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Chinese Chemical Letters 2022年第5期33卷 2625-2629页

作者： Ying Yang Fangsheng Tao Lijuan Zhang Yunshan Zhou Yuxu Zhong Shubo Tian Yong’an Wang state key laboratory of Chemical Resource Engineering Institute of ChemistryBeijing University of Chemical TechnologyBeijing100029 China toxicology and medical countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing100850China

By combining 5,10,15,20-tetra(4-chlorine)phenylporphyrin(TClPP)andα-Keggin polyoxometalate H_(5)PV_(2)Mo_(10)O_(40)(H 5 PVMo)via a simple ion-exchange method,an organic-inorganic hybrid material[C_(44)H_(28)N_(4)Cl_(4)]_(1.5)[H_(2)PMo_(10)V_(2)O_(40)]·2C_(2)H_(6)O(H_(2 )TClPP-H_(2) PVMo)was prepared and thoroughly characterized by a variety of techniques.The homogeneous photocatalytic degradation of 2-chloroethyl ethyl sulfide(CEES)(5μL)by H_(2) TClPP-H_(2) PVMo(1×10^(−6)mol/L)was studied in methanol and methanol-water mixed solvent(v/v=1:1),in which the degradation rate of CEES reached 99.52%and 99.14%,respectively.The reaction followed first-order reaction kinetics,and the half-life and kinetic constant in methanol and the mixed solvent were respectively 33.0min,−0.021 min−1 and 15.7min,−0.043 min−1.Mechanism analysis indicated that under visible light irradiation in the air,CEES was degraded via oxidation and alcoholysis/hydrolysis in methanol and the mixed solvent.O_(2)·−and ^(1)O_(2) generated by H_(2) TClPP-H_(2) PVMo selectively oxidized CEES into a nontoxic sulfoxide.Singlet oxygen capture experiments showed that H_(2) TClPP-H_(2) PVMo(φ=0.73)had a higher quantum yield of singlet oxygen than TClPP(φ=0.35)under an air atmosphere and visible light irradiation.

关键词： Chemical warfare agent Mustard gas simulant Porphyrin Polyoxometalate Photooxidation

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

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Neural Regeneration Research 2024年第3期19卷 629-635页

作者： Jingzhou Liu Xin Xin Jiejie Sun Yueyue Fan Xun Zhou Wei Gong Meiyan Yang Zhiping Li Yuli Wang Yang Yang Chunsheng Gao State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijingChina Academy of medical Engineering and Translational Medicine Medical CollegeTianjin UniversityTianjinChina

Traumatic brain injury results in neuronal loss and glial scar formation.Replenishing neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain injury.Neuronal reprogramming is a promising strategy to convert glial scars to neural tissue.However,previous studies have reported inconsistent results.In this study,an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target effects.The results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive astrocytes.Moreover,neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain injury.In summary,this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

关键词： AAV9P1 astrocytes astrocyte-to-neuron conversion GFAP promoter glial scar induced neurons neuronal reprogramming P1 peptide PTBP1 traumatic brain injury

Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma

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Bioactive Materials 2021年第12期6卷 4402-4414页

作者： Yueyue Fan Yuexin Cui Wenyan Hao Mengyu Chen Qianqian Liu Yuli Wang Meiyan Yang Zhiping Li Wei Gong Shiyong Song Yang Yang Chunsheng Gao College of Pharmacy Henan UniversityKaifeng475000PR China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing100850PR China

Nanosuspensions,as a new drug delivery system for insoluble drugs,are only composed of a drug and a small amount of stabilizer,which is dispersed in an aqueous solution with high drug-loading,small particle size,high dispersion,and large specific surface area.It can significantly improve the dissolution,bioavailability,and efficacy of insoluble drugs.In this study,paclitaxel nanosuspensions((PTX)NS)were prepared by an ultrasonic precipitation method,with the characteristics of simple preparation and easy repetition.With the help of a homologous targeting mechanism,a kind of glioma C6 cancer cell membrane(CCM)-coated(PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting.The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier(BBB)and selectively target tumor tissues.Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased.Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice.Finally,the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape.This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.

