast-like synoviocytes from osteoarthritis patients and trauma patients. Overexpression of miR-26a-5p RA-FLS promoted cells proliferation, G1/S transition, cells invasion, and resisted apoptosis in RA-FLS, whereas it led to contrary effects when inhibiting the expression of miR-26a-5p. The 3'UTR of tensin homolog (PTEN) was directly targetted by miR-26a-5p and activation of phosphoinositide 3-kinase (PI3K)/AKT pathway was observed when overexpression of miR-26a-5p. Our study suggested that miR-26a-5p has a complementary role in cells proliferation, invasion, and apoptosis of RA-FLS, which may be attributed to its activation effect on PI3K/AKT signaling pathway via targetting PTEN. MiR-26a-5p is likely to be a clinically helpful target for novel therapeutic strategies in RA. 10.1042/BSR20182192
Up-regulation of miR-365 promotes the apoptosis and restrains proliferation of synoviocytes through downregulation of IGF1 and the inactivation of the PI3K/AKT/mTOR pathway in mice with rheumatoid arthritis. Wang Xiaojun,Gong Sha,Pu Dan,Hu Nan,Wang Yanhua,Fan Ping,Zhang Jing,Lu Xiaohong International immunopharmacology BACKGROUND:There is growing evidence of the ability of microRNAs (miRs) in rheumatoid arthritis (RA), thus our objective was to discuss the impact of miR-365 on the apoptosis and proliferation of synoviocytes in mice with RA by targeting IGF1 and mediating the PI3K/AKT/mTOR pathway. METHODS:RA model mice was induced by type II collagen and freund's adjuvant. The successfully modeled mice were injected with normal saline, miR-365 mimics, miR-365 inhibitors or their controls. TUNEL assay was adopted to detect apoptosis in synovial tissues, and expression of IL-1β and IL-6 in serum and synovial tissues was measured by ELISA and RT-qPCR. Mouse synoviocytes were isolated and cultured in vitro and identified by experiments. Cells were transfected with miR-365 mimics, IGF1 siRNA, or their controls to verify the role of miR-365 and IGF1 in cell vitality, proliferation and apoptosis of synoviocytes. RESULTS:Upregulation of miR-365 increased the number of TUNEL positive cells, depressed arthritis index, X-ray imaging score, and the expression of IL-1β and IL-6. High expression of miR-365 and low expression of IGF1 restrained the proliferation and facilitated apoptosis of synoviocytes. MiR-365 inhibited the expression of IGF1 and inhibited the activation of the PI3K/AKT/mTOR pathway. CONCLUSION:Our study presents that up-regulation of miR-365 drives on apoptosis and restrains proliferation of synoviocytes in RA through downregulation of IGF1 and the inhibition of the PI3K/AKT/mTOR pathway. Thus, miR-365 may be a potential candidate for treatment of RA. 10.1016/j.intimp.2019.106067
Jinwu Jiangu Capsule affects synovial cells in rheumatoid arthritis through PI3K/Akt/mTOR signaling pathway. Wang Qiuyi,Yao Xueming,Xu Hui,Lu Daomin,Huang Ying,Tang Fang,Xiao Lina,Ma Wukai Acta biochimica Polonica Jinwu Jiangu Capsule is a medicinal formula from the Chinese Miao nationality. Leflunomide is recommended in organizational guidelines for the treatment of rheumatoid arthritis (RA). To investigate the effect of Jinwu Jiangu Capsule on PI3K/Akt/mTOR signal pathway in cells taken from RA patients New Zealand rabbits were administrated with Jinwu Jiangu Capsule suspension to prepare serum containing medicine. Lyophilized powder was prepared from this serum for cell treatment. The expression of LC3-II and PI3K, AKT, mTOR were detected by IF and western blot. Moreover, the levels of Atg1, Atg5, Atg14 were detected by RT-qPCR. The results showed that the expression of LC3-II was increased, and fluorescence spot of LC3-II was obvious in high-dose of Jinwu Jiangu Capsule group. Jinwu Jiangu Capsule decreased the level of PI3k, Akt, and mTOR protein, and increased the levels of Atg1, Atg5 and Atg14. Specially, the high-dose of Jinwu Jiangu Capsule had the most obvious inhibitory and up-regulation effects. However, there was no significant difference in the expression of Akt, mTOR and Atg1 in the medium-dose of Jinwu Jiangu Capsule group compared with the leflunomide group. In conclusion, Jinwu Jiangu Capsule regulates autophagy by inhibiting the PI3K/AKT/mTOR pathway in RA. 10.18388/abp.2020_5514
miR-125 regulates PI3K/Akt/mTOR signaling pathway in rheumatoid arthritis rats via PARP2. Liu Kai,Zhang Yingang,Liu Liang,Yuan Qiling Bioscience reports The present study aimed to explore miR-125 effects on rheumatoid arthritis (RA) development to provide a potential target for RA. Briefly, rat RA model was established (Model group) by injection of Freund's Complete Adjuvant into the left hind toe. Normal rats injected with saline in the same location were set as Normal group. All rats' secondary foot swelling degree, polyarthritis index score, spleen and thymus index were measured. Synovial tissues were subjected to Hematoxylin-Eosin (HE) staining and immunohistochemistry. Synovial cells of each group were isolated and named as Normal-C group and Model-C group, respectively. Synovial cells of Model-C group further underwent cotransfection with miR-125 mimics and PARP2-siRNA (mimics+siPARP2 group) or with miR-125 negative control (NC) and PARP2-siRNA NC (NC group). Quantitative reverse transcriptase PCR (qRT-PCR), Western blot, luciferase reporter assay, ELISA, and MTT assay were performed. As a result, compared with Normal group, rats of Model group showed significantly higher secondary foot swelling degree, polyarthritis index score, spleen and thymus index (<0.01). Down-regulated miR-125 and up-regulated PARP2 was found in synovial tissues of Model group when compared with Normal group (<0.01). Synovial tissues of Model-C group exhibited severe hyperplasia and inflammatory cell infiltration. Luciferase reporter assay indicated that PARP2 was directly inhibited by miR-125. Compared with NC group, cells of mimics+siPARP2 group had significantly lower IL-1β, MMP-1 and TIMP-1 levels, absorbance value, and p-PI3K, p-Akt and p-mTOR relative expression (<0.01 or <0.05). Thus, miR-125 might attenuate RA development by regulating PI3K/Akt/mTOR signaling pathway via directly inhibiting PARP2 expression. 10.1042/BSR20180890
Peroxiredoxin 4 regulates tumor-cell-like characteristics of fibroblast-like synoviocytes in rheumatoid arthritis through PI3k/Akt signaling pathway. Clinical immunology (Orlando, Fla.) Peroxiredoxin-4 (PRDX4), a member of PRDX family, which played an important role in scavenging reactive oxygen species (ROS). The up-regulation of PRDX4 in synovial tissue and synovial fluid from rheumatoid arthritis (RA) patients has been reported. However, the biological functions of PRDX4 in fibroblast-like synoviocytes (RA-FLS) remains unclear. In this research, we reveal that expression of PRDX4 was notably increased in RA synovial tissue, especially in hyperplastic synovial tissue. PRDX4 silencing significantly inhibited the tumor cell-like behaviors and mRNA expression of matrix metalloproteinases (MMPs) in RA-FLS. Furthermore, overexpression of PRDX4 markedly activated PI3K/Akt signaling pathway, which can be reverted by Akt inhibitor MK-2206. These observations identified elevated PRDX4 may regulates the tumor cell-like biological characteristic of RA-FLS via Pi3k/Akt pathway. Targeting PRDX4 and its downstream signaling pathway might provide a potential diagnostic markers and therapeutic target for RA. 10.1016/j.clim.2022.108964
Baicalein Induces Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts through Inactivation of the PI3K/Akt/mTOR Pathway. Evidence-based complementary and alternative medicine : eCAM Purpose:Rheumatoid arthritis (RA) shows abnormal proliferation, apoptosis, and invasion in fibroblast-like synoviocytes (FLSs). Baicalein (BAI), extracted from , is used as an anticancer drug through inducing cancer cells apoptosis. However, the mechanism of BAI in RA progression still remains unknown. Here, we demonstrated that BAI inhibited FLS proliferation and migration, whereas it enhanced apoptosis via the PI3K/Akt/mTOR pathway . Methods:Cell viability and colony formation were analyzed by MTT and plate colony formation assays in SW982 cells, respectively. Apoptosis was detected by flow cytometry and western blotting. Epithelial-mesenchymal transition (EMT), MMP family proteins (MMP2/9), and the PI3K/Akt/mTOR pathway were detected by western blot. Cell migration was detected by scratch healing assay under BAI treatment in SW982 cells. Results:BAI dose-dependently inhibited cell viability and colony forming in SW982 cells. BAI upregulated apoptotic proteins and downregulated EMT-related proteins, resulting in enhanced cell apoptosis and inhibited cell migration in SW982 cells. BAI also dose-dependently inhibited the phosphorylation of PI3K, Akt, and mTOR. Conclusions:These results indicated that BAI inhibited FLSs proliferation and EMT, whereas induced cell apoptosis through blocking the PI3K/Akt/mTOR pathway, supporting clinical application for RA progression. 10.1155/2022/3643265
Dendrobium huoshanense stem polysaccharide ameliorates rheumatoid arthritis in mice via inhibition of inflammatory signaling pathways. Carbohydrate polymers The present study explored the beneficial effect of Dendrobium huoshanense stem polysaccharide (cDHPS) after oral administration on rheumatoid arthritis (RA) using type Ⅱ collagen-induced arthritis (CIA) mouse model. It was found that cDHPS effectively alleviated joint swelling, synovial hyperplasia, pannus formation, cartilage erosion and bone destruction in CIA mice. Concurrently, cDHPS remodeled the balance of Th17 and regulatory T cells, reduced the secretion of pro-inflammatory mediators related to fibroblast-like synoviocyte activation, angiogenesis, articular cartilage degradation and osteoclast differentiation, inhibited HIF-1α expression and promoted anti-inflammatory mediator release in the joint tissues and serum of CIA mice. Western blot of joint tissues showed that cDHPS significantly inhibited the phosphorylation of IκB, p65, JNK, p38, ERK1/2, AKT, PI3K, JAK1 and STAT3 in CIA mice. These results suggest that cDHPS possesses the potential of ameliorating RA and its anti-RA effect may be attributed to the inhibition of inflammatory signaling pathways. 10.1016/j.carbpol.2021.117657
Bavachinin Ameliorates Rheumatoid Arthritis Inflammation via PPARG/PI3K/AKT Signaling Pathway. Inflammation Bavachinin (BVC) is a natural small molecule from the Chinese herb Fructus Psoraleae. It exhibits numerous pharmacological effects, including anti-cancer, anti-inflammation, anti-oxidation, anti-bacterial, anti-viral, and immunomodulatory properties. BVC may serve as a novel drug candidate for the treatment of rheumatoid arthritis (RA). Nevertheless, the effects and mechanisms of BVC against RA are still unknown. BVC targets were selected by Swiss Target Prediction and the PharmMapper database. RA-related targets were collected from the GeneCards, OMIM, DrugBank, TTD, and DisGeNET databases. PPI network construction and enrichment analysis were conducted by taking the intersection target of BVC targets and RA-related targets. Hub targets were further screened using Cytoscape and molecular docking. MH7A cell lines and collagen-induced arthritis (CIA) mice were used to confirm the preventive effect of BVC on RA and its potential mechanism. Fifty-six RA-related targets of BVC were identified through databases. These genes were primarily enriched in PI3K/AKT signaling pathway according to KEGG enrichment analysis. Molecular docking analysis suggested that BVC had the highest binding energy with PPARG. The qPCR and western blotting results showed that BVC promoted the expression of PPARG at both the mRNA level and protein level. Western blotting indicated that BVC might affect MH7A cell functions through the PI3K/AKT pathway. Furthermore, treatment with BVC inhibited the proliferation, migration, and production of inflammatory cytokines in MH7A cells and induced cell apoptosis to a certain extent. In vivo, BVC alleviated joint injury and inflammatory response in CIA mice. This study revealed that BVC may inhibit the proliferation, migration, and production of inflammatory cytokines in MH7A cells, as well as cell apoptosis through the PPARG/PI3K/AKT signaling pathway. These findings provide a theoretical foundation for RA therapy. 10.1007/s10753-023-01855-w
Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis. Malemud Charles J International journal of molecular sciences Elevated levels of pro-inflammatory cytokines are generally thought to be responsible for driving the progression of synovial joint inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA). These cytokines activate several signal transduction pathways, including the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-Activated/Mitogen-Activated Protein Kinase (SAPK/MAPK) and phosphatidylinositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathways which regulate numerous cellular responses. However, cytokine gene expression, matrix metalloproteinase gene expression and aberrant immune cell and synoviocyte survival via reduced apoptosis are most critical in the context of inflammation characteristic of RA and OA. Negative regulation of JAK/STAT signaling is controlled by Suppressor of Cytokine Signaling (SOCS) proteins. SOCS is produced at lower levels in RA and OA. In addition, gaining further insight into the role played in RA and OA pathology by the inhibitors of the apoptosis protein family, cellular inhibitor of apoptosis protein-1, -2 (c-IAP1, c-IAP2), X (cross)-linked inhibitor of apoptosis protein (XIAP), protein inhibitor of activated STAT (PIAS), and survivin (human) as well as SOCS appears to be a worthy endeavor going forward. 10.3390/ijms18030484
A Novel Drug Combination of Mangiferin and Cinnamic Acid Alleviates Rheumatoid Arthritis by Inhibiting TLR4/NFκB/NLRP3 Activation-Induced Pyroptosis. Frontiers in immunology Growing evidence shows that Baihu-Guizhi decoction (BHGZD), a traditional Chinese medicine (TCM)-originated disease-modifying anti-rheumatic prescription, may exert a satisfying clinical efficacy for rheumatoid arthritis (RA) therapy. In our previous studies, we verified its immunomodulatory and anti-inflammatory activities. However, bioactive compounds (BACs) of BHGZD and the underlying mechanisms remain unclear. Herein, an integrative research strategy combining UFLC-Q-TOF-MS/MS, gene expression profiling, network calculation, pharmacokinetic profiling, surface plasmon resonance, microscale thermophoresis, and pharmacological experiments was carried out to identify the putative targets of BHGZD and underlying BACs. After that, both and experiments were performed to determine the drug effects and pharmacological mechanisms. As a result, the calculation and functional modularization based on the interaction network of the "RA-related gene-BHGZD effective gene" screened the TLR4/PI3K/AKT/NFκB/NLRP3 signaling-mediated pyroptosis to be one of the candidate effective targets of BHGZD for reversing the imbalance network of "immune-inflammation" during RA progression. In addition, both mangiferin (MG) and cinnamic acid (CA) were identified as representative BACs acting on that target, for the strong binding affinities between compounds and target proteins, good pharmacokinetic features, and similar pharmacological effects to BHGZD. Notably, both BHGZD and the two-BAC combination of MG and CA effectively alleviated the disease severity of the adjuvant-induced arthritis-modified rat model, including elevating pain thresholds, relieving joint inflammation and bone erosion inhibiting NF-κB TLR4/PI3K/AKT signaling to suppress the activation of the NLRP3 inflammasome, leading to the downregulation of downstream caspase-1, the reduced release of IL-1β and IL-18, and the modulation of GSDMD-mediated pyroptosis. Consistent data were obtained based on the pyroptosis cellular models of RAW264.7 and MH7A cells induced by LPS/ATP. In conclusion, these findings offer an evidence that the MG and CA combination identified from BHGZD may interact with TLR4/PI3K/AKT/NFκB signaling to inhibit NLRP3 inflammasome activation and modulate pyroptosis, which provides the novel representative BACs and pharmacological mechanisms of BHGZD against active RA. Our data may shed new light on the mechanisms of the TCM formulas and promote the modernization development of TCM and drug discovery. 10.3389/fimmu.2022.912933
