Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction in the progression of obesity-associated diseases. The aim of the study was to evaluate the mechanisms of UDCA during obesity-linked hepatic mitochondrial dysfunction and obesity-associated adipose tissue macrophage-induced inflammation in obese mice. UDCA significantly decreased lipid droplets, reduced free fatty acids (FFA) and triglycerides (TG), improved mitochondrial function, and enhanced white adipose tissue browning in ob/ob mice. This is associated with increased hepatic energy expenditure, mitochondria biogenesis, and incorporation of bile acid metabolism (Abca1, Abcg1 mRNA and BSEP, FGFR4, and TGR5 protein). In addition, UDCA downregulated NF-κB and STAT3 phosphorylation by negative regulation of the expression of SOCS1 and SOCS3 signaling. These changes were accompanied by decreased angiogenesis, as shown by the downregulation of VEGF, VCAM, and TGF-βRII expression. Importantly, UDCA is equally effective in reducing whole body adiposity. This is associated with decreased adipose tissue expression of macrophage infiltration (CD11b, CD163, and CD206) and lipogenic capacity markers (lipofuscin, SREBP-1, and CD36). Furthermore, UDCA significantly upregulated adipose browning in association with upregulation of SIRT-1-PGC1-α signaling in epididymis adipose tissue (EWAT). These results suggest that multi-targeted therapies modulate glucose and lipid biosynthesis fluxes, inflammatory response, angiogenesis, and macrophage differentiation. Therefore, it may be suggested that UDCA treatment may be a novel therapeutic agent for obesity.

No abstract

Background. The relationship between inflammatory bowel disease and gut microbiota is inextricable. Electroacupuncture (EA) can alleviate acute experimental colitis, but the performance of intestinal microorganisms and the mechanism are still not fully understood. We investigated the relationship between the EA and gut microbes and clarified the role of tight junction and adiponectin in the anti-inflammatory effect of EA. Methods. Male C57BL/6 mice were randomized into three groups: normal control, dextran sulfate sodium- (DSS-) induced ulcerative colitis (DSS), and DSS with EA ST36 (DSS + EA). Mice body weight, DAI score, colon length, and histological score were evaluated for colitis severity. Colonic inflammation and tight junctions were demonstrated by the immunohistochemical (IHC) method. Systemic responses were confirmed by plasma cytokines and adiponectin with multiplex immunoassays. Gut microbiome profiling was conducted by 16S rRNA gene sequencing. Results. EA had benefit in relieving both macroscopic and microscopic colonic inflammation. It can reduce disease activity, maintain colon length, and ameliorate histological inflammatory reaction. In IHC stain, EA decreased CD11b, F4/80, TLR4, and MyD88 and preserved claudin-1 and ZO-1 expression. Compared with the control group, the DSS group showed elevated levels of CRP, IFN-γ, TNF-α, and IL-6, but decreased adiponectin. These changes were reversed by EA, accompanied by modulation of the overall structure of gut microbiota. Conclusion. Our findings suggest that EA exerts its therapeutic effect by TLR4 signaling via the MyD88-dependent pathway. EA could increase adiponectin, maintain mucosal tight junctions, and modulate gut microbiota.

Inflammatory bowel disease (IBD) involves chronic inflammation, loss of epithelial integrity, and gastrointestinal microbiota dysbiosis, resulting in the development of a colon cancer known as colitis-associated colorectal cancer (CAC). In this study, we evaluated the effects of corylin in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The results showed corylin could improved the survival rate and colon length, maintained body weight, and ameliorated the inflammatory response in the colon. Then, we further identified the possible antitumor effects after 30-day treatment of corylin on an azoxymethane (AOM)/DSS-induced CAC mouse model. Biomarkers associated with inflammation, the colon tissue barrier, macrophage polarization (CD11c, CCR7, CD163, and CD206), and microbiota dysbiosis were monitored in the AOM/DSS group versus corylin groups. Corylin downregulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) mRNA expression and inflammatory signaling-associated markers (TLR4, MyD88, AP-1, CD11b, and F4/80). In addition, a colon barrier experiment revealed that epithelial cell proliferation of the mucus layer (Lgr5, Cyclin D1, and Olfm4) was downregulated and tight junction proteins (claudin-1 and ZO-1) were upregulated. Furthermore, the Firmicutes/Bacteroidetes ratio changed with corylin intervention, and the microbial diversity and community richness of the AOM/DSS mice were improved by corylin. The comparative analysis of gut microbiota revealed that Bacteroidetes, Patescibacteria, Candidatus Saccharimonas, Erysipelatoclostridium, and Enterorhabdus were significantly increased but Firmicutes, Turicibacter, Romboutsia, and Blautia decreased after corylin treatment. Altogether, corylin administration showed cancer-ameliorating effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Therefore, corylin could be a novel, potential health-protective, natural agent against CAC.

Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66shc. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A (20 mg/kg). Results showed that the cytokines, TNF-α, IL-6, IFN-γ, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66shc expression.