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1.
J Nat Med ; 78(3): 709-721, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38575838

RESUMO

Methanol extract of the Cnidium officinale Makino rhizome, which is used as a crude drug Cnidium Rhizome (Cnidii Rhizoma; "Senkyu" in Japanese) and is listed in the Japanese Pharmacopoeia XVIII, showed intracellular triglyceride metabolism-promoting activity in high glucose-pretreated HepG2 cells. Thirty-five constituents, including two new alkylphthalide glycosides, senkyunosides A (1) and B (2), and a neolignan with a new stereoisomeric structure (3), were isolated in the extract. Their stereostructures were elucidated based on chemical and spectroscopic evidence. Among the isolates, several alkylphthalides, (Z)-3-butylidene-7-methoxyphthalide (9) and senkyunolides G (10), H (14), and I (15), and a polyacetylene falcarindiol (26), were found to show significant activity without any cytotoxicity at 10 µM.


Assuntos
Benzofuranos , Cnidium , Rizoma , Triglicerídeos , Humanos , Rizoma/química , Células Hep G2 , Cnidium/química , Triglicerídeos/metabolismo , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/isolamento & purificação , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação
2.
Biochim Biophys Acta Mol Basis Dis ; 1869(7): 166819, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37499930

RESUMO

BACKGROUND: Thoracic aortic aneurysm and aortic dissection (TAAD) is one of the most fatal cardiovascular diseases. Senkyunolide I (SEI) is a component of traditional Chinese medicine with remarkable anti-inflammatory properties and exhibits remarkable protective effects, but its impact on TAAD remains unclear. Our study aimed to explore the role of SEI in a murine model of TAAD and further explore the immunopharmacological mechanism. METHODS AND MATERIALS: The in vivo model were assessed using echocardiography, gross anatomy, and tissue staining. Western blot and immunofluorescence were performed to evaluate the effects of SEI in vivo and in vitro. A SEI solution injection containing 1 % dimethyl sulfoxide (DMSO) was administered intraperitoneally to the TAAD model group, while a normal saline injection comprising 1 % DMSO was administered to the sham group. RESULTS: SEI prevented TAAD formation induced by BAPN/Ang II and reduced the TAAD incidence in mice. SEI treatment significantly inhibited the degradation of collagen and elastin fibers in the extracellular matrix. Furthermore, it reduced the expression of inflammatory factors in the aortic intima. Western blot analysis revealed that SEI-treated mice showed a significant decrease in apoptosis-related protein levels in the aorta compared with the TAAD group. PI3K, Akt, and mTOR in the SEI treatment group were significantly lower than in the model group. SEI could also attenuate H2O2-induced Human umbilical vein endothelial cells (HUVECs) damage and reverse the decline in migrant cells. The apoptosis of HUVECs was considerably reduced by the SEI treatment. CONCLUSIONS: Conclusively, SEI may alleviate the progression of TAAD by suppressing the PI3K/Akt/NF-κB signaling pathway. The SEI's ability to inhibit inflammation and oxidative stress opens the way to restore the function of endothelial cells and vascular homeostasis, and thus to provide novel and promising options for the treatment of TAAD patients.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Humanos , Camundongos , Animais , Células Endoteliais/metabolismo , Dimetil Sulfóxido/efeitos adversos , Peróxido de Hidrogênio , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Cultivadas , Aneurisma da Aorta Torácica/metabolismo , Dissecção Aórtica/tratamento farmacológico , Apoptose , Estresse Oxidativo
3.
Front Pharmacol ; 14: 1104243, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37234713

RESUMO

Suxiao Jiuxin Pill (SJP) is a well-known traditional Chinese medicine drug used to manage heart diseases. This study aimed at determining the pharmacological effects of SJP in acute myocardial infarction (AMI), and the molecular pathways its active compounds target to induce coronary artery vasorelaxation. Using the AMI rat model, SJP improved cardiac function and elevated ST segment. LC-MS and GC-MS detected twenty-eight non-volatile compounds and eleven volatile compounds in sera from SJP-treated rats. Network pharmacology analysis revealed eNOS and PTGS2 as the key drug targets. Indeed, SJP induced coronary artery relaxation via activation of the eNOS-NO pathway. Several of SJP's main compounds, like senkyunolide A, scopoletin, and borneol, caused concentration-dependent coronary artery relaxation. Senkyunolide A and scopoletin increased eNOS and Akt phosphorylation in human umbilical vein endothelial cells (HUVECs). Molecular docking and surface plasmon resonance (SPR) revealed an interaction between senkynolide A/scopoletin and Akt. Vasodilation caused by senkyunolide A and scopoletin was inhibited by uprosertib (Akt inhibitor) and eNOS/sGC/PKG axis inhibitors. This suggests that senkyunolide A and scopoletin relax coronary arteries through the Akt-eNOS-NO pathway. In addition, borneol induced endothelium-independent vasorelaxation of the coronary artery. The Kv channel inhibitor 4-AP, KCa2+ inhibitor TEA, and Kir inhibitor BaCl2 significantly inhibited the vasorelaxant effect of borneol in the coronary artery. In conclusion, the results show that Suxiao Jiuxin Pill protects the heart against acute myocardial infarction.

