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1.
Biomed Res Int ; 2021: 9963732, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34545331

RESUMO

Acute kidney injury (AKI) is responsible for significant mortality among hospitalized patients that is especially troubling aged people. An effective self-made Chinese medicine formula, Xiaoyu Xiezhuo Drink (XXD), displayed therapeutic effects on AKI. However, the compositions and underlying mechanisms of XXD remain to be elucidated. In this study, we used the ultra-high-performance liquid chromatography method coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) to investigate the chemical components in XXD. Then, the absorbable components of XXD were identified based on the five principles and inputted into the SwissTargetPrediction and STITCH databases to identify the drug targets. AKI-related targets were collected from the GenCLiP 3, GeneCards, and DisGeNET databases. The crossover genes of XXD and AKI were identified for functional enrichment analysis. The protein-protein interaction (PPI) network of crossover genes was constructed, followed by the identification of hub genes. Subsequently, the effects and potential mechanisms of XXD on AKI predicted by the network pharmacology and bioinformatics analyses were experimentally validated in ischemia-reperfusion (I/R) injury-induced AKI aged mouse models. A total of 122 components in XXD were obtained; among them, 58 components were found that could be absorbed in the blood. There were 800 potential drug targets predicted from the 58 absorbable components in AKI which shared 36 crossover genes with AKI-related targets. The results of functional enrichment analysis indicated that crossover genes mostly associated with the response to oxidative stress and the HIF1 signaling pathway. In the PPI network analysis, 12 hub genes were identified, including ALB, IL-6, TNF, TP53, VEGFA, PTGS2, TLR4, NOS3, EGFR, PPARG, HIF1A, and HMOX1. In AKI aged mice, XXD prominently alleviated I/R injury-induced renal dysfunction, abnormal renal pathological changes, and cellular senescence, inflammation, and oxidative damage with a reduction in the expression level of the inflammatory mediator, α-SMA, collagen-1, F4/80, TP53, VEGFA, PTGS2, TLR4, NOS3, EGFR, PPARG, HIF1A, ICAM-1, TGF-ß1, Smad3, and p-Smad3 and an increase of nephridial tissue p-H3, Ki67, HMOX1, MMP-9, and Smad7 levels. In summary, our findings suggest that XXD has renoprotective effects against AKI in aged mice via inhibiting the TGF-ß1/Smad3 and HIF1 signaling pathways.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Animais , China , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Isquemia/patologia , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Reperfusão , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos
2.
Sci Rep ; 11(1): 16307, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381116

RESUMO

Structure-based drug design targeting the SARS-CoV-2 virus has been greatly facilitated by available virus-related protein structures. However, there is an urgent need for effective, safe small-molecule drugs to control the spread of the virus and variants. While many efforts are devoted to searching for compounds that selectively target individual proteins, we investigated the potential interactions between eight proteins related to SARS-CoV-2 and more than 600 compounds from a traditional Chinese medicine which has proven effective at treating the viral infection. Our original ensemble docking and cooperative docking approaches, followed by a total of over 16-micorsecond molecular simulations, have identified at least 9 compounds that may generally bind to key SARS-CoV-2 proteins. Further, we found evidence that some of these compounds can simultaneously bind to the same target, potentially leading to cooperative inhibition to SARS-CoV-2 proteins like the Spike protein and the RNA-dependent RNA polymerase. These results not only present a useful computational methodology to systematically assess the anti-viral potential of small molecules, but also point out a new avenue to seek cooperative compounds toward cocktail therapeutics to target more SARS-CoV-2-related proteins.


Assuntos
Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , SARS-CoV-2/efeitos dos fármacos , Proteínas Virais/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Gatos , Biologia Computacional , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/metabolismo , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , RNA Polimerase Dependente de RNA/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-Atividade
3.
Artigo em Inglês | MEDLINE | ID: mdl-34333214

RESUMO

Zuojin decoction (ZJD) is a classic pair composed of Coptidis Rhizoma and Evodiae Fructus, which is suitable for treating gastrointestinal diseases and tumours, etc. In recent years, scientists have been widely focused on research into the treatment of liver cancer using ZJD; however, the effective substances have not yet been comprehensively elucidated. The difference between the co-decoction and the single decoction of ZJD is revealed in this paper based on the UPLC-QE-Orbitrap-MS, and the chemical components absorbed into the blood and liver of mice have been analyzed simultaneously. In addition, the combination of prototype components absorbed into the liver with liver cancer-related targets has been performed via molecular docking to explore the mechanism of ZJD in treating liver cancer. By comparing the co-decoction and single decoction of ZJD, 44 new components appeared during co-decoction and 76 known chemical compounds have been identified at the same time. It has been confirmed that 35 known components and 11 new components were absorbed into the blood. Furthermore, 20 known components were discovered from the sample of liver tissue. Molecular docking results showed that 3-O-feruloylquinic acid has good conjugation with Bcl-2, Stat3, mTOR, and mmp9. Catechin has the lowest binding energy with CDK6 and ß-catenin. The study provides data for the further confirmation of the material basis and mechanism of ZJD in treating liver cancer, and provides a new idea for the researches on the compatibility mechanism of prescriptions of traditional Chinese medicine.


