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Acta Pharmaceutica Sinica B 2021年第6期11卷 1412-1433页

作者： Yani Liu Zongtao Liu Kewei Wang Department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drugs Qingdao UniversityQingdao 266021China Department of Clinical Laboratory Qingdao Third People's HospitalQingdao 266041China

Anoctamin 1(ANO1) or TMEM16 A gene encodes a member of Ca^(2+) activated Cl^(-) channels(CaCCs) that are critical for physiological functions,such as epithelial secretion,smooth muscle contraction and sensory signal transduction.The attraction and interest in ANO1/TMEM16 A arise from a decade long investigations that abnormal expression or dysfunction of ANO1 is involved in many pathological phenotypes and diseases,including asthma,neuropathic pain,hypertension and cancer.However,the lack of specific modulators of ANO1 has impeded the efforts to validate ANO1 as a therapeutic target.This review focuses on the recent progress made in understanding of the pathophysiological functions of CaCC ANO1 and the current modulators used as pharmacological tools,hopefully illustrating a broad spectrum of ANO1 channelopathy and a path forward for this target validation.

关键词： Ca^(2+)-activated Cl^(-)channels(CaCCs) ANO1 TMEM16A CaCCinh-A01 T16Ainh-A01 Drug target Cancer Cystic fibrosis

Stem cell therapy for Alzheimer’s disease:An overview of experimental models and reality

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Animal Models and Experimental Medicine 2022年第1期5卷 15-26页

作者： Chuan Qin Kewei Wang Ling Zhang Lin Bai Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences(CAMS)Comparative Medicine CenterPeking Union Medical College(PUMC)NHC Key Laboratory of Human Disease Comparative MedicineKey Laboratory of Human Diseases Animal ModelBeijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases BeijingBeijingChina

Alzheimer's disease(AD)is a neurodegenerative disorder.The pathology of AD is characterized by extracellular amyloid beta(Aβ)plaques,neurofibrillary tangles com-posed of hyperphosphorylated tau,neuronal death,synapse loss,and brain atrophy.Many therapies have been tested to improve or at least effectively modify the course of AD.Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease.Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction,although certain weak-nesses or limitations need to be overcome.This review recapitulates rodent models for AD,the therapeutic efficacy of stem cells,influencing factors,and the underlying mechanisms behind these changes.Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.

关键词： Alzheimer's disease animal model cognitive deficits memory loss stem cell therapy

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

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Acta Pharmaceutica Sinica B 2016年第6期6卷 522-530页

作者： Xiaoling Chen Kewei Wang Department of Molecular and Cellular Pharmacology State Key Laboratory of Natural and Biomimetic Drugs Peking University School of Pharmaceutical Sciences Department of Pharmacology Qingdao University School of Pharmacy

Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators(rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995–2015and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

关键词： Thrombosis Neuroprotective agent Ischemic stroke Traditional Chinese medicine Non-NMDA mechanism Ion channel

Inhibition of intracellular proton-sensitive Ca^(2+)-permeable TRPV3 channels protects against ischemic brain injury

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2330-2347页

作者： Xiaoling Chen Jingliang Zhang Kewei Wang Department of Molecular and Cellular Pharmacology State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Pharmacology Qingdao University School of PharmacyQingdao 266021China

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-D-aspartate(NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca^(2+)-permeable transient receptor potential vanilloid 3(TRPV3) channel protects against cerebral ischemia/reperfusion(I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion(tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

关键词： TRPV3 Ca^(2+)influx Acidosis Cerebral ischemia/reperfusion injury Excitotoxicity Neural excitability Forsythoside B tMACO OGD TRP

Highlights for the 6th International Ion Channel Conference:ion channel structure,function,disease and therapeutics

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Acta Pharmaceutica Sinica B 2017年第6期7卷 665-669页

作者： Limei wang Kewei Wang Department of Pharmacology Qingdao University School of PharmacyQingdao 266021China

To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6 th International Ion Channel Conference(IICC-2017) was held between June 23–27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on(1) Ion channel structure and function;(2) Ion channel physiology and human diseases;(3) Ion channels as targets for drug discovery;(4) Technological advances in ion channel research. An insightful overview was presented on the structure and function of the mechanotransduction channel Drosophila NOMPC(No mechanoreceptor potential C), a member of the transient receptor potential(TRP) channel family. Recent studies on Transmembrane protein 16 or Anoctamin-1(TMEM16A, a member of the calcium-activated chloride channel [CaCC] family) were summarized as well. In addition, topics for ion channel regulation, homeostatic feedback and brain disorders were thoroughly discussed. The presentations at the IICC-2017 offer new insights into our understanding of ion channel structures and functions, and ion channels as targets for drug discovery.

