Rhizoma Alismatis Decoction improved mitochondrial dysfunction to alleviate SASP by enhancing autophagy flux and apoptosis in hyperlipidemia acute pancreatitis

• Published in: Phytomedicine (Stuttgart) 2024-07, Vol.129, p.155629-155629, Article 155629
• Main Authors: Zhang, Rongzhan, Zhu, Zhiyong, Ma, Yumei, Tang, Tiantian, Wu, Jiejie, Huang, Fang, Xu, Luzhou, Wang, Yaping, Zhou, Jia
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy flux; HLAP; Mitochondrial function; Mitophagy; SASP
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2024.155629

•RAD improved pancreatic structure and SASP in the HLAP murine model.•RAD attenuated mitochondrial dysfunction in vivo and in vitro.•RAD enhances autophagic flux in lesions of the pancreas and CER-induced AR42J.•RAD suppresses mitochondrial damage and NLRP3 activation by activating mitophagy.•RAD alleviates SASP by suppressing IL-1β secretion via the apoptosis pathway. Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal–autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation. The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP. C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP. In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1β in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitocho