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关键词： COVID-19   Genetic susceptibility   Single nucleotide polymorphisms   Cytokines   Interleukin-6   Mexico  

摘要： Background COVID-19 was the leading cause of death in Mexico between 2020 and 2021. SARS-CoV-2 infection varies widely among individuals and populations. Since variations in genes related to the immune response may play a role in the susceptibility to and outcome of COVID-19, the associations of gene polymorphisms (SNPs) of IL-6 (- 573G > C, rs1800796), TNF-alpha (- 308G > A, rs1800629), and IFN-gamma (- 1615 C > T, rs2069705) with the expression levels of these proteins in the nasopharynx and serum were evaluated in a Mexican population with mild, severe, or critical COVID-19. Methods A total of 560 COVID-19 patients (309 mild, 163 severe, and 88 critical cases) and 560 age- and sex-matched COVID-19-negative controls were recruited for this case-control study. The selected SNPs were genotyped via allelic discrimination. Logistic regression analysis was conducted considering four models of inheritance, and ORs were determined for each genotypic variant, adjusting for associated comorbidities in the multivariate model. The nasopharyngeal mRNA expression levels of IL-6, IFN-gamma and TNF-alpha were determined. The levels of IL-6, IFN-gamma, IFN-alpha 2, and TNF-alpha in the serum were quantified. Significant differences were assessed via the Wilcoxon Mann-Whitney U test. Results The C allele of the IL-6 - 573 SNP was associated with a greater risk of mild and severe COVID-19 (OR: 2.3, CI: 1.897-2.838, p = 0.0001;and OR: 1.5, CI: 1.167-1.949, p = 0.002, respectively), whereas the A allele of the TNF-alpha - 308 SNP and the T allele of the IFN-gamma - 1615 SNP were shown protective roles against severe COVID-19 (OR: 0.3, CI: 0.189-0.537, p = 0.0001;and OR: 0.7, CI: 0.563-1.006, p = 0.05) and against critical COVID-19 (OR: 0.3, CI: 0.158-0.640, p = 0.001;and OR: 0.4, CI: 0.290-0.678, p = 0.0001), adjusting for diabetes and hypertension. Nasopharyngeal IL-6 expression levels were lower in mild COVID-19 patients (p = 0.001) than in critical patients (p = 0.005). Serum IL-6

关键词： Acute severe ulcerative colitis   Anti-TNF   Colectomy   Infliximab  

关键词： Autoimmune disorders   AlphaFold protein modeling   fusion protein   IL-1 receptor antagonist   glycosylation,eukaryotic protein expression  

摘要： Introduction The extended IL-1 activity is implicated in autoimmune disorders, such as rheumatoid arthritis, diabetes mellitus, and Parkinson's disease, as well as delayed wound healing. Additionally, it can result in cytokine storms during pathogenic *** The regulation was carried out by Interleukin-1 receptor antagonist (IL-1RA), a key anti-inflammatory molecule. IL-1RA serves as a decoy protein that competes with Interleukin-1 receptors (IL-1RI and IL-1RII) for binding, effectively counteracting the activity of Interleukin-1 (IL-1). The deficiency was substantiated by commercially available recombinant IL-1RA called Anakinra. The main problem with the existing drug is that it has less pharmacokinetics and reduced binding affinity to its receptor, which requires frequent administration of the drug. To overcome these drawbacks, we have designed a new fusion protein by adding an Fc fragment of Human IgGI fused with IL-1RA using a linker in between, and the design aimed to transport the protein into the N-glycosylation pathway. These characteristic features increase the pharmacokinetics, solubility, and binding efficiency of the protein. As the protein was designed to be expressed in a eukaryotic system, to understand the possibility of the proposed hypothesis, we used machine learning-based AlphaFold2 to model the protein structure and molecular simulation studies to understand the functional integrity of the designed *** The in silico results showed that the modeled fusion protein structure has very good binding to its receptor with the support of 21 H bonds and 7 salt bridges and maintained the binding stability over the MD *** These findings support fusion protein's potential as a promising and stable therapeutic candidate.

