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关键词： H3K4me3   RIPK1   Serotonin   TG2   TNF  

摘要： The receptor interacting protein kinase 3 (RIPK3) is the main player in the activation of necroptosis, a pro-inflammatory regulated cell death modality induced by many different stimuli. RIPK3 is epigenetically regulated by DNA methylation and can be expressed when its promoter is associated with H3K4me3 histone. In this study, we show that Transglutaminase 2 protein (TG2) is necessary to induce necroptosis pathway allowing the expression of Ripk3 gene. Indeed, cells lacking TG2 show a strong downregulation of Ripk3 gene and are resistant to necroptotic stimuli. TG2 is known to promote the serotonylation of H3K4me3 histone (H3K4me3Q5ser) regulating in this way the target gene expression. Interestingly, we find that TG2 interacts with both histones H3K4me3 and H3K4me3Q5ser and these post-translational modifications are associated with the Ripk3 promoter only in presence of TG2. In addition, the absence of the H3K4me3Q5ser, in cells lacking TG2, is correlated with Ripk3 gene methylation. Altogether, these results indicate that RIPK3 expression requires TG2 mediated serotonylation of H3K4me3 to prevent Ripk3 promoter methylation, thus favouring its expression and necroptosis induction.

关键词： 5-aza-C   ADSCs   IL-6   Myoblast   STAT1  

摘要： BACKGROUND:Ectopic fat is also formed in muscles as well as the liver, where adipose-derived mesenchymal stem cells (ADSCs) promote adipogenesis. On the other hand, after muscle injury, muscle satellite cells (SCs) contribute to muscle repair through myodifferentiation. Human ADSCs are multipotent stem cells, but it remains unclear whether they are involved in myoblast differentiation. The aim is to find a novel myogenic cytokine and its signaling pathway that promotes the differentiation of human ADSCs-a potential source of new muscle precursor cells-into myoblasts. METHODS:An array kit was used to detect cytokines produced by ADSCs. After treating ADSCs with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-C) and different JAK inhibitors, MyHC1, a myodifferentiation marker, was detected by immunofluorescence staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression status of signaling molecules was determined by Western blotting and the recruitment of transcription factors to the MYOG promoter by chromatin immunoprecipitation (ChIP). RESULTS:IL-6 was detected at high concentrations in the culture supernatant of ADSCs. ADSCs stimulated with 5-aza-C became strongly positive for MyHC1 on day 21 post-stimulation. When co-stimulated with 5-aza-C and IL-6/sIL-6R, ADSCs became positive for MyHC1 protein and upregulated MYOG mRNA as early as day 14 post-stimulation. Co-stimulation with 5-aza-C and IL-6/sIL-6R resulted in phosphorylation of STAT1 and STAT3. The addition of a JAK2 inhibitor, but not JAK1/3 inhibitors, abolished the MyHC1 positivity and phosphorylation of STAT1 and STAT3. Co-stimulation with 5-aza-C and IL-6/sIL-6R during the myogenesis process resulted in the recruitment of STAT1, but not STAT3, to the MYOG promoter. Myoblast differentiation induced by stimulation with 5-aza-C was enhanced by activation of the IL-6/JAK2/STAT1/MYOG pathway. CONCLUSIONS:Therefore, sustained IL-6/JAK2/STAT1 activation

关键词： Flash nanocomplexation   Flash nanoprecipitation   TNF-alpha antibody   Sustained release   Hyaluronic acid hydrogel   Long-acting injectable   Inflammatory bowel disease   Chronic colitis  

摘要： Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-alpha mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-alpha LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.

