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Magnoflorine alleviates dextran sulfate sodium-induced ulcerative colitis via inhibiting JAK2/STAT3 signaling pathway. Phytotherapy research : PTR Magnoflorine (Mag), a natural alkaloid component originating from the Ranunculaceae Juss. Family, has a various of pharmacological activities. This study aimed to investigate the therapeutic effects and potential mechanism of Mag on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) based on comprehensive approaches. Therapeutic effects of Mag on 3% DSS-induced UC mice were analyzed. UHPLC-Q-TOF/MS was performed to investigate the potential metabolites and signaling pathway of Mag on DSS-induced UC. Furthermore, the predicted mRNA and protein levels of JAK2/STAT3 signaling pathway in colon tissue were verified and assessed by qRT-PCR and Western Blotting, respectively. Therapeutic effects of Mag on UC mice were presented in down-regulation serum biochemical indices, alleviating histological damage of colon tissue. Serum untargeted metabolomics analysis showed that the potential mechanism of Mag on UC is mainly associated with the regulation of six biomarkers and 11 pathways, which may be responsible for the therapeutic efficacy of UC. The "component-metabolites-targets" interactive network indicated that Mag exerts its anti-UC effect by regulating PTGS1 and PTGS2, thereby regulating arachidonic acid. Moreover, the results of qRT-PCR showed that Mag could substantially decrease the relative mRNA expression level of Hub genes. In addition, it was found that Mag could inhibit the relative mRNA and protein expression of JAK2/STAT3 signaling pathway. The present results highlighted the role of Mag ameliorated colon injury in DSS-induced UC mice by inhibiting the JAK2/STAT3 signaling pathway. These results suggest that Mag may be an effective agent for the treatment of UC. 10.1002/ptr.8271
Artemvulactone E isolated from L. ameliorates lipopolysaccharide-induced inflammation in both RAW264.7 and zebrafish model. Frontiers in pharmacology Introduction:Natural plants are valuable resources for exploring new bioactive compounds. L. is a traditional Chinese medicinal herb that has been historically used for treating multiple diseases. Active compounds isolated and extracted from L. typically possess immunomodulatory and anti-inflammatory properties. Artemvulactone E (AE) is a new sesquiterpene lactone isolated and extracted from L. with unclear biological activities. Methods:The immunoregulatory effects of AE on macrophages were assessed by ELISA, RT-qPCR, immunofluorescence, and western blot assay. The effect of AE on lipopolysaccharide (LPS) -relates signaling pathways was examined by western blot assay. In zebrafish models, the larvae were yolk-microinjected with LPS to establish inflammation model and the effect of AE was evaluated by determining the survival rate, heart rate, yolk sac edema size, neutrophils and macrophages infiltration of zebrafish. The interaction between AE and Toll-like receptor 4 (TLR4) was examined by molecular docking and dynamic stimulation. Results:AE reduced the expression and secretion of pro-inflammatory cytokines (TNF-α and IL-6), inflammatory mediators iNOS and COX-2, as well as decreases the production of intracellular NO and ROS in LPS-stimulated macrophages. In addition, AE exerted its anti-inflammatory effect synergistically by inhibiting MAPK/JAK/STAT3-NF-κB signaling pathways. Furthermore, AE enhanced the survival rate and attenuated inflammatory response in zebrafish embryos treated with LPS. Finally, the molecular dynamics results indicate that AE forms stable complexes with LPS receptor TLR4 through the Ser127 residue, thus completely impairing the subsequent activation of MAPK-NF-κB signaling. Conclusion:AE exhibits notable anti-inflammatory activity and represents as a potential agent for treating inflammation-associated diseases. 10.3389/fphar.2024.1415352