4.
Biomed Pharmacother ; 164: 114902, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37209628

RESUMO

BACKGROUND: Intestinal mucositis (IM) is characterized by damage to the intestinal mucosa resulting from inhibition of epithelial cell division and loss of renewal capacity following anticancer chemotherapy and radiotherapy. Cytarabine (Ara-C), the main chemotherapy drug for the treatment of leukemia and lymphoma, is a frequent cause of IM. Guiqi Baizhu prescription (GQBZP) is a traditional Chinese medicine with anti-cancer and anti-inflammatory effects. PURPOSE: To determine if GQBZP can ameliorate Ara-C induced IM and identify and characterize the pharmacologic and pharmacodynamic mechanisms. STUDY DESIGN AND METHODS: IM was induced in mice with Ara-C and concurrently treated with orally administered GQBZP. Body weight and food intake was monitored, with HE staining to calculate ileal histomorphometric scoring and villus length/crypt depth. Immunoblotting was used to detect intestinal tissue inflammatory factors. M1 macrophages (M1) were labeled with CD86 by flow cytometry and iNOS + F4/80 by immunofluorescence. Virtual screening was used to find potentially active compounds in GQBZP that targeted JAK2. In vitro, RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-γ (INF-γ) and treated orally with GQBZP or potential active compounds. M1 was labeled with CD86 by flow cytometry and iNOS by immunofluorescence. ELISA was used to detect inflammatory factor expression. Active compounds against JAK2, p-JAK2, STAT1 and p-STAT1 were identified by western blotting and HCS fluorescence. Molecular dynamics simulations and pharmacokinetic predictions were carried out on representative active compounds. RESULTS: Experimental results with mice in vivo suggest that GQBZP significantly attenuated Ara-C-induced ileal damage and release of pro-inflammatory factors by inhibiting macrophage polarization to M1. Molecular docking was used to identify potentially active compounds in GQBZP that targeted JAK2, a key factor in macrophage polarization to M1. By examining the main components of each herb and applying Lipinski's rules, ten potentially active compounds were identified. In vitro experimental results suggested that all 10 compounds of GQBZP targeted JAK2 and could inhibit M1 polarization in RAW264.7 cells treated with LPS and INF-γ. Among them, acridine and senkyunolide A down-regulated the expression of JAK2 and STAT1. MD simulations revealed that acridine and senkyunolide A were stable in the active site of JAK2 and exhibited good interactions with the surrounding amino acids. CONCLUSIONS: GQBZP can ameliorate Ara-C-induced IM by reducing macrophage polarization to M1, and acridine and senkyunolide A are representative active compounds in GQBZP that target JAK2 to inhibit M1 polarization. Targeting JAK2 to regulate M1 polarization may be a valuable therapeutic strategy for IM.


Assuntos
Mucosite , Camundongos , Animais , Mucosite/patologia , Citarabina/farmacologia , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Simulação de Acoplamento Molecular , Macrófagos/metabolismo , Interferon gama/metabolismo
5.
Molecules ; 28(8)2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-37110869

RESUMO

Senkyunolide I (SI) is a natural phthalide that has drawn increasing interest for its potential as a cardio-cerebral vascular drug candidate. In this paper, the botanical sources, phytochemical characteristics, chemical and biological transformations, pharmacological and pharmacokinetic properties, and drug-likeness of SI are reviewed through a comprehensive literature survey, in order to provide support for its further research and applications. In general, SI is mainly distributed in Umbelliferae plants, and it is relatively stable to heat, acid, and oxygen, with good blood-brain barrier (BBB) permeability. Substantial studies have established reliable methods for the isolation, purification, and content determination of SI. Its pharmacological effects include analgesic, anti-inflammatory, antioxidant, anti-thrombotic, anti-tumor effects, alleviating ischemia-reperfusion injury, etc. Pharmacokinetic parameters indicate that its metabolic pathway is mainly phase Ⅱ metabolism, and it is rapidly absorbed in vivo and widely distributed in the kidneys, liver, and lungs.


