JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2023
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IF 3.4
Wanbing Rao,Lijun Li,Chenxia Zhang,Jinfu Zheng,Xiaomei Fan,Baolei Luan,Jiaxiang Sun,Meiyan Qiu,Shuming Wu,Yanhua Li,Zhongqing Wang
A simple and stability-indicating reverse phase high-performance liquid chromatographic (RP-HPLC) method for the determination of rivaroxaban (RIX) and its related substances was developed. Fifteen impurities of RIX, including three unreported isomers, were identified, synthesized, purified, and confirmed using MS, 1 H NMR, 13 C NMR, and HSQC spectral methods. This new method offered baseline separation for all monitored impurities, and was fast and reliable when compared to the European Pharmacopoeia method. Optimum separation for RIX and its related impurities was achieved on an octyldecyl silica column (YMC Core C18, 4.6 ×100 mm, 2.7 µm) by using a gradient HPLC method in 38 min. The final method was validated with respect to precision, LOD and LOQ, linearity, accuracy, and robustness. This developed method was suitable for routine quality control and drug analysis of RIX active substance.
研究领域:
药学
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分析化学
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DOI
PubMed
高影响因子
Bioanalysis
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2019
·Vol. 12
·期 1
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IF 2.321
Libin Wang,Shouchang Gai,Xiaorui Zhang,Xiaohui Xu,Nan Gou,Xingchen Wang,Nan Zhou,Tian Feng
Aim: A sensitive and reliable LC–MS/MS method has been established and validated to the quantitation of rivaroxaban (RIV) and TAK-438 in rat plasma using carbamazepine as internal standard. Results: The procedure of method validation was conducted according to the guidelines of EMA and US FDA. At the same time, the method was applied to pharmacokinetic interactions study between RIV and TAK-438 for the first time. When RIV and TAK-438 co-administration to rats, main pharmacokinetic parameters of TAK-438 like AUC(0-t), AUC(0-∞) and Cmax had statistically significant increase. The main pharmacokinetic parameters of RIV have no statistically significant difference (p > 0.05) when co-administered except for t1/2 (p < 0.01). Conclusion: The results indicated that drug–drug interactions occurred between RIV and TAK-438 when co-administered to rats.
研究领域:
药理学
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分析化学
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DOI
PubMed
高影响因子
Frontiers in Microbiology
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2025
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IF 4.5
Wencheng Liu,Yanbin Cheng,Xue Han,Junlin Xia,Qingyu Wei,Bing Chang,Quansheng Li
Introduction: Hepatic sinusoidal obstruction syndrome (HSOS) is a vascular liver disease with a high mortality rate, and treatment methods are limited. Rivaroxaban is an oral anticoagulant. This study aimed to investigate the pharmacological effect and potential mechanism of rivaroxaban on HSOS.Methods: In this study, we induced an HSOS mouse model in male C57BL/6J mice by administering monocrotaline orally. The mice were randomly divided into four groups: the control group, the rivaroxaban (RIV) group, the monocrotaline (MCT) group, and the monocrotaline + rivaroxaban (MCT + RIV) group. Liver function and histopathology were evaluated. 16S rDNA sequencing of the small intestinal contents, transcriptomic sequencing of small intestine tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis were conducted. Antibiotic (ABX) treatment and fecal microbiota transplantation (FMT) experiments were also performed to explore the role of the gut microbiota.Results: Compared with the MCT group, rivaroxaban alleviated serum biochemical liver function analysis and liver histopathology in the MCT + RIV group. Additionally, 16S rDNA sequencing of the small intestinal contents revealed that, compared with the MCT group, the MCT + RIV group presented increased relative abundances of Allobaculum and Pediococcus but decreased relative abundances of Streptococcus, Staphylococcus, and Candidatus Arthromitus. Mechanistically, integrated analyses, including transcriptomic sequencing of small intestin e tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis, demonstrated that rivaroxaban protected against MCT-HSOS by inhibiting the PI3K/Akt signaling pathway. In addition, antimicrobial cocktail (ABX) treatment eliminated the beneficial effects of rivaroxaban on liver function and histopathological injury, whereas fecal microbiota transplantation (FMT) from rivaroxaban-treated donors significantly ameliorated liver dysfunction and histological damage in MCT-HSOS mice.Discussion: These findings suggest that rivaroxaban alleviates hepatic sinusoidal obstruction syndrome in mice by modulating the gut microbiota and inhibiting the PI3K/Akt signaling pathway. Rivaroxaban may be a promising therapeutic option for treating HSOS.