Isolation and anti-neuroinflammation activity of sesquiterpenoids from Artemisia argyi: computational simulation and experimental verification. BMC complementary medicine and therapies BACKGROUND:Artemisia argyi is a traditional herbal medicine belonging to the genus Artemisia that plays an important role in suppressing inflammation. However, the chemical constituents and underlying mechanisms of its therapeutic potential in neuroinflammation are still incompletely understood, and warrant further investigation. METHODS:Several column chromatography were employed to isolate and purify chemical constituents from Artemisia argyi, and modern spectroscopy techniques were used to elucidate their chemical structures. The screening of monomeric compounds with nitric oxide inhibition led to the identification of the most effective bioactive compound, which was subsequently confirmed for its anti-inflammatory capability through qRT‒PCR. Predictions of compound-target interactions were made using the PharmMapper webserver and the TargetNet database, and an integrative protein-protein interaction network was constructed by intersecting the predicted targets with neuroinflammation-related targets. Topological analysis was performed to identify core targets, and molecular docking and molecular dynamics simulations were utilized to validate the findings. The result of the molecular simulations was experimentally validated through drug affinity responsive target stability (DARTS) and Western blot experiments. RESULTS:Seventeen sesquiterpenoids, including fifteen known sesquiterpenoids and two newly discovered guaiane-type sesquiterpenoids (argyinolide S and argyinolide T) were isolated from Artemisia argyi. Bioactivity screening revealed that argyinolide S (AS) possessed the most potent anti-inflammatory activity. However, argyinolide T (AT) showed weak anti-inflammatory activity, so AS was the target compound for further study. AS may regulate neuroinflammation through its modulation of eleven core targets: protein kinase B 1 (AKT1), epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein Kinase (FYN), Janus Kinase (JAK) 1, mitogen-activated protein (MAP) Kinase 1,8 and 14, matrix metalloproteinase 9 (MMP9), ras-related C3 botulinum toxin substrate 1 (RAC1), nuclear factor kappa-B p65 (RELA), and retinoid X receptor alpha (RXRA). Molecular dynamics simulations and DARTS experiments confirmed the stable binding of AS to JAK1, and Western blot experiments demonstrated the ability of AS to inhibit the phosphorylation of downstream Signal transducer and activator of transcription 3 (STAT3) mediated by JAK1. CONCLUSIONS:The sesquiterpenoid compounds isolated from Artemisia argyi, exhibit significant inhibitory effects on inflammation in C57BL/6 murine microglia cells (BV-2). Among these compounds, AS, a newly discovered guaiane-type sesquiterpenoid in Artemisia argyi, has been demonstrated to effectively inhibit the occurrence of neuroinflammation by targeting JAK1. 10.1186/s12906-024-04578-z
Therapeutic Efficacy of Quercetin and Its Nanoformulation Both the Mono- or Combination Therapies in the Management of Cancer: An Update with Molecular Mechanisms. Journal of tropical medicine Quercetin, a major representative of the flavonol subclass found abundantly in almost all edible vegetables and fruits, showed remarkable therapeutic properties and was beneficial in numerous degenerative diseases by preventing lipid peroxidation. Quercetin is beneficial in different diseases, such as atherosclerosis and chronic inflammation. This study aims to find out the anticancer activities of quercetin and to determine different mechanisms and pathways which are responsible for the anticancer effect. It also revealed the biopharmaceutical, toxicological characteristics, and clinical utilization of quercetin to evaluate its suitability for further investigations as a reliable anticancer drug. All of the relevant data concerning this compound with cancer was collected using different scientific search engines, including PubMed, Springer Link, Wiley Online, Web of Science, SciFinder, ScienceDirect, and Google Scholar. This review demonstrated that quercetin showed strong anticancer properties, including apoptosis, inhibition of cell proliferation, autophagy, cell cycle arrest, inhibition of angiogenesis, and inhibition of invasion and migration against various types of cancer. Findings also revealed that quercetin could significantly moderate and regulate different pathways, including PI3K/AKT-mTORC1 pathway, JAK/STAT signaling system, MAPK signaling pathway, MMP signaling pathway, NF-B pathway, and p-Camk2/p-DRP1 pathway. However, this study found that quercetin showed poor oral bioavailability due to reduced absorption; this limitation is overcome by applying nanotechnology (nanoformulation of quercetin). Moreover, different investigations revealed that quercetin expressed no toxic effect in the investigated subjects. Based on the view of these findings, it is demonstrated that quercetin might be considered a reliable chemotherapeutic drug candidate in the treatment of different cancers. However, more clinical studies are suggested to establish the proper therapeutic efficacy, safety, and human dose. 10.1155/2024/5594462