Assuntos
Apiaceae , Compostos Fitoquímicos , Compostos Fitoquímicos/farmacologia , Fígado , Transporte Biológico , Etnofarmacologia , Extratos Vegetais/química
6.
Molecules ; 27(14)2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35889462

RESUMO

The separation of chemical components from wild plants to develop new pesticides is a hot topic in current research. To evaluate the antimicrobial effects of metabolites of Ligusticum chuanxiong (CX), we systematically studied the antimicrobial activity of extracts of CX, and the active compounds were isolated, purified and structurally identified. The results of toxicity measurement showed that the extracts of CX had good biological activities against Botrytis cinerea, Sclerotinia sclerotiorum, Alternaria alternata and Pythium aphanidermatum, and the value of EC50 were 130.95, 242.36, 332.73 and 307.29 mg/L, respectively. The results of in vivo determination showed that under the concentration of 1000 mg/L, the control effect of CX extract on Blumeria graminis was more than 40%, and the control effect on Botrytis cinerea was 100%. The antifungal active components of CX were identified as Senkyunolide A and Ligustilide by mass spectrometry and nuclear magnetic resonance. The MIC (minimum inhibitory concentration) value of Senkyunolide A and Ligustilide against Fusarium graminearum were 7.81 and 62.25 mg/L, respectively. As a new botanical fungicide with a brightly exploitative prospect, CX extract has potential research value in the prevention and control of plant diseases.


Assuntos
Medicamentos de Ervas Chinesas , Ligusticum , Antifúngicos/farmacologia , Botrytis , Medicamentos de Ervas Chinesas/química , Ligusticum/química
7.
Biomed Chromatogr ; 36(9): e5422, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35677958

RESUMO

The radix of Angelica sinensis (Oliv.) Diels (RAS) is widely used in medicinal and dietary applications in China, and has the function for replenishing and invigorating the blood, stopping pain and moistening the intestines. In this study, RAS from the main geoherb regions showed better efficacy in inhibiting Adenosine diphosphate- or arachidonic acid-induced platelet aggregation than those from non-geoherb regions. In addition, the HPLC fingerprints of 30 batches of RAS, as part of the comprehensive evaluation of RAS, were established and used for spectral efficiency to screen the quality markers for anti-platelet aggregation activities. Five compounds in RAS-senkyunolide I, uridine, guanine, ferulic acid and adenosine-were demonstrated to contribute significantly to the anti-platelet aggregation activity. These bioactive compounds, especially senkyunolide I and ferulic acid with stronger activities, could be used as quality markers of RAS for quality control of RAS.


Assuntos
Angelica sinensis , Medicamentos de Ervas Chinesas , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Raízes de Plantas , Controle de Qualidade
8.
J Ethnopharmacol ; 282: 114659, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34543683

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Senkyunolide H (SNH) is a bioactive phthalide isolated from Ligusticum chuanxiong Hort rhizome and was reported to have multiple pharmacological effects. AIM OF THE STUDY: The study was performed to verify the potency of SNH protecting PC12 cells from oxygen glucose deprivation/reperfusion (OGD/R)-induced injury and to elucidate the underlying mechanisms. MATERIALS AND METHODS: OGD/R model was established in PC12 cells and the cell viability was measured by MTT assay. The cell morphology was observed using scanning electron microscope (SEM). The potential targets of SNH and related targets of OGD/R were screened, and a merged protein-protein interaction (PPI) network of SNH and OGD/R was constructed based on the network pharmacology analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for pathway analysis. Intracellular cAMP level and the protein expression levels were measured to elucidate the underlying mechanisms. RESULTS: SNH pretreatment protected PC12 cells against OGD/R-induced cell death. SNH also significantly protected the cell protrusion. A merged PPI network was constructed and the shared candidate targets significantly enriched in cAMP signaling pathway. The level of intracellular cAMP and the protein level of p-CREB, p-AKT, p-PDK1 and PKA protein were up-regulated after the treatment of SNH compared with OGD/R modeling. CONCLUSIONS: The present study indicated that SNH protected PC12 cells from OGD/R-induced injury via cAMP-PI3K/AKT signaling pathway.