Celastrol inhibits rheumatoid arthritis by inducing autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway. International immunopharmacology OBJECTIVE:Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder of the synovial joints. Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii Hook F (TwHF) that has been proven to be effective in treating RA. However, the underlying molecular mechanism of celastrol in the treatment of RA remains unknown. This study explored the protective effect of celastrol against RA and the specific mechanisms of celastrol in vitro and in vivo. METHODS:A chicken type II collagen (CII)-induced arthritis (CIA) mouse model was used to explore the anti-arthritic effects of celastrol, and paw swelling degree, the poly-arthritis index score and serum cytokine levels were determined. Pathological morphology was observed using hematoxylin and eosin (H&E) staining. The influences of celastrol on the proliferation of tumor necrosis factor-α (TNF-α)-induced fibroblast-like synoviocytes (FLSs) were tested by Cell Counting Kit-8 (CCK-8) assays and5-ethynyl-2'-deoxyuridine (EdU) staining assays. The level of autophagy was detected by transmission electron microscopy (TEM). Furthermore, the PI3K/AKT/mTOR pathway and the status of autophagy in the CIA model and FLSs were also detected by western blot and immunofluorescence staining. RESULTS:The results showed that celastrol decreased arthritis severity and inhibited TNF-α-induced FLSs proliferation. Additionally, celastrol decreased the secretion of pro-inflammatory cytokines. Moreover, celastrol increased autophagosome levels and LC3B protein expression in TNF-α-treated FLSs. Furthermore, celastrol increased the protein expression of LC3-II and Beclin-1 and decreased the phosphorylation degree of mTOR and AKT. CONCLUSION:In conclusion, our findings confirmed that celastrol ameliorates RA via the up-regulation of autophagy by inhibiting the PI3K/AKT/mTOR axis. 10.1016/j.intimp.2022.109241
Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways. Liu Chunfang,He Lianhua,Wang Jingxia,Wang Qianqian,Sun Congcong,Li Yiqun,Jia Kexin,Wang Jinxia,Xu Tengteng,Ming Ruirui,Wang Qingwen,Lin Na Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Zicao is the dried root of Lithospermum erythrorhizon Sieb, et Zucc, Arnebia euchroma (Royle) Johnst, or Arnebia guttata Bunge and commonly used to treat viral infection, inflammation, arthritis and cancer in China.Shikonin (SKN) is a major active chemical component isolated from zicao. Previous research showed that SKN has anti-inflammatory, immunomodulatory and analgesic effects, and inhibits the development of arthritis and the condition of collagen arthritis (CIA) mice; nevertheless, its role in the angiogenesis of rheumatoid arthritis (RA) has not been elucidated. AIM OF THE STUDY:The purpose of this study was to investigate the antiangiogenic activity of SKN in CIA rats and various angiogenesis models. MATERIAL AND METHODS:The anti-arthritic effect of SKN on CIA rats was tested by arthritis score, arthritis incidence, radiological observation and histopathology evaluation of inflamed joints. Vessel density evaluated with CD31 immunohistochemistry/immunofluorescence in joint synovial membrane tissues of CIA rats, chick chorioallantoic membrane assay, rat aortic ring assay, and the migration, invasion, adhesion and tube formation of human umbilical vein endothelial (HUVEC) cells induced by tumor necrosis factor (TNF)-α were used to measured the antiangiogenenic activity of SKN. Moreover, the effect of SKN on the expression of angiogenic mediators, such as vascular endothelial growth factor (VEGF), VEGFR2, TNF-α, interleukin (IL)-1β, platelet derived growth factor (PDGF) and transforming growth factor (TGF)-β in sera and joint synovia of rats, and in TNF-α-induced MH7A/HUVEC cells were measured by immunohistochemistry, enzyme linked immunosorbent assay, Western blot and/or real-time polymerase chain reaction (PCR). Through the analysis of protein and mRNA levels of phosphoinositide 3-kinase (PI3K), Akt and PTEN, and the autophosphorylation of ERK1/2, JNK and p38 in joint synovia of rats and in TNF-α-induced HUVEC cells, the molecular mechanism of its inhibition was elucidated by using Western blot and/or real-time PCR. RESULTS:SKN significantly reduced the arthritis score and arthritis incidence, and inhibited inflammation, pannus formation, cartilage and bone destruction of inflamed joints in CIA rats. Partially, SKN remarkably decreased the immature blood vessels in synovial membrane tissues of inflamed joints from CIA rats. It also suppressed in vivo angiogenesis in chick embryo and VEGF-induced microvessel sprout formation ex vivo. Meanwhile, SKN inhibited TNF-α-induced migration, invasion, adhesion and tube formation of HUVEC cells. Moreover, SKN significantly decreased the expression of angiogenic activators including VEGF, VEGFR2, TNF-α, IL-1β, PDGF and TGF-β in synovia of CIA rats and/or in MH7A/HUVEC cells. More interestingly, SKN downregulated PI3K and Akt, and simultaneously upregulated PTEN both at protein and mRNA levels in synovia tissues and/or in TNF-α-induced HUVEC cells. It also suppressed the phosphorylation and gene level of TNF-α-induced signaling molecules, as ERK1/2, JNK, and p38 in synovium and/or in TNF-α-induced HUVEC cells. CONCLUSION:These findings indicate for the first time that SKN has the anti-angiogenic effect in RA in vivo, ex vivo and in vitro by interrupting the PI3K/AKT and MAPKs signaling pathways. 10.1016/j.jep.2020.113039
WTD Attenuating Rheumatoid Arthritis Suppressing Angiogenesis and Modulating the PI3K/AKT/mTOR/HIF-1α Pathway. Ba Xin,Huang Ying,Shen Pan,Huang Yao,Wang Hui,Han Liang,Lin Wei Ji,Yan Hui Jia,Xu Li Jun,Qin Kai,Chen Zhe,Tu Sheng Hao Frontiers in pharmacology Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported. The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy. A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion . The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by and experiments. WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed and that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway. WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway. 10.3389/fphar.2021.696802
RETRACTED: Effects of Artesunate on chondrocyte proliferation, apoptosis and autophagy through the PI3K/AKT/mTOR signaling pathway in rat models with rheumatoid arthritis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.Concern was raised about the reliability of the Western blot results in Figure 5D and 5F, which appear to have a similar phenotype as contained within another publication, as detailed here: https://pubpeer.com/publications/CD4DF7B6DCA28182EC6809846F3653; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. Concerns were also raised about the provenance of the flow cytometry data in Figure 7A. In addition, suspected duplications were detected in Western blots contained within Figure 5E and 5F. The journal requested the corresponding author comment on these concerns and provide raw data. The corresponding author communicated that the raw data was not available and some of the results were not repeatable and therefore not solid enough to support the conclusions. The authors requested retraction of this article. The Editor-in-Chief assessed this case and decided to retract the article. 10.1016/j.biopha.2018.03.142
Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis. Cell death & disease Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68 synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway. 10.1038/s41419-022-05065-4
Gut microbiota combined with fecal metabolomics reveals the effects of FuFang Runzaoling on the microbial and metabolic profiles in NOD mouse model of Sjögren's syndrome. BMC complementary medicine and therapies OBJECTIVE:Sjögren's syndrome (SS) is an inflammatory autoimmune disease characterized by high levels of chronic lymphocyte infiltration. Differences and dysfunction in the gut microbiota and metabolites may be closely related to the pathogenesis of SS. The purpose of this study was to reveal the relationship between the gut microbiota and metabolome in NOD mice as a model of SS and the role of FuFang Runzaoling (FRZ), which is a clinically effective in treating SS. METHODS:NOD mice were gavaged with FRZ for 10 weeks. The ingested volume of drinking water, submandibular gland index, pathologic changes of the submandibular glands, and serum cytokines interleukin (IL)-6, IL-10, IL-17 A, and tumor necrosis factor-alpha (TNF-α) were determined. The roles of FRZ on gut microbiota and fecal metabolites were explored by 16 S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MC), respectively. The correlation between them was determined by Pearson correlation analysis. RESULTS:Compared with the model group, the drinking water volume of NOD mice treated with FRZ increased and the submandibular gland index decreased. FRZ effectively ameliorated lymphocyte infiltration in the small submandibular glands in mice. Serum levels of IL-6, TNF-α, and IL-17 A decreased, and IL-10 increased. The Firmicutes/Bacteroidetes ratio in the FRZ treatment group was higher. FRZ significantly downregulated the relative abundance of the family Bacteroidaceae and genus Bacteroides, and significantly upregulated the relative abundance of genus Lachnospiraceae_UCG-001. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed the significant change in fecal metabolites after FRZ treatment. Based on criteria of OPLS-DA variable influence on projection > 1, P < 0.05, and fragmentation score > 50, a total of 109 metabolites in the FRZ-H group were differentially regulated (47 downregulated and 62 upregulated) compared to their expressions in the model group. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enriched metabolic of sphingolipid metabolism, retrograde endocannabinoid signaling, GABAergic synapse, necroptosis, arginine biosynthesis, and metabolism of histidine, alanine, aspartate, and glutamate. Correlation analysis between gut microbiota and fecal metabolites suggested that the enriched bacteria were related to many key metabolites. CONCLUSIONS:Taken together, we found FRZ could reduce the inflammatory responses in NOD mice by regulating the gut microbiota, fecal metabolites, and their correlation to emerge a therapeutic effect on mice with SS. This will lay the foundation for the further studies and applications of FRZ, and the use of gut microbiotas as drug targets to treat SS. 10.1186/s12906-023-04017-5
Arachidonic acid metabonomics study for understanding therapeutic mechanism of Huo Luo Xiao Ling Dan on rat model of rheumatoid arthritis. Wang Nannan,Zhao Xiaoning,Huai Jiaxin,Li Yiran,Cheng Congcong,Bi Kaishun,Dai Ronghua Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Huo Luo Xiao Ling Dan (HLXLD), a traditional Chinese medicine (TCM), is commonly used for the treatment of rheumatoid arthritis (RA). AIM OF THE STUDY:To explore the potential therapeutic mechanism of HLXLD on anti-inflammatory activity. MATERIALS AND METHODS:A metabolomic approach based on UFLC-MS/MS to profile arachidonic acid (AA) metabolic changes was used. The cyclooxygenase (COX) and lipoxygenase (LOX) catalyzed metabolites in plasma were quantified on 7, 14, 21, and 28 days after the rats injected with Complete Freund's adjuvant and orally administrated with HLXLD, methotrexate and dexamethasone in parallel as the positive control drugs. RESULTS:Nineteen metabolites involved in COX and LOX pathways in RA model group were significant increased compared with normal group (P < 0.05), including 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, 8-HETE, leukotriene B(LTB), prostaglandin E (PGE), PGI, PGD, PGF, thromboxane B (TXB), etc. From day 7 to day 28, the trajectory direction of HLXLD group and positive control groups gradually moved towards the initial space, and the concentrations of AA and its metabolites after HLXLD treatment were significantly reduced in dual pathways compared to control groups. CONCLUSION:HLXLD induced a substantial change in the AA metabolic profiles through refrain the expression of COX and LOX. The present investigation also highlights that distinct ingredients of this formula tend to inhibit different target to achieve a therapeutic effect. 10.1016/j.jep.2018.02.027
Taurine Metabolism Aggravates the Progression of Lupus by Promoting the Function of Plasmacytoid Dendritic Cells. Li Jun,Ding Huihua,Meng Yao,Li Guanhua,Fu Qiong,Guo Qiang,Yin Zhihua,Ye Zhizhong,Zhou Haibo,Shen Nan Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:Type I interferons (IFNs) are critical in the development of systemic lupus erythematosus (SLE). Metabolic abnormalities cause dysregulation of multiple immune cells, but the metabolic regulation of type I IFN production is not well clarified in SLE. We undertook this study to define amino acid metabolism features in SLE and to explore the function of disease-relevant metabolites in the control of plasmacytoid dendritic cell (pDC)-mediated type I IFN production and the progression of SLE. METHODS:Metabolomic profiling of the serum from SLE patients and healthy controls was performed by mass spectrometry. The effects of SLE-related metabolites on type I IFN production were explored in human and mouse pDCs. The reactive oxygen species (ROS) levels of pDCs from wild-type and Ncf1 mice were measured by flow cytometry. Mechanisms were investigated by RNA sequencing and immunoblotting. In vivo effects of SLE-relevant metabolites were systemically analyzed in B6.Cg-Sle1 Yaa/DcrJ mice. RESULTS:Taurine was higher in the serum from SLE patients compared to healthy controls (P < 0.001) and rheumatoid arthritis patients (P < 0.001). Taurine content was positively correlated with disease activity and the expression of IFN signature genes. The addition of taurine facilitated IFN regulatory factor 7 phosphorylation and enhanced type I IFN production by reducing the ROS levels in pDCs in a neutrophil cytosolic factor 1-dependent manner. Taurine supplementation promoted expression of type I IFN-induced genes, activated lymphocytes, and increased autoantibodies and proteinuria, leading to more serious nephritis. CONCLUSION:Taurine metabolism is involved in the development of SLE by enhancing pDC-mediated type I IFN production. Targeted inhibition of taurine or implementation of a taurine-restricted diet has therapeutic potential in SLE. 10.1002/art.41419
Metabolites from specific intestinal bacteria in vivo fermenting Lycium barbarum polysaccharide improve collagenous arthritis in rats. International journal of biological macromolecules Rheumatoid arthritis (RA) is an autoimmune disease affected patients' quality of life severely. Our previous study found Lycium barbarum polysaccharide (LBP) alleviated RA, but it remains unknown whether gut microbiota is necessary for the alleviation. Here, RA models were established in rats with microbiota and rats treated by antibiotic cocktail, and LBP was applied for the intervention on rats. The biochemical test, 16S rDNA sequencing and metabolome analysis were applied to analyze the effects of LBP on gut microbiota, their metabolites and hosts. Results showed the LBP intervention improved RA by inhibiting pro-inflammatory cytokines IL-1α, IL-1β, TNF-α and IL-6 only in rats with microbiota, but not in pseudo-germ-free rats. The abundance of specific bacteria, including Romboutsia, Lactobacillus, Turicibacter, Clostridium_sensu_stricto_1, Faecalibacterium and Adlercreutzia, and several metabolites, including O-desmethylangolensin, 3-hydroxydodecanedioic acid, N-formyl-L-methionine, suberic acid, (S)-oleuropeic acid, prolyl-histidine, 13,14-dihydro PGF-1a, (R)-pelletierine and short-chain fatty acids increased only in RA rats with microbiota after the intervention. Our results suggest that intestinal bacteria are necessary for LBP alleviating RA alleviation. The fermentation metabolite acts on the host instead of LBP itself, which may be the reason for the improvement of RA. 10.1016/j.ijbiomac.2022.11.257
