Circular RNAs are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. In the current study, we evaluate the function of a novel circRNA derived from the β-catenin gene locus, circβ-catenin. Circβ-catenin is predominantly localized in the cytoplasm and displays resistance to RNase-R treatment. We find that circβ-catenin is highly expressed in liver cancer tissues when compared to adjacent normal tissues. Silencing of circβ-catenin significantly suppresses malignant phenotypes in vitro and in vivo, and knockdown of this circRNA reduces the protein level of β-catenin without affecting its mRNA level. We show that circβ-catenin affects a wide spectrum of Wnt pathway-related genes, and furthermore, circβ-catenin produces a novel 370-amino acid β-catenin isoform that uses the start codon as the linear β-catenin mRNA transcript and translation is terminated at a new stop codon created by circularization. We find that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to activation of the Wnt pathway. Our findings illustrate a non-canonical function of circRNA in modulating liver cancer cell growth through the Wnt pathway, which can provide novel mechanistic insights into the underlying mechanisms of hepatocellular carcinoma.

OBJECTIVE COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of ACE2 may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on ACE2 lung expression. RESEARCH DESIGN AND METHODS We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant. RESULTS The most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N = 898,130), T2DM was causally linked to raised ACE2 expression (P = 2.91E−03; MR-IVW). Significant associations (at nominal level; P < 0.05) with ACE2 expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor–positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. CONCLUSIONS Our analysis suggested that diabetes and related traits may increase ACE2 expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.

The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.

Glucagon-like peptide-1 (GLP-1) is a novel antidiabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the human kidney-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analog, liraglutide, in the presence of high glucose. However, most of the previous findings mainly focused on its indirect effect in inhibiting the advanced glycation end products. Here, besides glycemic control, we also demonstrated a stimulatory role of liraglutide in promoting autophagy and relieving oxidative stress in Zucker diabetic fatty rats. The renoprotective effect of liraglutide has been demonstrated by significantly decreasing urinary albumin ( P < 0.01) and ameliorating renal pathological changes ( P < 0.001) in vivo. Besides that, proliferation of human epithelial kidney cell line HKC-8 and human embryonic kidney-293 cells has increased after treating with exendin-4, a GLP-1 receptor (GLP-1R) agonist. Moreover, GLP-1 could positively improve the progression of autophagy in vivo and in vitro through regulating the autophagy-related protein light chain 3 and p62 via AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway. Simultaneously, it could reverse NF-erythroid 2-related factor 2 (NRF2) translocation into the nuclei and suppress oxidative stress. In terms of mechanism, the renoprotective effect of GLP-1 would be exerted via the GLP-1R-AMPK-mTOR-autophagy-reactive oxygen species signaling axis. The present study not only illustrates the renoprotective effect of GLP-1 in diabetic kidney disease (DKD) rats, but also for the first time elucidates the underlying mechanism that is independent of controlling glucose, which implies that GLP-1 might be a novel therapeutic strategy for the prevention and treatment of DKD.