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PubMed | Beijing Hospital, Shenyang Pharmaceutical University, State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process and Peking Union Medical College
Type: Journal Article | Journal: Clinical drug investigation | Year: 2016

Baicalein, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, is a neuroprotective agent under development to treat Parkinsons disease. This study investigated the pharmacokinetics, safety and tolerability of baicalein after a multiple-ascending-dose protocol in healthy Chinese volunteers.In this single-center, double-blind, placebo-controlled, parallel-group study, participants were randomized to receive baicalein (n=8 per dose regimen) or placebo (n=2 per dose regimen). Dosing regimens were 200, 400, and 800mg once daily on days 1 and 10, twice daily on days 3-9. Plasma, urine, and feces samples were assayed for baicalein and its predominant metabolite baicalin using validated HPLC-MS/MS methods. Pharmacokinetic parameters were computed using standard non-compartmental analysis. Dose proportionality was assessed with a method combining equivalence criterion and power model. Drug safety and tolerability were assessed by monitoring adverse events and laboratory parameters.Thirty-three of 36 enrolled participants completed the study. A total of 44 adverse events occurred in 23 participants. A steady-state concentration of analytes in plasma was achieved on day 8 after repeated dosing. Analytes concentrations and exposure increased with increasing dose. The dose proportionality constant () for AUCss of baicalein and baicalin was 0.922 (90% confidence interval, 0.650-1.195) and 0.942 (90% confidence interval, 0.539-1.345), respectively. The accumulation index varied from 1.66 to 2.07 for baicalein and from 1.68 to 2.45 for baicalin.In dose range of 200-800mg, multiple-dose oral baicalein administration was safe and well tolerated, dose proportionality was inconclusive, and no serious accumulation of baicalein was observed.

PubMed | University of Manchester, State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process and Peking Union Medical College
Type: Journal Article | Journal: British journal of pharmacology | Year: 2016

Endoplasmic reticulum (ER) stress is increasingly recognized as an important causal factor of many diseases. Targeting ER stress has now emerged as a new therapeutic strategy for treating cardiovascular diseases. Here, we investigated the effects and underlying mechanism of ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) on cardiac ER stress.Cell death, apoptosis and ER stress-related signalling pathways were measured in cultured neonatal rat cardiomyocytes, treated with the ER stress inducers tunicamycin, hydrogen peroxide and thapsigargin. Acute myocardial infarction was established using left coronary artery occlusion in mice, and infarct size was measured by triphenyltetrazolium chloride staining. Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.Ginkgolide K (GK) significantly decreased ER stress-induced cell death in both in vitro and in vivo models. In ischaemic injured mice, GK treatment reduced infarct size, rescued heart dysfunction and ameliorated ER dilation. Mechanistic studies revealed that the beneficial effects of GK occurred through enhancement of inositol-requiring enzyme 1 (IRE1)/X box-binding protein-1 (XBP1) activity, which in turn led to increased ER-associated degradation-mediated clearance of misfolded proteins and autophagy. In addition, GK was also able to partly repress the pro-apoptotic action of regulated IRE1-dependent decay and JNK pathway.In conclusion, GK acts through selective activation of the IRE1/XBP1 pathway to limit ER stress injury. GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.

PubMed | University of Florida, CAS Dalian Institute of Chemical Physics, Hubei University for Nationalities, Northwest Agriculture and Forestry University and 2 more.
Type: | Journal: Journal of ethnopharmacology | Year: 2015

Migraine is the most common neurovascular disorder that imparts a considerable burden to health care system around the world. However, currently there are still no effective and widely applicable pharmacotherapies for migraine patients. Herbal formulae, characterized as multiple herbs, constituents and targets, have been acknowledged with clinical effects in treating migraine, which attract more and more researchers attention although their exact molecular mechanisms are still unclear. In this work, a novel systems pharmacology-based method which integrates pharmacokinetic filtering, target fishing and network analysis was developed and exemplified by a probe, i.e. Tianshu formula, a widely clinically used anti-migraine herbal formula in China which comprises of Rhizoma chuanxiong and Gastrodia elata. The results exhibit that 20 active ingredients of Tianshu formula possess favorable pharmacokinetic profiles, which have interactions with 48 migraine-related targets to provide potential synergistic therapeutic effects. Additionally, from systematic analysis, we speculate that R. chuanxiong as the monarch herb mediates the major targets like PTGS2, ESR1, NOS2, HTR1B and NOS3 to regulate the vascular and nervous systems, as well as the inflammation and pain-related pathways to benefit migraine patients. Meanwhile, as an adjuvant herb, G. elata may not only assist the monarch herb to improve the outcome of migraine patients, but also regulate multiple targets like ABAT, HTR1D, ALOX15 and KCND3 to modify migraine accompanying symptoms like vomiting, vertigo and gastrointestinal disorders.

