Caveolin-1 differentially regulates the transforming growth factor-ß and epidermal growth factor signaling pathways in MDCK cells.

Caveolin-1 is critical for interacting with the TGF-ß receptor (TGFßR) and EGF receptor (EGFR) signaling, often observed in advanced cancers and tissue fibrosis. However, the mechanism underlying caveolin-1-mediated transactivation of TGFßR and EGFR signaling remains unclear. Therefore, we sought to determine whether caveolin-1 is involved in canonical and non-canonical TGFßR and EGFR signaling transactivation in this study. Methyl-ß-cyclodextrin (MßCD) was used to disrupt the cholesterol-containing membranes domains, and the caveolin-1 scaffolding domain (CSD) peptide was used to mimic the CSD of caveolin-1. Additionally, we transfected the Madin-Darby canine kidney cells with wild-type or phosphorylation-defective caveolin-1. We discovered that tyrosine 14 of caveolin-1 was critical for the negative regulation of TGFßR and EGFR canonical signaling. On the contrary, caveolin-1 inhibited TGF-ß1-induced ERK2 activation independent of tyrosine 14 phosphorylation. Although EGF failed to induce Smad3 phosphorylation in caveolin-1 knockdown cells, it activated Smad3 upon MßCD co-treatment, indicating that caveolin-1 indirectly regulated the non-canonical pathway of EGF. In conclusion, caveolin-1 differentially modulates TGFßR and EGFR signaling. Thus, targeting caveolin-1 is a potential strategy for treating diseases involving TGF-ß1 and EGF signaling.

Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats.

Clinical and animal experiments indicated that gut-derived endotoxin and imbalanced intestinal microbiota contribute to the pathogenesis of alcoholic liver disease (ALD). In this study, we investigated whether synbiotic supplementation could improve ALD in rats by altering the intestinal microbial composition and improving the intestinal integrity. Male Wistar rats were divided into four groups according to plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and subjected to either a normal liquid diet (C), a normal liquid diet with synbiotic supplementation (C + S), an ethanol liquid diet (E), or an ethanol liquid diet with synbiotic supplementation (E + S) for 12 weeks. Results revealed that the ethanol-fed group showed increases in plasma AST and ALT activities, the endotoxin level, the hepatic triglyceride (TG) level, and hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 levels, and a decrease in the hepatic IL-10 level. Ethanol-feeding also contributed to increased intestinal permeability and decreased fecal bifidobacteria and lactobacilli amounts. However, synbiotic supplementation effectively attenuated the plasma endotoxin, hepatic TG and TNF-α levels, and increased the hepatic IL-10 level. Furthermore, synbiotic supplementation protected the rats against ethanol-induced hyperpermeability of the intestine, and significantly increased amounts of bifidobacteria and lactobacilli in the feces. This study demonstrated that synbiotics possess a novel hepatoprotective function by improving the intestinal permeability and microbiota in rats with ethanol-induced liver injury.