杠柳苷元在预防对乙酰氨基酚诱导的药物性肝损伤中的保护作用及机制  

The protective effects and mechanisms of periplogenin in preventing acetaminophen-induced drug-induced liver injury

作　　者：王何月 胡旺 王小妮 徐涛[3] 周焕 WANG He-yue;HU Wang;WANG Xiao-ni;XU Tao;ZHOU Huan(Graduate School,Bengbu Medical University,the First Affiliated Hospital of Bengbu Medical University,Bengbu,Anhui 233030,China;National Institute of Clinical Drug Trials,the First Affiliated Hospital of Bengbu Medical University,Bengbu,Anhui 233030,China;School of Pharmacy,Anhui Medical University,Hefei 230032,China)

机构地区：[1]蚌埠医科大学研究生院,安徽蚌埠233030 [2]蚌埠医科大学第一附属医院国家临床药物试验中心,安徽蚌埠233030 [3]安徽医科大学药学院,安徽合肥230032

出　　处：《中国药理学通报》2025年第4期709-717,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No.82373932);安徽省高等学校科学研究项目(No.2023AH040290);蚌埠医科大学第一附属医院优秀青年科学基金项目(No.2021byyfyyq02)。

摘　　要：目的探究杠柳苷元(periplogenin,Ppg)预防性干预对由对乙酰氨基酚(acetaminophen,APAP)诱导的药物性肝损伤的保护作用及其分子机制。方法通过体内和体外实验,构建APAP诱导的药物性肝损伤模型,观察肝脾指数的变化,测定血清中AST、ALT的水平,采用HE染色观察各组小鼠肝组织的病理变化。利用ELISA、qPCR和Western blot技术分析Ppg对APAP诱导的AML-12细胞中炎症因子IL-6、TNF-α和IL-1β等指标表达的影响,同时检测谷胱甘肽(GSH)、丙二醛(MDA)水平和超氧化物歧化酶(SOD)活性,通过qPCR、Western blot和免疫荧光实验对NF-κB信号通路的相关指标进行检测。结果体内实验结果显示,Ppg改善了药物性肝损伤肝损伤小鼠的肝脾指数,血清中AST、ALT水平明显下降,减轻了肝组织的病理损伤。体外实验表明,Ppg明显抑制了APAP诱导的AML-12细胞中IL-6、TNF-α和IL-1β的表达,降低了GSH和MDA的水平,提高了SOD的活性。同时,通过PDTC(NF-κB信号通路抑制剂)抑制NF-κB信号通路,减少了炎症因子的表达,明显减少了p65在细胞核中的积累,效果与Ppg高剂量组相仿。结论Ppg能够减轻由APAP引起的肝损伤,其分子机制可能通过抑制肝细胞中的NF-κB信号通路,从而抑制炎症反应,保护APAP诱导的小鼠肝脏损伤。Aim To explore the protective effects and underlying molecular mechanisms of periplogenin(Ppg)in preventing acetaminophen(APAP)-induced drug-induced liver injury(DILI).Methods An APAP-induced liver injury model was established in vivo and in vitro.Liver/spleen indices were recorded,and serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were measured.The pathological changes in liver tissue were observed using hematoxylin-eosin(HE)staining.The influence of Ppg on inflammatory cytokines(IL-6,TNF-α,IL-1β)and key proteins within the associated signaling pathways was examined using enzyme-linked immunosorbent assay(ELISA),quantitative polymerase chain reaction(qPCR),and Western blot.Additionally,glutathione(GSH),malondialdehyde(MDA),and superoxide dismutase(SOD)activity levels were measured.The expression of markers related to the NF-κB signaling pathway was assessed using qPCR,Western blot,and immunofluorescence.Results In vivo experiments showed that Ppg improved the liver and spleen index of mice with drug-induced liver injury,and the levels of AST and ALT in the serum decreased significantly,reducing the pathological damage of liver tissue.In vitro experiments showed that Ppg significantly inhibited the expression of IL-6,TNF-αand IL-1β,and decreased the levels of GSH and MDA and increased SOD activity in AML-12 cells.Additionally,the inhibition of the NF-κB signaling pathway using pyrrolidinedithiocarbamate ammonium(PDTC),an NF-κB signaling pathway inhibitor reduced inflammatory cytokine expression and significantly decreased p65 nuclear translocation,showing results comparable to those observed in the high-dose Ppg group.Conclusions Ppg alleviates APAP-induced liver injury,potentially by inhibiting the NF-κB signaling pathway in hepatocytes,thereby reducing the inflammatory response and protecting liver from APAP-induced damage.

关 键 词：杠柳苷元 对乙酰氨基酚 药物性肝损伤 炎症 氧化应激 NF-ΚB信号通路 

分 类 号：R-332[医药卫生] R284.1R322.47R364.5R349.1R575.1