关键词： Mesh-augmented surgery   Pelvic organ prolapse   PRP-DAS sandwich  

摘要： Introduction and Hypothesis Mesh-augmented surgery in urogynecology involves the use of surgical mesh to support and reinforce weakened pelvic tissue. Although it can be effective, there are potential complications, including mesh extrusion and dyspareunia related to excessive inflammatory response. One possible approach to preventing excessive inflammation and promoting mesh-tissue integration is to utilize a mesh sandwiched between two layers of platelet-rich plasma-decellularized amnion scaffold (PRP-DAS). Methods This experimental study was performed on 24 menopausal rabbit models. The treatment group consisted of a polypropylene (PP) mesh coated with PRP-DAS on both sides, whereas the control group included a PP mesh without PRP-DAS. Mesh-tissue integration was evaluated through macroscopic, histological, and immunohistochemical analyses. Macroscopic assessment focused on mesh extrusion and contraction, whereas histology and immunohistochemistry were done by assessing inflammatory response (inflammatory infiltrates [ININ] and interleukin-17 [IL-17] expression), neovascularization (angiogenesis score and cluster of differentiation 31/CD31 expression) and collagen deposition using image J on days 14, 28, and 90 following mesh implantation. Data were analyzed using one-way ANOVA followed by Tukey post hoc test. Results Results demonstrated that no mesh extrusion was found in either group;however, mesh contraction was significantly lower in the PRP-DAS group than in controls. On days 28 and 90, ININ was significantly lower (p < 0.01;p = 0.011) and IL-17 expression was markedly elevated (p < 0.01) in the PRP-DAS group compared with the controls. Moreover, collagen deposition was significantly higher (p < 0.01) in the PRP-DAS group by day 90. Conclusion The PRP-DAS sandwich prevents excessive inflammatory response and enhanced mesh-tissue integration in the menopausal rabbit model.

关键词： combination therapy   oncolytic adenovirus   TNF   TNFR2   tumor microenvironment  

摘要： Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.

关键词： IRF8   Common carp (Cyprinus carpio. L)   Poly I:C   Aeromonas hydrophila   IFN   NF-kappa B  

摘要： BackgroundInterferon (IFN) regulatory factors (IRF) are the crucial transcription factors for IFN expression and leading host cells response to viral infection. IRF8 in mammals plays vital roles in the innate and adaptive immune systems. In this study, we identified and characterized the common carp (Cyprinus carpio. L) IRF8 gene (ccIRF8) to further clarify the function of IRF8 in teleost fish. ResultsThe complete cDNA sequence of ccIRF8 was 1431 bp and encodes a polypeptide of 431 amino acids. Analysis of the putative amino acid sequence showed that ccIRF8 encodes structures typical of the IRF family, including a DNA-binding domain (DBD), an IRF-association domain (IAD) and two nuclear localization signals (NLS). Comparison with homologous proteins showed that the deduced protein has the highest sequence identity to grass carp IRF8 (92.7%). Phylogenetic analysis grouped ccIRF8 with other IRF8s of teleosts. Quantitative RT-PCR analysis showed that ccIRF8 transcripts were detectable in all investigated tissues of healthy fish with the highest level in spleen. Following poly I: C and Aeromonas hydrophila challenge, ccIRF8 transcripts were induced significantly in immune relevant tissues. In addition, ccIRF8 was induced by poly I: C and ipopolysaccharide (LPS), peptidoglycan (PGN) and flagellin in HKLs. Overexpression of ccIRF8 increased the expression of IFN and IFN-stimulated genes (ISGs), and a dual-luciferase reporter assay revealed that ccIRF8 decreased the activation of NF-kappa B though TRAF6. ConclusionsOverall, our findings provide a new perspective on the role of IRF8 in innate immunity in fish, as well as insights that will help the prevention and control of disease in the common carp farming industry.

关键词： lactic acid bacteria   interleukin-10   anti-inflammation   Toll-like receptor 2   macrophage inducible C-type lectin receptor   phagocytosis  

摘要： We showed that Lactiplantibacillus plantarum OLL2712 (OLL2712) strongly induces interleukin (IL)-10 production in immune cells. Although beneficialeffects of this strain have been observed in both mice and humans, the mechanisms underlying IL-10 induction remain unclear. In this study, we found that OLL2712 co-activates two pattern recognition receptors, leading to IL-10 production in the mouse-derived thermosensitive dendritic cell line, tsDC. We first revealed the involvement of the Toll-like receptor (TLR)2-Myeloid differentiation primary response gene (MYD) 88 pathway in OLL2712-induced IL-10 production in tsDCs. However, stimulation with the TLR2 agonist alone was insufficient to induce IL-10 production. Consequently, we explored additional signaling pathways and found that the phosphorylation of spleen tyrosine kinase (Syk) was important in response to OLL2712, which was not triggered by a TLR2 agonist alone. Notably, the activation of Syk was found to depend on macrophage-inducible C-type lectin receptor (Mincle), one of the C-type lectin receptors. However, the surface-expressed Mincle is not responsible for the IL-10 production by OLL2712. Instead, it depends on the incorporation of OLL2712 into tsDCs, suggesting that Mincle recognizes incorporated OLL2712 intracellularly. In summary, OLL2712 is initially recognized by TLR2, which subsequently induces the expression of Mincle to recognize incorporated OLL2712, ultimately inducing IL-10 production.

