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关键词： Fusobacterium nucleatum   Colorectal cancer   IL-8   Metastasis   MicroRNA  

摘要： BACKGROUND:The association between the intestinal microbiota and colorectal cancer (CRC) has been extensively studied, with Fusobacterium nucleatum (F. nucleatum, FN) being found in high abundance in colorectal cancer tissues. Previous research has emphasized the significant role of F. nucleatum in the occurrence of CRC. However, the impact of F. nucleatum on CRC liver metastasis has not been well understood. METHODS:The effects of F. nucleatum on metastasis ability of CRC cell were evaluated in vitro were examined by wound-healing assay and transwell assay. The mouse model of CRC liver metastasis was constructed by spleen injection, and the degree of liver metastasis was assessed by in vivo bioluminescence imaging. The gene expression changes in CRC cells after co-culture with F. nucleatum was analyzed through transcriptome sequencing. qRT-PCR and Western Blot assays were performed to validate the expression of related genes and proteins. RESULTS:The metastasis ability of CRC cells was significantly enhanced after co-culture with F. nucleatum in vitro. In the mouse model, F. nucleatum also promoted the development of liver metastasis in CRC. Mechanistically, F. nucleatum infection increased the expression of IL-8 by downregulated the level of miR-5692a, a regulatory microRNA of IL-8. This led to the activation of the ERK pathway and resulted in the epithelial-mesenchymal transition (EMT) of CRC cells. CONCLUSIONS:Our results suggest that F. nucleatum promotes CRC liver metastasis by inducing epithelial-mesenchymal transition through the miR-5692a/IL-8 axis. These findings provide new insights for the prevention and treatment of colorectal cancer liver metastasis.

关键词： Antigen persistence   Human Leukocyte Antigen   Long COVID-19  

摘要： Here we offer a perspective on recent findings of persistent SARS-CoV-2 antigens in Long COVID through the lens of immunogenetic risk and protection, namely in the context of the fundamental role of Human Leukocyte Antigen (HLA) in eliminating viral infections. Specifically, we attribute the persistence of viral antigens to the lack or weak protection conferred by HLA against SARS-CoV-2 in individuals carrying HLA alleles with low binding affinities to the virus. We suggest that determining the HLA Class I and II makeup of Long COVID patients will provide valuable new information in elucidating the cause for antigen persistence underlying the development of Long COVID and pave the way for successful interventions.

关键词： IFN-α   LADA   T1D   autoimmunity   latent autoimmune diabetes in adults   neutralizing antibody   type 1 diabetes  

摘要： CONTEXT:Autoantibodies against IFN-α (AAb-IFN-α) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D). OBJECTIVE:To investigate the presence and clinical relevance of the positivity to AAb-IFN-α in people with LADA compared to T1D. RESEARCH DESIGN AND METHODS:Serum levels of AAb against IFN-α isoforms were measured using a cell-based approach in 41 subjects with LADA and in 90 subjects with T1D. OUTCOMES:The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for AAb against ≥2 and against 3 IFN-α isoforms, respectively. Presence and levels of AAb-IFN-α were related to clinical and biochemical features of participants with LADA. RESULTS:Seven (17.1%) and 5(12.2%) participants with LADA, and 3(3.3%) and 0 participants with T1D showed positivity for AAb against ≥2 and 3 IFN-α isoforms (p=0.011, and p=0.0025, respectively). Fasting blood glucose and HbA1c levels were numerically lower among people with LADA testing positive for AAb against ≥2 IFN-α isoforms, than among those who were either negative or positive for AAb against one IFN-α isoform. Among LADA-positive individuals, levels of AAb against IFN-α2 isoform were inversely correlated with GADA levels (rho= -0.513; p=0.025). CONCLUSIONS:Autoimmunity against IFN-α is peculiar to autoimmune diabetes and appears to be distinctive of its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.

关键词： Axial Spondyloarthritis   Etanercept   Magnetic Resonance Imaging   Spondylitis Ankylosing   Tumor Necrosis Factor Inhibitors  