关键词： Ion channel Structure Function Channelopathy Drug target Mechanotransduction Voltage-gated Ca2+ channel Anoctamin-1 Calcium activated chloride channel M-type potassium channel GIRK channel Voltage-gated sodium channel

Inhibition of temperature-sensitive TRPV3 channel by two natural isochlorogenic acid isomers for alleviation of dermatitis and chronic pruritus

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Acta Pharmaceutica Sinica B 2022年第2期12卷 723-734页

作者： Hang Qi Yuntao Shi Han Wu Canyang Niu Xiaoying Sun Kewei Wang Department of Pharmacology School of PharmacyQingdao UniversityQingdao 266021China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Institue of Innovative Drugs Qingdao UniversityQingdao 266021China

Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3(TRPV3)channel cause Olmsted syndrome characterized by severe itching and keratoderma,indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases.However,currently available TRPV3 tool inhibitors are either nonselective or less potent,thus impeding the validation of TRPV3 as therapeutic target.Using whole-cell patch-clamp and single-channel recordings,we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A(IAA)and isochlorogenic acid B(IAB)that selectively inhibit TRPV3 currents with IC50 values of 2.7±1.3 and 0.9±0.3μmol/L,respectively,and reduce the channel open probability to 3.7±1.2%and 3.2±1.1%from 26.9±5.5%,respectively.In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus.Furthermore,the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol.Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers.Taken together,our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology,but also holds developmental potential for treatment of dermatitis and chronic pruritus.

关键词： TRPV3 Dicaffeoylquinic acid Gate modifier Chronic pruritus Dermatitis Olmsted syndrome Ear swelling

A brief procedure for big data analysis of gene expression

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Animal Models and Experimental Medicine 2018年第3期1卷 189-193页

作者： Kewei Wang Wenji wang Mang Li Institute of Cell Biotechnology China and Russia Medical Research Center Center for Endemic Disease Control Chinese Center for Disease Control and Prevention Key Laboratory of Etiology and Epidemiology National Health and Family Planning Commission of the People's Republic of China Harbin Medical University Departments of Surgery University of Illinois College of Medicine Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences&Peking Union Medical College

There are a lot of biological and experimental data from genomics, proteomics, drug screening, medicinal chemistry, etc. A large amount of data must be analyzed by special methods of statistics, bioinformatics, and computer science. Big data analysis is an effective way to build scientific hypothesis and explore internal mechanism.Here, gene expression is taken as an example to illustrate the basic procedure of the big data analysis.

关键词： big data analysis cluster analysis microarray PCA analysis regression model

The current agonists and positive allosteric modulators ofα7 nAChR for CNS indications in clinical trials

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Acta Pharmaceutica Sinica B 2017年第6期7卷 611-622页

作者： Taoyi Yang Ting Xiao Qi Sun Kewei Wang Department of Molecular and Cellular Pharmacology School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Pharmacology School of PharmacyQingdao UniversityQingdao 266021China

The alpha-7 nicotinic acetylcholine receptor(α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca^(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease(AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the α7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of α7 nAChR modulators used in clinical trials.

关键词： Alpha7 nAChR Positive allosteric modulators Schizophrenia Alzheimer’s disease Acetylcholine Ion channel

The molecular regulation of autophagy in antimicrobial immunity

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Journal of Molecular Cell Biology 2022年第4期14卷 3-17页

作者： Chuan Qin Yalan Lu Lin Bai Kewei Wang Institute of Laboratory Animal Sciences Chinese Academy of Medical Sciences&Comparative Medical CenterPeking Union Medical CollegeBejing100021China

Autophagy is a catabolic process that can degrade worn-out organelles and invading pathogens.The activation of autophagy regulates innate and adaptive immunity,playing a key role in the response to microbial invasion.Microbial infection may cause different consequences such as the elimination of invaders through autophagy or xenophagy,host cell death,and symbiotic relationships.Pathogens adapt to the autophagy mechanism and further relieve intracellular stress,which is conducive to host cell survival and microbial growth.The regulation of autophagy forms a complex network through which host immunity is modulated,resulting in a variety of pathophysiological manifestations.Modification of the autophagic pathway is an essential target for the development of antimicrobial drugs.

关键词： autophagy microbe antimicrobial immunity endoplasmic reticulum stress unfolded protein response apoptosis infectious disease

Cold weather and Kashin-Beck disease

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Frigid Zone Medicine 2023年第1期3卷 30-36页

作者： Kewei Wang Jun Yu Dianjun Sun Center for Endemic Disease Control Chinese Center for Disease Control and PreventionKey Laboratory of Etiology and EpidemiologyNational Health and Family Planning Commission of the People's Republic of ChinaHarbin Medical UniversityHarbin 150081China

Kashin-Beck disease(KBD)is an endemic osteoarthropathy.Its distribution region covers a long and narrow belt on the Pacific side and belongs to continental climate with short summer,long frost period,and large temperature differences between day and night.In particular,KBD patients are typically scattered in the rural areas with seasonal features such as cold winters and rainy autumns.Etiological studies have demonstrated that the carrier of pathogenic factors is the grains produced in endemic areas.Risk factors for KBD include fungal contamination of grains due to poor storage conditions associated with cold weather.The epidemiological characteristics of KBD include agricultural area,early age of onset,gender equality,family aggregation,regional differences,and annual fluctuations.A series of preventive measures have been successfully taken in the past decades.National surveillance data indicate that the annual incidence of KBD is gradually declining.

关键词： Kashin-Beck disease epidemiology etiology national surveillance fungal contamination of grain unbalanced dietary protein intake