Gallic Acid Enhances the Efficacy of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia through Inhibition of Mitochondrial Respiration and Modulation of Oncogenic Signaling Pathways. International journal of molecular sciences While BCR::ABL1 tyrosine kinase inhibitors have transformed the treatment paradigm for chronic myeloid leukemia (CML), disease progression and treatment resistance due to BCR::ABL1-dependent and BCR::ABL1-independent mechanisms remain a therapeutic challenge. Natural compounds derived from plants have significantly contributed to cancer pharmacotherapy. This study investigated the efficacy of an active component of , a local medicinal plant, in CML. Using high-performance liquid chromatography-electrospray ionization-mass spectrometry, a chemical constituent from extract was isolated and identified as gallic acid. Commercially obtained gallic acid was used as a chemical standard. Gallic acid from inhibited proliferation and induced apoptosis in CML cell lines, as did the chemical standard. Furthermore, gallic acid induced apoptosis and decreased the colony formation of primary CML CD34 cells. The combination of isolated gallic acid or its chemical standard with BCR::ABL1 tyrosine kinase inhibitors resulted in a significantly greater inhibition of colony formation and cell growth compared to a single drug alone. Mechanistically, CML cells treated with gallic acid exhibited the disruption of multiple oncogenic pathways including ERK/MAPK, FLT3 and JAK/STAT, as well as impaired mitochondrial respiration. Rescue studies showed that gallic acid is significantly less effective in inducing apoptosis in mitochondrial respiration-deficient ρ cells compared to wildtype cells, suggesting that the action of gallic acid is largely through the inhibition of mitochondrial respiration. Our findings highlight the therapeutic potential of in CML and suggest that gallic acid may be a promising lead chemical constituent for further development for CML treatment. 10.3390/ijms25147958
Argel's stemmoside C as a novel natural remedy for mice with alcohol-induced gastric ulcer based on its molecular mechanistic pathways. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Solenostemma argel is widely distributed in Africa & Asia with traditional usage in alleviating abdominal colic, aches, & cramps. This plant is rich in phytochemicals, which must be explored for its pharmacological effects. PURPOSE:Peptic Ulcer Disease (PUD) is the digestion of the digestive tube. PUD not only interferes with food digestion & nutrient absorption, damages one of the largest defensive barriers against pathogenic micro-organisms, but also impedes drug absorption & bioavailability, rendering the oral route, the most convenient way, ineffective. Omeprazole, one of the indispensable cost-effective proton-pump inhibitors (PPIs) extensively prescribed to control PUD, is showing growing apprehensions toward multiple drug interactions & side effects. Hence, finding a natural alternative with Omeprazole-like activity & limited side effects is a medical concern. STUDY DESIGN:Therefore, we present Stemmoside C as a new gastroprotective phytochemical agent isolated from Solenostemma argel to be tested in upgrading doses against ethanol-induced gastric ulcers in mice compared to negative, positive, & reference Omeprazole groups. METHODS:We carried out in-depth pharmacological & histopathological studies to determine the possible mechanistic pathway. RESULTS:Our results showed that Stemmoside C protected the stomach against ethanol-induced gastric ulcers parallel to Omeprazole. Furthermore, the mechanistic studies revealed that Stemmoside C produced its effect using an orchestrated array of different mechanisms. Stemmoside C stimulates stomach defense by increasing COX-2, PGE-2, NO, & TFF-1 healing factors, IL-10 anti-inflammatory cytokine, & Nrf-2 & HO-1 anti-oxidant pathways. It also suppresses stomach ulceration by inhibiting leucocyte recruitment, especially neutrophils, leading to subsequent inhibition of NF-κBp65, TNF-α, IL-1β, & iNOS pro-inflammatory cytokines & JAK-1/STAT-3 inflammation-induced carcinogenicity cascade in addition to MMP-9 responsible for tissue degradation. CONCLUSION:These findings cast light on Stemmoside C's clinical application against gastric ulcer progression, recurrence, & tumorigenicity & concurrently with chemotherapy. 10.1016/j.jep.2024.117970