Assuntos
Benzofuranos/farmacologia , AMP Cíclico/metabolismo , Glucose/metabolismo , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Farmacologia em Rede , Oxigênio/administração & dosagem , Células PC12 , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt , Ratos , Transdução de Sinais/efeitos dos fármacos
9.
Biomed Pharmacother ; 140: 111696, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34044281

RESUMO

Glutamate-induced neurotoxicity is one of the most important pathogenic mechanisms in neurological diseases and is widely used as an in vitro model for ischemic stroke. Senkyunolide I (SEI), an active constituent derived from traditional Chinese medicine Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has been shown to have beneficial effects against focal cerebral ischemia-reperfusion in rats. However, the mechanisms underlying SEI-mediated neuroprotection remain not well understood. Thus, we explored the influence of SEI in glutamate-mediated injury to mouse neuroblastoma (Neuro2a) cells and determined the mechanisms involved. Neuro2a cells were treated with SEI under exposure to glutamate for 24 h. Cell viability was assessed by using WST-1 reagents, and apoptosis was evaluated using Annexin V-FITC and a PI double staining kit. The protein expression levels of p-AKT, AKT, p-GSK3ß, GSK3ß, p-p38, p38, p-ERK, ERK, p-JNK, JNK, Bcl-2, Bax, Bcl-xl, p-Bad, Bad, p53, and cleaved caspase-3 were determined by Western blot analysis. Glutamate significantly decreased cell viability and elevated the level of apoptosis. Treatment with SEI reversed those effects. Furthermore, the expression of p-JNK/JNK and cleaved caspase-3 were also reduced after treatment with SEI. Our findings demonstrate that SEI protected Neuro2a cells against glutamate toxicity by regulating JNK/caspase-3 pathway and apoptosis. Thus, SEI maybe a promising candidate for neuroprotection.


Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Camundongos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Zhongguo Zhong Yao Za Zhi ; 46(4): 972-980, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33645104

RESUMO

This study aims to establish a method for the determination of the concentration of five main components of phthalide target areas of Chaxiong(CPTA) and its inclusion of ß-CD in the plasma of rats, and determine the pharmacokinetic parameters, absolute bioavailability and relative bioavailability of CPTA/ß-CD inclusion compound in vivo. The plasma concentrations of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide were determined with UPLC-MS/MS. The content determination was conducted at the chromatographic conditions as follows: Shim-pack GIST C_(18)-AQ HP column(2.1 mm×100 mm, 3 µm), mobile phase of 0.1% formic acid solution(A)-acetonitrile(B), gradient elution, flow rate of 0.3 mL·min~(-1), column temperature of 35 ℃ and injection volume of 2 µL. The mass spectra were obtained with electrospray ion source(ESI), positive ion mode and multi reaction monitoring. CPTA/ß-CD inclusion compound was prepared by grinding method, DAS 2.0 software was used to model the data, and the absolute bioavailability of CPTA and relative bioavailability of inclusion compound were calculated. Finally, the methods for the determination of five components of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide in CPTA, were successfully established. The linear relationship among the five components was good within their respective ranges, r>0.99. The absolute bioavailability of the five components in rats was 22.30%, 16.32%, 21.90%, 10.16% and 12.43%, respectively. After CPTA/ß-CD inclusion was prepared, the relative bioavailability of the five components was 138.69%, 198.39%, 218.01%, 224.54% and 363.55%, respectively, significantly improved. This method is rapid, accurate and sensitive, so it is suitable for the pharmacokinetic study of extracts in traditional Chinese medicine and their preparations.


Assuntos
Espectrometria de Massas em Tandem , Animais , Benzofuranos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
11.
Zhongguo Zhong Yao Za Zhi ; (24): 972-980, 2021.
Artigo em Chinês | WPRIM | ID: wpr-878963

