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关键词： IL-1β   Immunosuppressive microenvironment   MDSCs   SAA1   Toll-like receptor  

摘要： Background: Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood. Methods: We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models. Results: MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival. Conclusion: This study uncovers a novel SAA1–IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor–immune interactions and suggest a potential biomarker and therapeutic target for EOC. © The Author(s) 2025.

摘要： Anecdotal evidence has suggested an association between psychiatric drugs and psoriasis, but consensus is absent due to contradicting reports, and the mechanism remains poorly defined. Here, we investigate the function of serotonin 2A receptor (HTR2A), a receptor commonly targeted by psychiatric drugs, in regulating psoriasis. HTR2A antagonistic drugs worsen psoriatic outcome, and HTR2A modulation reduces psoriatic inflammation. Using the Imiquimod-induced psoriasiform model, HTR2A-deficient mice manifest exacerbated inflammation. Hematopoietic cells, particularly monocyte-derived Langerhans cells (moLC), are involved in this phenotype. Mechanistically, the exacerbated inflammation is due to increased interleukin-23 (IL-23) secretion, and HTR2A suppresses this by inhibiting activation of the non-canonical NFκB pathway. Serotonin is the putative agonist modulating HTR2A, attenuating psoriatic inflammation. Lastly, our findings in mice are also validated clinically. Our data demonstrate that serotonin modulates HTR2A, attenuating psoriatic inflammation by suppressing IL-23 secretion via inhibiting the non-canonical NFκB pathway in moLCs. © The Author(s) 2025.

关键词： First-line standard therapy   IL-2R   Metastatic colorectal cancer   Prognostic biomarkers   Survival outcomes   TNF-α  

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关键词： Endotoxemia   Equine   NSAIDs   TNF-α   Neutrophils   Meloxicam   Flunixin meglumine  

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关键词： Allopurinol   Drug hypersensitivity   HLA-B*58:01   Severe cutaneous adverse reaction  

摘要： Evidence on the prevalence of HLA-B*58:01 genotyping and its association with allopurinol-induced severe cutaneous adverse reactions (SCARs) is lacking, especially in low-resource settings. We addressed these gaps by conducting comprehensive and race/ethnic origin-specific evaluations. We conducted a systematic search from inception to 31 December 2022 using databases (PubMed, Embase, and medRxiv), Google (for Vietnamese articles), and manual searching. We included original studies that investigated the association between HLA-B*58:01 genotyping and allopurinol-induced SCARs. We excluded studies on: (1) animals;(2) pharmacokinetics/pharmacodynamics;(3) genetic markers or genetic testing methods;(4) single group;and (5) cost-effectiveness of screening. Risk of bias was assessed using Newcastle–Ottawa Scale. We used random-effects model to report the summary estimates and 95% confidence interval (95% CI) in the meta-analysis. We included 13,719 patients from 24 case–control studies. The prevalences of HLA-B*58:01 genotyping (overall 5.8%;95% CI 2.9% to 11.5%;I² = 98%) varied by races (Asian [7.7%;95% CI 3.4% to 16.8%;I² = 98%] and White in Eastern/Western Europe [2.3%;95% CI 1.2% to 4.3%;I² = 86%]) and ethnic origins (East and Central Asia [5.5%;95% CI 1.5% to 17.8%;I² = 98%] and South and Southeast Asia [12.9%;95% CI 9.5% to 17.3%;I² = 79%]). HLA-B*58:01 genotyping was associated with substantially increasing risk of allopurinol-induced SCARs (odds ratio 117.6;95% CI 70.3 to 196.8;I² = 45%) regardless of the subgroups. We found a higher prevalence of HLA-B*58:01 genotyping in some Asian populations compared with the Whites. There is evidence to confirm a strong association between this allele and allopurinol-induced SCARs. © The Author(s) 2025.

关键词： Dermatomyositis   Interleukin-41   Interstitial lung disease   Lactate dehydrogenase   Myopathy   Polymyositis  

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TNF promotes osteoclastogenesis by secreting miR-31-5p into small extracellular vesicles via the autotaxin–LPA–LPAR1 axis in arthritic fibroblast-like synoviocytes

Thanh Nam Phan Minju Gal Okhwa Kim Hoang Long Le Cheol Hwangbo Jeong-Hyung Lee 

Department of Biochemistry  College of Natural Sciences Kangwon National University Chuncheon 24341 Republic of KoreaKangwon Institute of Inclusive Technology  Kangwon National University Chuncheon 24341 Republic of KoreaDivision of Applied Life Science (BK21 Four)  Division of Life Science College of Natural Sciences Gyeongsang National University Jinju 52828 Republic of Korea

来源 PubMed期刊 详细信息

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• PubMed期刊

关键词： Fibroblast-like synoviocytes   LATS2   Osteoclastogenesis   Small extracellular vesicles   miR-31-5p  

