Background 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s13059-019-1685-4) contains supplementary material, which is available to authorized users.

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Background Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation. Methods To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured. Results The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells. Conclusion MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.

BackgroundThere was no consistent recognition of the association between high or low body mass index (BMI) and health related quality of life (HRQL). The aim of this research was to study the association between BMI and HRQL in Chinese adults, and to further explore the stability of that association in the subgroup analysis stratified by status of chronic conditions.MethodsA total of 21,218 adults aged 18 and older were classified as underweight, normal weight, overweight, class I obese, and class II obese based on their BMI. HRQL was measured by the SF-36 Health Survey. The independent impact of each BMI category on HRQL was examined through standard least squares regression by comparing the difference of SF-36 scores and the minimum clinically important differences (MCID), which was defined as 3 points.ResultsCompared to the normal weight, the class I obese was significantly associated with better HRQL scores in the mental component summary (MCS) (75.1 vs. 73.4, P<0.001). The underweight had the lowest score in both the physical components summary (PCS) (75.4 vs. 77.5, P<0.001) and mental components summary (MCS) (71.8 vs. 73.4, P<0.001). For the MCID, the HRQL score was reduced by more than 3 points in the physical functioning for the class II obese (D=-3.43) and the general health for the underweight (D=-3.71). Stratified analyses showed a similar result in the health subjects and chronic conditions, and it was significant in the chronic conditions.ConclusionsThe class I obese showed the best HRQL, especially in the mental domain. The worst HRQL was found in the underweight. The class II obese reduced HRQL in the physical functioning only. “Obesity paradox” was more obvious in the participants with chronic conditions.