Mechanism of Nephrotoxicity Induced by Ecliptasaponin A Based on Computational Toxicology
10.13422/j.cnki.syfjx.20241102
- VernacularTitle:基于计算毒理学的旱莲苷A致肾损伤机制
- Author:
Han LI
1
;
Ling SONG
1
;
Yunhang GAO
1
;
Tengfei CHEN
1
;
Suzhen MU
1
;
Weiya CHEN
1
;
Guangping ZHANG
1
;
Wang HUO
2
Author Information
1. Institute of Chinese Materia Medica，China Academy of Chinese Medical Sciences， Beijing 100700，China
2. Sixth Medical Center of PLA General Hospital，Beijing 100853，China
- Publication Type:Journal Article
- Keywords:
nephrotoxicity;
computational toxicology;
safety of traditional Chinese medicine;
ecliptasaponin A;
network pharmacology
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2024;30(23):72-80
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo predict the potential nephrotoxic components in traditional Chinese medicine health food products based on the Traditional Chinese Medicine Toxicity Alert System and Basic Toxicology Database （TCMTAS-BTD）， screen and validate the predicted components by cell and animal experiments， and decipher the mechanism of nephrotoxicity by network pharmacology. MethodTCMTAS-BTD was utilized to predict the toxicity of 3 540 compounds found in the catalogue of traditional Chinese health food ingredients. In the cell experiment， the top 5 compounds with high toxicity probability were screened by measurement of cell proliferation and viability （CCK-8） and high-content screening. ICR mice were randomized into a control group， a low-dose （2.91 mg·kg-1·d-1） ecliptasaponin A， and a high-dose （29.1 mg·kg-1·d-1） ecliptasaponin A group， with 10 mice in each group， and treated continuously for 28 days. During the experiment， the general conditions of the rats were observed， and the kidney index was calculated. The levels of serum creatinine （SCr） and blood urea nitrogen （BUN） in the serum as well as the content of malondialdehyde （MDA） and superoxide dismutase （SOD） in the renal tissue were measured. The pathological changes of the kidney were observed. Network pharmacology was employed to predict the potential pathways of nephrotoxicity. Finally， the pathway-associated proteins were validated by Western blot. ResultThe top 5 compounds with high probability of nephrotoxicity were ecliptasaponin A， chrysophanol， rutaecarpine， tanshinoneⅠ， and geniposidic acid. In the cell experiment， CCK-8 results showed that 10 μmol·L-1 ecliptasaponin A， 60 μmol·L-1 chrysophanol， 40 μmol·L-1 rutaecarpine， and 20 μmol·L-1 tanshinone I altered the viability of HK-2 cells. High-content analysis showed that 10 μmol·L-1 ecliptasaponin A， chrysophanol， rutaecarpine， and tanshinone Ⅰ reduced the cell number （P<0.05， P<0.01）. The animal experiment showed that the mice in the high-dose ecliptasaponin A group presented slow movement， slow weight gain （P<0.01）， increased kidney index （P<0.01）， elevated SCr， BUN， and MDA levels （P<0.01）， and lowered SOD level （P<0.01）. Mild histopathological changes were observed in the high-dose ecliptasaponin A group. The network pharmacology results showed that the key targets of nephrotoxicity induced by ecliptasaponin A were mainly enriched in the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， prostatic cancer and lipid and atherosclerosis pathways. Western blot results verified that high dose of ecliptasaponin A raised the phosphorylation levels of PI3K and Akt （P<0.01）. ConclusionOn day 28 of administration， 29.1 mg·kg-1 ecliptasaponin A was found to induce renal injury in rats. The mechanism may be related with the PI3K/Akt signaling pathway， which implied that excessive and prolonged usage of Ecliptae Herba may increase the incidence of adverse drug reactions.
