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关键词： Ghrelin   High glucose   Pyroptosis   TNF-alpha   Caspase-8   Caspase-3   GSDME  

摘要： Diabetic liver injury (DLI) refers to liver injury resulting from prolonged chronic hyperglycemia and represents a significant complication associated with diabetes, The specific pathogenic mechanism of DLI remains incompletely understood. Tumor necrosis factor alpha (TNF-alpha) has been demonstrated to play a crucial role in diabetic complications through intricate signalling pathways, including pyroptosis. However, it remains uncertain whether TNF-alpha mediates pyroptosis in DLI, we initially established an in vitro model of DLI and confirmed the presence of an inflammatory state characterized by TNF-alpha in DLI. Furthermore, evidence of gasdermin E (GSDME)-mediated pyroptosis and the activation of cysteinyl aspartate specific proteinase (caspase)-8 was observed in AML-12 cell exposed to high glucose concentrations. We subsequently demonstrated that TNF-alpha can trigger caspase-8 activation, leading to GSDME-mediated cellular pyroptosis. Furthermore, treatment with ghrelin effectively suppressed hepatic cell pyroptosis induced by high glucose concentrations and provided protection against liver injury. Therefore, we propose that the TNF-alpha/caspase-8/caspase-3/GSDME pathway represents a novel mechanism underlying pyrodeath in DLI cells and to explore the protective role and molecular mechanisms underlying the effects of ghrelin on DLI by this special pathway, These findings may present potential therapeutic implications for the management of DLI.

关键词： alendronate sodium bisphosphonate   bone mineral density   insulin-like growth factor   interleukin   osteoporosis  

摘要： Objective: To assess the effects of bisphosphonates (zoledronic acid injection) plus alendronate sodium on bone mineral density (BMD) and levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and insulin-like growth factor I (IGF-I) in patients with osteoporosis. Materials and methods: A total of 94 patients recruited from osteoporosis patients hospitalized in the period October 2021 to December 2022 were assigned to either a control group or an observation group using a random number table. The control group was treated with alendronate sodium alone, whereas the observation group received zoledronic acid injection in combination with alendronate sodium administered orally. Results: Pre-treatment values for BMD, serum levels of IL-6, TNF-alpha, and IGF-I did not differ between the two groups (p > 0.05). However, post-treatment BMD measured at the femoral neck, in lumbar vertebrae, and Ward's triangle were increased, as was serum IGF-I level (p < 0.05). In contrast, in comparison with the control group, reductions were observed in serum IL-6 and TNF-alpha (p < 0.05). The incidence of adverse reactions such as nausea and vomiting, diarrhea, musculoskeletal pain, and hypocalcemia was significantly lower in the observation group (p < 0.05). Conclusion: Zoledronic acid injection in combination with alendronate sodium increases the expression of IL-6, TNF-alpha, and IGF-I, suppresses bone resorption and promotes bone recovery in patients with osteoporosis.

关键词： Hepatocellular carcinoma   Lenvatinib   Neutrophil   Neutrophil extracellular trap   Cuproptosis  

摘要： BackgroundLenvatinib is a potent first-line therapy for patients with hepatocellular carcinoma (HCC), but it also increased the number of neutrophils in HCC tumor ***3, MPO-DNA, elastase and MPO activity were measured for assessing neutrophil extracellular traps (NETs) in vivo and in vitro. Cell cuproptosis was assessed by measurement of copper content, FDX1, and pyruvate. The functions of lenvatinib, DNase I, interleukin 33 (IL33) neutralizing antibody and GPX4 in tumor growth were explored in *** induced NETs in the HCC tumor microenvironment via HCC cells, but not through the direct stimulation of neutrophils. In addition, NET clearance by DNase I improves the efficacy of lenvatinib therapy in HCC mouse models. Mechanistically, lenvatinib promoted the expression and secretion of IL33 by HCC cells that triggered NET formation. Moreover, IL33 knockdown in Hepa1-6 cells improved lenvatinib efficacy in Hepa1-6-bearing HCC model mice and reduced NET formation in the tumor microenvironment. Subsequently, lenvatinib increased IL33 production by increasing the NDUFA4L2 expression in HCC cells. Furthermore, we found that IL33 triggered NET formation in neutrophils by increasing the protein expression of PADI4 via the Akt/mTOR signaling pathway. Rapamycin inhibition of mTOR reduced PADI4 expression and NET formation. Consistently, PADI4 inhibition by the selective PAD4 inhibitor GSK484 hydrochloride (GSK484) improved lenvatinib response to HCC therapy. Importantly, NETs contribute to lenvatinib resistance by inhibiting cuproptosis, but not apoptosis, pyroptosis, or ferroptosis in HCC cells. Treatment with GSK484 reversed the inhibitory effects of NETs on cuproptosis and sensitized the HCC cells to *** study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resi

