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Tong Xie,
Yan Liang,
Haiping Hao,
Jiye A,
Lin Xie, Ping Gong,
Chen Dai,
Linsheng Liu,
An Kang,
Xiao Zheng,
Guangji Wang
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ABSTRACT: This study was to develop and evaluate a practical approach of mass defect filtering (MDF), a post-acquisition data processing technique, for the rapid classification of complicated peaks into well-known chemical families based on the exact mass acquired by high resolution mass spectrometry. The full-scan LC-MS/MS data of the Ophiopogon japonicus extract was acquired using high performance liquid chromatography coupled with hybrid quadrupole-time of flight (LCMS-Q-TOF) system which features high resolution, mass accuracy, and sensitivity. To remove the interferences of the complex matrix, MDF approach was developed and employed to rapidly pick out the peaks of ophiopogonins and ophiopogonones from full-scan mass chromatograms. The accuracy of MDF was evaluated in reference to the result of structural identification. After the MDF based classification, both target and non-target components in Ophiopogon japonicus extract were characterized based on the detailed fragment ions analysis in the hybrid ion trap and time-of-flight mass spectrometry (LCMS-IT-TOF). By this approach, more than 50 ophiopogonins and 27 ophiopogonones were structurally characterized. The present results of rapid detection and identification of ophiopogonins and ophiopogonones suggest that the proposed MDF approach based on the high-resolution mass spectrometry data would be expected adaptable to the analysis of other herbal components.
Journal of chromatography. A 03/2012; 1227:234-44. · 4.19 Impact Factor
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ABSTRACT: Global metabolite identification of complex compound mixtures in biological systems is a very challenging task. Herein, we developed and validated a chemicalome to metabolome matching approach by taking herbal medicine as an example to delineate the metabolic networks of complex systems. This approach consists of five steps of data processing including raw data output, endogenous background subtraction, parent compound and metabolite differentiation, chemicalome to metabolome correlation, and the final validation via manual fragment comparison. Chemicalome to metabolome correlation, the core step of this approach, was performed based on matching the accurate mass differences of pseudomolecular ions between them with the accurate mass changes of known metabolic pathways and validating the matches by validation ions. A step-forward approach that confers a gradual identification of metabolites generated from different steps (1-4) and types (degradation, phase I/II, or mixed) of metabolic reactions was further proposed for chemicalome to metabolome matching. This approach was validated to be very useful and powerful for the metabolite identification of a single compound, a homologous compound mixture, and a complex herbal system. Using this approach, all metabolites (162) detected from urine samples of rats treated with Mai-Luo-Ning injection could be linked to their respective parent compounds, and 143 of them were supported by the final validation via manual fragment analysis. In most cases, more than 80% of the automatic matching results could be supported by the manual fragment validations. A complex metabolic network showing all the possible links between precursors and metabolites was successfully constructed. This study provides a generally applicable approach to global metabolite identification of complex compound mixtures in complex matrixes.
Analytical Chemistry 02/2012; 84(6):2995-3002. · 5.86 Impact Factor
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Kun Hao, Ping Gong,
Shi-Qing Sun,
Hai-Ping Hao,
Guang-Ji Wang,
Yue Dai,
Yuan-Cheng Chen,
Yan Liang,
Lin Xie,
Fei-Yan Li,
Hao-Ye Li
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ABSTRACT: We sought to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the effects of ginsenoside Rb1 (Rb1) and estradiol (E(2)) on neural 5-hydroxytryptamine (5-HT) concentration in ovariectomized mice. PK data of Rb1 and E(2) were obtained in plasma and brain. Brain levels of 5-HT, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA) were determined after a single intravenous injection of Rb1 (20mg/kg) and E(2) (0.2mg/kg) in ovariectomized mice. The activities of tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AAAD), and monoamine oxidase (MAO) were also evaluated. Rb1 and E(2) elevated neural 5-HT levels via TPH activation and MAO inhibition, respectively. Effects were well described by the mechanism-based PK-PD model. The net effect of increased 5-HT induced by MAO inhibition is greater than TPH activation. The increased brain levels of 5-HT induced by Rb1 and E(2) were well described by the present PK-PD model, suggesting the use and further development of this mechanism-based model for the effects of ginsenoside on brain 5-HT levels.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 09/2011; 44(1-2):117-26. · 2.61 Impact Factor
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ABSTRACT: Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5- to 2.5-fold and 2.5- to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.
Drug metabolism and disposition: the biological fate of chemicals 07/2011; 39(10):1815-22. · 3.74 Impact Factor
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ABSTRACT: Polyphenol-aspirin interactions were recently identified; however, the interaction mode and underlying mechanisms remained elusive. Here, we quantitatively assessed the potential interactions among two important polyphenolic compounds, caffeic acid (CA) and protocatechualdehyde (Pro), and aspirin in the AA-induced platelet aggregation model by applying the isobologram and universal response surface approach (URSA) methods. A molecular docking approach and an originally developed platelet-associated aspirin clearance approach (PAACA) were then applied to explore the potential interaction mechanisms. Although Pro and CA themselves exhibited weak inhibitory effect on arachidonic acid (AA)-induced platelet aggregation and the production of thromboxane B₂ (TXB₂), both Pro and CA potentiated aspirin action in a synergistic manner. The most prominent synergism was found between Pro and aspirin. Pro formed a stable complex into the cyclooxygenase-1 (COX-1) channel by in silico docking and significantly promoted the platelet-associated aspirin clearance, suggesting that the Pro interaction with COX-1 was favorable to the binding of aspirin with COX-1. Taken together, our findings suggest that the capacity of Pro and potentially other structurally similar polyphenolic compounds on promoting the binding of aspirin on platelet COX-1 might be the main mechanism of their synergism with aspirin.