Echinacoside inhibits tumor immune evasion by downregulating inducible PD-L1 and reshaping tumor immune landscape in breast and colorectal cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Targeting PD-L1 has become a crucial approach in tumor immunotherapy. Echinacoside (ECH) is a natural compound known for its extensive biological activities, its impact on antitumor immunity remains uncertain. PURPOSE:This work was designed to assess the effects of ECH on the PD-L1/PD-1-mediated tumor immune evasion and its underlying mechanisms. METHODS:Flow cytometry and RT-qPCR were utilized to explore the influence of ECH on PD-L1 expression. Western blot was employed to examine the mechanism by which ECH might modulate PD-L1 expression. Flow cytometry was conducted to evaluate the influence of ECH therapy, or the synergistic effects of ECH combined with immune checkpoint blockade (ICB) on tumor immune microenvironment (TIME) in tumor-burden mice. Blood biochemistry tests were used to evaluate the safety of ECH treatment. RESULTS:ECH downregulated both the protein and mRNA expression levels of IFN-γ-induced PD-L1 through JAK/STAT1/IRF1 signaling pathway. ECH treatment upregulated the infiltration of IFN-γCD8 T cells and Ki-67CD8 T cells, lowered the frequency of TIM-3PD-1 T cells, promoted the infiltration of effector CD4 T cells and total CD8 T cells while suppressed the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Moreover, the combination of ECH and anti-PD-1 or anti-CTLA-4 therapy exhibited synergistic anti-tumor effects, reshaping TIME. Blood biochemistry tests unveiled that ECH did not show additional toxicity. CONCLUSION:ECH upregulates the expression of inducible PD-L1 through the JAK/STAT1/IRF1 signaling pathway, enhances T cell function, and reshapes the tumor immune landscape into an anti-tumor phenotype. Importantly, ECH markedly enhances the efficacy of ICB treatment, indicating its potential application in anti-tumor therapy. 10.1016/j.phymed.2024.156188
Alizarin attenuates oxidative stress-induced mitochondrial damage in vascular dementia rats by promoting TRPM2 ubiquitination and proteasomal degradation via Smurf2. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Alizarin (AZ) is a natural anthraquinone with anti-inflammatory and moderate antioxidant properties. PURPOSE:In this study, we characterized the role of AZ in a rat model of vascular dementia (VaD) and explored its underlying mechanisms. METHODS:VaD was induced by bilateral common carotid artery occlusion. RESULTS:We found that AZ attenuated oxidative stress and improved mitochondrial structure and function in VaD rats, which led to the improvement of their learning and memory function. Mechanistically, AZ reduced transient receptor potential melastatin 2 (TRPM2) expression and activation of the Janus-kinase and signal transducer activator of transcription (JAK-STAT) pathway in VaD rats. In particular, the reduction in the expression of TRPM2 channels was the key to the attenuation of the oxidative stress-induced mitochondrial damage, which may be achieved by increasing the expression of the E3 ubiquitin ligase, Smad-ubiquitination regulatory factor 2 (Smurf2); thereby increasing the ubiquitination and degradation levels of TRPM2. CONCLUSION:Our results suggest that AZ is an effective candidate drug for ameliorating VaD and provide new insights into the current clinical treatment of VaD. 10.1016/j.phymed.2024.156119
Inhibits Proliferation and Induces Apoptosis of Hepatocellular Carcinoma via JAK-STAT Pathway: A Preclinical Study. Biology Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. (), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of s effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that has promising anticancer activity and potential utility in liver cancer therapy. 10.3390/biology13070528
