Frontiers in pharmacology · 2024
Elucidating the mechanism of stigmasterol in acute pancreatitis treatment: insights from network pharmacology and in vitro/in vivo experiments.
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Zhao Xuanlin, Li Fan, Wen Ao, Yu Xiuxian, Xu Xinrui, Wan Chengyu, Cao Yu, Xin Guang, Huang Wen
Аннотация
INTRODUCTION: Acute pancreatitis (AP) is a severe inflammatory disease of the pancreas that could trigger a systemic inflammation and multi-organ dysfunction. Stigmasterol, a natural plant sterol found in various herbs and vegetables, exhibits a significant anti-inflammatory, antioxidant, and cholesterol-lowering effects. However, its therapeutic potential in AP have not been thoroughly investigated.
METHODS: The present study employed network pharmacology combined with experimental verification to explore the protective effect of stigmasterol on AP and its molecular mechanism in a sodium taurocholate (STC)-induced AP mouse model.
RESULTS: Protein-protein interaction (PPI) analysis pinpointed out MAPK3, also named as ERK1, as a promising stigmasterol target in AP therapy. Molecular docking analysis further revealed a strong binding capacity of stigmasterol to ERK1 (-6.57 kL/mol). Furthermore, both in vivo and in vitro studies demonstrated that stigmasterol treatment notably attenuated STC-induced pancreatic injury, as evidented by decreased serum levels of lipase and amylase, improved systemic inflammation, and reduced acinar cell necrosis. At the molecular level, stigmasterol treatment exhibited a significant inhibition on STC-induced activation of ERK signaling pathway in pancreatic acinar cells, leading to the transition of acinar cell death from necrosis to apoptosis, thereby preventing acinar cell necrosis-induced systemic inflammation.
CONCLUSION: This study demonstrated that stigmasterol exhibits a significant protective effect aganist AP, at least in part through enhancing acinar cell apoptosis via modulating the ERK signaling pathways.
METHODS: The present study employed network pharmacology combined with experimental verification to explore the protective effect of stigmasterol on AP and its molecular mechanism in a sodium taurocholate (STC)-induced AP mouse model.
RESULTS: Protein-protein interaction (PPI) analysis pinpointed out MAPK3, also named as ERK1, as a promising stigmasterol target in AP therapy. Molecular docking analysis further revealed a strong binding capacity of stigmasterol to ERK1 (-6.57 kL/mol). Furthermore, both in vivo and in vitro studies demonstrated that stigmasterol treatment notably attenuated STC-induced pancreatic injury, as evidented by decreased serum levels of lipase and amylase, improved systemic inflammation, and reduced acinar cell necrosis. At the molecular level, stigmasterol treatment exhibited a significant inhibition on STC-induced activation of ERK signaling pathway in pancreatic acinar cells, leading to the transition of acinar cell death from necrosis to apoptosis, thereby preventing acinar cell necrosis-induced systemic inflammation.
CONCLUSION: This study demonstrated that stigmasterol exhibits a significant protective effect aganist AP, at least in part through enhancing acinar cell apoptosis via modulating the ERK signaling pathways.