Hotspots and future trends of autophagy in Traditional Chinese Medicine: A Bibliometric analysis.
Heliyon
Objective:To discuss the hotspots and future trends of autophagy in traditional Chinese medicine (TCM) and provide a reference for researchers in this field. Method:Using visual analysis tools, metrological statistics and visual research on the pertinent literature in the area of autophagy use in TCM were undertaken in the core collection database of the Web of Science. By examining the authors, keywords, research circumstances, research hotspots, and trends of linked research, the use of autophagy in TCM was investigated. Results and Conclusions:A total of 916 studies were included, among which Beijing University Chinese Medicine was the largest number of advantageous research institutions, followed by Shanghai University Traditional Chinese Medicine and Guangzhou University Chinese Medicine.The keywords of literature research primarily comprise apoptosis, activation, inhibition, pathway, mechanism, oxidative stress, proliferation, NF-κB, cancer, mtor, etc. At present, the research on autophagy in the field of TCM is increasing on a year-to-year basis. The research has focused on the role played by TCM in malignant tumors, atherosclerosis, Alzheimer's disease through autophagy, and the regulation of autophagy signaling pathways (e.g., PI3K/AKT/mTOR signaling pathway, TLR4 signaling pathway,nrf2 signaling pathway and NF-κB signaling pathway). In the future, the therapeutic effect of TCM on chemotherapy-resistant tumor cells through autophagy pathway, the role of TCM mediating mitophagy and activating autophagy function, and the therapeutic effect of TCM components represented by luteolin on tumors, asthma, myocardial injury and other diseases through autophagy mechanism will be the research hotspots in the future.
10.1016/j.heliyon.2023.e20142
Targeting ferroptosis using Chinese herbal compounds to treat respiratory diseases.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Respiratory diseases pose a grave threat to human life. Therefore, understanding their pathogenesis and therapeutic strategy is important. Ferroptosis is a novel type of iron-dependent programmed cell death, distinct from apoptosis, necroptosis, and autophagy, characterised by iron, reactive oxygen species, and lipid peroxide accumulation, as well as glutathione (GSH) depletion and GSH peroxidase 4 (GPX4) inactivation. A close association between ferroptosis and the onset and progression of respiratory diseases, including chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, pulmonary fibrosis, and lung cancer, has been reported. Recent studies have shown that traditional Chinese medicine (TCM) compounds exhibit unique advantages in the treatment of respiratory diseases owing to their natural properties and potential efficacy. These compounds can effectively regulate ferroptosis by modulating several key signalling pathways such as system Xc -GSH-GPX4, NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1, thus playing a positive role in improving respiratory diseases. PURPOSE:This comprehensive review systematically outlines the regulatory role of ferroptosis in the onset and progression of respiratory diseases and provides evidence for treating respiratory diseases by targeting ferroptosis with TCM compounds. These insights aim to offer potential remedies for the clinical prevention and treatment of respiratory diseases. STUDY DESIGN AND METHODS:We searched scientific databases PubMed, Web of Science, Scopus, and CNKI using keywords such as "ferroptosis","respiratory diseases","chronic obstructive pulmonary disease","bronchial asthma","acute lung injury","pulmonary fibrosis","lung cancer","traditional Chinese medicine","traditional Chinese medicine compound","monomer", and "natural product" to retrieve studies on the therapeutic potential of TCM compounds in ameliorating respiratory diseases by targeting ferroptosis. The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS:TCM compounds possess unique advantages in treating respiratory diseases, stemming from their natural origins and proven clinical effectiveness. TCM compounds can exert therapeutic effects on respiratory diseases by regulating ferroptosis, which mainly involves modulation of pathways such as system Xc -GSH-GPX4,NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1. CONCLUSION:TCM compounds have demonstrated promising potential in improving respiratory diseases through the regulation of ferroptosis. The identification of specific TCM-related inducers and inhibitors of ferroptosis holds great significance in developing more effective strategies. However, current research remains confined to animal and cellular studies, emphasizing the imperative for further verifications through high-quality clinical data.
10.1016/j.phymed.2024.155738
Asthma in the era of SARS CoV-2 virus.
The Journal of asthma : official journal of the Association for the Care of Asthma
OBJECTIVES:It is well established in international literature that respiratory viruses can trigger asthma exacerbations. However, not all viruses affect patients in the same manner and extent. The pandemic of the SARS CoV-2 virus has brought interest to study the association of this novel virus on patients with mild-moderate and severe asthma in terms of susceptibility, severity and treatment. DATA SOURCES – STUDY SELECTION:We performed an extensive search of current literature in the databases PubMed, Scopus and Google Scholar for original articles. We decided to include all types of articles, except for case studies, published until the end of February 2021 focusing on the effects of COVID-19 on the respiratory system and the main treatment recommendations up to date for patients with bronchial asthma. RESULTS:Until now there is no clear evidence that asthmatics have a higher risk of experiencing exacerbations when infected, nor higher mortality rates than the general population. Nevertheless, our knowledge on molecular pathways behind asthma phenotypes in the past decades is growing, and it underlines the need to predict the unique response each patient may have to infection from the novel coronavirus. It is not clear yet if certain sub-populations of asthmatics are at higher risk than others. CONCLUSION:Despite the lack of evidence for higher susceptibility and/or mortality in relation to COVID-19, all asthmatic patients, whether treated with inhaled bronchodilators/corticosteroids or even biologics, should maintain their controller therapy without making any alterations.
10.1080/02770903.2021.1941093
Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling.
Clinical immunology (Orlando, Fla.)
Asthma is a heterogeneous disease characterized by chronic airway inflammation, reversible airflow limitation, and airway remodeling. Eosinophil peroxidase (EPX) is the most abundant secondary granule protein unique to activated eosinophils. In this study, we aimed to illustrate the effect of EPX on the epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Our research found that both EPX and ADAM33 were negatively correlated with FEV1/FVC and FEV1%pred, and positively correlated with IL-5 levels. Asthma patients had relatively higher levels of ADAM33 and EPX compared to the healthy control group. The expression of TSLP, TGF-β1 and ADAM33 in the EPX intervention group was significantly higher. Moreover, EPX could promote the proliferation, migration and EMT of BEAS-2B cells, and the effect of EPX on various factors was significantly improved by the PI3K inhibitor LY294002. The findings from this study could potentially offer a novel therapeutic target for addressing airway remodeling in bronchial asthma, particularly focusing on EMT.
10.1016/j.clim.2024.110228
Endotypes of chronic rhinosinusitis based on inflammatory and remodeling factors.
The Journal of allergy and clinical immunology
BACKGROUND:Previous studies on the endotyping of chronic rhinosinusitis (CRS) that were based on inflammatory factors have broadened our understanding of the disease. However, the endotype of CRS combined with inflammatory and remodeling features has not yet been clearly elucidated. OBJECTIVE:We sought to identify the endotypes of patients with CRS according to inflammatory and remodeling factors. METHODS:Forty-eight inflammatory and remodeling factors in the nasal mucosal tissues of 128 CRS patients and 24 control subjects from northern China were analyzed by Luminex, ELISA, and ImmunoCAP. Sixteen factors were used to perform the cluster analysis. The characteristics of each cluster were analyzed using correlation analysis and validated by immunofluorescence staining. RESULTS:Patients were classified into 5 clusters. Clusters 1 and 2 showed non-type 2 signatures with low biomarker concentrations, except for IL-19 and IL-27. Cluster 3 involved a low type 2 endotype with the highest expression of neutrophil factors, such as granulocyte colony-stimulating factor, IL-8, and myeloperoxidase, and remodeling factors, such as matrix metalloproteinases and fibronectin. Cluster 4 exhibited moderate type 2 inflammation. Cluster 5 exhibited high type 2 inflammation, which was associated with relatively higher levels of neutrophil and remodeling factors. The proportion of CRS with nasal polyps, asthma, allergies, anosmia, aspirin sensitivity, and the recurrence of CRS increased from clusters 1 to 5. CONCLUSION:Diverse inflammatory mechanisms result in distinct CRS endotypes and remodeling profiles. The explicit differentiation and accurate description of these endotypes will guide targeted treatment decisions.
10.1016/j.jaci.2022.10.010
Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis.
The Journal of experimental medicine
Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also enhances injury resolution to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) prechallenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis and functional assays showed greater capacity of trained AMs for efferocytosis of cellular debris and injury resolution. Single-cell high-dimensional mass cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AM subset with a proresolving phenotype. Reprogrammed AMs upregulated expression of the efferocytosis receptor MERTK mediated by the transcription factor KLF4. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal P. aeruginosa. Thus, our study has identified a subset of tissue-resident trained macrophages that prevent hyperinflammation and restore tissue homeostasis following repeated pathogen challenges.
10.1084/jem.20221388
Clinical implications of T cell exhaustion for cancer immunotherapy.
Nature reviews. Clinical oncology
Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.
10.1038/s41571-022-00689-z
The pharmacotherapeutic management of allergic rhinitis in people with asthma.
Expert opinion on pharmacotherapy
INTRODUCTION:Up to 90% of asthmatic patients have comorbid allergic rhinitis (AR). Although appropriate therapy of AR can improve asthma symptoms and management, AR is often underdiagnosed and under-treated in asthmatics.A non-systematic literature research was conducted on AR as a comorbidity and risk factor of asthma. Latest international publications in medical databases, international guidelines, and the Internet were reviewed. AREAS COVERED:Based on the conducted literature research there is proved evidence of the necessity of diagnosis and treatment of AR in patients with asthma because it affects health care utilization. Therefore, it is recommended in national and global guidelines. EXPERT OPINION:AR increases the risk of asthma development and contributes to the severity of an existing asthma. Early treatment of AR with drugs as intranasal steroids, antihistamines, leukotriene receptor antagonists, and especially allergen-specific immunotherapy can reduce the risk of asthma development and the concomitant medication use in addition to severity of symptoms in AR and asthma.
