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1.
Biomed Chromatogr ; 34(2): e4726, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31654585

RESUMO

Multicompound determination for the quality control of traditional Chinese medicine (TCM) may often be inadequate, since these compounds may not be associated with, or fully represent, the clinical effects of TCM. Moreover, the individual contributions of each constituent to the pharmacological effect are often not considered. In China, Porana sinensis is widely used as a substitute for Erycibe sources to treat joint pain and rheumatoid arthritis. The existing quality control methods for P. sinensis neither consider the individual contributions of various compounds nor control the actual quality associated with different clinical efficacies. In the present study, a novel efficacy-oriented approach, named the effect-constituent index (ECI), was established for P. sinensis. Analyses of the spectrum-effect relationship and components in rat plasma were conducted to systematically and scientifically select quality markers. Quantitative analysis of multicomponents via a single marker method was introduced to enhance the practical application value of the established ECI. The established ECI shows a good ability to distinguish and predict the bioeffect-based quality of P. sinensis. The present study also provides a reference for the establishment and application of ECI as a quality control method for TCMs.


Assuntos
Convolvulaceae/química , Medicamentos de Ervas Chinesas , Animais , Ácido Clorogênico/sangue , Ácido Clorogênico/química , Ácido Clorogênico/farmacocinética , Cromatografia Líquida de Alta Pressão , Cumarínicos/sangue , Cumarínicos/química , Cumarínicos/farmacocinética , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/normas , Glucosídeos/sangue , Glucosídeos/química , Glucosídeos/farmacocinética , Modelos Lineares , Medicina Tradicional Chinesa , Controle de Qualidade , Ácido Quínico/análogos & derivados , Ácido Quínico/sangue , Ácido Quínico/química , Ácido Quínico/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
2.
J Mass Spectrom ; 55(1): e4484, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786817

RESUMO

Qixianqingming granules (QXQM) comprise a traditional Chinese medicine (TCM) formula that was developed based on the combination of TCM theory and clinical practice. This formula has been proven to effectively treat asthma. In this study, an analytical procedure using ultraperformance liquid chromatography, coupled with electrospray ionization quadrupole time-of-flight mass spectrometry, was established for the rapid separation and sensitive identification of the chemical components in QXQM and its metabolites in serum of rats. Seventy-two compounds were systematically identified in QXQM, including flavonoids, terpenoids, anthraquinones, phenylethanoid glycosides, stilbenes, alkaloids, and organic acids. Thirteen prototype compounds and 29 metabolites were detected in the serum of rats. The results provided fundamental information for further studying the mechanisms and clinical application of QXQM.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Alcaloides/análise , Alcaloides/metabolismo , Animais , Antraquinonas/análise , Antraquinonas/metabolismo , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/metabolismo , Flavonoides/análise , Flavonoides/metabolismo , Glicosídeos/análise , Glicosídeos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Estilbenos/análise , Estilbenos/metabolismo , Terpenos/análise , Terpenos/metabolismo
3.
J Agric Food Chem ; 68(1): 409-417, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31833363

RESUMO

Naringin has been documented to possess various bioactivities. Due to thorny endogenous interferences, the metabolism pathways of naringin and exact amounts of derived phenolic catabolites have not been definitely assigned. In this work, stable isotope-labeling-based liquid chromatography-mass spectrometry methods were developed to eliminate the endogenous interferences. [2',3',5',6'-D4]-naringin was orally administrated to rats. Urine and feces samples were collected and then analyzed with ultrahigh-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). A total of 21 flavonoid metabolites and 11 phenolic catabolites were screened. The metabolism and catabolism pathways were proposed. Furthermore, deuterated naringin and its main metabolites were determined with rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QqQ-MS/MS). The overall recovery of ingested deuterated naringin was calculated as 56.9% without endogenous interferences. The obtained results provide essential information for further pharmacological studies of naringin.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Fezes/química , Flavanonas/química , Flavanonas/metabolismo , Marcação por Isótopo/métodos , Espectrometria de Massas/métodos , Animais , Medicamentos de Ervas Chinesas/metabolismo , Feminino , Flavanonas/urina , Masculino , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Zhong Yao Za Zhi ; 44(21): 4704-4712, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872668