关键词： Nanosuspensions Cancer cell membrane Biomimetic drug-delivery systems Gliomas Blood-brain barrier Paclitaxel

Protection against respiratory depression by novel allosteric AMPA receptor modulator

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中国药理学与毒理学杂志 2018年第9期32卷 735-736页

作者： DAI Wei GAO Xiang LI Yu-lei YONG Zheng SU Rui-bin State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

OBJECTIVE Respiratory depression hinders the use of anaesthetics and sedative hypnotics.For emergency use,specific antagonists are currently administered to counteract respiratory depression.However,antagonists are often short-lasting and can have multiple unexpected side effects.A novel AMPA receptor modulator LCX001,synthesized by our Institute of Medicinal Chemistry,is expected to relieve suppressed respiration.To explore the mechanism and impact of LCX001 on protection against respiratory depression.METHODS LCX001 was tested to alleviate respiratory depression triggered by opioid,propofol and pentobarbital in the plethysmography recording.The acetic acid writhing and hot-plate tests were conducted to evaluate potential analgesic effect of LCX001.Binding assay and whole-cell recording were used to analyze the property of LCX001 on positive modulation.The function of AMPA receptors were determined by location of receptors inthe membrane and state of channel opening,and both processes were impressed by AMPA receptor regulatory proteins.According to the theory,the effect of LCX001 on the expression of stargazin was measured firstly by Western blotting.The variation of receptor surface location were observed by live cell imaging.The regulation on neuronal Ca2+and cell function was investigated intensively by Ca2+imaging to clarify mechanism of LCX001.RESULTS LCX001 effectively rescued and prevented opioid(fentanyl and TH-030418),propofol,and pentobarbitalinduced respiratory depression by strengthening respiratory frequency and minute ventilation by 30%-50% in rats.The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001 on increasing the inhibition rate and %MPE to 80% and 65% respectively,in contrast to some ampakines that did not affect analgesia.Furthermore,LCX001 potentiated[3 H]AMPA and L-glutamate binding affinity to AMPA receptors,and facilitated glutamateevoked inward currents in HEK293 cells stably expressing GluA2(R).At 10 mmol·L^(-1) glutamate evoked amplitude

关键词： respiratory depression glutamate AMPA receptor modulator

Salvianolic acid A attenuates ischemia reperfusion induced rat brain damage by protecting the blood brain barrier through MMP-9 inhibition and anti-inflammation

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Chinese Journal of Natural Medicines 2018年第3期16卷 184-193页

作者： ZHANG Wen SONG Jun-Ke ZHANG Xue ZHOU Qi-Meng HE Guo-Rong XU Xiao-Na Yan Rong ZHOU Wen-Xia DU Guan-Hua Beijing key laboratory of Drug Target Identification and Drug Screening Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Department of Neuroimmunopharmacology Beijing Institute of Pharmacology and Toxicology State Key Laboratory of Toxicology and Medical Countermeasures

Salvianolic acid A(SAA) is a water-soluble component from the root of Salvia Miltiorrhiza Bge, a traditional Chinese medicine, which has been used for the treatment of cerebrovascular diseases for centuries. The present study aimed to determine the brain protective effects of SAA against cerebral ischemia reperfusion injury in rats, and to figure out whether SAA could protect the blood brain barrier(BBB) through matrix metallopeptidase 9(MMP-9) inhibition. A focal cerebral ischemia reperfusion model was induced by middle cerebral artery occlusion(MCAO) for 1.5-h followed by 24-h reperfusion. SAA was administered intravenously at doses of 5, 10, and 20 mg?kg–1. SAA significantly reduced the infarct volumes and neurological deficit scores. Immunohistochemical analyses showed that SAA treatments could also improve the morphology of neurons in hippocampus CA1 and CA3 regions and increase the number of neurons. Western blotting analyses showed that SAA downregulated the levels of MMP-9 and upregulated the levels of tissue inhibitor of metalloproteinase 1(TIMP-1) to attenuate BBB injury. SAA treatment significantly prevented MMP-9-induced degradation of ZO-1, claudin-5 and occludin proteins. SAA also prevented cerebral NF-κB p65 activation and reduced inflammation response. Our results suggested that SAA could be a promising agent to attenuate cerebral ischemia reperfusion injury through MMP-9 inhibition and anti-inflammation activities.

关键词： Salvianolic 酸 A 局部缺血 MCAO 血大脑障碍 NF-B MMP-9

Novel small molecule retrograde transport blocker confers post-exposure protection against ricin intoxication

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Acta Pharmaceutica Sinica B 2020年第3期10卷 498-511页

作者： Xu Zhao Haixia Li Jia Li Kunlu Liu Bo Wang Yuxia Wang Xingzhou Li Wu Zhong National Engineering Research Center for the Emergency Drug Beijing Institute of Pharmacology and ToxicologyBeijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

Ricin is a highly toxic type 2 ribosome-inactivating protein(RIP)which is extracted from the seeds of castor beans.Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far.In this study,by structural modification of a retrograde transport blocker Retro-2cyc1,a series of novel compounds were obtained.The primary screen revealed that compound 27 has an improved antiricin activity compare to positive control.In vitro pre-exposure evaluation in Madin-Darby Canine Kidney(MDCK)cells demonstrated that 27 is a powerful anti-ricin compound with an EC50 of 41.05 nmol/L against one LC(lethal concentration,5.56 ng/mL)of ricin.Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication.An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice.A drug combination of 27 with monoclonal antibody mAb4 C13 rescued mice from one LD(lethal dose)ricin challenge and the survival rate of tested animals is 100%.These results represent,for the first time,indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines.

