Collage of Pharmacology, Dalian Medical University, 9 West Section, South Road of Lushun, 116044, Dalian, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
The Key Laboratory of Neural and Vascular Biology, The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Ministry of Education, Hebei Medical University, Shijiazhuang, China.
Chem Biol Interact. 2024 Sep 1;400:111147. doi: 10.1016/j.cbi.2024.111147. Epub 2024 Jul 21.
Doxorubicin (DOX), a chemotherapy drug widely recognized for its efficacy in cancer treatment, unfortunately, has significant nephrotoxic effects leading to kidney damage. This study explores the nephroprotective potential of Phosphocreatine (PCr) in rats, specifically examining its influence on Nrf2 (Nuclear factor erythroid 2-related factor 2) and PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) pathways, its role in apoptosis inhibition, and effectiveness in preserving mitochondrial function. The research employed in vivo experiments in rats, focusing on PCr's capacity to protect renal function against doxorubicin-induced damage. The study entailed evaluating Nrf2 and PGC-1α pathway activation, apoptosis rates, and mitochondrial health in renal tissues. A significant aspect of this research was the use of high-resolution respirometry (HRR) to assess the function of isolated kidney mitochondria, providing in-depth insights into mitochondrial bioenergetics and respiratory efficiency under the influence of PCr and doxorubicin. Results demonstrated that PCr treatment significantly enhanced the activation of Nrf2 and PGC-1α pathways, reduced apoptosis, and preserved mitochondrial structure in doxorubicin-affected kidneys. Observations included upregulated expression of Nrf2 and PGC-1α target genes, stabilization of mitochondrial membranes, and a notable improvement in cellular antioxidant defense, evidenced by the activities of enzymes like superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) This study positions phosphocreatine as a promising agent in mitigating doxorubicin-induced kidney damage in rats. The findings, particularly the insights from HRR on isolated kidney mitochondria, highlight PCr's potential in enhancing mitochondrial function and reducing nephrotoxic side effects of chemotherapy. These encouraging results pave the way for further research into PCr's applications in cancer treatment, aiming to improve patient outcomes by managing chemotherapy-related renal injuries.
阿霉素（DOX）是一种广泛用于癌症治疗的化疗药物，但其具有显著的肾毒性作用，会导致肾脏损伤。本研究探讨了磷酸肌酸（PCr）在大鼠中的肾保护作用，特别研究了其对 Nrf2（核因子红细胞 2 相关因子 2）和 PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子 1-α）通路的影响、对细胞凋亡的抑制作用以及对线粒体功能的保护作用。本研究采用大鼠体内实验，重点研究 PCr 对阿霉素诱导的肾损伤的保护作用。研究评估了肾组织中 Nrf2 和 PGC-1α 通路的激活、细胞凋亡率以及线粒体功能。本研究的一个重要方面是使用高分辨率呼吸测定法（HRR）评估分离肾线粒体的功能，深入了解 PCr 和阿霉素影响下的线粒体生物能学和呼吸效率。结果表明，PCr 处理可显著增强 Nrf2 和 PGC-1α 通路的激活、减少细胞凋亡并保护阿霉素作用下的肾脏线粒体结构。观察到 Nrf2 和 PGC-1α 靶基因的表达上调、线粒体膜的稳定以及细胞抗氧化防御的显著改善，这表现为超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、丙二醛（MDA）等酶的活性增加。本研究将磷酸肌酸定位为一种有前途的减轻大鼠阿霉素肾损伤的药物。这些发现，特别是 HRR 对分离的肾线粒体的见解，突出了 PCr 增强线粒体功能和减少化疗肾毒性副作用的潜力。这些令人鼓舞的结果为进一步研究 PCr 在癌症治疗中的应用铺平了道路，旨在通过管理化疗相关的肾脏损伤来改善患者的治疗效果。