关键词： Akkermansia muciniphila   Crohn’s disease   IL-6   STAT3   colitis  

摘要： BACKGROUND:Inflammatory bowel disease is a long-standing inflammatory disorder that influences the intestinal tract. The intent of this research is to explore whether the relative abundance of Akkermansia muciniphila is related to the IL6/STAT3 pathway and the fundamental molecular mechanisms of A. muciniphila on a trinitrobenzene sulfonic acid (TNBS)-induced enteritis mouse model, including the expression of inflammatory cytokines and proteins in the IL6/STAT3 signaling pathway. METHODS:The association between the A. muciniphila and IL6/STAT3 was investigated by using mucosal biopsies and fecal samples. TNBS-induced colitis mouse models were performed to elucidate the underlying mechanisms. The alteration of intestinal microbiota was organized by 16s rRNA sequencing. RESULTS:In Crohn's disease patients, the level of STAT3 and IL-6 presented a negative relationship with A. muciniphila. The expression of IL-6, p-STAT3, and STAT3 was downregulated in A.m+TNBS group, indicating A. muciniphila may inhibit the IL6/STAT3 pathway in TNBS-induced enteritis in vivo. To investigate the potential defensive role of A. muciniphila supplementation in vivo with TNBS-induced enteritis, 16S rRNA sequencing was performed to analyze changes in the intestinal microbiota composition. The results revealed a marked increase in microbial diversity and abundance within the A. muciniphila-treated group, suggesting a beneficial modulation of the gut microbiome associated with the supplementation. CONCLUSIONS:Our findings declared that A. muciniphila supplementation alleviates gastrointestinal inflammation through IL-6/STAT3 signaling pathway. This protective effect was mediated by the downregulation of the IL-6 and STAT3, highlighting a potential mechanism by which A. muciniphila modulates inflammatory responses. This work disclosed that A. muciniphila demonstrates a defensive influence against TNBS-induced enteritis in vivo, proposing it qualified as a unique therapeutic focusing on modulati

摘要： The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.

关键词： Angelica gigas Nakai   Intestinal barrier function   Permeability   Tight junction   Inflammatory bowel disease  

摘要： Inflammatory bowel disease (IBD) is a chronic disease that includes Crohn’s disease and ulcerative colitis (UC). Tight junctions (TJs) play an important role in intestinal barrier function. In intestinal epithelial cells, TJs are composed of different junction molecules, including claudin and occludin (OCLN), and regulate the paracellular permeability of water, ions, and macromolecules in adjacent cells. The TJ structure also provides a physical barrier to luminal inflammatory molecules, although impaired integrity and structure of the TJ barrier can result in the forcible activation of immune cells and inflammation. This study aimed to investigate the protective effects of Angelica gigas Nakai extracts (AGNE) on intestinal barrier and TJ activation. AGNE exhibited no cytotoxic activity against Caco-2 cells and showed potent antioxidant activity. Moreover, AGNE treatment significantly increased transepithelial electrical resistance (TEER) values and reduced epithelial permeability. In addition, the expression of Zonula Occludens (ZO)-1 and OCLN increased in a concentration-dependent manner with AGNE treatment. Conversely, myosin light chain kinase (MLCK) expression decreased in a concentration-dependent manner upon AGNE treatment. Notably, the most significant improvement was observed in the AGNE 200 μg/mL group compared to the IL-6 control group. Our findings highlight the potential usefulness of AGNE as a novel therapeutic agent for maintaining epithelial barrier integrity in IBD.