摘要： Objectives In this post-hoc analysis of ESTHER trial, we aimed to investigate the longitudinal relationship between inflammation on MRI and the achievement of inactive disease/low disease activity in patients with axial spondyloarthritis (axSpA) treated with long-term tumor necrosis factor (TNF) inhibitor etanercept. Methods Of the 76 patients with active axSpA in the ESTHER trial, we included all patients treated with etanercept for at least 6 months for main analysis. All clinical and MRI data from 4.5 years of follow-up were used in the analysis. MRIs of the spine and sacroiliac (SI) joints were performed at baseline, week 24, week 48 and yearly thereafter and were evaluated for active inflammatory lesions according to the Berlin MRI score. Results Longitudinal analysis showed that higher SI joint osteitis score was associated with higher Axial Spondyloarthritis Disease Activity Score (ASDAS) at the same time point (β=0.08, 95% CI (0.05;0.11)) and at the next time point 6 months later (β=0.05, 95% CI (0.02;0.07)). Furthermore, resolution of osteitis in the SI joint (Berlin MRI osteitis score of ≤1) was associated with lower ASDAS at the next time point (β=-0.26, 95% CI (-0.42;-0.09)), higher odds of achieving ASDAS low disease activity (OR=5.61, 95% CI (1.06;29.67)) and inactive disease status (OR=2.23, 95% CI (1.01;4.94)) at the next time point. Conclusions The presence of inflammation on SI joints-MRI is associated with higher disease activity in axSpA. Resolution of inflammation on MRI is associated with better clinical outcomes in the long-term follow-up. Thus, achieving complete resolution of inflammation is favourable for meeting the treatment goals in axSpA. Trial registration number NCT00844142. © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

关键词： 谷子可溶性膳食纤维   结肠癌   氧化还原系统   细胞因子   线粒体膜电位损伤  

摘要： 为探究谷子可溶性膳食纤维（FMB-SDF）对结肠癌细胞HT-29生长和凋亡的影响及作用机制，以2.5、5.0、7.5、10.0 mg/mL不同质量浓度FMB-SDF作为试验组，采用噻唑蓝（MTT）法检测FMB-SDF对小鼠巨噬细胞RAW264.7增殖的影响，采用试剂盒法分别检测超氧化物歧化酶（SOD）活性和乳酸脱氢酶（LDH）活性，利用ELISA法检测结肠癌细胞HT-29肿瘤坏死因子（TNF-α）、细胞因子白介素-6(IL-6)、白介素-10(IL-10)的分泌，用Rhodamine 123探针检测结肠癌细胞HT-29的线粒体膜电位变化。结果表明，FMB-SDF能够通过干预氧化还原系统抑制结肠癌细胞HT-29的生长，通过抑制炎症因子IL-6和TNF-α的分泌，增强抗炎因子IL-10的分泌，进而抑制结肠癌细胞炎症的发展，同时能够增强HT-29细胞线粒体膜电位损伤。综上所述，FMB-SDF通过干预HT-29细胞氧化还原系统、抑制炎症发展及促进线粒体膜电位损伤来诱导结肠癌细胞HT-29的凋亡。

关键词： Alzheimer′s disease   neuroinflammation   brain-targeted drug delivery   tau neuropathology   reactive oxygen species  

摘要： Alzheimer's disease (AD) is a progressive neurodegenerative disorder with prolonged latency during the prodromal stage. However, current clinical approaches to pharmacological interventions for AD remain challenge. An effective treatment strategy is to eliminate protein aggregates and prevent their regeneration. In this study, interleukin (IL)-3-loaded porous manganese (Mn 2+ )-doped Prussian blue (PB) nanoparticles (NPs) were coated with dopaminergic MES23.5 neuronal cell membranes (PBMn-IL3@CM) and then used to combat AD progression. The PBMn-IL3@CM NPs possessed a high targeting efficiency, being able to traverse the blood-brain barrier and specifically affect the brain to reduce oxidative stress. The Mn 2+ -doped PB NPs effectively scavenged reactive oxygen radicals produced by microglia, inducing the pro-inflammatory M1 microglia. In addition, the released IL-3 activated microglia, causing the polarization of the M1 phenotype to the anti-inflammatory M2 phenotype in vitro and in vivo . The transition reduced phosphorylated tau accumulation, mediated neurotoxicity, and eliminated tau aggregates, which reversed cognitive impairment in AD mice. The PBMn-IL3@CM NPs showed excellent biocompatibility without significant adverse effects; consequently, they represent a promising AD treatment.