Saussurea involucrata oral liquid regulates gut microbiota and serum metabolism during alleviation of collagen-induced arthritis in rats. Phytotherapy research : PTR Saussurea involucrata oral liquid (SIOL) can clinically relieve symptoms, such as joint pain and swelling, and morning stiffness, in patients with rheumatoid arthritis (RA). However, the mechanism of action remains unclear. This study used a combination of gut microbiota and serum metabolomics analysis to investigate the effects and potential mechanisms of SIOL intervention on rats with RA induced by type II bovine collagen and Freund's complete adjuvant. Results showed that SIOL treatment consequently improved the degree of ankle joint swelling, joint histopathological changes, joint pathological score, and expression of serum-related inflammatory cytokines (interleukin (IL)-1β, IL-4, IL-6, IL-10, and tumor necrosis factor-α) in RA model rats. 16 S rRNA sequencing results showed that SIOL increased the relative richness of the Lactobacillus and Bacteroides genus and decreased the relative richness of Romboutsia, Alloprevotella, Blautia, and Helicobacter genus. Serum nontargeted metabolomic results indicated that SIOL could regulate metabolites related to metabolic pathways, such as glycine, serine, threonine, galactose, cysteine, and methionine metabolism. Spearman correlation analysis showed that the regulatory effects of SIOL on the tricarboxylic acid (TCA) cycle, phenylalanine metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and glyoxylate and dicarboxylate metabolism pathways were correlated with changes in the richness of the Lactobacillus, Romboutsia, Bacteroides, and Alloprevotella genus in the gut microbiome. In conclusion, this study revealed the ameliorative effects of SIOL on RA and suggested that the therapeutic effects of SIOL on RA may be related to the regulation of the community richness of the Lactobacillus, Romboutsia, Bacteroides, and Alloprevotella genus, thereby improving the TCA cycle; phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis, and glyoxylate and dicarboxylate metabolism-related pathways. 10.1002/ptr.7681
Exploring the effect of the Uyghur medicine Munziq Balgam on a collagen-induced arthritis rat model by UPLC-MS/MS-based metabolomics approach. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Munziq Balgam (MBm) is a classic preparation of a traditional Uyghur medicine used for many years to treat abnormal body fluid diseases. The formula, as an in-hospital preparation, has already been used in the Hospital of Xinjiang Traditional Uyghur Medicine to treat rheumatoid arthritis (RA) with significant clinical effects. AIM OF THE STUDY:This study intends to reveal the intervention effect of MBm on collagen-induced arthritis (CIA) rats, discover the potential biomarkers with efficacy, and explore the mechanisms of metabolic regulation by using metabolomics method. MATERIAL AND METHODS:Sprague Dawley (SD) rats were randomly divided into five groups: blank group, CIA model group, Munziq Balgam nomal-dosage, Munziq Balgam high-dosage group and control group. Body weight, paw swelling, arthritis index, immune indices and histopathological experiments were carried out. Plasma from rats were detected by UPLC-MS/MS. Metabolomics of plasma was performed to analyze metabolic profiles, potential biomarkers, and metabolic pathways of MBm for CIA rats. The main metabolic result of Uyghur medicine MBm was compared with that of Zhuang medicine Longzuantongbi granules (LZTBG) to explore the characteristics of two ethnic medicines from different regions for RA. RESULTS:MBm could significantly alleviate symptoms of CIA rats by relieving arthritis symptoms on paw redness and swelling, inflammatory cell infiltration, synovial hyperplasia, pannus, cartilage and bone tissue destruction, as well as inhibiting the expression of IL-1β, IL-6, TNF-α, UA and ALP. Linoleic acid, alpha-linolenic acid, pantothenate and CoA biosynthesis, achidonic acid, gycerophospholipid, sphingolipid metabolism, primary bile acid biosynthesis, porphyrin and chlorophyll metabolism and fatty acid degradation served as the main nine pathways of the interventional effect of MBm on CIA rats. Twenty-three different metabolites were screened out and strongly associated with the indicator makes of RA. Eight potential efficacy-related biomarkers were finally discovered in metabolic pathway network (phosphatidylcholine, bilirubin, sphinganine 1-phosphate, phytosphingosine, SM (d18:1/16:0), pantothenic acid, l-palmitoylcarnitine, chenodeoxycholate). Three metabolites (chenodeoxycholate, hyodeoxycholic acid and O-palmitoleoylcarnitine) were changed in both the metabolic study of MBm and LZTBG intervention effects on CIA rats. Additionally, MBm and LZTBG shared the same 6 metabolic pathways including linoleic acid, alpha-linolenic acid, pantothenate and CoA biosynthesis, achidonic acid, gycerophospholipid, and primary bile acid biosynthesis. CONCLUSION:The study suggested that MBm may effectively alleviate RA by regulating inflammation, immunity-related pathways and multiple targets. Metabolomics analysis showed that MBm (Xinjiang, the north of China) and LZTBG (Guangxi, the south of China), two ethnic medicines from different regions in China, share common metabolites and pathways but also have distinct differences in their interventions for RA. 10.1016/j.jep.2023.116437
Simultaneous profiling of eicosanoid metabolome in plasma by UPLC-MS/MS method: Application to identify potential makers for rheumatoid arthritis. Wang Nannan,Dai Ronghua,Wang Weihui,Peng Yan,Zhao Xiaoning,Bi Kaishun Talanta To evaluate the potential relationship between rheumatoid arthritis and arachidonic acid (AA) metabonomics via cyclooxygenase (COX) and lipoxygenase (LOX) pathways, a UPLC-MS/MS method has been developed and validated for simultaneous and quantitative profiling of eicosanoid metabolome in rat plasma. The analytes were extracted from plasma samples by protein precipitation procedure, and then separated on a Shim-pack XR-ODS column with mobile phase A (0.05% formic acid in water, pH=3.3 adjusted with dilute ammonium hydroxide) and mobile phase B [methanol: acetonitrile (20:80, v/v)]. The detection was performed on UPLC-MS/MS system with an electro spray ion source in the negative ion and multiple reaction-monitoring modes. The developed method was optimized to completely separate all twenty-three analytes and three internal standards in 12min. All standard calibration curves were linear and the calibration regression coefficients were ranged from 0.9903 to 0.9992 for all analytes. The recoveries of analytes were all more than 60%. By means of the method developed, the plasma samples from model rats and normal rats had been successfully determined. Results showed that AA and fifteen kinds of metabolites by LOX and COX pathways in model rat plasma were significant higher than those in normal ones(P<0.05), while 5-HpETE and LTD in model rat plasma were significantly lower than those in normal ones(P<0.05). The methods demonstrated the changes of eicosanoid metabolome occurring in plasma from rat subjects with rheumatoid arthritis. It could be a powerful manner to diagnostic and/or prognostic values for rheumatoid arthritis. 10.1016/j.talanta.2016.08.038
Non-target metabolomic analysis reveals the therapeutic effect of Saposhnikovia divaricata decoction on collagen-induced arthritis rats. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Saposhnikovia divaricata (SD), a Chinese crude drug, has long been recognized for therapeutic effect to rheumatoid arthritis (RA). At present, the mechanisms of SD treatment in RA have not been fully understood especially on the perspective of metabolomics. AIM OF THE STUDY:To study the pharmacodynamic effects of Saposhnikovia divaricata decoction on CIA rats, and explore the therapeutic mechanism by metabolomics methods. MATERIALS AND METHODS:Wistar rats were randomly divided into normal group, CIA model group, dexamethasone group and SD decoction groups (10 g crude drug/kg, 5 g crude drug/kg and 2.5 g crude drug/kg of SDD). Body weight, arthritis scores, serum cytokine levels and histopathological parameters of rats were assessed. A metabolomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS) was established to collect the metabolic profiles of rats and explore the metabolic changes that occurred after SDD treatment. RESULTS:SDD showed its protective effect on the affected joints, especially in the middle dosage group of SDD. Eighteen and 13 potential biomarkers for the SDD treatment of CIA rats were identified in the plasma and urine, respectively. SDD could regulate the disturbed metabolic pathways including tryptophan metabolism, glycerophospholipid catabolism, primary bile acid biosynthesis and fatty acid metabolism. CONCLUSIONS:In summary, SDD treatment could effectively alleviate symptoms of RA and regulate metabolic disorders in CIA rats. 10.1016/j.jep.2021.113837
Effects of Atractylodes Oil on Inflammatory Response and Serum Metabolites in Adjuvant Arthritis Rats. Linghang Qu,Yiyi Xu,Guosheng Cao,Kang Xu,Jiyuan Tu,Xiong Lin,Guangzhong Wang,Shuiqing Li,Yanju Liu Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Atractylodes Rhizoma is one of two principal components in Ermiaosan, a well-known traditional Chinese medicine for the treatment of rheumatoid arthritis (RA). Atractylodes oil (AO) represents a potential alternative treatment for RA. The purpose of this study was to investigate the effect of AO in rats with Adjuvant Arthritis (AA) by exploration of changes in serum metabolites using gas chromatography-mass spectrometry (GC-MS). Foot thickness and arthritis score, ankle joint pathological structure, the concentrations of TNF-α, IL-1β, IL-6, IL-17 and the expression of MMPs in ankle joint tissue were measured as indicators of efficacy of treatment using AO. In addition, multivariate statistical analysis was used to identify differential production of metabolites and biomarkers, and to analyze metabolic pathways. The results demonstrate that administration of AO resulted in a good therapeutic effect in the AA rat model, with significantly improved joint swelling, reduced joint score, and inhibition of inflammation, synovial pannus hyperplasia, and bone and cartilage destruction. Furthermore, AO was found to exert its effect against rheumatoid arthritis principally by differentially affecting 11 metabolites and six metabolic pathways, predominantly related to abnormal amino acid metabolism, in addition to energy-related metabolic pathways. This study evaluated the capability of AO to effectively treat AA rats, providing a novel strategy for the treatment of RA. 10.1016/j.biopha.2020.110130
S-Propargyl-Cysteine Remodels the Gut Microbiota to Alleviate Rheumatoid Arthritis by Regulating Bile Acid Metabolism. Wang Zhou,Yu Yue,Liao Junyi,Hu Wei,Bian Xiqing,Wu Jianlin,Zhu Yi Zhun Frontiers in cellular and infection microbiology Background:Rheumatoid arthritis (RA) is a long-term autoimmune disorder characterized by chronic inflammation that results in swollen and painful joints and even cartilage and bone damage. The gut microbiota, a novel anti-inflammatory target, is considered an important environmental factor in the development of RA. S-propargyl-cysteine (SPRC), an amino acid analogue, exerts anti-inflammatory, cardioprotective effects, and neuroprotective effects on various diseases. In recent studies, an SPRC treatment exerted anti-inflammatory effects on RA. Meanwhile, gut microbiome dysbiosis in individuals with RA has also been reported by many researchers. However, the relationship between SPRC and gut microbiota in individuals with RA remains unclear. Methods:Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups of 10 each, including the Control, Model, and SPRC groups. Adjuvant-induced arthritis (AIA) rats in SPRC group were treated with SPRC. Measurement of paw volume and serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were applied to evaluate the inflammatory status. Fecal samples were collected on the 14 day and 28 day. Gut microbiota were analyzed using 16S ribosomal RNA (rRNA) gene amplicon sequencing. Untargeted metabolomics on plasma samples was applied to investigate the metabolic changes induced by the altered gut microbiota by using derivatization-UHPLC-Q-TOF/MS. Findings:Using 16S rRNA amplicon sequencing, we found that SPRC significantly altered the gut microbiota structure in AIA rats. In particular, , a genus of BSH (Bile Salt Hydrolase)-producing microbes, was overrepresented in SPRC-treated AIA rats. Additionally, a subsequent metabolomics analysis indicated that bile acid metabolism was also altered by SPRC treatment. Interestingly, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), which are formed with the participation of BSH-producing microbes in the intestine, were identified as crucial biomarkers responding to SPRC treatment with significantly lowered levels. Interpretation:A mechanistic link between the gut microbiota and plasma metabolites was revealed in this study, which provides insights into the mechanism of SPRC treatment for RA from the perspective of the gut microbiota. 10.3389/fcimb.2021.670593
A GC-MS Based Metabonomics Study of Rheumatoid Arthritis and the Interventional Effects of the Simiaowan in Rats. Wang Yuming,Guo Xuejun,Xie Jiabin,Hou Zhiguo,Li Yubo Molecules (Basel, Switzerland) Simiaowan (SMW) is a famous Chinese prescription widely used in clinical treatment of rheumatoid arthritis (RA). The aim of the present study is to determine novel biomarkers to increase the current understanding of RA mechanisms, as well as the underlying therapeutic mechanism of SMW, in RA-model rats. Plasma extracts from control, RA model, and SMW-treated rats were analyzed by gas chromatography coupled with mass spectrometry (GC-MS). An orthogonal partial least-square discriminant analysis (OPLS-DA) model was created to detect metabolites that were expressed in significantly different amounts between the RA model and the control rats and investigate the therapeutic effect of SMW. Metabonomics may prove to be a valuable tool for determining the efficacy of complex traditional prescriptions. 10.3390/molecules201219776
Inhibitory effects of Ganoderma lucidum spore oil on rheumatoid arthritis in a collagen-induced arthritis mouse model. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Holistic healthcare practitioners have now started to focus on specific traditional medicinal mushrooms to treat rheumatoid arthritis (RA). Ganoderma lucidum (GL) is one of the oldest mushrooms that have been used in ancient Chinese medicine to treat inflammatory ailments, including autoimmune diseases such as RA. Spores from this mushroom have specific effects on immunomodulation, aging, and cancer. However, the effect of G. lucidum spores (GLS) on arthritis remains unclear. Therefore, we investigated the effects of GLS oil in a collagen-induced rheumatoid arthritis (CIA) model. Metabolomics analysis revealed that GLS oil contains ten acids, of which oleic acid (52.12%) and linoleic acid (16.77%) predominated. The GLS oil-treated CIA mice had a significantly lower clinical score (p = 0.0384) for RA than the control CIA mice. Moreover, GLS oil reduced CIA-induced cartilage degeneration and synovial membrane inflammation in the knee. The GLS oil group showed significantly reduced knee eosinophilia (p = 0.0056). Immunostaining of neutrophils revealed that neutrophils infiltrated the CIA group; however, infiltrated neutrophils were significantly reduced in the GLS oil group in both the knees (p = 0.0006) and ankles (p = 0.0023). GLS oil treatment substantially suppressed LPS- or TNF-α-induced IL-6 mRNA expression in primary cultured chondrocytes. IL-6 immunohistochemistry results showed that the protein levels of IL-6 were attenuated in the GLS oil group compared to the CIA group. These findings suggest that GLS oil may be useful for the development of RA drugs. Further clinical research is required to identify significant improvements. 10.1016/j.biopha.2022.114067
