Department of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an 71111, Jordan.
Department of Biology, Faculty of Science, Al-Hussein Bin Talal University, Ma'an 71111, Jordan.
Biomolecules. 2019 Aug 5;9(8):346. doi: 10.3390/biom9080346.
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-κB) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-κB 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 (PPARγ) 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.
环磷酰胺（CP）是一种广泛应用的化疗药物；然而，由于其多器官毒性，其临床应用受到限制。高良姜素（Gal）是一种具有良好生物活性的类黄酮，具有广阔的应用前景。本研究探讨了 Gal 在 CP 诱导的大鼠中的肝保护作用。大鼠连续 15 天给予 Gal（15、30 和 60mg/kg/天），第 16 天给予单次 CP 剂量。CP 引起的肝损伤表现为血清转氨酶、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 给药大鼠肝内活性氧、丙二醛、一氧化氮和氧化 DNA 损伤增加，谷胱甘肽和抗氧化酶水平降低。CP 诱导肝核因子-κB（NF-κB）磷酸化，诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）mRNA 丰度增加，肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）表达和血清水平升高。Gal 可预防 CP 引起的肝损伤，增强抗氧化剂，抑制氧化应激、DNA 损伤、NF-κB 磷酸化和促炎介质。Gal 降低 CP 给药大鼠肝组织中 Bax 和 caspase-3 的表达，增加 B 细胞淋巴瘤-2（Bcl-2）的表达。此外，Gal 增加过氧化物酶体增殖物激活受体γ（PPARγ）的表达，激活肝核因子红细胞 2 相关因子 2（Nrf2）信号通路，CP 给药大鼠中 Nrf2、NAD（P）H：醌氧化还原酶-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 Nrf2/HO-1 信号通路和减轻氧化损伤、炎症和细胞死亡来预防 CP 肝毒性。因此，Gal 可能代表一种有前途的辅助治疗方法，可预防 CP 治疗患者的肝毒性。
