ABSTRACT
Objective:To investigate the effect of different extracts of Lysimachiae Herba on the main toxicity induced by Tripterygii Radix et Rhizoma. Method:Ninety male SPF Kunming mice were randomly divided into 9 groups according to their body weight，control group， Lysimachiae Herba water extract group， Lysimachiae Herba 30% ethanol extract group， Tripterygii Radix et Rhizoma group， Tripterygii Radix et Rhizoma combined with Lysimachiae Herba water extract group， Tripterygii Radix et Rhizoma combined with Lysimachiae Herba 30% ethanol extract group， Tripterygii Radix et Rhizoma combined with Lysimachiae Herba 60% ethanol extract group， Tripterygii Radix et Rhizoma combined with Lysimachiae Herba 95% ethanol extract group and Tripterygii Radix et Rhizoma combined with Lysimachiae Herba ethyl acetate extract group. The dosage of Tripterygii Radix et Rhizoma and Lysimachiae Herba were 2，1 g·kg<sup>-1</sup> based on crude drugs， respectively. The control group was given an equal volume of solvent， and each group was given by gavage for 14 consecutive days. The blood and liver tissues were taken 24 hours after the last administration. The enzyme linked immunosorbent assay （ELISA） was used to detect serum biochemical indexes and liver lipid peroxidation/antioxidant indexes in mice. Meanwhile， principal component analysis was used to evaluate the attenuating effect and the mechanism of Lysimachiae Herba extract on toxicity of Tripterygii Radix et Rhizoma. Result:Compared with control group， Tripterygii Radix et Rhizoma caused the levels of alanine aminotransferase（ALT），aspartic acid amino transferase（AST），alkaline phosphatase（ALP） in serum of mice， and the levels of malondialdehyde （MDA） in liver， and comprehensive score of toxicity （Z value） produced by the above four indexes increased significantly （<italic>P</italic><0.01）. The levels of total superoxide dismutase （T-SOD），glutathione-peroxidase （GPX），glutathione-S transferase （GST） decreased significantly （<italic>P</italic><0.01） in liver. Compared with Tripterygii Radix et Rhizoma group， after intervention with extracts of two solvents （water， 30% ethanol） of Lysimachiae Herba， the levels of serum ALT， AST， ALP and liver MDA were significantly decreased （<italic>P</italic><0.05， <italic>P</italic><0.01）， while the levels of liver T-SOD， GPX and GST were significantly increased （<italic>P</italic><0.01）. After intervention with extracts of two solvents （60% ethanol， 95% ethanol） of Lysimachiae Herba， the levels of serum ALT， AST， ALP were significantly decreased （<italic>P</italic><0.01）， and liver GPX levels were significantly increased （<italic>P</italic><0.01）. After the intervention with ethyl acetate extract of Lysimachiae Herba， only the level of serum AST was significantly decreased （<italic>P</italic><0.05） and the level of GPX was significantly increased （<italic>P</italic><0.05）. After the intervention with extracts of different solvents （water， 30% ethanol， 60% ethanol， 95% ethanol， ethyl acetate） of Lysimachiae Herba， it can significantly reduce the comprehensive score of toxicity （<italic>P</italic><0.01）. The overall decline rates of toxicity were 127.5%， 113.4%， 98.1%， 56.3% and 31.0% respectively. Among them， the toxicity reduction rate of the extracts with water as a solvent was 14.1%， 29.4%， 71.2%， 96.5% higher than those of other solvent extracts with ethanol. Conclusion:The extracts of different solvents （water， 30% ethanol， 60% ethanol， 95% ethanol and ethyl acetate） of Lysimachiae Herba can reverse the toxicity induced by Tripterygii Radix et Rhizoma in varying degrees. Among them， water and 30% ethanol are the best solvents for detoxification， especially water as the extraction solvent， and with the increase of ethanol content or fat solubility of extraction solvent， the detoxification shows a downward trend.
ABSTRACT
In recent years, Tripterygii Radix et Rhizoma polyglycosides have been used more and more widely in clinic, mostly in the treatment of rheumatoid arthritis. Besides, it is also used as a basic immunosuppressive drug to treat various kidney diseases, such as nephrotic syndrome. However, there are many adverse reactions in clinic, as well as controversies over its medication regimen, especially its dosage and time. To make rational use of Tripterygii Radix et Rhizoma polyglycosides in clinic and further study, the pharmacological and toxicological research progress of Tripterygii Radix et Rhizoma polyglycosides was reviewed. The author collected pharmacological and toxicological research literatures of Tripterygii Radix et Rhizoma polyglycosides at home and abroad in recent years, finding that Tripterygii Radix et Rhizoma polyglycosides have the pharmacological effects of anti-inflammation, anti-tumor, kidney protection and immunosuppression, and mainly plays a pharmacological role by regulating the expression of cytokines in NF-<italic>κ</italic>B signaling pathway, mTOR signaling pathway and apoptosis-related signaling pathway. And the toxicological effects of Tripterygii Radix et Rhizoma polyglycosides mostly focused on hepatotoxicity, nephrotoxicity and reproductive system toxicity, which are mostly related to oxidative stress response and expression of inflammatory factors. The main components of Tripterygii Radix et Rhizoma polyglycosides are triptolide and celastrol. The pharmacological and toxicological studies of Tripterygii Radix et Rhizoma polyglycosides are in-depth, the results showed that the efficacy and toxicity were dose-dependent and time-dependent, with no toxicity study of Tripterygii Radix et Rhizoma polyglycosides varying with dosage and time in the context of efficacy, indicating dose-effect, time-effect, dose-toxicity, time-toxicity relationships. Relevant mechanisms still need further study.
