Severe acute pancreatitis (SAP) is an inflammatory disorder of the exocrine pancreas associated with high morbidity and mortality. SAP has been proven to trigger mitochondria dysfunction in the pancreas. We found that Deoxyarbutin (dA) recovered impaired mitochondrial function. High-temperature requirement protein A2 (HtrA2), a mitochondrial serine protease upstream of PGC-1α, is charge of quality control in mitochondrial homeostasis. The molecular docking study indicated that there was a potential interaction between dA and HtrA2. However, whether the protective effect of dA against SAP is regulated by HtrA2/PGC-1α remains unknown. Our study in vitro showed that dA significantly reduced the necrosis of primary acinar cells and reactive oxygen species (ROS) accumulation, recovered mitochondrial membrane potential (ΔΨm) and ATP exhaustion, while UCF-101 (HtrA2 inhibitor), and SR-18292 (PGC-1α inhibitor) eliminated the protective effect of dA. Moreover, HtrA2 siRNA transfection efficiently blocked the protective of dA on HtrA2/PGC-1α pathway in 266-6 acinar cells. Meanwhile, dA also decreased LC3II/I ration, as well as p62, and increased Parkin expression, while UCF-101 and Bafilomycin A1 (autophagy inhibitor) reversed the protective effect of dA. Our study in vivo confirmed that dA effectively alleviated severity of SAP by reducing pancreatic edema, plasma amylase, and lipase levels and improved the HtrA2/PGC-1α pathway. Therefore, this is the first study to identify that dA inhibits pancreatic injury caused by oxidative stress, mitochondrial dysfunction, and impaired autophagy in a HtrA2/PGC-1α dependent manner.
Apoptosis is a main cause of myocardial injury in myocardial ischemia/reperfusion injury (MIRI). Brain abundant membrane attached signal protein 1 (BASP1) was an apoptosis regulator that may be involved in the myocardial apoptosis during MIRI. In this study, we established the MIRI mouse model by ligating the left anterior descending coronary artery of mice for 30 min followed by reperfusion for 24 h. BASP1 was upregulated in the MIRI model. The adenoviruses carrying shRNA that specifically targets BSAP1 were used to downregulate BASP1 expression in myocardium. BASP1 silencing alleviated myocardial infarction and improved cardiac function. Furthermore, BASP1 silencing inhibited MIRI-induced myocardial apoptosis as evidenced by decreased TUNEL-positive cells and reduced caspase-3 and caspase-9 activities. Meanwhile, cell model was also established by culturing mouse HL-1 cells in a hypoxic (H) environment for 8 h, followed by reoxygenation (R) for 12 h. H/R upregulated BASP1 expression and BASP1 knockdown reduced H/R-induced apoptosis. Besides, the mRNA-sequencing analysis was conducted to explore the underlying mechanism by which BASP1 functions. HtrA serine peptidase 2 (HTRA2), one of the 1975 differentially expressed genes ( p < 0.05, |log 2 FC| > 1.5), was identified as candidates of molecular targets of BASP1 through gene ontology annotation and enrichment analysis. Introduction of HTRA2 to HL-1 cells counteracted the impact of BASP1 knockdown. MiR-7a-5p was found to target the 3′-untranslated regions of BASP1 and inhibit its expression through dual luciferase reporter assay. Collectively, BASP1/HTRA2 axis, regulated by miR-7a-5p, may be the promoter of MIRI process, indicating that BASP1/HTRA2 axis is a potential target for treating MIRI.
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