10.1080/14656566.2024.2307476
Airway hyperresponsiveness in asthma: The role of the epithelium.
The Journal of allergy and clinical immunology
Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.
10.1016/j.jaci.2024.02.011
Poly-l-arginine promotes ferroptosis in asthmatic airway epithelial cells by modulating PBX1/GABARAPL1 axis.
International journal of biological macromolecules
Eosinophils play a featured role among inflammatory cells participating in the onset and development of asthma. Activated eosinophils release several cytotoxic granular proteins, such as major basic protein (MBP), posing a significant threat to airway epithelium. Ferroptosis, a novel form of cell death, is gaining recognition for its involvement in asthma pathogenesis, though the specific mechanisms remain largely unknown. Herein, we revealed that poly-l-arginine (PLA), an MBP mimic, induced ferroptosis in airway epithelium by downregulating γ-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1). Reduced GABARAPL1 expression was further confirmed in ovalbumin (OVA)-induced asthma mice and PLA-treated human airway organoids (hAOs). Mechanistically, PLA activated mechanistic target of rapamycin complex 1 (mTORC1) signaling, inhibiting pre-B-cell leukemia transcription factor 1 (PBX1), which in turn leads to transcriptional downregulation of GABARAPL1. Furthermore, MBP extracted from eosinophils, similar to PLA, induced ferroptosis in airway epithelial cells, as well as modulating mTORC1/PBX1/GABARAPL1 pathway. Finally, Ferrostatin-1 treatment or GABARAPL1 overexpression alleviated ferroptosis and airway inflammation in asthmatic mice. Overall, our findings highlight the cell communication between eosinophils and airway epithelial cells. MBP modulates the mTORC1/PBX1/GABARAPL1 axis, thereby serving as a significant contributor to ferroptosis in airway epithelium and airway inflammation. This suggests that suppressing ferroptosis in airway epithelium or targeting eosinophils and MBP could lead to novel therapeutic strategies for asthma management.
10.1016/j.ijbiomac.2024.138478
PM2.5 exposure regulates Th1/Th2/Th17 cytokine production through NF-κB signaling in combined allergic rhinitis and asthma syndrome.
International immunopharmacology
BACKGROUND:Particulate matter (PM) is a major component of air pollution from emissions from anthropogenic and natural sources and is a serious problem worldwide due to its adverse effects on human health. Increased particulate air pollution increases respiratory disease-related mortality and morbidity. However, the impact of PM with an aerodynamic diameter of ≤ 2.5 μm (PM2.5) on combined allergic rhinitis and asthma syndrome (CARAS) remains to be elucidated. Accordingly, in the present study, we investigated the effect of PM2.5 in an ovalbumin (OVA)-induced CARAS mouse model with a focus on NF-κB signaling. METHODOLOGY:We established an OVA-induced mouse model of CARAS to determine the effects of exposure to PM2.5. BALB/c mice were randomly divided into four groups: (1) naive, (2) PM2.5, (3) CARAS, and (4) CARAS/PM2.5. Mice were systemically sensitized with OVA and challenged with inhalation of ultrasonically nebulized 5% OVA three times by intranasal instillation of OVA in each nostril for 7 consecutive days. Mice in the PM2.5 and CARAS/PM2.5 groups were then exposed to PM2.5 by intranasal instillation of PM2.5 for several days. We then examined the impacts of PM2.5 exposure on histopathology and NF-κB signaling in our OVA-induced CARAS mouse model. RESULTS:PM2.5 increased infiltration of eosinophils in bronchoalveolar lavage fluid (BALF) samples and inflammatory cells in lung tissue. It also increased production of GATA3, RORγ, IL-4, IL-5, IL-13, and IL-17 in nasal lavage fluid (NALF) and BALF samples in the CARAS mouse model, but secretion of IL-12 and IFN-γ was suppressed. Exposure to PM2.5 increased OVA-specific IgE and IgG levels in serum, inflammatory cell infiltration in the airways, and fibrosis in lung tissue. It also activated the NF-κB signaling pathway, increasing Th2/Th17 cytokine levels while decreasing Th1 cytokine expression, thereby inducing an inflammatory response and promoting inflammatory cell infiltration in nasal and lung tissue. CONCLUSION:Our results demonstrate that PM2.5 can aggravate OVA-induced CARAS.
10.1016/j.intimp.2023.110254
Control of endothelial quiescence by FOXO-regulated metabolites.
Nature cell biology
Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.
10.1038/s41556-021-00637-6
Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma.
Sun Eun Jin,Wankell Miriam,Palamuthusingam Pranavan,McFarlane Craig,Hebbard Lionel
Biomedicines
Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
10.3390/biomedicines9111639
Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis.
Acta pharmaceutica Sinica. B
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.
10.1016/j.apsb.2021.07.023
Wogonin inhibits H2O2-induced angiogenesis via suppressing PI3K/Akt/NF-κB signaling pathway.
Zhou Mi,Song Xiuming,Huang Yujie,Wei Libin,Li Zhiyu,You Qidong,Guo Qinglong,Lu Na
Vascular pharmacology
Wogonin, a natural monoflavonoid extracted from Scutellariae radix, has been reported for its ability of inhibiting tumor angiogenesis. In this study, we assessed the effect of wogonin on angiogenesis induced by low level of H2O2 (10 μM) in human umbilical vein endothelial cells (HUVECs). Wogonin suppressed H2O2-induced migration and tube formation of HUVECs as well as microvessel sprouting from rat aortic rings in vitro. Meanwhile, wogonin suppressed vessel growth in chicken chorioallantoic membrane (CAM) model in vivo. Mechanistic studies showed that wogonin suppressed H2O2-activated PI3K/Akt pathway and reduced the expression of vascular endothelial growth factor (VEGF) up-regulated by H2O2 in both protein and mRNA levels. In addition, wogonin also inhibited nuclear translocation of NF-κB, and decreased the binding ability of NF-κB with exogenous consensus DNA oligonucleotide. Then we further investigated the effect of wogonin on over-activated PI3K/Akt pathway by insulin-like growth factor-1 (IGF-1) and H2O2. We found that wogonin suppressed phosphorylation of Akt, up-regulation of VEGF and angiogenesis in vitro which was further induced by IGF-1 and H2O2. Moreover, in NF-κB overexpressed HUVECs, wogonin could also reduce the expression of VEGF and inhibited the migration and tube formation. Taken together, these results suggested that wogonin was potential in inhibiting H2O2-induced angiogenesis in vitro and in vivo via suppressing PI3K/Akt pathway and NF-κB signaling.
10.1016/j.vph.2014.01.010
β-Sitosterol Enhances Lung Epithelial Cell Permeability by Suppressing the NF-κB Signaling Pathway.
Discovery medicine
BACKGROUND:The dysregulation between pro-inflammatory and anti-inflammatory responses during sepsis is a crucial factor in driving sepsis progression. Acute lung injury (ALI) resulting from excessive production and accumulation of inflammatory mediators in the lungs contributes to impaired lung barrier function. The activation of the NF-κB signaling pathway during inflammation leads to the transcriptional activation of multiple inflammatory genes. Given the plausible impact of NF-κB signaling suppression in mitigating lung injury, substantive evidence demonstrates beta-sitosterol (BS)'s proficient ability to block NF-κB activation. Therefore, the aim of the present investigation was to delve into the impacts of BS in the context of sepsis-induced acute lung injury, employing both a mouse model and a model involving lung epithelial cells. METHODS:Sepsis-induced lung injury was simulated in mice through cecum ligation and puncture (CLP). To emulate injury in murine lung epithelial (MLE-12) cells, an experiment involving lipopolysaccharide (LPS) was administered. Evaluation of alterations in lung tissue permeability encompassed techniques such as lung wet/dry (W/D) mass ratio, Evans blue staining, and quantification of total protein concentration in bronchoalveolar lavage fluid (BALF). Lung tissue histopathological shifts were ascertained via hematoxylin and eosin (HE) staining. Additionally, the concentrations of inflammatory cytokines IL-6 and TNF-α were quantified in every lung tissue and cell group by implementing enzyme-linked immunosorbent assay (ELISA). Protein quantification for signal biomarkers was carried out using Western blotting and immunofluorescence methodologies. In tandem, the assessment of MLE-12 cell permeability was conducted by evaluating fluorescein isothiocyanate (FITC)-dextran extravasation. RESULTS:BS mitigated lung tissue pathologies, reduced inflammatory factors, and lowered tissue and cell permeability. BS inhibited NF-κB signaling and increased claudin-4 and claudin-5 expression, enhancing septic lung epithelial cell permeability. CONCLUSIONS:Through suppressing the NF-κB signaling cascade, BS effectively curtails the levels of inflammatory mediators. Simultaneously, it orchestrates the modulation of claudin-4 and claudin-5 expression, culminating in the augmentation of lung epithelial cell barrier competence, thus improving sepsis-induced lung injury.
10.24976/Discov.Med.202335179.90
Herb-CMap: a multimodal fusion framework for deciphering the mechanisms of action in traditional Chinese medicine using Suhuang antitussive capsule as a case study.
