Phytotherapeutics and Metabolic Endocrinology Division, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India.
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912,USA.
Toxicol Appl Pharmacol. 2018 Dec 1;360:99-108. doi: 10.1016/j.taap.2018.09.034. Epub 2018 Sep 28.
Acute liver injury is frequently associated with oxidative stress. Here, we investigated the therapeutic potential of carbon monoxide releasing molecule A-1 (CORM A-1) in oxidative stress-mediated liver injury. Overnight-fasted mice were injected with acetaminophen (APAP; 300 mg/kg; intraperitoneally) and were sacrificed at 4 and 12 h. They showed elevated levels of serum transaminases, depleted hepatic glutathione (GSH) and hepatocyte necrosis. Mice injected with CORM A-1 (20 mg/kg) 1 h after APAP administration, had reduced serum transaminases, preserved hepatic GSH and reduced hepatocyte necrosis. Mice that received a lethal dose of APAP (600 mg/kg), died by 10 h; but those co-treated with CORM A-1 showed a 50% survival. Compared to APAP-treated mice, livers from those co-treated with CORM A-1, had upregulation of Nrf2 and ARE genes (HO-1, GCLM and NQO-1). APAP-treated mice had elevated hepatic mRNA levels of inflammatory genes (Nf-κB, TNF-α, IL1-β and IL-6), an effect blunted in those co-treated with CORM A-1. In tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells, CORM A-1 augmented cell viability, reduced oxidative stress, activated the nuclear factor erythroid 2-related factor 2 (Nrf2) and anti-oxidant response element (ARE) genes. The molecular docking profile of CO in the kelch domain of Keap1 protein suggested that CO released from CORM A-1 mediated Nrf2 activation. Collectively, these data indicate that CORM A-1 reduces oxidative stress by upregulating Nrf2 and related genes, and restoring hepatic GSH, to reduce hepatocyte necrosis and thus minimize liver injury that contributes to an overall improved survival rate.
急性肝损伤常与氧化应激有关。在这里，我们研究了一氧化碳释放分子 A-1（CORM A-1）在氧化应激介导的肝损伤中的治疗潜力。 overnight-fasted 小鼠注射了对乙酰氨基酚（APAP；300mg/kg；腹腔内），并在 4 和 12 小时后处死。它们表现出血清转氨酶升高、肝内谷胱甘肽（GSH）耗竭和肝细胞坏死。在 APAP 给药后 1 小时给予 CORM A-1（20mg/kg）的小鼠，血清转氨酶降低，肝内 GSH 保留，肝细胞坏死减少。接受致死剂量 APAP（600mg/kg）的小鼠在 10 小时内死亡；但那些用 CORM A-1 共同治疗的小鼠显示出 50%的存活率。与 APAP 治疗的小鼠相比，用 CORM A-1 共同治疗的小鼠肝脏中 Nrf2 和 ARE 基因（HO-1、GCLM 和 NQO-1）上调。APAP 治疗的小鼠肝脏中炎症基因（NF-κB、TNF-α、IL1-β 和 IL-6）的 mRNA 水平升高，用 CORM A-1 共同治疗可减弱这种升高。在 tert-butyl hydroperoxide（t-BHP）处理的 HepG2 细胞中，CORM A-1 增强细胞活力，减少氧化应激，激活核因子红细胞 2 相关因子 2（Nrf2）和抗氧化反应元件（ARE）基因。CO 在 Keap1 蛋白的 kelch 结构域中的分子对接谱表明，CORM A-1 释放的 CO 介导了 Nrf2 的激活。总之，这些数据表明，CORM A-1 通过上调 Nrf2 及其相关基因，以及恢复肝内 GSH，来减少肝细胞坏死，从而最大限度地减少导致总体生存率提高的肝损伤，从而减轻氧化应激。