Assuntos
Antineoplásicos , Medicamentos de Ervas Chinesas , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Interações Ervas-Drogas , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Espectrometria de Massas , Medicina Tradicional Chinesa , Camundongos , Simulação de Acoplamento Molecular
4.
Artigo em Inglês | MEDLINE | ID: mdl-34224965

RESUMO

The metabolomics approach based on the gas chromatography coupled to mass spectrometry (GC-MS) was adopted to explore the underlying mechanism of the anti-fatigue effect of Radix Salviae Miltiorrhizae (RSM), a famous herbal medicine in China used for multiple biological functions, in load-weighted swimming test in rat, combined with biochemical parameters evaluations. As a result, the metabolomics study followed by orthogonal partial least-square (OPLS) analysis could differentiate metabolic profiling between the control and exhaustive exercise group, showing the rats underwent an obvious metabolic perturbation, whereas RSM treatment restored scores plot close to normal and showed regulatory effects on the muscle metabolic profiles. The changed metabolic pathways of the potential biomarkers in response to the effect of RSM treatment for exhaustive exercise rats included in glucose metabolism (glucose, lactic acid, alanine), glutathione metabolism (glycine, glutamate, 5-oxo-proline), TCA cycle (succinic acid), arginine biosynthesis (glutamine, ornithine, urea), glyoxylate and dicarboxylate metabolism (serine, glycine), oxidative stress (taurine) and purine metabolism (inosine). In addition, intervention of RSM increased hepatic glycogen, muscle glycogen and serum glucose, and decreased triglyceride and blood urea nitrogen levels, indicating RSM treatment may regulate energy metabolism by increasing the rate of fat utilization, decrease the protein and carbohydrate utilization. Furthermore, RSM reduced exhaustive exercise-induced accumulation of the lipid peroxidation byproduct malonaldehyde and elevated antioxidants' levels, including reduced glutathione and superoxide dismutase, which might be a positive reflection of improved oxidant-antioxidant balance. Moreover, RSM could protect against exercise-induced muscle damage by attenuating creatine kinase release. In summary, RSM provided a good anti-fatigue effect by regulating energy metabolism, oxidant-antioxidant balance, and the endogenous metabolites in the exercising muscle. This study demonstrates that metabolomics is an effective tool for the estimation of the potential anti-fatigue effect of RSM and for the illustration of its pharmacological mechanism.


Assuntos
Medicamentos de Ervas Chinesas , Fadiga/metabolismo , Metaboloma/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Salvia miltiorrhiza , Animais , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Metabolômica , Ratos , Ratos Sprague-Dawley
5.
Biomed Res Int ; 2021: 5575443, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195269

RESUMO

Xiaoxuming decoction (XXMD) is a traditional Chinese herbal medicine (CHM) that is used for the treatment of stroke in China. Stroke injury damages the cerebral vasculature and disrupts the autoregulation of vasoconstriction and vasodilatation, which is crucial for maintaining constant cerebral blood flow (CBF). It has been reported that XXMD exerts a positive effect on cerebral circulation in animal models of stroke. However, the mechanisms underlying the regulatory effect of XXMD on vascular tone, and the interactions among the multiple components of XXMD, remain unclear. In this study, XXMD was found to induce relaxation of the basilar artery rings of rats precontracted by 5-hydroxytryptamine (5-HT) in vitro, in a dose-dependent manner. The modulation of vascular tone and the process of cerebral ischemia are mediated via the interactions between G protein-coupled receptors (GPCRs) and their ligands, including 5-HT, angiotensin II (Ang II), and urotensin II (UII). Thus, the potential synergistic effects of the different components of XXMD on the regulation of vasoconstriction and vasodilation were further investigated by molecular docking based on network pharmacology. We constructed and analyzed a database comprising 963 compounds of XXMD and studied the interactions between five vascular GPCRs (5-HT1A receptor (5-HT1AR), 5-HT1B receptor (5-HT1BR), Ang II type 1 receptor (AT1R), beta 2-adrenergic receptor (ß2-AR), and UII receptor (UTR)) and the various herbal constituents of XXMD using molecular docking. By constructing and analyzing the compound-target networks of XXMD, we found that Glycyrrhizae Radix et Rhizoma, Ginseng Radix et Rhizoma, and Paeoniae Radix Alba were the three major herbs that contained a large number of compounds with high docking scores. We additionally observed that several constituents of XXMD, including gallotannin, liquiritin apioside, nariutin, 1,2,3,4,6-pentagalloylglucose, folic acid, and ginsenoside Rb1, targeted multiple vascular GPCRs. Moreover, the interactions between the components of XXMD and the targets related to vascular tone constituted the comprehensive cerebrovascular regulatory function of XXMD and provided a material basis of the vasoregulatory function of XXMD. The study reports the contributions of various components of XXMD to the regulatory effects on vascular tone and provides scientific evidence for the multicomponent and multitargeting characteristics of XXMD.


