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Crude Radix Aconiti Lateralis Preparata (Fuzi) with Glycyrrhiza Reduces Inflammation and Ventricular Remodeling in Mice through the TLR4/NF-?B Pathway.

ABSTRACT: Radix Aconiti Lateralis Preparata (Fuzi) is a traditional Chinese medicine. Its alkaloids are both cardiotonic and cardiotoxic; however, the underlying mechanisms are unclear. Compatibility testing and processing are the primary approaches used to reduce the toxicity of aconite preparations. The purpose of this study was to compare the effects of crude Fuzi (CFZ), CFZ combined with Glycyrrhiza (Gancao) (CFZ+GC), and prepared materials of CFZ (PFZ) on heart failure (HF) in C57BL/6J mice and explore the potential mechanisms of action of CFZ. Transverse aortic constriction (TAC) was used to generate the HF state, and CFZ (1.5?g·mL-1), PFZ (1.5?g·mL-1), or CFZ+GC (1.8?g·mL-1) was orally administered to the HF-induced mice daily. For the subsequent 8 weeks, hemodynamic indicators, ventricular pressure indices, and mass indices were evaluated, and histopathological imaging was performed. CFZ, CFZ+GC, and PFZ significantly improved left ventricular function and structure and reduced myocardial damage. CFZ+GC was more effective than CFZ and PFZ, whereas CFZ had higher toxicity than CFZ+GC and PFZ. CFZ and CFZ+GC attenuated ischemia-induced inflammatory responses and also inhibited Toll-like receptor-4 (TLR4) and nuclear factor kappa beta (NF-?B) action in the heart. Moreover, mass spectrometry analysis revealed a decrease in the levels of toxic components of CFZ+GC, whereas those of the protective components were increased. This study suggested that GC reduces the toxicity and increases the efficacy of CFZ on HF induced by TAC. Furthermore, GC+CFZ reduces the risk of HF by ameliorating the inflammation response, which might be partially related to the inhibition of the TLR4/NF-?B pathway.

SUBMITTER: Yan P

PROVIDER: S-EPMC7593747 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Crude Radix Aconiti Lateralis Preparata (Fuzi) with Glycyrrhiza Reduces Inflammation and Ventricular Remodeling in Mice through the TLR4/NF-κB Pathway.

Yan Ping P Mao Wen W Jin Lushuai L Fang Mingsun M Liu Xia X Lang Jiali J Jin Lu L Cao Beibei B Shou Qiyang Q Fu Huiying H

Mediators of inflammation 20201020

Radix Aconiti Lateralis Preparata (Fuzi) is a traditional Chinese medicine. Its alkaloids are both cardiotonic and cardiotoxic; however, the underlying mechanisms are unclear. Compatibility testing and processing are the primary approaches used to reduce the toxicity of aconite preparations. The purpose of this study was to compare the effects of crude Fuzi (CFZ), CFZ combined with Glycyrrhiza (Gancao) (CFZ+GC), and prepared materials of CFZ (PFZ) on heart failure (HF) in C57BL/6J ...[more]

PMID: 33132755

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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.

Project description:Radix Aconiti Lateralis Preparata (fuzi) is the processed product of Aconitum carmichaelii Debeaux tuber, and has great potential anti-myocardial infarction effects, including improving myocardial damage and energy metabolism in rats. However, the effects of Radix Aconiti Lateralis Preparata extracts in a rat model of myocardial infarction have not yet been fully illustrated. Herein, Radix Aconiti Lateral Preparata was used to prepare Radix Aconiti Lateralis Preparata extract (RAE), fuzi polysaccharides (FPS), and fuzi total alkaloid (FTA). Then, we aimed to compare the effects of RAE, FPS, and FTA in MI rats and further explore their influence on small molecules in the heart. We reported that Radix Aconiti Lateralis Preparata extract (RAE) and fuzi total alkaloid (FTA) significantly improved left ventricular function and structure, and reduced myocardial damage and infarct size in rats with myocardial infarction by the left anterior descending artery ligation. In contrast, fuzi polysaccharides (FPS) was less effective than RAE and FTA, indicating that alkaloids might play a major role in the treatment of myocardial infarction. Moreover, via matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI), we further showed that RAE and FTA containing alkaloids as the main common components regulated myocardial energy metabolism-related molecules and phospholipids levels and distribution patterns against myocardial infarction. In particular, it was FTA, not RAE, that could also regulate potassium ions and glutamine to play a cardioprotective role in myocardial infarction, which revealed that an appropriate dose of alkaloids generated more obvious cardiotonic effects. These findings together suggested that Radix Aconiti Lateralis Preparata extracts containing an appropriate dose of alkaloids as its main pharmacological active components exerted protective effects against myocardial infarction by improving myocardial energy metabolism abnormalities and changing phospholipids levels and distribution patterns to stabilize the cardiomyocyte membrane structure. Thus, RAE and FTA extracted from Radix Aconiti Lateralis Preparata are potential candidates for the treatment of myocardial infarction.