Briefings in bioinformatics
Herbal medicines, particularly traditional Chinese medicines (TCMs), are a rich source of natural products with significant therapeutic potential. However, understanding their mechanisms of action is challenging due to the complexity of their multi-ingredient compositions. We introduced Herb-CMap, a multimodal fusion framework leveraging protein-protein interactions and herb-perturbed gene expression signatures. Utilizing a network-based heat diffusion algorithm, Herb-CMap creates a connectivity map linking herb perturbations to their therapeutic targets, thereby facilitating the prioritization of active ingredients. As a case study, we applied Herb-CMap to Suhuang antitussive capsule (Suhuang), a TCM formula used for treating cough variant asthma (CVA). Using in vivo rat models, our analysis established the transcriptomic signatures of Suhuang and identified its key compounds, such as quercetin and luteolin, and their target genes, including IL17A, PIK3CB, PIK3CD, AKT1, and TNF. These drug-target interactions inhibit the IL-17 signaling pathway and deactivate PI3K, AKT, and NF-κB, effectively reducing lung inflammation and alleviating CVA. The study demonstrates the efficacy of Herb-CMap in elucidating the molecular mechanisms of herbal medicines, offering valuable insights for advancing drug discovery in TCM.
10.1093/bib/bbae362
The Role of PPAR-γ in Allergic Disease.
Current allergy and asthma reports
PURPOSE OF REVIEW:The incidence of allergic diseases such as asthma, rhinitis and atopic dermatitis has risen at an alarming rate over the last century. Thus, there is a clear need to understand the critical factors that drive such pathologic immune responses. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that has emerged as an important regulator of multiple cell types involved in the inflammatory response to allergens; from airway epithelial cells to T Helper (TH) cells. RECENT FINDINGS:Initial studies suggested that agonists of PPAR-γ could be employed to temper allergic inflammation, suppressing pro-inflammatory gene expression programs in epithelial cells. Several lines of work now suggest that PPAR-γ plays an essential in promoting 'type 2' immune responses that are typically associated with allergic disease. PPAR-γ has been found to promote the functions of TH2 cells, type 2 innate lymphoid cells, M2 macrophages and dendritic cells, regulating lipid metabolism and directly inducing effector gene expression. Moreover, preclinical models of allergy in gene-targeted mice have increasingly implicated PPAR-γ in driving allergic inflammation. Herein, we highlight the contrasting roles of PPAR-γ in allergic inflammation and hypothesize that the availability of environmental ligands for PPAR-γ may be at the heart of the rise in allergic diseases worldwide.
10.1007/s11882-021-01022-x
IL-1β and TNF-α Modulation of Proliferated and Committed Myoblasts: IL-6 and COX-2-Derived Prostaglandins as Key Actors in the Mechanisms Involved.
Alvarez Angela M,DeOcesano-Pereira Carlos,Teixeira Catarina,Moreira Vanessa
Cells
In this study, we investigated the effects and mechanisms of the pro-inflammatory cytokines IL-1β and TNF-α on the proliferation and commitment phases of myoblast differentiation. C2C12 mouse myoblast cells were cultured to reach a proliferated or committed status and were incubated with these cytokines for the evaluation of cell proliferation, cyclooxygenase 2 (COX-2) expression, release of prostaglandins (PGs) and myokines, and activation of myogenic regulatory factors (MRFs). We found that inhibition of the IL-6 receptor reduced IL-1β- and TNF-α-induced cell proliferation, and that the IL-1β effect also involved COX-2-derived PGs. Both cytokines modulated the release of the myokines myostatin, irisin, osteonectin, and IL-15. TNF-α and IL-6 reduced the activity of Pax7 in proliferated cells and reduced MyoD and myogenin activity at both proliferative and commitment stages. Otherwise, IL-1β increased myogenin activity only in committed cells. Our data reveal a key role of IL-6 and COX-2-derived PGs in IL-1β and TNF-α-induced myoblast proliferation and support the link between TNF-α and IL-6 and the activation of MRFs. We concluded that IL-1β and TNF-α induce similar effects at the initial stages of muscle regeneration but found critical differences between their effects with the progression of the process, bringing new insights into inflammatory signalling in skeletal muscle regeneration.
10.3390/cells9092005
TGF-β1 - A truly transforming growth factor in fibrosis and immunity.
Lodyga Monika,Hinz Boris
Seminars in cell & developmental biology
'Jack of all trades, master of everything' is a fair label for transforming growth factor β1 (TGF-β) - a cytokine that controls our life at many levels. In the adult organism, TGF-β1 is critical for the development and maturation of immune cells, maintains immune tolerance and homeostasis, and regulates various aspects of immune responses. Following acute tissue damages, TGF-β1 becomes a master regulator of the healing process with impacts on about every cell type involved. Divergence from the tight control of TGF-β1 actions, for instance caused by chronic injury, severe trauma, or infection can tip the balance from regulated physiological to excessive pathological repair. This condition of fibrosis is characterized by accumulation and stiffening of collagenous scar tissue which impairs organ functions to the point of failure. Fibrosis and dysregulated immune responses are also a feature of cancer, in which tumor cells escape immune control partly by manipulating TGF-β1 regulation and where immune cells are excluded from the tumor by fibrotic matrix created during the stroma 'healing' response. Despite the obvious potential of TGF-β-signalling therapies, globally targeting TGF-β1 receptor, downstream pathways, or the active growth factor have proven to be extremely difficult if not impossible in systemic treatment regimes. However, TGF-β1 binding to cell receptors requires prior activation from latent complexes that are extracellularly presented on the surface of immune cells or within the extracellular matrix. These different locations have led to some divergence in the field which is often either seen from the perspective of an immunologists or a fibrosis/matrix researcher. Despite these human boundaries, there is considerable overlap between immune and tissue repair cells with respect to latent TGF-β1 presentation and activation. Moreover, the mechanisms and proteins employed by different cells and spatiotemporal control of latent TGF-β1 activation provide specificity that is amenable to drug development. This review aims at synthesizing the knowledge on TGF-β1 extracellular activation in the immune system and in fibrosis to further stimulate cross talk between the two research communities in solving the TGF-β conundrum.
10.1016/j.semcdb.2019.12.010
Huangqi Baihe Granules alleviate hypobaric hypoxia-induced acute lung injury in rats by suppressing oxidative stress and the TLR4/NF-κB/NLRP3 inflammatory pathway.
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Huangqi Baihe Granules (HQBHG) are a modified formulation based on the traditional recipe "Huangqi Baihe porridge" and the Dunhuang medical prescription "Cistanche Cistanche Soup." The Herbal medicine moistens the lungs and tones the kidneys in addition to replenishing Qi and feeding Yin, making it an ideal choice for enhancing adaptability to high-altitude hypoxic environments. AIM OF THE STUDY:The purpose of this study was to examine a potential molecular mechanism for the treatment and prevention of hypoxic acute lung injury (ALI) in rats using Huangqi Baihe Granules. MATERIALS AND METHODS:The HCP-III laboratory animal low-pressure simulation chamber was utilized to simulate high-altitude environmental exposure and establish an ALI model in rats. The severity of lung damage was evaluated using a battery of tests that included spirometry, a wet/dry lung ratio, H&E staining, and transmission electron microscopy. Using immunofluorescence, the amount of reactive oxygen species (ROS) in lung tissue was determined. Superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and myeloperoxidase (MPO) levels in lung tissue were determined using this kit. Serum levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta), and antiinflammatory cytokines like interleukin-10 (IL-10) were measured using an enzyme-linked immunosorbent assay kit. Gene expression changes in lung tissue were identified using transcriptomics, and the relative expression of proteins and mRNA involved in the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB p65)/Nod-like receptor protein 3 (NLRP3) pathway were determined using western blotting and quantitative real-time PCR. RESULTS:HQBHG was shown to enhance lung function considerably, decrease the wet/dry ratio of the lungs, attenuate lung tissue damage, suppress ROS and MDA formation, and increase SOD activity and GSH expression. The research also demonstrated that HQBHG inhibited the activation of the TLR4/NF-κB p65/NLPR3 signaling pathway in lung tissue, reducing the release of downstream pro-inflammatory cytokines. CONCLUSIONS:HQBHG exhibits potential therapeutic effects against ALI induced by altitude hypoxia through suppressing oxidative stress and inflammatory response. This suggests it may be a novel drug for treating and preventing ALI.
10.1016/j.jep.2024.117765
USP19 Inhibits TNF-α- and IL-1β-Triggered NF-κB Activation by Deubiquitinating TAK1.
Lei Cao-Qi,Wu Xin,Zhong Xuan,Jiang Lu,Zhong Bo,Shu Hong-Bing
Journal of immunology (Baltimore, Md. : 1950)
The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-β-activated kinase 1 (TAK1)-mediated NF-κB activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-α- and IL-1β-triggered NF-κB activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-α- and IL-1β-triggered NF-κB activation and transcription of downstream genes, whereas USP19 deficiency had the opposite effects. mice produced higher levels of inflammatory cytokines and were more susceptible to TNF-α- and IL-1β-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-α- or IL-1β-dependent manner and specifically deconjugated K63- and K27-linked polyubiquitin chains from TAK1, leading to the impairment of TAK1 activity and the disruption of the TAK1-TAB2/3 complex. Our findings provide new insights to the complicated molecular mechanisms of the attenuation of the inflammatory response.
10.4049/jimmunol.1900083
COVID-19 infection: an overview on cytokine storm and related interventions.
Virology journal
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health. This virus affects the respiratory tract and usually leads to pneumonia in most patients and acute respiratory distress syndrome (ARDS) in 15% of cases. ARDS is one of the leading causes of death in patients with COVID-19 and is mainly triggered by elevated levels of pro-inflammatory cytokines, referred to as cytokine storm. Interleukins, such as interleukin-6 (1L-6), interleukin-1 (IL-1), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α) play a very significant role in lung damage in ARDS patients through the impairments of the respiratory epithelium. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. The eradication of COVID-19 is currently practically impossible, and there is no specific treatment for critically ill patients with COVID-19; however, suppressing the inflammatory response may be a possible strategy. In light of this, we review the efficacy of specific inhibitors of IL6, IL1, IL-17, and TNF-α for treating COVID-19-related infections to manage COVID-19 and improve the survival rate for patients suffering from severe conditions.
