Beijing Institute of Pharmacology and Toxicology

Beijing, China

Beijing Institute of Pharmacology and Toxicology

Beijing, China
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Xi Z.-X.,U.S. National Institute on Drug Abuse | Peng X.-Q.,U.S. National Institute on Drug Abuse | Li X.,U.S. National Institute on Drug Abuse | Song R.,U.S. National Institute on Drug Abuse | And 7 more authors.
Nature Neuroscience | Year: 2011

The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB 1 also known as Cnr1 mice, but not in CB2 (Cnr2 ) mice. This inhibition was mimicked by GW405833, another CB 2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB 1 mice, but not in CB2 mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB 2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism. © 2011 Nature America, Inc. All rights reserved.

Zhuang X.,Beijing Institute of Pharmacology and Toxicology | Lu C.,Biogen Idec
Acta Pharmaceutica Sinica B | Year: 2016

Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed. © 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

Huang Y.,Beijing Institute of Pharmacology and Toxicology | Zhou W.,Beijing Institute of Pharmacology and Toxicology | Zhang Y.,Beijing Institute of Pharmacology and Toxicology
Behavioural Brain Research | Year: 2012

In this study, we investigated the performance of BALB/c mice in Morris water maze task under two different illumination (bright and dim light) conditions. The results show that BALB/c mice could not complete the Morris water maze task under bright light (BLC), but performed very well under dim light (DLC). Animals that swam under BLC had a higher serum corticosterone level than those under DLC. Animals pretrained under DLC had a lower serum corticosterone level than those directly exposed to BLC. Our results also show that animals under BLC had a higher level of thigmotaxis (a behavioral anxiety measure during testing) than under DLC. Correlation analysis shows that corticosterone and thigmotaxis levels have a positive correlation with escape latency, indicating that corticosterone and thigmotaxis levels have a negative correlation with learning/memory performance. These results suggest that BALB/c mice have the ability to learn a spatial task; under BLC, they performed poorly owing to a high level of thigmotaxis. © 2011 Elsevier B.V.

Cui C.-B.,Beijing Institute of Pharmacology and Toxicology
Journal of International Pharmaceutical Research | Year: 2010

Generally absolute majority of wild-type microbial strains do not produce bioactive metabolites, resulting in large numbers of so-called 'useless strains' stocked or destroyed. These strains, however, would become a great source of bioactive meabolites if their secondary metabolism could be altered to produce diverse metabolites. We have therefore undertaken a research work on exploiting microbial new strain resources for drug screening by altering secondary metabolism of the 'useless strains' to discover bioactive metabolites. A considerable progress with expectant advantage desired has been made in the studies on marine-derived actinomycetic and fungal strains. This paper summarizes our research results including several new developments in brief.

Zhang W.,Beijing Institute of Pharmacology and Toxicology | Zhang Z.,Zhengzhou University | Zhang Y.,Beijing Institute of Pharmacology and Toxicology
Nanoscale Research Letters | Year: 2011

Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3) they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies. © 2011 Zhang et al; licensee Springer.

Cheng X.-R.,Beijing Institute of Pharmacology and Toxicology | Zhou W.-X.,Beijing Institute of Pharmacology and Toxicology | Zhang Y.-X.,Beijing Institute of Pharmacology and Toxicology
Ageing Research Reviews | Year: 2014

Alzheimer's disease (AD) is a widespread and devastating progressive neurodegenerative disease. Disease-modifying treatments remain beyond reach, and the etiology of the disease is uncertain. Animal model are essential for identifying disease mechanisms and developing effective therapeutic strategies. Research on AD is currently being carried out in rodent models. The most common transgenic mouse model mimics familial AD, which accounts for a small percentage of cases. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging. Many studies indicate that SAMP8 mice harbor the behavioral and histopathological signatures of AD, namely AD-like cognitive and behavioral alterations, neuropathological phenotypes (neuron and dendrite spine loss, spongiosis, gliosis and cholinergic deficits in the forebrain), β-amyloid deposits resembling senile plaques, and aberrant hyperphosphorylation of Tau-like neurofibrillary tangles. SAMP8 mice are useful in the development of novel therapies, and many pharmacological agents and approaches are effective in SAMP8 mice. SAMP8 mice are considered a robust model for exploring the etiopathogenesis of sporadic AD and a plausible experimental model for developing preventative and therapeutic treatments for late-onset/age-related AD, which accounts for the vast majority of cases. © 2013 Elsevier B.V.