Choline kinase inhibition in rheumatoid arthritis. Annals of the rheumatic diseases OBJECTIVES:Little is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage. METHODS:Choline metabolic profile of FLS cells was determined by (1)H magnetic resonance spectroscopy ((1)HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC₅₀=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration. RESULTS:The enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease. CONCLUSIONS:These data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions. 10.1136/annrheumdis-2014-205696
Analysis of Hepatic Lipid Metabolism and Immune Function During the Development of Collagen-Induced Arthritis. Frontiers in immunology The liver is essential for metabolic and immune functions and has been linked to systemic inflammatory diseases. However, the role of the liver is still elusive during the development of rheumatoid arthritis (RA), although there have been indeed some reports. We used label-free quantitative proteomics and experimental verification in this study to reveal the hepatic lipid metabolism and immune function during collagen-induced arthritis (CIA) development. The proteomics results revealed that the role of the liver differs in different phases of CIA rats. In terms of specific performance, hepatic lipid metabolism, which is primarily concerned with cholesterol, triacylglycerol, and phospholipid, was significantly influenced in the CIA induction phase, whereas the immune function, which includes binding of granulocytes, adhesion of immune cells, etc., was affected considerably at the peak phase of CIA rats compared to normal rats. Finally, the hepatic dynamic changes in CIA rats were further confirmed using targeted metabolomics and ELISA. We found that most fatty acids of the liver in the CIA induction phase were significantly decreased, and proteins related to complement activation and migration or adhesion of immune cells including C3, MMP-8, CTSZ, and S100A9 were significantly increased in the liver of CIA rats in the peak phase. Our findings indicated that the lipid metabolism and immune function of the liver were influenced in CIA rats. Thus, the conditions of the liver during RA development should be considered in therapeutic and nutritional interventions. 10.3389/fimmu.2022.901697
Synovial tissue metabolomics analysis of the therapeutic effects of stir-fried Xanthii Fructus on rheumatoid arthritis in rats. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Rheumatoid arthritis (RA) is a rheumatic disease that easily causes synovial hyperplasia and joint damage. Comprehensive metabolomic profiling of synovial tissue can reveal local pathological changes during RA and identify metabolites as candidate biomarkers. Detecting metabolites in synovial tissue can more directly reflect the pathological state and disease activity associated with it. stir-fried Xanthii Fructus has demonstrated efficacy in treating RA, but its pharmacodynamic property and mechanism of action are unclear. In this study, the molecular composition of the extract of stir-fried Xanthium Fructus was determined through HPLC. The major components that exert anti-inflammatory and analgesic effects were speculated to be phenolic acids. Next, the effect of stir-fried Xanthii Fructus extracts in RA treatment was comprehensively evaluated using rat body weight, foot volume, inflammatory factors, and histopathological sections of the ankle joint as evaluation indicators. The results showed that the extract of stir-fried Xanthii Fructus could significantly reduce the inflammatory response and improve the degree of joint swelling and the imbalance between pro-inflammatory and anti-inflammatory in adjuvant arthritis rats. Finally, non-targeted metabolomics based on UPLC-Q-TOF/MS and multivariate statistical analysis were used to explore the changes of endogenous metabolites in synovium tissues and to search for potential biomarkers and related metabolic pathways in stir-fried Xanthii Fructus extract-treated AA rats. The results showed that stir-fried Xanthii Fructus mainly treated RA by regulating energy metabolism, hormone metabolism, amino acid metabolism and oxidative stress response in adjuvant arthritis rats. This study provides a theoretical basis for the mechanism of action of stir-fried Xanthii Fructus extract in treating RA. 10.1016/j.jchromb.2023.123594
Joint Synovial Fluid Metabolomics Method to Decipher the Metabolic Mechanisms of Adjuvant Arthritis and Geniposide Intervention. Zhan Xiang,Wu Huan,Wu Hong Journal of proteome research Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is mainly characterized by joint lesions and permanent loss of joint function. To discover the metabolic characteristics of RA and the underlying mechanisms in treatment with geniposide (GE), untargeted metabolomic analysis based on hydrophilic interaction liquid chromatography coupled to high-resolution mass spectrometry (HILIC-HRMS) was performed using the joint synovial fluid samples from adjuvant arthritis (AA) rats. Microdialysis (MD) was utilized to collect the dialysate samples precisely from the articular cavity of AA rats. Multivariate statistical analysis was then conducted to discover the metabolite changes induced by AA and to differentiate GE-related biomarkers. The mass spectrometry data are available on the Chorus website (https://chorusproject.org/pages/index.html) with the data set identifier 1680. The results showed that 20 metabolites differed significantly between AA rats and normal rats. GE treatment recovered the altered levels of the 13 metabolites mentioned above, such as palmitoylethanolamide (PEA), Cer (d18:0/22:0), and PC (18:1(11Z)/16:1(9Z)), and normalized glycerophospholipid metabolism. As evidenced by western blotting, the changes in PEA levels adjusted by GE were associated with the down-regulated expression of -acylethanolamine-hydrolyzing acid amidase (NAAA) in synovial tissues. Taken together, the elucidation of metabolic changes of joint synovial fluid and how this is influenced by GE will promote future therapeutic interventions of RA. 10.1021/acs.jproteome.0c00300
Metabolomics analysis of Danggui Sini decoction on treatment of collagen-induced arthritis in rats. Cheng Bang,Zheng Hua,Wu Fang,Wu Jinxia,Liu Xuwen,Tang Chaoling,Lu Shiyin,Chen Zhaoni,Song Fangming,Ruan Junxiang,Zhang Hongye,Song Hui,Liu Wei,Guo Hongwei,Liang Yonghong,Su Zhiheng Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent joint inflammation leading to bone and cartilage damage and even disability. However, the pathogenesis of RA is multi-factorial and to a large degree, remains unknown. Danggui Sini decoction (DSD), a traditional Chinese medicine (TCM) formula, has been widely used as a remedy for rheumatoid arthritis (RA) in recent years. In our study, H-nuclear magnetic resonance (H NMR) based metabolomics analysis of 7 potential biomarkers, including taurine (1), urea (2), betaine (3), pyruvate (4), hippurate (5), succinate (6) and acetone (7) was performed to investigate the progression of RA and assess the efficacy of DSD in collagen-induced arthritis (CIA) rats. According to pathway analysis using identified metabolites and correlation construction, taurine and hypotaurine metabolism, gut microbiota metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, the citrate cycle (TCA cycle) and lipid metabolism were recognized as being the most influenced metabolic pathways associated with RA. As a result, deviations of metabolites 1, 3, 4, 5, 6 and 7 in CIA rats were improved by DSD, which suggested that DSD mediated the abnormal metabolic pathways synergistically. In summary, the efficacy and its underlying therapeutic mechanisms of DSD on RA were systematically investigated and expect to provide a new insight in relevant studies of other TCM formulas. 10.1016/j.jchromb.2017.07.043
Arsenic trioxide modulates the composition and metabolic function of the gut microbiota in a mouse model of rheumatoid arthritis. International immunopharmacology The mechanism of rheumatoid arthritis (RA) has been widely investigated, and studies on the use of arsenic trioxide (ATO) in the treatment of RA have been reported in recent years. However, the exact mechanism of action of ATO in RA remains unclear. This study explores alterations in the gut microbiota and metabolism during ATO treatment in a mouse model of RA and provides an integrative analysis of the biomechanism. The purpose of this study was to verify whether ATO can alleviate RA by altering the gut microbiota. In this study, the mice were randomly divided into four different groups: the normal control (NC) group, the collagen-induced arthritis (CIA) group, the ATO 1.0 mg/kg/day group, and the ATO 2.0 mg/kg/day group. Fecal samples were collected. Through 16S rDNA gene sequencing and metabolomic analysis, the effect of ATO on the composition and metabolites of gut microbiota in CIA mice was investigated. The results showed that compared with NC mice, CIA mice showed differences at both the phylum level (Firmicutes and Bacteroidetes) and the genus level (Muribaculaceae_unclassified and Alistipes). Meanwhile, many metabolites were significantly changed between the two groups, including benzoic acid and (s)-2-acetolactate. However, these alterations were partially reversed in ATO-treated CIA mice. These results indicated that ATO treatment modulated gut microbiota disorder and improved fecal metabolite abnormalities. In conclusion, this study provided important evidence for alterations of the gut microbiota and metabolites and the role of these alterations in a potential novel mechanism of ATO treatment in RA. 10.1016/j.intimp.2022.109159
Metabolomics and molecular docking-directed antiarthritic study of the ethyl acetate extract from Celastrus orbiculatus Thunb. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Celastrus orbiculatus Thunb., an important folk medicine, has long been used for the treatment of rheumatoid arthritis and its ethyl acetate extract (COE) has been reported to possess anticancer, antiinflammation and antiarthritic effects. However, the therapeutic effect and mechanism of COE treatment in rheumatoid arthritis has been rarely studied especially from the perspective of metabolomics. AIM OF STUDY:To reveal the therapeutic effects of COE on adjuvant-induced arthritis (AIA) rats through histopathological analysis, non-targeted metabolomics, and molecular docking study. MATERIALS AND METHODS:Forty-three Wistar rats were randomly divided into normal group, AIA model group, methotrexate group, and COE groups (80 mg/kg, 160 mg/kg and 320 mg/kg of ethyl acetate extract). Paw swelling and arthritis score were monitored through the experiment. Serum levels of tumor necrosis factor α (TNF-α) and nitric oxide were determined and histopathological evaluation was performed. Furthermore, Ultra-high performance liquid chromatography-linear trap quadrupole-Orbitrap-based metabolomics was employed to characterize metabolic changes of AIA rats after COE treatment and molecular docking was performed to predict the potential phytochemicals of COE against TNF-α. RESULTS:COE at three dosages could significantly relieve paw swelling and reduce arthritis scores of AIA rat. Histopathological analysis revealed remarkable decrease in synovial inflammation and bone erosion after COE treatment, especially at middle and high dosage. Additionally, COE down-regulated serum levels of TNF-α and nitric oxide. Serum metabolomics showed that 22 potential biomarkers for the COE treatment of AIA rats were identified, which were closely related to fatty acid metabolism, glycerophospholipid catabolism, and tryptophan metabolism. The molecular docking models predicted that olean-type triterpenes in COE may contribute most to therapeutic effects of rheumatoid arthritis through targeting TNF-α. CONCLUSIONS:COE could significantly relieve the arthritic symptoms in AIA rats and the ultra-high performance liquid chromatography-mass spectrometry based metabolomics proved to be an efficient method to characterize subtle metabolic changes of AIA rats after COE treatment. 10.1016/j.jep.2022.115369
Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance. Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. METHODS:Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. RESULTS:Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. CONCLUSION:Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis. 10.1002/art.42616
Metabolomics analysis of the therapeutic effects of Qiwei Tongbi oral liquid on rheumatoid arthritis in rats. Tang Ming,Gao Xia,Geng Ting,Chen Xialin,Wang Jiajia,Shen Canjie,Gao Huifang,Qian Mengyu,Wang Zhenzhong,Cao Liang,Xiao Wei Journal of pharmaceutical and biomedical analysis Qiwei Tongbi oral liquid (QWTB), a classical traditional Chinese medicine (TCM) formula, has a good therapeutic effect on rheumatoid arthritis (RA) and is widely used in China. To comprehensively elucidate the therapeutic mechanism of QWTB in the treatment of RA, the effects of QWTB on biomarkers and metabolic pathways in a rat model of kidney deficiency arthritis were investigated in this study. The effects of QWTB on pharmacodynamic indicators, including paw swelling, arthritis score; interleukin-1β, interleukin-6, interleukin-17 F, tumor necrosis factor-α, tartrate-resistant acid phosphatase 5b, bone alkaline phosphatase, bone-specific alkaline phosphatase, bone glaprotein, urea, and creatinine levels; and histopathology, suggested that QWTB significantly improved renal function, inhibited the inflammatory response, and reduced bone loss. In total, 39 differential metabolites were screened by comparing the endogenous components between blank and model rat plasma, among which 16 metabolites were altered by QWTB. The metabolism pathway analysis revealed that α-linolenic acid metabolism, phenylalanine metabolism, sphingolipid metabolism, histidine metabolism and glycerophospholipid metabolism were greatly disturbed. Thus, the biomarkers investigated included (1) α-linolenic acid, (2) hippuric acid, (3) phosphatidylethanolamine (15:0/22:2(13Z,16Z)), (4) phenylpyruvic acid, (5) sphinganine, and (6) urocanic acid. QWTB affected three abnormal biomarkers: (3), (4), and (6). Phenylphruvic acid, sphinganine and urocanic acid were significantly associated with pharmacodynamic indicators, as shown by Pearson correlation analysis. These results indicated that RA-related biomarkers had certain reliability and biological significance. In summary, QWTB regulated the metabolic disorders in rats with RA. Its therapeutic mechanism may involve the regulation of phenylalanine metabolism, histidine metabolism, and glycerophospholipid metabolism. The results of this study are useful for understanding the therapeutic mechanisms of TCM. 10.1016/j.jpba.2021.114166