Assuntos
Artéria Basilar/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/metabolismo , Ligantes , Masculino , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Paeonia/metabolismo , Panax/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/farmacologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-34130203

RESUMO

San Miao Wan (SMW), composed of Phellodendri Chinensis Cortex, Atractylodis Lanceae Rhizoma and Achyranthis Bidentatae Radix, is widely used for the treatment of gout, hyperuricemia and other diseases. In the present study, an overall identification strategy based on ultra-high performance liquid chromatography tandem Q-Exactive Orbitrap mass spectrometry (UPLC-Q-Exactive Orbitrap/MS) method was established to characterize the multiple chemical constituents of SMW and its metabolites in rat plasma after oral administration of SMW. A total of 76 constituents including alkaloids, organic acids, lactones, terpenes, saponins, sterones and others types of components were identified in the extract of SMW. After the oral administration of SMW, 47 prototype constituents and 66 metabolites were identified in rat plasma samples. The related metabolic pathways mainly involved reduction, demethylation, hydroxylation, methylation and glucuronide conjunction. The proposed method could be a useful approach to identify the chemical constituents of SMW and its metabolic components. Our study provide a universal strategy for the analysis of the components and metabolites of the traditional Chinese medicine prescription (TCP) extracts and plasma after administration using UPLC-Q-Exactive Orbitrap/MS method. It will assist with clarifying the substance basis of effective components in SMW. It also provides a rapid method for overall analysis of chemical constituents and metabolites of SMW.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem/métodos , Administração Oral , Alcaloides/sangue , Alcaloides/química , Alcaloides/metabolismo , Animais , Ácidos Carboxílicos/sangue , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Lactonas/sangue , Lactonas/química , Lactonas/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
7.
Food Chem Toxicol ; 153: 112257, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34000341

RESUMO

Drug-induced liver injury (DILI) is a major side effect, sometimes can't be exactly evaluated by current approaches partly as the covalent modification of drug or its reactive metabolites (RMs) with proteins is a possible reason. In this study, we developed a rapid, sensitive, and specific analytical method to assess the hepatotoxicity induced by drug covalently modified proteins based on the quantification of the modified amino acids using toosendanin (TSN), a hepatotoxic chemical, as an example. TSN RM-protein adducts both in rat liver and blood showed good correlation with the severity of hepatotoxicity. Thus, TSN RM-protein adducts in serum can potentially serve as minimally invasive biomarkers of hepatotoxicity. Meanwhile, large-scale chemical proteomics analysis showed that at least 84 proteins were modified by TSN RMs in rat liver, and the bioinformatics analysis revealed that TSN might induce hepatotoxicity through multi-target protein-protein interaction especially involved in energy metabolism. These findings suggest that our approach may serve as a valuable tool to evaluate DILI and investigate the possible mechanism, especially for complex compounds.


Assuntos
Proteínas Sanguíneas/análise , Doença Hepática Induzida por Substâncias e Drogas/sangue , Medicamentos de Ervas Chinesas/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/química , Proteínas Sanguíneas/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Humanos , Fígado/efeitos dos fármacos , Lisina/química , Masculino , Microssomos Hepáticos/metabolismo , Proteômica , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
8.
Neurochem Res ; 46(7): 1881-1894, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33988813

RESUMO

Ginkgo biloba L. leaves (GBLs), as widely used plant extract sources, significantly improve cognitive, learning and memory function in patients with dementia. However, few studies have been conducted on the specific mechanism of Neurodegenerative diseases (NDs). In this study, network pharmacology was employed to elucidate potential mechanism of GBLs in the treatment of NDs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to obtain the chemical components in accordance with the screening principles of oral availability and drug-like property. Potential targets of GBLs were integrated with disease targets, and intersection targets were exactly the potential action targets of GBLs for treating NDs; these key targets were enriched and analyzed by the protein protein interaction (PPI) analysis and molecular docking verification. Key genes were ultimately used to find the biological pathway and explain the therapeutic mechanism by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Twenty-seven active components of GBLs may affect biological processes such as oxidative reactions and activate transcription factor activities. These components may also affect 120 metabolic pathways, such as the PI3K/AKT pathway, by regulating 147 targets, including AKT1, ALB, HSP90AA1, PTGS2, MMP9, EGFR and APP. By using the software iGEMDOCK, the main target proteins were found to bind well to the main active components of GBLs. GBLs have the characteristics of multi-component and multi-target synergistic effect on the treatment of NDs, which preliminarily predicted its possible molecular mechanism of action, and provided the basis for the follow-up study.


