Doxorubicin (DOX) is a broad‐spectrum antibiotic with potent anti‐cancer activity. Nevertheless, despite having effective anti‐neoplasm activity, its use has been clinically restricted due to its life‐threatening side effects, such as cardiotoxicity. It is evident that betaine has anti‐oxidant, and anti‐inflammatory activity and has several beneficial effects, such as decreasing the amyloid‐β generation, reducing obesity, improving steatosis and fibrosis, and activating AMP‐activated protein kinase (AMPK). However, whether betaine could mitigate DOX‐induced cardiomyopathy is still unexplored. Cardiomyopathy was induced in male Sprague Dawley rats using DOX (4 mg/kg dose with a cumulative dose of 20 mg/kg, i.p.). Further, betaine (200 and 400 mg/kg) was co‐treated with DOX through oral gavage for 28 days. After the completion of the study, several biochemical, oxidative stress parameters, histopathology, western blotting, and qRT‐PCR were performed. Betaine treatment significantly reduced CK‐MB, LDH, SGOT, and triglyceride levels, which are associated with cardiotoxicity. DOX‐induced increased oxidative stress was also mitigated by betaine intervention as the SOD, catalase, MDA, and nitrite levels were restored. The histopathological investigation also confirmed the cardioprotective effect of betaine against DOX‐induced cardiomyopathy as the tissue injury was reversed. Further, molecular analysis revealed that betaine suppressed the DOX‐induced increased expression of phospho‐p53, phospho‐p38 MAPK, NF‐kB p65, and PINK 1 with an upregulation of AMPK and downregulation of Nrf2 expression. Interestingly, qRT‐PCR experiments show that betaine treatment alleviates the DOX‐induced increase in inflammatory (TNF‐α, NLRP3, and IL‐6) and fibrosis (TGF‐β and Acta2) related gene expression, halting the cardiac injury. Interestingly, betaine also improves the mRNA expression of Nrf2, thus modulating the expression of antioxidant proteins and preventing oxidative damage. Here, we provide the first evidence that betaine treatment prevents DOX‐induced cardiomyopathy by inhibiting oxidative stress, inflammation, and fibrosis by regulating AMPK/Nrf2/TGF‐β expression. We believe that betaine can be utilized as a potential novel therapeutic strategy for preventing DOX‐induced cardiotoxicity.

中文翻译：

---

甜菜碱通过调节 AMPK/Nrf2/TGF-β 表达抑制氧化应激、炎症和纤维化，从而改善阿霉素诱导的心肌病

阿霉素 (DOX) 是一种广谱抗生素，具有有效的抗癌活性。然而，尽管具有有效的抗肿瘤活性，但由于其危及生命的副作用（例如心脏毒性），其使用在临床上受到限制。显然，甜菜碱具有抗氧化和抗炎活性，并具有多种有益作用，例如减少β-淀粉样蛋白的生成、减少肥胖、改善脂肪变性和纤维化以及激活 AMP 激活蛋白激酶 (AMPK)。然而，甜菜碱是否可以减轻阿霉素引起的心肌病仍有待探索。使用 DOX（4 mg/kg 剂量，累积剂量为 20 mg/kg，ip）。此外，通过口服灌胃将甜菜碱（200 和 400 mg/kg）与 DOX 联合治疗 28 天。研究完成后，进行了多项生化、氧化应激参数、组织病理学、蛋白质印迹和 qRT-PCR。甜菜碱治疗显着降低了与心脏毒性相关的 CK-MB、LDH、SGOT 和甘油三酯水平。随着 SOD、过氧化氢酶、MDA 和亚硝酸盐水平的恢复，DOX 诱导的氧化应激增加也可以通过甜菜碱干预得到缓解。组织病理学研究还证实了甜菜碱对 DOX 诱导的心肌病具有心脏保护作用，因为组织损伤得到逆转。此外，分子分析表明，甜菜碱可抑制 DOX 诱导的磷酸化 p53、磷酸化 p38 MAPK、NF-kB p65 和 PINK 1 表达增加，并上调 AMPK 和下调 Nrf2 表达。有趣的是，qRT-PCR 实验表明，甜菜碱治疗可减轻 DOX 诱导的炎症（TNF-α、NLRP3 和 IL-6）和纤维化（TGF-β 和 Acta2）相关基因表达的增加，从而阻止心脏损伤。有趣的是，甜菜碱还可以提高 Nrf2 的 mRNA 表达，从而调节抗氧化蛋白的表达并防止氧化损伤。在这里，我们提供了第一个证据，证明甜菜碱治疗可以通过调节 AMPK/Nrf2/TGF-β 表达来抑制氧化应激、炎症和纤维化，从而预防 DOX 诱导的心肌病。我们相信甜菜碱可以作为一种潜在的新型治疗策略来预防 DOX 引起的心脏毒性。