关键词： Ricin toxin Ribosome-inactivating proteins Retrograde transport Post-exposure antidote Ricin antibody

Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity

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Chinese medical Journal 2023年第24期136卷 2983-2992页

作者： Yingjie Du Yunfeng Li Xiangting Zhao Yishan Yao Bin Wang Liming Zhang Guyan Wang Department of Anesthesiology Beijing Tongren HospitalCapital Medical UniversityBeijing 100730China Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical CountermeasuresBeijing Key Laboratory of NeuropsychopharmacologyBeijing 100850China Beijing Institute of Basic medical Sciences Beijing 100850China key laboratory of Microecology-Immune Regulatory Network and Related Diseases Basic medical College of Jiamusi University JiamusiHeilongjiang 154000China

Background:Posttraumatic stress disorder(PTSD)and depression are highly comorbid.Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity.Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD.We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.Methods:First,we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning(FC)and fear extinction paradigm in mice.Psilocybin was administered 30 min before extinction training.Fear extinction testing was performed on the first day;fear extinction retrieval and fear renewal were tested on the sixth and seventh days,respectively.Furthermore,we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density,Western blotting for the protein levels of brain derived neurotrophic factor(BDNF)and mechanistic target of rapamycin(mTOR),and immunofluorescence staining for the numbers of doublecortin(DCX)-and bromodeoxyuridine(BrdU)-positive cells.Results:A single dose of psilocybin(2.5 mg/kg,i.p.)reduced the increase in the percentage of freezing time induced by FC at 24 h,6th day and 7th day after administration.In terms of structural neuroplasticity,psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC;in terms of neuroplasticity related proteins,psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC;in terms of neurogenesis,psilocybin rescued the decrease in the numbers of DCX-and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.Conclusions:A single dose of psilocybin facilitated rapid and sustained fear extinction;this effect might be partially mediated by the promotion of hippocampal neuroplasticity.This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characte

关键词： Brain-derived neurotrophic factor Bromodeoxyuridine Depression Doublecortin domain proteins Extinction,psychological Freezing Hippocampus Neuronal plasticity Psilocybin Stress disorders,post-traumatic

Mechanism and impact of a novel allosteric AMPA receptor modulator on protection against respiratory depression

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中国药理学与毒理学杂志 2018年第4期32卷 276-277页

作者： Wei DAI Xiang GAO Yu-lei LI Zheng YONG Rui-bin SU State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

OBJECTIVE Respiratory depression hinders the use of anaesthetics and sedative hyp.notics.To explore the mechanism of LCX001 on protection against respiratory depression,a novel AMPA receptor modulator LCX001,synthesized by our Institute of Medicinal Chemistry,is expected to relieve suppressed respiration.METHODS LCX001 was tested to alleviate respiratory depression triggered by opioid(fentanyl and TH-030418),propofol and pentobarbital in the plethysmography recording.The acetic acid writhing and hot-plate tests were conducted to evaluate analgesic effect of LCX001.Binding assay and whole-cell recording were used to analyze the property of LCX001 on positive modulation.The function of AMPA receptors were determined by location of receptors in the membrane and state of channel opening,and both processes were impressed by AMPA receptor regulatory proteins.Ac.cording to the theory,the effect of LCX001 on the expression of stargazin was measured firstly by west.ern blotting.The variation of receptor surface location was observed by live cell imaging.The regula.tion on neuronal Ca^(2+) and cell function was investigated intensively by Ca^(2+) imaging to clarify mecha.nism of LCX001.RESULTS LCX001 effectively rescued and prevented opioid(fentanyl and TH-030418),propofol,and pentobarbital-induced respiratory depression by strengthening respiratory fre.quency and minute ventilation in rats.The acetic acid writhing test and hot-plate test revealed potent anti-nociceptive efficacy of LCX001,in contrast to some ampakines that did not affect analgesia.Fur.thermore,LCX001 potentiated [3 H]AMPA and L-glutamate binding affinity to AMPA receptors,and facili.tated glutamate-evoked inward currents in HEK293 cells stably expressing GluA2(R).Importantly,appli.cation of LCX001 generated a significant increase in GluA2(R) surface expression in a mechanism of stargazin up-regulation,and restrained opioid-induced abnormal intracellular Ca^(2+) load,which might par.ticipate in breathing modulation.CONCLUSION The novel pharmacological effe