摘要：

Fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis of arthritis. However, the impact of small extracellular vesicles (sEVs) secreted by FLSs on osteoclastogenesis remains incompletely understood. In this study, we aimed to investigate the role of tumor necrosis factor (TNF)- and lysophosphatidic acid (LPA)-activated FLSs in sEV-mediated release of osteoclastogenic miRNAs and elucidate their functional contribution to osteoclastogenesis. Stimulation of SW982 cells with LPA or TNF significantly increased sEV secretion. TNF upregulated autotaxin expression and promoted sEV release; however, small interfering RNA (siRNA)-mediated knockdown (KD) of LPAR1 attenuated the increase in sEV release induced by the TNF–autotaxin–LPA axis. Notably, stimulation with TNF or LPA elevated syntenin-1 expression without altering its mRNA level. Furthermore, KD of the syntenin-1 gene (SDCBP) suppressed the LPA-induced increase in sEV release, indicating that syntenin-1 may mediate sEV secretion induced by the TNF–autotaxin–LPA–LPAR1 axis. sEVs derived from TNF- or LPA-treated SW982 cells stimulated osteoclastogenesis. We identified miR-31-5p as an osteoclastogenic miRNA enriched in sEVs. Expression levels of miR-31-5p in sEVs from TNF- and LPA-stimulated rheumatoid arthritis (RA) FLSs were significantly higher than in those from unstimulated RA FLSs. Treatment with a miR-31-5p mimic enhanced osteoclastogenesis by targeting large tumor suppressor kinase 2 (LATS2), whereas treatment with its inhibitor suppressed the sEV-mediated promotion of osteoclastogenesis. These findings reveal a mechanism by which TNF- and LPA-activated FLSs may facilitate sEV-mediated delivery of osteoclastogenic miRNAs, such as miR-31-5p, to osteoclast precursors, thereby contributing to osteoclast formation and bone destruction.

Impact of interaction between IL-21 gene variants and smoking status on susceptibility to rheumatoid arthritis

Lu, Xiang Xue, Yuan Yan, Shanle 

Department of Rheumatology and Immunology  The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital) No.9 Chongwen Road Industrial Park Jiangsu Province Suzhou 215123 ChinaDepartment of Rheumatology and Immunology  Shanxi Yuncheng Central Hospital Shanxi Province Yuncheng 044099 China

来源 PubMed期刊 Springer期刊 详细信息

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• PubMed期刊
• Springer期刊

关键词： Interaction   Interleukin-21   Rheumatoid arthritis   Single nucleotide polymorphisms   Smoking  

摘要： Background: In recent years, interleukin-21 (IL-21) has been found to be a key player in RA pathogenesis and progression, despite accumulating evidence on rheumatoid arthritis (RA) etiology, the precise contribution of IL-21 gene variants interacting with environmental exposures remains unexplored in population-based studies. Therefore, we performed this study to evaluate the impact of gene single nucleotide polymorphisms (SNPs) and their interaction with environment on RA risk. Methods: In this study, Genomic DNA was extracted from whole blood samples (Invitrogen PureLink™ Genomic DNA Mini Kit), and targeted genotyping of four SNPs (rs2055979, rs12508721, rs2221903 and rs907715) of IL-21 gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Genotypic relationship testing in this case-control study was performed by using SNPStats online software (https://***/), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The interaction combinations among four SNPs and environmental factors including smoking and alcohol drinking were screened using generalized multifactor dimensionality reduction (GMDR). Results: Logistic regression analysis showed that the risks of RA were significantly higher in carriers with rs2055979- CA genotype (OR = 1.63, 95% CI = 1.28–1.97), rs2055979-AA genotype (OR = 2.02, 95% CI = 1.47–2.59), rs2055979-AA + CA genotype (OR = 1.78, 95% CI = 1.32–2.26), compared to carriers with rs2055979-CC genotype. In allele genetic model, rs2055979-A was also associated with increased RA risk (OR = 1.72, 95% CI = 1.39–2.06). However, we did not find any significant association of rs2221903, rs907715 and rs12508721 with RA risk. The GMDR model found a statistically significant two locus model (P = 0.018), including rs2055979 and smoking, indicating that the interaction between rs2055979 and smoking was significantly associated with the risk of RA. Smokers with rs2055979-A

关键词： Apoptosis   Cytochrome c   Extrinsic pathway   Intrinsic pathway   TNF-α   Vitamin c  

摘要： This study investigates the effect of vitamin C on cytochrome c and TNF-α expression, representing intrinsic and extrinsic apoptotic pathways in B16-F10 melanoma cells. B16-F10 melanoma cells (ATCC^® CRL-6475™) were treated with vitamin C for 12 and 24 h. Expression of cytochrome c, TNF-α, caspase-3, and caspase-9 proteins was evaluated using in-cell western (ICW) assay. RT-qPCR was used to assess gene expression of Caspase-8, IL-6, PARP-γ, and TGF-β1. Morphological signs of cell death appeared within 12 h. A significant increase in cytochrome c expression at 3,000 µM concentrations of vitamin C was observed (p = 0.002), along with increases at 3,500 µM (p = 0.023), 4,000 µM (p = 0.0001), and 5,000 µM (p = 0.0001). Caspase-3 expression significantly increased at 3,000 µM (p = 0.012) and 5,000 µM (p = 0.048), while caspase-9 was not significant. TNF-α expression also increased significantly from 3,000 to 5,000 µM (all p < 0.01). Caspase-8 and PARP-γ mRNA levels were upregulated at 3,000 and 5,000 µM (p < 0.05). IL-6 and TGF-β1 changes further supported apoptosis activation. Vitamin C induces apoptosis in B16-F10 melanoma cells via intrinsic and extrinsic pathways, particularly at 3,000 and 5,000 µM concentrations, as shown by cytochrome c, TNF-α, and caspase-3 expression. © The Author(s) 2025.

关键词： Biobanking   Cytokine storage   Psychiatric patients   Biomarker   Cytokine stability - inflammation  

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