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关键词： Molecular dynamics  

摘要： Tumor Necrosis Factor-alpha (TNF-α) is a key pro-inflammatory cytokine that plays a central role in the development and progression of several inflammatory and autoimmune disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Targeting TNF-α has become a crucial therapeutic strategy for managing these conditions. In this study, a virtual screening approach was employed to identify potential TNF-α inhibitors from an in-house natural compound library maintained at CSIR-IIIM, Jammu. Molecular docking analyses were performed to evaluate the binding affinities of these natural compounds to the TNF-α protein. The top-ranked compounds were further refined through a similarity search against known natural product TNF-α inhibitors to identify promising candidates. Based on molecular docking and similarity search analyses, 13 potential compounds were identified and subjected to in vitro validation. The experimental results confirmed that compounds IN00569 and IN00007 exhibited strong inhibitory activity by significantly reducing TNF-α secretion in LPS-stimulated RAW 264.7 macrophages, supporting their potential as lead anti-inflammatory agents. Molecular dynamics simulations and MM/GBSA analyses further validated the stability and binding potential of IN00007 and IN00569 with TNF-α, reinforcing their in vitro anti-inflammatory activity. These findings suggest that natural product-based inhibitors may serve as promising candidates for TNF-α-targeted drug development. © 2025 Elsevier B.V.

摘要： *** awaiting a solid organ transplant require pretransplant testing including high-resolution HLA typing and screening of HLA antibodies. However, the standard HLA antibody testing cannot encompass all the HLA alleles available in the Australian donor pool. With the advent of high-resolution HLA typing for organ allocation, there is an increased prevalence of detecting uncommon HLA alleles. It is challenging to manually determine whether patients have donor-specific HLA antibodies against these antigens. To address this issue, a bioinformatic pipeline, HLA-EP-RESOLVER, was developed to assess eplet reactivity for rare HLA unacceptable antigens (UAs).*** HLA-EP-RESOLVER pipeline was validated against sensitized patients, and a list of candidate UAs was identified for each patient. The candidate UAs must meet the following criteria: (1) match at the first field with existing UAs, (2) share eplets or serological types with the current UAs, (3) do not share the patient's self-eplets or eplets on negative beads, and/or (4) in the exception rules. The Australian deceased donor pool was used as the initial model. The predicted UAs were then confirmed with physical *** pipeline proved to be highly accurate at predicting high-risk antigens by utilizing eplet analysis through HLA Matchmaker, and the HLA data extracted from the Australian donor population. The reactivity of several candidate UAs were confirmed by cellular *** HLA-EP-RESOLVER program was shown to be rapid, useful, and highly accurate in determining acceptable or unacceptable HLA alleles in the new era of rapid high-resolution donor typing before allocation.

关键词： humans   hidradenitis suppurativa   psoriasis   psoriatic arthritis   inflammatory dermatoses   inflammatory bowel disease   Crohn's disease   ulcerative colitis   IL-17 inhibitors  

关键词： Interleukin-6 (IL-6)   Neutrophil extracellular traps (NETs)   T follicular helper (Tfh) cell   Toll-like receptor 9 (TLR9)  

摘要： ObjectiveAlthough neutrophil extracellular traps (NETs) are recognized as key contributors to rheumatoid arthritis (RA) progression, their immunomodulatory effects on T follicular helper (Tfh) cell differentiation remain enigmatic. Based on the effect of NETs on RA fibroblast-like synoviocytes (RA-FLSs), our study is aimed at investigating the effect of NETs on Tfh cell differentiation in ***, western blotting, and flow cytometry were used to investigate whether NETs mediated the inflammatory phenotype transformation of synovium fibroblasts to produce IL-6 and promote Tfh cell differentiation through TLR9/MyD88/NF-kappa B pathway. The expressions of Cit H3, MPO, TLR9, and Bcl-6 in the synovial tissues of the trauma control group and the RA group were analyzed by *** findings indicated that the plasma concentrations of IL-6 and MPO-DNA in RA patients were positively correlated with the level of IL-21 in lymphocytes and the proportion of circulating T follicular helper cells in peripheral blood. Further analysis revealed that NETs mediate the release of IL-6 from RA-FLSs through the TLR9/MyD88/NF-kappa B pathway, thereby inducing the differentiation of CD4 + T cells into Tfh cells and promoting the development of adaptive immunity in *** study demonstrated that NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-kappa B pathway. Targeting TLR9 may be a potential target for the treatment of RA. Key Points center dot NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-kappa B *** dot Targeting TLR9 may be a potential target for the treatment of RA.

关键词： Inflammatory signaling   oxidative stress signaling   immune signaling   myocardial cell injury   elderly  

摘要： Introduction The mutual activations of multiple signaling pathways are the key factors in the development and progression of myocardial cell injuries. Objective This research aimed to compare the different degrees of myocardial injury after coronary stenting, permanent pacemaker implantations, or cardiac radiofrequency ablation and to investigate the effects of the mutual activation of TNF-alpha/NF-kappa B, TLR2/TLR4, and ROS/MDA signaling pathways on myocardial injury in elderly patients after coronary stents or permanent pacemakers or radiofrequency ablation. Methods We determined reactive oxygen species (ROS), malondialdehyde (MDA), toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha) and high-sensitive cardiac troponin T (hs-cTnT) as a marker of myocardial injury in patients. Results The levels of ROS, MDA, TLR2, TLR4, NF-kappa B, TNF-alpha, and hs-cTnT were increased in patients with permanent pacemaker implantations when compared to patients with cardiac radiofrequency ablation (P < 0.01) at 6 months and were further increased in patients with coronary stenting compared to patients with cardiac radiofrequency ablation and permanent pacemaker implantations at 6 months, respectively (P < 0.01). This research confirmed that ROS, MDA, TLR2, TLR4, NF-kappa B, and TNF-alpha predicted myocardial injury severity. Conclusion Oxidative stress (ROS/MDA signaling pathway) may be linked to immune response (TLR2/TLR4 signaling pathway) and pro-inflammatory response (TNF-alpha/NF-kappa B signaling pathway) in myocardial injury, and ROS/MDA signaling may play a dominant role.

摘要： Background: Melanoma dedifferentiation has been viewed as state of resistance to therapeutics as cancer cells revert to a more primitive state. Previously, we showed that dedifferentiation is induced by IFN-γ via epigenetic remodeling and that pat...