Al-Amarat Wesam, Abukhalil Mohammad H, Alruhaimi Reem S, Alqhtani Haifa A, Aldawood Nouf, Alfwuaires Manal A, Althunibat Osama Y, Aladaileh Saleem H, Algefare Abdulmohsen I, Alanezi Abdulkareem A, AbouEl-Ezz Ali M, Ahmeda Ahmad F, Mahmoud Ayman M
Department of Medical Support, Al-karak University College, Al-Balqa' Applied University, As-Salt 206, Jordan.
Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an 71111, Jordan.
Metabolites. 2022 Jul 14;12(7):648. doi: 10.3390/metabo12070648.
Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling.
肝损伤是化疗药物环磷酰胺（CP）的不良反应之一。本研究调查了黄酮芹菜素（API）对CP诱导的肝损伤的保护作用，指出Nrf2/HO-1信号通路参与其中。大鼠连续15天接受API（20和40mg/kg）治疗，并在第16天接受CP（150mg/kg）。CP导致肝损伤，表现为转氨酶、碱性磷酸酶（ALP）和乳酸脱氢酶（LDH）升高，以及组织学改变，包括颗粒空泡化、单核细胞浸润和水样变性。给予CP的大鼠肝脏活性氧（ROS）、丙二醛（MDA）和一氧化氮（NO）增加，谷胱甘肽（GSH）和抗氧化酶减少。CP上调炎症标志物NF-κB p65、TNF-α、IL-6和诱导型一氧化氮合酶（iNOS），以及促凋亡蛋白Bax和半胱天冬酶-3。用API预处理可改善CP中毒大鼠的循环转氨酶、ALP和LDH，并预防组织病理学变化。API抑制CP中毒大鼠的ROS、MDA、NO、NF-κB p65、iNOS、炎性细胞因子、氧化性DNA损伤、Bax和半胱天冬酶-3。此外，API增强肝脏抗氧化剂和Bcl-2，并提高Nrf2和HO-1的mRNA丰度和蛋白水平。总之，API通过减轻氧化应激、炎症反应和细胞凋亡，有效预防CP肝毒性。API的肝脏保护作用与Nrf2/HO-1信号通路的上调有关。