RESUMO

This study aims to establish a method for the determination of the concentration of five main components of phthalide target areas of Chaxiong(CPTA) and its inclusion of β-CD in the plasma of rats, and determine the pharmacokinetic parameters, absolute bioavailability and relative bioavailability of CPTA/β-CD inclusion compound in vivo. The plasma concentrations of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide were determined with UPLC-MS/MS. The content determination was conducted at the chromatographic conditions as follows: Shim-pack GIST C_(18)-AQ HP column(2.1 mm×100 mm, 3 μm), mobile phase of 0.1% formic acid solution(A)-acetonitrile(B), gradient elution, flow rate of 0.3 mL·min~(-1), column temperature of 35 ℃ and injection volume of 2 μL. The mass spectra were obtained with electrospray ion source(ESI), positive ion mode and multi reaction monitoring. CPTA/β-CD inclusion compound was prepared by grinding method, DAS 2.0 software was used to model the data, and the absolute bioavailability of CPTA and relative bioavailability of inclusion compound were calculated. Finally, the methods for the determination of five components of senkyunolide A, N-butylphthalide, new osthol lactone, Z-ligustilide and butenyl phthalide in CPTA, were successfully established. The linear relationship among the five components was good within their respective ranges, r>0.99. The absolute bioavailability of the five components in rats was 22.30%, 16.32%, 21.90%, 10.16% and 12.43%, respectively. After CPTA/β-CD inclusion was prepared, the relative bioavailability of the five components was 138.69%, 198.39%, 218.01%, 224.54% and 363.55%, respectively, significantly improved. This method is rapid, accurate and sensitive, so it is suitable for the pharmacokinetic study of extracts in traditional Chinese medicine and their preparations.


Assuntos
Animais , Ratos , Benzofuranos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
12.
Biol Pharm Bull ; 43(12): 1867-1875, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33268704

RESUMO

The rhizome of Cnidium officinale (Umbelliferae) (known as Senkyu in Japan; COR) has been used as a crude drug in Japanese Kampo formulas, such as Jumihaidokuto (to treat eczema and urticaria) and Kakkontokasenkyushin'i (to treat rhinitis). COR contains phthalides, which are thought to be potent principal constituents. Few studies have been reported about the comparison of anti-inflammatory activity of COR constituents. We aimed to identify the constituents in COR and compare their anti-inflammatory activity. COR was extracted with methanol and fractionated into ethyl acetate (EtOAc)-soluble, n-butanol-soluble, and water-soluble fractions. Primary cultured rat hepatocytes were used to assess anti-inflammatory activity by monitoring the interleukin (IL)-1ß-induced production of nitric oxide (NO), an inflammatory mediator. The EtOAc-soluble fraction significantly suppressed NO production without showing cytotoxicity in IL-1ß-treated hepatocytes, whereas the n-butanol-soluble fraction showed less potency, and the water-soluble fraction did not significantly affect the NO levels. Four constituents were isolated from the EtOAc-soluble fraction and identified as senkyunolide A, (3S)-butylphthalide, neocnidilide, and cnidilide. Among these phthalides and (Z)-ligustilide, senkyunolide A and (Z)-ligustilide efficiently suppressed NO production in hepatocytes, whereas the others showed less potency in the suppression of NO production. Furthermore, senkyunolide A decreased the levels of the inducible nitric oxide synthase (iNOS) protein and mRNA, as well as the levels of mRNAs encoding proinflammatory cytokines (e.g., tumor necrosis factor α) and chemokine C-C motif ligand 20. These results suggest that senkyunolide A may cause the anti-inflammatory and hepatoprotective effects of COR by suppressing the genes involved in inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Cnidium , Hepatócitos/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Extratos Vegetais/farmacologia , Rizoma , Animais , Anti-Inflamatórios/isolamento & purificação , Células Cultivadas , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar
13.
Pharmacol Res ; 159: 104963, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32497719

RESUMO

Thrombotic events act as a critical factor that interferes with Cardiovascular Diseases (CVDs), and antithrombotic herbal medicine is a long-standing controversial issue. Although a dispute is involved in their clinical application, all parties unanimously agree that herbal products have been widely used in folk medicine, and their interactions with conventional drugs are of high concern. This study aims to investigate how antithrombotic herbal medicines interact with Western cardiovascular drugs on the molecular level by taking an example of the most frequently used herbal pair, Danshen-Chuanxiong (DS-CX), and to discover more scientific evidence on their potential herb-drug interactions. Network pharmacology (NP), as an analytical approach of a complex system, is used to visualize and compare target profiles of DS-CX and Western cardiovascular drugs, which can be applied to predict common herb-drug targets and to construct a solid context for discussing herb-drug interactions. These interactions are further validated by in vitro assays, while in vivo zebrafish model employed for evaluating an overall pharmacological efficacy of herbal pairs in specific combination ratios. The study finds that DS could react directly to the Western cardiovascular drug targets relevant to antithrombotic pathways (i.e., thrombin, coagulation factor Xa and cyclooxygenase-1), whereas CX could not react directly and can synergistically affect antithrombotic effects with DS in specific combination ratios. Moreover, it is indicated that DS-CX may generate wide biological functions by a complicated mechanism of "neuro-immune-metabolism/endocrine" (NIM), which can further cause multiple direct and indirect interactions with Western cardiovascular drugs. From the clinical perspective, herb-drug interactions should be given high attention, especially when multiple herbs are used simultaneously.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrinolíticos/uso terapêutico , Interações Ervas-Drogas , Medicina Tradicional Chinesa , Trombose/tratamento farmacológico , Animais , Fármacos Cardiovasculares/efeitos adversos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/efeitos adversos , Fibrinolíticos/efeitos adversos , Humanos , Ligusticum , Salvia miltiorrhiza , Biologia de Sistemas , Trombose/sangue
14.
Front Pharmacol ; 11: 622787, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33519488