2-Deoxy-D-glucose Alleviates Collagen-Induced Arthritis of Rats and Is Accompanied by Metabolic Regulation of the Spleen and Liver. Wang Hongxing,Zhang Nanyang,Fang Kehua,Chang Xiaotian Frontiers in immunology Rheumatoid arthritis (RA) is significantly associated with glycolysis. This study used 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, to treat rats with collagen-induced arthritis (CIA) and investigate the metabolic regulatory mechanism of glycolysis in the disease. 2-DG significantly alleviated CIA. Metabolomics and transcriptomics, as well as their integrative analysis, detected significant changes in the pathways of bile secretion, cholesterol and linoleic acid metabolism in the plasma, liver and spleen during the CIA process and the opposite changes following 2-DG treatment, whereas the expression of the genes regulating these metabolic pathways were changed only in the spleen. In the rat liver, levels of (S)-5-diphosphomevalonic acid in the terpenoid backbone biosynthesis pathway were significantly decreased during CIA progression and increased following 2-DG treatment, and levels of taurochenodeoxycholic acid in the pentose and glucuronate interconversions pathway showed the opposite results. In the spleen, levels of 3-methoxy-4-hydroxyphenylglycol glucuronide in bile secretion and 12(S)-leukotriene B4 in arachidonic acid metabolism were significantly decreased during CIA progression and increased following 2-DG treatment. The changes in the gene-metabolite network of bile secretion in the spleen correlated with a decreased plasma L-acetylcarnitine level in CIA rats and an increase following 2-DG treatment. Our analysis suggests the involvement of spleen and liver metabolism in CIA under the control of glycolysis. 10.3389/fimmu.2021.713799
Suppression of up-regulated LXRα by silybin ameliorates experimental rheumatoid arthritis and abnormal lipid metabolism. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:As dysregulation of immunometabolism plays a key role in the immunological diseases, dyslipidemia frequently observed in rheumatoid arthritis (RA) patients (60%) is associated with the disease activity and has been considered as the potential target of anti-inflammatory strategy. However, targeting of metabolic events to develop novel anti-inflammatory therapeutics are far from clear as well as the mechanism of dyslipidemia in RA. PURPOSE:To explore the therapeutic potential and mechanisms of silybin again RA through the regulation of lipid metabolism. METHODS:Adjuvant-induced arthritis (AIA) rat model was used to examine the effects of silybin on modulating dysregulated lipid metabolism and arthritis. Metabolomics, docking technology, and biochemical methods such as western blots, qRT-PCR, immunofluorescence staining were performed to understanding the underlying mechanisms. Moreover, knock-down of LXRα and LXRα agonist were used on LO2 cell lines to understand the action of silybin. RESULTS:We are the first to demonstrate that silybin can ameliorate dyslipidemia and arthritis in AIA rats. Overexpression of LXRα and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL), cholesterol 7α and 27α hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that anti-arthritis effects of silybin related to suppressing the up-regulated LXRα and abnormal lipid metabolism. Notably, activation of LXRα could potentiate cell inflammatory process induced by LPS through the regulation of NF-κB pathway, however, suppression of LXRα agonism by siRNA or silybin reduced the nuclear translocation of NF-κB as well as the induction of downstream cytokines, indicating LXRα agonism is the important factor for the arthritis development and could be a potential target. CONCLUSION:The up-regulation of LXRα can activate lipogenesis enzymes to worsen the inflammatory process in AIA rats as well as the development of dyslipidemia, therefore, rectifying lipid disorder via suppression of LXRα agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia. 10.1016/j.phymed.2020.153339
Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylopic acid in a bioinspired lipoprotein nanoformulation. Alolga Raphael N,Opoku-Damoah Yaw,Alagpulinsa David A,Huang Feng-Qing,Ma Gaoxiang,Chavez Leon Maria A S C,Kudzai Chifodya,Yin Xiaojian,Ding Yang Biomaterials Xylopic acid (XA), a diterpene kaurene and the major active ingredient of the African spice Xylopia aethiopica (Annonaceae), is reported to possess anti-inflammatory and analgesic properties. Here, we investigated the therapeutic potential of XA for rheumatoid arthritis (RA), a debilitating autoimmune inflammatory disease characterized by joint damage, in the complete Freund's adjuvant (CFA)-induced arthritis model in rats. We synthesized bioinspired reconstituted high-density lipoprotein (rHDL) nanoparticles loaded with purified XA crystals (rHDL/XA) that passively accumulate in inflamed joints of CFA-induced arthritic rats. Treatment with rHDL/XA minimized mononuclear cell infiltration of CFA-induced arthritic sites and ameliorated disease burden. Metabolomic and transcriptomic analyses revealed that the major molecular pathways perturbed following CFA-induced arthritis correlated with amino acid and lipid metabolism, which were restored to normal states by rHDL/XA treatment. This work demonstrates the anti-RA potential of XA in a nanoformulation and uncovers its underlying therapeutic mechanisms at the transcript and metabolite levels. 10.1016/j.biomaterials.2020.120482
Metabolomics analysis of collagen-induced arthritis in rats and interventional effects of oral tolerance. Ding Xinghong,Hu Jinbo,Li Jinfeng,Zhang Yan,Shui Bingjie,Ding Zhishan,Yao Li,Fan Yongsheng Analytical biochemistry A serum metabolomics method based on rapid resolution liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (RRLC-Q-TOF-MS) was performed for a holistic evaluation of the metabolic changes of collagen-induced arthritis (CIA) in rats and to assess the interventional effects of type II collagen (CII) in this model. Partial least-squares-discriminant analysis (PLS-DA) was employed to study the metabolic profiling of CIA rats and control rats. Ten metabolites, namely, 12(S)-HHTrE, 12(S)-HEPE, PGE2, TXB2, 12(S)-HETE, LysoPE(16:0), PE(O-18:0/0:0), Lyso-PE(18:2), Lyso-PE(20:4), and Lyso-PC(22:5) were identified as differential metabolites associated with the pathogenesis of CIA. These results suggested that dysregulation of the arachidonic acid (AA) and phospholipid metabolic networks is involved in the pathomechanism of CIA. Differential metabolomics and histopathological analyses demonstrated that CII inhibits the progress of arthritis. Furthermore, the therapeutic effects of CII on CIA may involve regulation of the disordered AA and phospholipid metabolic networks. This metabolomics study provides new insights into the pathogenesis of arthritis and, furthermore, indicates the potential mechanism underlying the significantly increased prevalence of metabolic syndrome, defined as a clustering of cardiovascular disease (CVD) risk factors, in arthritis patients. 10.1016/j.ab.2014.04.035
Metabolomics profiling of the free and total oxidised lipids in urine by LC-MS/MS: application in patients with rheumatoid arthritis. Fu Junzeng,Schoeman Johannes C,Harms Amy C,van Wietmarschen Herman A,Vreeken Rob J,Berger Ruud,Cuppen Bart V J,Lafeber Floris P J G,van der Greef Jan,Hankemeier Thomas Analytical and bioanalytical chemistry Oxidised lipids, covering enzymatic and auto-oxidation-synthesised mediators, are important signalling metabolites in inflammation while also providing a readout for oxidative stress, both of which are prominent physiological processes in a plethora of diseases. Excretion of these metabolites via urine is enhanced through the phase-II conjugation with glucuronic acid, resulting in increased hydrophilicity of these lipid mediators. Here, we developed a bovine liver-β-glucuronidase hydrolysing sample preparation method, using liquid chromatography coupled to tandem mass spectrometry to analyse the total urinary oxidised lipid profile including the prostaglandins, isoprostanes, dihydroxy-fatty acids, hydroxy-fatty acids and the nitro-fatty acids. Our method detected more than 70 oxidised lipids biosynthesised from two non-enzymatic and three enzymatic pathways in urine samples. The total oxidised lipid profiling method was developed and validated for human urine and was demonstrated for urine samples from patients with rheumatoid arthritis. Pro-inflammatory mediators PGF2α and PGF3α and oxidative stress markers iPF2α- IV, 11-HETE and 14-HDoHE were positively associated with improvement of disease activity score. Furthermore, the anti-inflammatory nitro-fatty acids were negatively associated with baseline disease activity. In conclusion, the developed methodology expands the current metabolic profiling of oxidised lipids in urine, and its application will enhance our understanding of the role these bioactive metabolites play in health and disease. 10.1007/s00216-016-9742-2
Dual inhibition of glycolysis and glutaminolysis for synergistic therapy of rheumatoid arthritis. Arthritis research & therapy BACKGROUND:Synovial fibroblasts in rheumatoid arthritis (RAFLS) exhibit a pathological aberration of glycolysis and glutaminolysis. Henceforth, we aimed to investigate if dual inhibition of these pathways by phytobiological compound c28MS has the potential of synergistic therapy for arthritis by targeting both glucose and glutamine metabolism. METHODS:The presence of HK2 and GLS across various cell types and associated gene expression in human synovial cells and a murine model of arthritis was evaluated by scRNA-seq. The metabolic profiling of RAFLS cells was done using H-nuclear magnetic resonance spectroscopy under glycolytic and glutaminolytic inhibitory conditions by incubating with 3-bromopyruvate, CB839, or dual inhibitor c28MS. FLS functional analysis was conducted under similar conditions. ELISA was employed for the quantification of IL-6, CCL2, and MMP3. K/BxN sera was administered to mice to induce arthritis for in vivo arthritis experiments. RESULTS:scRNA-seq analysis revealed that many fibroblasts expressed Hk2 along with Gls with several genes including Ptgs2, Hif1a, Timp1, Cxcl5, and Plod2 only associated with double-positive fibroblasts, suggesting that dual inhibition can be an attractive target for fibroblasts. Metabolomic and functional analysis revealed that c28MS decreased the aggressive behavior of RAFLS by targeting both upregulated glycolysis and glutaminolysis. c28MS administered in vivo significantly decreased the severity of arthritis in the K/BxN model. CONCLUSION:Our findings imply that dual inhibition of glycolysis and glutaminolysis could be an effective approach for the treatment of RA. It also suggests that targeting more than one metabolic pathway can be a novel treatment approach in non-cancer diseases. 10.1186/s13075-023-03161-0
Study on the pharmacodynamics and metabolomics of five medicinal species in Atractylodes DC. on rats with rheumatoid arthritis. Liu Yuqiang,Zhang Beixue,Cai Qian Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Atractylodes DC. mainly includes Atractylodis Rhizoma and Atractylodis macrocephalae Rhizoma. According to Chinese Pharmacopoeia, Atractylodis Rhizoma is the rhizome of Atractylodes lancea (Thunb.) DC. (A. lancea) and Atractylodes chinensis (DC.) Koidz. (A. chinensis), while Atractylodis macrocephalae Rhizoma is the rhizome of Atractylodes macrocephala Koidz. (A. macrocephala). Although Atractylodes japonica Koidz. ex Kitam. (A. japonica) and Atractylodes coreana (Nakai) Kitam. (A. coreana) are not included in the Pharmacopoeia, they are often used as Atractylodis Rhizoma in northern China. But in Japan, A. japonica is used as Atractylodis macrocephalae Rhizoma. In order to compare the efficacy of A. japonica and A. coreana with that of Atractylodis Rhizoma and Atractylodis macrocephalae Rhizomain in Pharmacopoeia, this paper studies the anti rheumatism of the five medicinal species in Atractylodes DC., and provides the basis for the rational application of A. japonica and A. coreana. With this purpose, the rheumatoid model of rats was established by Freund's complete adjuvant. Then, Enzyme-linked immunosorbent assay (ELISA) was used to determine the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF - α), arthritis factor (RF), anti cyclic citrullinated peptide (anti-CCP), interleukin-1β (IL-1β), Nuclear factor-κB (NF - κB), interleukin-10 (IL-10) and Prostaglandin E2 (PGE2) in rats of each group. Ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to analyze the plasma of each group. After that, multivariate statistical analysis method was used to analyze the data. The results showed that the five medicinal species in Atractylodes DC. can reduce the levels of IL-6, IL-1 β, PGE2 and NF - κB in the plasma of rheumatoid arthritis (RA) rats in varying degrees, among which the regulation of A. macrocephala is relatively weak. A. chinensis, A. lancea, A. coreana and A. japonica can significantly reduce the content of TNF - α, in which A. japonica and A. lancea have better and similar regulatory effects. A. chinensis and A. coreana can significantly reduce the content of RF in arthritis rats. A. coreana, A. lancea and A. japonica can significantly reduce the anti-CCP level, that is, the regulatory effect of A. coreana and A. chinensis is similar. The metabolic disorder of 11-deoxycortisol, taurocholate and other small molecules in the body of rats with RA directly affects the metabolic pathways of primary bile acid biosynthesis and steroid hormone biosynthesis, leading to the decline of immune function and other symptoms. Most of the metabolic pathways tend to be normal after oral administration of five medicinal species in Atractylodes DC. Among them, the regulating effect of A. coreana and A. chinensis is similar, while that of A. japonica and A. lancea are similar. A. macrocephala had little effect of intervention. 10.1016/j.biopha.2020.110554
Combined 16S rRNA gene sequencing and metabolomics to investigate the protective effects of Wu-tou decoction on rheumatoid arthritis in rats. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Wu-tou decoction (WTD) is a traditional Chinese medicine (TCM) formula which has been used for treating rheumatoid arthritis (RA) for a thousand years. However, the underlying mechanism of WTD in treating RA is still unclear. In recent years, more and more attention has been paid to the role of gut microbiota and microbiota-derived metabolites in the treatment of RA. Hence, this study aims to investigate the roles of microbiota and microbial metabolites in the treatment of RA with WTD. Firstly, the therapeutic effects of WTD on adjuvant-induced arthritis (AIA) rats were evaluated. Then, the 16S rRNA sequencing analysis was used to clarify the changes of the intestinal microbiota and obtain the key microbiota affected by WTD. The important microbial metabolites were quantitated to explore the metabolic characteristics of WTD against RA by targeted metabolomics method. Finally, correlation analysis was performed to investigate the functional correlation among the gut microbiota, metabolites and RA-related serum indexes. The results indicated that WTD could relieve arthritis and reverse gut microbiota dysbiosis. The variation of short-chain fatty acids, bile acids, tryptophan metabolites and amino acids, which are important microbial metabolites, were reversed by WTD intervention. The correlation studies proved that WTD could regulate inflammation and intestinal barrier function partially by modulating Bacteroides, Prevotella, Akkermansia and their associated acetic acid, butyric acid, cholic acid and indole propionic acid. The anti-RA effects of WTD were partially mediated by gut microbiota and microbial metabolites. This study provides a new insight for treating RA and highlights the importance of gut microbiota in the treatment of diseases. 10.1016/j.jchromb.2022.123249
