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中国药理学与毒理学杂志 2023年第7期37卷 551-551页

作者： SHI Tianyao FU Yuan LI Fengan XIAO Zhiyong ZHOU Wenxia State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Nanjing University of Chinese Medicine

OBJECTIVE Human beings possess the ability to indirectly acquire the emotions of others. This also known as emotional contagion or empathy, enables us to rapidly perceive the emotions of others. However,an excessive empathy may result in heightened fear and sensitivity to pain. Therefore, the establishment of appropriate animal models for analyzing neural mechanisms underlying empathy would contribute to pharmacological research on pain sensitivity caused by psychological susceptibility. METHODS We used the observed fear paradigm for assessing contagion of negative emotions in mice. To minimize the impact of emotional contagion differences caused by the subject change, we established a bilateral observation area and the two mice were trained to observe fear simultaneously. First, two observer(OB)mice were placed on either side of the observational area.Next, a demonstrator(DM) mouse was introduced into the cylindrical shock cage located at the center of the apparatus. The shock cage is made of transparent organic plastic with air holes and has provided ample space for free movement by the DM mouse. During the shock stage, DM mice were subjected to electric stimulation while the behaviors of OB mice on both sides was observed, including freezing, the side and corner time,social interaction behavior. Additionally, c-Fos staining was utilized to confirm distinct local brain activities.RESULTS In the habituation stage, OB mice on both sides showed more social preference for DM mouse, as evidenced by an increase in duration time in the designated interaction zone. During the shock phase, OB mice observed the DM mouse receiving electric shocks and displayed significantly higher levels of fear contagion;however, their fear behavior was not entirely consistent.Some mice exhibited a significant increase in freezing time, while others demonstrated a significant increase in corner and side exploration time. We utilized Z-normalization to evaluate changes in emotionality across various behaviors and identified mice with dist

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Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

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药学学报:英文版 2023年第6期13卷 2715-2735页

作者： Pengyun Li Changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu Shiyang Sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li National Engineering Research Center for Strategic Drugs Beijing Institute of Pharmacology and Toxicology InstitutionBeijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China National Center for Protein Sciences(Beijing) Beijing Institute of LifeomicsState Key Laboratory of ProteomicsBeijing Proteome Research CenterBeijing 102206China Beijing key laboratory for Radiobiology Beijing Institute of Radiation MedicineBeijing 100850China

Various c-mesenchymal-to-epithelial transition(c-MET) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras(PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC_(50) values and achieved picomolar DC_(50) values and>99% of maximum degradation(D_(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion.Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^(Y1230H) and c-MET^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

关键词： Cancer therapy Drug design c-MET Proteolysis targeting chimeras(PROTACs) Drug resistance

Manufacturing MMB4 DMS Nanoparticle Suspension with Enhanced Formulation and Stability

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Manufacturing MMB4 DMS Nanoparticle Suspension with Enhanced...

Cannabinoid CB1 receptors are expressed in a subset of dopamine neurons and underlie cannabinoid modulation of DA release and DA-related behavior in mice

2018年第十二届中国药物制剂大会

作者：张洵 Aiping Zheng State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

＜正＞Object 1,1’-Methylenebis-4-[（hydroxyimino）methyl]pyridinium dimethanesulfonate（MMB4 DMS）is currently under development for the treatment of organophosphorus poisoning.It is more stable than other bis-pyridinium oximes.However,due to the hydrolytic cleavage,it will degrade quickly in aqueous solution at around 40℃.As a result,it is essential to develop a non-aqueous suspension of MMB4 DMS nanoparticle

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中国药理学与毒理学杂志 2023年第7期37卷 535-536页

作者： HAN Xiao WU Ning XI Zhengxiong LI Jin Beijing key laboratory of Neuropsychopharmacology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Addiction Biology Unit Molecular Targets and Medications Discovery Branch Intramural Research Program National Institute on Drug Abuse

OBJECTIVE Cannabinoids modulate dopamine(DA) transmission and DA-related behavior,which has been thought to be mediated initially by activation of cannabinoid CB1 receptors(CB1Rs) on GABA neurons. However, the cellular and receptor mechanisms underlying cannabinoids′ psychoactive effects are not fully understood. The present study is to explore the possible expression character of CB1Rs and elucidated the underlying mechanism of them. METHODS We took advantage of RNAscope in situ hybridization(ISH)assays and triple-staining assays to detect the CB1Rexpressing neurons. We established an optical intracranial self-stimulation(OICSS) behavioral model by using optogenetics to study dopaminergic reinforcement function.Natural and synthetic cannabinoids were used to study the function of CB1Rs. Conditional genetic depletion of CB1Rs and behavioral assay were performed to study the modulatory role of CB1Rs in DA-related behaviors.RESULTS We found that CB1Rs are also expressed in a subset of DA neurons and functionally underlie cannabinoid action in male and female mice. ISH assays demonstrated CB1 mRNA in tyrosine hydroxylase(TH)-positive DA neurons in the ventral tegmental area(VTA) and glutamate decarboxylase 1(GAD1)-positive GABA neurons. The CB1R expressing DA neurons were located mainly in the middle portion of the VTA with the number of CB1-TH colocalization progressively decreasing from the medial to the lateral VTA. Triple-staining assays indicated CB1R mRNA colocalization with both TH and vesicular glutamate transporter 2(VgluT2, a glutamate neuronal marker) in the medial VTA close to the midline of the brain. Optogenetic activation of this population of DA neurons was rewarding as assessed by OICSS.D9-tetrahydrocannabinol(D9-THC) or ACEA(a selective CB1R agonist) dose-dependently inhibited optical intracranial self-stimulation in DAT-Cre control mice, but not in conditional knockout mice with the CB1R gene absent in DA neurons. In addition, deletion of CB1Rs from DA neurons attenuated D9-THC-induced reduction i