An insight into the anticancer potentials of lignan arctiin: A comprehensive review of molecular mechanisms. Heliyon Natural products are being developed as possible treatment options due to the rising prevalence of cancer and the harmful side effects of synthetic medications. Arctiin is a naturally occurring lignan found in numerous plants and exhibits different pharmacological activities, along with cancer. To elucidate the anticancer properties and underlying mechanisms of action, a comprehensive search of various electronic databases was conducted using appropriate keywords to identify relevant publications. The findings suggest that arctiin exhibits anticancer properties against tumor formation and various cancers such as cervical, myeloma, prostate, endothelial, gastric, and colon cancers in several preclinical pharmacological investigations. This naturally occurring compound exerts its anticancer effect through different cellular mechanisms, including mitochondrial dysfunction, cell cycle at different phases (G2/M), inhibition of cell proliferation, apoptotic cell death, and cytotoxic effects, as well as inhibition of migration and invasion of various malignant cells. Moreover, the study also revealed that, among the various cellular pathways, arctiin was shown to be more potent in terms of the PI3K/AKT and JAK/STAT signaling pathways. However, pharmacokinetic investigation indicated the compound's poor oral bioavailability. Because of these findings, arctiin might be considered a promising chemotherapeutic drug candidate. 10.1016/j.heliyon.2024.e32899
Chaetocin inhibits the progression of neuroblastoma by targeting JAK2/STAT3 signaling pathway in SH-SY5Y cells. Naunyn-Schmiedeberg's archives of pharmacology Chaetocin is a fungal mycotoxin that extensively found in various natural products and has anticancer and anti‑inflammatory activities. Herein, the anticancer effects of chaetocin against the progression of neuroblastoma were studied with SHSY-5Y human neuroblastoma cells and examined the underlying molecular mechanisms. The effects of chaetocin on cellular viability, apoptosis, cell migration, and invasion were investigated. The underlying mechanism of anticancer effects of chaetocin was found to mediate via activating JAK2/STAT3 signaling pathway. Furthermore, when SHSY-5Y cells were exposed to a higher concentration of chaetocin, the induction of cell apoptosis significantly increased by enhancing the expression of pro-apoptotic protein Bcl-2, resulting in anticancer activity against neuroblastoma. In addition, chaetocin significantly decreased the SHSY-5Y cell invasion and migration at 50 μM treatment. Moreover, it was shown that increasing chaetocin treatments greatly decreased the activity of proteins connected to the JAK2/STAT3 signaling pathway. In conclusion, chaetocin exhibits a diverse range of actions on neuroblastoma cells, including the inhibition of proliferation, induction of apoptosis, perturbation of cellular morphology, and modulation of critical signaling pathways, with a specific focus on the JAK/STAT3 pathway. These results contribute valuable insights that underscore the potential therapeutic utility of chaetocin in the context of neuroblastoma treatment, suggesting its multifaceted impact on key cellular processes involved in cancer progression. 10.1007/s00210-024-03426-8
Antiviral effect of palmatine against infectious bronchitis virus through regulation of NF-κB/IRF7/JAK-STAT signalling pathway and apoptosis. British poultry science 1. Infectious bronchitis virus (IBV), a gamma-coronavirus, can infect chickens of all ages and leads to an acute contact respiratory infection. This study evaluated the anti-viral activity of palmatine, a natural non-flavonoid alkaloid, against IBV in chicken embryo kidney (CEK) cells.2. The half toxic concentration (CC) of palmatine was 672.92 μM, the half inhibitory concentration (IC) of palmatine against IBV was 7.76 μM and the selection index (SI) was 86.74.3. Mode of action assay showed that palmatine was able to directly inactivate IBV and inhibited the adsorption, penetration and intracellular replication of IBV.4. Palmatine significantly upregulated , and compared with the IBV-infected group, leading to the increased expressions of pro-inflammatory cytokines and in the downstream NF-κB signalling pathway.5. Palmatine significantly up-regulated the levels of MDA5, MAVS, IRF7, IFN-α and IFN-β in the IRF7 pathway, inducing type I interferon production. It up-regulated the expression of 2'5'-oligoadenylate synthase (OAS) in the JAK-STAT pathway.6. IBV infection induced cell apoptosis and palmatine-treatment delayed the process of apoptosis by regulation of the expression of apoptosis-related genes (, , and ).7. Palmatine could exert anti-IBV activity through regulation of NF-κB/IRF7/JAK-STAT signalling pathways and apoptosis, providing a theoretical basis for the utilisation of palmatine to treat IBV infection. 10.1080/00071668.2023.2296929