CCFM1074 Alleviates Collagen-Induced Arthritis in Rats Balancing Treg/Th17 and Modulating the Metabolites and Gut Microbiota. Fan Zhexin,Ross R Paul,Stanton Catherine,Hou Bao,Zhao Jianxin,Zhang Hao,Yang Bo,Chen Wei Frontiers in immunology Gut microbiota and their influence on metabolites are receiving increasing attentions in autoimmune diseases including rheumatoid arthritis (RA). Probiotics become a promising manipulator to prevent or attenuate the progression of arthritis, some evidences suggesting that lactobacilli treatment influence the responses to RA therapy but the underlying mechanisms are limited. By using a collagen-induced arthritis (CIA) rats, the study assessed the effects of two strains (CCFM1074, CCFM1075) on the immune responses, gut microbiota and plasma metabolites an integrated cross-omics approach including fecal 16S rRNA high-throughput sequencing and plasma metabolomics. The genome of the two strains was analyzed and compared using whole-genome sequencing approach to further confirm biology functions. CCFM1074 reduced arthritic symptoms while CCFM1075 did not, though both strains down-regulated the plasma IL-6 and Th17 cells proportion. CCFM1074 enhanced the proportion of Treg cells in mesenteric lymph nodes which was significantly associated with SCFAs upregulation, as well as with genomic evidence that CCFM1074 possesses more functional genes involved in carbohydrate metabolism. Moreover, CCFM1074 regulated the gut microbiota, including modulating community structure, decreasing the abundance of and and increasing the abundance of . The differential metabolites modulated by CCFM1074 including eicosapentaenoic acid and docosapentaenoic acid which involved in unsaturated fatty acids metabolism. Furthermore, alterations of gut microbial community were correlated with the plasma metabolome. In summary, CCFM1074 alleviated arthritis rebalancing gut microbiota, immune responses and plasma metabolites. 10.3389/fimmu.2021.680073
Ershiwuwei Lvxue Pill alleviates rheumatoid arthritis by different pathways and produces changes in the gut microbiota. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Rheumatoid arthritis (RA) is a systemic autoimmune disease that often results in joint destruction. Ershiwuwei Lvxue Pill (ELP), a prescription of Tibetan medicine, has been used for centuries for the clinical treatment of RA in Tibet, China. In a previous study, we reported that ELP could ameliorate RA symptoms in CIA rats by inhibiting the inflammatory response and inducing apoptosis in synovial tissues. It is still needed further to clarify the mechanisms of action of ELP in mitigating RA. PURPOSE:In this study, we aim to elucidate the mechanism of action of ELP to improve RA joint damage and explore the changes in the intestinal flora and host metabolites. METHODS:Firstly, we analyzed the main absorbed constituents of ELP in the serum of rats by ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF/MS). Then, we verified the alleviating effects of ELP on cartilage injury and bone erosion as well as the inflammatory response in CIA rats by microCT, H&E staining, safranin-O staining, and ELISA. Moreover, we investigated the main factors that mediate joint damage, including the production of matrix metalloproteinases (MMPs) and osteoclast activity in the ankle of rats by immunohistochemistry and tartrate-resistant acid phosphatase (TRAP) staining. Further, we explored the molecular mechanisms of the MMPs production and osteoclast activity in CIA rats treated with ELP through various experiments such as ELISA, qRT-PCR, western blotting, and immunofluorescence assay. Besides, we investigated gut microbiota composition by 16S rDNA sequencing and serum metabolites through untargeted metabolomics. In addition, we analyzed the correlation between gut microbiota and metabolites by Spearman correlation analysis. RESULTS:In this study, we identified 20 compounds from rat serum samples, which could be the ELP components that improve RA. Moreover, we found that ELP could alleviate cartilage and bone injury by reducing MMP-1, MMP-3, and MMP-13 expression and osteoclast activity in CIA rats. Further studies demonstrated that ELP could reduce joint damage by inhibiting osteoprotegerin (OPG)/receptor activator for nuclear factor-κB ligand (RANKL) /nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinases (JNK) signal pathways. The 16S rDNA sequencing analysis indicated that there was a significant difference in the gut microbiota composition between the normal and CIA rats, and these differences were changed after ELP administration. ELP could alter the gut microbiota by increasing the abundance of the genus Lactobacillus and decreasing the abundance of Dorea, [Eubacterium]_ventriosum_group, Anaerostipes, Collinsella, Coprococcus_1, Ruminiclostridium_5, Ruminococcus_1, Family_XIII_UCG-001, Butyricicoccus, Erysipelotrichaceae_UCG-003, Lachnoclostridium, Faecalibacterium, Lachnospiraceae_UCG-010, Roseburia, Rs-E47_termite_group_norank, Treponema_2 genera. Non-targeted metabolomics analysis showed that ELP reduced arachidonic acid levels. The serum arachidonic acid level was significantly correlated with the abundance of 41 genera, particularly Collinsella and Lactobacillus. CONCLUSION:Our study shows that ELP can improve RA joint damage by inhibiting MMPs production and osteoclast activity, and regulating intestinal flora and host metabolites, which provides a novel insight into the ELP in alleviating RA. 10.1016/j.phymed.2022.154462
Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects. Wang Qirui,Ye Chanqi,Sun Shukun,Li Rong,Shi Xiaojian,Wang Shuai,Zeng Xiaoping,Kuang Nanzhen,Liu Yulin,Shi Qiaofa,Liu Renping International immunopharmacology Curcumin is a natural herbal product that has been popularly used to treat autoimmune diseases in China; however, its effects on rheumatoid arthritis and its mechanism are not clear. The main purposes of this study are to explore the therapeutic effects of curcumin on collagen-induced arthritis (CIA) rats and the pharmacological mechanism. In the present study, CIA rats were established by injecting bovine type II collagen. Curcumin and methotrexate were then orally administered daily, and the swelling degree of the hind limb joints was scored every two days. Histopathological changes were observed by hematoxylin-eosin staining. The levels of cytokines (TNF-α, IL-1β, IL-17 and TGF-β) were detected by radioimmunoassay, while the expression of IκBα and COX-2 was detected by Western blot. In addition, cell viability was detected by CCK-8 assay, and the effect of curcumin on macrophage apoptosis was detected by flow cytometry and TUNEL assay. The results indicated that in vivo curcumin attenuated the degree of joint swelling of rats and the further development of joint histopathology. Moreover, it downregulated the levels of cytokines. In vitro curcumin inhibited the degradation of IκBα and reduced the production of COX-2 in LPS-induced inflammatory RAW264.7 cells. Importantly, curcumin significantly induced macrophage apoptosis. In conclusion, in this study, we have demonstrated that curcumin exerts therapeutic effects on arthritis in CIA rats and has a strong pharmacological activity on reducing the inflammatory response in macrophages. Its mechanism may be related to the inhibition of the NF-κB signaling pathway and the promotion of macrophage apoptosis. 10.1016/j.intimp.2019.04.027
Gut commensal alleviates inflammatory arthritis. Gut OBJECTIVE:Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA. DESIGN:Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal in RA. The effects of -derived microbial metabolites on the differentiation of CD4 T cells and macrophage polarisation were also investigated. RESULTS:The relative abundance of in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of . CONCLUSIONS: and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA. 10.1136/gutjnl-2022-327756
Metabolomics in rheumatic diseases: the potential of an emerging methodology for improved patient diagnosis, prognosis, and treatment efficacy. Priori Roberta,Scrivo Rossana,Brandt Jessica,Valerio Mariacristina,Casadei Luca,Valesini Guido,Manetti Cesare Autoimmunity reviews Metabolomics belongs to the family of "-omics" sciences, also comprised of genomics, transcriptomics, and proteomics, all of which share the advantage of a non-targeted approach for identifying biomarkers and profiling the patient. This means that they do not require a preliminary knowledge of the substances to be studied. Moreover, even small quantities of biological fluids or tissues may be utilized for analysis. Metabolomic procedure has become feasible only recently with the advent and accessibility of new high-throughput technologies, including mass spectrometry and nuclear magnetic resonance. The methodology generally involves three defining steps: 1) the acquisition of experimental data, 2) the multivariate statistical analysis, and 3) the projection of the acquired information (profiles) to construct the patient map. Metabolomic analysis has been applied to several disorders: as far as rheumatic diseases are concerned, a few studies have focused on rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, and osteoarthritis. Both murine models and clinical data have shown the potential of this novel tool to contribute to deciding a diagnosis, discriminate between patients based on disease activity, and even predict the response to a particular treatment. The present review fully reports these findings and offers a critical view of the challenges still to be met. 10.1016/j.autrev.2013.04.002
Bioanalytical insights into mediator lipidomics. Kasuga Kie,Suga Takahiro,Mano Nariyasu Journal of pharmaceutical and biomedical analysis The importance of lipids in health and disease has been widely acknowledged. Lipids are well known to undergo enzymatic and/or non-enzymatic conversions to lipid mediators (LMs), which demonstrate potent actions in various biological events, such as the regulation of cellular signaling pathways and the promotion and resolution of inflammation. LMs activate G-protein-coupled receptors (GPCRs) to exert various functions. Monitoring these mediators in disease is essential to uncover the mechanisms of pathogenesis for many diseases, such as asthma, rheumatoid arthritis, Alzheimer's disease, and cancer. Along with technical developments in mass spectrometry, highly sensitive and multiplexed analyses of LMs in the human periphery and other tissues have become available. These advancements enable the temporal and spatial profiling of LMs; therefore, the findings obtained from LM profiling are expected to decode pathology. As trace amounts of LMs can exert functions, the development of a highly sensitive, accurate, and robust analytical method is necessary. Although not mandatory, mediator lipidomics validation is becoming popular and remains challenging. Because LMs already exist in biological matrices, evaluations of the matrix effect and extraction efficiencies are important issues. Thus, more careful analyses are required. In this review, we focus on mediator lipidomics, including polyunsaturated fatty acids (PUFAs), such as omega-3 and omega-6 fatty acids, and LMs derived from PUFAs, such as eicosanoids, lipoxins and resolvins. In addition to the recent progress in human mediator lipidomics, bioanalytical insights derived from this field (i.e., effective sample preparation from biological matrices and evaluation of the matrix effect) are described herein. 10.1016/j.jpba.2015.02.011
Fibroblast-Like Synoviocytes Glucose Metabolism as a Therapeutic Target in Rheumatoid Arthritis. de Oliveira Patricia Gnieslaw,Farinon Mirian,Sanchez-Lopez Elsa,Miyamoto Shigeki,Guma Monica Frontiers in immunology Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable. Among them, glucose metabolism and glycolytic intermediaries seem to have an important role in fibroblast-like synoviocytes (FLS) phenotype and might contribute to early stage disease pathogenesis. RA FLS are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS. Glycolytic inhibitors reduce not only FLS aggressive phenotype but also decrease bone and cartilage damage in several murine models of arthritis. Essential glycolytic enzymes, including hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) enzymes, have important roles in FLS behavior. Of interest, HK2 is an inducible enzyme present only in the inflamed rheumatic tissues compared to osteoarthritis synovium. It is a contributor to glucose metabolism that could be selectively targeted without compromising systemic homeostasis as a novel approach for combination therapy independent of systemic immunosuppression. More information about metabolic targets that do not compromise global glucose metabolism in normal cells is needed. 10.3389/fimmu.2019.01743
Metabolomics approach in allergic and rheumatic diseases. Scrivo Rossana,Casadei Luca,Valerio Mariacristina,Priori Roberta,Valesini Guido,Manetti Cesare Current allergy and asthma reports Metabolomics is the analysis of the concentration profiles of low molecular weight compounds present in biological fluids. Metabolites are nonpeptide molecules representing the end products of cellular activity. Therefore, changes in metabolite concentrations reveal the range of biochemical effects induced by a disease or its therapeutic intervention. Metabolomics has recently become feasible with the accessibility of new technologies, including mass spectrometry and high-resolution proton nuclear magnetic resonance, and has already been applied to several disorders. Indeed, it has the advantage of being a nontargeted approach for identifying potential biomarkers, which means that it does not require a preliminary knowledge of the substances to be studied. In this review, we summarize the main studies in which metabolomic approach was used in some allergic (asthma, atopic dermatitis) and rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus) to explore the feasibility of this technique as a novel diagnostic tool in these complex disorders. 10.1007/s11882-014-0445-5
Metabolomic Profiling in the Characterization of Degenerative Bone and Joint Diseases. Swank Katherine R,Furness Jamie E,Baker Erin A,Gehrke Corinn K,Biebelhausen Stephen P,Baker Kevin C Metabolites Osteoarthritis and inflammatory arthropathies are a cause of significant morbidity globally. New research elucidating the metabolic derangements associated with a variety of bone and joint disorders implicates various local and systemic metabolites, which further elucidate the underlying molecular mechanisms associated with these destructive disease processes. In osteoarthritis, atty acid metabolism has been implicated in disease development, both locally and systemically. Several series of rheumatoid arthritis patients have demonstrated overlapping trends related to histidine and glyceric acid, while other series showed similar results of increased cholesterol and glutamic acid. Studies comparing osteoarthritis and rheumatoid arthritis reported elevated gluconic acid and glycolytic- and tricarboxylic acid-related substrates in patients with osteoarthritis, while lysosphingolipids and cardiolipins were elevated only in patients with rheumatoid arthritis. Other bone and joint disorders, including osteonecrosis, intervertebral disc degeneration, and osteoporosis, also showed significant alterations in metabolic processes. The identification of the molecular mechanisms of osteoarthritis and inflammatory arthropathies via metabolomics-based workflows may allow for the development of new therapeutic targets to improve the quality of life in these patient populations. 10.3390/metabo10060223