研究领域:
肝脏病学
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药理学
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微生物组学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2020
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IF 2.971
Jia Chong,Hao Chen,Dapeng Dai,Shuanghu Wang,Quan Zhou,Junpeng Liu,You Lü,Hualan Wu,Minghui Du,Feifei Chen,Hui Jiang,Yunfang Zhou,Jiefu Yang
Context Rivaroxaban and ticagrelor are two common drugs for the treatment of atrial fibrillation and acute coronary syndrome. However, the drug–drug interaction between them is still unknown.Objective To investigate the effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats both in vivo and in vitro.Materials and methods A sensitive and reliable UPLC-MS/MS method was developed for the determination of rivaroxaban in rat plasma. Ten Sprague-Dawley rats were randomly divided into ticagrelor pre-treated group (10 mg/kg/day for 14 days) and control group. The pharmacokinetics of orally administered rivaroxaban (10 mg/kg, single dose) with or without ticagrelor pre-treatment was investigated with developed UPLC-MS/MS method. Additionally, Sprague-Dawley rat liver microsomes were also used to investigate the drug–drug interaction between these two drugs in vitro.Results The Cmax (221.34 ± 53.33 vs. 691.18 ± 238.31 ng/mL) and the AUC(0–t) (1060.97 ± 291.21 vs. 3483.03 ± 753.83 μg·h/L) of rivaroxaban increased significantly (p < 0.05) with ticagrelor pre-treatment. The MRT(0–∞) of rivaroxaban increased from 4.41 ± 0.79 to 5.97 ± 1.11 h, while the intrinsic clearance decreased from 9.93 ± 2.55 to 2.89 ± 0.63 L/h/kg (both p < 0.05) after pre-treated with ticagrelor. Enzyme kinetic study indicated that ticagrelor decreased rivaroxaban metabolic clearance with the IC50 value of 14.04 μmol/L.Conclusions Our in vivo and in vitro results demonstrated that there is a drug–drug interaction between ticagrelor and rivaroxaban in rats. Further studies need to be carried out to verify whether similar interactions truly apply in humans and whether these interactions have clinical significance.
研究领域:
药理学
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临床医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Wang Xu,Fa Jingjing,Zhang Yuanjin,Huang Shengbo,Liu Jie,Gao Junqing,Xing Lina,Liu Zongjun,Wang Xin
The combination of Salvia miltiorrhiza (Danshen) and rivaroxaban is a promising treatment option in clinical practice in China, but the herb–drug interaction between Danshen and rivaroxaban remains unclear. Therefore, this study aims to reveal the interaction between Danshen and rivaroxaban. We not only investigated the inhibitory properties of Danshen tablet on rivaroxaban metabolism in rat and human liver microsomes but also evaluated the inhibitory effects of Danshen tablet and its eight active components (dihydrotanshinone I, tanshinone I, tanshinone IIA, cryptotanshinone, danshensu, salvianolic acid A, salvianolic acid B, and salvianolic acid C) on cytochrome P450 (CYP) enzymes. The results showed that Danshen tablet potently inhibited the metabolism of rivaroxaban in rat and human liver microsomes. In the CYP inhibition study, we found that dihydrotanshinone I, the active component of Danshen tablet, potently inhibited the activities of rat CYP3A and CYP2J, with IC50 values at 13.85 and 6.39 μM, respectively. In further inhibition kinetic study, we found that Danshen tablet is a mixed inhibitor in rivaroxaban metabolism in rat and human liver microsomes, with the Ki value at 0.72 and 0.25 mg/ml, respectively. In conclusion, there is a potential interaction between Danshen tablet and rivaroxaban. Danshen tablet inhibits the metabolism of rivaroxaban, which may be because its lipid-soluble components such as dihydrotanshinone I strongly inhibit the activities of CYP enzymes, especially CYP3A and CYP2J. Therefore, when Danshen tablet and rivaroxaban are used simultaneously in the clinic, it is necessary to strengthen the drug monitoring of rivaroxaban and adjust the dosage.