RESUMO

Rosmarinic acid,a hydrosoluble polyphenolic hydroxyl compound,is the active ingredient in such traditional Chinese medicines as Menthae Haplocalycis Herba,Salviae Miltiorrhizae Radix et Rhizoma,Rosemary,Perillae Folium. Because of its good anti-inflammatory,anti-oxidant and anti-tumor effects,it is widely used in food,medicine and other fields. However,the metabolic process and metabolites of rosmarinic acid in vivo have not been completely defined. In this study,an efficient method of ultra-high performance liquid chromatography combined with linear ion trap-Orbitrap(UHPLC-LTQ-Orbitrap) mass spectrometer was used to analyze the metabolites in vivo of rosmarinic acid in rats. Plasma,urine and feces samples were collected after oral administration of rosmarinic acid. After biological samples were processed by solid phase extraction,Acquity UPLC  BEH C18 column(2. 1 mm × 100 mm,1. 7 µm) was used with 0. 1% formic acid(A)-acetonitrile(B) solution as the mobile phase at the speed of 0. 30 m L·min-1 and temperature of 35 ℃ under gradient conditions. The plasma,urine,feces and the blank samples were then analyzed by ESI-LTQ-Orbitrap under both negative and positive ion modes. Based on the accurate mass measurement(<5),MS/MS fragmentation patterns,standards and literatures,a total of 36 metabolites were screened out and identified in the biological samples collected from rats after intragastric administration. Three were identified 3 from rat plasma,31 from urine,and 7 from feces. The main metabolic pathways of rosmarinic acid in rats can be divided into five parts. Rosmarinic acid were first decomposed into small molecules,such as trans-caffeic acid,coumaric acid,m-hydroxybenzoic acid and Danshensu,which were followed by sulfation,methylation,glucuronic acid conjugation and glucose conjugation. The results showed that UHPLC-LTQ-Orbitrap mass spectrometer could be used to analyze the metabolism of rosmarinic acid in rats,and provide reference for further studies on toxicology,pharmacodynamics and secondary development of Chinese medicine.


Assuntos
Cinamatos/metabolismo , Depsídeos/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Ratos
5.
Zhongguo Zhong Yao Za Zhi ; 44(21): 4720-4727, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872670

RESUMO

An ultra-performance liquid chromatography hybrid triple quadrupole-linear ion trap mass spectrometry(UPLC-QtrapMS) method was established to identify the metabolites in rat plasma,bile,urine and feces after oral administration of Cinnamomi Cortex(CC) aqueous extract. Several survey experiments,such as enhanced mass spectrum scan(EMS),precursor ion scan(PI),neutral loss scan(NL) and multiple ions monitoring(MIM) were applied to search target components,and two separate enhanced product ion(EPI) scans were triggered via information-dependent acquisition(IDA) method to generate the MS/MS spectra. According to the mass spectrometric data collected from reference standards and reported literature,the structures of metabolites were deduced. A total of76 metabolites and 5 original compounds were tentatively identified in rats after oral administration of CC aqueous extract. Deglycosylation,methylation,sulfonation,and glucuronidation were observed as the primary metabolic pathways for the chemical constituents of CC. These data are able to benefit the clarification of the therapeutic material basis,the clinical usage and further R&D of CC.


Assuntos
Bile , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas em Tandem , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Fezes , Ratos
6.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4257-4262, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872707

RESUMO

This study is to investigate the compatibility mechanism of Danshen-Chuanxiong drug pair on the pharmacokinetics of four phenolic acids. A UPLC-MS/MS method for quantitative determination of salvianolic acid B( Sal B),rosmarinic acid( RA),lithospermic acid( LA) and ferulic acid( FA) in plasma and heart tissue of rats was established. After single salvianolic acids and Chuanxiong-extract or combined intravenous infusion was given to rats,plasma samples and heart tissues in different time were collected. The chromatographic separation was performed on a BEH C18 column using 0. 15% formic acid-acetonitrile as mobile phase for gradient elution. A triple-quadrupole tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating on multiple-reaction monitoring( MRM) scanning in negative ionization mode. Full validation of UPLC method including calibration curves,accuracy,precision,repeatability and matrix effect was investigated to comply with quantitative analysis requirements for biological samples. There were significant differences in the major pharmacokinetic parameters of Sal B,FA and RA for intravenous infusion of salvianolic acids and Chuanxiong-extract or combined in rat plasma. The AUC of Sal B and FA were increased above 40% and100%,respectively. Their Vd and CL were dropped evidently. t1/2 and Vd of RA increased above 130%. The concentration of four phenolic acids were all increased obviously in heart tissue comparing with single infusion. These results demonstrated that the compatibility mechanism of Danshen-Chuanxiong drug pair showed synergistic effect.


