Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
Department of Histology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
J Biochem Mol Toxicol. 2021 Apr;35(4):e22716. doi: 10.1002/jbt.22716. Epub 2021 Jan 23.
This study investigated the potential mechanism(s) and the signaling pathway(s) underlying the prophylactic effect of proanthocyanidin extract (PE) against doxorubicin (DOX)-induced cardiotoxicity in rats. A total of 32 male albino rats were randomly allocated into four groups. Control rats were orally administrated normal saline. Rats in the second group were orally administrated PE (50 mg/kg bw/once daily) for 4 weeks. Rats in the third group were intraperitoneally injected with DOX (10 mg/kg on Days 3, 9, 15, and 21 of the experiment). Rats in the fourth group were injected with DOX and PE simultaneously for 4 weeks. DOX significantly augmented the levels of serum heart damage biomarkers. In addition, histopathology indicated that DOX-induced cardiac tissue injury upregulated the expression of fibrogenic factors, alpha smooth muscle actin (α-SMA), transforming growth factor β1 (TGF- β1), and p16 . Downregulation of cell proliferation markers, cyclin-dependent kinase-4 (CDK4), and retinoblastoma (Rb) was also observed. Furthermore, DOX-induced oxidative and inflammatory stress resulted in increased cardiac malondialdehyde (MDA), protein carbonyl (PC), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Decreased cardiac glutathione (GSH) levels and enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) were observed. Treatment of DOX-induced rat cardiotoxicity with PE normalized serum parameters for the aforementioned parameters and alleviated cardiac tissue structure. Furthermore, reduced cardiac tissue α-SMA and TGF-β1, and increased CDK4 and Rb protein expression, along with the amelioration of oxidative and inflammatory effects were observed. PE attenuates DOX-induced cardiomyocyte inflammation possibly by attenuating the nuclear factor kappa-B (NF- kB) signaling pathway. These results indicate that PE may be useful as a preventative agent against DOX-induced cardiac toxicity.
本研究旨在探讨原花青素提取物（PE）预防阿霉素（DOX）诱导的大鼠心脏毒性的潜在机制和信号通路。总共 32 只雄性白化大鼠被随机分配到四组。对照组大鼠口服生理盐水。第二组大鼠每天口服 PE（50mg/kg·bw/次）4 周。第三组大鼠腹腔注射 DOX（实验第 3、9、15 和 21 天，每次 10mg/kg）。第四组大鼠同时注射 DOX 和 PE，持续 4 周。DOX 显著增加了血清心脏损伤生物标志物的水平。此外，组织病理学表明，DOX 诱导的心脏组织损伤上调了纤维化因子的表达，包括α平滑肌肌动蛋白（α-SMA）、转化生长因子β1（TGF-β1）和 p16。细胞增殖标志物细胞周期蛋白依赖性激酶 4（CDK4）和视网膜母细胞瘤（Rb）的表达也下调。此外，DOX 诱导的氧化和炎症应激导致心脏丙二醛（MDA）、蛋白羰基（PC）、白细胞介素-2（IL-2）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）增加。心脏谷胱甘肽（GSH）水平降低，过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和谷胱甘肽 S-转移酶（GST）的酶活性降低。PE 治疗 DOX 诱导的大鼠心脏毒性可使上述参数的血清水平正常化，并减轻心脏组织结构损伤。此外，观察到心脏组织 α-SMA 和 TGF-β1 减少，CDK4 和 Rb 蛋白表达增加，氧化和炎症作用得到改善。PE 通过减轻核因子 kappa-B（NF-κB）信号通路可能减轻 DOX 诱导的心肌细胞炎症。这些结果表明，PE 可能是预防 DOX 诱导的心脏毒性的有用药物。
