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  3. JuA alleviates liver ischemia-reperfusion injury by activating AKT/NRF2/HO-1 pathways

JuA alleviates liver ischemia-reperfusion injury by activating AKT/NRF2/HO-1 pathways

  • Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167496. doi: 10.1016/j.bbadis.2024.167496.
Haoran Fang 1,  Min Xu 1,  Jiakai Zhang 1,  Hong Qin 1,  Hongwei Tang 2,  Yuting He 3,  Wenzhi Guo 4
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 2 Henan Key Laboratory for Hepatopathy and Transplantation Medicine, Zhengzhou, China; Department of Henan Key Laboratory of Digestive Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Henan Key Laboratory of Digestive Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: fccheyt1@zzu.edu.cn.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory for Hepatopathy and Transplantation Medicine, Zhengzhou, China; Department of Henan Key Laboratory of Digestive Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: fccguowz@zzu.edu.cn.
PMID: 39237046 DOI: 10.1016/j.bbadis.2024.167496
Abstract

Liver ischemia-reperfusion (I/R) injury is a detrimental complication of organ transplantation, shock, and sepsis. However, the available drugs to mitigate I/R injury remain limited. Jujuboside A (JuA) is renowned for its antioxidant, anti-inflammatory, and anti-apoptotic properties; nevertheless, its potential in liver I/R injury remains unknown. Thus, this study aimed to explore the role and underlying mechanisms of JuA in liver I/R injury. Mouse models of I/R and AML12 cell models of hypoxia/reoxygenation (H/R) were constructed. Haematoxylin and eosin staining, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) detection, and cell viability analysis were used to assess liver injury. To evaluate oxidative stress, inflammation, Apoptosis, and mitochondrial damage, immunofluorescence staining, transmission electron microscopy analysis, enzyme-linked immunosorbent assay, and flow cytometry were conducted. Moreover, molecular docking techniques and western blot were employed to identify downstream target molecules and pathways affected by JuA. The results showed that JuA pretreatment effectively attenuated liver necrosis and ALT and AST level elevations induced by I/R while enhancing AML12 cell viability following H/R. Furthermore, JuA pretreatment suppressed oxidative stress triggered by I/R and H/R, thereby inhibiting the level of pro-inflammatory factors and NLRP3 inflammasome activation. Notably, JuA pretreatment alleviated mitochondrial damage and Apoptosis. Mechanistically, JuA pretreatment resulted in the activation of the Akt/NRF2/HO-1 signalling pathways, whereas MK2206, the inhibitor of Akt, partially reversed the hepatoprotective effects of JuA during liver I/R. Collectively, our findings illustrated that JuA mitigated oxidative stress, inflammation, Apoptosis, and mitochondrial damage by facilitating the Akt/NRF2/HO-1 signalling pathway, thereby alleviating liver I/R injury.

Keywords

AKT/NRF2/HO-1; Apoptosis; Inflammation; Ischemia-reperfusion injury; JuA; Mitochondrial damage; Oxidative stress.

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