Assuntos
Medicamentos de Ervas Chinesas/química , Ginkgo biloba/química , Doenças Neurodegenerativas/tratamento farmacológico , Nootrópicos/química , Folhas de Planta/química , Bases de Dados de Produtos Farmacêuticos , Medicamentos de Ervas Chinesas/metabolismo , Ontologia Genética , Humanos , Simulação de Acoplamento Molecular , Nootrópicos/metabolismo , Farmacologia/métodos , Ligação Proteica , Mapas de Interação de Proteínas , Proteínas/metabolismo
9.
PLoS One ; 16(5): e0251300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34010329

RESUMO

Dynamic changes in flavonoid, total phenol, and antioxidant potential in different Prunus humilis accessions during fruit development stages were studied in order to provide a reference for the optimum harvest time for flavonoid extraction. 'Nongda 4', 'Nongda 5', 'DS-1' and '02-16' were selected as plant materials to determine the content of flavonoid, total phenol and antioxidant indices during six fruit development stages. Changes in total flavonoid content (TFC) and total phenol content (TPC) in different accessions of P. humilis were slightly different depending on the development stage of P. humilis fruit. TFC and TPC in 'Nongda 5' fruit showed a trend of continuous decline. There was a small increase in TFC and TPC from the young fruit stage to the stone hardening stage, followed by a decreasing trend, and then to the lowest level at the ripening stage of 'Nongda 4', 'DS-1', and '02-16' fruits. The trend of antioxidant capacity (ABTS, FRAP, DPPH) with the TFC and TPC of P. humilis fruit was basically the same, and the correlation analysis results showed that the TFC of P. humilis fruit was positively correlated with the antioxidant indices (P<0.01). Catechin (CC), rutin (RT), and quercetin-7-O-ß-D-glucopyranoside (Q7G) were detected in all the fruit development stages of the four P. humilis fruits. Among them, catechin was the most abundant component, accounting for approximately 10%. Myricetin (MC) and quercetin (QC) were generally detected only in the early fruit development stage, but not in the later fruit development stage. Correlation analysis showed that the flavonoid components with TFC, TPC, and antioxidant indices differed between the different accessions. RT, CC, and liquiritigenin (LR) had a stronger correlation with TFC and antioxidant indices. Cyanidin-3-O-glucoside (C3G) was not detected until the coloring stage in two red P. humilis accessions ('Nongda 4' and 'DS-1'), and so it is better to choose a red P. humilis fruit to extract C3G at the ripening stage. Selecting an early stage of fruit development, especially the stone hardening stage, was important for extracting flavonoids, total phenols and other components. We believe that our results will provide basic information and reference for evaluation of fruit nutrition and health benefits, breeding of functional new varieties, and efficient utilization of P. humilis fruit.


Assuntos
Prunus/crescimento & desenvolvimento , Prunus/metabolismo , Antioxidantes/metabolismo , China , Produção Agrícola , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/metabolismo , Frutas/crescimento & desenvolvimento , Frutas/metabolismo , Humanos , Fenóis/metabolismo , Melhoramento Vegetal , Plantas Comestíveis/crescimento & desenvolvimento , Plantas Comestíveis/metabolismo , Análise de Componente Principal
10.
Sci Rep ; 11(1): 11300, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050227

RESUMO

Vancomycin-resistant enterococci (VRE) are prominent causes of nosocomial infections. Japanese traditional (Kampo) medicine promotes intestinal immunity and protects against bacterial infections. We assessed potential differences in the clinical course of VRE-positive patients, based on their characteristics and treatment with Kampo medicines. This retrospective observational study collected data from VRE-positive patients from August 2018 to July 2019 at a tertiary-care hospital in Japan. The data of 122 consecutive VRE-positive inpatients were analyzed. Sixty-nine patients were treated with probiotics, among whom, 18 were further treated with Kampo medicines. Twenty-six of the 122 patients subsequently died. In univariate analyses, subsequent VRE negative conversion significantly reduced the mortality of VRE-detected patients (p = .0003). Administration of probiotics (p = .0065) and Kampo medicines with probiotics (p = .0002), especially of the Kampo medicine hochuekkito (p = .0014), and a higher serum albumin level positively contributed to the subsequent VRE negative conversion. Multivariate analyses demonstrated that Kampo medicines and body mass index contributed to VRE negative conversion. Hochuekkito shortened the time needed for VRE negative conversion (p = 0.0485). Administration of Kampo medicines, especially of hochuekkito, in addition to probiotics in VRE patients may promote VRE negative conversion.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Medicina Tradicional do Leste Asiático/métodos , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana/efeitos dos fármacos , Medicamentos de Ervas Chinesas/metabolismo , Enterococcus/efeitos dos fármacos , Feminino , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Japão/epidemiologia , Masculino , Medicina Tradicional Chinesa/métodos , Medicina Kampo/métodos , Pessoa de Meia-Idade , Probióticos/uso terapêutico , Estudos Retrospectivos , Vancomicina/farmacologia , Enterococos Resistentes à Vancomicina/patogenicidade
11.
Oxid Med Cell Longev ; 2021: 6673828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055197