Planta Medica 07/2011; 77(17):1898-904. · 2.15 Impact Factor
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ABSTRACT: Decreased 5-hydroxytryptamine (5-HT) concentration in the brain has been linked to central nervous system dysfunctions, especially in menopausal women. Ginsenoside Rb1, a potential phytoestrogen, has been shown to improve central nervous system dysfunctions, comparable to the estrogen treatment. To investigate the estrogen-like effects of ginsenoside Rb1 on neural 5-HT disposition and behavioral tasks, we quantified the concentrations of 5-HT and other related endogenous substances in the frontal cortex and striatum of ovariectomized mice. The activities of tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AAAD) and monoamine oxidase (MAO) were also measured to evaluate the synthesis and metabolism of neural 5-HT. Our work shows that both ginsenoside Rb1 and estradiol increased the neural 5-HT concentration. Ginsenoside Rb1 and estradiol administration resulted in elevated TPH and depressed MAO activities, indicating that modulating the synthesis and metabolism of neural 5-HT successfully elevated 5-HT concentration. Ginsenoside Rb1 and estradiol also improved object recognition and decreased immobility time in the forced swimming test. However, a pretreatment with clomiphene (an estrogen receptor antagonist) blocked the beneficial effects of ginsenoside Rb1 and estradiol, suggesting that the estrogen-like effects of ginsenoside Rb1 were estrogen receptor-dependent.
European journal of pharmacology 03/2011; · 2.59 Impact Factor
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ABSTRACT: Although the biotransformation of ginsenosides in the gastrointestinal tract has been extensively studied, much less is known about hepatic cytochrome P450 (P450)-catalyzed metabolism. The major aims of this study were to clarify the metabolic pathway and P450 isoforms involved and to explore the structure-metabolism relationship of protopanaxatriol (PPT)-type ginsenosides in hepatic microsomes. Efficient depletion of ginsenoside Rh1, Rg2, Rf, and PPT was found, whereas the elimination of Re and Rg1, characterized by a glucose substitution at the C20 hydroxy group, was negligible in microsomal incubation systems. Based on high-performance liquid chromatography hybrid ion trap and time-of-flight mass spectrometry analysis, the oxygenation metabolism on the C20 aliphatic branch chain was identified as the predominant metabolic pathway of PPT ginsenosides in both human and rat hepatic microsomes. By a comparison with authentic standards, the C24-25 double bond was identified as one of the oxygenation sites to produce the metabolites of C20-24 epoxide (ocotillol-type ginsenosides). Both chemical inhibition and human recombinant P450 isoform assays indicated that CYP3A4 was the predominant isozyme responsible for the oxygenation metabolism of PPT ginsenosides. Enzyme kinetic evaluations in rat and human hepatic microsomes and human recombinant CYP3A4 isozyme incubation systems showed generally consistent results in that the intrinsic clearance ranked as Rf ≤ Rg2 < Rh1 < PPT, closely correlating with logP values and the number of glycosyl substitutions. Results obtained from this study suggest that CYP3A4-catalyzed oxygenation metabolism plays an important role in the hepatic disposition of ginsenosides and that glycosyl substitution, especially at the C20 hydroxy group, determines their intrinsic clearances by CYP3A4.
Drug metabolism and disposition: the biological fate of chemicals 10/2010; 38(10):1731-9. · 3.74 Impact Factor
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Haiping Hao,
Nan Cui,
Guangji Wang,
Binren Xiang,
Yan Liang,
Xiangyang Xu,
Hui Zhang,
Jun Yang,
Chaonan Zheng,
Liang Wu, Ping Gong,
Wei Wang
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ABSTRACT: Although the current literature has recorded many reports of identifying components from herbal preparations, all of them were largely limited to target components. This paper provides a novel and generally applicable approach to identifying nontarget components from herbal preparations, based on the use of liquid chromatography ion trap time-of-flight mass spectrometry (LC/MS-IT-TOF). A simple program was originally developed for searching the common diagnostic ions from all experimentally generated ions. The components sharing the exact same ions (mass error < 5 mDa) were classified into a family. All families were then connected into a coherent network by the bridging components that are present in two or more families. With the benefit from such a network, it is feasible to sequentially characterize the structures of all diagnostic ions once a single component has been de novo identified. The structures of the diagnostic ions could then be used as "a priori" information for selecting the exact candidates containing the substructures of the corresponding diagnostic ions from the primary database hits. This strategy enables a nearly 7-fold narrowing of the database hits and thus substantially enhances the analytical efficiency and sharpness. With the use of such an approach, 43 out of 53 components incorporated into the network have been successfully identified from the test herbal preparation. For the rest, components failed to be identified using this approach; a complementary approach to screening by sequential loss of specific chemical groups, proposed from the accurate mass differences between fragments, was established to narrow the database hits. All of the 87 peaks detected have been successfully identified by combining the use of both approaches except failed to differentiate some isomers. The presently developed approach and methodology would be useful for the identifications of complicated nontarget components from various complex mixtures such as herbal preparations, biological, and environmental samples.
Analytical Chemistry 10/2008; 80(21):8187-94. · 5.86 Impact Factor