关键词：麻醉药镇静催眠药临床分析治疗方法

Supramolecular liquid barrier for sulfur mustard utilizing host-guest complexation of pillar[5]arene with triethylene oxide substituents

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Chinese Chemical Letters 2023年第4期34卷 254-257页

作者： Yahan Zhang Junyi Chen Longming Chen Liang Zhao Mengke Ma Xinbei Du Zhao Meng Han Zhang Zhibing Zheng Yongan Wang Chunju Li Qingbin Meng State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China key laboratory of Inorganic-Organic Hybrid Functional Material Chemistry Ministry of EducationTianjin Key Laboratory of Structure and Performance for Functional MoleculesCollege of ChemistryTianjin Normal UniversityTianjin 300387China

Sulfur mustard(SM) can be absorbed by skin quickly and cause serious system damage via reacting with nearly all cell constituents. Until now, there is still lack of effective antidotal therapy for SM and skin protection is highly important to defend SM. In this article, supramolecular liquid barrier based on pillar[5]arene with triethylene oxide substituents(EGP5) has been designed to impede the skin permeation of SM and further interaction with the skin tissue. EGP5 could encapsulate SM within its cavity, with a Kavalue of(5.10 ± 0.47) × 10^(2)L/mol. In vitro skin absorption test proved that EGP5 was capable to effectively prevent SM from penetrating through skin. This supramolecular liquid barrier was employed on rat models to systematically evaluate protective effect against SM intoxication. Pretreatment of EGP5could alleviate skin and system damage induced by SM and improve survival rate of poisoned rat models from 10% to 90%. Additionally, EGP5 served as protective materials could be highly reused after recycling several times. Overall, these findings have provided the first insight into the construction of convenient liquid material for SM protection.

关键词： Supramolecular barrier Host-guest complexation Liquid pillararene Sulfur mustard Skin protection

Thienorphine induces analgesia by binding κ -and δ-, or by partially binding μ-opioid receptor,thus further regulating cAMP-PKA activity

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中国药理学与毒理学杂志 2018年第9期32卷 721-722页

作者： ZHOU Pei-lan LI Yu-lei YONG Zheng SU Rui-bin GONG Ze-hui State Key Laboratory of Toxicology and Medical Countermeasures Beijing Key Laboratory of Neuropsychopharmacology Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

OBJECTIVE Thienorphine,a new oripavine derivative,has shown to possess stronger antinociceptive effects and better oral bioavailability compared to buprenorphine.The present study examines the effect of thienorphine on c AMP-dependent protein kinase A(PKA) activity in CHO cells expressing μ-,κ-,δ-and ORL1 receptors.In addition,we further examined its analgesic effect in vivo.METHODS The effect of thienorphine on cA MP-dependent PKA redistribution and cA MP inhibition were analyzed in CHO-PKAcatEGFP cells.PKA redistribution assays in CHO-PKAcatEGFP cells stably expressing μ-,κ-,δ-and ORL1 receptors were analyzed by high-throughput screening system to elucidate the efficacy of agonists or antagonists on opioid receptors.Moroever,the antinociceptive effects of thienorphine in vivo were examined using hot plate test.RESULTS Briefly,the maximum inhibition of thienorphine on PKA activity was about 36%,100%,100%and 12% in CHO-μ/κ/δ/ORL1-PKAcatE GFP cel s,respectively.In addition,thienorphine concentrationdependently inhibited the PKA activity with EC50 value of(22.7±18.1) nmol·L^(-1) in CHO-κ-PKAcatE GFP cels and(12.4±7.7) nmol·L^(-1) in CHO-δ-PKAcatE GFP cells.Thienorphine induced approximately 50%antinociceptive effect in mice lacking μ receptors compared to their wild-type controls(P<0.05).Also,the κ and δ selective antagonist nor-binaltorphimine,naltrindole decreased approximately 50%-60% in % MPE of theinorphine in μ-KO mice,respectively.The ORL1 receptor selective antagonist J113397 had no effect in %MPE of theinorphine in μ-KO mice.CONCLUSION Thienorphine induces analgesia through bindingκ-and δ-,or by partially binding μ-opioid receptor,thus further regulating the cAMP-PKA activity.Therefore,thienorphine may be used in acute or chronic pain with minimal addictive potential.

关键词： thienorphine opioid receptor analgesia cAMP protein kinase A