State Key Laboratory of Toxicology and Medical Countermeasures

Beijing, China

State Key Laboratory of Toxicology and Medical Countermeasures

Beijing, China
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Liu Y.,Chinese Institute of Basic Medical Sciences | Liu Y.,State Key Laboratory of Toxicology and Medical Countermeasures | Mu R.,Peking University | Gao Y.-P.,Chinese Institute of Basic Medical Sciences | And 16 more authors.
Cell Host and Microbe | Year: 2016

Human cytomegalovirus (hCMV), a ubiquitous beta-herpesvirus, has been associated with several autoimmune diseases. However, the direct role of hCMV in inducing autoimmune disorders remains unclear. Here we report the identification of an autoantibody that recognizes a group of peptides with a conserved motif matching the Pp150 protein of hCMV (anti-Pp150) and is shared among patients with various autoimmune diseases. Anti-Pp150 also recognizes the single-pass membrane protein CIP2A and induces the death of CD56bright NK cells, a natural killer cell subset whose expansion is correlated with autoimmune disease. Consistent with this finding, the percentage of circulating CD56bright NK cells is reduced in patients with several autoimmune diseases and negatively correlates with anti-Pp150 concentration. CD56bright NK cell death occurs via both antibody- and complement-dependent cytotoxicity. Our findings reveal that a shared hCMV-induced autoantibody is involved in the decrease of CD56bright NK cells and may thus contribute to the onset of autoimmune disorders. © 2016 Elsevier Inc.

Xing C.,Chinese Institute of Basic Medical Sciences | Ma N.,Chinese Institute of Basic Medical Sciences | Ma N.,Jilin University | Xiao H.,Chinese Institute of Basic Medical Sciences | And 11 more authors.
Journal of Leukocyte Biology | Year: 2015

This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19+CD5+CD1dhigh B cell subset that may play a critical role in the maintenance of immune homeostasis. Indeed, this population was identified in the murine thymus, and furthermore, when cocultured with CD4+T cells, this population of B cells supported the maintenance of CD4+Foxp3+Tregsin vitro, in part, via the CD5–CD72 interaction. Mice homozygous for Cd19Cre(CD19–/–) express B cells with impaired signaling and humoral responses. Strikingly, CD19–/–mice produce fewer CD4+Foxp3+Tregsand a greater percentage of CD4+CD8–and CD4–CD8+T cells. Consistent with these results, transfer of thymic CD19+CD5+CD1dhiB cells into CD19–/–mice resulted in significantly up-regulated numbers of CD4+Foxp3+Tregswith a concomitant reduction in CD4+CD8–and CD4–CD8+T cell populations in the thymus, spleen, and LNs but not in theBMof recipient mice. In addition, thymic CD19+CD5+CD1dhi B cells significantly suppressed autoimmune responses in lupus-likemice via up-regulation of CD4+Foxp3+ Tregsand IL-10-producing Bregs. This study suggests that thymic CD19+CD5+CD1dhiIL-10+Bregsplay a critical role in the maintenance of immune homeostasis. © Society for Leukocyte Biology.

Jiang X.,Chinese Institute of Basic Medical Sciences | Jiang X.,State Key laboratory of Toxicology and Medical Countermeasures | Jiang X.,Beijing Institute of Transfusion Medicine | Yu J.,Henan University | And 15 more authors.
Clinical Immunology | Year: 2015

Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy. © 2015 Elsevier Inc.

Ning C.,Chinese Institute of Basic Medical Sciences | Ning C.,State Key Laboratory of Toxicology and Medical Countermeasures | Li Y.-Y.,Henan University | Wang Y.,Chinese Institute of Basic Medical Sciences | And 19 more authors.
Mucosal Immunology | Year: 2015

Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1β levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1β promoted colon carcinogenesis by eliciting IL-17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1β in neutrophil, accounting for downregulation of IL-1β levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation-related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic.

