Beijing Institute of Pharmacology and Toxicology

Beijing, China

Beijing Institute of Pharmacology and Toxicology

Beijing, China

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Zhang Y.,Beijing University of Chinese Medicine | Wang Z.-Z.,Beijing Institute of Pharmacology and Toxicology | Sun H.-M.,Beijing University of Chinese Medicine
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2012

Previous clinical trials have evaluated the association between Parkin p.Ser167Asn (c.601G>A) variant and Parkinson's disease (PD) risk. However, the results remain conflicting rather than conclusive. Therefore, we performed this meta-analysis to assess whether pooled results show the association. We performed structured literature searches for studies addressing the association between the Parkin p.Ser167Asn variant and PD risk. We conducted analyses of study characteristics, heterogeneity, and funnel plot asymmetry in analyses analogous to additive, dominant, recessive, and general genetic models with the odds ratio (OR) as the measure of association. When 15 eligible studies (n=4,739 subjects) were pooled into the meta-analysis, there was no evidence for significant association in additive genetic model between Parkin p. Ser167Asn variant and PD risk (OR=1.02, 95% confidence interval (CI)=0.83-1.25; P=0.866). The OR for the dominant model was 1.06 (95% CI=0.80-1.41) while the OR for the recessive model was 0.90 (95% CI=0.71-1.14). The OR for the heterozygous was 1.07 (95% CI=0.80-1.43) while the OR for the homozygotes was 1.19 (95% CI=0.81-1.74). In the subgroup analysis by ethnicity, no significant association was found in any genetic model. Begg's funnel plot and Egger's test provided visual and statistical evidences for funnel plot symmetry, suggesting no presence of publication bias. In summary, the meta-analysis strongly suggests that Parkin p. Ser167Asn variant is not associated with PD risk. © 2011 Wiley Periodicals, Inc.


Yu G.,Beijing Institute of Pharmacology and Toxicology
Digestive diseases and sciences | Year: 2014

Ilaprazole is a novel proton pump inhibitor that has been marketed as an oral therapy for acid-related diseases in China and Korea. This study aimed to compare the gastroprotective effects of intravenous and enteral ilaprazole in rat models. The rats were divided into 7-8 groups receiving vehicle, esomeprazole, and different doses of intravenous and enteral ilaprazole. The rats were then exposed to indomethacin (30 mg/kg, i.g.), or water-immersion stress and gastric lesions were examined. The effects of different treatments on histamine (10 μmol/kg/h)-induced acid secretion were also observed. Intravenous ilaprazole exhibited high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreased ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine-induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole. Intravenous ilaprazole is more potent than oral ilaprazole against indomethacin- or stress-induced gastric lesions, with faster and longer inhibition of acid secretion.


Guo M.,Key Laboratory of Functional Polymer Materials | Que C.,Key Laboratory of Functional Polymer Materials | Wang C.,Beijing Institute of Pharmacology and Toxicology | Liu X.,Key Laboratory of Functional Polymer Materials | And 2 more authors.
Biomaterials | Year: 2011

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe3O4 nanoparticle cores with a mixture of the triblock copolymer methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-n-butyl methacrylate)-b-poly(glycerol monomethacrylate) and the folate-conjugated block copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate). The model anticancer agent adriamycin (ADR), containing an amine group and a hydrophobic moiety, was loaded into the nanocarrier at pH 7.4 by ionic bonding and hydrophobic interactions. The release rate of the loaded drug molecules was slow at pH 7.4 (i.e. mimicking the blood environment) but increased significantly at acidic pH (i.e. mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the polycarboxylate protonation of poly(methacrylic acid), which broke the ionic bond between the carrier and ADR. Cellular uptake by folate receptor-overexpressing HeLa cells of the folate-conjugated ADR-loaded nanoparticles was higher than that of non-folated-conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. These findings show the potential viability of a folate-targeting, pH-responsive nanocarrier for amine-containing anticancer drugs. © 2010 Elsevier Ltd.


Jin X.-F.,Beijing Institute of Pharmacology and Toxicology | Jin X.-F.,Central South University | Wu N.,Beijing Institute of Pharmacology and Toxicology | Wang L.,Beijing Institute of Pharmacology and Toxicology | Li J.,Beijing Institute of Pharmacology and Toxicology
Cellular and Molecular Neurobiology | Year: 2013

As a class of important endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, microRNAs (miRNAs) play a critical role in many physiological and pathological processes. It is believed that miRNAs contribute to the development, differentiation, and synaptic plasticity of the neurons, and their dysregulation has been linked to a series of diseases. MiRNAs exist in the tissues and as circulating miRNAs in several body fluids, including plasma or serum, cerebrospinal fluid, urine, and saliva. There are significant differences between the circulating miRNA expression profiles of healthy individuals and those of patients. Consequently, circulating miRNAs are likely to become a novel class of noninvasive and sensitive biomarkers. Although little is known about the origin and functions of circulating miRNAs at present, their roles in the clinical diagnosis and prognosis of diseases make them attractive markers, particularly for tumors and cardiovascular diseases. Until now, however, there have been limited data regarding the roles of circulating miRNAs in central nervous system (CNS) diseases. This review focuses on the characteristics of circulating miRNAs and their values as potential biomarkers in CNS diseases, particularly in Alzheimer's disease, Huntington's disease, multiple sclerosis, schizophrenia, and bipolar disorder. © 2013 Springer Science+Business Media New York.


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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