研究领域:
药理学
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中药学
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临床医学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Xiao-yu Xu,Zhe-yan Zhang,Xiao-dan Zhang,Jian-chao Luo,Yun-shan Zhong,Le-hao Jin,Da-peng Dai,Jian-chang Qian
To study the effects of metabolic enzyme activity inhibition and genetic polymorphisms on the pharmacokinetics and pharmacodynamics of rivaroxaban, we established an in vitro enzymatic reaction system to screen for inhibitors, and used the UPLC-MS/MS method to detect the levels of rivaroxaban and its metabolite M2-1. Additionally, in vivo pharmacokinetic-pharmacodynamic studies were conducted using Sprague-Dawley rats. Human recombinant CYP2J2 baculosomes were prepared using a baculovirus-insect expression system to investigate the impact of genetic polymorphisms on rivaroxaban metabolism through enzyme kinetics methods. The results demonstrated that acid-suppressing drugs strongly inhibited the metabolism of rivaroxaban in vitro . Among them, vonoprazan significantly increased the systemic exposure of rivaroxaban in vivo , while also prolonging prothrombin time, likely due to the competitive binding of vonoprazan and rivaroxaban to CYP2J2. Moreover, the genetic polymorphisms of CYP2J2 determined the metabolic characteristics of rivaroxaban and the inhibitory potency of vonoprazan. Overall, our findings suggest that vonoprazan-induced inhibition of CYP2J2 activity can affect the pharmacokinetics and pharmacodynamics of rivaroxaban, with the extent of inhibition determined by the genetic polymorphism of CYP2J2. These insights have important implications for the precise management of rivaroxaban in humans.
研究领域:
药理学
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临床医学
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分子生物学
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DOI
PubMed
高影响因子
DRUG DELIVERY
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2022
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IF 6.819
Peng Sun,Haoliang Wu,Hao He,Liwei Zhang,Yuanfeng Liu,Cong Zhang,Chunyang Lou,Jingan Li,Hualong Bai
Neointimal hyperplasia is a complex process after vascular interventions, acute platelet deposition and smooth muscle cell proliferation both contributed to this process. There are still no perfect solutions to solve this problem. Rivaroxaban is a novel anticoagulant that has been widely used in clinic, it has a good pharmacological effects both in vivo and in vitro. Chitosan microparticle rapamycin (MP-rapa) was fabricated, interspaces of polyglycolic acid (PGA) scaffold were used as a reservoir of MP-rapa, and the scaffold was coated with hyaluronic acid rivaroxaban (MP-rapa-riva). Scanning electronic microscopy (SEM) photographs were taken and water contact angles were measured, rat inferior vena cava (IVC) patch venoplasty model was used; patches were harvested at day 14 and examined by immunohistochemistry and immunofluorescence. SEM photographs showed the microparticles rapamycin were inside the interspace of the scaffold, hyaluronic acid rivaroxaban was also successfully coated onto the surface of the scaffold. There was a thinner neointima, fewer proliferating cell nuclear antigen (PCNA) positive cells, fewer macrophages in the MP-rapa and MP-rapa-riva grafts compared to the control PGA graft. The result showed that this scaffold with dual anticoagulation and antiproliferation functions can effectively inhibit venous neointimal hyperplasia, although this is an animal experiment, it showed promising potential clinical application in the future.
