Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages.

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

LncUBE2R2-AS1 acts as a microRNA sponge of miR-302b to promote HCC progression via activation EGFR-PI3K-AKT signaling pathway.

Hepatocellular carcinoma (HCC) is a main cause of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) play important roles in diverse cancers. LncRNA-UBE2R2-AS1 has been reported to promote apoptosis in glioma cell. However, the expressions, functions, and mechanisms of action of UBE2R2-AS1 in HCC are still unclear. UBE2R2-AS1 is increased in HCC tissues and cell lines. Increased expression of UBE2R2-AS1 is associated with large tumor size, multiple tumor number, advanced TNM stage, and poor survival of HCC patients. Functional experiments showed that knockdown UBE2R2-AS1 inhibited HCC growth and metastasis through in vitro and in vivo experiments. Regarding the mechanism, UBE2R2-AS1/miR-302b/EGFR established the ceRNA network involved in the modulation of cell progression of HCC cells via activation of PI3K-AKT signaling pathway. Overall, UBE2R2-AS1 may exhibit an oncogenic function in HCC via acting as a sponge for miR-302b to up-regulate EGFR, and may serve as a potential therapeutic target and a prognostic biomarker for HCC patients.