Xu Y.,Beijing Institute of Pharmacology and Toxicology | Xu Y.,State Key Laboratory of Toxicology and Medical Countermeasures | Cheng X.,Beijing Institute of Pharmacology and Toxicology | Cheng X.,State Key Laboratory of Toxicology and Medical Countermeasures | And 15 more authors.
Neurobiology of Learning and Memory | Year: 2015

Stress induces cognitive impairments, which are likely related to the damaged dendritic morphology in the brain. Treatments for stress-induced impairments remain limited because the molecules and pathways underlying these impairments are unknown. Therefore, the aim of this study was to find the potential molecules and pathways related to damage of the dendritic morphology induced by stress. To do this, we detected gene expression, constructed a protein-protein interaction (PPI) network, and analyzed the molecular pathways in the brains of mice exposed to 5-h multimodal stress. The results showed that stress increased plasma corticosterone concentration, decreased cognitive function, damaged dendritic morphologies, and altered APBB1, CLSTN1, KCNA4, NOTCH3, PLAU, RPS6KA1, SYP, TGFB1, KCNA1, NTRK3, and SNCA expression in the brains of mice. Further analyses found that the abnormal expressions of CLSTN1, PLAU, NOTCH3, and TGFB1 induced by stress were related to alterations in the dendritic morphology. These four genes demonstrated interactions with 55 other genes, and configured a closed PPI network. Molecular pathway analysis use the Database for Annotation, Visualization, and Integrated Discovery (DAVID), specifically the gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG), each identified three pathways that were significantly enriched in the gene list of the PPI network, with genes belonging to the Notch and transforming growth factor-beta (TGF-B) signaling pathways being the most enriched. Our results suggest that TGFB1, PLAU, NOTCH3, and CLSTN1 may be related to the alterations in dendritic morphology induced by stress, and imply that the Notch and TGF-B signaling pathways may be involved. © 2015 Elsevier Inc.

Cheng X.-R.,Beijing Institute of Pharmacology and Toxicology | Cheng X.-R.,State Key Laboratory of Toxicology and Medical Countermeasures | Cui X.-L.,Beijing Institute of Radiation Medicine | Zheng Y.,Beijing Institute of Pharmacology and Toxicology | And 14 more authors.
Current Alzheimer Research | Year: 2015

There are currently no approved effective therapies for Alzheimer’s disease (AD). AD is a classic, multifactorial, complex syndrome. Thus, a polypharmacological or multitargeted approach to AD might provide better therapeutic benefits than monotherapies. However, it remains elusive which biological processes and biomolecules involved in the pathophysiologic processes of AD would constitute good targets for multitargeted therapy. This study proposes that a co-module, consisting of biological processes, cellular pathways and nodes, in a molecular subnetwork perturbed by different therapeutic drugs may be the optimal therapeutic target for an AD multitarget-based intervention. Based on this hypothesis, genes regulated in the hippocampus and cortex of senescence-accelerated mouse prone-8 (SAMP8) mice by traditional Chinese medicine (TCM) prescriptions with different constituents and the same beneficial effects on AD, including the decoctions Liu-Wei-Di-Huang (LW), Ba-Wei-Di-Huang (BW), Danggui-Shaoyao-San (DSS), Huang-Lian-Jie-Du (HL) and Tiao-Xin-Fang (TXF), were investigated via cDNA microarray, and the perturbed subnetworks were constructed and interpreted. After comparing 15 perturbed subnetworks based on genes affected byLW, BW, HL, DSS and TXF, the results showed that the most important common nodes perturbed by these interventions in the brains of SAMP8 mice were RPS6KA1 and FHIT, and that other important common nodes included UBE2D2, STUB1 and AMFR. These five drugs simultaneously and significantly disturbed the regulation of apoptosis and protein ubiquitination among biological processes. These nodes and processes were key components of the co-module regulated by therapeutic drugs in a molecular subnetwork of AD. These results suggest that targeting candidate regulator of apoptosis and protein ubiquitination might be effective for AD treatment, and that RPS6KA1, FHIT, UBE2D2, STUB1 and AMFR might be optimal combinational targets of an AD multitarget-based therapy. ©2015 Bentham Science Publishers.