关键词： Drug induced liver injury   HLA genotype associations  

摘要： BACKGROUND AND AIMS:Fluoroquinolones (FQ) have a favorable safety profile, but the risk of drug-induced liver injury (DILI) is well described. The aim of this study was to identify clinical features and HLA genetic variants associated with FQ-DILI in a large national registry. METHODS:Analysis of FQ-DILI cases enrolled in DILIN between 2004-2022. HLA class I and II alleles were sequenced by the Illumina MiSeq platform. RESULTS:61 cases (32 ciprofloxacin, 22 levofloxacin, 7 moxifloxacin) were included. Clinical features between the 3 drugs were similar. The median duration of therapy was 7 (range 2-54) days; median age 53 (range 22-80) years; and 67% were female. Median latency to onset was 12 (range 2-1370) days with 44% hepatocellular, 30% mixed, and 26% cholestatic pattern of liver injury. Median time to recovery was 65 days, but 13% had persistent injury at 6 months, 15% died (11% due to liver failure). Two HLA alleles were associated with an increased risk of liver injury: HLA-DQA1*03:01 (carriage frequency (CF) 38% in cases vs 19% in controls) and HLA B*57:01 (15% vs 6%). There was a significant difference between the combined CF of the 2 alleles of 48% in cases vs 24% controls, (p = 0.0001). No clinical characteristics or outcomes were associated with carriers compared to non-carriers. CONCLUSION:FQ DILI is a class effect that presents with a short latency, variable pattern of liver injury, and carries a significant risk of chronicity and mortality. There is a significant association with HLA-DQA1*03:01 and HLA B*57:01.

关键词： Long-stranded noncoding RNA   Osteoarthritis   PCBP1   SNHG7   chondrocytes  

摘要： PURPOSE:We probed the roles of SNHG7, miR-146b, PCBP1, and IL-β in the development of osteoarthritis (OA). MATERIALS AND METHODS:OA models were established using anterior cruciate ligaments, and chondrocytes were obtained from mouse cartilage tissue. Cells were treated with 10 ng/ml Il-1β. RT-qPCR was used to detect the expression of SNHG7, miR-146b, PCBP1, and IL-β in tissues and cells. Safranin-O/Fast Green staining was performed to analyze the cartilage damage in each group of mice. RESULTS:SNHG7 and PCBP1 expressions were down-regulated, and miR-146b expression was up-regulated in OA tissue and IL-1β-treated chondrocytes compared to normal cartilage tissue and chondrocytes. Forced SNHG7 expression improved cartilage structure, enhanced proliferative viability of chondrocytes, and inhibited apoptosis and IL-1β release in IL-1β-treated chondrocytes in OA mice. In contrast, miR-146b upregulation decreased proliferative viability and promoted apoptosis and IL-1β release in chondrocytes. Rescue assays showed that miR-146b attenuated the protective effects of SNHG7 on apoptosis and inflammation in IL-1β-treated chondrocytes, and activation of PCBP1 expression significantly inhibited the cytotoxic effects of miR-146b. Mechanistically, SNHG7 acted as a competitive endogenous RNA by targeting miR-146b to promote the expression of PCBP1. CONCLUSIONS:This study confirms that SNHG7 inhibits IL-1β-mediated inflammatory responses in chondrocytes via the miR-146b/PCBP1 axis, thereby suppressing IL-1β-induced OA.

关键词： Health care associated infection   LPS-induced TNF-α   Multi-organ dysfunction syndrome   Sepsis  

摘要： The present study estimated lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) levels and its association with health care associated infection (HAI) and duration of multi-organ dysfunction syndrome (MODS). LPS-induced TNF-α levels were estimated in 67 children on day 3 of MODS. Variables recorded were Pediatric Index of Mortality (PIM-3), cultures, diagnosis, HAI, days of MODS, survivors and non-survivors. Of 67 children, 37 (52.2%) were male and 27 (40.2%) expired. Sixty-three (94%) children had reduced TNF-α levels (<200 pg/ml); 23.11 (10.38, 40.59). The median number of days in MODS was 7 (5, 12) and prolonged MODS (≥7 d) was observed in 49/67 (73.1%) children. Forty-five (67.1%) children had HAI, among these 33/45 (73.3%) had ventilator associated pneumonia (VAP). TNF-α levels were significantly lower in children with MODS, prolonged MODS, children who developed HAI and non-survivors as compared to healthy children (p <0.0001), children with MODS <7 d (p=0.01), children without HAI (p=0.009) and survivors (p=0.04), respectively. HAI was independently associated with reduced levels of TNF-α (p=0.01).