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关键词： Psoriasis   Arthritis   Gut microbiota   Interleukin 17   Carbohydrate-Active enZymes  

摘要： Objectives: To explore the evolution of gut microbiota in taxonomy and function in PsA patients during IL-17i treatment. Methods: Twenty PsA patients treated with secukizumab were included. Fecal samples were collected before treatment (0 mo.), first month (1 mo.) and third month (3 mo.) after treatment, and a total of 60 samples were collected. Shotgun metagenomic sequencing was used to detect all fecal samples. Results: In the 1 mo. and 3 mo. after IL-17i treatment, the disease activity in PsA patients decreased significantly. Compared with 0 mo., alpha-diversity calculated by Shannon index and Pielou index increased significantly at 1 mo. and 3 mo. after treatment. Microbial genes encoding Carbohydrate-Active enZymes (CAZymes) tended to be upregulated after treatment. After treatment, Bacteroidota phylum expanded, especially the abundance of Phocaeicola genus increased gradually with the treatment time (P < 0.05). The abundance of Phocaeicola genus was positively correlated with the alpha-diversity. The Polysaccharide Lyases and Carbohydrate Esterases in CAZymes were significantly positively correlated with most of species in Phocaeicola genus. Conclusions: Treatment with IL-17i induces gut microbiota evolution in PsA patients. The key features of this evolution include increased alpha-diversity, expansion of the Phocaeicola genus, and upregulation of CAZymes. Species within the Phocaeicola genus may be the critical bacteria driving this evolution. (c) 2025 Socioto Franoaise de Rhumatologie. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： NLRC3   RIP2   TRAF6   STING   TBK1   Large yellow croaker  

摘要： As a member of the NLRs family, NLRC3 has been determined to function in the NF-kappa B, MAPK, and type I IFN signaling, which are crucial for the host innate immunity and inflammatory response. In this study, an NLRC3 ortholog, named as Lc-NLRC3, was cloned and identified in large yellow croaker (Larimichthys crocea). The gene characteristics analysis revealed that Lc-NLRC3 consists of 18 exons and 17 introns, with a full-length open reading frame (ORF) of 3405 bp, encoding a protein of 1134 amino acids (aa), that containing a N-terminal CARD domain, a central NACHT domain, and a C-terminal LRRs domain. It was shown that Lc-NLRC3 is predominantly found in the cytosol, and was widely distributed across various tissues/organs, with the highest expression detected in the intestine, and could be induced by poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulation. Importantly, Lc-NLRC3 overexpression significantly activate NF-kappa B, TNF alpha, IL-1 beta, IRF3, IRF7, and IFN1 promoters, whereas when co-expressed with RIP2, STING, or TBK1, it down-regulated those promoter activation compared to their individual overexpression alone, thereby suppressing downstream antiviral and inflammatory gene expression. Interestingly, Lc-NLRC3 associated with TRAF6 in IRF3/IRF7 promoter activation, and enhanced the expression of IRF7, Mx, ISG15, and TNF-alpha. Co-immunoprecipitation assays also confirmed interactions of Lc-NLRC3 with RIP2, STING, TBK1, and TRAF6. The above results imply that Lc-NLRC3 is an important regulator in RIP2, STING, TBK1, and TRAF6 mediated type I IFN signaling and inflammatory response.