RESUMO

Chinese herbal Fu-Zheng-Qu-Xie (FZQX) prescription has been found to improve the immune function and survival of patients with early-stage lung cancer. However, the therapeutic efficacy needs to be evaluated objectively, and the precise mechanism remains unclear. In the present study, a double-center, prospective cohort study was carried out to assess the clinical efficacy of the FZQX prescription in preventing the recurrence and metastasis of postoperative early-stage lung adenocarcinoma. Our results indicated that the FZQX prescription could significantly reduce the 3-year postoperative recurrence rate and improve the life quality. Moreover, the peripheral blood indices showed that the positive immune index (CD4 +T/CD8 +T) increased and the negative immune indices (CD8 +T, Myeloid-derived suppressor cells (MDSCs), Treg) decreased after treatment with the FZQX prescription. Since the positive regulatory effect of the FZQX prescription on immune function, a series of experiments were conducted to verify the tumor-suppressive effect and elucidate the underlying mechanisms. Through the MDSC clearance xenograft model, we confirmed that the FZQX prescription could effectively suppress tumor growth with lesser side effects in vivo, and MDSCs may be involved in the biological process of the FZQX prescription's intervention in lung cancer progression. By establishing the coculture system of MDSCs/LLC to simulate the immune microenvironment of lung cancer, the tumor suppression effect of the FZQX prescription was further validated by in vitro experiments. Besides, it was confirmed that the FZQX prescription could regulate MDSCs to remodel the immunosuppressive tumor microenvironment, thus exerting its preventive effect on relapse of lung cancer. Finally, the pathway activator and inhibitor were further used to explore the potential molecular mechanism. Results demonstrated that the IL-1ß/NF-κB signaling pathway was one of the critical signaling pathways of FZQX prescription regulating MDSCs to prevent the recurrence and metastasis of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Medicamentos de Ervas Chinesas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Feminino , Ginsenosídeos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Estudos Prospectivos
12.
Drug Des Devel Ther ; 15: 1779-1795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33958856

RESUMO

Background: This study used network pharmacology, molecular docking and experimental validation to assess the effects of Huanglian Jiedu Decoction (HLJDD) on atherosclerosis (AS). Methods: The components and targets of HLJDD were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and information on the genes associated with AS was retrieved from the GeneCards and OMIM platforms. Protein-protein interactions were analyzed using the STRING platform. A component-target-disease network was constructed using Cytoscape. GO and KEGG analyses were performed to identify molecular biological processes and signaling pathways, and the predictions were verified experimentally. Molecular docking was conducted with ChemOffice software, PyMOL software and Vina to verify the correlation of targets and compounds. Results: HLJDD contained 31 active compounds, with quercetin, kaempferol, moupinamide and 5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chromone as the core compounds. The most important biotargets of HLJDD in AS were ICAM-1, CD31 and RAM-11. The molecular docking results showed that the molecular docking interaction energy between the 3 key targets and the 4 high-degree components were much less than -5 kJ∙mol-1. The experimental validation results showed that HLJDD might treat AS mainly by reducing TC, TG and LDL-C and increasing HDL-C, upregulating CD31 expression, reducing ICAM-1 and RAM-11 expression, and downregulating inflammatory factors, including CRP, IL-6 and TNF-α. These results support the network pharmacology data and demonstrate that HLJDD affects the expression of core genes and alters the leukocyte transendothelial migration signaling pathway. Conclusion: Based on network pharmacology and experimental validation, our study indicated that HLJDD exerted anti-AS effect through upregulating CD31 expression and reducing the expression of ICAM-1 and RAM-11. HLJDD may be a potential therapeutic drug to the prevention of AS.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Aterosclerose/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Masculino , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Coelhos
13.
Drug Des Devel Ther ; 15: 1883-1902, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976539

RESUMO

Background: Rhubarb, as a traditional Chinese medicine, is the preferred drug for the treatment of stagnation and constipation in clinical practice. It has been reported that rhubarb possesses hepatotoxicity, but its mechanism in vivo is still unclear. Methods: In this study, the chemical components in rhubarb were identified based on UPLC-Q-TOF/MS combined with data postprocessing technology. The metabolic biomarkers obtained through metabolomics technology were related to rhubarb-induced hepatotoxicity. Furthermore, the potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology involving the above components and metabolites. Meanwhile, GO gene enrichment analysis and KEGG pathway analysis were performed on the common targets. Results: Twenty-eight components in rhubarb were identified based on UPLC-Q-TOF/MS, and 242 targets related to rhubarb ingredients were predicted. Nine metabolic biomarkers obtained through metabolomics technology were closely related to rhubarb-induced hepatotoxicity, and 282 targets of metabolites were predicted. Among them, the levels of 4 metabolites, namely dynorphin B (10-13), cervonoyl ethanolamide, lysoPE (18:2), and 3-hydroxyphenyl 2-hydroxybenzoate, significantly increased, while the levels of 5 metabolites, namely dopamine, biopterin, choline, coenzyme Q9 and P1, P4-bis (5'-uridyl) tetraphosphate significantly decreased. In addition, 166 potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology. The KEGG pathway analysis was performed on the common targets to obtain 46 associated signaling pathways. Conclusion: These data suggested that rhubarb may cause liver toxicity due to its action on dopamine D1 receptor (DRD1), dopamine D2 receptor (DRD2), phosphodiesterase 4B (PDE4B), vanilloid receptor (TRPV1); transient receptor potential cation channel subfamily M member 8 (TRPM8), prostanoid EP2 receptor (PTGER2), acetylcholinesterase (ACHE), muscarinic acetylcholine receptor M3 (CHRM3) through the cAMP signaling pathway, cholinergic synapses, and inflammatory mediators to regulate TRP channels. Metabolomics technology and network pharmacology were integrated to explore rhubarb hepatotoxicity to promote the reasonable clinical application of rhubarb.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Fígado/efeitos dos fármacos , Metabolômica , Extratos Vegetais/efeitos adversos , Rheum/química , Animais , Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Fígado/lesões , Fígado/metabolismo , Masculino , Medicina Tradicional Chinesa , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ratos , Ratos Wistar
14.
Drug Des Devel Ther ; 15: 1915-1930, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976541

