Lisha You

Simultaneous determination of puerarin, daidzein, baicalin, wogonoside and liquiritin of GegenQinlian decoction in rat plasma by ultra-performance liquid chromatography-mass spectrometry

A specific ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method was developed for the simultaneous determination of puerarin, daidzein, baicalin, wogonoside and liquiritin in rat plasma. Chromatographic separation was performed on a C(18) column packed with 1.7 microm particles by a linear gradient elution. The analytes and carbamazepine (internal standard, I.S.) were monitored in a selected-ion reaction (SIR) mode with a positive electrospray ionization (ESI) interface by the following ions: m/z 417.2 for puerarin, m/z 255.2 for daidzein, m/z 271.0 for baicalin, m/z 461.0 for wogonoside, m/z 441.0 for liquiritin and m/z 237.2 for carbamazepine (I.S.), respectively. The calibration curves of these analytes were linear over the concentration ranges from 0.00254-1.02 microg mL(-1) to 0.0102-10.2 microg mL(-1). Within-batch and between-batch precisions (RSD%) were all within 15% and accuracy (RE%) ranged from -10% to 10%. The extraction recoveries were on average 79.8% for puerarin, 90.8% for daidzein, 74.4% for baicalin, 70.2% for wogonoside and 84.7% for liquiritin. The validated method was successfully applied to investigate the pharmacokinetics of five bioactive compounds of GegenQinlian decoction (GQD) in rats.

Discovery of novel osthole derivatives as potential anti-breast cancer treatment.

Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, was used as a lead compound for structural modification. A series of osthole derivatives bearing aryl substituents at 3-position of coumarin, has been prepared and evaluated for their growth inhibitory activity against human breast cancer cell lines MCF-7 and MDA-MB-231. Interestingly, some derivatives exhibited good inhibition, among them compound 8e was found to be the most potent compound with IC(50) values of 0.24 μM, 0.31 μM against MCF-7 and MDA-MB-231, respectively, which was improved more than 100-folds compared with its parent compound osthole.

Macrocyclic Compounds: Emerging Opportunities for Current Drug Discovery

The macrocycles representing a unique chemical structure bridging conventional small molecules and large biomolecules, have attracted more and more attention in drug discovery over the past decade, and tremendous progress has been made toward the macrocyclization synthesis and structure diversification recently. Because of their favored size, flexibility and complexity, macrocycles can engage previously undruggable targets through numerous and spatially distributed binding interactions, and offer many privileged features including high potency, prominent selectivity, as well as favorable pharmacokinetics properties, and unique intellectual property(IP) space, and even safety profiles, etc. Currently around 70 macrocyclic molecules have been approved for clinical therapy, over 76 macrocycles are being evaluated in clinical trials from phase I to phase III. It is believed that the macrocycles will play more and more important role in the future, and provide very distinctive and promising opportunities for drug discovery along with the development of synthetic methodology, phenotypical screening, and computational studies.

A rapid UPLC method for simultaneous determination of eleven components in 'Ge-Gen-Qin-Lian' decoction.

Background: ‘Ge-Gen-Qin-Lian’ Decoction derived from ‘Shang-Han-Lun’ compiled by Zhang Zhongjing. It is widely used in the treatment of acute gastroenteritis, bacillary dysentery, virus diarrhea. This paper describes a sensitive and specific assay for the determination of the 11-marker compounds using ultra performance liquid chromatography (UPLC). Objective: To develop an UPLC method for simultaneous determination of 11 bioactive compounds in ‘Ge-Gen-Qin-Lian’ preparations. Materials and Methods: The chromatography analysis was performed on an Agilent Proshell 120 EC-C18 column (4.6 × 50 mm, 2.7 μm) at 30°C with a gradient elution of methanol, 0.5% formic acid and 0.5% ammonium acetate at a flow rate 1.0 ml/min and UV detected at 270 nm. Results: All calibration curves showed good linear regression (r ≥ 0.9993) within tested ranges. Limits of detection (LOD) and limits of quantification (LOQ) fell in the range between 0.0691-1.04 μg/ml and 0.23–3.43 μg/ml, respectively. The mean recovery of each herbal medicine ranged from 96.60 to 102.11%. Conclusion: The method was validated for repeatability, precision, stability, accuracy, and selectivity. The validated method was successfully applied to simultaneous analysis of these active components in ‘Ge-Gen-Qin-Lian’ decoction.

