TRPC6 inhibits renal tubular epithelial cell pyroptosis through regulating zinc influx and alleviates renal ischemia-reperfusion injury.

Canonical transient receptor potential-6 (TRPC6) has been reported to be involved in cell damage after ischemia/reperfusion (I/R) injury in target organs. While the effect and of TRPC6 on pyroptosis in renal I/R injury remain unclear. In our study, we first established the renal I/R mouse model and oxygen-glucose deprivation and re-oxygenation (OGD/R) cell model, and investigated the impacts of TRPC6 on the pyroptosis-related proteins using CCK-8, western blot, ELISA, and immunofluorescence probes. Besides, we also explored the mechanism of TRPC6 in pyroptosis of renal tubular epithelial cells through A20 knockdown or overexpression and zinc chloride (ZnCl2 ) or a zinc ion chelator (TPEN) treatment. Our results indicated that I/R injury could cause downregulation of TRPC6 both in vivo and in vitro. In the I/R injury murine model, TRPC6 inhibition exacerbated tissue damage and upregulated NLRP3, ASC, caspase-1, IL-18, and IL-1ß, which could be alleviated by the administration of ZnCl2 . In the OGD/R cell model, inhibitor of TRPC6 (SAR7334) reduced zinc ion influx, aggravated cell death and upregulated pyroptosis-related protein. The pyroptosis phenotype also could be alleviated by ZnCl2 and intensified by TPEN. Overexpression of A20 reduced the expression of pyroptosis-related protein, increased cell viability in the sh-TRPC6 and TPEN-treated OGD/R cell models, while A20 deficiency impaired the protective effect of zinc ion. Therefore, our results indicate that TRPC6 could promote zinc ion influx in renal tubular epithelial cells, thereby upregulating intracellular A20, inhibiting the activation of inflammasome NLRP3, and ultimately attenuating renal I/R injury.

Intermittent hypoxia reduces infarct size in rats with acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: To determine whether intermittent hypoxia (IH) can reduce the infarct size (IS) after acute myocardial infarction (AMI) in rats. METHODS: Articles were identified in PubMed, EMBASE and the Web of Science and were included if they evaluated the effect of IH on the changes in the infarcted area after AMI in rats. RESULTS: A preliminary search identified 3633 articles and 29 data sets from 23 articles (12 in vivo, 16 in vitro). The IS decreased after AMI in IH rats both in vitro (SMD -1.46, 95% CI [- 2.37, - 0.55]; I2 = 85.6%, P = 0.000) and in vivo (SMD -1.43, 95% CI [- 2.05, - 0.82], I2 = 73.6%, P = 0.000). Sensitivity analysis indicated that IH had a strong protective effect against myocardial infarction, and the hypoxia concentration was significantly correlated with the change in IS after AMI. CONCLUSION: IH can reduce IS after AMI in rats. This effect of IH may be related to the dose of hypoxia, and the oxygen concentration may be one of the most important influencing factors.

Asymmetric Synthesis of Spirocyclopentane Oxindoles Containing Four Consecutive Stereocenters and Quaternary α-Nitro Esters via Organocatalytic Enantioselective Michael-Michael Cascade Reactions.

An enantioselective domino Michael-Michael reaction of nitroolefins and 2-nitro-3-arylacrylates has been established, which provided a series of spirocyclopentane oxindoles with four consecutive stereocenters including quaternary α-nitro esters with good yields (up to 73%) and excellent enantioselectivities (up to 97% ee). The reaction was realized and optimized with the aid of a chiral squaramide-amine catalyst. The structures of 11 products were confirmed by single-crystal X-ray diffraction analysis.