RESUMO

Background: S. baicalensis, a traditional herb, has great potential in treating diseases associated with aberrant lipid metabolism, such as inflammation, hyperlipidemia, atherosclerosis and Alzheimer's disease. Aim of the Study: To elucidate the mechanism by which S. baicalensis modulates lipid metabolism and explore the medicinal effects of S. baicalensis at a holistic level. Materials and Methods: The potential active ingredients of S. baicalensis and targets involved in regulating lipid metabolism were identified using a network pharmacology approach. Metabolomics was utilized to compare lipids that were altered after S. baicalensis treatment in order to identify significantly altered metabolites, and crucial targets and compounds were validated by molecular docking. Results: Steroid biosynthesis, sphingolipid metabolism, the PPAR signaling pathway and glycerolipid metabolism were enriched and predicted to be potential pathways upon which S. baicalensis acts. Further metabolomics assays revealed 14 significantly different metabolites were identified as lipid metabolism-associated elements. After the pathway enrichment analysis of the metabolites, cholesterol metabolism and sphingolipid metabolism were identified as the most relevant pathways. Based on the results of the pathway analysis, sphingolipid and cholesterol biosynthesis and glycerophospholipid metabolism were regarded as key pathways in which S. baicalensis is involved to regulate lipid metabolism. Conclusion: According to our metabolomics results, S. baicalensis may exert its therapeutic effects by regulating the cholesterol biosynthesis and sphingolipid metabolism pathways. Upon further analysis of the altered metabolites in certain pathways, agents downstream of squalene were significantly upregulated; however, the substrate of SQLE was surprisingly increased. By combining evidence from molecular docking, we speculated that baicalin, a major ingredient of S. baicalensis, may suppress cholesterol biosynthesis by inhibiting SQLE and LSS, which are important enzymes in the cholesterol biosynthesis pathway. In summary, this study provides new insights into the therapeutic effects of S. baicalensis on lipid metabolism using network pharmacology and lipidomics.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipidômica , Medicamentos de Ervas Chinesas/metabolismo , Humanos , Medicina Tradicional Chinesa , Metabolômica
15.
J Ethnopharmacol ; 276: 114200, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-33989737

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine suggests the use of natural extracts and compounds is a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity and resulting diarrhea. Previous work from our lab indicated the protective effect of Gegen Qinlian decoction; given this, we further speculated that Gegen Qinlian Pill (GQP) would exhibit similar therapeutic effects. The effective material basis as well as potential mechanisms underlying the effect of GQP for the treatment of CPT-11-induced diarrhea have not been fully elucidated. AIM OF THE STUDY: The application of natural extracts or compounds derived from Chinese medicine is deemed to a promising strategy to prevent irinotecan (CPT-11)-induced gut toxicity. The aim of this study was to investigated the beneficial effects of GQP on CPT-11-induced gut toxicity and further explored its anti-diarrheal mechanism. METHODS: First, the beneficial effect of GQP in alleviating diarrhea in mice following CPT-11 administration was investigated. We also obtained the effective ingredients in GQP from murine serum samples using HPLC-Q-TOF-MS analysis. Based on these active components, we next established an interaction network linking "compound-target-pathway". Finally, a predicted mechanism of action was obtained using in vivo GQP validation based on Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: A total of 19, GQP-derived chemical compounds were identified in murine serum samples. An interaction network linking "compound-target-pathway" was then established to illuminate the interaction between the components present in serum and their targets that mitigated diarrhea. These results indicated GQP exerted a curative effect on diarrhea and diarrhea-related diseases through different targets, which cumulatively regulated inflammation, oxidative stress, and proliferation processes. CONCLUSION: Taken together, this study provides a feasible strategy to elucidate the effective constituents in traditional Chinese medicine formulations. More specifically, this work detailed the basic pharmacological effects and underlying mechanism behind GQP's effects in the treatment of CPT-11-induced gut toxicity.