研究领域:
药理学
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生物医学工程
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血管外科
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材料科学
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DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2021
·
IF 3.205
Yu-Fei Zhang,Xiao-Qin Liu,Yang Wang,Xin Xu,Ming-Kang Zhong,Pu Zhang,Chun-Lai Ma
Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0–500 ng/mL for dabigatran etexilate, 0.1–500 ng/mL for dabigatran, and 0.5–500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05–0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r 2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.
研究领域:
临床药理学
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分析化学
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DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2024
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IF 3.6
Chengzhi Wang,Dayang Jiang,Huipeng Ge,Jianping Ning,Xia Li,Mingmei Liao,Xiangcheng Xiao
Anticoagulation treatment for patients with high bleeding risk during hemodialysis is challenging. Contact between the dialysis membrane and the blood leads to protein adsorption and activation of the coagulation cascade reaction. Activated coagulation Factor X (FXa) plays a central role in thrombogenesis, but anticoagulant modification of the dialysis membrane is rarely targeted at FXa. In this study, we constructed an anticoagulant membrane using the polydopamine coating method to graft FXa inhibitors (apixaban and rivaroxaban) on the membrane surface. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the membranes. The apixaban- and rivaroxaban-modified membranes showed lower water contact angles, decreased albumin protein adsorption, and suppressed platelet adhesion and activation compared to the unmodified PES membranes. Moreover, the modified membranes prolonged the blood clotting times in both the intrinsic and extrinsic coagulation pathways and inhibited FXa generation and complement activation, which suggested that the modified membrane enhanced biocompatibility and antithrombotic properties through the inhibition of FXa. Targeting FXa to design antithrombotic HD membranes or other blood contact materials might have great application potential.
研究领域:
材料科学
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生物医学工程
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血液透析
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药学
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产品关联
DOI
PubMed
高影响因子
Results in Chemistry
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2025
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IF 4.2
Oushan Tang,Shitong Wang,Guanguan Qiu,Majun Zhang,Liping Ling,Yan Zhang,Meiqun Guo,Chunxia Shen,Bin Quan,Hongjie Lang,Qing Shen,Keyun Cheng
This study proposes a method combining the Captiva enhanced matrix removal (EMR)-Lipid solid-phase extraction column with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the qualitative and quantitative analysis of five common oral anticoagulants (OACs) (rivaroxaban, apixaban, edoxaban, dabigatran, and warfarin) in plasma samples. The method, through a simplified sample pretreatment, significantly enhances the recovery rate of OACs (ranging from 88% to 96%), demonstrating superior purification effects compared to traditional solid-phase extraction methods, and effectively removes matrix interference. The method exhibits good linearity over a concentration range of 0.010 to 5.0 × 10 2 ng·mL −1 (r 2 = 0.9514 to 0.9998), with high sensitivity, detection limits of 0.010 to 0.10 ng·mL −1 , and quantification limits of 0.10 to 1.0 ng·mL −1 . The recovery and precision analysis indicate that the method is highly accurate and stable, suitable for the analysis of large batches of plasma samples containing OACs. This method provides an efficient and reliable testing tool for clinical drug monitoring, contributing to the optimization and enhancement of safety in personalized anticoagulation therapy.