关键词： anemia of inflammation   iron deficiency   hepcidin regulation   erythropoietin (EPO)   Erythroferrone (ERFE)   Recessive Dystrophic Epidermolysis Bullosa (RDEB)   AI   anemia of inflammation   BSA   body surface area   CRP   C-Reactive protein   EBDASI   Epidermolysis Bullosa Disease Activity and Scarring Index   EPO   erythropoietin   ERFE   erythroferrone   FID   functional iron deficiency   HC   healthy controls   HULP   Hospital Universitario La Paz   ID   iron deficiency   IDA   iron deficiency anemia   IDWA   iron deficiency without anemia   IVFe   intravenous iron   NR   normal range   RDEB   Recessive Dystrophic Epidermolysis Bullosa   RIOL   Risk of iron overload   TNF   tumor necrosis factor   TSat   transferrin saturation index   WHO   World Health Organization  

摘要： Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis characterized by severe cutaneous and mucosal fragility, and frequently complicated by multifactorial chronic anemia that responds poorly to conventional therapies. This cross-sectional study investigates the factors contributing to anemia in RDEB by analyzing a representative cohort, that was stratified by disease severity, anemia and iron status, to examine their hematological parameters, cytokine profile and erythropoietin (EPO)-erythroferrone (ERFE)-hepcidin axis. Anemia was present in 50% of the cohort. Hemoglobin levels showed a strong negative correlation with the percentage of body surface area affected and C-reactive protein levels (CRP), identifying these as anemia risk factors in RDEB. Moderate-severe inflammation (CRP≥15mg/L) was observed in all anemics, but no specific cytokine profile was linked with anemia risk due to variability in IL6, IL1β, IL10, TNF, and IFN-γ levels. The regulation of the EPO-ERFE-hepcidin axis showed discrepancies with the patterns expected based on patients' anemia severity and iron status. According to reticulocyte production index, an inadequate bone marrow response was observed in 90% of anemics, irrespective of EPO levels. Patients with functional or true iron deficiency had higher ERFE levels, though ERFE showed no consistent correlation with EPO and was elevated in both anemic and non-anemic patients. Elevated hepcidin was primarily linked to the highest ferritin levels mostly in patients with a history of iron infusions and/or transfusions. These findings highlight the need for personalized, targeted approaches that address the complex interplay between inflammation and iron dysregulation, to improve anemia management in RDEB and other chronic inflammatory conditions.

关键词： Extracellular matrix   fibrosis   matrix metalloproteinases   pro-inflammatory cytokines   tissue remodeling  

摘要： Purpose To evaluate matrix metalloprotease-1 (MMP-1), matrix metalloprotease-3 (MMP-3), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) levels in the eyelid skin and fibroadipose tissue in patients with inactive moderate-to-severe Graves' orbitopathy (GO). Methods This prospective study included 23 patients with inactive moderate-to-severe GO who underwent upper blepharoplasty and medial fat excision, and 22 age- and sex-matched healthy subjects. MMP-1, MMP-3, TNF-alpha, and IL-6 levels in the skin and fibroadipose tissue obtained during surgery were measured using the ELISA method. Results The mean MMP-1 level in the eyelid skin (p = .003) and the mean MMP-3 level in the fibroadipose tissue (p = .04) were significantly lower in the GO group compared to the healthy control group. There were no differences in other mediators in both tissues between the two groups (p > .05). Conclusions The lower levels of proteolytic enzymes such as MMP-1 and MMP-3 in the eyelid skin and orbital fibroadipose tissue of patients with chronic inactive GO may play a role in the increase of collagen and glycosaminoglycans in orbital soft tissues.

关键词： SLE   Anifrolumab   Deucravacitinib   Daxdilimab   Litifilimab  

摘要： Introduction: Patients with Systemic Lupus Erythematosus (SLE) experience varied manifestations and unpredictable flares, complicating treatment and drug development. Despite these challenges, anifrolumab, voclosporin, and belimumab were approved by FDA. These treatments complement, but don't replace, traditional therapies like NSAIDs, corticosteroids, antimalarials, and immunosuppressives. Therefore, there remains an unmet need for more effective medications targeting excessive proinflammatory cytokines in SLE patients. Areas covered: This review summarizes the clinical trial outcomes of four upcoming medications targeting cytokine activity: Litifilimab showed a 7-point reduction in CLASI-A in its phase II trial. Daxdilimab was unsuccessful in its phase II trial. Anifrolumab reduced SLE activity in both phase II and III trials. Deucravacitinib decreased disease activity by multiple measures in its phase II trial. Expert opinion: High levels of IFN-I (type 1 interferon) are present in most SLE patients, making this pathway an attractive target for drug development. Litifilimab downregulates IFN-I by targeting BDCA2, while dexadilimab targets ILT7 to recruit effector cells, reducing IFN-I production by killing PDCs. Anifrolumab binds to the IFN-I receptor, blocking the activity of all IFN-Is, and deucravacitinib reduces IFN-I by inhibiting TYK2, thereby interfering with downstream signaling. Therapies that target IFN-I represents a promising class of medications for SLE patients.