Lipid and Metabolic Changes in Rheumatoid Arthritis. McGrath Catherine M,Young Stephen P Current rheumatology reports While the most obvious manifestations of rheumatoid arthritis (RA) involve inflammation and damage in the synovial joints, the systemic effects of the condition are widespread and life-threatening. Of particular interest is the 'lipid paradox' of RA, where patients with a numerically equivocal starting lipid profile have a significantly raised risk of cardiovascular (CV) events and response to therapy results in a 'normalization' of lipid levels and reduction in events. Changes in lipids can be seen before overt disease manifestations which suggest that they are closely linked to the more widespread inflammation-driven metabolic changes associated with tumour necrosis factor (TNF). Cachexia involves a shift in body mass from muscle to fat, which may or may not directly increase the cardiovascular risk. However, since TNF inhibition is associated with reduction in cardiovascular events, it does suggest that these widespread metabolic changes involving lipids are of importance. Analysis of single lipids or metabolites have been used to identify some of the key changes, but more recently, metabolomic and lipidomic approaches have been applied to identify a broad spectrum of small molecule changes and identify potentially altered metabolic pathways. Further work is needed to understand fully the metabolic changes in lipid profiles and identify novel ways of targeting desired profile changes, but work so far does suggest that a better understanding may allow management of patients to downregulate the systemic effects of their disease that puts them at risk of cardiovascular complications. 10.1007/s11926-015-0534-z
Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis. Cells Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA. 10.3390/cells9040827
The interplay between inflammation and metabolism in rheumatoid arthritis. Chimenti M S,Triggianese P,Conigliaro P,Candi E,Melino G,Perricone R Cell death & disease Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone that lead to joint destruction. The autoimmune process in RA depends on the activation of immune cells, which use intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. An intricate cytokine network participates in inflammation and in perpetuation of disease by positive feedback loops promoting systemic disorder. The widespread systemic effects mediated by pro-inflammatory cytokines in RA impact on metabolism and in particular in lymphocyte metabolism. Moreover, RA pathobiology seems to share some common pathways with atherosclerosis, including endothelial dysfunction that is related to underlying chronic inflammation. The extent of the metabolic changes and the types of metabolites seen may be good markers of cytokine-mediated inflammatory processes in RA. Altered metabolic fingerprints may be useful in predicting the development of RA in patients with early arthritis as well as in the evaluation of the treatment response. Evidence supports the role of metabolomic analysis as a novel and nontargeted approach for identifying potential biomarkers and for improving the clinical and therapeutical management of patients with chronic inflammatory diseases. Here, we review the metabolic changes occurring in the pathogenesis of RA as well as the implication of the metabolic features in the treatment response. 10.1038/cddis.2015.246
Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy. Biomedicines Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota-immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota-immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions. 10.3390/biomedicines11020294
Lipid metabolism and rheumatoid arthritis. Frontiers in immunology As a chronic progressive autoimmune disease, rheumatoid arthritis (RA) is characterized by mainly damaging the synovium of peripheral joints and causing joint destruction and early disability. RA is also associated with a high incidence rate and mortality of cardiovascular disease. Recently, the relationship between lipid metabolism and RA has gradually attracted attention. Plasma lipid changes in RA patients are often detected in clinical tests, the systemic inflammatory status and drug treatment of RA patients can interact with the metabolic level of the body. With the development of lipid metabolomics, the changes of lipid small molecules and potential metabolic pathways have been gradually discovered, which makes the lipid metabolism of RA patients or the systemic changes of lipid metabolism after treatment more and more comprehensive. This article reviews the lipid level of RA patients, as well as the relationship between inflammation, joint destruction, cardiovascular disease, and lipid level. In addition, this review describes the effect of anti-rheumatic drugs or dietary intervention on the lipid profile of RA patients to better understand RA. 10.3389/fimmu.2023.1190607
Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cellular & molecular immunology The gut microbiota has a critical role in the maintenance of immune homeostasis. Alterations in the intestinal microbiota and gut microbiota-derived metabolites have been recognized in many immune-related inflammatory disorders. These metabolites can be produced by gut microbiota from dietary components or by the host and can be modified by gut bacteria or synthesized de novo by gut bacteria. Gut microbiota-derived metabolites influence a plethora of immune cell responses, including T cells, B cells, dendritic cells, and macrophages. Some of these metabolites are involved in the pathogenesis of immune-related inflammatory diseases, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Here, we review the role of microbiota-derived metabolites in regulating the functions of different immune cells and the pathogenesis of chronic immune-related inflammatory diseases. 10.1038/s41423-021-00661-4
Metabolomics in rheumatoid arthritis: Advances and review. Frontiers in immunology Rheumatoid arthritis (RA) is an autoimmune disease accompanied by metabolic alterations. The metabolic profiles of patients with RA can be determined using targeted and non-targeted metabolomics technology. Metabolic changes in glucose, lipid, and amino acid levels are involved in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, the arachidonic acid metabolic pathway, and amino acid metabolism. These alterations in metabolic pathways and metabolites can fulfill bio-energetic requirements, promote cell proliferation, drive inflammatory mediator secretion, mediate leukocyte infiltration, induce joint destruction and muscle atrophy, and regulate cell proliferation, which may reflect the etiologies of RA. Differential metabolites can be used as biomarkers for the diagnosis, prognosis, and risk prediction, improving the specificity and accuracy of diagnostics and prognosis prediction. Additionally, metabolic changes associated with therapeutic responses can improve the understanding of drug mechanism. Metabolic homeostasis and regulation are new therapeutic strategies for RA. In this review, we provide a comprehensive overview of advances in metabolomics for RA. 10.3389/fimmu.2022.961708
Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast-like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset-specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early-stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area. 10.1002/art.40504
A Non-targeted Metabolomics Reveals Therapeutical Effect and Mechanism of Sanmiao Pill on Adjuvant-induced Arthritis Rats. Current pharmaceutical design BACKGROUND AND OBJECTIVE:Rheumatoid arthritis (RA) is an increasingly serious disease worldwide that can damage the joints and bones of sufferers. Sanmiao Pill (SMP), a classical traditional Chinese medicine (TCM) prescription, has been used for effective treatments for RA in the clinic. To comprehensively illuminate the therapeutic mechanism of SMP in the treatment of RA, the effects of SMP on biomarkers and metabolic pathways in rats with adjuvant-induced arthritis (AIA) were examined. > Methods: Sprague Dawley rats were randomly divided into two control (CC, Control) groups, two model (MM, Model) groups, a methotrexate group (MTX, 7.6 mg/kg body weight per week), and two SMP groups (San-L, 28.7 mg/kg body weight per day and San-H, 57.4 mg/kg body weight per day). Rats' body weight, paw swelling, arthritis scores, biochemical parameters, histopathology, and so on were used to evaluate the success of the model and the therapeutic effects of SMP. The metabolic techniques were used to characterize the metabolic profile and biomarkers of the serum and urine samples of rats to reveal the metabolic changes that occurred after SMP treatment. > Results: After 21 days of treatment, SMP improved weight gain, reduced the severity of paw swelling, lowered the levels of biochemical indicators (CCP-Ab, IL-6, TNF-α, RF), decreased destruction of articular cartilage and bone erosion, and protected the affected joints.Additionally, 17 and 19 potential biomarkers associated with RA were identified in the serum and urine, respectively. SMP significantly reversed 14 potential biomarkers, such as arachidonic acid, lysoPC(20:4(5Z,8Z,11Z,14Z)), L-tryptophan, 9-cis-Retinoic acid, hippuric acid, pyridoxine, and pantothenic acid. These metabolites are associated with arachidonic acid metabolism, glycerophospholipid catabolism, tryptophan metabolism, phenylalanine metabolism, vitamin B6 metabolism, etc. > Conclusion: These results indicated that RA-related biomarkers reflected the metabolic profile of AIA rats. Meanwhile, SMP could effectively treat RA mainly by reducing inflammation and regulating abnormal lipid metabolic pathways and amino acid metabolisms. It showed that metabolomics could be used to analyze the metabolic profiles involved in RA and reveal the mechanism of SMP treatment of RA.>. 10.2174/1381612829666230511161308
Cytokines in the pathogenesis of rheumatoid arthritis. McInnes Iain B,Schett Georg Nature reviews. Immunology Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis. 10.1038/nri2094
Ocular inflammatory diseases associated with rheumatoid arthritis. Artifoni Mathieu,Rothschild Pierre-Raphaël,Brézin Antoine,Guillevin Loïc,Puéchal Xavier Nature reviews. Rheumatology The extra-articular complications of rheumatoid arthritis (RA) include ophthalmological manifestations, which can, in some cases, be the first signs of the disease. These inflammatory ophthalmological conditions include episcleritis, scleritis and peripheral ulcerative keratitis (PUK). RA is the leading cause of necrotizing scleritis and of PUK, which are the two most severe ocular conditions associated with the disease. These conditions can rapidly threaten ocular prognosis and are associated with excess mortality in patients with RA owing to their association with systemic vasculitis. Close collaboration between the ophthalmologist and the rheumatologist or internal medicine expert is required for the diagnosis and therapeutic management of these patients. In this Review, we provide an overview of ocular inflammatory diseases in patients with RA with particular focus on the diagnosis and current available therapies (including biologic agents) for these conditions. Furthermore, we propose a decision tree to assist clinicians in their choice of treatment for patients with RA who also have ocular inflammatory disease. 10.1038/nrrheum.2013.185
The eye: a window of opportunity in rheumatoid arthritis? Tong Louis,Thumboo Julian,Tan York Kiat,Wong Tien-Yin,Albani Salvatore Nature reviews. Rheumatology Rheumatoid arthritis (RA), the most common autoimmune disorder associated with dry eye syndrome, is also associated with sight-threatening ocular diseases such as peripheral ulcerative keratitis, scleritis and corneal melts. Tissue damage on the ocular surface of patients with RA is autoimmune-mediated. Findings from patients with dry eye have implicated defects in innate immunity (Toll-like receptors, S100A and resident antigen-presenting cells), cytokines, chemokines and T helper (TH)-cell subsets (including TH1 and TH17) in disease pathogenesis. Some of these features are probably important in dry eye related to RA, which can occur at a different time from articular disease and is more clinically severe than idiopathic dry eye. Ocular surface immune factors can be influenced by the systemic immune landscape. Depending on the severity of ocular inflammation in RA, treatment can include ciclosporin, topical corticosteroids, tacrolimus, autologous serum and systemic immunosuppression. Tissue damage is treated by inhibiting matrix metalloproteinases. Potential therapeutic strategies benefit from an improved understanding of ocular surface immunology, and include targeting of T-cell subsets, B-cell signalling or cytokines. 10.1038/nrrheum.2014.85
Rheumatoid cachexia and cardiovascular disease. Summers Gregory D,Metsios Giorgos S,Stavropoulos-Kalinoglou Antonios,Kitas George D Nature reviews. Rheumatology Both cachexia and cardiovascular disease are strongly associated with rheumatoid arthritis (RA) and linked to the chronic inflammatory process. Typically, rheumatoid cachexia occurs in individuals with normal or increased BMI (reduced muscle mass and increased fat mass). Classic cachexia (reduced muscle mass and reduced fat mass) is rare in RA but is associated with high inflammatory activity and aggressive joint destruction in patients with a poor cardiovascular prognosis. Conversely, obesity is linked to hypertension and dyslipidemia but, paradoxically, lower RA disease activity and less cardiovascular disease-related mortality. Rheumatoid cachexia might represent the 'worst of both worlds' with respect to cardiovascular outcome, but until diagnostic criteria for this condition are agreed upon, its effect on cardiovascular disease risk remains controversial. 10.1038/nrrheum.2010.105
Vitamin D in rheumatoid arthritis-towards clinical application. Jeffery Louisa E,Raza Karim,Hewison Martin Nature reviews. Rheumatology In addition to its well-documented involvement in mineral homeostasis, vitamin D seems to have broad effects on human health that go beyond the skeletal system. Prominent among these so-called nonclassical effects of vitamin D are its immunomodulatory properties. In vitro studies have shown anti-inflammatory effects of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D. In addition, epidemiological analysis of patients with established inflammatory disease identified associations between vitamin D deficiency (low serum concentrations of inactive 25-hydroxyvitamin D, abbreviated to 25(OH)D) and inflammatory conditions, including rheumatoid arthritis (RA). The association of vitamin D deficiency with RA severity supports the hypothesis of a role for vitamin D in the initiation or progression of the disease, or possibly both. However, whether 25(OH)D status is a cause or consequence of RA is still incompletely understood and requires further analysis in prospective vitamin D supplementation trials. The characterization of factors that promote the transition from preclinical to clinical phases of RA has become a major focus of research, with the aim to facilitate earlier diagnosis and treatment, and improve therapeutic outcomes. In this Review, we aim to describe the current knowledge of vitamin D and the immune system specifically in RA, and discuss the potential benefits that vitamin D might have on slowing RA progression. 10.1038/nrrheum.2015.140
Mechanisms of lung disease development in rheumatoid arthritis. Wang Dan,Zhang Jie,Lau Jessica,Wang Shaohua,Taneja Veena,Matteson Eric L,Vassallo Robert Nature reviews. Rheumatology Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and damage. Extra-articular manifestations occur in many patients and can include lung involvement in the form of airway or parenchymal inflammation and fibrosis. Although the pathophysiology of articular RA has been extensively investigated, the mechanisms causing airway and parenchymal lung disease are not well defined. Infections, cigarette-smoking, mucosal dysbiosis, host genetics and premature senescence are all potentially important contributors to the development of lung disease in patients with RA. RA-associated lung disease (which can predate the onset of articular disease by many years) probably originates from chronic airway and alveolar epithelial injury that occurs in an individual with a genetic background that permits the development of autoimmunity, leading to chronic inflammation and subsequent airway and lung parenchymal remodelling and fibrosis. Further investigations into the specific mechanisms by which lung disease develops in RA will be crucial for the development of effective therapies. Identifying mechanisms by which environmental and host factors cooperate in the induction of autoimmunity in the lung might also help to establish the order of early events in RA. 10.1038/s41584-019-0275-x