Assuntos
Medicamentos de Ervas Chinesas/metabolismo , Coração/fisiologia , Salvia miltiorrhiza , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Hidroxibenzoatos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
7.
Artigo em Inglês | MEDLINE | ID: mdl-31704622

RESUMO

Puerariae Radix (PR) serves as food and medicinal plant for thousands of years with explicit efficacy for heart diseases, while biological target specifically binding-oriented screening of the active components in PR remains a preliminary stage. Cell membrane chromatography (CMC) is newly developed approach where interactions between active components and certain biological targets can be effectively studied, Human umbilical vein endothelial cell (HUVEC) membrane, with its abundant receptors such as ß and AT1, is most eligible for constructing CMC. In this study, an HUVEC/CMC-LC-MS2 system was developed for screening active components in PR, 11 compounds were screened out and four of them were identified. Besides puerarin, the rest identified are daidzin, pueroside D and 3'-hydroxypuerarin. The study provides more reference for CMC applications and PR exploitation.


Assuntos
Membrana Celular/metabolismo , Cromatografia de Afinidade/métodos , Medicamentos de Ervas Chinesas/análise , Isoflavonas/análise , Espectrometria de Massas/métodos , Linhagem Celular , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Isoflavonas/metabolismo , Reprodutibilidade dos Testes
8.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121782, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31778946

RESUMO

Traditional Chinese medicine (TCM) represents a valuable resource for lead compounds discovery. Given the complexity of TCM components, analytical methods play a key role in novel drug development. In our study, we established a high specific and reliable bio-active components screen system, where ß2 adrenergic receptor (ß2-AR) was immobilized on silica by non-covalent bonds and packed into a stainless steel column (4.6 × 50 mm, 7 µm) to form ß2-AR chromatography column. The column was further coupled with high performance liquid chromatography-time of flight tandem mass spectrometry (TOF-MS/MS). By utilizing this strategy, we successfully identified four ß2-AR-targeting compounds: tetrahydroberberine, tetrahydrocolumbamine, fumarine and corydaline from Corydalis Rhizome. The association constants between ß2-AR and tetrahydroberberine (9.04 × 104/M) as well as fumarine (4.30 × 104/M) were determined by frontal chromatography. We also found that these two compounds shared the identical binding site on immobilized ß2-AR with corresponding concentrations of 6.67 × 10-4 M and 5.88 × 10-4 M, respectively. The newly established method represents an efficient tool to identify the target specific natural compounds.


Assuntos
Alcaloides de Berberina , Cromatografia de Afinidade/métodos , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Receptores Adrenérgicos beta 2/metabolismo , Alcaloides de Berberina/análise , Alcaloides de Berberina/metabolismo , Corydalis/química , Avaliação Pré-Clínica de Medicamentos/métodos , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/metabolismo , Receptores Adrenérgicos beta 2/química
9.
Artigo em Inglês | MEDLINE | ID: mdl-31610480

RESUMO

Naoshuantong capsule (NSTC) is an oral traditional Chinese medicine formula used widely in the clinic for ischemic stroke. The absorbed ingredients and metabolites of NSTC have never been reported before. In this study, a method incorporating rapid resolution liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to identify absorbed ingredients and metabolites after oral administration of NSTC. A total of 15 constituents were detected and identified as prototypes of NSTC. 109 metabolites related to catechin, gallic acid, paeoniflorin, chlorogenic acid, protocatechuate, typhaneoside, ß-elemene, calycosin were identified in serum, urine and brain. 19 metabolites of typhaneoside, 3 metabolites of ß-elemene, 12 metabolites of calycosin were reported for the first time. This is the first time to explore the absorption and metabolism of NSTC. The work will provide helpful information for further research of the mechanism and application of NSTC.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Líquidos Corporais/metabolismo , Encéfalo/metabolismo , Catequina/sangue , Ácido Clorogênico/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ácido Gálico/sangue , Glucosídeos/sangue , Glicosídeos/metabolismo , Hidroxibenzoatos/sangue , Isoflavonas/sangue , Masculino , Medicina Tradicional Chinesa/métodos , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/sangue , Sesquiterpenos/sangue
10.
Med Sci Monit ; 25: 7836-7844, 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31628297