关键词： SARS-CoV-2   Human leukocyte antigen   HLA evolutionary divergence  

摘要： Immunogenetic factors such as human leukocyte antigen (HLA) alleles, have yielded contrasting associations with protection or increased chances of hospitalization due to COVID-19 worldwide. This case-control study included 834 patients with confirmed COVID-19 diagnosis from five Brazilian states: Ceara (n = 110), Mato Grosso (n = 192), Para (n = 209), Rio de Janeiro (n = 211) and Rio Grande do Sul (n = 112). Genotyping was performed using the AxiomTM Human Genotyping SARS-CoV-2 array, targeting single nucleotide polymorphisms in HLA class I and II genes;HLA alleles were imputed for eight loci. Among the 15 preselected candidate alleles, only DQA1*05:01 (p = 0.015) in the state of Ceara remained significantly associated with hospitalization. The meta-analysis of the most frequent alleles in all states revealed that HLA-DPA1*01:03 (p = 0.0229, OR = 0.76, Pathogenesis 95 % CI = 0.60-0.96) and HLA-DPB1*04:01 (p = 0.0474, OR = 0.78, 95 % CI = 0.611.00) were associated with protection against hospitalization, whereas HLA-DPA1*02:01 (p = 0.0259, OR = 1.37, 95 % CI = 1.04-1.80), HLA-DQA1*05:01 (p = 0.0133, OR = 1.40, 95 % CI = 1.07-1.82), and HLA-DRB1*03:01 (p = 0.0276, OR: 1.59, 95 % CI: 1.05-2.40) associated with increased risk of hospitalization. HLA evolutionary divergence (HED) scores were significantly higher among the non-hospitalized group for the HLA-A locus, which has been shown to be a protective factor for the most severe forms and consequently hospitalization due to COVID-19.

关键词： Mitochondrial uncoupling proteins 1   TLR4/NLRP3/IL-1 beta signaling pathway   Aortic dissection/aneurysms   Inflammation   Phenotype switching  

摘要： Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/ interleukin-1(3 (IL-1(3) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1(3 signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the (3-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1(3 signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/ IL-1(3 signaling pathway and VSMC phenotype switching.

关键词： Gene delivery   Genetically engineered cells   Cell-based delivery   Interleukin-6   Gene therapeutics   Anti-cytokine therapy   IL-6 trans-signaling  

摘要： Interleukin-6 (IL-6) is a highly pro-inflammatory cytokine involved in the etiopathology of several inflammatory diseases and cancer. As so, the inhibition of IL-6 signaling pathways has emerged as an attractive therapeutic avenue for the treatment of several chronic diseases. Since IL-6 trans-signaling was described as the pathological branch of IL-6, selective inhibitors were developed. Next-generation variants with increased trans-signaling specificity and potency emerged as great candidates for the treatment of several diseases, with reduced off-target effects. The highly time-consuming and costly processes involving recombinant protein production, however, have hampered the progress of anti-cytokine pharmaceuticals in clinic so far. Herein, we developed gene therapeutic modalities of IL-6-trans-signaling inhibitors as alternatives for sustained recombinant protein secretion. By using an IL-6-dependent lymphoma cell line and xenograft tumor model, we demonstrated the superior inhibitory potential of second-generation anti-IL-6 trans-signaling therapeutic. We compared the efficiency of distinct gene delivery modalities using a bioluminescent biomarker probe and observed consistent protein production via cell-based delivery. When delivered intratumorally, genetically engineered sgp130FlyRFc-secreting cells significantly reduced tumor burden and increased animal survival, representing a promising therapeutic avenue to be explored in clinically relevant gene delivery applications.

关键词： Ammonia detoxication   Functional amino acids   Gut health   Inflammatory cytokine   Microbiota   Nile tilapia fingerlings   Nutrigenomics  

摘要： This study aimed to evaluate the effects of dietary glutamine (Gln) and glutamic acid (Glu) blend on growth performance, plasmatic biochemical parameters, intestinal bacteriome composition, short-chain fatty acids (SCFAs) production, digestive enzyme activity, and histomorphometry of Nile tilapia fingerlings. The study also aimed to evaluate the effects of this blend on liver antioxidant status and gene expression of anti-inflammatory interleukin 10 (IL-10), pre-inflammatory interleukin 1 beta (IL-1 beta), glutamine synthetase (GS), and peroxisome proliferator-activated receptor alpha (PPAR-alpha). Fish (n = 408;1.0 +/- 0.0 g) were randomly distributed into eight aquaria (51 fish each) and fed micro-extruded diets either unsupplemented (CON) or supplemented with 20 g kg-1 of Gln and Glu (1:1) blend (AMG). Fish were hand-fed six times daily until apparent satiety for 30 days. Fish fed AMG diet showed higher body weight gain (+3.0 %) than those fed CON diet. Additionally, these fish exhibited a higher abundance of Staphylococcus saprophyticus, a SCFA-producing bacterium known for its probiotic-like potential in fish. Consequently, fish fed AMG diet exhibited higher intestinal butyric acid production and increased intestinal fold height relative to fish fed CON diet. The upregulation of PPAR-alpha and GS genes suggested that fish fed AMG diet exhibited improved energy metabolism and ammonia excretion, respectively. Furthermore, the upregulated expression of the anti-inflammatory cytokine IL-10 gene in fish fed AMG diet indicated enhanced immune responses. Fish fed AMG diet showed increased activity of superoxide dismutase and glutathione-S-transferase and decreased malondialdehyde concentration in the liver. Dietary supplementation with 20 g kg-1 of Gln plus Glu promoted fish growth and survival through beneficial modulation of the bacteriome, improving intestinal health and function, supporting nutrient absorption and metabolism, strengthening innate immunity, and red

