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关键词： clear cell renal cell carcinoma   histone deacetylase inhibitor   immunoproteasome   major histocompatibility complex class I   immune checkpoint inhibitor   low molecular mass polypeptide 2   anti-PD-1 antibody   OBP-801  

摘要： Background: Histone deacetylase (HDAC) inhibitors have been reported to exhibit immunomodulatory activities, including the upregulation of major histocompatibility complex class I (MHC class I). Although the immunoproteasome plays a pivotal role in MHC class I antigen presentation, its effect on immunotherapy for clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: This study assessed whether OBP-801, a novel HDAC inhibitor, affects the expression of immunoproteasome subunits and subsequently the MHC class-I-mediated anti-cancer immunity in ccRCC. We analyzed the data of 531 patients with ccRCC from the Cancer Genome Atlas Kidney Clear Cell Carcinoma database. We further evaluated the treatment efficacy of the combination of OBP-801 and anti-PD-1 in a ccRCC mouse model. Results: Low molecular mass polypeptide (LMP) 2 was correlated most positively with CD3E, CD8A, and CD8B expression and estimated CD8+ T cell number. In vitro studies showed that OBP-801 upregulated MHC class I presentation by inducing LMP2 expression in the ccRCC cell lines RENCA, 786-O, and Caki-1. In vivo studies in a syngeneic mouse model with subcutaneous implantation of RENCA cells showed that OBP-801 treatment increased the percentage of CD45+CD3e+ T cells in tumor-infiltrating lymphocytes. The combination of anti-PD-1 antibody and OBP-801 enhanced the anti-tumor effect, LMP2 protein expression, and MHC class I presentation in tumor cells. MHC class I presentation in the tumors of each mouse was positively correlated with the percentage of CD45+CD3e+ T cells. Conclusions: Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC.

摘要： This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA. Rheumatoid arthritis is a disease where the body's defense system wrongly attacks the joints, leading to swelling and pain. This research explores the role of neutrophil extracellular traps in RA. NETs are net-like structures released by a type of white blood cell to catch harmful germs

关键词： intermediate-ef fi cacy medication (eg   golimumab   ustekinumab   IBD   inflammatory bowel disease   IL   interleukin   IV   intravenous   JAK   Janus   tumor necrosis factor   UC   ulcerative colitis.  

摘要： Association (AGA) living guideline is intended to support practitioners in the pharmacological management of moderate-tosevere ulcerative colitis (UC). METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations on the pharmacological management of moderate-to-severe UC. RESULTS: The AGA guideline panel made 14 recommendations. In adult outpatients with moderate-to-severe UC, the AGA recommends the

关键词： Adjuvant-induced arthritis (AIA)   Inflammation   IL-17   Piperine   Albumin nanoparticles  

摘要： Aim: Rheumatoid arthritis (RA) is one of the most common chronic, inflammatory, autoimmune diseases affecting mainly the joints. Piperine (PIP), an alkaloid found in black pepper, has anti-inflammatory properties and its use in drug delivery systems such as nanoparticles might be a treatment for RA. This study aims to evaluate the possible anti-inflammatory and anti-arthritic effects of PIP and its use in albumin nanoparticles as a possible approach for the treatment of Adjuvant-induced arthritis (AIA) rats. Methods: PIP-loaded Bovine Serum Albumin nanoparticles (PIP-BSA NPs) were prepared using a desolvation method. AIA rats were given intraperitoneal injections of either 40 mg PIP or 131 mg PIP-BSA NPs every two days until day 28 when animals were sacrificed. Clinical score, histopathology, X-ray radiography, and serum levels of pro-inflammatory cytokines such as IL-1 beta, IL-17, and TNF-alpha were evaluated. Results: PIP and PIP-BSA NPs significantly reduced clinical scores, and alleviated inflammation within the joints. PIP was superior to PIP-BSA NPs for the alleviation of fibrin deposition and periosteal reactions while bone inflammation and erosion were less severe in the case of PIP-BSA NPs. Besides, both of the treatments suppressed serum levels of IL-17 in AIA rats (p = 0.003 and p = 0.02;respectively). Conclusions: PIP and PIP-BSA NPs effectively alleviate the severity of AIA and suppress inflammation. Due to the superiority of PIP in improving fibrin deposition and periosteal reactions and the efficacy of PIP-BSA NPs in suppressing bone inflammation and erosion, their simultaneous use might be investigated.

