Background Structural variations (SVs; defined as DNA variants ≥ 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. Objectives To investigate the association of SVs and psoriasis. Methods Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population.
Our aim was to investigate whether genetic polymorphism of IL-1Beta-511, IL-1RN, TNF-A-308 are involved in the susceptibility to duodenal ulcer (DU). 437 unrelated Chinese Han patients with DU and 148 healthy controls were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method for the IL-1B-511, TNF-A-308 gene polymorphisms and the VNTR polymorphism in intron 2 of the IL-1RN gene polymorphisms. There was no difference in the genetic polymorphism of IL-1Beta-511, IL-1RN and TNF-A-308 in the patients with DU compared with control. After stratified by Helicobacter pylori infection, they also could not reach significant differences in this study. No statistically significant differences were observed in DU group compared with control according to combination of the IL-1Beta-511 and IL-1RN genotypes regardless of H. pylori positivity. These findings show that no evidence for the involvement of a proinflammatory polymorphism in the IL-1Beta-511, IL-1RN and TNF-A-308 in the susceptibility to DU in China.
Background It is widely accepted that high-fat diet (HFD) has been considered as one of the risk factors of inflammatory bowel disease(IBD), while the mechanism is little known. We aimed to examined whether dietary high fat promotes colonic inflammation through modulating gut microbial tryptophan metabolites. Methods The C57BL/6 female mice were fed with chow diet (12kcal% fat) or HFD (60kcal% fat) for 2 weeks. Fresh fecal samples were collected before administration of 2% DSS. LC-MS/MS analysis was performed to detect fecal microbial tryptophan metabolites. Next, 8-week-old mice were administrated 3-indoleacetic acid (IAA) for 7 days prior to 2.5% DSS treatment. The severity of colitis was assessed and the colonic sections were collected. RNA sequencing was performed to analyze the differential genes in intestinal tissue of mice fed with IAA or not. Real-time PCR and Western blotting were performed to detect the transcription and protein expression of mucin sulfation-related genes. High iron diamine-alcian blue (HID-AB) staining of colon tissues and LS174T cells was used to detect the abundance of sulfated mucin. Additionally, the Chromatin immunoprecipitation (ChIP) sequencing is performed to confirm the binding of aryl hydrocarbon receptor(AHR) to 3’-phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2). Results Short-term HFD increased the susceptibility to colitis of mice. Mice fed with HFD have impaired tryptophan metabolism with remarkable lower level of IAA. IAA supplementation resulted in ameliorative colitis symptoms. Mechanistically, the transcriptome sequencing detected that IAA supplementation enriched the the cytosolic sulfonation pathway and significantly increased the expression of PAPSS2 of colon tissue, a rate-limiting enzyme on the mucin sulfation pathway. Next, in vivo and in vitro experiments verified IAA increased the expression of PAPSS2 and its downstream genes and promoted the mucin sulfation in golgi apparatus of colon through AHR. ChIP sequencing and ChIP-PCR verified IAA can enhance the binding of AHR to the promoter region of PAPSS2 , which further promoted the expression of PAPS transporter 2 (PAPST2 or Slc35b3) and ultimately promotes the mucin sulfation. Conclusion HFD altered the gut microbial tryptophan metabolites and disrupt the protective effect of IAA on the intestinal barrier. IAA could relief colitis through AHR-PAPSS2-PAPST2-mucin sulfation axis, which may present a potential approach for precise prevention and treatment of IBD.
Background Colorectal cancer (CRC) is related to gut microbiota dysbiosis, especially butyrate-producing bacteria reduction. Our previous study suggested administration of Clostridium butyricum (C. butyricum), a butyrate-producing bacterium, exerts a crucial effect against CRC. Methyltransferase-like 3 (METTL3) contributes to tumorigenic epigenetic regulation. We aimed to investigate the effects of C. butyricum on METTL3 in the prevention of CRC. Methods TCGA and CancerSEA databases were used to investigate METTL3 co-expressed genes, and the GO and KEGG enrichment analysis was conducted on METTL3. Tissue specimens of human normal colonic tissue, adenoma and carcinoma were obtained and examined the expression of METTL3, EMT-associated markers, and VM formation. We overexpressed METTL3 in CRC cells to assess cell migration and tube formation. Meanwhile, the effects of C. butyricum on METTL3, epithelial-mesenchymal transition (EMT), and vasculogenic mimicry (VM) formation in CRC cells were evaluated. Furthermore, a murine xenograft model was established to provide further evidence of the inhibition of C. butyricum on tumor growth. Results Database analysis suggested that METTL3 showed a positive correlation with proliferation, EMT, DNA repair, metastasis, and invasion. The expression of METTL3 gradually increased from human normal colon tissue, adenoma to carcinoma, and was positively correlated with VM formation and EMT. METTL3 overexpression promoted the proliferation, migration, and invasion of CRC cells and induced VM formation. C. butyricum could downregulate METTL3 expression in CRC cells and decrease the expression of vimentin and vascular endothelial growth factor receptor 2 to reduce EMT and VM formation. Moreover, C. butyricum alleviated the pro-oncogenic effect of METTL3 overexpressing plasmid in CRC cells. Accordingly, C. butyricum downregulated the expression of METTL3 in tumors and prevented EMT in nude mice. Conclusion C. butyricum could inhibit EMT and VM of intestinal carcinogenesis through downregulating METTL3. These findings broaden our understanding of probiotics supplement in the prevention and treatment of CRC.