关键词： HLA-B51   HLA-B27   spondyloarthritis   axial spondyloarthritis   peripheral spondyloarthritis   Beh & ccedil   et's syndrome   major histocompatibility complex  

摘要： Objective The study aimed to estimate the prevalence of HLA-B51 and HLA-B52 in Lebanese patients with spondyloarthritis (SpA) compared with healthy controls (HC). We further aimed to evaluate the impact of HLA-B51 on phenotype and identify the distribution of the alleles in the HLA-B *** A case-control study enrolled consecutive SpA patients from three rheumatology clinics in Lebanon, including axial (axSpA), peripheral SpA (pSpA), and psoriatic arthritis (PsA) and HCs from blood donors. Demographic and disease data were collected through interviews and file reviews, with testing of the entire HLA-B locus using molecular techniques. The prevalence of HLA-B51 and B52 was estimated in SpA patients vs controls. Prevalence comparisons were made, and logistic regression identified factors associated with HLA-B51 in *** Data from 120 HCs and 86 SpA patients (65 axSpA, 15 pSpA, 6 PsA), mean age 25.6 and 46.4 years, respectively, showed a higher HLA-B51 prevalence in SpA (25.6%), especially axSpA (29.2%) vs HC (12.5%) (P = 0.016), and a numerically higher HLA-B52 prevalence (8.1% vs 4.2%, P = 0.230). HLA-B51 correlated with recurrent oral ulcerations (OR 7.99;95% CI: 2.14, 29.84) and radiographic juxta-articular erosions (OR 7.65;95% CI: 1.14, 38.03). HLA-B35 was the most dominant allele in both groups (18.7%), followed by HLA-B27 (15.7%) and HLA-B51 (13.4%) in *** HLA-B51 was identified more frequently in patients with SpA compared with HC and was associated with recurrent oral ulcerations and juxta-articular radiographic erosions. Longitudinal studies are needed to determine whether this association indicates a disease overlap or might correlate with a specific SpA phenotype.

关键词： IL-6   microglia   retina regeneration   M & uuml   ller glia (MG)   reprogramming   zebrafish  

摘要： PURPOSE. Inflammation activates the Jak1-Stat3 signaling pathway in zebrafish M & uuml;ller glia (MG), leading to their status transition and proliferation following retinal injury. However, the source of Stat3-activating molecules remains unclear. This study aims to explore the expression and function of a Stat3-activating cytokine IL-6 in zebrafish retina regeneration. METHODS. Mechanical retinal injury was induced in adult zebrafish by a needle-poke lesion. Single-cell RNA sequencing (scRNAseq) and PCR were used to determine gene expression. Microglia ablation was performed by using the mpeg1:nsfb-mcherry trans-genic zebrafish. Morpholino oligonucleotides, a recombinant zebrafish IL-6 protein and drugs, were used to manipulate IL-6 or Stat3 signaling in the retina. The 5-Ethynyl-2'- deoxyuridine (EdU) labeling was used to evaluate MG proliferation and the formation of MG-derived progenitor cells (MGPCs). Neuronal regeneration in the retina was analyzed by lineage tracing and immunostaining. RESULTS. The scRNAseq reveals that IL-6 is mainly expressed by a subset of pro-inflammatory microglia in the injured retina. Loss-and gain-of-function experiments demonstrate that IL-6 signaling promotes MG proliferation and the formation of MGPCs following retinal injury. Additionally, IL-6 facilitates MG status transition by modulating Jak1-Stat3 signaling and the expression of regeneration-associated genes. Interestingly, IL-6 may also regulate MGPC formation via phase-dependent pro-inflammatory and antiinflammatory mechanisms. Finally, IL-6 promotes the early differentiation of MGPCs and contributes to the regeneration of retinal neurons in the injured retina. CONCLUSIONS. Our study unveils the critical role of microglia-derived IL-6 in zebrafish retina regeneration, with potential implications for mammalian MG reprogramming.

关键词： IL-12R beta 1 deficiency   leukocytoclastic vasculitis   Mendelian susceptibility to mycobacterial disease   BCGitis   immune dysregulation  

摘要： Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic condition caused by mutations in the interleukin-12/interferon-gamma pathway, leading to vulnerability to infection by weakly virulent mycobacteria. IL-12R beta 1 deficiency, the most common cause of MSMD, has rarely been associated with cutaneous leukocytoclastic vasculitis (LCV). We report the case of a 9-year-old girl with IL-12R beta 1 deficiency who presented with recurrent maculopapular skin lesions confirmed as LCV on biopsy. The patient's clinical course included disseminated BCGitis, a history of kidney anomalies, and periodic erythematous rashes exacerbated by physical pressure. Laboratory findings revealed elevated inflammatory markers and immune dysregulation, and a skin biopsy confirmed leukocytoclastic vasculitis. Treatment with topical corticosteroids and antihistamines resulted in clinical improvement. This case highlights the importance of recognizing LCV as a potential manifestation of IL-12R beta 1 deficiency and underscores the need for a multidisciplinary approach in managing these patients.

