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Allopurinol ameliorates liver injury in type 1 diabetic rats through activating Nrf2
International Journal of Immunopathology and Pharmacology ( IF 3.5 ) Pub Date : 2021-07-09 , DOI: 10.1177/20587384211031417
Fei Zeng 1 , Jierong Luo 2, 3 , Hong Han 1 , Wenjie Xie 1 , Lingzhi Wang 1 , Ronghui Han 4 , Hao Chen 4 , Yin Cai 4, 5 , Huansen Huang 1 , Zhengyuan Xia 3, 4, 6
Affiliation  

Hyperglycemia-induced oxidative stress plays important roles in the development of non-alcoholic fatty liver disease (NAFLD), which is a common complication in diabetic patients. The Nrf2-Keap1 pathway is important for cell antioxidant protection, while its role in exogenous antioxidant mediated protection against NAFLD is unclear. We thus, postulated that antioxidant treatment with allopurinol (ALP) may attenuate diabetic liver injury and explored the underlying mechanisms. Control (C) and streptozotocin (STZ)-induced diabetes rats (D) were untreated or treated with ALP for 4 weeks starting at 1 week after diabetes induction. Serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), production of lipid peroxidation product malondialdehyde (MDA), and serum superoxide dismutase (SOD) were detected. Liver protein expressions of cleaved-caspase 3, IL-1β, nuclear factor-erythroid-2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), P62, Kelch-like ECH-associated protein 1 (Keap1), and LC3 were analyzed. In vitro, cultured rat normal hepatocytes BRL-3A were grouped to normal glucose (5.5 mM, NG) or high glucose (25 mM, HG) and treated with or without allopurinol (100 µM) for 48 h. Rats in the D group demonstrated liver injury evidenced as increased serum levels of ALT and AST. Diabetes increased apoptotic cell death, enhanced liver protein expressions of cleaved-caspase 3 and IL-1β with concomitantly increased production of MDA while serum SOD content was significantly reduced (all P < 0.05 vs C). In the meantime, protein levels of Nrf2, HO-1, and P62 were reduced while Keap1 and LC3 were increased in the untreated D group as compared to control (P < 0.05 vs C). And all the above alterations were significantly attenuated by ALP. Similar to our findings obtained from in vivo study, we got the same results in in vitro experiments. It is concluded that ALP activates the Nrf2/p62 pathway to ameliorate oxidative stress and liver injury in diabetic rats.



中文翻译:

别嘌醇通过激活Nrf2改善1型糖尿病大鼠肝损伤

高血糖诱导的氧化应激在非酒精性脂肪性肝病 (NAFLD) 的发展中起重要作用,这是糖尿病患者的常见并发症。Nrf2-Keap1 通路对细胞抗氧化保护很重要,而其在外源性抗氧化剂介导的 NAFLD 保护中的作用尚不清楚。因此,我们假设用别嘌醇 (ALP) 进行抗氧化治疗可以减轻糖尿病肝损伤并探索其潜在机制。对照组 (C) 和链脲佐菌素 (STZ) 诱导的糖尿病大鼠 (D) 在糖尿病诱导后 1 周开始未经治疗或用 ALP 治疗 4 周。检测血清丙氨酸氨基转移酶 (ALT) 和天冬氨酸转氨酶 (AST) 水平、脂质过氧化产物丙二醛 (MDA) 和血清超氧化物歧化酶 (SOD) 的产生。cleaved-caspase 3、IL-1β、核因子-红细胞-2相关因子-2 (Nrf2)、血红素加氧酶-1 (HO-1)、P62、Kelch样ECH相关蛋白1 (Keap1)的肝蛋白表达) 和 LC3 进行了分析。在体外,将培养的大鼠正常肝细胞 BRL-3A 分为正常葡萄糖(5.5 mM,NG)或高葡萄糖(25 mM,HG),用或不用别嘌醇(100 µM)处理 48 小时。D组大鼠表现出肝损伤,表现为血清ALT和AST水平升高。糖尿病增加了凋亡细胞死亡,增强了裂解的 caspase 3 和 IL-1β 的肝蛋白表达,同时增加了 MDA 的产生,而血清 SOD 含量显着降低(所有 和 LC3 进行了分析。在体外,将培养的大鼠正常肝细胞 BRL-3A 分为正常葡萄糖(5.5 mM,NG)或高葡萄糖(25 mM,HG),用或不用别嘌醇(100 µM)处理 48 小时。D组大鼠表现出肝损伤,表现为血清ALT和AST水平升高。糖尿病增加了凋亡细胞死亡,增强了裂解的 caspase 3 和 IL-1β 的肝蛋白表达,同时增加了 MDA 的产生,而血清 SOD 含量显着降低(所有 和 LC3 进行了分析。在体外,将培养的大鼠正常肝细胞 BRL-3A 分为正常葡萄糖(5.5 mM,NG)或高葡萄糖(25 mM,HG),用或不用别嘌醇(100 µM)处理 48 小时。D组大鼠表现出肝损伤,表现为血清ALT和AST水平升高。糖尿病增加了凋亡细胞死亡,增强了裂解的 caspase 3 和 IL-1β 的肝蛋白表达,同时增加了 MDA 的产生,而血清 SOD 含量显着降低(所有P  < 0.05 与 C)。与此同时,与对照组相比,未处理的 D 组中 Nrf2、HO-1 和 P62 的蛋白质水平降低,而 Keap1 和 LC3 的蛋白质水平升高(P  < 0.05 vs C)。并且所有上述改变都被ALP显着减弱。与我们从体内研究中获得的结果相似,我们在体外实验中得到了相同的结果。得出的结论是,ALP 激活 Nrf2/p62 通路以改善糖尿病大鼠的氧化应激和肝损伤。

更新日期:2021-07-09
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