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Rhein activated Fas-induced apoptosis pathway causing cardiotoxicity in vitro and in vivo
Toxicology Letters ( IF 2.9 ) Pub Date : 2022-05-16 , DOI: 10.1016/j.toxlet.2022.04.006
Gang Min Li 1 , Jun Ren Chen 1 , Hui Qiong Zhang 2 , Chen Sun 1 , Guan Ru Chen 1 , Qiu Yun Xiong 1 , Xiao Yu Cao 1 , Lei Yu 1 , Zi Wei Lin 1 , Jun Yuan Qin 1 , Liu Jun Wu 1 , Jing Li 1 , Lin Pu 1 , Fu Peng 1 , Xiao Fang Xie 1 , Cheng Peng 1
Affiliation  

Rhein, one of the main active components of rhubarb (Dahuang) and Polygonum multiflorum (Heshouwu), has a wide range of effective pharmacological effects. Recently, increasing studies have focused on its potential hepatorenal toxicity, but the cardiotoxicity is unknown. In this study, we found that the IC50 of rhein to H9c2 cells at 24 h and 48 h were 94.5 and 45.9μmol/L, respectively, with positive correlation of dose-toxicity and time-toxicity. After the treatment of rhein (106, 124 and 132μmol/L), the number of H9c2 cells decreased significantly, and the morphology of H9c2 cells showed atrophy, round shape and wall detachment. Moreover, the proportion of apoptotic cells in H9c2 cells treated with rhein was significantly increased in a dose-dependent manner. And rhein induced S phase arrest of H9c2 cells and inhibited cell proliferation. Rhein up-regulated ROS, LDH levels and low MMP but down-regulated SOD content in H9c2 cells. Additionally, the results showed that the cardiac function LVEF and LVFS of rhein high-medium-low dose groups (350, 175, 87.5 mg/kg) were significantly reduced. And the contents of Ca2+, cTnT, CK and LDH in serum of KM mice were significantly up-regulated by rhein. Furthermore, western blot results suggested that rhein the above effects via promoting Fas-induced apoptosis pathway in vitro and in vivo. In general, rhein may cause cardiotoxicity via Fas-induced apoptosis pathway in vivo and in vitro, which provides reference for the safe use of medicinal plant containing rhein and its preparations.



中文翻译:

大黄酸激活 Fas 诱导的细胞凋亡途径,在体外和体内引起心脏毒性

大黄(大黄)和何首乌(何首乌)的主要活性成分之一大黄酸具有广泛的有效药理作用。最近,越来越多的研究集中在其潜在的肝肾毒性上,但心脏毒性尚不清楚。在这项研究中,我们发现IC 5024 h和48 h大黄酸对H9c2细胞的抑制作用分别为94.5和45.9μmol/L,剂量毒性和时间毒性呈正相关。大黄酸(106、124和132μmol/L)处理后,H9c2细胞数量明显减少,H9c2细胞形态呈萎缩、圆形、壁脱落。此外,用大黄酸处理的H9c2细胞中凋亡细胞的比例以剂量依赖性方式显着增加。大黄酸诱导H9c2细胞S期阻滞,抑制细胞增殖。Rhein 上调 ROS、LDH 水平和低 MMP 但下调 H9c2 细胞中的 SOD 含量。此外,结果显示大黄酸高中低剂量组(350、175、87.5 mg/kg)的心功能LVEF和LVFS显着降低。和 Ca 2+的含量大黄酸显着上调KM小鼠血清中的cTnT、CK和LDH。此外,蛋白质印迹结果表明,大黄酸通过在体外和体内促进 Fas 诱导的细胞凋亡途径发挥上述作用。总体而言,大黄酸在体内外均可通过Fas诱导的细胞凋亡途径引起心脏毒性,为含大黄酸的药用植物及其制剂的安全使用提供参考。

更新日期:2022-05-16
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