Sun J.,Beijing Institute of Pharmacology and Toxicology | Guo L.,Beijing Institute of Pharmacology and Toxicology | Bao Y.,Beijing Institute of Pharmacology and Toxicology | Xie J.,Beijing Institute of Pharmacology and Toxicology
Biosensors and Bioelectronics | Year: 2011

Here, a simple label-free colorimetric sensing method for organophosphate (OP) nerve agents and pesticide based on catalytic reaction of acetylcholine esterase (AChE) and the aggregation of lipoic acid (LA) capped AuNPs has been established, which is highly sensitive with a limit of detection (LOD) lowered to pM level. In this method, only the AChE hydrolysis product of acetylthiocholine (ATCh), i.e., cationic thiocholine (TCh) can induce the aggregation of LA capped AuNPs along with a distinct color change from red to steel-blue. When OPs as enzyme inhibitors exist, the generation of TCh can be suppressed and the color change of LA capped AuNPs is gradually diminished according to different concentrations of OPs. The feasibility of this method has been demonstrated by sensitive measurement of OP nerve agents and pesticide in a spiked fruit sample with reliable results. This distinct and rapid colorimetric response enables us to readily probe OPs without more technical demand. © 2011 Elsevier B.V.

Zhang X.,Uppsala University | Wang B.,Beijing Institute of Pharmacology and Toxicology | Li J.-P.,Uppsala University
Matrix Biology | Year: 2014

Heparan sulfate proteoglycans (HSPGs), expressed on the cell surface and in the extracellular matrix of most animal tissues, have essential functions in development and homeostasis, and have been implicated in several pathological conditions. The functions of HSPGs are mainly mediated through interactions of the heparan sulfate (HS) polysaccharide side chains with different protein ligands. The molecular structure of HS is highly diverse, expressed in a cell-type specific manner. The flexible yet controlled structure of HS is primarily generated through a strictly regulated biosynthesis process and is further modified post-synthetically, such as desulfation by endosulfatases and fragmentation by heparanase. Heparanase is an endo-glucuronidase expressed in all tissues. The enzyme has been found up-regulated in a number of pathological conditions, implying a role in diseases mainly through degradation of HS. Emerging evidence demonstrates important roles of HS and heparanase in inflammatory reactions, particularly in the regulation of leukocyte activation and extravasation. Neuroinflammation is a common feature of various central nervous system disorders, thus it is a great interest to understand the implications of HS and heparanase in neuroinflammation. © 2013 International Society of Matrix Biology.

Zhang Y.,Beijing Institute of Pharmacology and Toxicology
Nano Biomedicine and Engineering | Year: 2011

All of the natural substances can be viewed as particles. According to the sizes of particles, the natural substances may be classified at six levels from small to large, and heir functional spectra can be established in the order from simple to complex. They are respectively point particles (?ppspPs), fundamental structural particles (FSPs), chemical particles (ChPs), nanoparticles (NPs), macroparticles (MPs) and celestial particles (CePs). The particles in one of these levels have their independent functional activities and interaction patterns different from those in the levels lower than them, representing a new leaping. There are very close relations between the size and functions of the particles. It is especially suitablefor biological particles. As far as the present human knowledges, the activity of the PPs is the simplest without interactions; the activities of FSPs are rather complex, their interactions result in the production of various FSPs; ChPs have more complex activities, their interactions produce inumberous sorts of ions and molecules, forming the collorful chemical world; the functional activities of NPs are much more complex than those of the ChPs, their interactions cause the production of inumberous sorts of biological NPs with the characteristics of biological phenomenon; the functional activities of MPs are the most complicated, their interactions result in the production of hundreds and southands sorts of individual living bodies with the feature of high level functional activities such as learnig, thinking and reproduction; we still know little about the functional activities of the CePs. In conclusion, the establishent of the size-function spectrum will be helpful to investigate the substance world as a whole, and reveal the interaction principles of the particles and biological essential fundamentals. © 2011 Y. Zhang, et al.

Xie X.,Beijing Institute of Pharmacology and Toxicology
Biochimica et biophysica acta | Year: 2015

BACKGROUND: Selective PPARγ modulators (sPPARγM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer.METHODS: We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARγ in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice.RESULTS: L312 interacted with PPARγ-LBD in a manner similar to known sPPARγM. L312 showed similar PPARγ binding affinity, but displayed partial PPARγ agonistic activity compared to PPARγ full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg·day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARγ phosphorylation and displayed a selective gene expression profile in epididymal WAT.CONCLUSIONS: L312 is a novel sPPARγM.GENERAL SIGNIFICANCE: L312 may represent a novel lead for designing ideal sPPARγM for T2DM treatment with advantages over current TZDs. Copyright © 2014 Elsevier B.V. All rights reserved.

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