RESUMO

BACKGROUND Iron overload is a prominent characteristic of liver injury, but there is no effective treatment at present. Qizhufang (ZSF) is a Chinese herbal formula showed anti-HBV activities, improved liver function, and anti-fibrosis effect. ZSF showed a series of liver-protection functions, but whether ZSF can relieve hepatic iron overload is still unclear. MATERIAL AND METHODS Ferric ammonium citrate (FAC) was used to construct iron-overloaded LO2 cells. The cell apoptosis and proliferation were measured by flow cytometry and CCK-8 assay, respectively. ROS level was analyzed by fluorescence probe. RNA and protein expressions were assessed by real-time PCR and Western blot. RESULTS FAC upregulated apoptosis rate, ROS level, and expression of hepcidin and p-STAT3, but suppressed proliferation and expression of DMT1, FPN1, and CP in LO2 cells. However, Qizhufang (ZSF) reversed the effect of FAC. We also found that hepcidin overexpression suppressed the expressions of DMT1, FPN1, and CP, which were reversed by ZSF. Additionally, STAT3 inhibitor AG490 suppressed hepcidin expression. Moreover, exogenous IL-6 reversed the effect of ZSF on apoptosis rate, ROS level, and the expression of hepcidin, DMT1, FNP1, CP, and p-STAT3. CONCLUSIONS Qizhufang (ZSF) can ameliorate iron overload-induced injury by suppressing hepcidin via the STAT3 pathway in LO2 cells.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Sobrecarga de Ferro/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Medicamentos de Ervas Chinesas/metabolismo , Compostos Férricos/farmacologia , Hepcidinas/metabolismo , Humanos , Interleucina-6/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Medicina Tradicional Chinesa , Compostos de Amônio Quaternário/farmacologia , Espécies Reativas de Oxigênio , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos
11.
Med Sci Monit ; 25: 7735-7745, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613871

RESUMO

This study aimed to investigate the intrinsic mechanisms of Qishen granules (QSG) in the treatment of HF, and to provide new evidence and insights for its clinical application. Information on QSG ingredients was collected from Traditional Chinese medicine systems pharmacology (TCMSP), TCM@Taiwan, TCMID, and Batman, and input into SwissTargetPrediction to identify the compound targets. HF-related targets were detected from Therapeutic Target Database (TTD), Disgenet-Gene, Drugbank database, and Online Mendelian Inheritance in Man (OMIM) database. The overlap targets of QSG and HF were identified for pathway enrichment analysis by utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The protein-protein interaction (PPI) network of QSG-HF was constructed, following by the generation of core targets, construction of core modules, and KEGG analysis of the core functional modules. There were 1909 potential targets predicted from the 243 bioactive compounds in QSG which shared 129 common targets with HF-related targets. KEGG pathway analysis of common targets indicated that QSG could regulated 23 representative pathways. In the QSG-HF PPI network analysis, 10 key targets were identified, including EDN1, AGT, CREB1, ACE, CXCR4, ADRBK1, AGTR1, BDKRB1, ADRB2, and F2. Further cluster and enrichment analysis suggested that neuroactive ligand-receptor interaction, cGMP-PKG signaling pathway, renin secretion, vascular smooth muscle contraction, and the renin-angiotensin system might be core pathways of QSG for HF. Our study elucidated the possible mechanisms of QSG from a systemic and holistic perspective. The key targets and pathways will provide new insights for further research on the pharmacological mechanism of QSG.


