Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, West zone, Tuanbo New-City, Jinghai-District, Tianjin, 301617, China.
J Ethnopharmacol. 2024 Jan 10;318(Pt B):116949. doi: 10.1016/j.jep.2023.116949. Epub 2023 Jul 26.
Tripterygium wilfordii Hook. f (TwHF) has been used as a traditional Chinese medicine for the treatment of rheumatoid arthritis and nephritis for hundreds of years.
Although the efficacy of TwHF in the treatment of RA is definite, its serious side effects and toxicity have also received close attention from domestic and international researchers, so the clinical application of TwHF has been controversial. Most of the current TwHF toxicity studies have been conducted with animals in normal body states, but ignore the effects in pathological states. In this study, we aimed to find out the material basis and metabolic mechanism of the "toxicity/effectiveness" of TwHF on rat kidneys in different body states by using two-way orthogonal partial least squares (O2PLS) method.
In the present study, TwHF was extracted by reflux extraction method using ethanol as the extraction solvent. Firstly, the effects of TwHF on rat kidneys in different body states were first evaluated by detecting creatinine and urea nitrogen levels and morphological changes in kidney pathology identified the components of TwHF in rats in different body states using UPLC-Q-TOF/MS technique. Serum and urine metabolomics were used to search for biomarkers and metabolic pathways by which TwHF exerts renal injury and protection, and finally, O2PLS correlation analysis was used to correlate the components with renal protective and injury biomarkers.
TwHF was found to have a protective effect on the kidney of RA rats and an injurious effect on the kidney of normal rats at a dose of 11.25 g/kg/d. The UPLC-Q-TOF/MS technique was used to identify 34 components in TwHF extracts; 23 components and 57 metabolites were identified in the administered rats. O2PLS screened three substances as both toxic and pharmacodynamic components of TwHF, namely 3,5-dimethoxyphenyl-2-propenl-ol, kaurane-16,19,20-triol, and demethylzeylasteral + O, and found that these three components may exert nephrotoxic effects via the nicotinic acid and nicotinamide metabolic pathways and nephroprotective effects via the tryptophan metabolic pathway.
In this study, O2PLS analysis was used for the first time to combine biomarkers and components in vivo and found the material basis and metabolic mechanism of nephrotoxicity and efficacy of TwHF, which provided key clues for further study on the biological mechanism of toxicity and efficacy of TwHF.
雷公藤（TwHF）作为一种传统中药，已被用于治疗类风湿关节炎和肾炎数百年。
虽然 TwHF 在治疗 RA 方面的疗效是确定的，但它的严重副作用和毒性也引起了国内外研究人员的密切关注，因此 TwHF 的临床应用一直存在争议。目前大多数关于 TwHF 毒性的研究都是在正常生理状态下的动物身上进行的，但忽略了在病理状态下的影响。在这项研究中，我们旨在通过双向正交偏最小二乘法（O2PLS）方法，找出 TwHF 在不同生理状态下对大鼠肾脏的“毒性/疗效”的物质基础和代谢机制。
本研究采用乙醇回流提取法提取 TwHF。首先，通过检测肌酐和尿素氮水平以及肾脏病理学的形态变化，评价 TwHF 对不同生理状态下大鼠肾脏的影响，采用 UPLC-Q-TOF/MS 技术鉴定大鼠在不同生理状态下 TwHF 的成分。采用血清和尿液代谢组学方法，寻找 TwHF 发挥肾损伤和保护作用的生物标志物和代谢途径，最后采用 O2PLS 相关分析将成分与肾保护和损伤生物标志物相关联。
研究发现，雷公藤在 11.25 g/kg/d 剂量下对 RA 大鼠肾脏有保护作用，对正常大鼠肾脏有损伤作用。采用 UPLC-Q-TOF/MS 技术鉴定雷公藤提取物中的 34 种成分；在给药大鼠中鉴定出 23 种成分和 57 种代谢物。O2PLS 筛选出 3 种物质作为雷公藤的毒性和药效成分，分别为 3,5-二甲氧基苯基-2-丙烯醇、贝壳杉-16,19,20-三醇和去甲基泽拉司他醇+O，并发现这三种成分可能通过烟酸和烟酰胺代谢途径发挥肾毒性作用，通过色氨酸代谢途径发挥肾保护作用。
本研究首次采用 O2PLS 分析方法将体内生物标志物与成分相结合，发现了雷公藤肾毒性和疗效的物质基础和代谢机制，为进一步研究雷公藤毒性和疗效的生物学机制提供了关键线索。
