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西地那非对胆管结扎诱导的大鼠肝纤维化具有保护作用:沉默信息调节因子1(SIRT1)的潜在作用。

Sildenafil protects against bile duct ligation induced hepatic fibrosis in rats: Potential role for silent information regulator 1 (SIRT1).

作者信息

Abd El Motteleb Dalia M, Ibrahim Islam A A E-H, Elshazly Shimaa M

机构信息

Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Egypt.

Pharmacology and Toxicology Department, Faculty of Pharmacy, Zagazig University, Egypt.

出版信息

Toxicol Appl Pharmacol. 2017 Nov 15;335:64-71. doi: 10.1016/j.taap.2017.09.021. Epub 2017 Sep 30.

Abstract

Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-β content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1.

摘要

肝纤维化是一个潜在的健康问题,可能最终发展为危及生命的肝硬化和原发性肝癌。最近的研究指出沉默信息调节因子1(SIRT1)对不同器官纤维化模型具有保护作用。这项工作旨在研究西地那非(一种SIRT1激活剂)对胆管结扎(BDL)诱导的肝纤维化可能的保护作用。首先,研究了三种不同剂量的西地那非(5、10、20mg/kg/天),以检测对BDL诱导的肝功能障碍和肝纤维化最具保护作用的剂量。然后使用最具保护作用的剂量,研究其对BDL诱导的SIRT1下调、氧化/抗氧化状态失衡、炎性细胞因子增加和纤维化的影响。西地那非(20mg/kg/天)是最具保护作用的剂量,它可使SIRT1上调,降低肝脏丙二醛(MDA)含量,增加核因子红细胞2相关因子2(Nrf2)、血红素加氧酶(HO)-1的表达,提高还原型谷胱甘肽(GSH)含量和超氧化物歧化酶(SOD)活性。西地那非治疗可使肿瘤坏死因子-α(TNF-α)的肝脏含量以及核因子κB(NFκB)的表达和含量显著降低。此外,西地那非可使转化生长因子(TGF)-β含量、纤溶酶原激活物抑制剂-1(PAI-1)、基质金属蛋白酶-9(MMP-9)、金属蛋白酶组织抑制剂-1(TIMP-1)、α-平滑肌肌动蛋白(α-SMA)、纤连蛋白、I型胶原(α1)和羟脯氨酸含量显著降低。然而,联合使用EX527(一种SIRT1抑制剂)可显著降低西地那非的保护作用。我们的研究首次表明,西地那非对BDL诱导的肝功能障碍和肝纤维化具有良好的保护作用。这些作用可能部分是由SIRT1的上调介导的。

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