RESUMO

Thrombosis is a key pathological event in cardiovascular diseases, and is also the most important targeting process for their clinical management. New drug development in thrombosis treatment is still in great demand. According to the traditional Chinese medicine (TCM) theory, thrombosis belongs to the syndrome of blood stasis. Salvia miltiorrhiza Bunge and Ligusticum striatum DC. are two common TCM herbs with long-term documented function in promoting blood circulation and inhibiting thrombosis, especially when used together. Guanxinning Tablet, a modern Chinese drug which contains extracts of the two herbs, also showed strong therapeutic effects in coronary heart disease. However, the pharmacological mechanism is still lacking for the compatibility of the two herbs. Here, through zebrafish-based in vivo fluorescence screening, we demonstrated the synergistic effects between S. miltiorrhiza Bunge and L. striatum DC. in regulating endogenous thrombosis. Moreover, combined with high-resolution mass spectrometry, the main compounds of the botanical drugs were analyzed and screened in our model system. Interestingly, cryptotanshinone and senkyunolide I, two representative compounds, respectively derived from the two herbs, also showed synergistic antithrombotic effects. Further analysis suggested that they may regulate thrombi formation at different levels via multiple signaling pathways, including oxidative stress, platelet activation and coagulation cascade. Taken together, our findings provided solid biological supports toward the drug compatibility theory of TCM, and suggested cryptotanshinone and senkyunolide I as promising drug candidates in thrombosis management.

15.
Biomed Chromatogr ; 33(10): e4625, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31222844

RESUMO

The herb couple has special clinical significance in reducing the toxicity and increasing the efficacy of drugs. The combination of Radix Angelicae Dahuricae (Baizhi, BZ) and Rhizoma Chuanxiong (ChuanXiong, CX) is a traditional herb couple. The combination performs better than the CX extract alone in the treatment of migraine and has been used for thousands of years. However, the specific compatibility mechanisms are still unclear. Ligustilide, dl-3-n-butylphthalide and senkyunolide A are the major active ingredients in CX and BZ-CX decoction. However, a comprehensive study of the pharmacokinetics of CX has not been carried out. A gas chromatography-mass spectroscopy (GC-MS) method with high selectivity, sensitivity and accuracy was developed. An SH-Rxi-5Sil (30 m × 0.25 mm i.d., and 0.25 µm film thickness) column was employed in the GC separation. Selectivity, linearity, precision, accuracy, recovery, matrix effect and stability were used to validate the current GC-MS method. Using the validated method, this is the first time to study on the comparative pharmacokinetics of ligustilide, dl-3-n-butylphthalide and senkyunolide A from CX alone and BZ-CX decoction in rat plasma. The pharmacokinetic parameters (Cmax , Tmax , T1/2 , AUC0-t , AUC0-∞ and CLz/F) of all of the detected ingredients showed significant differences between the two groups (P < 0.05). The results are helpful for further investigation of the compatibility mechanism of BZ-CX decoction.


Assuntos
4-Butirolactona/análogos & derivados , Benzofuranos/sangue , Medicamentos de Ervas Chinesas , Cromatografia Gasosa-Espectrometria de Massas/métodos , 4-Butirolactona/sangue , 4-Butirolactona/química , 4-Butirolactona/farmacocinética , Administração Oral , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
16.
J Ethnopharmacol ; 235: 227-242, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30703496

