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Impact of alpha-synuclein pathology on adult neurogenesis: evidence for multilayered mechanisms

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Neural Regeneration Research 2022年第7期17卷 1491-1492页

作者： Jana Bonsberger Franziska Richter Milos Stanojlovic Department of pharmacology Toxicology and PharmacyUniversity of Veterinary MedicineHannoverGermany

Parkinson’s disease(PD)is the second most common neurodegenerative disease affecting 8–10 million people worldwide.Moreover,PD is the fastest-growing neurodegenerative disease and it is predicted that the number of patients will double in the next thirty years.Neuropathologically,PD is characterized by the presence of protein aggregations called Lewy bodies(LB)and by degeneration of dopaminergic neurons in the substantia nigra pars compacta.

关键词： degeneration pathology Impact

Engineered microneedles arrays for wound healing

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Engineered Regeneration

Engineered Regeneration 2022年第3期3卷 232-240页

作者： Shun Yao Yuan Luo Yongan Wang State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

Wound healing is the regenerative process of original skin structure after destructing by different damage sources.Due to their transdermal delivery capability and high specific surface area,microneedles arrays(MAs)have been recognized as encouraging biomaterials for wound healing.In this review,we have outlined the engineered MAs used for tissue regeneration and wound healing.Engineered MAs were first classified by design methodologies such as bionic design,intelligent-responsive design,actively-triggered design,matrix materials innovation,and composite smart design.Then,the MAs were divided into two categories based on the different loading substances:drug-loaded MAs and living component-loaded MAs.Finally,we have summed up the important elements of the preceding discussions and forecasted their future evolution.

关键词： Engineered design Microneedles arrays Wound healing

Enterovirus A71 antivirals:Past,present,and future

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1542-1566页

作者： Jun Wang Yanmei Hu Madeleine Zheng Department of Pharmacology and Toxicology College of Pharmacythe University of ArizonaTucsonAZ 85721USA

Enterovirus A71(EV-A71)is a significant human pathogen,especially in children.EV-A71 infection is one of the leading causes of hand,foot,and mouth diseases(HFMD),and can lead to neurological complications such as acute flaccid myelitis(AFM)in severe cases.Although three EV-A71 vaccines are available in China,they are not broadly protective and have reduced efficacy against emerging strains.There is currently no approved antiviral for EV-A71.Significant progress has been made in developing antivirals against EV-A71 by targeting both viral proteins and host factors.However,viral capsid inhibitors and protease inhibitors failed in clinical trials of human rhinovirus infection due to limited efficacy or side effects.This review discusses major discoveries in EV-A71 antiviral development,analyzes the advantages and limitations of each drug target,and highlights the knowledge gaps that need to be addressed to advance the field forward.

关键词： Enterovirus A71 EV-A71 AntiviralsAcute flaccid myelitis Hand Foot and mouth disease(HFMD) Picornavirus 2C protein

Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1636-1651页

作者： Chunlong Ma Haozhou Tan Juliana Choza Yuyin Wang Jun Wang Department of Pharmacology and Toxicology College of Pharmacythe University of ArizonaTucsonAZ 85721USA

SARS-CoV-2 main protease(M^(pro))is one of the most extensively exploited drug targets for COVID-19.Structurally disparate compounds have been reported as M^(pro) inhibitors,raising the question of their target specificity.To elucidate the target specificity and the cellular target engagement of the claimed M^(pro) inhibitors,we systematically characterize their mechanism of action using the cell-free FRET assay,the thermal shift-binding assay,the cell lysate Protease-Glo luciferase assay,and the cell-based FlipGFP assay.Collectively,our results have shown that majority of the M^(pro) inhibitors identified from drug repurposing including ebselen,carmofur,disulfiram,and shikonin are promiscuous cysteine inhibitors that are not specific to M^(pro),while chloroquine,oxytetracycline,montelukast,candesartan,and dipyridamole do not inhibit M^(pro) in any of the assays tested.Overall,our study highlights the need of stringent hit validation at the early stage of drug discovery.