Background Ulcerative Colitis (UC) combine both inflammation and coagulation in their pathogenesis and clinical manifestations. Although platelets (PLT) are well known for their role in hemostasis, there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions. However, whether PLT are related to the efficacy of biologic agents is unknown. This study aimed to investigate whether platelet ratio before and after induction therapy can be predictive biomarkers for the therapeutic outcomes of vedolizumab therapy in UC. Methods Patients with moderate-to-severe UC receiving vedolizumab in our hospital between November 2020 and November 2022 were retrospectively evaluated. Patients with concomitant corticosteroid treatment≥20 mg, immunomodulators, or other conditions that could modify the platelet count were excluded. The primary endpoint was clinical response at the end of the induction period (at 14 weeks). We analyzed the association between platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), fecal calprotectin, and the clinical efficacy of vedolizumab. The above indicators between the response and nonresponse groups were compared via a univariate analysis. The independent risk factors of nonresponse were identified via a multivariate analysis. Results Seventy-one patients with moderate-to-severe active UC started treatment with vedolizumab and 20 patients (28.2%) experienced loss of response (LOR) after induction therapy. The platelet count, albumin, CRP, NLR, PLR, MLR, and Particul Mayo score between the LOR and response groups significantly differed. The Platelet ratio before and after induction therapy cut-off value of 1.077 was predictive of LOR, using receiver operating characteristic analysis (sensitivity:78.0%, specificity:81.8%). A univariate analysis revealed a significant relationship between LOR and the platelet ratio (P<0.05). Multivariate analysis indicated the platelet ratio as an independent prognostic factor for LOR (OR=11.219, 95% CI:3.316-37.959, P<0.05). Conclusion Platelet ratio before and after induction therapy is a useful prognostic marker in patients with moderate-to-severe active UC treated with vedolizumab, and may contribute to appropriate use of vedolizumab LOR. A large sample from multiple centers is needed to validate the association between platelet-related measures and the rate of vedolizumab response.
Background High-fat diet (HFD) is closely related to the occurrence and development of IBD, which increases the level of deoxycholic acid (DCA). DCA-treated mice showed pro-inflammatory cell infiltration and colonic inflammation. Ferroptosis, a newly recognized form of cell death characterized by iron overload and the generation of reactive oxygen species (ROS) has recently been observed in colitis. Whether DCA affects ferroptosis and whether it contributes to colitis has not been explored. Methods Twenty-four Female C57BL/6 mice were randomly divided into 4 groups: control group, DCA group, DSS group, and DSS plus DCA group. Real-time PCR and Western blotting were used to detect the transcription and protein expression of ferroptosis-related genes. RNA sequencing was used to analyze the changes of differential genes in the intestinal tissue of mice treated with DCA. Transmission electron microscope was employed to observed the changes of intestinal epithelial cell morphology and intracellular mitochondria. Finally, the binding force between DCA and HIF-2α was calculated by molecular dynamics to explore the structural biological basis of the interaction between DCA and HIF-2α, and screen innovative drugs. Results We found that DCA exacerbated the disease activity index, histological damage and cell death in mice with colitis. In vivo, ferroptosis KEGG pathway was enriched by RNA sequencing in colonic tissues. DCA treatment significantly induced ferroptosis in DSS-induced mice, as evidenced by iron overload, ROS and MDA production, accompanied by decreased expression of GPX4 and increased expression of ACSL4. Transmission electron microscopy also confirmed the occurrence of ferroptosis in colonic tissues. In vitro, DCA induced ferroptosis were also observed in IEC-6 cells and Caco-2 cells under the combined treatment of Lipopolysaccharide (LPS). Interestingly, RNA sequencing revealed that the expression levels of the apical iron divalent metal transporter-1 (DMT1) were significantly upregulated in DCA treated-mice with colitis. DMT1 is a direct target gene of hypoxia inducible factor (HIF)-2α. We also found that DCA could increase the level of DMT1 and HIF-2α in the intestinal epithelial cell lines. Pharmacological inhibition of HIF-2α significantly inhibited the expression of DMT1 and blocked the promotion of ferroptosis by DCA. These data provide a mechanistic basis for the widely reported link between ferroptosis and colitis risk. Conclusion Taken together, these findings suggest that DCA aggravates colitis through the induction of ferroptosis in the HIF2α-DMT1 signaling pathway and provides a new perspective for UC prevention in the future.
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