Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity
Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity
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DOI：
10.3390/biom9080346
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发表时间：
2019-08-01
期刊：
影响因子：
5.5
通讯作者：
Mahmoud, Ayman M.
中科院分区：
文献类型：
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作者：
Aladaileh, Saleem H.;Abukhalil, Mohammad H.;Mahmoud, Ayman M.
环磷酰胺（Cyclophosphamide，CP）是一种广泛应用的化疗药物，但其多器官毒性限制了其临床应用。高良姜素（Galangin，Gal）是一种具有良好生物活性的黄酮类化合物。本研究探讨了半乳糖对CP诱导的大鼠肝损伤的保护作用。大鼠接受Gal（15、30和60 mg/kg/天）给药15天，然后在第16天单次给予CP。环磷酰胺引发肝损伤，其特征在于血清转氨酶、碱性磷酸酶（ALP）和乳酸脱氢酶（LDH）升高以及组织病理学表现。CP给药大鼠的肝脏活性氧、丙二醛、一氧化氮和氧化性DNA损伤沿着增加，谷胱甘肽和抗氧化酶下降。CP引起肝核因子-κ B（NF-κ B）磷酸化，并增加诱导型一氧化氮合酶（iNOS）和环氧合酶-2（考克斯-2）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1 β（IL-1 β）的mRNA丰度表达和血清水平。半乳糖预防CP诱导的肝损伤，增强抗氧化剂和抑制氧化应激，DNA损伤，NF-κ B磷酸化和促炎介质。半乳糖减少CP给药大鼠肝脏中Bax和caspase-3，并增加B细胞淋巴瘤-2（Bcl-2）。此外，半乳糖增加过氧化物酶体增殖物激活受体γ（PPAR γ）表达和激活肝核因子红细胞2相关因子2（Nrf 2）信号传导，表现为CP给药大鼠中Nrf 2、NAD（P）H：醌受体氧化还原酶-1（NQO-1）和血红素加氧酶1（HO-1）增加。这些发现表明Gal通过激活Nrf 2/HO-1信号传导和减弱氧化损伤、炎症和细胞死亡来预防CP肝毒性。因此，Gal可能是一种有前途的辅助治疗，以防止CP治疗患者的肝毒性。
Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical application is limited because of its multi-organ toxicity. Galangin (Gal) is a bioactive flavonoid with promising biological activities. This study investigated the hepatoprotective effect of Gal in CP-induced rats. Rats received Gal (15, 30 and 60 mg/kg/day) for 15 days followed by a single dose of CP at day 16. Cyclophosphamide triggered liver injury characterized by elevated serum transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and histopathological manifestations. Increased hepatic reactive oxygen species, malondialdehyde, nitric oxide, and oxidative DNA damage along with declined glutathione and antioxidant enzymes were demonstrated in CP-administered rats. CP provoked hepatic nuclear factor-kappaB (NF-kappa B) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-kappa B phosphorylation and pro-inflammatory mediators. Gal diminished Bax and caspase-3, and increased B-cell lymphoma-2 (Bcl-2) in liver of CP-administered rats. In addition, Gal increased peroxisome proliferator-activated receptor gamma (PPAR gamma) expression and activated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling showed by the increase in Nrf2, NAD(P)H: quinone acceptor oxidoreductase-1 (NQO-1) and heme oxygenase 1 (HO-1) in CP-administered rats. These findings suggest that Gal prevents CP hepatotoxicity through activation of Nrf2/HO-1 signaling and attenuation of oxidative damage, inflammation and cell death. Therefore, Gal might represent a promising adjuvant therapy to prevent hepatotoxicity in patients on CP treatment.