关键词： SARS-CoV-2 Antiviral Main protease Ebselen Carmofur FlipGFP assay Protease-Glo luciferase assay

Restoration of GABA_(B) receptor expression in cerebral ischemia:a promising novel neuroprotective strategy

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Neural Regeneration Research 2023年第12期18卷 2659-2660页

作者： Musadiq A.Bhat Mohammad Hleihil Dietmar Benke Institute of Pharmacology and Toxicology University of ZurichZurichSwitzerland

Although stroke is a major global health problem, a pharmacological treatment to inhibit ongoing neuronal death in patients is still lacking. In cerebral ischemia, the prevailing form of stroke, severely reduced blood supply by obstruction of blood vessels deprives neurons from oxygen and glucose, eventually leading to metabolic derailment and death of neurons in the affected brain area.

关键词： cerebral ischemia death

Comparative effects of parenteral antimalarials in Swiss albino mice after chronic exposure to Plasmodium berghei

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Animal Models and Experimental Medicine 2018年第3期1卷 235-241页

作者： Sylvester Aghahowa Kenka Okolocha Department of Pharmacology and Toxicology University of Benin

Mice are considered to be a similar model to humans in the pathogenesis of malaria. This study evaluates the effect of parenteral antimalarials on the spleen and liver of Swiss albino mice after chronic exposure to Plasmodium berghei. After chronic exposure to P. berghei NK65 strain, the level of parasitemia was assessed.The mice were treated for 3 days using chloroquine(5 mg/kg), quinine(10 mg/kg),and artemether(2 mg/kg). The effect of chronic exposure and the pattern of recovery were evaluated. There was significant decrease in total body weight after chronic exposure to P. berghei(P < 0.05). An increase in total weight recovery was seen after day 15 of treatment with the antimalarials; this was more pronounced with artemether. A significant increase in liver and spleen weights due to P. berghei infection was seen. There was a recovery pattern due to decrease in liver and spleen weights following antimalarial administration, which was greatest with artemether(P < 0.05). Significant changes were more in parasitized, quinine and artemether groups(P < 0.05). There was a significant decrease in total spleen protein due to chloroquine but a decrease due to quinine and artemether(P < 0.05). No significant changes in liver and spleen albumin were observed after treatment. The highest parasite clearance was observed with artemether, followed by quinine. Five mice died after chronic exposure in all the groups prior to treatment. There was significant enlargement and discoloration of spleen and liver after chronic exposure. This study showed that artemether aided recovery of the liver and spleen better than quinine and chloroquine in albino mice after chronic exposure to P. berghei. This suggests there is potential for improvement in antimalarial therapy.

关键词： antimalarials mice Plasmodium berghei

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

Size,shape,charge and“stealthy”surface:Carrier properties affect the drug circulation time in vivo

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Asian Journal of Pharmaceutical Sciences 2021年第4期16卷 444-458页

作者： Jinwei Di Xiang Gao Yimeng Du Hui Zhang Jing Gao Aiping Zheng State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.

关键词： Drug carrier Circulation time Physical and chemical properties Macrophages Phagocytosis

Characteristics of the traditional Liu-Wei-Di-Huang prescription reassessed in modern pharmacology

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Chinese Journal of Natural Medicines 2019年第2期17卷 103-121页

作者： CHENG Xiao-Rui QI Chun-Hui WANG Tong-Xing ZHOU Wen-Xia ZHANG Yong-Xiang Academy of Military Medical Science Institute of Pharmacology and Toxicology State Key Laboratory of toxicology and Medical Countermeasures

Liu-Wei-Di-Huang(LW) is a Yin nourishing and kidney tonifying prescription in traditional Chinese medicine with promising pharmacological characteristics that can be further exploited and developed in modern medicine. We provide a comprehensive and detailed literature report on the clinical and experimental pharmacology of LW,including its quality control parameters, phytochemistry, pharmacokinetics, and toxicology. Our literature review indicates that the LW prescription possesses a unique combination of pharmacological characteristics that can be safely used for treating very different diseases. Quality control and pharmacokinetic parameters of LW are mostly based on its major bioactive phytochemical constituents. We postulate that modulating or rebalancing the neuroendocrine immunomodulation network in the body is the underlying mechanism of the multiple pharmacological activities displayed by LW.

关键词： Liu-Wei-Di-Huang Traditional Chinese medicine pharmacology Phytochemistry Pharmacokinetics toxicology