10.1186/s12985-022-01814-1
Farnesoid X Receptor Protects Murine Lung against IL-6-promoted Ferroptosis Induced by Polyriboinosinic-Polyribocytidylic Acid.
American journal of respiratory cell and molecular biology
Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.
10.1165/rcmb.2023-0172OC
Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD.
Frontiers in immunology
The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and remodelling in asthma and COPD. Mechanistic understanding of injury susceptibility and damage response may lead to improved therapies for these diseases.
10.3389/fimmu.2023.1201658
Sphingosine kinase 1-specific inhibitor PF543 reduces goblet cell metaplasia of bronchial epithelium in an acute asthma model.
American journal of physiology. Lung cellular and molecular physiology
Sphingosine kinase 1 (SPHK1) has been shown to play a key role in the pathogenesis of asthma where SPHK1-generated sphingosine-1-phosphate (S1P) is known to mediate innate and adaptive immunity while promoting mast cell degranulation. Goblet cell metaplasia (GCM) contributes to airway obstruction in asthma and has been demonstrated in animal models. We investigated the role of PF543, a SPHK1-specific inhibitor, in preventing the pathogenesis of GCM using a murine (C57BL/6) model of allergen-induced acute asthma. Treatment with PF543 before triple allergen exposure (DRA: House dust mite, Ragweed pollen, and Aspergillus) reduced inflammation, eosinophilic response, and GCM followed by reduced airway hyperreactivity to intravenous methacholine. Furthermore, DRA exposure was associated with increased expression of SPHK1 in the airway epithelium which was reduced by PF543. DRA-induced reduction of acetylated α-tubulin in airway epithelium was associated with an increased expression of NOTCH2 and SPDEF which was prevented by PF543. In vitro studies using human primary airway epithelial cells showed that inhibition of SPHK1 using PF543 prevented an allergen-induced increase of both NOTCH2 and SPDEF. siRNA silencing of SPHK1 prevented the allergen-induced increase of both NOTCH2 and SPDEF. NOTCH2 silencing was associated with a reduction of SPDEF but not that of SPHK1 upon allergen exposure. Our studies demonstrate that inhibition of SPHK1 protected allergen-challenged airways by preventing GCM and airway hyperreactivity, associated with downregulation of the NOTCH2-SPDEF signaling pathway. This suggests a potential novel link between SPHK1, GCM, and airway remodeling in asthma. The role of SPHK1-specific inhibitor, PF543, in preventing goblet cell metaplasia (GCM) and airway hyperreactivity (AHR) is established in an allergen-induced mouse model. This protection was associated with the downregulation of NOTCH2-SPDEF signaling pathway, suggesting a novel link between SPHK1, GCM, and AHR.
10.1152/ajplung.00269.2023
Eosinophil extracellular traps drive asthma progression through neuro-immune signals.
Nature cell biology
Eosinophilic inflammation is a feature of allergic asthma. Despite mounting evidence showing that chromatin filaments released from neutrophils mediate various diseases, the understanding of extracellular DNA from eosinophils is limited. Here we show that eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid are associated with the severity of asthma in patients. Functionally, we find that EETs augment goblet-cell hyperplasia, mucus production, infiltration of inflammatory cells and expressions of type 2 cytokines in experimental non-infection-related asthma using both pharmaceutical and genetic approaches. Multiple clinically relevant allergens trigger EET formation at least partially via thymic stromal lymphopoietin in vivo. Mechanically, EETs activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, which is potentiated by eosinophil peroxidase. Subsequently, the pulmonary neuroendocrine cells amplify allergic immune responses via neuropeptides and neurotransmitters. Therapeutically, inhibition of CCDC25 alleviates allergic inflammation. Together, our findings demonstrate a previously unknown role of EETs in integrating immunological and neurological cues to drive asthma progression.
10.1038/s41556-021-00762-2
Morita-Baylis-Hillman adduct 2-(3-hydroxy-1-methyl-2-oxoindolin-3-il) acrylonitrile (CISACN) ameliorates the pulmonary allergic inflammation in CARAS model by increasing IFN-γ/IL-4 ratio towards the Th1 immune response.
International immunopharmacology
Combined allergic rhinitis and asthma syndrome (CARAS) is an airway-type 2 immune response with a profuse inflammatory process widely affecting the world population. Due to the compromise of quality of life and the lack of specific pharmacotherapy, the search for new molecules becomes relevant. This study aimed to evaluate the effectiveness of the Morita-Bailys-Hillman adduct (CISACN) treatment in the CARAS experimental model. Female BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with CISACN. The treatment decreased the eosinophil migration to the nasal and lung cavities and tissues and the goblet cell hyperplasia/hypertrophy, attenuated airway hyperactivity by reducing the hyperplasia/hypertrophy of the smooth muscle and the extracellular matrix's thickness. Also, the treatment reduced the clinical signs of rhinitis as nasal rubbing and sneezing in a histamine-induced nasal hyperreactivity assay. The immunomodulatory effect of CISACN was by reducing OVA-specific IgE serum level, and IL-33, IL-4, IL-13, and TGF-β production, dependent on IFN-γ increase. Furthermore, the effect of CISACN on lung granulocytes was by decreasing the p-p38MAPK/p65NF-κB signaling pathway. Indeed, CISACN reduced the p38MAPK and p65NF-κB activation. These data demonstrated the anti-inflammatory and immunomodulatory effects of the CISACN with scientific support to become a pharmacological tool to treat airway inflammatory diseases.
10.1016/j.intimp.2024.111737
Club cell CREB regulates the goblet cell transcriptional network and pro-mucin effects of IL-1B.
Frontiers in physiology
Club cells are precursors for mucus-producing goblet cells. Interleukin 1β (IL-1B) is an inflammatory mediator with pro-mucin activities that increases the number of mucus-producing goblet cells. IL-1B-mediated mucin production in alveolar adenocarcinoma cells requires activation of the cAMP response element-binding protein (CREB). Whether the pro-mucin activities of IL-1B require club cell CREB is unknown. We challenged male mice with conditional loss of club cell and wild type littermates with intra-airway IL-1B or vehicle. Secondarily, we studied human "club cell-like" H322 cells. IL-1B increased whole lung mRNA of secreted () and tethered () mucins independent of genotype. However, loss of club cell Creb1 increased whole lung mRNA of , decreased mRNA of the and prevented IL-1B mediated increases in mRNA. IL-1B increased the density of goblet cells containing neutral mucins in wildtype mice but not in mice with loss of club cell Creb1. These findings suggested that club cell Creb1 regulated mucin secretion. Loss of club cell Creb1 also prevented IL-1B-mediated impairments in airway mechanics. Four days of pharmacologic CREB inhibition in H322 cells increased mRNA abundance of , a repressor of goblet cell expansion, and decreased mRNA expression of , a driver of goblet cell expansion. Chromatin immunoprecipitation demonstrated that CREB directly bound to the promoter region of , but not to the promoter region of . Treatment of H322 cells with IL-1B increased cAMP levels, providing a direct link between IL-1B and CREB signaling. Our findings suggest that club cell Creb1 regulates the pro-mucin properties of IL-1B through pathways likely involving FOXA2.
10.3389/fphys.2023.1323865
Naringenin regulates cigarette smoke extract-induced extracellular vesicles from alveolar macrophage to attenuate the mouse lung epithelial ferroptosis through activating EV miR-23a-3p/ACSL4 axis.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Alveolar macrophages are one of the momentous regulators in pulmonary inflammatory responses, which can secrete extracellular vesicles (EVs) packing miRNAs. Ferroptosis, an iron-dependent cell death, is associated with cigarette smoke-induced lung injury, and EVs have been reported to regulate ferroptosis by transporting intracellular iron. However, the regulatory mechanism of alveolar macrophage-derived EVs has not been clearly illuminated in smoking-related pulmonary ferroptosis. Despite the known anti-ferroptosis effects of naringenin in lung injury, whether naringenin controls EVs-mediated ferroptosis has not yet been explored. PURPOSE:We explore the effects of EVs from cigarette smoke-stimulated alveolar macrophages in lung epithelial ferroptosis, and elucidate the EV miRNA-mediated pharmacological mechanism of naringenin. STUDY DESIGN AND METHODS:Differential and ultracentrifugation were conducted to extract EVs from different alveolar macrophages treatment groups in vitro. Both intratracheal instilled mice and treated epithelial cells were used to investigate the roles of EVs from alveolar macrophages involved in ferroptosis. Small RNA sequencing analysis was performed to distinguish altered miRNAs in EVs. The ferroptotic effects of EV miRNAs were examined by applying dual-Luciferase reporter assay and miRNA inhibitor transfection experiment. RESULTS:Here, we firstly reported that EVs from cigarette smoke extract-induced alveolar macrophages (CSE-EVs) provoked pulmonary epithelial ferroptosis. The ferroptosis inhibitor ferrostatin-1 treatment reversed these changes in vitro. Moreover, EVs from naringenin and CSE co-treated alveolar macrophages (CSE+Naringenin-EVs) markedly attenuated the lung epithelial ferroptosis compared with CSE-EVs. Notably, we identified miR-23a-3p as the most dramatically changed miRNA among Normal-EVs, CSE-EVs, and CSE+Naringenin-EVs. Further experimental investigation showed that ACSL4, a pro-ferroptotic gene leading to lipid peroxidation, was negatively regulated by miR-23a-3p. The inhibition of miR-23a-3p diminished the efficacy of CSE+Naringenin-EVs. CONCLUSION:Our findings firstly provided evidence that naringenin elevated the EV miR-23a-3p level from CSE-induced alveolar macrophages, thereby inhibiting the mouse lung epithelial ferroptosis via targeting ACSL4, and further complemented the mechanism of cigarette-induced lung injury and the protection of naringenin in a paracrine manner. The administration of miR-23a-3p-enriched EVs has the potential to ameliorate pulmonary ferroptosis.
