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Investigation of Efficacy Enhancing and Toxicity Reducing Mechanism of Combination of Aconiti Lateralis Radix Praeparata and Paeoniae Radix Alba in Adjuvant-Induced Arthritis Rats by Metabolomics.

ABSTRACT: Combination of Aconiti Lateralis Radix Praeparata (FZ) and Paeoniae Radix Alba (BS) shows a significant effect in rheumatoid arthritis (RA). This study aimed to investigate the efficacy enhancing and toxicity reducing mechanism of combination of them in adjuvant-induced arthritis (AIA) rats by metabolomics. Rats were randomly divided into seven groups, including A (healthy control), B (model control), C1 (therapy group), C2 (efficacy enhancing group), D1 (toxicity group), and D2 (toxicity reducing group), and dexamethasone group was used as positive control. The plasma biochemical indexes showed that therapeutic dose of lipid-soluble alkaloids of FZ could significantly inhibit the concentrations of IL-1?, TNF-?, and IFN-? in AIA rats, and combination with total glucosides of peony could further reduce the concentration of IL-1?. Then, UPLC-LTQ/Orbitrap MS with untargeted metabolomics was performed to identify the possible metabolites and pathways. Through multivariate data analysis of therapeutic dose groups (A vs. B vs. C1 vs. C2) and multivariate data analysis of toxic dose groups (A vs. B vs. D1 vs. D2), 10 and 7 biomarkers were identified based on biomarker analysis, respectively. After inducing AIA model, the plasma contents of spermidine, vanillylmandelic acid, catechol, and linoleate were increased significantly, and the contents of citric acid, L-tyrosine, L-phenylalanine, leucine, L-tryptophan, and uridine 5'-monophosphate (UMP) were decreased significantly. High dose of lipid-soluble alkaloids of FZ could increase the plasma contents of L-lysine, L-arginine, and deoxycholic acid, while the plasma contents of UMP, carnitine, N-formylanthranilic acid, and adenosine were decreased significantly. The pathway analysis indicated that therapeutic dose of lipid-soluble alkaloids of FZ could regulate energy and amino acid metabolic disorders in AIA rats. However, toxic dose could cause bile acid, fat, amino acid, and energy metabolic disorders. And combination with total glucosides of peony could enhance the therapeutic effects and attenuate the toxicity induced by lipid-soluble alkaloids of FZ.

SUBMITTER: Xie YF

PROVIDER: S-EPMC6442482 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Investigation of Efficacy Enhancing and Toxicity Reducing Mechanism of Combination of Aconiti Lateralis Radix Praeparata and Paeoniae Radix Alba in Adjuvant-Induced Arthritis Rats by Metabolomics.

Xie Yun-Fei YF Feng Wu-Wen WW Liu Mei-Chen MC Xie Jun J Yu Lei L Gong Xiao-Hong XH Li Yun-Xia YX Peng Cheng C Peng Cheng C

Evidence-based complementary and alternative medicine : eCAM 20190318

Combination of Aconiti Lateralis Radix Praeparata (FZ) and Paeoniae Radix Alba (BS) shows a significant effect in rheumatoid arthritis (RA). This study aimed to investigate the efficacy enhancing and toxicity reducing mechanism of combination of them in adjuvant-induced arthritis (AIA) rats by metabolomics. Rats were randomly divided into seven groups, including A (healthy control), B (model control), C1 (therapy group), C2 (efficacy enhancing group), D1 (toxicity group), and D2 (toxicity reduci ...[more]

PMID: 31011359

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Project description:Background:Radix Paeoniae Alba (RPA) and other natural medicines have remarkable curative effects and are widely used in traditional Chinese Medicine (TCM). However, due to their multi-component and multi-target characteristics, it is difficult to study the detailed pharmacological mechanisms for those natural medicines in vivo. Therefore, their real effects on organisms is still uncertain. Methods:RPA was selected as research object, the present study was designed to study the complex mechanisms of RPA in vivo by integrating and interpreting the transcriptomic based RNA-seq and metabolomic based NMR spectrum after RPA administration in mice. A variety of dimension-reduction algorithms and classifier models were applied to the processing of high-throughput data. Results:Among serum metabolites, the contents of PC and glucose were significantly increased, while the contents of various amino acids, lipids and their metabolites were significantly decreased in mice after RPA administration. Based on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, differential analysis showed that the liver was the site where RPA exerted a significant effect, which confirmed the rationality of "meridian tropism" in the theory in TCM. In addition, RPA played a role in lipid metabolism by regulating genes encoding enzymes of the glycerolipid metabolism pathway, such as 1-acyl-sn-glycerol-3-phosphate acyltransferase (Agpat), phosphatidate phosphatase (Lpin), phospholipid phosphatase (Plpp) and endothelial lipase (Lipg). We also found that RPA regulates several substance addiction pathways in the brain, such as the cocaine addiction pathway, and the related targets were predicted based on the sequencing data from pathological model in the GEO database. The overall effective pattern of RPA was intuitively presented with a multidimensional radar map through a self-designed model which found that liver and brain were mainly regulated by RPA compared with the traditional meridian tropism theory. Conclusions:Overall this study expanded the potential application of RPA and provided possible targets and directions for further mechanism study, meanwhile, it also established a multi-dimensional evaluation model to represent the overall effective pattern of TCM for the first time. In the future, such study based on the high-throughput data sets can be used to interpret the theory of TCM and to provide a valuable research model and clinical medication reference for the TCM researchers and doctors.

