No abstract

Ischemic heart disease is a leading cause of mortality and occurs due to coronary arterial atherosclerosis, vascular cavity stenosis and occlusion. It has previously been demonstrated that berberine treatment may ameliorate and help to prevent cardiovascular diseases due to its anti-inflammatory and anti-apoptotic effects in myocardial cells. However, the potential signaling mechanisms mediated by berberine in the progression of myocardial injury remain to be elucidated. The aim of the present study was to investigate the therapeutic effects of berberine and its potential mechanism in a mouse model of myocardial cell injury. The results revealed that berberine treatment downregulated the serum expression of inflammatory factors, including interleukin (IL)-6, tumor necrosis factor-α, IL-10 and IL-17A in mice with anoxia-reoxygenation injury. Berberine treatment also decreased myocardial cell apoptosis following anoxia-reoxygenation injury via regulating the expression of apoptosis-associated genes. Histological analysis revealed that the area, circumference fragmentation and segmentation of myocardial cells were significantly decreased by berberine treatment compared with the control group. The body weight, blood lipid levels, blood pressure and heart rate were markedly improved in mice with anoxia-reoxygenation injury following berberine treatment compared with untreated mice. The expression of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB expression was downregulated in myocardial cells from in mice with anoxia-reoxygenation injury following berberine treatment compared with untreated mice. However, p38 MAPK overexpression ameliorated the berberine-induced decrease in NF-κB activity and expression, as well as the berberine-induced inhibition of myocardial apoptosis in myocardial cells isolated from experimental mice. In conclusion, the results of the present study indicate that berberine is able to decrease the expression of inflammatory cytokines expression and inhibit myocardial cell apoptosis via downregulating the p38 MAPK-mediated NF-κB signaling pathway. These results suggest that berberine may be an effective treatment for anoxia-reoxygenation injury.

Objective: To investigate the immunological mechanism of bone marrow–derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD).Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)–induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor–induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs–infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry.Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown.Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.

No abstract

The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4β7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4β7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4β7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4β7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.