Rheumatoid arthritis and pregnancy; not only for rheumatologists interested in female health issues. Annals of the rheumatic diseases 10.1136/ard.2009.120741
Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Koning Frits,Thomas Ranjeny,Rossjohn Jamie,Toes Rene E Nature reviews. Rheumatology Rheumatoid arthritis (RA) and coeliac disease are inflammatory diseases that both have a strong association with class II HLAs: individuals carrying HLA-DQ2.5 and/or HLA-DQ8 alleles have an increased risk of developing coeliac disease, whereas those carrying HLA-DR shared epitope alleles exhibit an increased risk of developing RA. Although the molecular basis of the association with specific HLA molecules in RA remains poorly defined, an immune response against post-translationally modified protein antigens is a hallmark of each disease. In RA, understanding of the pathogenetic role of B-cell responses to citrullinated antigens, including vimentin, fibrinogen and α-enolase, is rapidly growing. Moreover, insight into the role of HLAs in the pathogenesis of coeliac disease has been considerably advanced by the identification of T-cell responses to deamidated gluten antigens presented in conjunction with predisposing HLA-DQ2.5 molecules. This article briefly reviews these advances and draws parallels between the immune mechanisms leading to RA and coeliac disease, which point to a crucial role for T-cell-B-cell cooperation in the development of full-blown disease. Finally, the ways in which these novel insights are being exploited therapeutically to re-establish tolerance in patients with RA and coeliac disease are described. 10.1038/nrrheum.2015.59
Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Olumuyiwa-Akeredolu Oore-Ofe,Page Martin J,Soma Prashilla,Pretorius Etheresia Nature reviews. Rheumatology Rheumatoid arthritis (RA) is an autoimmune disease in which a variety of circulating pro-inflammatory cells and dysregulated molecules are involved in disease aetiology and progression. Platelets are an important cellular element in the circulation that can bind several dysregulated molecules (such as collagen, thrombin and fibrinogen) that are present both in the synovium and the circulation of patients with RA. Platelets not only respond to dysregulated molecules in their environment but also transport and express their own inflammatory mediators, and serve as regulators at the boundary between haemostasis and immunity. Activated platelets also produce microparticles, which further convey signalling molecules and receptors to the synovium and circulation, thereby positioning these platelet-derived particles as strategic regulators of inflammation. These diverse functions come together to make platelets facilitators of cellular crosstalk in RA. Thus, the receptor functions, ligand binding potential and dysregulated signalling pathways in platelets are becoming increasingly important for treatment in RA. This Review aims to highlight the role of platelets in RA and the need to closely examine platelets as health indicators when designing effective pharmaceutical targets in this disease. 10.1038/s41584-019-0187-9
The case for periodontitis in the pathogenesis of rheumatoid arthritis. Potempa Jan,Mydel Piotr,Koziel Joanna Nature reviews. Rheumatology Rheumatoid arthritis (RA), an autoimmune disease that affects ∼1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ∼11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented. 10.1038/nrrheum.2017.132
Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways. Sturgeon John A,Finan Patrick H,Zautra Alex J Nature reviews. Rheumatology In addition to recurrent pain, fatigue, and increased rates of physical disability, individuals with rheumatoid arthritis (RA) have an increased prevalence of some mental health disorders, particularly those involving affective or mood disturbances. This narrative Review provides an overview of mental health comorbidities in RA, and discusses how these comorbidities interact with disease processes, including dysregulation of inflammatory responses, prolonged difficulties with pain and fatigue, and the development of cognitive and behavioural responses that could exacerbate the physical and psychological difficulties associated with RA. This article describes how the social context of individuals with RA affects both their coping strategies and their psychological responses to the disease, and can also impair responses to treatment through disruption of patient-physician relationships and treatment adherence. Evidence from the literature on chronic pain suggests that the resulting alterations in neural pathways of reward processing could yield new insights into the connections between disease processes in RA and psychological distress. Finally, the role of psychological interventions in the effective and comprehensive treatment of RA is discussed. 10.1038/nrrheum.2016.112
Pros and cons of causative association between periodontitis and rheumatoid arthritis. Periodontology 2000 Research in recent decades has brought significant advancements in understanding of the molecular basis of the etiology of autoimmune diseases, including rheumatoid arthritis, a common systemic disease in which an inappropriate or inadequate immune response to environmental challenges leads to joint destruction. Recent studies have indicated that the classical viewpoint of the immunological processes underpinning the pathobiology of rheumatoid arthritis is restricted and needs to be expanded to include a more holistic and interdisciplinary approach incorporating bacteria-induced inflammatory reactions as an important pathway in rheumatoid arthritis etiology. Here, we discuss in detail data showing the clinical and molecular association of rheumatoid arthritis development with periodontal diseases. We also describe the unique role of periopathogens, which have been proposed to be crucial in the initiation and progression of this autoimmune pathological disorder. 10.1111/prd.12432
Macrophage heterogeneity in the context of rheumatoid arthritis. Udalova Irina A,Mantovani Alberto,Feldmann Marc Nature reviews. Rheumatology Macrophages are very important in the pathogenesis of rheumatoid arthritis (RA). The increase in the number of sublining macrophages in the synovium is an early hallmark of active rheumatic disease, and high numbers of macrophages are a prominent feature of inflammatory lesions. The degree of synovial macrophage infiltration correlates with the degree of joint erosion, and depletion of these macrophages from inflamed tissue has a profound therapeutic benefit. Research has now uncovered an unexpectedly high level of heterogeneity in macrophage origin and function, and has emphasized the role of environmental factors in their functional specialization. Although the heterogeneous populations of macrophages in RA have not been fully characterized, preliminary results in mouse models of arthritis have contributed to our understanding of the phenotype and ontogeny of synovial macrophages, and to deciphering the properties of monocyte-derived infiltrating and tissue-resident macrophages. Elucidating the molecular mechanisms that drive polarization of macrophages towards proinflammatory or anti-inflammatory phenotypes could lead to identification of signalling pathways that inform future therapeutic strategies. 10.1038/nrrheum.2016.91
Mechanisms, impact and management of pain in rheumatoid arthritis. Walsh David A,McWilliams Daniel F Nature reviews. Rheumatology People with rheumatoid arthritis (RA) identify pain as their most important symptom, one that often persists despite optimal control of inflammatory disease. RA pain arises from multiple mechanisms, involving inflammation, peripheral and central pain processing and, with disease progression, structural change within the joint. Consequently, RA pain has a wide range of characteristics-constant or intermittent, localized or widespread-and is often associated with psychological distress and fatigue. Dominant pain mechanisms in an individual are identified by critical evaluation of clinical symptoms and signs, and by laboratory and imaging tests. Understanding these mechanisms is essential for effective management, although evidence from preclinical models should be interpreted with caution. A range of pharmacological analgesic and immunomodulatory agents, psychological interventions and surgery may help manage RA pain. Pain contributes importantly to the clinical assessment of inflammatory disease activity, and noninflammatory components of RA pain should be considered when gauging eligibility for or response to biologic agents. Further randomized controlled trials are required to determine the optimal usage of analgesics in RA, and novel agents with greater efficacy and lower propensity for adverse events are urgently needed. Meanwhile, targeted use of existing treatments could reduce pain in people with RA. 10.1038/nrrheum.2014.64
Synovial tissue research: a state-of-the-art review. Orr Carl,Vieira-Sousa Elsa,Boyle David L,Buch Maya H,Buckley Christopher D,Cañete Juan D,Catrina Anca I,Choy Ernest H S,Emery Paul,Fearon Ursula,Filer Andrew,Gerlag Danielle,Humby Frances,Isaacs John D,Just Søren A,Lauwerys Bernard R,Le Goff Benoit,Manzo Antonio,McGarry Trudy,McInnes Iain B,Najm Aurélie,Pitzalis Constantino,Pratt Arthur,Smith Malcolm,Tak Paul P,Thurlings Rogier,Fonseca João E,Veale Douglas J,Tas Sander W Nature reviews. Rheumatology The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response. 10.1038/nrrheum.2017.115
Periodontitis and rheumatoid arthritis: What have we learned about their connection and their treatment? González-Febles Jerián,Sanz Mariano Periodontology 2000 Rheumatoid arthritis and periodontitis are chronic inflammatory diseases defined respectively by the destruction of the articular cartilage and tooth-supporting periodontal tissues. Although the epidemiologic evidence for an association between these two diseases is still scarce, there is emerging scientific information linking specific bacterial periodontal pathogens, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, in the citrullination process, leading to autoantibody formation and compromised immunotolerance of the susceptible patient to rheumatoid arthritis. In this review, we update the existing information on the evidence, not only regarding the epidemiologic association, but also the biologic mechanisms linking these two diseases. Finally, we review information emerging from intervention studies evaluating whether periodontal treatment could influence the initiation and progression of rheumatoid arthritis. 10.1111/prd.12385
Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nature reviews. Rheumatology Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a failure of spontaneous resolution of inflammation. Although the pro-inflammatory cytokines and mediators that trigger RA have been the focus of intense investigations, the regulatory and anti-inflammatory cytokines responsible for the suppression and resolution of disease in a context-dependent manner have been less well characterized. However, knowledge of the pathways that control the suppression and resolution of inflammation in RA is clinically relevant and conceptually important for understanding the pathophysiology of the disease and for the development of treatments that enable long-term remission. Cytokine-mediated processes such as the activation of T helper 2 cells by IL-4 and IL-13, the resolution of inflammation by IL-9, IL-5-induced eosinophil expansion, IL-33-mediated macrophage polarization, the production of IL-10 by regulatory B cells and IL-27-mediated suppression of lymphoid follicle formation are all involved in governing the regulation and resolution of inflammation in RA. By better understanding these immune-regulatory signalling pathways, new therapeutic strategies for RA can be envisioned that aim to balance and resolve, rather than suppress, inflammation. 10.1038/s41584-018-0109-2
The gut-joint axis in rheumatoid arthritis. Nature reviews. Rheumatology Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA. 10.1038/s41584-021-00585-3
Rheumatoid arthritis and depression: an inflammatory perspective. Nerurkar Louis,Siebert Stefan,McInnes Iain B,Cavanagh Jonathan The lancet. Psychiatry The coexistence of immune-mediated inflammatory diseases with depression has long been recognised. Data that illustrate the intimate associations between peripheral and brain immune responses raise the possibility of shared pathophysiological mechanisms. These associations include the negative effects of proinflammatory cytokines on monoaminergic neurotransmission, neurotrophic factors, and measures of synaptic plasticity. The evidence supporting this association is accumulating and includes findings from clinical trials of immunomodulatory therapy, indicating that these interventions can provide benefits to mental health independent of improvements in physical disease scores. In this Review, we assess this evidence in relation to rheumatoid arthritis and depression, with a focus on innate immune and molecular responses to inflammation, and discuss the challenges of assessing causation in this population, acknowledging the difficulty of assessing the confounding and contributory effects of pain and fatigue. We also discuss how future clinical and preclinical research might improve diagnosis of depression in people with rheumatoid arthritis and shed light on mechanisms that could be substrates for therapeutic interventions. 10.1016/S2215-0366(18)30255-4
Immunopathogenesis of Rheumatoid Arthritis. Firestein Gary S,McInnes Iain B Immunity Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics. 10.1016/j.immuni.2017.02.006
Rheumatoid arthritis. Smolen Josef S,Aletaha Daniel,Barton Anne,Burmester Gerd R,Emery Paul,Firestein Gary S,Kavanaugh Arthur,McInnes Iain B,Solomon Daniel H,Strand Vibeke,Yamamoto Kazuhiko Nature reviews. Disease primers Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA. 10.1038/nrdp.2018.1
Rheumatoid arthritis and metabolic syndrome. Kerekes György,Nurmohamed Michael T,González-Gay Miguel A,Seres Ildikó,Paragh György,Kardos Zsófia,Baráth Zsuzsa,Tamási László,Soltész Pál,Szekanecz Zoltán Nature reviews. Rheumatology Rheumatoid arthritis (RA), especially active disease, is associated with considerable changes in body composition, lipids, adipokines and insulin sensitivity. Metabolic changes, such as increased total cholesterol, LDL cholesterol and triglyceride levels, occur even in preclinical RA. Active RA is associated with decreased lipid levels, BMI, fat and muscle mass, as well as altered lipid profiles. Some of these changes are also seen in metabolic syndrome, and could increase cardiovascular mortality. Importantly, the systemic inflammation underlying RA is an independent risk factor for cardiovascular disease. This Perspectives article summarizes data on the associations of various components of metabolic syndrome with RA, and discusses the effects of biologic therapy on these factors. The authors propose that components of metabolic syndrome should be monitored in patients with RA throughout the disease course, and argue that optimal disease control using biologic agents might attenuate several adverse effects of metabolic syndrome in these patients. 10.1038/nrrheum.2014.121