Zhao Y.,Changchun University of Chinese Medicine | Yao B.,Changchun University of Chinese Medicine | Zhang M.,Changchun University of Chinese Medicine | Wang S.,Changchun University of Chinese Medicine | And 3 more authors.
Molecular Biology Reports | Year: 2013

Deer antlers serve as useful models of rapid growth and mineralization in mammals. During the period of rapid growth, the antlers of many species of deer will elongate by more than 2 cm per day, after which the antlers gradually ossify. However, little is known about the genes that are involved in their development, particularly the molecular mechanisms responsible for rapid growth and ossification. In our previous studies, we have reported on the transcriptome analysis of deer antlers at rapid growth and ossification stages. With the aim to get a comprehensive understanding of gene expression patterns during antler growth, in the present study, we performed a rigorous algorithm to identify differentially expressed genes between two different stages (60 and 90 days) during antler growth. A total of 16,905 significantly changed transcripts were identified. Those sequences were mapped to 5,573 genes with 2,217 genes up-regulated and 3,356 genes down-regulated (60 days vs. 90 days), including ribosomal proteins, translation initiation and elongation factors, transcription factors, signaling molecules and extracellular matrix proteins. We also performed the gene ontology (GO) functional enrichment and pathway enrichment analysis of gene expression patterns with hypergeometric test and Bonferroni Correction. Both the two stages were enriched with members of GO categories and distinct pathways. Our data represent the most comprehensive sequence resource available for the deer antler and provide a basis for further research on deer antler molecular genetics and functional genomics. © 2012 Springer Science+Business Media Dordrecht.

PubMed | Tianjin University of Traditional Chinese Medicine, Northwest Agriculture and Forestry University, State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process and Dalian University of Technology
Type: | Journal: Evidence-based complementary and alternative medicine : eCAM | Year: 2015

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future.

PubMed | Northwest University, China and State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process
Type: Journal Article | Journal: PloS one | Year: 2015

As a rich natural resource for drug discovery, Traditional Chinese Medicine (TCM) plays an important role in complementary and alternative medical systems. TCM shows a daunting complexity of compounds featuring multi-components and multi-targets to cure diseases, which thus always makes it extremely difficult to systematically explain the molecular mechanisms adequately using routine methods. In the present work, to reveal the systematic mechanism of herbal formulae, we developed a pathway-based strategy by combining the pathways integrating, target selection, reverse drug targeting and network analysis together, and then exemplified it by Reduning injection (RDN), a clinically widely used herbal medicine injection, in combating inflammation. The anti-inflammatory effects exerted by the major ingredients of RDN at signaling pathways level were systematically investigated. More importantly, our predicted results were also experimentally validated. Our strategy provides a deep understanding of the pharmacological functions of herbal formulae from molecular to systematic level, which may lead to more successful applications of systems pharmacology for drug discovery and development.

Li Y.,State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process | Li Y.,Hainan Medical University | Wang P.,Jiangsu Kanion Pharmaceutical Co. | Xiao W.,State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process | And 5 more authors.
American Journal of Chinese Medicine | Year: 2013

In this paper, a useful method for screening and analyzing the potential bioactive components from Reduning Injection was developed using macrophage cell extraction and ultra-high performance liquid chromatography coupled with Q-TOF/MS spectrometry. In addition, the protective effects on macrophage cell damage induced by LPS in vitro were also investigated. The results showed that chlorogenic acid, 3, 4-dicaffeoylquinic acid, 3, 5-dicaffeoylquinic acid and 4, 5-dicaffeoylquinic acid significantly inhibited the prostaglandin E2 (PGE2) release and reversed the interleukin-6 (IL-6) secretion of macrophages (p < 0.05). These data indicated that the method of macrophage cell extraction coupled with UPLC-MS technology is feasible, rapid and useful for screening and analyzing potential bioactive components from TCM injection. © 2013 World Scientific Publishing Company.