关键词： Rheumatoid arthritis   IL-17   Natural herbal medicines   Fibroblast-like synoviocytes  

摘要： Rheumatoid arthritis (RA) is characterized by processive synovial hyperplasia and abnormal proliferation of fibroblast-like synoviocytes (FLSs), and can eventually lead to progressive joint destruction. Increasing evidence has demonstrated that cytokines play pivotal roles in the pathogenesis of RA. In particular, the production of interleukin (IL)-17 by T helper 17 (Th17) cells is closely associated with the development of RA, and inhibition of IL-17/IL-17R could regulate the production of inflammatory factors by FLSs, which may be a feasible way to reduce inflammation and bone destruction in RA. Currently, accumulating evidence suggests that the utilization of natural herbal medicines is advantageous in the management of RA. In our present paper, a comprehensive reference search was conducted of the classic Materia Medica books, literature, online databases, academic search engines, and MS. or Ph. D theses. In conclusion, natural herbal medicines with antirheumatic activities that modulate FLSs by targeting IL-17/IL-17R were summarized. Furthermore, we also discuss the limitations and potential research directions for the future development of natural herbal medicines as candidate drugs for RA management in the clinic.

关键词： Psoriasis   IL-17   Plet1   N-Acetylglucosamine   Macrophages   Lymphocytes   Inflammation  

摘要： Psoriasis (Ps) is a chronic inflammatory disorder marked by skin plaque formation, driven by immune dysregulation and genetic factors. Despite the available treatments, incidence of Ps is increasing in the dermatology patients. Novel strategies are crucial due to current treatment limitations. The interleukin 17 (IL-17) pathway is pivotal in Ps pathogenesis, however the expression of its putative target gene placenta expressed transcript 1 (Plet1) remains unstudied in Ps. Considering the potential anti-inflammatory properties of N-Acetylglucosamine (GlcNAc), our study explored its role in modulating Plet1 expression in an imiquimod (IMQ)-induced Ps mouse model. Our data demonstarted a significant reduction of inflammation and Psoriasis Area and Severity Index (PASI) scores, downregulation of growth factors (GFs), IL-17 A, and MAPK expression after GlcNAc treatment. In addition, GlcNAc treatment reduced neutrophils, monocyte-dendritic cells (Mo-DC) and conventional T cells (Tcons) while increasing monocyte-macrophages (Mo-Macs) and regulatory T cells (Tregs). GlcNAc treatment also downregulated Plet1 overexpression in psoriatic mouse skin and in vitro, reduced proliferation and apoptosis in IL-17 A stimulated human dermal fibroblasts (HDF), along with IL-17 A and TGF-beta mRNA expression. Together, these data suggest that, GlcNAc interferes with downstream mechanisms in IL-17 pathway and downregulating Plet1 expression, presenting a promising strategy for Ps treatment.

关键词： Anti-inflammatory   Quinazoline   Indoline   TNF-alpha   Molecular modeling  

摘要： Inflammation is central to numerous diseases, highlighting the need for new anti-inflammatory agents. This study explores the potential of novel spirofused indoline-quinazoline hybrids (4a-p) as anti-inflammatory compounds, inspired by a spiroisatin analogue (VI) that showed modest TNF-alpha inhibition. We aimed to enhance activity by modifying the isatin scaffold: first, introducing N-alkylation (propyl, butyl, or isobutyl) to improve hydrophobic interactions within the TNF-alpha dimer active site;second, adding halogens (F, Cl, Br) at the 5-position to increase lipophilicity. Anti-inflammatory activity against TNF-alpha was confirmed in-vivo for all synthesized analogues, with 4b, 4e, 4k, and 4n emerging as the top candidates. Further studies on these four compounds assessed their analgesic effects, as well as their impact on PGE2, NF-kappa B, paw thickness, and paw weight. In-vitro analyses revealed nanomolar TNFR2-TNF-alpha binding inhibition for the four leads. Safety evaluations included histopathology, ulcerogenic potential, kidney and liver functions, and acute hemotoxicity. In-silico studies examined drug-likeness, pharmacokinetics, and TNF-alpha dimer interactions. These results suggest that the four lead compounds possess promising profiles compared to standard therapies.