关键词： H. pylori   NLRP3 inflammasome   TNF/TNFR1 axis   Macrophage   Gastritis  

摘要： BackgroundMacrophages play a crucial role in chronic gastritis induced by the pathogenic Helicobacter pylori (H. pylori) infection. NLRP3 inflammasome has emerged as an important component of inflammatory processes. However, the molecular mechanism by which H. pylori infection drives NLRP3 inflammasome and macrophages activation remains *** gastritis tissues were collected for clinical significance of NLRP3. Infection with H. pylori was performed using in vitro and in vivo models. Bone marrow-derived macrophages (BMDMs) from wild-type (WT), Nlrp3-knockout (KO) and Tnfr1-KO mice were infected with H. pylori. Western blotting, qRT-PCR, immunofluorescence, immunohistochemistry and ELISA were utilized for functional and mechanistic ***-cell RNA sequencing (ScRNA-seq) analysis of human gastric tissues, followed by validation, indicated that NLRP3 was primarily expressed in myeloid cells and was significantly increased in H. pylori-positive gastritis compared to H. pylori-negative gastritis. Infection with PMSS1 and NCTC11637 H. pylori strains induced NLRP3 inflammasome activation in vitro (THP1 cells) and in the insulin-gastrin (INS-GAS) transgenic mouse model. Deletion of NLRP3 in BMDMs showed marked inhibition of H. pylori-induced M1 macrophage polarization. Furthermore, NLRP3 inflammasome activation upon TNF alpha, or H. pylori stimulation, was partially blocked by TNF alpha/TNFR1 signaling inhibitors. Deletion of TNFR1 in BMDMs significantly impaired NLRP3 inflammasome activation and M1 macrophages induced by H. *** study revealed that the activation of NLRP3 inflammasome, regulated by the TNF/TNFR1 signaling axis, is a key regulator of H. pylori-induced M1 macrophage activation and gastritis.

关键词： IL-17   JAK/STAT   CD4+T   dilated cardiomyopathy  

摘要： Purpose: Studying the effect of interleukin-17 (IL-17) on the mechanism of CD4+ T-cell immune regulation and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may offer new ideas and methods for the therapy of dilated cardiomyopathy. Methods: Naive CD4+ T cells were isolated from mice using a magnetic bead sorting reagent and manipulated by overexpression or knockdown of IL-17. Protein levels of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were determined by Western blotting. Quantitative polymerase chain reaction was used to assess the levels of JAK2, STAT3, MMP-2, and MMP-9. Expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-4 (IL-4), and interferon-gamma (IFN gamma) was determined by enzyme-linked immunosorbent assay test kits. TNF-alpha, IL-1 beta, IL-4, and IFN gamma secretion was measured by flow cytometry. Results: In CD4+ T cells, IL-17 overexpression increased TNF-alpha, IL-1 beta, IL-4, IFN gamma, p-JAK2, p-STAT3, MMP-2, MMP-9 levels, and apoptosis. Knockdown of IL-17 reduced the levels of TNF-alpha, IL-1 beta, IL-4, IFN gamma, p-JAK2, p-STAT3, MMP-2, and MMP-9, as well as the level of apoptosis. Conclusion: Through regulation of IL-17 expression in CD4+ T cells, this study reveals its crucial role in regulating the secretion of inflammatory factors, activation of the JAK/STAT signaling pathway, expression of matrix metalloproteinases, and apoptosis of CD4+ T cells.

关键词： LPS   Pulmonary fibrosis   Mast cell   IL-13   Cromolyn sodium   Sepsis  

摘要： BackgroundSepsis is a systemic inflammatory response caused by infection. When this inflammatory response spreads to the lungs, it can lead to acute lung injury (ALI) or more severe acute respiratory distress syndrome (ARDS). Pulmonary fibrosis is a potential complication of these conditions, and the early occurrence of pulmonary fibrosis is associated with a higher mortality rate. The underlying mechanism of ARDS-related pulmonary fibrosis remains *** evaluate the role of mast cell in sepsis-induced pulmonary fibrosis and elucidate its molecular mechanism. We investigated the level of mast cell and epithelial-mesenchymal transition(EMT) in LPS-induced mouse model and cellular model. We also explored the influence of cromolyn sodium and mast cell knockout on pulmonary fibrosis. Additionally, we explored the effect of MC-derived IL-13 on the EMT and illustrated the relationship between mast cell and pulmonary *** cell was up-regulated in the lung tissues of the pulmonary fibrotic mouse model compared to control groups. Cromolyn sodium and mast cell knockout decreased the expression of EMT-related protein and IL-13, alleviated the symptoms of pulmonary fibrosis in vivo and in vitro. The PI3K/AKT/mTOR signaling was activated in fibrotic lung tissue, whereas Cromolyn sodium and mast cell knockout inhibited this *** expression level of mast cell is increased in fibrotic lungs. Cromolyn sodium intervention and mast cell knockout alleviate the symptoms of pulmonary fibrosis probably via the PI3K/AKT/mTOR signaling pathway. Therefore, mast cell inhibition is a potential therapeutic target for sepsis-induced pulmonary fibrosis.

关键词： Elite controllers   HIV-1   AIDS   Genetics   GWAS   HLA   MHC   Haploblock  

摘要： Introduction We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). Methods A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results Two thousand six hundred twenty-six SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference;a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. Conclusion Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK ce