10.1016/j.phymed.2023.155256
Naringenin attenuates inflammation, apoptosis, and ferroptosis in silver nanoparticle-induced lung injury through a mechanism associated with Nrf2/HO-1 axis: In vitro and in vivo studies.
Life sciences
With the wide application of silver nanoparticles (AgNPs), their potential damage to human health needs to be investigated. Lung is one of the main target organs after inhalation of AgNPs. Naringenin has been reported to have anti-inflammatory and anti-oxidative properties. This study aims to evaluate the protective effects of naringenin against AgNPs-induced lung injury and determine the underlying mechanism. In in vivo experiments, AgNPs were intratracheally instilled into ICR mice (l mg/kg) to establish a lung injury model. These mice were then treated with naringenin by oral gavage (25, 50, 100 mg/kg) for three days. Naringenin treatment decreased the levels of white blood cells, neutrophils, and lymphocytes in the blood, ameliorated lung injury, suppressed the release of pro-inflammatory cytokines, normalized ferroptotic markers and prevented oxidative stress with elevating Nrf2 and HO-1 protein expressions in lung. In in vitro experiments, BEAS-2B cells were firstly treated with AgNPs (320 μg/mL) and then naringenin (25, 50, and 100 μM), respectively. Naringenin attenuated AgNPs-induced oxidative stress and inflammatory response. Moreover, naringenin attenuated AgNPs-induced apoptosis with modulated low BAX, CytC, cleaved Caspase9, cleaved Caspase3 but high Bcl2. Furthermore, naringenin effectively decreased ferroptotic markers and increased the protein expressions of Nrf2 and HO-1, as well as increased the nuclear translocation of Nrf2. Importantly, the anti-apoptotic and anti-ferroptotic effects of naringenin in BEAS-2B cells were found to be at least partially Nrf2-dependent. These results indicated that naringenin exerted anti-inflammation, anti-apoptosis, and anti-ferroptosis effects and protected against AgNPs-induced lung injury at least partly via activating Nrf2/HO-1 signaling pathway.
10.1016/j.lfs.2022.121127
Licochalcone A protects against LPS-induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2).
British journal of pharmacology
BACKGROUND AND PURPOSE:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. EXPERIMENTAL APPROACH:A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. KEY RESULTS:Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. CONCLUSION AND IMPLICATIONS:In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.
10.1111/bph.15999
Respiratory syncytial virus infection and novel interventions.
Nature reviews. Microbiology
The large global burden of respiratory syncytial virus (RSV) respiratory tract infections in young children and older adults has gained increased recognition in recent years. Recent discoveries regarding the neutralization-specific viral epitopes of the pre-fusion RSV glycoprotein have led to a shift from empirical to structure-based design of RSV therapeutics, and controlled human infection model studies have provided early-stage proof of concept for novel RSV monoclonal antibodies, vaccines and antiviral drugs. The world's first vaccines and first monoclonal antibody to prevent RSV among older adults and all infants, respectively, have recently been approved. Large-scale introduction of RSV prophylactics emphasizes the need for active surveillance to understand the global impact of these interventions over time and to timely identify viral mutants that are able to escape novel prophylactics. In this Review, we provide an overview of RSV interventions in clinical development, highlighting global disease burden, seasonality, pathogenesis, and host and viral factors related to RSV immunity.
10.1038/s41579-023-00919-w
Licochalcone A plays dual antiviral roles by inhibiting RSV and protecting against host damage.
Journal of medical virology
Respiratory syncytial virus (RSV) causes lower respiratory tract diseases and bronchiolitis in children and elderly individuals. There are no effective drugs currently available to treat RSV infection. In this study, we report that Licochalcone A (LCA) can inhibit RSV replication and mitigate RSV-induced cell damage in vitro, and that LCA exerts a protective effect by reducing the viral titer and inflammation in the lungs of infected mice in vivo. We suggest that the mechanism of action occurs through pathways of antioxidant stress and inflammation. Further mechanistic results demonstrate that LCA can induce nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus, activate heme oxygenase 1 (HO-1), and inhibit reactive oxygen species-induced oxidative stress. LCA also works to reverse the decrease in I-kappa-B-alpha (IкBα) levels caused by RSV, which in turn inhibits inflammation through the associated nuclear factor kappa B and tumor necrosis factor-α signaling pathways. The combined action of the two cross-talking pathways protects hosts from RSV-induced damage. To conclude, our study is the first of its kind to establish evidence of LCA as a viable treatment for RSV infection.
10.1002/jmv.29059
Stigmasterol alleviates allergic airway inflammation and airway hyperresponsiveness in asthma mice through inhibiting substance-P receptor.
Pharmaceutical biology
CONTEXT:Stigmasterol has significant anti-arthritis and anti-inflammatory effects, but its role in immune and inflammatory diseases is still unclear. OBJECTIVE:The potential advantages of stigmasterol in asthma were explored in IL-13-induced BEAS-2B cells and asthmatic mice. MATERIALS AND METHODS:The optimal target of stigmasterol was confirmed in asthma. After detecting the cytotoxicity of stigmasterol in BEAS-2B cells, 10 μg/mL and 20 μg/mL stigmasterol were incubated with the BEAS-2B cell model for 48 h, and anti-inflammation and antioxidative stress were verified. Asthmatic mice were induced by OVA and received 100 mg/kg stigmasterol for 7 consecutive days. After 28 days, lung tissues and BAL fluid were collected for the following study. To further verify the role of NK1-R, 0.1 μM WIN62577 (NK1-R specific antagonist), and 1 μM recombinant human NK1-R protein were applied. RESULTS:NK1-R was the potential target of stigmasterol. When the concentration of stigmasterol is 20 μg/mL, the survival rate of BEAS-2B cells is about 98.4%, which is non-toxic. Stigmasterol exerted anti-inflammation and antioxidant stress in a dose-dependent manner and decreased NK1-R expression in IL-13-induced BEAS-2B. Meanwhile, assay also indicated the anti-inflammation and antioxidant stress of stigmasterol after OVA challenge. Stigmasterol inhibited inflammation infiltration and mucus hypersecretion, and NK1-R expression. DISCUSSION AND CONCLUSIONS:The protective effect of stigmaterol on asthma and its underlying mechanism have been discussed in depth, providing a theoretical basis and more possibilities for its treatment of asthma.
10.1080/13880209.2023.2173252
Stigmasterol inhibits lipopolysaccharide-induced innate immune responses in murine models.
Antwi Aaron O,Obiri David D,Osafo Newman,Forkuo Arnold D,Essel Leslie B
International immunopharmacology
Stigmasterol is a naturally occurring steroid alcohol which occurs in vegetables, soya and a large variety of medicinal plants. Stigmasterol and other phytosterols have been documented as immunomodulators with huge therapeutic potential. We assessed the mitigating effect of stigmasterol on non-fatal and fatal innate immune responses in murine models after intraperitoneal challenge with an endotoxin, lipopolysaccharide, LPS. The effect of stigmasterol on LPS-induced febrile response, inflammatory cell proliferation, multiple organ damage and mortality were respectively investigated. Pretreatment with stigmasterol 10, 50 and 100mg/kg reduced total LPS-induced fever response by 39.93±10.52%, 53.05±5.84% and 77.27±6.25% respectively. Neutrophil proliferation both in blood and recovered peritoneal fluid was significantly reversed by stigmasterol at 50 and 100mg/kg. Lung and liver histopathology showed stigmasterol effectively controlled organ damage. The lung inflammation score of 9.20±0.73 for the polyethylene glycol, PEG-treated disease control mice was reduced respectively to 6.50±0.54, 4.60±0.40 and 4.10±0.42 with 10, 50 and 100mg/kg of stigmasterol. Serum levels of liver enzyme markers, alanine transaminase, ALT and aspartate transaminase, AST were consistent with the observed histological changes. Stigmasterol at 50 and 100mg/kg significantly protected mice from LPS-induced mortality with 40% survival. Overall, stigmasterol inhibits LPS-induced innate immune responses in murine models.
10.1016/j.intimp.2017.10.018
Coadministration of Stigmasterol and Dexamethasone (STIG+DEX) Modulates Steroid-Resistant Asthma.
Mediators of inflammation
Airway inflammation in asthma is managed with anti-inflammatory steroids such as dexamethasone (DEX). However, about 20% of asthmatics do not respond to this therapy and are classified as steroid-resistant. Currently, no effective therapy is available for steroid-resistant asthma. This work therefore evaluated the effect of a plant sterol, stigmasterol (STIG), and stigmasterol-dexamethasone combination (STIG+DEX) in LPS-ovalbumin-induced steroid-resistant asthma in Guinea pigs. To do this, the effect of drugs on inflammatory features such as airway hyperreactivity and histopathology of lung tissue was evaluated. Additionally, the possible pathway of drug action was assessed by measuring events such neutrophil levels, oxidative and nitrative stress, and histone deacetylase 2 (HDAC2) and interleukin 17 (IL-17) levels. STIG alone did not affect inflammatory features, although it caused some changes in the molecular events associated with steroid-resistant asthma. However, STIG+DEX caused significant modulation of inflammatory features by protecting against destruction of lung tissue. The modulation of inflammatory features was associated with significant inhibition of neutrophilia and oxidative and nitrative stress, decrease in HDAC2, and increase in IL-17 levels that are usually associated with steroid-resistant asthma. Our findings show that although STIG and DEX individually do not protect against steroid-resistant asthma, their coadministration results in significant modulation of inflammatory features and the associated molecular events that lead to steroid-resistant asthma.