研究领域:
临床药理学
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药物代谢
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分析化学
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个体化医学
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毒理学
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生物分析
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抗凝治疗
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产品关联
DOI
高影响因子
Chinese Medicine
·
2020
·Vol. 15
·期 1
·1-14
·
IF 2.96
Yang Yi-Yao,Wu Zhao-Yu,Xia Fang-Bo,Zhang Hao,Wang Xu,Gao Jian-Li,Yang Feng-Qing,Wan Jian-Bo
Background The dry root and rhizome of Ligusticum chuanxiong Hort., or Chuanxiong, has been used as a blood-activating and stasis-removing traditional Chinese medicine for 1000 years. Our previous studies have shown the inhibitory activity on platelet and thrombin (THR) of Chuanxiong. THR and factor Xa (FXa) play significant roles in the coagulation cascade and their inhibitors are of valuable in the treatment of thromboembolic diseases. The aim of the present study is to screen THR and FXa inhibitors from Chuanxiong.Methods Four extracts [ethyl acetate (EA), butanol (BA) and remained extract (RE) from 75% ethanol extract, and water extract (WE)] of Chuanxiong were prepared, and their THR/FXa inhibitory activities were assessed in vitro. Following silica-gel column chromatography (SC), the active EA extract and BA extract was further partitioned, respectively. Their active fractions (EA-SC1 to EA-SC5; BA-SC1 to BA-SC5) were obtained and analyzed by LC–MS. After modeling by the principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA), the specific marker compounds were predicted and identified. Their enzyme inhibitory was assessed in vitro and interactions with THR/FXa were investigated by molecular docking analysis.Results Chuanxiong EA extract showed strong activity against THR and BA extract was more effective in inhibiting FXa activity, and their fractions exhibited obvious difference in enzyme inhibitory activity. Furthermore, marker compounds a–h were predicted by PCA and OPLS-DA, and their chemical structures were identified. Among them, senkyunolide A, Z-ligustilide, ferulic acid and senkyunolide I (IC50 was determined as 0.77 mM) with potential THR inhibitory activity, as well as isochlorogenic acid A with FXa inhibitory activity were screened out. It was found that the four components could interact with the active site of THR, and the binding energy was lower than − 5 kcal/mol. Isochlorogenic acid A were bound to the active site of FXa, and the binding energy was − 9.39 kcal/mol. The IC50 was determined as 0.56 mM.Conclusion sTHR/FXa inhibitory components in different extracts of Chuanxiong were successfully characterized by the method of enzyme inhibition activity assays with ultra performance liquid chromatography-quadrupole time of flight mass spectrometry-based multivariate statistical analysis.
研究领域:
中药学
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2020
·Vol. 15
·期 1
·1-13
·
IF 2.96
Yang Yi-Yao,Wu Zhao-Yu,Zhang Hao,Yin Shi-Jun,Xia Fang-Bo,Zhang Qian,Wan Jian-Bo,Gao Jian-Li,Yang Feng-Qing
Background The dry root and rhizome of Salvia miltiorrhiza Bunge, or Danshen, is a well-known traditional Chinese medicine with anticoagulant activity. Taking into account that thrombin (THR) and factor Xa (FXa) play crucial roles in the coagulation cascade, it is reasonable and meaningful to screening THR and/or FXa inhibitors from Danshen. Methods Four extracts [butanol (BA), ethyl acetate (EA) and remained extract (RE) from 75% ethanol extract, and water extract (WE)] of Danshen were prepared, and their THR/FXa inhibitory activities were assessed in vitro. Then, the active EA extract was further separated by silica-gel column chromatography (SC), and its fractions (SC1–SC5) were analyzed by LC–MS. The principal component analysis (PCA) and orthogonal partial least squares discriminate analysis (OPLS-DA) were employed for predicting the specific marker compounds. The chemical structures of targeted compounds were identified by LC–MS/MS and their interactions with THR/FXa were analyzed by the molecular docking analysis. Results Danshen EA extract showed strong activity against THR and FXa, and its fractions (SC1–SC5) exhibited obvious difference in inhibitory activity against these two enzymes. Furthermore, four marker compounds with potential THR/FXa inhibitory activity were screened by PCA and OPLS-DA, and were identified as cryptotanshinone, tanshinone I, dihydrotanshinone I and tanshinone IIA. The molecular docking study showed that all these four tanshinones can interact with some key amino acid residues of the THR/FXa active cavities, such as HIS57 and SER195, which were considered to be promising candidates targeting THR and/or FXa with low binding energy (< − 7 kcal mol −1 ). Conclusions LC–MS combined with multivariate statistical analysis can effectively screen potential THR/FXa inhibitory components in Danshen.
研究领域:
中药学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）