1. Academic Validation
  2. Deoxyarbutin attenuates severe acute pancreatitis via the HtrA2/PGC-1α pathway

Deoxyarbutin attenuates severe acute pancreatitis via the HtrA2/PGC-1α pathway

  • Free Radic Res. 2023 Jan 2;1-15. doi: 10.1080/10715762.2022.2163244.
Yangying Li 1 Yuda Zhu 1 Shiyi Li 1 Yuman Dong 1 Chengyu Wan 1 Xiuxian Yu 1 Guang Xin 1 Zeliang Wei 1 Fan Li 1 Yilan Wang 1 Kun Zhang 1 Qingqiu Chen 1 Cuicui Zhang 1 E Wen 1 Hai Niu 1 Wen Huang 1
Affiliations

Affiliation

  • 1 Laboratory of Ethnopharmacology, Tissue-orientated Property of Chinese Medicine Key Laboratory of Sichuan Province, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China.
Abstract

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.

Keywords

high-temperature requirement protein A2; Deoxyarbutin; PGC-1α; mitochondria; severe acute pancreatitis.

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