PubMed | Tianjin University of Traditional Chinese Medicine, Nanjing University of Traditional Chinese Medicine, State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process and Jiangsu Kanion Pharmaceutical Co.
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2015

In this study, a sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determinate andrographolide (AP), dehydroandrographolide (DP), and neoandrographolide (NP) in plasma of beagle dogs after oral administration of Andrographis paniculata tablet (A. paniculata). The analytes and bilobalide (internal standard) were separated on an Agilent ZORBAX XDB-C18 column (50mm2.1mm, 3.5m) by using gradient elution consisting of methanol and water at a flow rate of 0.50mL/min in 7min. Multiple reaction monitoring (MRM) mode was performed to quantify data under monitoring precursor-product ion transitions of m/z 348.8286.9, 330.9107.9, 479.1160.8 and 325.0163.0 for AP, DP, NP and internal standard (IS) at negative ion mode, respectively. This method was developed at linearity ranging from 0.50 to 250ng/mL for AP, 1.00 to 500ng/mL for DP and 0.20 to 100ng/mL for NP. The accuracy of each analyte ranged between 94.8% and 107.1% and the precision was within 14.6%. No significant matrix effect was observed. AP, DP and NP were stable during sample storage, preparation and analytic procedures. Furthermore, this method was successfully applied in the investigation of the pharmacokinetic profile of AP, DP and NP in beagle dogs after oral administration of A. paniculata tablet (49.5mg for AP, 7.0mg for DP, 22.0mg for NP). Biological half-life (t1/2) was 2.080.99, 3.131.19 and 1.070.38h for AP, DP and NP, respectively. The areas under curves (AUC0-t) of AP, DP and NP was 494.50150.64, 26.018.72 and 78.7818.29ngh/mL, respectively.

Tang L.-P.,Jinan University | Xiao W.,State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process | Li Y.-F.,Jinan University | Li H.-B.,State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process | And 4 more authors.
Chinese Journal of Integrative Medicine | Year: 2014

Objective: To evaluate the protective effects of Reduning Injection (RDN), a patent Chinese medicine, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and its underlying mechanisms of action. Methods: Sixty male Sprague-Dawley rats were randomly divided into 6 groups, including normal control, model, dexamethasone (DEX, 5 mg/kg), RDN-H (720 mg/kg), RDN-M (360 mg/kg) and RDN-L (180 mg/kg) groups, with 10 rats in each group. Rats were challenged with intravenous injection of LPS 1 h after intraperitoneal treatment with RDN or DEX. At 6 h after LPS challenge, lung tissues and bronchoalveolar lavage fluid (BALF) were collected, and the number of inflammatory cells was determined. The right lungs were collected for histopathologic examination, measurement of gene and protein expressions, superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Results: In vivo pretreatment of RDN (360, 720 mg/kg) significantly reduced the weight of wet to dry (W/D) ratio of lung, protein content in BALF, and led to remarkable attenuation of LPS-induced histopathological changes in the lungs. Meanwhile, RDN enormously decreased BALF total inflammatory cells, especially neutrophil and macrophage cell numbers. Moreover, RDN increased SOD activity, inhibited MPO activity, alleviated LPS-induced tumor neurosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression in lung tissues. Furthermore, RDN (720 mg/kg) efficiently weakened nuclear factorkappa B (NF-κB) gene and protein expression. Conclusion: Anti-inflammatory effects of RDN was demonstrated to be preventing pulmonary neutrophil infiltration, lowering MPO activity, TNF-α and iNOS gene expression by inhibiting NF-κB activity in LPS-induced ALI. © 2014 Chinese Association of the Integration of Traditional and Western Medicine and Springer-Verlag.

PubMed | State Key Laboratory of New Technology for Chinese Medicine Pharmaceutical Process and China Pharmaceutical University
Type: | Journal: Journal of separation science | Year: 2016

The aim of this study was to develop an analytical method for the simultaneous determination of ultra-trace levels of 35 organophosphorus pesticide residues in Sanjie Zhentong capsules, a traditional Chinese medicine prescription. A method based on multiclass and multiresidue sample preparation was developed. First, samples were hydrated with water at 4C. A ratio of 1:3 sample/water was used for each of the sample amounts. Then, different extraction solvents were screened. This step was followed by a dispersive solid-phase extraction clean-up procedure using both primary secondary amine and polyamide. A comprehensive sensitive multiresidue liquid chromatography tandem mass spectrometry method was investigated and validated. Good linearity was achieved in the range of 10-500 g/kg for each analyte. The average recovery ranged from 70 to 120%, except for methamidophos, fonophos, diazinon, and chlorpyriphos-ethyl, the recoveries of which ranged from 60-70% at the lower concentration level. The precision values were lower than 10% for all the compounds in three concentration levels. The limits of detection and limits of quantification values were 0.01-2.1 and 0.05-3.4 g/kg, respectively. The matrix effects were determined, and most of the compounds showed signal suppression. Finally, this optimized procedure was applied for the analysis of real samples.

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