10.1155/2022/2222270
Stigmasterol Modulates Allergic Airway Inflammation in Guinea Pig Model of Ovalbumin-Induced Asthma.
Antwi Aaron Opoku,Obiri David Darko,Osafo Newman
Mediators of inflammation
We explored the potential benefits of stigmasterol in the treatment of asthma, an airway disorder characterized by immune pathophysiology and with an ever-increasing worldwide prevalence. We assessed the modulatory effect of the intraperitoneal administration of stigmasterol on experimentally induced airway inflammation in guinea pigs. The effect of stigmasterol on inflammatory cell proliferation, oxidative stress, lung histopathology, and remodeling was investigated. The results showed significant suppressive effects on ovalbumin-induced airway inflammatory damage. Stigmasterol at 10-100 mg/kg reduced proliferation of eosinophils, lymphocytes, and monocytes while reducing peribronchiolar, perivascular, and alveolar infiltration of inflammatory cells. Histopathology revealed stigmasterol maintained lung architecture and reversed collagen deposition, an index of lung remodeling. Overexpression of serum vascular cell adhesion molecule-1 (VCAM-1) and ovalbumin-specific immunoglobulin E (OVA sIgE) elicited by ovalbumin sensitization and challenge was significantly controlled with stigmasterol. Taken together, stigmasterol possessed significant antiasthmatic properties and had suppressive effects on key features of allergen-induced asthma.
10.1155/2017/2953930
β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling.
Zhou Bei-Xian,Li Jing,Liang Xiao-Li,Pan Xi-Ping,Hao Yan-Bing,Xie Pei-Fang,Jiang Hai-Ming,Yang Zi-Feng,Zhong Nan-Shan
Acta pharmacologica Sinica
β-Sitosterol (24-ethyl-5-cholestene-3-ol) is a common phytosterol Chinese medical plants that has been shown to possess antioxidant and anti-inflammatory activity. In this study we investigated the effects of β-sitosterol on influenza virus-induced inflammation and acute lung injury and the molecular mechanisms. We demonstrate that β-sitosterol (150-450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Moreover, β-sitosterol treatment attenuated RIG-I-mediated apoptotic injury of alveolar epithelial cells (AEC) via downregulation of pro-apoptotic factors. In a mouse model of influenza, pre-administration of β-sitosterol (50, 200 mg·kg·d, i.g., for 2 days) dose-dependently ameliorated IAV-mediated recruitment of pathogenic cytotoxic T cells and immune dysregulation. In addition, pre-administration of β-sitosterol protected mice from lethal IAV infection. Our data suggest that β-sitosterol blocks the immune response mediated by RIG-I signaling and deleterious IFN production, providing a potential benefit for the treatment of influenza.
10.1038/s41401-020-0403-9
Luteolin Inhibits Proliferation and Induces Apoptosis of Human Placental Choriocarcinoma Cells by Blocking the PI3K/AKT Pathway and Regulating Sterol Regulatory Element Binding Protein Activity.
Lim Whasun,Yang Changwon,Bazer Fuller W,Song Gwonhwa
Biology of reproduction
Luteolin is a natural compound known for its anticancer effects on various human cancers by regulating signal transduction cascades. However, the effects of luteolin on human placental choriocarcinoma are not known. Results of the present study revealed that luteolin decreased viability of JAR and JEG-3 cells, which are valuable placental models, in a dose-dependent manner, and it induced apoptosis and loss of mitochondrial membrane potential in JAR and JEG-3 cells. The results also suggested that the PI3K/AKT pathway was inhibited by luteolin treatment of JAR and JEG-3 cells in a dose- and time-dependent manner. Next, we established effects of luteolin in the presence of pharmacological inhibitors of PI3K/AKT, ERK1/2 MAPK, and mTOR on proliferation of JAR and JEG-3 cells. In addition, these inhibitors were used to verify phosphorylation of AKT, GSK3beta, and ERK1/2 and to confirm mechanisms regulated by luteolin in JAR and JEG-3 cells. We also determined levels of SREBP1 and SREBP2 expression to investigate regulatory functions of luteolin in lipid metabolism in JAR and JEG-3 cells. Expression levels of both SREBP1 and SREBP2 mRNAs were significantly reduced, but only SREBP1 protein was influenced by luteolin. We compared viability of JAR and JEG-3 cells in response to luteolin alone or in combination with other chemotherapeutic drugs (etoposide, cisplatin, and paclitaxel) and found that luteolin has synergistic effects with the conventional chemotherapeutic drugs as an anticancer agent. Collectively, these results showed that luteolin plays an important role in the treatment of human choriocarcinoma cells by inhibiting the PI3K/AKT/mTOR/SREBP cascade and expression of lipogenic genes.
10.1095/biolreprod.116.141556
Luteolin attenuates glucocorticoid-induced osteoporosis by regulating ERK/Lrp-5/GSK-3β signaling pathway in vivo and in vitro.
Jing Zheng,Wang Changyuan,Yang Qining,Wei Xuelian,Jin Yue,Meng Qiang,Liu Qi,Liu Zhihao,Ma Xiaodong,Liu Kexin,Sun Huijun,Liu Mozhen
Journal of cellular physiology
Glucocorticoid-induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase-3, caspase-9, and Bax protein expressions and increased Bcl-2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt-related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal-regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3β (GSK-3β) phosphorylation, mRNA expression levels of lipoprotein-receptor-related protein 5 (Lrp-5) and β-catenin. Further study revealed that Lrp-5 small interfering RNA (siRNA )and ERK-siRNA reduced the effects of LUT on GSK-3β phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK-siRNA decreased Lrp-5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp-5/GSK-3β pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.
10.1002/jcp.27252
Exploring the mechanism of luteolin by regulating microglia polarization based on network pharmacology and in vitro experiments.
Scientific reports
Neuroinflammation manifests following injury to the central nervous system (CNS) and M1/M2 polarization of microglia is closely associated with the development of this neuroinflammation. In this study, multiple databases were used to collect targets regarding luteolin and microglia polarization. After obtaining a common target, a protein-protein interaction (PPI) network was created and further analysis was performed to obtain the core network. Molecular docking of the core network with luteolin after gene enrichment analysis. In vitro experiments were used to examine the polarization of microglia and the expression of related target proteins. A total of 77 common targets were obtained, and the core network obtained by further analysis contained 38 proteins. GO and KEGG analyses revealed that luteolin affects microglia polarization in regulation of inflammatory response as well as the interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways. Through in vitro experiments, we confirmed that the use of luteolin reduced the expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, p-NFκBIA (p-IκB-α), p-NFκB p65, and MMP9, while upregulating the expression of Arg-1 and IL-10. This study reveals various potential mechanisms by which luteolin induces M2 polarization in microglia to inhibit the neuroinflammatory response.
10.1038/s41598-023-41101-9
Antimicrobial mechanism of luteolin against Staphylococcus aureus and Listeria monocytogenes and its antibiofilm properties.
Microbial pathogenesis
Luteolin (LUT) is a naturally occurring compound found in a various of plants. Few recent studies have reported LUT antimicrobial activities against bacterial pathogens, however, the fundamental LUT mediated antimicrobial mechanism has never been elucidated. This study aimed to investigate the antimicrobial activities of LUT and its mode of action against Staphylococcus aureus and Listeria monocytogenes, either as planktonic cells or as biofilms. Here, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of LUT against S. aureus and L. monocytogenes were determined using the broth microdilution method, and the antimicrobial mode of LUT was elucidated by evaluating the variations in both cell membrane integrity and cell morphology. Moreover, the biofilm inhibition was measured by crystal violet staining assay, while its qualitative imaging was achieved by confocal laser scanning microscope and field emission scanning electron microscope. MIC and MBC values of LUT against S. aureus were 16-32 and 32-64 μg/mL, and 32-64 and 64-128 μg/mL for L. monocytogenes. LUT destroyed the cell membrane integrity, as evidenced by a significant increase in the number of non-viable cells, and well-defined variations in cell morphology. Moreover, LUT presented robust inhibitory effects on the biofilm formation, enhanced antibiotics diffusion within biofilms and killed efficiently mono- and dual-species biofilm cells. Overall, LUT demonstrates potent antimicrobial properties on planktonic and biofilm cells, and the biofilm formation, and thus has the potential use as a natural food preservative in foods.
10.1016/j.micpath.2020.104056
Luteolin as a modulator of skin aging and inflammation.
Gendrisch Fabian,Esser Philipp R,Schempp Christoph M,Wölfle Ute
BioFactors (Oxford, England)
Luteolin belongs to the group of flavonoids and can be found in flowers, herbs, vegetables and spices. It plays an important role in defending plants, for example against UV radiation by partially absorbing UVA and UVB radiation. Thus, luteolin can also decrease adverse photobiological effects in the skin by acting as a first line of defense. Furthermore, anti-oxidative and anti-inflammatory activities of luteolin were described on keratinocytes and fibroblasts as well as on several immune cells (e.g., macrophages, mast cell, neutrophils, dendritic cells and T cells). Luteolin can suppress proinflammatory mediators (e.g., IL-1β, IL-6, IL-8, IL-17, IL-22, TNF-α and COX-2) and regulate various signaling pathway (e.g., the NF-κB, JAK-STAT as well as TLR signaling pathway). In this way, luteolin modulates many inflammatory processes of the skin. The present review summarizes the recent in vitro and in vivo research on luteolin in the field of skin aging and skin cancer, wound healing as well as inflammatory skin diseases, including psoriasis, contact dermatitis and atopic dermatitis. In conclusion, luteolin might be a promising molecule for the development of topic formulations and systemic agents against inflammatory skin diseases.