Assuntos
Diarreia/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Diarreia/sangue , Diarreia/induzido quimicamente , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Gastroenteropatias/sangue , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/patologia , Irinotecano/efeitos adversos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas de Membrana/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/uso terapêutico , Comprimidos
16.
J Ethnopharmacol ; 275: 114045, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831463

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Dang-Gui-Si-Ni (DGSN) decoction as a classic prescription has been widely used for thousands of years in the clinical practice of traditional Chinese medicine (TCM). Especially in recent years, the potential efficacy of TCM for the treatment of Raynaud's syndrome has attracted great attention as there are still no specific remedies for this disease. However, the active constituents and underlying mechanisms responsible for the therapeutic benefits are not well understood, which makes it difficult to ensure quality control or to design research and drug development strategies. To identify the potential pharmacodynamic ingredients (PPIs) of TCM will help to achieve suitable process control procedures for industrial production and large-scale manufacturing. AIM OF THE STUDY: In the present study, we propose a multi-dimensional qualitative analysis method combining water-decoction spectra, in-vitro intestinal absorption spectra, in-vivo plasma spectra, and molecular docking of components to quickly identify the PPIs for the DGSN decoction of TCM. MATERIALS AND METHODS: Water-based decoctions of DGSN were prepared in accordance with the clinical use registered in ancient books. Ultra-high-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q/TOF-MS) coupled with computerized modelling activity screening was used to quickly identify the PPIs of the DGSN decoction. Bioactive compounds absorbed in vitro were identified using the everted intestinal sac model from rats and compounds absorbed in vivo were confirmed in portal vein blood samples obtained following oral administration in rats. Molecular docking validation experiments were adopted to predict the binding activity to coagulation factors I, II, VII, X, and IX. The active components were further confirmed by pharmacodynamics analysis. The anticoagulant activity of the DGSN decoction was verified using rat models. RESULTS: Thirty-one compounds were identified in the DGSN decoction. According to the in vivo experiments, 22 compounds that could be absorbed in vivo were detected by the everted intestinal sac model in rats. This model greatly reduces the scope of PPIs and is easy to perform. Ten compounds were detected in the portal vein blood in rats. The compounds detected in plasma provide stronger evidence supporting the PPIs. Molecular docking in vitro experiments indicated that 7 compounds exhibited better binding activity with coagulation factors I, II, VII, X, and IX. The animal experiments confirmed that the DGSN decoction could improve the microcirculation, providing indirect proof of anticoagulant activity suggested by the molecular docking studies. Finally, based on the multi-dimensional methods, 9 potential compounds present in the DGSN decoction were identified as PPIs (i.e., ferulic acid, paeoniflorin, albiflorin, chlorogenic acid, cryptochlorogenic acid, liquiritin, liquiritin apioside, cinnamaldehyde and glycyrrhizic acid). CONCLUSION: Overall, this study combined the water-decoction spectra, intestinal absorption spectra in vitro, plasma spectra in vivo, and molecular docking studies to establish a multi-dimensional qualitative analysis method of the DGSN decoction. Meanwhile, 9 compounds in DGSN decoction were identified as PPIs using this method, and are proposed for application as quality standards for complex TCM prescriptions.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Administração Oral , Animais , Fatores de Coagulação Sanguínea/química , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/análise , Flavonoides/química , Hidroxibenzoatos/análise , Hidroxibenzoatos/química , Absorção Intestinal , Masculino , Medicina Tradicional Chinesa , Microcirculação/efeitos dos fármacos , Simulação de Acoplamento Molecular , Nucleosídeos/análise , Nucleosídeos/química , Plasma/química , Ratos Sprague-Dawley , Doença de Raynaud/tratamento farmacológico , Terpenos/análise , Terpenos/química
17.
Molecules ; 26(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804230

RESUMO

The fruit of Lycium barbarum L. (goji berry) is used as traditional Chinese medicine, and has the functions of immune regulation, anti-tumor, neuroprotection, anti-diabetes, and anti-fatigue. One of the main bioactive components is L. barbarum polysaccharide (LBP). Nowadays, LBP is widely used in the health market, and it is extracted from the fruit of L. barbarum. The planting of L. barbarum needs large amounts of fields, and it takes one year to harvest the goji berry. The efficiency of natural LBP production is low, and the LBP quality is not the same at different places. Goji berry-derived LBP cannot satisfy the growing market demands. Engineered Saccharomyces cerevisiae has been used for the biosynthesis of some plant natural products. Recovery of LBP biosynthetic pathway in L. barbarum and expression of them in engineered S. cerevisiae might lead to the yeast LBP production. However, information on LBP biosynthetic pathways and the related key enzymes of L. barbarum is still limited. In this review, we summarized current studies about LBP biosynthetic pathway and proposed the strategies to recover key enzymes for LBP biosynthesis. Moreover, the potential application of synthetic biology strategies to produce LBP using engineered S. cerevisiae was discussed.