Shen G.,Beijing Institute of Pharmacology and Toxicology | Zhuang X.,Beijing Institute of Pharmacology and Toxicology | Zhuang X.,State Key Laboratory of Toxicology and Medical Countermeasures | Xiao W.,Beijing Institute of Pharmacology and Toxicology | And 6 more authors.
Food and Chemical Toxicology | Year: 2014

Triptolide (TP) is an active component of Tripterygium wilfordii Hook. F and widely used to treat autoimmune and inflammatory diseases. It has been demonstrated that cytochrome P450 (CYP) are involved in the metabolism of TP. However, the underlying mechanisms of TP-induced toxicity mediated by hepatic CYP have not been well delineated. In this study, rat liver microsomes (RLM) and sandwich-cultured rat hepatocytes (SCRH) were used to identify the mechanism involving the CYP3A inhibition by TP and to evaluate TP-induced liver damage after CYP3A modulation by the known inhibitor, ketoconazole, and the known inducer, dexamethasone. The results showed that TP itself had a time- and concentration-dependent inhibitory effect on CYP3A. When the CYP3A inhibitor and inducer were added, the enzyme activity and hepatotoxicity changed significantly. The enzyme inducer increased CYP3A activity and decreased the metabolic half life (t1/2) of TP when compared to the control group, while the enzyme inhibitor had an opposite effect. Our findings reveal that TP is a weak CYP3A inhibitor involving the time-dependent inhibition mechanism. The induction or inhibition of CYP3A played an important role in TP-induced hepatotoxicity. Clinicians should be aware of the metabolic characteristics of TP to maximize therapeutic efficacy and reduce TP-induced toxicity. © 2014 Elsevier Ltd.

Zhuang X.-M.,Beijing Institute of Pharmacology and Toxicology | Zhuang X.-M.,State Key Laboratory of Toxicology and Medical Countermeasures | Wei X.,Beijing Institute of Pharmacology and Toxicology | Wei X.,State Key Laboratory of Toxicology and Medical Countermeasures | And 11 more authors.
Toxicological Sciences | Year: 2014

Organophosphorus pesticides are the most widely used pesticides in modern agricultural systems to ensure good harvests. Isocarbophos (ICP), with a potent acetylcholinesterase inhibitory effect is widely utilized to control a variety of leaf-eating and soil insects. However, the characteristics of the bioactivation and detoxification of ICP in humans remain unclear. In this study, the oxidative metabolism, esterase hydrolysis, and chiral inversion of ICP in human liver microsomes (HLMs) were investigated with the aid of a stereoselective LC/MS/MS method. The depletion of ICP in HLMs was faster in the absence of carboxylesterase inhibitor (BNPP) than in the presence of NADPH and BNPP, with t1/2 of 5.2 and 90 min, respectively. Carboxylesterase was found to be responsible for the hydrolysis of ICP, the major metabolic pathway. CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19 were all involved in the secondary metabolism pathway of desulfuration of ICP. Flavin-containing monooxygenase (FMO) did not contribute to the clearance of ICP. The hydrolysis and desulfuration of (±)ICP, (+)ICP, and (-)ICP in HLMs follow Michaelis-Menten kinetics. Individual enantiomers of ICP and its oxidative desulfuration metabolite isocarbophos oxon (ICPO) were found to be inhibitors of acetylcholinesterases at different extents. For example, (±)ICPO is more potent than ICP (IC50 0.031μM vs. 192μM), whereas (+)ICPO is more potent than (-)ICPO (IC50 0.017μM vs. 1.55μM). Given the finding of rapid hydrolysis of ICP and low abundance of oxidative metabolites presence in human liver, the current study highlights that human liver has a greater capacity for detoxification of ICP. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Wang J.,Beijing Institute of Pharmacology and Toxicology | Wang J.,State Key Laboratory of Toxicology and Medical Countermeasures | Cheng X.,Beijing Institute of Pharmacology and Toxicology | Cheng X.,State Key Laboratory of Toxicology and Medical Countermeasures | And 12 more authors.
Oncotarget | Year: 2016

Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12-and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA-and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1β, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-β, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.

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