Assuntos
Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , China , Humanos , Medicina Tradicional Chinesa , Mapas de Interação de Proteínas , Transdução de Sinais/efeitos dos fármacos
12.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614687

RESUMO

The demand for licorice and its natural product derivatives in domestic and foreign market is considerably huge. The core production areas of licorice are covered with salinity and drought land in northwestern China. Studies have shown that suitable environmental stress can promote the accumulation of glycyrrhizin and liquiritin to improve its quality as medicinal materials. However, there are few reports on other bioactive constituents of licorice, not to mention their dynamic accumulation under stressed conditions. To explore the quality formation of licorice from the perspective of salt influence, a reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS) was established for simultaneous determination of sixteen bioactive constituents, including triterpenoids, flavonoids, chalcones and their glycosides. Physiological experiments were performed to investigate salt tolerance of licorice under different salinity treatments. The expressions of crucial genes (bAS and CHS), key enzymes of triterpenoid and flavonoid synthesis, were also tested by qRT-PCR. Our study found that 50 mM NaCl treatment (low stress) was the most favorable to promote the accumulation of bioactive constituents in the long term, without harming the plants. Flavonoid accumulation of non-stressed and low-stressed groups became different in the initial synthesis stage, and glycosyltransferases may have great influence on their downstream synthesis. Furthermore, bAS and CHS also showed higher levels in low-stressed licorice at harvest time. This work provides valuable information on dynamic variations in multiple bioactive constituents in licorice treated by salt and insight into its quality formation under stressed conditions.


Assuntos
Medicamentos de Ervas Chinesas/química , Flavonoides/química , Glycyrrhiza/química , Extratos Vegetais/química , Chalconas/química , Chalconas/metabolismo , Cromatografia Líquida , Medicamentos de Ervas Chinesas/metabolismo , Flavanonas/química , Flavanonas/metabolismo , Flavonoides/metabolismo , Glucosídeos/química , Glucosídeos/metabolismo , Ácido Glicirrízico/química , Ácido Glicirrízico/metabolismo , Humanos , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Estresse Salino , Espectrometria de Massas em Tandem , Triterpenos/química , Triterpenos/metabolismo
13.
Phys Chem Chem Phys ; 21(42): 23501-23513, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617551

RESUMO

YIV-906 (formally PHY906, KD018) is a four-herb formulation that is currently being developed to improve the therapeutic index and ameliorate the side effects of many chemotherapeutic drugs including sorafenib, irinotecan, and capecitabine. However, as a promising anti-cancer adjuvant, the molecular mechanism of action of YIV-906 remains unrevealed due to its multi-component and multi-target features. Since YIV-906 has been shown to induce apoptosis and autophagy in cancer cells through modulating the negative regulators of ERK1/2, namely DUSPs, it is of great interest to elucidate the key components that cause the therapeutic effect of YIV-906. In this work, we investigated the mechanism of YIV-906 inhibiting DUSPs, using a broad spectrum of molecular modelling techniques, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. In total, MD simulations and binding free energy calculations were performed for 99 DUSP-ligand complexes. We found that some herbal components or their metabolites could inhibit DUSPs. Based on the docking scores and binding free energies, the sulfation and glucuronidation metabolites of the S ingredient in YIV-906 play a leading role in inhibiting DUSPs, although several original herbal chemicals with carboxyl groups from the P and Z ingredients also make contributions to this inhibitory effect. It is not a surprise that the electrostatic interaction plays the dominant role in the ligand binding process, given the fact that several charged residues reside in the binding pockets of DUSPs. Our MD simulation results demonstrate that the sulfate moieties and carboxyl moieties of the advantageous ligands from YIV-906 can occupy the enzymes' catalytic sites, mimicking the endogenous phosphate substrates of DUSPs. As such, the ligand binding can inhibit the association of DUSPs and ERK1/2, which in turn reduces the dephosphorylation of ERK1/2 and causes cell cycle arrest in the tumor. Our modelling study provides useful insights into the rational design of highly potent anti-cancer drugs targeting DUSPs. Finally, we have demonstrated that multi-scale molecular modelling techniques are able to elucidate molecular mechanisms involving complex molecular systems.