Project description:BackgroundHeart failure (HF) is the end stage of the development of heart disease, whose prognosis is poor. The previous research of our team indicated that the formulae containing Aconiti Lateralis Radix Praeparata and Lepidii Semen Descurainiae Semen (ALRP-LSDS) could inhibit myocardial hypertrophy, inhibit cardiomyocyte apoptosis, delay myocardial remodeling (REM), and improve the prognosis of patients with HF effectively. In order to explore the mechanism of ALRP-LSDS for the treatment of HF, a combined approach of network pharmacology and molecular docking was conducted.MethodsPublic database TCMSP was used to screen the active compounds of ALRP-LSDS. The targets of screened active compounds were obtained from the TCMSP database and predicted using the online analysis tool PharmMapper. The targets of HF were obtained from 6 databases including GeneCards, OMIM, DrugBank, TTD, PharmGKB, and DisGeNET. Protein-protein interaction and enrichment analysis were performed, respectively, by STRING and Metascape online tools after merging the targets of active compounds and HF. Cytoscape software was used to conduct networks. Finally, molecular docking was performed by Vina to verify the correlation between key targets and active compounds.ResultsFinal results indicated that the active compounds including β-sitosterol, isorhamnetin, quercetin, kaempferol, and (R)-norcoclaurine, the targets including AKT1, CASP3, and MAPK1 might be the main active compounds and key targets of ALRP-LSDS for the treatment of HF separately. The binding ability of AKT1 to the main active compounds was better compared with the other 2 key targets, which means it might be more critical. The pathways including AGE-RAGE signaling pathway in diabetic complications, Pathways in cancer, and Fluid shear stress and atherosclerosis might play important roles in the treatment of HF with ALRP-LSDS. In general, ALRP-LSDS could inhibit cardiomyocyte apoptosis, delay REM, and improve cardiac function through multicompound, multitarget, and multipathway, which contributes to the treatment of HF.ConclusionsBased on the combined approach of network pharmacology and molecular docking, this study screened out the main active compounds, key targets, and main pathways of ALRP-LSDS for the treatment of HF, and revealed its potential mechanisms, providing a theoretical basis for further research.

Project description:Fuzi-Gancao herb couple is one of the commonly used herb couples involved in the traditional Chinese medicine formulations, with radix aconiti lateralis (Fuzi in Chinese) and radix glycyrrhizae (Gancao in Chinese) as a ratio of 1:1. Alkaloids and flavonoids were considered as the main active ingredients of Fuzi-Gancao herb couple. However, no analytical methods have been reported to quantitatively analyze these activity ingredients in Fuzi-Gancao herb couple simultaneously.To develop a simple, rapid, and sensitive UHPLC-MS/MS method for simultaneous quantitation of six alkaloid and three flavonoid compounds, namely, aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconitine (BAC), benzoylmesaconitine (BMA), benzoylhypaconitine (BHA), liquiritin, isoliquiritin, and licochalcone A (LCA) in Fuzi-Gancao herb couple.The chromatographic separation was achieved using a reversed phase C18 column and a mobile phase consisted of water (0.1% formic acid in water, v/v) and acetonitrile. The detection was achieved in multiple reaction monitoring modes. The optimal mass transition ion pairs (m/z) for quantitation were 646.3/586.5 for AC, 632.4/572.5 for MA, 616.3/556.4 for HA, 604.5/572.5 for BAC, 590.4/540.4 for BMA, 574.1/542.5 for BHA, 419.4/257.1 for liquiritin, 419.4/257.1 for isoliquiritin, and 339.2/121.1 for LCA.Good linearity was observed in validated concentration range for each analyte (r > 0.9992), and the intra- and inter-day precisions were <3.12% and 3.65%, respectively. The recovery ranged from 85.36% to 110.14%.The results demonstrated that the method developed was reliable, rapid, and specific. Moreover, this method was successfully applied to control the quality of Fuzi-Gancao herb couple.A simple, rapid, and sensitive UHPLC-MS/MS method for simultaneous quantitation of six alkaloid and three flavonoid compounds in Fuzi-Gancao herb couple has been developed. Abbreviations used: UHPLC-ESI-MS/MS: Ultra High Performance Liquid Chromatography-electrospray ionization-mass spectrometry; RSD: Relative standard deviations; LOD: Limit of detection; LOQ: Limit of quantification; MRM: Multiple reaction monitor; TCMs: Traditional Chinese medicines.

Dataset Information

Investigation of Efficacy Enhancing and Toxicity Reducing Mechanism of Combination of Aconiti Lateralis Radix Praeparata and Paeoniae Radix Alba in Adjuvant-Induced Arthritis Rats by Metabolomics.

Publications

Investigation of Efficacy Enhancing and Toxicity Reducing Mechanism of Combination of Aconiti Lateralis Radix Praeparata and Paeoniae Radix Alba in Adjuvant-Induced Arthritis Rats by Metabolomics.

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