Project description: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-1β, TNF-α, and IFN-γ in AIA rats, and combination with total glucosides of peony could further reduce the concentration of IL-1β. 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.

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:Background: Gouty arthritis (GA) is a common metabolic disease caused by a long-term disorder of purine metabolism and increased serum levels of uric acid. The processed product of dried root of Aconitum carmichaeli Debeaux (Aconiti Radix cocta, ARC) is used often in traditional Chinese medicine (TCM) to treat GA, but its specific active components and mechanism of action are not clear. Methods: First, we used ultra-performance liquid chromatography-quadrupole/time-of-flight tandem mass spectrometry to identify the chemical spectrum of ARC. Based on this result, we explored the active components of ARC in GA treatment and their potential targets and pathways. Simultaneously, we used computer simulations, in vitro cell experiments and animal experiments to verify the prediction results of systems pharmacology. In vitro, we used aurantiamide acetate (AA) to treat monosodium urate (MSU)-stimulated THP-1 cells and demonstrated the reliability of the prediction by western blotting and real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). ELISAs kit were used to measure changes in levels of proinflammatory factors in rats with GA induced by MSU to demonstrate the efficacy of ARC in GA treatment. Results: Forty-three chemical constituents in ARC were identified. ARC could regulate 65 targets through 29 active components, and then treat GA, which involved 1427 Gene Ontology (GO) terms and 146 signaling pathways. Signaling pathways such as proteoglycans in cancer, C-type lectin receptor signaling pathway, and TNF signaling pathway may have an important role in GA treatment with ARC. In silico results showed that the active components songoramine and ignavine had high binding to mitogen-activated protein kinase p38 alpha (MAPK14) and matrix metallopeptidase (MMP)9, indicating that ARC treatment of GA was through multiple components and multiple targets. In vitro experiments showed that AA in ARC could effectively reduce expression of MAPK14, MMP9, and cyclooxygenase2 (PTGS2) in THP-1 cells stimulated by MSU, whereas it could significantly inhibit the mRNA expression of Caspase-1, spleen tyrosine kinase (SYK), and PTGS2. Animal experiments showed that a ARC aqueous extract could significantly reduce expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and intereleukin (IL)-18 in the serum of GA rats stimulated by MSU. Hence, ARC may inhibit inflammation by regulating the proteoglycans in cancer-associated signaling pathways. Conclusion: ARC treatment of GA may have the following mechanisms, ARC can reduce MSU crystal-induced joint swelling, reduce synovial tissue damage, and reduce the expression of inflammatory factors in serum. AA in ARC may inhibit inflammation by regulating the protein expression of MAPK14, MMP9, and PTGS2 and the mRNA expression of caspase-1, SYK, and PTGS2.

Dataset Information

Crude Radix Aconiti Lateralis Preparata (Fuzi) with Glycyrrhiza Reduces Inflammation and Ventricular Remodeling in Mice through the TLR4/NF-?B Pathway.

Publications

Crude Radix Aconiti Lateralis Preparata (Fuzi) with <i>Glycyrrhiza</i> Reduces Inflammation and Ventricular Remodeling in Mice through the TLR4/NF-<i>κ</i>B Pathway.

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