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Involvement of VGLUT2 in Neuropathic Pain and Its Regulation by Wnt1/β-Catenin Signaling

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神经药理学报 2019年第Z1期 52-53页

作者： YU Gang SU Rui-bin State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of NeuropsychopharmacologyBeijing Institute of Pharmacology and Toxicology

Backgrounds:Vesicular glutamate transporters(VGLUTs),which transport glutamate into presynaptic vesicles selectively,are fundamental in glutamate storage and release. The distribution of VGLUT2 isoform in CNS suggests a possible involvement of VGLUT2 in pain signaling. Objective:The present study was aimed to investigate the involvement of VGLUT2 in neuropathic pain and to elucidate the regulatory mechanism of VGLUT2,in a mouse spared nerve injury(SNI) model. Methods:The temporal changes in VGLUT2 expression were determined by western blot and immunohistochemistry in the spinal cord and pain-related brain regions of SNI mice. The cell distribution characteristics of VGLUT2 in the pathological condition were observed by immunofluorescent staining. Then,we regulated the expression and function of VGLUT2 by shRNA interference and VGLUT inhibitors respectively,and the behavioral consequences were observed. We also investigated the effects of VGLUT2 down-regulation or inhibition on glutamate release. Finally,the effects of Wnt/β-catenin signaling on VGLUT2 expression and pain behavior were investigated by using Wnt agonist,Wnt1,and Wnt/β-catenin pathway inhibitor XAV939 in SNI mice. Results:SNI surgery induced significant up-regulation of VGLUT2 in the spinal cord and supraspinal regions. In SNI mice,VGLUT2 is mainly co-locolized with NeuN and MAP2,but not Iba-1 and GFAP. Intrathecal or intracerebral administration of VGLUT2 shRNAs or CSB6 B significantly attenuated mechanical allodynia and decreased glutamate release. Meanwhile,Wnt1/β-catenin signaling was also activated in SNI mice. Wnt agonist or Wnt1 significantly increased VGLUT2 expression,while Wnt/β-catenin pathway inhibitor XAV939 decreased VGLUT2 expression. Additionally,XAV939 attenuated mechanical allodynia in mice,and this effect was in accordance with down-regulation of VGLUT2 protein levels. VGLUT2 shRNAs significantly attenuated mechanical allodynia induced by Wnt agonist or Wnt1. Conclusion:The changes in VGLUT2 expression and function are involved in

关键词： VGLUT2 neuropathic pain RNA interference Glutamate release Wnt1 β-catenin

S4A-5 Screening ofμOpioid Receptor-Interacting Proteins and Effects of ABIN-1 on Receptor Function

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神经药理学报 2018年第4期8卷 67-69页

作者： ZHOU Pei-lan JIANG Jie-bing YAN Hui LI Yu-lei ZHAO Jun-ru WANG Xiao GONG Ze-hui SU Rui-bin State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of NeuropsychopharmacologyBeijing Institute of Pharmacology and ToxicologyBeijingChina

Aim:To determine the proteins that interact with the carboxyl-terminal of theμopioid receptor(MOR-C)after chronic morphine exposure.Methods:The brain cDNA library of chronic morphine treatment rats was screened using rat MOR-C to investigate the regulator of opioids dependence in the present study.The brain cDNA library from chronic morphine-dependent rats was constructed using the SMART(Switching Mechanism At 5′end of RNA Transcript)technique.Bacterial two-hybrid system was used to screening the rat MOR-C interacting proteins from the cDNA library.RT-qPCR and immunoblotting were used to determine the variation of MOR-C interacting proteins in rat brain after chronic morphine treatment.Column overlay assays,immunocytochemistry and coimmunoprecipitation were used to demonstrate the interaction of MOR-C and p75NTR-associated cell death executor(NADE)or A20-binding inhibitor of nuclear factor kB(ABIN-1).Results:21 positive proteins,including 19 known proteins were screened to interact with rat MOR-C.Expression of several of these proteins was altered in specific rat brain regions after chronic morphine treatment.Among these proteins,ABIN-1 and NADE were confirmed to interact with rat MOR-C by in vitro proteinprotein binding and coimmunoprecipitation in Chinese hamster ovary(CHO)cells and rat brain with or without chronic morphine treatment.Saturation binding studies showed that ABIN-1 had no effect on MOR binding.However,the interaction of ABIN-1 and MOR inhibited the activation of G proteins induced by DAMGO([D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin).MOR phosphorylation,ubiquitination,and internalization induced by DAMGO were decreased in Chinese hamster ovary cells that coexpressed MOR and ABIN-1.The suppression of forskolinstimulated adenylylcyclase by DAMGO was also inhibited by the interaction of ABIN-1with MOR.In addition,extracellular signal-regulated kinase activation was also negatively regulated by overexpression of ABIN-1.These data suggest that ABIN-1 is a negative coregulator of MOR activation,phosphorylati

