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^INK4A. 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.

中文翻译：

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原花青素可通过抑制NF-kB途径并调节氧化应激，细胞周期和纤维生成来减轻阿霉素引起的心脏损伤

这项研究调查了原花青素提取物（PE）对阿霉素（DOX）诱导的大鼠心脏毒性的预防作用的潜在机制和信号通路。总共32只雄性白化病大鼠被随机分为四组。对照组大鼠口服生理盐水。第二组大鼠口服PE（每天一次50 mg / kg bw /天），持续4周。第三组大鼠腹膜内注射DOX（实验第3、9、15和21天为10 mg / kg）。第四组大鼠同时注射DOX和PE 4周。DOX显着增加了血清心脏损害生物标志物的水平。此外，组织病理学表明，DOX引起的心脏组织损伤上调了纤维化因子的表达，^墨水4A。还观察到细胞增殖标志物，细胞周期蛋白依赖性激酶-4（CDK4）和成视网膜细胞瘤（Rb）的下调。此外，DOX诱导的氧化应激和炎症应激导致心脏丙二醛（MDA），蛋白羰基（PC），白介素-2（IL-2），白介素-6（IL-6）和肿瘤坏死因子-α（TNF）升高-α）。观察到心脏谷胱甘肽（GSH）水平和过氧化氢酶（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。用PE对上述参数通过归一化血清参数治疗DOX诱导的大鼠心脏毒性，并减轻心脏组织结构。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，同时氧化和炎症作用得到改善。 k B）信号传导途径。这些结果表明，PE可用作预防DOX引起的心脏毒性的预防剂。