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui buxue Decoction (DBD) has been frequently used to treat with blood deficiency, which consisted of Danggui (DG) and Huangqi (HQ) at a ratio of 1:5. Accumulating evidence showed that blood deficiency in traditional Chinese medicine (TCM) was similar to anemia in modern medicine. AIM OF THE STUDY: The purpose of this study was to explore its therapeutic mechanism of with network pharmacology approach. MATERIALS AND METHODS: We explored the chemical compounds of DBD and used compound ADME screening to identify the potential compounds. Targets for the therapeutic actions of DBD were obtained from the PharmMapper, Swiss, SEA and STITCH. GO analysis and pathway enrichment analysis was performed using the DAVID webserver. Cytoscape was used to visualize the compound-target-pathway network for DBD. The pharmacodynamics and crucial targets were also validated. RESULTS: Thirty-six potential active components in DBD and 49 targets which the active components acted on were identified. 47 KEGG pathways which DBD acted on were also come to light. And then, according to KEGG pathway annotation analysis, only 16 pathways seemed to be related to the blood nourishing effect of DBD, such as PI3K-AKT pathway, and so on. Only 32 targets participated in these 16 pathways and they were acted on by 29 of the 36 active compounds. Whole pharmacodynamic experiments showed that DBD had significant effects to blood loss rats. Furthermore, DBD could promote the up-regulation of hematopoietic and immune related targets and the down-regulation of inflammatory related targets. Significantly, with the results of effective rate, molecular docking and experimental validation, we predicted astragaloside IV in HQ, senkyunolide A and senkyunolide K in DG might be the major contributing compounds to DBD's blood enriching effect. CONCLUSION: In this study, a systematical network pharmacology approach was built. Our results provided a basis for the future study of senkyunolide A and senkyunolide K as the blood enriching compounds in DBD. Furthermore, combined network pharmacology with validation experimental results, the nourishing blood effect of DBD might be manifested by the dual mechanism of enhancing immunity and promoting hematopoiesis.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Animais , Células CACO-2 , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
17.
Front Neurol ; 10: 1299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31920923

RESUMO

Senkyunolide-H (SEH), a major bioactive compound extracted from Ligusticum chuanxiong, has been reported to be effective in preventing cerebral ischemic stroke (CIS). In this study, we employed network pharmacology to reveal potential mechanism of SEH against CIS on a system level and confirmed the therapeutic effects of SEH on CIS by models of cerebral ischemia-reperfusion in vivo and in vitro. Through protein-protein interaction networks construction of SEH- and CIS-related targets, a total of 62 key targets were obtained by screening topological indices and analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Gene Ontology analysis indicated that SEH might have a role in treating CIS via regulating some biological processes including regulation of transcription from RNA polymerase II promoter, epidermal growth factor receptor signaling pathway, phosphatidylinositol-mediated signaling, and some molecular function, such as transcription factor and protein phosphatase binding and nitric oxide synthase regulator activity. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes analysis showed that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was significantly enriched. In addition, our result showed that SEH posttreatment significantly decreased the neurological scores, infarct volume, and neuronal death in the middle cerebral artery occlusion mice. Moreover, the PI3K/Akt/nuclear factor kappa B signaling pathway was activated by intragastric administration of 40 mg/kg SEH, as verified by Western blot. In vitro, treatment of PC12 cells with 100 µM SEH markedly reduced cell death induced by oxygen-glucose deprivation through the activation of PI3K/Akt/nuclear factor kappa B pathway, and the therapeutic effect of SEH was obviously inhibited by 10 µM LY294002. In summary, these results suggested that SEH carries a therapeutic potential in CIS involving multiple targets and pathways, and the most crucial mechanism might be through the activation of PI3K/Akt/nuclear factor kappa B (NF-κB) signaling pathway to inhibit inflammatory factor releases and increase the antiapoptosis capacity. Our study furnishes the future traditional Chinese medicine research with a network pharmacology framework.

18.
Artigo em Chinês | WPRIM | ID: wpr-801958

RESUMO

Objective: To evaluate the effect of manual decocting and machine decocting on the chemical constituents in Bazhentang based on non-targeted metabolomics, and to find the differential chemical constituents of these two decocting methods. Method: Bazhentang was boiled by standardized manual decocting and machine decocting methods,respectively. Orthogonal partial least square-discriminate analysis(OPLS-DA) and other multivariate statistical methods, combined with variable importance in the projection(VIP) value and t-test, were employed to analyze the effect of two decocting methods on the chemical constituents in Bazhentang. The differential chemical constituents were analyzed by UPLC-LTQ-Orbitrap MS under positive and negative ion modes,mobile phase was acetonitrile-0.1%formic acid aqueous solution for gradient elution,the scanning range was m/z 50-1 500. Result: Under the positive and negative ion modes of high-resolution mass spectrometry, a total of 87 differential components were found,40 of them were identified according to the mass spectrometry data and literature reports, including senkyunolide A, glycyrrhizin, ferulic acid, etc. Conclusion: Based on the analysis of color and chemical compositions of Bazhentang, there are obvious differences between the standardized manual decocting and machine decocting. If the advantages of these two methods are combined,a standardized decoction process can be established on the basis of maintaining the advantages of manual decocting, the effectiveness of traditional Chinese medicine decoction will be maximized and it will be convenient for patients to take it.