关键词： Effects treatment Switching after overlay cDNA was MOR

Comparison between cannabidiol and sertra⁃line in modulation of post-traumatic stress dis⁃order-like behaviors and fear memory in mice

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中国药理学与毒理学杂志 2021年第9期35卷 680-681页

作者： HAN Xiao SONG Xian-kui SONG Da-ke XIE Guan-bo GUO Hong-yan WU Ning LI Jin Beijing key laboratory of Neuropsychopharma-cology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Institute of Pharmacology and ToxicologyBeijing 100850China Shanxi medical University School and Hospital of Stomatology Taiyuan 030001China

OBJECTIVE Post-traumatic stress disorder(PTSD)is characterized by poor adapta⁃tion to a traumatic experience and disturbances in fear memory regulation,and currently lacks effective medication.Cannabidiol(CBD)is the primary component of the Cannabis sativa plant;it does not have any psychoactive effects and has been implicated in modulating fear learning in mammals.The present study investigated the effect of CBD on PTSD-like behaviors in a mouse pre-shock model,the effect of CBD in the modulation of trauma-related fear memory,a crucial process leading to core symptoms of PTSD.METHODS Pre-shock model was applied in which mice were submitted to training with two days of 0.8 mA×12 times of foot-shock,and PTSD-like behaviors was evaluated during 3 and 26 d,including freezing time to the conditioned context,open field test,elevated plus maze test and social interaction test.RESULTS CBD(10 mg·kg^(-1))administration alleviated main PTSD-like symptoms in the mouse pre-shock model by attenuating trauma-related fear memory,decreasing anxiety-like behavior,and increasing social interaction behavior.However,sertraline(15 mg·kg^(-1))was only effective when adminis⁃tered throughout the test period.Furthermore,CBD reduced the formation,retrieval,and recon⁃solidation of trauma-related fear memory,whereas sertraline only reduced fear-memory retrieval.Neither CBD nor sertraline influenced the acquisi⁃tion of trauma-related fear memory.CONCLU⁃SION CBD produced anti-PTSD-like actions in mice,and could disrupt trauma-related fear mem⁃ory by interfering with multiple aspects of fear memory processing in mice.These findings indi⁃cate that CBD may be a promising candidate for treating PTSD.

关键词： post-traumatic stress disorder can⁃nabidiol sertraline trauma-related fear memory processing endocannabinoid system

LW-AFC,a new traditional Chinese medicine formula,shows promising therapeutic effects on Alzheimer disease

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中国药理学与毒理学杂志 2017年第5期31卷 460-460页

作者： ZHOU Wen-xia WANG Jian-hui CHENG Bing HUANG Yan CHENG Xiao-rui ZHANG Yong-xiang Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical Countermeasures

Alzheimer disease(AD) is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy. Liuwei Dihuang decoction(LW),a classical traditional Chinese medicine(TCM) formula,has long been used to treat various diseases,including dementia. A large number of pharmacological studies have showed that LW has beneficial effects on AD. LW-AFC is a new formula consisted of the main active components prepared fromLW.In this study,we found that administration of LW-AFC significantly improved behavioral performances in spontaneous locomotor activity,object recognition memory,spatial learning and memory,passive and active avoidance impairment in some AD mouse models,such as SAMP8 and APP/PS1 transgenic mice. Meanwhile,the impairments of long-term potentiation(LTP) were significantly ameliorated by LW-AFC administration in SAMP8 mice,as well as in corticosterone-induced LTP inhibition mice model.These effects were companied by alleviating of the neuron loss in the hippocampus,suppressing of A-beta deposition in the brain,and reducing of the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice. The restoring and correcting of imbalance of hypothalamic-pituitary-adrenal(HPA) and hypothalamic-pituitary-gonadal(HPG) axis,the disorder of lymphocyte subsets,the abnormality of production of cytokine were also observed in LW-AFC treated SAMP8 and APP/PS1 mice.These findings indicated that LW-AFC ameliorated the behavioral and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way,suggesting that LW-AFC might bea promising therapy for AD.

关键词： Alzheimer disease Liuwei Dihuang decoction hypothalamic-pituitary-adrenal axis

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

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Journal of medical Colleges of PLA(China) 2015年第1期30卷 21-27页

作者： Ni-ni Lin Jia Chen Bin Xu Xia Wei Lei Guo Jian-wei Xie State Key Laboratory of Toxicology and Medical Countermeasures and Laboratory of Toxicant Analysis Institute of Pharmacology and ToxicologyAcademy of Military Medical Sciences

Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.

关键词： T-2 toxin Cytochrome P450 Carboxylesterase Metabolism Human liver microsomes