10.1002/biof.1699
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance.
Biochimica et biophysica acta
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis. Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf). Mutations also occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types (e.g., breast and prostate cancers). Importantly, this increased expression is associated with a poor prognosis. The Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of activated Akt to phosphorylate and inactivate different Rafs. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell lineage specific effects. For example, Raf/MEK/ERK is usually associated with proliferation and drug resistance of hematopoietic cells, while activation of the Raf/MEK/ERK cascade is suppressed in some prostate cancer cell lines which have mutations at PTEN and express high levels of activated Akt. Furthermore the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt pathways also interact with the p53 pathway. Some of these interactions can result in controlling the activity and subcellular localization of Bim, Bak, Bax, Puma and Noxa. Raf/MEK/ERK may promote cell cycle arrest in prostate cells and this may be regulated by p53 as restoration of wild-type p53 in p53 deficient prostate cancer cells results in their enhanced sensitivity to chemotherapeutic drugs and increased expression of Raf/MEK/ERK pathway. Thus in advanced prostate cancer, it may be advantageous to induce Raf/MEK/ERK expression to promote cell cycle arrest, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK induced proliferation and drug resistance. Thus the Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
10.1016/j.bbamcr.2006.10.001
Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.
Cell reports
EGFR mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFR mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFR and inducing the degradation of EGFR. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFR-harboring NSCLCs and delays the acquisition of the EGFR mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFR mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFR-driven TKI resistance by directly targeting G6PD.
10.1016/j.celrep.2023.113417
Virus-induced senescence is a driver and therapeutic target in COVID-19.
Nature
Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. ). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections.
10.1038/s41586-021-03995-1
Altered microRNA expression of nasal mucosa in long-term asthma and allergic rhinitis.
Suojalehto Hille,Lindström Irmeli,Majuri Marja-Leena,Mitts Camilla,Karjalainen Jouko,Wolff Henrik,Alenius Harri
International archives of allergy and immunology
BACKGROUND:Asthma and allergic rhinitis (AR) commonly coexist and can be taken as manifestations of one syndrome. Evidence exists that microRNAs (miRNAs) are important in controlling inflammatory processes and they are considered promising biomarkers. However, little is known about the differences in miRNA expression in patients with chronic allergic airway disease. This study evaluated the inflammatory and miRNA profiles of the nasal mucosa of patients with long-term asthma with and without AR. METHODS:We analyzed inflammatory cells, cytokines, and miRNAs in nasal biopsies and measured exhaled and nasal nitric oxide levels during the nonpollen season in 117 middle-aged men who had suffered mainly from allergic asthma for approximately 20 years and also in 33 healthy controls. RESULTS:The differences in the number of nasal eosinophils and cytokine expression levels were modest in nasal biopsies taken from asthmatics. Downregulation of miR-18a, miR-126, let-7e, miR-155, and miR-224 and upregulation of miR-498, miR-187, miR-874, miR-143, and miR-886-3p were observed in asthmatic patients in comparison to controls. The differences in miRNA expression were mainly similar in asthmatics with and without AR. With regard to asthma severity, a trend of increased miRNA expression in persistent asthma was seen, whereas the downregulation of certain miRNAs was most distinct in nonpersistent-asthma patients. CONCLUSIONS:Differences in miRNA expression in the nasal mucosa of subjects with long-term asthma and AR can be seen also when no markers of Th2-type inflammation are detected. Asthma severity had only a minor impact on miRNA expression.
10.1159/000358486
miR-21-5p Modulates Airway Inflammation and Epithelial-Mesenchymal Transition Processes in a Mouse Model of Combined Allergic Rhinitis and Asthma Syndrome.
International archives of allergy and immunology
INTRODUCTION:Combined allergic rhinitis and asthma syndrome (CARAS) is a concurrent allergic symptom of diseases of allergic rhinitis and asthma. However, the mechanism of CARAS remains unclear. The study aimed to investigate the impact of microRNA-21 (miR-21) on CARAS via targeting poly (ADP-ribose) polymerase-1 (PARP-1) and phosphoinositide 3-kinase (PI3K)/AKT pathways. METHODS:The levels of miR-21-5p and PARP-1 in CARAS patients were detected by quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). An ovalbumin-sensitized mouse model of CARAS was established. And knock down of miR-21-5p was constructed by intranasally administering with miR-21-5p shRNA-encoding adeno-associated virus vector. Airway resistance and airway inflammatory response were detected. ELISA was used to evaluate IL-4/IL-5/IL-13 levels in bronchoalveolar lavage fluid (BALF). Expression levels of E-cadherin, fibronectin, and α-SMA were determined using Western blotting. The levels of PARP-1 and the activation of PI3K/AKT were assayed. RESULTS:Downregulation of miR-21-5p relieved pathophysiological symptoms of asthma including airway hyperreactivity and inflammatory cell infiltration. Downregulation of miR-21-5p significantly reduced the levels of IL4, IL-5, and IL-13 in BALF. Additionally, downregulation of miR-21-5p inhibited the epithelial-mesenchymal transition (EMT) process in CARAS mice. Furthermore, miR-21-5p regulated PARP-1 and was involved in PI3K/AKT activation in CARAS mice. CONCLUSION:Downregulation of miR-21-5p ameliorated CARAS-associated lung injury by alleviating airway inflammation, inhibiting the EMT process, and regulating PARP-1/PI3K/AKT in a mouse model of CARAS.
10.1159/000538252
Exploration of the mechanism of aloin ameliorates of combined allergic rhinitis and asthma syndrome based on network pharmacology and experimental validation.
Frontiers in pharmacology
Aloin, as a bioactive compound, has a variety of pharmacological functions, but its effects on combined allergic rhinitis and asthma syndrome (CARAS) have not been studied. To clarify the protective effect and mechanism of aloin in the treatment of CARAS by network pharmacology, molecular dynamics simulation and experiment. The targets of aloin, allergic rhinitis and asthma were obtained from various databases. The protein interaction network was constructed for the common targets, and molecular docking and molecular dynamics simulations were performed for the core targets. Functional and pathway enrichment analysis of common targets was also performed using R software. Varieties of biological experiments were conducted to verify the effect of aloin on the inflammatory changes of CARAS and its regulatory mechanism. A total of 42 anti-allergic rhinitis and 58 anti-asthma targets were obtained, and 5 core anti-allergic rhinitis and 6 core anti-asthma targets were identified using topological analysis. GO and KEGG analyses showed that endopeptidase activity and MAPK signaling pathway played important roles in allergic rhinitis and asthma. Molecular docking and molecular dynamics simulations showed that aloin could stably bind to the core target proteins. Experimental verification showed that aloin significantly inhibited the expression of inflammatory factors, and may regulate CARAS by down-regulating MAPK signaling related proteins. This study identified the protective effect, potential target and mechanism of aloin on CARAS. It provides reference for understanding the molecular mechanism and clinical application of aloin in the ameliorates of CARAS.
10.3389/fphar.2023.1218030
[Professor -'s academic thought and clinical application of "no allergy without any deficiency"].
Xiong Jun,Chen Yan-Qi,Chen Ri-Xin
Zhongguo zhen jiu = Chinese acupuncture & moxibustion
The academic thought of professor - on "no allergy without any deficiency" was explored. Theory and the clinical application were elaborated on allergic diseases treated with heat-sensitive moxibustion. It is believed that the critical pathogenesis of allergic diseases is deficiency, particularly the deficiency of the lung, the spleen and the kidney. The invasion of exogenous factors or the disturbance of the retained pathogens in the body may induce allergy. Regarding the therapeutic method, the warming method is applicable for the deficiency and the heat-sensitization counteracts allergy. The sensitized points are detected in accordance with the two-step location method and they are stimulated with the suspended moxibustion. The feeling of heat-sensitive moxibustion is a sign of activation of endogenous regulatory function in the human body. It is a kind of external therapy for the internal disorders, directly acting on the pathogenesis, strengthening the antipathogenic and removing the allergic factors. This therapy is a new endogenous anti-allergic approach.
10.13703/j.0255-2930.20190720-k00024
Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms.
Pharmacology & therapeutics
COVID-19 has remained an uncontained, worldwide pandemic. While battling for the disease in China, six Traditional Chinese Medicine (TCM) recipes have been shown to be remarkably effective for treating patients with COVID-19. The present review discusses principles of TCM in curing infectious disease, and clinical evidence and mechanisms of the 6 most effective TCM recipes used in treating COVID-19 in 92% of all of the confirmed cases in China. Applications of TCM and specific recipes in the treatment of other viral infections, such as those caused by SARS-CoV, MERS-CoV, hepatitis B virus, hepatitis C virus, influenza A virus (including H1N1 and H7N9), influenza B, dengue virus as well as Ebola virus, are also discussed. Among the 6 TCM recipes, Jinhua Qinggan (JHQG) granules and Lianhua Qingwen (LHQW) capsules are recommended during medical observation; Lung Cleansing and Detoxifying Decoction (LCDD) is recommended for the treatment of both severe and non-severe patients; Xuanfeibaidu (XFBD) granules are recommended for treating moderate cases; while Huashibaidu (HSBD) and Xuebijing (XBJ) have been used in managing severe cases effectively. The common components and the active ingredients of the six TCM recipes have been summarized to reveal most promising drug candidates. The potential molecular mechanisms of the active ingredients in the six TCM recipes that target ACE2, 3CL and IL-6, revealed by molecular biological studies and/or network pharmacology prediction/molecular docking analysis/visualization analysis, are fully discussed. Therefore, further investigation of these TCM recipes may be of high translational value in enabling novel targeted therapies for COVID-19, potentially via purification and characterization of the active ingredients in the effective TCM recipes.