关键词： ileitis   tumor necrosis factor   IBD mouse models   arthritis   transcriptomics  

摘要： Background Tumor necrosis factor (TNF) is a pleiotropic cytokine that plays a critical role in the pathogenesis of immune-mediated diseases including inflammatory bowel disease (IBD). The stability of its mRNA transcript, determined in part by destabilizing sequences in its AAUU repeats (ARE) gene region, is an important regulator of its tissue and systemic levels. A deletion in the ARE region of the gene resulted in IBD and arthritis in mice and pigs, supporting a critical role for the cytokine in human IBD and several human arthritides. A mutation in the same area of the mouse genome by Genentech scientists (T.Y., M.K.) resulted in a similar but not identical *** Here, we compare histopathological, cellular, and molecular features of the strains and propose reasons for their distinct phenotypes. First, while homozygous TNF Delta ARE mice develop severe arthritis and die after weaning, homozygous Genentech TNF Delta ARE (Delta G/Delta G) mice have normal lifespans, and males are often *** We found that while the ileitic phenotype had peaked at 12 weeks of age in all mice, colitis progressed mostly after 20 weeks of age in heterozygous mice. Their variably penetrant arthritic phenotype progressed mostly after 20 weeks, also in heterozygous mice from both strains. There was expansion of central memory T and B cells in lymphoid organs of TNF-overproducing strains and their transcriptional profile shared well-known pathogenetic pathways with human IBD. Finally, we found differences in the mutated sequences within the ARE regions of the TNF gene and in their microbiota composition and genetic background. These differences likely explain their phenotypic *** In summary, we describe a different strain of TNF-overproducing mice with an overlapping, yet not identical phenotype, which may have differential applications than the original strain.

关键词： Deccani   Feacal egg count   Ovar-DRB1 gene   PCR-SSCP  

摘要： Backgroung: Major histocompatibility complex (MHC) is linked with the ability of sheep to resist infection by GIN as measured by feacal egg count. Present study was carried out to genotype Deccani sheep for DRB1 locus and associate it with parasitic resistance. Methods: PCR SSCP analysis for Ovar-DRB1 exon 2 and part of intron-1 was carried out under optimum conditions. Effect of genetic and nongenetic factors along with the genotype was performed using linear model of least square analysis by considering log transferred faecal egg count as a dependent variable. Result: PCR SSCP analysis revealed presence of 14 SSCP patterns. The factors such as age, sex, farm and birth type demonstrated a non significant effect on faecal egg count however, season was observed to be significant source of variation. Further, it was observed that, genotype J and F could be possibly associated with resistance and susceptibility to parasitic infection. Thus, it was inferred that DRB1 gene is may be associated with immune response to parasitic invasion and selection for genotype associated with Ovar-Mhc-DRB1 gene could improve the parasitic resistance in Deccani sheep.

关键词： Tumor microenvironment   IL-7R   breast cancer   prognostic indicator   TCGA   immunity  

摘要： Background The tumor microenvironment (TME) exerts a significant influence on the development, invasion, metastasis, and drug resistance of breast cancer. Therefore, this study sought to investigate potential prognostic factors and markers indicative of TME remodeling in breast cancer, utilizing data from the TCGA *** In this study, transcriptome RNA-seq data from 1222 breast cancer samples were processed using CIBERSORT and ESTIMATE algorithms. We conducted a differential gene expression analysis utilizing COX regression analysis and constructed protein-protein interaction (PPI) networks for enhanced visualization. Through univariate COX analysis and cross-analysis within PPI networks, the Interleukin-7 receptor (IL-7R) emerged as a potential predictor. Subsequently, we performed a comprehensive investigation encompassing single-gene survival analysis, clinical correlation assessment, and GSEA enrichment analysis targeting IL-7R as a core gene associated with prognosis. We examined the expression of IL-7R in human breast cancer and normal breast tissue through clinical studies and cytology experiments, followed by an in-depth analysis of the relationship between IL-7R and breast *** The survival analysis revealed that breast cancer patients with elevated IL-7R expression experienced prolonged survival compared to those with lower IL-7R levels. Results obtained from the Wilcoxon rank-sum test, along with clinical and cellular experiments, indicated higher IL-7R expression in tumor samples compared to normal samples. Correlation tests conducted between IL-7R expression and clinicopathological stage characteristics highlighted statistically significant associations between IL-7R expression and the T and M stages. Additionally, cell classification analysis of tumor-infiltrating immune cells (TIC) proportion showed that activated CD4+ T cells and CD8 T cells of memory B cells were positively correlated with IL-7R expression. These findings furthe