A dicoumarol-graphene oxide quantum dot polymer inhibits porcine reproductive and respiratory syndrome virus through the JAK-STAT signaling pathway. Frontiers in microbiology Introduction:Porcine reproductive and respiratory syndrome virus (PRRSV) causes substantial economic losses in the global swine industry. The current vaccine options offer limited protection against PRRSV transmission, and there are no effective commercial antivirals available. Therefore, there is an urgent need to develop new antiviral strategies that slow global PRRSV transmission. Methods:In this study, we synthesized a dicoumarol-graphene oxide quantum dot (DIC-GQD) polymer with excellent biocompatibility. This polymer was synthesized via an electrostatic adsorption method using the natural drug DIC and GQDs as raw materials. Results:Our findings demonstrated that DIC exhibits high anti-PRRSV activity by inhibiting the PRRSV replication stage. The transcriptome sequencing analysis revealed that DIC treatment stimulates genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway. In porcine alveolar macrophages (PAMs), DIC-GQDs induce TYK2, JAK1, STAT1, and STAT2 phosphorylation, leading to the upregulation of JAK1, STAT1, STAT2, interferon-β (IFN-β) and interferon-stimulated genes (ISGs). Animal challenge experiments further confirmed that DIC-GQDs effectively alleviated clinical symptoms and pathological reactions in the lungs, spleen, and lymph nodes of PRRSV-infected pigs. Discussion:These findings suggest that DIC-GQDs significantly inhibits PRRSV proliferation by activating the JAK/STAT signalling pathway. Therefore, DIC-GQDs hold promise as an alternative treatment for PRRSV infection. 10.3389/fmicb.2024.1417404
Navel orange peel essential oil inhibits the growth and progression of triple negative breast cancer. BMC complementary medicine and therapies BACKGROUND:Triple Negative Breast Cancer (TNBC) is a particular type of breast cancer with the highest mortality rate. Essential oils are concerned more and more as potential anti-cancer drugs. METHODS:TNBC cells were treated with different concentrations of navel orange peel essential oil (NOPEO), and then a variety of  experiments were performed to investigate the changes in the growth and progression of TNBC cells. MTT assay was performed to detect the proliferation of TNBC cells. The changes of cell cycle and apoptosis were analyzed by FACS. In order to explored the migration of TNBC cells, scratch wound assay was carried out. Western blotting and qPCR were used to examine the expression of proteins and mRNA of related genes. Furthermore, RNA-seq was used to analyze the altered genes and explored the possible signal pathway. RESULTS:NOPEO demonstrated dose- and time-dependent suppression of TNBC cell growth. TNBC cells showed an increased percentage of G2/M-phase cells and the protein levels of CyclinB1 and CyclinD1 were decreased after NOPEO treatment. The apoptotic cells were increased in the NOPEO treated TNBC cells. The migration mobility was significantly inhibited by NOPEO. In total, 1376 genes were found to be up-regulated and 1335 genes were down-regulated after NOPEO treatment. According to KEGG and GO pathways, the differentially expressed genes were related to MAPK, Jak/stat and FoxQ signaling pathways. CONCLUSION:This investigation explored the bio-activity and molecular mechanisms of NOPEO against TNBC cells. These results indicated that NOPEO could suppress TNBC growth and migration perhaps via the MAPK and Jak/stat signaling pathways, which may provide theoretical reference for anticancer drug development. NOPEO may be a potential natural product for the chemotherapeutic of TNBC. 10.1186/s12906-024-04525-y