Assuntos
Medicamentos de Ervas Chinesas/metabolismo , Lycium/metabolismo , Saccharomyces cerevisiae/metabolismo , Animais , Vias Biossintéticas/fisiologia , Fitoterapia/métodos , Biologia Sintética/métodos
18.
Biomed Chromatogr ; 35(8): e5120, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33749888

RESUMO

Knoxiae Radix (HDJ, usually used after being processed into CHDJ) is a traditional Chinese herbal medicine that has been recorded in the Chinese Pharmacopoeia for many years. It is said that Glycyrrhizae Radix et Rhizoma (GC) is incompatible with HDJ, but this is unproven. In this work, nontargeted metabolomics experiments were performed on rats to evaluate the effect of the combination of the two herbals. For this, we conducted a 28-day administration in rats. The plasma, urine and kidney tissues were collected for a metabolomics study based on 1 H NMR and LC-MS. The OPLS-DA method was used to screen biomarkers. In addition, the KEGG Pathway database and MetaboAnalyst were used to find metabolic pathways. Twenty-two significant metabolites were identified. These metabolites were related to many metabolic pathways such as amino acid metabolism, synthesis and degradation of ketone bodies. Significant changes in urine creatinine levels revealed that CHDJ is nephrotoxic. When the GC-CHDJ mass ratio was 1, the toxicity was strengthened; when the GC-CHDJ' mass ratio was 3, the toxicity was alleviated. This is the first time that a metabolomics approach has been used to investigate the incompatibility of GC-CHDJ.


Assuntos
Medicamentos de Ervas Chinesas , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Interações Ervas-Drogas , Espectroscopia de Ressonância Magnética/métodos , Masculino , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Ratos , Ratos Sprague-Dawley
19.
Biomed Pharmacother ; 138: 111445, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33711551

RESUMO

Whilst the popular use of herbal medicine globally, it poses challenges in managing potential drug-herb interaction. There are two folds of the drug-herb interaction, a beneficial interaction that may improve therapeutic outcome and minimise the toxicity of drug desirably; by contrast, negative interaction may evoke unwanted clinical consequences, especially with drugs of narrow therapeutic index. Scutellaria baicalensis Georgi is one of the most popular medicinal plants used in Asian countries. It has been widely used for treating various diseases and conditions such as cancer, diabetes, inflammation, and oxidative stress. Studies on its extract and bioactive compounds have shown pharmacodynamic and pharmacokinetic interactions with a wide range of pharmaceutical drugs as evidenced by plenty of in vitro, in vivo and clinical studies. Notably, S. baicalensis and its bioactives including baicalein, baicalin and wogonin exhibited synergistic interactions with many pharmaceutical drugs to enhance their efficacy, reduce toxicity or overcome drug resistance to combat complex diseases such as cancer, diabetes and infectious diseases. On the other hand, S. baicalensis and its bioactives also affected the pharmacokinetic profile of many drugs in absorption, distribution, metabolism and elimination via the regulatory actions of the efflux pumps and cytochrome P450 enzymes. This review provides comprehensive references of the observed pharmacodynamic and pharmacokinetic drug interactions of Scutellaria baicalensis and its bioactives. We have elucidated the interaction with detailed mechanistic actions, identified the knowledge gaps for future research and potential clinical implications. Such knowledge is important for the practice of both conventional and complementary medicines, and it is essential to ensure the safe use of related herbal medicines. The review may be of great interest to practitioners, consumers, clinicians who require comprehensive information on the possible drug interactions with S. baicalensis and its bioactives.


Assuntos
Interações Ervas-Drogas/fisiologia , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Scutellaria baicalensis , Animais , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/fisiologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Extratos Vegetais/isolamento & purificação
20.
Bioorg Med Chem Lett ; 40: 127919, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711444

RESUMO

We aimed to compare the estrogenic activities of compounds isolated from Moutan Cortex Radicis (MRC, Paeonia suffruticosa Andrews) and identify their potential use in hormone replacement therapy. We quantified seven marker components (gallic acid, oxypaeoniflorin, paeoniflorin, ethyl gallate, benzoic acid, benzoylpaeoniflorin, and paeonol) in MRC using a high-performance liquid chromatography simultaneous analysis assay. To investigate the estrogenic activity of MRC and the seven marker components, an E-screen assay was conducted using the estrogen receptor (ER)-positive MCF-7 human breast cancer cell line. Among them, ethyl gallate caused cell proliferation in a concentration-dependent manner at concentrations above 25 µM and was clearly suppressed by combination treatment with the ER antagonist ICI 182,780. Therefore, ethyl gallate may be a compound of MRC that can increase the estrogenic effect in ER-positive MCF-7 cells.


Assuntos
Estrona/química , Ácido Gálico/análogos & derivados , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Estrogênios , Ácido Gálico/química , Ácido Gálico/farmacologia , Glucosídeos/química , Terapia de Reposição Hormonal , Humanos , Monoterpenos/química , Paeonia/química , Paeonia/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
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