ABSTRACT
Objective: To explore the mechanism of renal toxicity of Tripterygii Radix et Rhizoma by establishing the active component-target, protein interaction, biological function and pathway network corresponding to the target, and using molecular docking technology. Method: The traditional Chinese medicine(TCM) systems pharmacology database(TCMSP) and the comparative toxicogenomics database (CTD) were used to screen The toxic candidate compounds.In PubChem database, convert all candidate compounds into standard Canonical SMILES format, SMILES format file import SwissTargetPrediction platform, target prediction, will be the target of the corresponding compounds in TCMSP supplement with uniprot converts protein antipodal gene name, and from the human genome database (GeneCards) seek to compare the renal related gene protein,overlapping proteins were screened as potential renal toxicity targets of Tripterygii Radix et Rhizoma.Cytoscape software was used to construct the candidate components-target network of Tripterygii Radix et Rhizoma.Cytoscape software was combined with String database to draw the protein interaction network, DAVID platform was used to analyze the biological function of the target and the pathways involved, and Glide software was used to verify the combination of the key protein and the candidate components of tripterygiumwildiitoxicity. Result: The screening of 30 kinds of candidates for toxic ingredients of Tripterygii Radix et Rhizoma, involving 209 renal toxicity targets, network analysis results showed that Tripterygii Radix et Rhizoma by amino acid metabolism,phospholipid metabolism, catecholamine metabolism, inhibiting renal organic anion transporter Oatl, Oat2, Oat3 function, and inducing apoptosis, and participate in the mitogen-activated protein kinase(MAPK) signaling pathways, JAK-STAT signaling pathway,vascular endothelial growth factor(VEGF)signaling pathways,Toll-like receptor signaling pathway,ERBB signaling pathway, FcεRI signaling pathway, peroxisome proliferators-activated receptors(PPAR) signaling pathway such as toxic to the kidneys. Conclusion: The mechanism of kidney toxicity of Tripterygii Radix et Rhizoma was explored by using the characteristics of multi-component, multi-target and multi-pathway of TCM, which provided new ideas and methods for further research on the mechanism of kidney toxicity of Tripterygii Radix et Rhizoma.
ABSTRACT
Objective: To overall evaluate the mutual detoxication mechanism of Tripterygii Radix et Rhizoma(LGT) compatible with Lysimachiae Herba(JQC) in tumor-bearing state.Method: Twelve differentially characteristic components before and after compatibility were used as chemical composition spectrum,six indicators including serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine(Cr) and urea nitrogen(BUN),malondialdehyde(MDA) levels in the liver and kidney tissues were used as attenuation spectrum,and twelve biological indicators including glutathione(GSH),glutathione-S-transferase(GST),glutathione peroxidase(GPx),superoxide dismutase(SOD),catalase(CAT) and interleukin(IL)-10 in the liver and kidney were used as the biological information spectrum.Mutual detoxication mechanisms of LGT compatible with JQC in tumor-bearing state were overall evaluated by principal component analysis(PCA),and the contribution of chemical components and biological indicators to mutual detoxication was further evaluated by gray correlation analysis(GCA) of "chemical composition spectrum-attenuation spectrum-biological information spectrum".Result: Compared with the model group,the attenuation spectrum scores Z values of S180(Z1 value) and H22(Z3 value) increased significantly after LGT being used alone(PZ1 value and Z3 value caused by LGT when the ratio of LGT and JQC was 4:1,2:1,1:1,1:2 and 1:4(PZ values(Z1 value and Z3 value) of LGT-JQC in the mass ratios including 4:1,1:1,1:2 and 1:4 was significantly higher than that in the ratio of 2:1(PZ values of the bioinformatics scores in the S180(Z2 value) and H22(Z4 value) tumor-bearing state,these two values were significantly increased after compatibility with JQC.The chemical components contributing the most to the attenuating effect of S180 and H22 in tumor-bearing state were 3# and 10#,respectively.The most important biological indicators were kidney GPx and renal GSH.Conclusion: LGT combined with JQC in the mass ratio of 4:1-1:4 can attenuate LGT-induced subacute toxicity in S180 and H22 tumor-bearing state,and the best ratio of such effect is 2:1.The attenuating effect reflects the thought of "there is no reason why there is no meteorology".The mechanism of attenuating action involves antioxidative damage and anti-inflammatory reaction of the liver and kidney,especially the renal GPx(S180) and renal GSH(H22) as the greatest contribution to the detoxication mechanism.