白藜芦醇甲醚通过抑制Sirt1和STAT3途径的相互作用，在活化的肝星状细胞上发挥细胞毒性作用，从而抑制过度增殖。
Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.
发表日期：2023 Sep 16
作者：
Jiayi Dou, Haozhen Cui, Zhenyu Cui, Meiyan Xuan, Chong Gao, Zhaoxu Li, Lihua Lian, Jixing Nan, Yanling Wu
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
白藜芦醇的天然类似物皮癫痫苷 (PTE) 在蓝莓和葡萄中存在丰富，并对氧化应激、炎症和癌症具有几种有益的潜力。在本研究中，我们研究了 PTE 对肝纤维化在体外和体内的影响。肝星形细胞 (HSCs) 的活化是肝纤维化发生的初始事件。MTT 实验显示，PTE (3.125-12.5 μM) 对活化的 HSCs 显示细胞毒性，对 AML-12 和静止的 HSCs 则没有细胞毒性。PTE 显著抑制了 α-SMA、胶原Ⅰ和 TIMP-1/MMP13 比值的表达；抑制炎症级联反应以减少炎性细胞因子的释放，如Caspase-1、IL-1β和IL-6。PTE 激活了 Sirt1 并降低了 STAT3 的磷酸化，起到了 SRT1720 和 Niclosamide 的作用。Sirt1 缺乏导致 p-STAT3 的表达升高，而 STAT3 缺乏则导致 Sirt1 的增加并抑制纤维化和炎性细胞因子的表达。在联合乙酰胺基硫代甲酸盐 (TAA) 诱导的肝纤维化小鼠中，PTE 显著降低了 ALT 和 AST 活性，减少了纤维化标志物、STAT3 的磷酸化和激活的 Sirt1 的表达。PTE 对活化的 HSCs 显示细胞毒性，通过调节纤维形成、能量代谢和炎症以及靶向 Sirt1 和 STAT3 的相互作用来改善肝纤维化。综上所述，PTE 可能作为一种天然植物代谢产物在预防和治疗肝纤维化中具有潜在益处。版权所有 © 2023 Elsevier Ltd.
Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 μM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1β and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.Copyright © 2023. Published by Elsevier Ltd.