19.
Phytomedicine ; 40: 1-9, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29496161

RESUMO

BACKGROUND: The nuclear factor erythroid 2-related factor 2 (Nrf2) is a potential molecular target for cancer chemoprevention. Si-Wu-Tang (SWT), a popular traditional Chinese medicine for women's health, was reported with a novel activity of cancer prevention. PURPOSE: The present study was aimed to identify the bioactive constituents in SWT responsible for the Nrf2 activating and cancer preventive activity and explore the pharmacological mechanisms. METHODS: Nine compounds detectable from various batches of SWT were ranked using in silico molecular docking based on their ability to interfere the forming of Nrf2-Keap1 complex. The predicted Nrf2 activating effect was validated using the antioxidant response element (ARE) luciferase reporter assay and quantitative RT-PCR analysis for select Nrf2 regulated genes Hmox1, Nqo1 and Slc7a11. The antimutagenic activity of the compounds were determined by the Ames test. The chemopreventive activity of these compounds were assessed on EGF-induced neoplastic transformation of JB6 P+ cells, an established non-cancerous murine epidermal model for studying tumor promotion and identifying cancer preventive agents. These compounds were further characterized using luciferase reporter assay on EGF-induced activation of AP-1, a known transcription factor mediating carcinogenesis. RESULTS: Three of the nine compounds predicted as Nrf2 activators by molecular docking, gallic acid (GA), Z-liguistilide (LIG), and senkyunolide A (SA), were confirmed with highest potency of increasing the Nrf2/ARE promoter activity and upregulating the expression of Hmox1, Nqo1 and Slc7a11. In addition, GA, LIG and SA exhibited an antimutagenic activity against the direct mutagen 2-nitrofluorene while no mutagenic effects were observed at the same time in Ames test. At nontoxic concentrations, GA, LIG, and SA inhibited EGF-induced neoplastic transformation of JB6 P+ cells. Combined treatment of GA, LIG and SA, in the same ratio as detected in SWT, showed enhanced effect against JB6 transformation compared with that of the single compound alone. GA, LIG and SA, alone or in combination, suppressed EGF-induced activation of AP-1. CONCLUSION: We identified three bioactive constituents in SWT responsible for the Nrf2 activating and cancer preventive activity. This study provides evidence supporting novel molecular basis of SWT in cancer prevention.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1 , Humanos , Medicina Tradicional Chinesa , Camundongos , Simulação de Acoplamento Molecular , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
20.
Biomed Chromatogr ; 32(5): e4182, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29314089

RESUMO

Senkyunolide I is one of the major bioactive components in the herbal medicine Ligusticum chuanxiong. The aim of this study was to develop and validate a fast, simple and sensitive LC-MS/MS method for the determination of senkyunolide I in dog plasma. The plasma samples were processed with acetonitrile and separated on a Waters Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 µm). The mobile phase consisted of 0.1% formic acid aqueous and acetonitrile was delivered at a flow rate of 0.3 mL min-1 . The detection was achieved in the positive selected reaction monitoring mode with precursor-to-product transitions at m/z 225.1 → 161.1 for senkyunolide I and at m/z 349.1 → 305.1 for an internal standard. The assay was linear over the tested concentration range, from 0.5 ng mL-1 to 1000 ng mL-1 , with a correlation coefficient >0.9992. The mean extraction recovery from dog plasma was within the range of 85.78-93.25%, while the matrix effect of the analyte was within the range of 98.23-108.89%. The intra- and inter-day precisions (RSD) were <12.12% and the accuracy (RR) ranged from 98.89% to 104.24%. The validated assay was successfully applied to pharmacokinetic and bioavailability studies of senkyunolide I in dogs. The results demonstrated that (a) senkyunolide I showed short elimination half-life (<1 h) in dog, (b) its oral bioavailability was >40% and (c) senkyunolide I showed dose-independent pharmacokinetic profiles in dog plasma over the dose range of 1-50 mg kg-1 .


Assuntos
Benzofuranos/sangue , Benzofuranos/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Benzofuranos/química , Disponibilidade Biológica , Cães , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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