10.1016/j.pharmthera.2021.107843
Association Between Immune-Related Disease and Allergic Rhinitis: A Two-Sample Mendelian Randomization Study.
American journal of rhinology & allergy
BACKGROUND:Immune-related diseases can interact with each other, and growing evidence suggests that these diseases are associated with allergic rhinitis (AR). However, it is unclear whether previously observed associations reflect causal relationships. OBJECTIVE:This study estimated the genetic association between various immune-related diseases and AR using two-sample Mendelian randomization (MR). METHODS:Eight immune-related diseases were selected as exposure factors, and AR was selected as the outcome. The 8 immune-related disease categories included atopic dermatitis (AD), Graves' disease (GD), asthma, Crohn's disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ulcerative colitis (UC). Data from GWAS (Genome-Wide Association Studies) were selected to construct instrumental variables (IVs) for each disease, and multiple single-nucleotide polymorphisms (SNPs) were selected as IVs. Corresponding data were retrieved according to the selected SNPs, and all data were summarized and analyzed. RESULTS:A total of 416 SNPs were screened as IVs, and the results of IVW support a causal relationship between AR risk and AD (OR: 1.026, 95% CI: 1.014-1.038, = 9.59 × 10), asthma (OR: 1.057, 95% CI: 1.029-1.086, = .0001), and CD (OR: 1.006, 95% CI: 1.002-1.011, = .0085). Furthermore, GD (OR: 0.995, 95% CI: 0.991-0.999, = .0213) and SLE (OR: 0.997, 95% CI: 0.995-1.000, = .025) may be protective factors. CONCLUSION:This MR study found that AD, asthma and CD increase the risk of AR in populations of European ancestry, GD and SLE may be protective factors. These results suggest that confounding factors may have influenced associations previously reported in observational studies.
10.1177/19458924231207131
Multicenter Prospective Observational Study to Evaluate the Therapeutic Effect and Safety of a Combination of Montelukast and Levocetirizine for Allergic Rhinitis when Administered to Patients with Allergic Rhinitis and Asthma.
International archives of allergy and immunology
INTRODUCTION:Allergic rhinitis and asthma share a common inflammatory mechanism and are closely related, recognized as "one airway disease." Thus, the guidelines recommend allergic rhinitis and asthma be treated together, and leukotriene antagonists and antihistamines have been administered simultaneously; however, there are few reports of the use of combination drugs so far. METHODS:The aim of the study was to evaluate the treatment effects and adverse events of Monterizine® (a combination of montelukast and levocetirizine); a total of 2,254 patients with perennial allergic rhinitis and asthma were prospectively enrolled from 60 hospitals nationwide in Korea. They were followed up for 3 (Period 1) or 6 months (Period 2). Total nasal symptom score (TNSS), satisfaction, and safety data were collected and compared to baseline. RESULTS:TNSS scores were analyzed for 2,254 subjects. At Period 1 (n = 2,024) and 2 (n = 1,861), the scores decreased significantly from baseline (-1.20 ± 2.49 and -1.63 ± 2.78, p < 0.001). The mean quality of life (QoL) was significantly improved at Period 1 and 2 relative to baseline (-3.75 ± 6.58, -4.83 ± 7.11, both p < 0.0001). There were no serious adverse drug reactions, but there were some minor reactions including nasopharyngitis (2.92%), rhinitis (0.37%), and somnolence (0.34%). CONCLUSIONS:TNSS score and QoL were significantly improved by 3-6 months' treatment with Monterizine without significant adverse reactions. These results indicate that Monterizine, as a combination drug, is effective and safe for improving nasal symptoms and quality of life in patients with allergic rhinitis who also have asthma.
10.1159/000526094
The Cost-Effectiveness of Allergen Immunotherapy Compared with Pharmacotherapy for Treatment of Allergic Rhinitis and Asthma.
Cox Linda S,Murphey Andrew,Hankin Cheryl
Immunology and allergy clinics of North America
This article evaluates the cost-effectiveness of allergy immunotherapy (AIT) in the treatment of allergic rhinitis, asthma, and other allergic conditions. An extensive search of the PubMed and Medline databases (up to December 2018) was conducted. There is strong evidence in the collective literature, which included individual studies and systematic reviews, that AIT is cost-effective in the management of allergic rhinitis and asthma as compared with standard drug treatment alone. The magnitude of AIT's cost-effectiveness is likely underestimated because most of the studies considered during-treatment costs and not the long-term benefits or preventive or prophylactic effects of AIT.
10.1016/j.iac.2019.09.003
Allergic Rhinitis: Rapid Evidence Review.
American family physician
Allergic rhinitis, the fifth most common chronic disease in the United States, is an immunoglobulin E-mediated process. A family history of allergic rhinitis, asthma, or atopic dermatitis increases a patient's risk of being diagnosed with allergic rhinitis. People in the United States are commonly sensitized to grass, dust mites, and ragweed allergens. Dust mite-proof mattress covers do not prevent allergic rhinitis in children two years and younger. Diagnosis is clinical and based on history, physical examination, and at least one symptom of nasal congestion, runny or itchy nose, or sneezing. History should include whether the symptoms are seasonal or perennial, symptom triggers, and severity. Common examination findings are clear rhinorrhea, pale nasal mucosa, swollen nasal turbinates, watery eye discharge, conjunctival swelling, and allergic shiners (i.e., dark circles under the eyes). Serum or skin testing for specific allergens should be performed when there is inadequate response to empiric treatment, if diagnosis is uncertain, or to guide initiation or titration of therapy. Intranasal corticosteroids are first-line treatment for allergic rhinitis. Second-line therapies include antihistamines and leukotriene receptor antagonists and neither shows superiority. If allergy testing is performed, trigger-directed immunotherapy can be effectively delivered subcutaneously or sublingually. High-efficiency particulate air (HEPA) filters are not effective at decreasing allergy symptoms. Approximately 1 in 10 patients with allergic rhinitis will develop asthma.
Allergic rhinitis and asthma: epidemiology and common pathophysiology.
Khan David A
Allergy and asthma proceedings
Allergic rhinitis and asthma are common diseases that frequently occur together. This concept has been referred to in the literature as united airway disease. Epidemiological studies have shown that the majority of patients with asthma have concomitant rhinitis and the presence of rhinitis is an increased risk factor for development of asthma. Patients with asthma and rhinitis share common physiology including heightened bronchial hyperresponsiveness and heightened reactivity to a variety of stimuli. Immunopathology of allergic rhinitis is also similar with the predominance of T-helper type 2 inflammation and tissue eosinophilia. Although several mechanisms have been proposed to explain the united airway theory, some of the best lines of evidence suggest that local airway inflammation can result in a systemic inflammatory response. Pharmacotherapeutic studies have shown that the treatment of rhinitis can improve asthma and vice versa. Nevertheless, systemic approaches such as immunotherapy lead to better outcomes for treating both disease states simultaneously. This article will focus on the data supporting the common epidemiology, shared pathophysiology, and therapeutic interventions aimed at allergic rhinitis and asthma as united airway diseases.
10.2500/aap.2014.35.3794
Combined allergic rhinitis and asthma syndrome (CARAS).
Paiva Ferreira Laércia K D,Paiva Ferreira Larissa A M,Monteiro Talissa M,Bezerra Grasiela Costa,Bernardo Larissa Rodrigues,Piuvezam Marcia Regina
International immunopharmacology
Combined allergic rhinitis and asthma syndrome (CARAS) is a concept of "one airway - one disease" or "unified airway disease ". The upper and lower airway inflammation characterizes allergic rhinitis and asthma, respectively and both diseases have shown an intimate connection in their genesis, coexistence and similarities as triggered by the same etiological agents; the same inflammatory cell profile and share therapeutic treatment. This review highlights the concept of CARAS by its phenotype, endotype and biomarker classification. Indeed, rhinitis is divided into four major phenotypes: allergic rhinitis; infectious rhinitis; non-infective/non-allergic rhinitis and mixed rhinitis. On the other hand, asthma has no common consensus yet; however, the most accepted classification is based on the stage of life (early- or late- onset asthma) in which the clinical symptoms are presented. Experimental researches where animals develop a syndrome similar to CARAS have been contributed to better understand the pathogenesis of the syndrome. Therefore, the aim of this review is to clarify current terms related to CARAS as definition, phenotypes, endotypes/biomarkers, physiopathology and treatments.
10.1016/j.intimp.2019.105718
[Integrated traditional Chinese and western medicine expert consensus on the diagnosis and treatment of combined allergic rhinitis and asthma syndrome].
Zhonghua yi xue za zhi
Combined allergic rhinitis and asthma syndrome (CARAS) refers to a common respiratory disease that occurs simultaneously with clinical or subclinical allergic symptoms of the upper respiratory tract (allergic rhinitis) and the lower respiratory tract (asthma). The incidence of CARAS is high and the quality of life of the patients is greatly affected. At present, treatment of this comprehensive disease is often carried out separately in the otorhinolaryngology and respiratory departments. One of the reasons is a lack of coordinated treatment consensus on the comprehensive management of this disease. As a common respiratory disease, this syndrome also has a profound clinical basis of traditional Chinese medicine in its diagnosis and treatment. Therefore, the Allergy Committee of Chinese Association of Integrative Medicine organized domestic experts in respiratory medicine, otolaryngology, allergy, pediatrics, traditional Chinese Medicine internal medicine and other related fields to discuss and summarize the etiology and anatomical characteristics, pathophysiology and pathogenesis, laboratory examination, diagnostic evaluation and differential diagnosis as well as treatment of both traditional Chinese medicine and western medicine, in order to provide integrated diagnosis and treatment opinions for this common integrative disease of upper and lower respiratory system in clinical practice.
10.3760/cma.j.cn112137-20231123-01176