关键词： Cytomegalovirus   HLA   Stem Cell Transplantation   Antigen Loand  

摘要： Among the complications occurring after allogeneic hematopoietic stem cell transplantation (HSCT), infection by human Cytomegalovirus (CMV) represents one of the most relevant in terms of morbidity/mortality and specific management is required by either monitoring viral load and administer anti-CMV therapies. Due to the physiological role of the Human Leucocyte Antigen (HLA) system in presenting foreign antigens to the adaptive immune system to enhance viral clearance, we measured here the HLA antigen load for two immunodominant CMV peptides and correlate with transplant outcome in 238 consecutive adult patients undergoing haploidentical HSCT at a single center. Interestingly, a higher class I antigen load (i.e. above the median) for protein IE1 correlated with an inferior absolute incidence of CMV infection;moreover, a statistically significant correlation with lower non-relapse mortality and higher overall survival was observed (HR: 0.32, 0.12-0.84, p = 0.02;0.34 (0.17-0.69, p = 0.003;respectively), with a protective effect in patients with high antigen load values. Despite additional research is needed, our exploratory data support the role of the HLA polymorphism on CMV infection and survival after HSCT. The introduction of CMV antigen load as a new potential predictive factor might contribute to further define the post-transplant risk on an individualised basis.

关键词： Chronic unpredictable mild stress   Depressed   Aerobic exercise   IL-33/ST2-MyD88   Inflammatory response  

摘要： Purpose: This study examined how aerobic exercise affect the IL-33/ST2-MyD88 signaling pathway in mice with chronic unpredictable mild stress (CUMS) induced depression Method: Thirty-six C57BL/6 mice were randomly assigned t three groups: a control group (CG), a model group (MG), and an exercise group (ME). We created a depression model using chronic unpredictable mild stress, after which the ME group underwent 8 weeks of aerobic training. After exercise intervention, neurobehavioral assessment was performed. ELISA was used to detect the levels of IL-33, IL-1(3 and IL-10 in the serum of mice. Toluidine blue Nissl staining was used to observe the structure of hippocampal neurons. Total RNA was extracted from blood samples using magnetic beads and from hippocampal tissue or neurons using Trizol. The levels of IL-33, ST2, MyD88, IL-1(3, IL-10 and NF-kappa B mRNA in mice were detected by RT-PCR Result: The number of lattice crossings and modification times were significantly reduced in MG group, the exercise time was significantly shortened, and the sugar and water preference index was significantly reduced, while the immobility time in forced swimming and tail suspension tests were significantly prolonged. The results indicated that CUMS successfully induced anhedonia and depression-like behaviors in the mice. In the ME group, there was a significant increase in the number of crossing lattices, modification times, exercise duration, and sugar and water preference index, while the immobility time in the forced swimming and tail suspension tests significantly decreased. Compared with the CG group, serum levels of inflammatory factors IL-33, IL-1(3, and NF kappa B significantly increased in the MG group, while these levels significantly decreased in the ME group. It decreased and IL-10 showed a very significant increase. Nissl staining results indicated that hippocampal nerve cells in MG group were sparsely arranged, with widened gaps, severe nucleus contraction, and shal