关键词： Inflammatory bowel disease   Gut   Inflammation   Colitis   SCFA  

摘要： Inflammatory bowel diseases (IBDs) are driven by an exaggerated inflammatory response, which leads to a marked increase in oxidative stress. This, in turn, exacerbates the inflammatory process and causes significant cellular and tissue damage. Intestinal dysbiosis, a common observation in IBD patients, alters the production of bacterial metabolites, including short-chain fatty acids (SCFAs), which are key by-products of dietary fiber fermentation. While the role of SCFAs in intestinal physiology is still being elucidated, this study aimed to investigate their effects on intestinal oxidative stress, particularly under inflammatory conditions induced by the proinflammatory mediator tumor necrosis factor alpha (TNF-alpha). The Caco-2/TC7 cell line was employed as an in vitro model of the intestinal epithelium, and the cells were treated with a range of SCFAs, including acetate, propionate, and butyrate. The levels of protein and lipid oxidation were quantified, as well as the activity of antioxidant enzymes. Our findings demonstrate that microbiota-derived SCFAs can effectively mitigate TNF-alpha-induced oxidative stress by modulating antioxidant enzyme activity. The proinflammatory mediator TNF-alpha induces lipid peroxidation by inhibiting catalase and glutathione peroxidase activities. SCFAs are able to upregulate antioxidant enzyme activity to restore lipid oxidative levels. These results underscore the critical role of the gut microbiota in maintaining intestinal homeostasis and highlight the therapeutic potential of SCFAs in managing oxidative stress-related pathologies.

关键词： HLA-C*12:419   HLA   next-generation sequencing   novel allele  

摘要： HLA-C*12:419 has a single nucleotide substitution at position 445 G>T when compared to the C*12:02:02:25 allele.

摘要： Human interferon (IFN) lambda (IFNL, IFN-L or IFN-R) R ) locus has several functional genetic variants but their role in regulating in vivo gene expression, and whether they associate with antiviral states in healthy individuals, is not clear. In this study, we recruited-550 healthy individuals belonging to both sexes, genotyped them for several IFNL genetic variants and measured, by qPCR, the expression of IFNL2/3, IFNL4 and four IFN-stimulated genes (ISGs) ( MX1, OAS1, ISG15 and RSAD2) ) from their peripheral blood mononuclear cells (PBMC) both before and after stimulation with a viral mimic, poly I: C. We also measured secreted levels of several cytokines including IFN-R1 R 1 and IFN-R3 R 3 in poly I:C stimulated PBMCs. We found that males secrete higher levels of IFN-Rs R s than females. The IFNL3/4 genetic variants significantly associated with secreted levels of both IFN-R1 R 1 and IFN-R3 R 3 in opposite directions, only in males. While the IFNL3/4 variants significantly associated with ISG expression either in basal or poly I:C induced or in both states, the direction of effect was opposite for the two sexes, suggesting that sex was a strong effect modifier. We did not see this trend in the association of ISG expression with the IFNL1 polymorphism, rs7247086, whose association with ISG expression and secreted IFN-R3 R 3 levels was seen in females but not in males. Further, expression of several genes was associated with the IFN-R4 R 4 activity-modifying variant rs117648444. However, we neither saw any strong correlation between levels of IFN-R1/3 R 1/3 and ISG expression, nor did we see any strong evidence of IFNL4 expression that could be responsible for the association between ISG expression and IFNL genetic variants. These results suggest that there are complex interactions involving gender, IFN-Rs, R s, IFN-R R genetic variants and antiviral states in humans.