Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation
Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation
复制标题
芹菜素通过抑制氧化应激和炎症改善阿霉素诱导的肾损伤
DOI：
10.1016/j.biopha.2021.111308
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发表时间：
2021-02-05
影响因子：
7.5
通讯作者：
Gao, Kun
中科院分区：
文献类型：
--
作者：
Wu, Qijing;Li, Wei;Gao, Kun
背景与目的：阿霉素（DOX）是一种蒽环类抗肿瘤抗生素，广泛应用于多种肿瘤的治疗。然而，DOX对正常细胞的毒性限制了其适用性，肾毒性被认为是主要的剂量限制性不良反应。芹菜素（Apigenin，APG）是一种广泛存在于天然植物中的黄酮类化合物，具有抗氧化、抗炎和轻微的肿瘤抑制作用。方法：雄性BALB/c小鼠经尾静脉注射DOX（11.5mg/kg）建立DOX肾病模型，观察APG对DOX肾毒性的影响。给药组和不给药组（125、250和500 mg/kg）2周后，取尿、血清和组织，检测尿蛋白、血清白蛋白、血清肌酐（Scr）、血尿素氮（BUN）、超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽（GSH）及病理学改变。利用大鼠肾小管上皮细胞（NRK 52 E）、小鼠足细胞（MPC 5）和小鼠乳腺癌细胞（4 T1）来验证APG对DOX诱导的细胞损伤的影响。采用MTT法分析细胞活力。采用TUNEL比色染色和Western印迹分析切割的caspase-3蛋白来评价细胞凋亡。采用活性氧（ROS）/超氧阴离子（O-2-）荧光探针检测氧化损伤。蛋白质印迹法用于分析nephrin、α-平滑肌肌动蛋白（α-SMA）、胶原I（科尔）、纤连蛋白（FN）和5 OD 2表达。采用逆转录-聚合酶链反应（RT-PCR）检测肿瘤坏死因子-α（TNF-α）、白细胞介素-18（IL-18）、IL-6、NACHT、LRR、PYD结构域蛋白3（NLRP 3）、caspase-1和IL-1 β的mRNA水平。与DOX组相比，DOX + APG组具有更低的组织MDA、IL-6、TNF-α、NLRP 3、caspase-1和IL-1 β水平以及细胞内ROS的产生，但显著较高的SOD活性和GSH水平。结论：APG对阿霉素肾毒性有保护作用，但不影响阿霉素对恶性肿瘤的细胞毒作用。因此，APG可能作为一种潜在的保护剂，对肾损伤和炎症性疾病，并可能是一个有前途的候选人，以减轻肾毒性的癌症患者与DOX治疗。
Background and objective: Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its applicability, with nephrotoxicity considered a major dose-limiting adverse effect. Apigenin (APG), a flavonoid widely distributed in natural plants, has been reported to have antioxidant, anti-inflammatory, and mild tumor-suppressive properties. In this study, we investigated the role of APG in DOX-induced nephrotoxicity and chemotherapeutic efficacy.Methods: Male BALB/c mice were administered DOX (11.5 mg/kg) via the tail vein to establish the DOX nephropathy model. After treatment with or without APG (125, 250, and 500 mg/kg) for two weeks, urine, serum, and tissue samples were collected to evaluate proteinuria, serum albumin, serum creatinine (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD) activity, malondialdehyde (MDA), glutathione (GSH), and pathological changes. Rat renal tubular epithelial cells (NRK52E), murine podocyte cells (MPC5), and murine breast cancer cells (4T1) were utilized to verify the effect of APG on DOX-induced cell injury. An MTT assay was employed to analyze cell viability. Apoptosis was evaluated using a colorimetric TUNEL staining and cleaved caspase-3 protein analysis by western blotting. A reactive oxygen species (ROS)/superoxide (O-2-) fluorescence probe was employed to determine oxidative injury. Western blotting was used to analyze nephrin, a-smooth muscle actin (alpha-SMA), collagen I (Coll), fibronectin (FN), and 5OD2 expression. The mRNA levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-18 (IL-18), IL-6, NACHT, LRR, PYD domain-containing protein 3 (NLRP3), caspase-1, and IL-1 beta were tested by reverse transcription-polymerase chain reaction (RT-PCR).Results: APG ameliorated DOX-elicited renal injuries in both the glomeruli and tubules. The DOX + APG groups had much lower tissue MDA, IL-6, TNF-alpha, NLRP3, caspase-1, and IL-1 beta levels and generation of intracellular ROS, but significantly higher SOD activity and GSH levels compared to those of the DOX group. Additionally, APG attenuated DOX-induced morphological changes, loss of cellular viability, and apoptosis in NRK-52E and MPC-5 cells, but not in 4T1 cells.Conclusion: APG has a protective role against DOX-induced nephrotoxicity, without weakening DOX cytotoxicity in malignant tumors. Thus, APG may serve as a potential protective agent against renal injury and inflammatory diseases and may be a promising candidate to attenuate renal toxicity in cancer patients treated with DOX.