Assuntos
Antineoplásicos Fitogênicos/química , Medicamentos de Ervas Chinesas/química , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Domínio Catalítico , Medicamentos de Ervas Chinesas/metabolismo , Fosfatases de Especificidade Dupla/antagonistas & inibidores , Fosfatases de Especificidade Dupla/metabolismo , Humanos , Ligantes , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Termodinâmica
14.
J Agric Food Chem ; 67(44): 12199-12207, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31595753

RESUMO

Salvianolic acid A (Sal A) has a wide range of pharmacological activities. To date, there have been no systematic and detailed metabolite research data of Sal A after oral administration in vitro and in vivo. In this study, a rapid and systematic method based on ultrafast liquid chromatography-quadrupole-time-of-flight mass spectrometry was developed to detect metabolites of Sal A in vitro (human liver microsome, human intestinal microbiota, artificial gastric, and intestinal juice) and in vivo (urine, plasma, feces, and various organs collected after oral administration of Sal A to normal rats and pseudo-germ-free rats). A total of 26 metabolites of Sal A were characterized. These metabolites were formed through extensive metabolic reactions, such as hydroxylation, hydrogenation, and glucuronidation reactions. This study provides novel possibility for exploring the potential biological mechanism of Sal A, and aids the promotion of clinical application.


Assuntos
Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Lactatos/química , Lactatos/metabolismo , Espectrometria de Massas/métodos , Salvia miltiorrhiza/química , Adulto , Animais , Feminino , Humanos , Masculino , Metaboloma , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Adulto Jovem
15.
Med Sci Monit ; 25: 7813-7825, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625533

RESUMO

BACKGROUND The aim of this study was to investigate the protective mechanism of neurovascular unit of Buyang Huanwu decoction (BYHWD) in an Alzheimer's disease (AD) cell model via RAGE/LRP1 pathway and find a reliable target for Alzheimer's disease treatment. MATERIAL AND METHODS Rat brain microvessel endothelial cells (BMECs) were cultured in 10% FBS and 1% penicillin/streptomycin. The AD model was established by administration of 24 µmol/L amyloid-ß peptides 25~35. Different concentrations of BYHWD (0.1 mg/mL, 1 mg/mL, and 10 mg/mL) were added as the drug intervention. The morphology of the cells was observed by light microscopy and the ultrastructure of the cells was observed by microscopy. The inflammatory factors IL-1ß, IL-6, TNF-alpha, and Aß25-35 were detected by ELISA. Flow cytometry was used to assess the apoptosis rate. The expressions of RAGE, LRP1, ICAM-1, VCAM-1, Apo J, Apo E, and NF-kappaBp65 were detected by Western blotting. RESULTS The structure of cells in BYHWDM and BYHWDH gradually recovered with increasing dose. BYHWD decreased the apoptotic rate of BMECs induced by Aß25-35. The cells treated with different concentrations of BYHWD had significant difference in terms of anti-apoptotic effect. The therapeutic effect of BYHWD on AD was via the RAGE/LRP1 and NF-kappaBp65 pathways. CONCLUSIONS BYHWD regulates Aß metabolism via the RAGE/LRP1 pathway, inhibits vascular endothelial inflammation induced by ICAM-1 and VCAM-1 via the NF-kappaBP65 pathway, and promotes morphological changes induced by Aß-induced brain microvascular endothelial cell damage.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/metabolismo , Células Endoteliais/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/efeitos dos fármacos , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Modelos Biológicos , Cultura Primária de Células , Ratos , Receptor para Produtos Finais de Glicação Avançada/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-31627161

RESUMO

Xiao Chai Hu Tang (XCHT) is sold as traditional medicine or dietary supplement in worldwide. To understand metabolism profile of traditional medicine is key point in their logical pharmacological research and clinical application. Based on our previous research of the chemical and absorption signature of XCHT in vitro, we proposed a novel strategy to identify the bioactive components of XCHT in vivo. This strategy have two steps: firstly, based on the parents' database in vitro, built-in and editable biotransformations for phase I and phase II metabolism reactions with MassHunter Metabolite ID software (building metabolites database). Secondly, mouse plasma, bile and urine samples were analyzed by UHPLC-ESI-Q-TOF/MS technique, and the absorbed parents and metabolites were compared and identified with the XCHT's digital library using MassHunter Metabolite ID software. In total, 27 parent compounds and 26 metabolites of XCHT were identified in vivo, 2'-O-xylosyl saikosaponin b2 or b1 was reported for the first time. Saponins and their related metabolites were predominantly excreted into the bile, but flavonoids were excreted by both hepatic as well as renal excretion. Flavonoids, saponins, gingerol and their related metabolites were the absorbed components in cardiovascular system and bioactive components of XCHT. Phase I reactions (hydrolysis, hydroxylation and oxidation) and phase II reactions (glucuronidation) were identified and involved in the mouse metabolism of XCHT.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Bile/química , Bile/metabolismo , Catecóis/análise , Catecóis/química , Catecóis/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Álcoois Graxos/análise , Álcoois Graxos/química , Álcoois Graxos/metabolismo , Flavonoides/análise , Flavonoides/química , Flavonoides/metabolismo , Masculino , Camundongos , Saponinas/análise , Saponinas/química , Saponinas/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-31487566

