Research Center of Transporter Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand.
Biomed Pharmacother. 2022 Apr;148:112732. doi: 10.1016/j.biopha.2022.112732. Epub 2022 Feb 24.
Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 µg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 μM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.
黏菌素是一种广泛用于治疗多重耐药革兰氏阴性菌感染的最后手段多肽抗生素。然而，这种治疗与肾毒性有关。本研究旨在研究Boesenbergia rotunda 的生物活性化合物 panduratin A 对体内和体外模型中黏菌素诱导的肾毒性的潜在保护作用。7 天内腹腔注射 15mg/kg 的黏菌素可明显促进肾小管变性，增加血尿素氮 (BUN) 水平，并上调肾损伤生物标志物和凋亡蛋白的表达。此外，黏菌素处理会增加小鼠肾脏组织中的氧化应激和细胞凋亡。有趣的是，当与 panduratin A（2.5 或 25mg/kg）联合使用时，这些缺陷会减轻。在人近端肾小管细胞 (RPTEC/TERT1) 中研究了 panduratin A 减轻黏菌素毒性的潜在机制。通过分析细胞死亡、活性氧 (ROS) 水平、线粒体功能以及与凋亡途径相关的蛋白质表达，确定了黏菌素触发细胞毒性的机制。黏菌素处理（200μg/ml）显著增加细胞凋亡，增加 ROS 产生，降低线粒体膜电位，并降低抗凋亡蛋白 (Bcl-2) 的表达。这些作用在 panduratin A（5μM）的共同处理下明显受到抑制。综上所述，panduratin A 通过减轻线粒体损伤和肾细胞凋亡，作为一种新型的肾保护剂，可防止黏菌素引起的肾损伤。