Development of in Silico Models for Predicting P-Glycoprotein Inhibitors Based on a Two-Step Approach for Feature Selection and Its Application to Chinese Herbal Medicine Screening

P-glycoprotein (P-gp) is regarded as an important factor in determining the ADMET (absorption, distribution, metabolism, elimination, and toxicity) characteristics of drugs and drug candidates. Successful prediction of P-gp inhibitors can thus lead to an improved understanding of the underlying mechanisms of both changes in the pharmacokinetics of drugs and drug-drug interactions. Therefore, there has been considerable interest in the development of in silico modeling of P-gp inhibitors in recent years. Considering that a large number of molecular descriptors are used to characterize diverse structural moleculars, efficient feature selection methods are required to extract the most informative predictors. In this work, we constructed an extensive available data set of 2428 molecules that includes 1518 P-gp inhibitors and 910 P-gp noninhibitors from multiple resources. Importantly, a two-step feature selection approach based on a genetic algorithm and a greedy forward-searching algorithm was employed to select the minimum set of the most informative descriptors that contribute to the prediction of P-gp inhibitors. To determine the best machine learning algorithm, 18 classifiers coupled with the feature selection method were compared. The top three best-performing models (flexible discriminant analysis, support vector machine, and random forest) and their ensemble model using respectively only 3, 9, 7, and 14 descriptors achieve an overall accuracy of 83.2%-86.7% for the training set containing 1040 compounds, an overall accuracy of 82.3%-85.5% for the test set containing 1039 compounds, and a prediction accuracy of 77.4%-79.9% for the external validation set containing 349 compounds. The models were further extensively validated by DrugBank database (1890 compounds). The proposed models are competitive with and in some cases better than other published models in terms of prediction accuracy and minimum number of descriptors. Applicability domain then was addressed by developing an ensemble classification model to obtain more reliable predictions. Finally, we employed these models as a virtual screening tool for identifying potential P-gp inhibitors in Traditional Chinese Medicine Systems Pharmacology (TCMSP) database containing a total of 13 051 unique compounds from 498 herbs, resulting in 875 potential P-gp inhibitors and 15 inhibitor-rich herbs. These predictions were partly supported by a literature search and are valuable not only to develop novel P-gp inhibitors from TCM in the early stages of drug development, but also to optimize the use of herbal remedies.

Improvement of Kidney yang syndrome by icariin through regulating hypothalamus-pituitary-adrenal axis

ObjectiveTo investigate whether Epimedium brevicornu Maxim (EB) and icariin could exert their protective effects on hydrocortisone induced (HCI) rats by regulating the hypothalamus-pituitary-adrenal (HPA) axis and endocrine system and the possible mechanism.MethodsMale 10-week-old Sprague Dawley (SD) rats were allotted to 6 groups (A–F) with 12 each, group A was injected normal saline (NS) 3 mL/kg day intraperitoneally, group A and B were given NS 6 mL/kg day by gastrogavage, group B–F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/(kg day) by gastrogavage, group E and F were given icariin 25 or 50 mg/(kg day) by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone (CRH) and pituitary proopiomelanocortin (POMC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and protein of pituitary POMC by Western-blot.ResultsThe serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B (P<0.05).The treatment with only icariin increased serum adrenocorticotropic hormone (ACTH) compared with group B (P<0.05).ConclusionEB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC-derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex.

The characterization, pharmacokinetic, and tissue distribution studies of TPGS-modified artesunate liposome in rats

Abstract Objective: The objective of this study (ARS-TPGS-Lipo) was to enhance the stability, encapsulation efficiency (EE), improve AUC, circulation time and liver targeting of ARS-TPGS-Lipo. Methods: ARS-TPGS-Lipo was prepared by thin-film dispersion method and characterized by TEM. The EE, in vitro release and stability of ARS-TPGS-Lipo were detected by HPLC and UV. In addition to the safety evaluation, the pharmacokinetics and tissue distribution studies were also carried out after i.v. administration. Results: The size, PDI, zeta potential, and EE of ARS-TPGS-Lipo were 126.7 ± 9.9 nm, 0.182 ± 0.016, −10.1 ± 1.43 mV, and 78.8 ± 1.89%, respectively. ARS-TPGS-Lipo showed the slow-release effect in vitro release experiments. The AUC of ARS in the ARS-TPGS-Lipo group was 7.51 times higher than in the ARS group after i.v. administration and the circulation time was significantly prolonged. The tissue distribution results showed the components of artesunate and its metabolism DHA of the ARS-TPGS-Lipo group were much higher in liver than the ARS-Lipo group. Conclusion: ARS-TPGS-Lipo was prepared successfully, which had the smaller vesicles size with a better PDI, better stability, higher EE, and slow-release. The results of safety evaluation indicated that ARS-TPGS-Lipo had no hematotoxicity and hepatorenal toxicity. The pharmacokinetic studies indicated ARS-TPGS-Lipo had higher AUC, longer circulation time and better liver targeting.