Liao Jian-Cheng, Xiang Jie, Gui Wan-Yu, Luo Hui-Zhi, You Qing, He Qi-Rui, Lu Ming-Xia, Yang Shu-Yun, Wang Qiong, Zou Jian-Dong, Li Chang-Yin
Department of Clinical Pharmacology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, 210029, China.
Department of Pharmacology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, 210029, China.
J Ethnopharmacol. 2025 Jan 31;340:119197. doi: 10.1016/j.jep.2024.119197. Epub 2024 Dec 2.
Huangkui Capsule (HKC) is a traditional Chinese medicinal preparation. Numerous clinical studies have reported that HKC has a good nephroprotection effect. The clinical application of cisplatin is greatly limited by its nephrotoxicity, and HKC shows promise in preventing cisplatin-induced nephrotoxicity (CIN).
To evaluate the effectiveness of HKC in alleviating CIN and explore its underlying action mechanisms.
A rat model of CIN was established via single-dose injection of cisplatin. The effectiveness of HKC was evaluated by biochemical indices and pathological sections. Then, serum, kidney, and cecal endogenous metabolic profiles as well as the gut microbiota were characterized using lipidomics, metabolomics, and 16S rRNA high-throughput sequencing technique. Spearman's correlation analysis was carried out between gut microbiota, biomarkers, and biochemical indices. Finally, antibiotic treatment was performed to establish a pseudo-sterile rat model and validate the nephroprotection of HKC in a gut microbiota-dependent manner.
HKC could significantly attenuate the abnormal elevation of serum creatinine and urea nitrogen, kidney index, and kidney injury score in CIN rats, remarkably alleviate the disturbance of metabolic profiles of serum, kidney, and cecal contents, corresponding to the endogenous metabolites such as fatty acids, phosphatidylcholines, amino acids, acylcarnitines, and short-chain fatty acids, and enrich the diversity of gut microbiota. Spearman's correlation analysis revealed that Clostridium_sensu_stricto_1 was positively correlated with the altered short-chain fatty acids in serum and negatively correlated with the altered acylcarnitine in the kidney. In the pseudo-sterile rat model, the attenuation effect of HKC on the abnormal elevation of serum creatinine and urea nitrogen, along with the alleviation of metabolic profile disorders, was greatly diminished or even abolished, demonstrating the nephroprotective effect of HKC in a gut microbiota-dependent manner.
HKC exerted the nephroprotective effect on CIN in a gut microbiota-dependent manner, mainly by regulating Clostridium_sensu_stricto_1 mediated metabolisms of phosphatidylcholines, acylcarnitines, fatty acids, tryptophan, and short-chain fatty acids, thereby reducing the inflammatory response. The present study could provide reliable scientific evidence for gut microbiota-dependent mechanisms of HKC in the treatment of kidney injury and may widen the clinical application of HKC in cisplatin-containing cancer therapy.
黄葵胶囊（HKC）是一种传统中药制剂。大量临床研究报道HKC具有良好的肾脏保护作用。顺铂的临床应用受到其肾毒性的极大限制，而HKC在预防顺铂诱导的肾毒性（CIN）方面显示出前景。
评估HKC减轻CIN的有效性并探索其潜在作用机制。
通过单次注射顺铂建立CIN大鼠模型。通过生化指标和病理切片评估HKC的有效性。然后，使用脂质组学、代谢组学和16S rRNA高通量测序技术对血清、肾脏和盲肠内源性代谢谱以及肠道微生物群进行表征。对肠道微生物群、生物标志物和生化指标进行Spearman相关性分析。最后，进行抗生素治疗以建立伪无菌大鼠模型，并以肠道微生物群依赖的方式验证HKC的肾脏保护作用。
HKC可显著减轻CIN大鼠血清肌酐、尿素氮、肾脏指数和肾损伤评分的异常升高，显著缓解血清、肾脏和盲肠内容物代谢谱的紊乱，对应于脂肪酸、磷脂酰胆碱、氨基酸、酰基肉碱和短链脂肪酸等内源性代谢物，并丰富肠道微生物群的多样性。Spearman相关性分析显示，严格梭菌1与血清中改变的短链脂肪酸呈正相关，与肾脏中改变的酰基肉碱呈负相关。在伪无菌大鼠模型中，HKC对血清肌酐和尿素氮异常升高的减轻作用以及代谢谱紊乱的缓解作用大大减弱甚至消失，表明HKC以肠道微生物群依赖的方式具有肾脏保护作用。
HKC以肠道微生物群依赖的方式对CIN发挥肾脏保护作用，主要通过调节严格梭菌1介导的磷脂酰胆碱、酰基肉碱、脂肪酸、色氨酸和短链脂肪酸的代谢，从而减轻炎症反应。本研究可为HKC治疗肾损伤的肠道微生物群依赖机制提供可靠的科学证据，并可能拓宽HKC在含顺铂癌症治疗中的临床应用。