RESUMO

ShenMai Injection (SMI) is a traditional Chinese medicine that has been extensively applied in the treatment of coronary artery disease and tumor for many years. However, there is still lack of deep research on the behaviors of SMI in vivo. In this study, a reliable, specific, and sensitive method was developed for simultaneous determination of sixteen saponins found in SMI using liquid chromatography tandem mass spectrometry (LC-MS/MS). This method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of sixteen active compounds after a single intravenous administration of SMI. These compounds included seven protopapaxdiol (PPD-type) ginsenosides (ginsenosides Rb1, Rb2, Rb3, Rc, Rd, S-Rg3, R-Rg3), six protopapaxtriol (PPT-type) ginsenosides (notoginsenoside R1, ginsenosides Re, Rf, Rg1, S-Rg2, R-Rg2), one oleanolic acid type ginsenoside (ginsenoside Ro) and two ophiopogonins (ophiopogonin D (MD-D) and ophiopogonin D' (MD-D')). Connection of the C-20 hydroxyl group to the glycoside and the chiral configuration of C-20 might significantly impact the pharmacokinetic behaviors in vivo of ginsenosides, particularly PPD-type ginsenosides. PPD-type ginsenosides were usually eliminated slowly in serum and tissues, but S/R-Rg3 bearing a free hydroxyl group at C-20 exhibited quick elimination, and R-Rg3 underwent quicker elimination than S-Rg3. The PPT-type ginsenosides, oleanolic acid type ginsenoside and ophiopogonins underwent a fast elimination from serum and tissues. There were 10 ginsenosides that could penetrate the blood-brain barrier. In contrast to other saponins, the distributions of S-Rg2, R-Rg2, S-Rg3, R-Rg3, MD-D and MD-D' in liver were higher than in kidney. Several PPD-type ginsenosides were found to have a long-term accumulation risk in some tissues, especially Rd in kidney. In the excretion study, Rg1, S-Rg2 and MD-D were mainly excreted in a prototype and other saponins were mainly excreted in the form of metabolites. Prototypes of S-Rg2, R-Rg2, S-Rg3, R-Rg3, MD-D and MD-D' exhibited higher distribution in the liver than kidney, were excreted mainly in the feces, whereas prototypes of the remaining saponins were primarily excreted via urine. To best our knowledge, this is the first study to quantitatively evaluate the tissue distribution and excretion of SMI in rats. Our research provides novel insight into the behaviors in vivo of PPD-type ginsenosides and delivers valuable information for further drug development of SMI.


Assuntos
Medicamentos de Ervas Chinesas , Saponinas , Administração Intravenosa , Animais , Cromatografia Líquida , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Saponinas/análise , Saponinas/metabolismo , Saponinas/farmacocinética , Espectrometria de Massas em Tandem , Distribuição Tecidual
18.
Artigo em Inglês | MEDLINE | ID: mdl-31369928

RESUMO

Tripterygium glycosides tablets (TGT) contain the main extract of tripterygium and are widely used clinically to treat autoimmune diseases such as rheumatoid arthritis and nephrotic syndrome. However, TGT can lead to liver and renal failure in clinic. The exposed components and their metabolites of TGT in vivo were rarely researched. In this study, the components and metabolites of TGT in mice liver, kidney and plasma were profiled by high performance liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (HPLC-Q/TOFMS) after TGT was orally administered to mice. The components and metabolites were detected and identified based on their retention time, accurate mass data of quasi-molecular ion, characteristic fragment ions, and the fragmentation rules. Finally, 48 prototype components, including 25 diterpenoids, 11 triterpenoids and 12 alkaloids, were detected in mice, as well as 99 metabolites, undergoing hydroxylation, dehydrogenation, ester bond hydrolysis of Phase I metabolism, and glutathione, glucuronic acid binding of Phase II metabolism. The components and metabolites in mice were compared between single- and multiple- low dose groups and between high and low dose groups. Furthermore, a total of 21 components and 35 metabolites were predicted to have potential toxic risk by software. The results would provide material basis to clarify the clinical efficacy and toxicity of TGT.