Wogonin suppresses proliferation, invasion and migration in gastric cancer cells via targeting the JAK-STAT3 pathway. Scientific reports Wogonin is a compound extracted from the medicinal plant Scutellaria baicalensis Geogi and has been found to exert antitumor activities in a variety of malignancies. However, the molecular mechanisms involved in the anti-gastric cancer (GC) effects of wogonin remain poorly understood. In the present study, we found that wogonin treatment inhibited the proliferation of GC cells, induced apoptosis and G0/G1 cell arrest, and suppressed the migration and invasion of SGC-7901 and BGC-823 cells in vitro. In addition, wogonin inhibited in vivo tumor growth in SGC-7901 xenograft mice. Transcriptomic analysis suggested that wogonin affected several signaling pathways closely related to tumor proliferation and metastasis, including the STAT3 signaling pathway. Further research indicated that wogonin may exert antitumor effects in GC cells by downregulating the JAK-STAT3 pathway. Altogether, our results demonstrate that wogonin exerts antitumor effects by perturbing JAK-STAT3 signaling in GC cells and that wogonin may be a potential therapeutic option for GC. 10.1038/s41598-024-81196-2
Bound polyphenols in insoluble dietary fiber of navel orange peel modulate LPS-induced intestinal-like co-culture inflammation through CSF2-mediated NF-κB/JAK-STAT pathway. Food & function Our laboratory previously extracted bound polyphenols (BPP) in insoluble dietary fiber from navel orange peel (NOP-IDF), and the aim of this study was to investigate the anti-inflammatory activity and potential molecular mechanisms of BPP by establishing an LPS-induced intestinal-like Caco-2/RAW264.7 co-culture inflammation model. The results demonstrated that BPP reduced the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as the production of pro-inflammatory cytokines, nitric oxide (NO), and reactive oxidative species (ROS) during the inflammatory damage process. Furthermore, BPP alleviated the lipopolysaccharides (LPS)-induced intestinal barrier damage by attenuating the decrease in -epithelial electrical resistance (TEER), diamine oxidase (DAO) activity, and intestinal alkaline phosphatase (IAP) activity, as well as the downregulation of ZO-1, Occludin, and Claudin-1 protein expression levels. RNA-seq results on RAW264.7 cells in the co-culture model showed that the NF-κB and JAK-STAT pathways belonged to the most significantly affected signaling pathways in the KEGG analysis, and western blot confirmed that they are essential for the role of BPP in intestinal inflammation. Additionally, overexpression of the granulocyte-macrophage colony-stimulating factor (CSF2) gene triggered abnormal activation of the NF-κB and JAK-STAT pathways and high-level expression of inflammatory factors, while BPP effectively improved this phenomenon. The above results suggested that BPP could inhibit intestinal inflammatory injury and protect intestinal barrier integrity through CSF2-mediated NF-κB and JAK-STAT pathways. 10.1039/d3fo05579e
Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway. Journal of medicinal chemistry Marine natural product (MNP) pretrichodermamide B (Pre B, ) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, ) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC value of 0.12 μM against HCT116. Notably, stood out with improved metabolic stability ( = 31 min) and more favorable oral bioavailability ( = 37.5%). Further studies indicated that blocked JAK/STAT3 signaling in dose- and time-dependent manner. , suppressed tumor growth (TGI = 65%) at a dose of 20 mg/kg in a HCT116-derived xenograft mouse model. Overall, might be a promising lead compound for colon cancer and is worthy of further investigation. 10.1021/acs.jmedchem.4c00278
Sokotrasterol Sulfate Suppresses IFN-γ-Induced PD-L1 Expression by Inhibiting JAK Activity. Journal of natural products PD-1/PD-L1 monoclonal antibodies exhibit promising therapeutic effectiveness in multiple cancers. However, developing a simple and efficient non-antibody treatment strategy using the PD-1/PD-L1 signaling pathway still remains challenging. In this study, we developed a flow cytometry assay to screen bioactive compounds with PD-L1 inhibitory activity. A total of 409 marine natural products were screened, and sokotrasterol sulfate (SKS) was found to efficiently suppress the IFN-γ-induced PD-L1 expression. SKS sensitizes the tumor cells to antigen-specific T-cell killing in the T cell-tumor cell coculture system. Mechanistically, SKS directly targeted Janus kinase (JAK) to inhibit the downstream activation of signal transducer and activator of transcription (STAT) and the subsequent transcription of . Our findings highlight the immunological role of SKS that may act as a basis for a potential immunotherapeutic agent. 10.1021/acs.jnatprod.3c00811