Assuntos
Medicamentos de Ervas Chinesas/química , Glicosídeos/química , Tripterygium/química , Animais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/metabolismo , Glicosídeos/metabolismo , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Comprimidos/química , Comprimidos/metabolismo
19.
J Chromatogr A ; 1608: 460417, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31416627

RESUMO

The characterization of metabolome for poorly absorptive natural medicines is challenging. Previous identification strategy often relies on nontargeted scanning biological samples from animals administered with natural medicines in a data-dependent acquisition (DDA) mode by LC-MS/MS. Substances that displayed significant increases following drug administration are thus assigned as potential metabolites. The accurate m/z of precursors and the corresponding MS/MS fragment ions are used to match with herbal ingredients and to infer possible metabolic reactions. Nevertheless, the low concentration of these metabolites within complex biological matrices has often hampered the detection. Herein we developed a strategy termed intestinal mucosal metabolome-guided detection (IMMD) to tackle this challenge using ginkgo biloba (GBE) as an example. The rationale is that poorly absorptive natural products are usually concentrated and extensively metabolized by enterocytes before they enter the blood stream and distribute to other organs. Therefore, we firstly identified the metabolites from intestinal mucosa of GBE-treated rats, and then used the identified intestinal mucosal GBE metabolome as targeted repository for MRM analysis. The presences of these metabolites were subsequently examined in rat plasma, liver and brain. The resultant GBE metabolome showed significantly improved coverage with 39, 45 and 6 metabolites identified in plasma, liver and brain compared to 22, 16 and 0 metabolites from the corresponding regions via the DDA-based strategy. In addition, we integrated the previously reported nontargeted diagnostic ion network analysis to facilitate the characterization of GBE components, and a chemicalome-metabolome matching approach (CMMA) to assist the identity assignment of GBE metabolome with IMMD. Combinatorially, we establish a multi-faceted platform to streamline the workflow of metabolome characterization for herbal medicines of low bioavailability. The metabolome information is expected to shed light on the elucidation of metabolic pathways for natural products, and the underlying mechanisms of their biological efficacies.


Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/análise , Mucosa Intestinal/química , Metabolômica/métodos , Extratos Vegetais/análise , Espectrometria de Massas em Tandem/métodos , Animais , Medicamentos de Ervas Chinesas/metabolismo , Ginkgo biloba/química , Mucosa Intestinal/metabolismo , Masculino , Redes e Vias Metabólicas , Metaboloma , Extratos Vegetais/metabolismo , Plantas Medicinais/metabolismo , Ratos , Ratos Sprague-Dawley
20.
J Chromatogr A ; 1608: 460412, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31400840

RESUMO

It is both challenging and meaningful for identifying the in vivo metabolites of the complex prescription owning to more complex chemical constituents and better therapeutic effect than those of the single medicine. In this paper, a target integration strategy combined with tandem mass spectrometry technology was developed for identification of metabolites from monomer composition of representative standard to Ding-Zhi-Xiao-Wan prescription (DZXW). The representative standards of each type in DZXW were utilized fully to explore the rule of mass fragmentation and the metabolism in vitro. These study were then extended to the single medicine and finally to the DZXW prescription. In addition, the order of metabolic research followed the metabolic order of oral drug in body, namely from in vitro, to intestine tract, to liver, to blood, and ultimately to target organs. As a result, a total of 150 prototypes and 51 metabolites of DZXW were effectively detected and identified in vivo. This result laid a material foundation for the better application of DZXW in treating Alzheimer's disease. More importantly, this analysis strategy provided a deep insight for the drug metabolism of traditional Chinese medicine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Espectrometria de Massas em Tandem/métodos , Doença de Alzheimer/tratamento farmacológico , Animais , Medicamentos de Ervas Chinesas/metabolismo , Humanos , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Sprague-Dawley
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