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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

急诊科反复喘息婴幼儿需要住院并接受呼吸支持治疗的预测因素

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中国当代儿科杂志 2021年第5期23卷 438-444页

作者： Jefferson Antonio Buendía Ranniery Acuña-Cordero Carlos E Rodriguez-Martinez Department of Pharmacology and Toxicology School of MedicineResearch Group in Pharmacology and Toxicology(INFARTO)Universidad de AntioquiaMedellínColombia

目的反复喘息患者多为2岁以下的婴幼儿。在热带国家,对该人群住院期间接受呼吸支持治疗的风险的临床预测模型研究较少。该研究旨在评估就诊于哥伦比亚急诊科的反复喘息婴幼儿需要住院并接受呼吸支持治疗的临床预测因素。方法该研究是一... 详细信息

目的反复喘息患者多为2岁以下的婴幼儿。在热带国家,对该人群住院期间接受呼吸支持治疗的风险的临床预测模型研究较少。该研究旨在评估就诊于哥伦比亚急诊科的反复喘息婴幼儿需要住院并接受呼吸支持治疗的临床预测因素。方法该研究是一项回顾性队列研究,纳入了2019年1~12月期间在哥伦比亚Rionegro的两个三级中心医院就诊的所有患有2次或2次以上喘息发作的婴幼儿(年龄均小于2岁)。主要结局指标是住院加呼吸支持治疗。采用多因素logistic回归模型确定需要住院并接受呼吸支持治疗的独立预测因素。结果共85名婴幼儿住院并接受呼吸支持治疗,其中34名(40%)予以高流量鼻导管吸氧,2名(2%)予以无创通气,6名(7%)予以机械通气,43名(51%)予以常规氧疗。多因素logistic回归模型分析显示,早产(OR=1.79,95%CI:1.04~3.10)、喂养困难(OR=2.22,95%CI:1.25~3.94)、鼻煽和/或咕噜声(OR=4.27,95%CI:2.41~7.56)和既往有1次以上喘息发作需要住院治疗(OR=3.36,95%CI:1.86~7.08)是需要住院并接受呼吸支持治疗的预测因素。该模型特异度高(99.6%),鉴别度中等,曲线下面积为0.70(95%CI:0.60~0.74)。结论该研究表明,早产、喂养困难、鼻煽和/或呼噜声,以及有1次以上需要住院治疗的喘息发作史,是急诊科就诊的反复喘息婴幼儿需要住院并接受呼吸支持治疗的独立预测因素。然而,还需收集更多的其他热带国家的证据来验证这个结论。

关键词：喘息呼吸支持风险预测因素婴幼儿

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

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Neural Regeneration Research 2022年第9期17卷 1913-1918页

作者： Heba M.Mansour Hala M.Fawzy Aiman S.El-Khatib Mahmoud M.Khattab department of pharmacology Egyptian Drug AuthorityEDAformerly NODCARGizaEgypt Department of Pharmacology and Toxicology Faculty of PharmacyCairo UniversityCairoEgypt

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

关键词： Alzheimer’s disease autophagy drug re-positioning epidermal growth factor receptor human epidermal growth factor receptor-2 neurodegenerative diseases neuroinflammation oxidative stress tyrosine kinase inhibitors

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

Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR

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Liver Research 2022年第4期6卷 227-237页

作者： Yssa Rodriguez Jack Dunfield Tyson Roderique Hong-Min Ni department of pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA

Background:Alcohol-associated liver disease(ALD)is a major chronic liver disease around the world without successful treatment.Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality,which is often associated with binge drinking.Alcohol drinking dysregulates lipid metabolism,increases adipose tissue lipolysis,and induces liver steatosis and adipose tissue atrophy.Increasing ev-idence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD.Mechanistic target of rapamycin(mTOR)is a phosphatidylinositol 3-kinase(PI3K)-like serine/threonine protein kinase that regulates lipid metabolism,cell proliferation and autophagy.However,the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear.Methods:We generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR(Rptor)knockout(Rptor LKO and Rptor AKO)as well as Mtor knockout(Mtor LKO and Mtor AKO)mice,by crossing Rptor flox and Mtor flox mice with albumin Cre or adiponectin Cre mice,respectively.In addition,we generated liver and adipocyte double deletion of Rptor or Mtor(Mtor LAKO and Rptor LAKO)mice.The knockout mice with their matched wild-type littermates(Rptor WT and Mtor WT)were subjected to acute gavage of 7 g/kg ethanol.Results:Mice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue at-rophy.Alcohol gavage increased liver injury,hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities,increased hepatic levels of tri-glyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage.Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor.Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNF a as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice,which were further increased in adipocyte-specific Mtor or Rptor knocko

关键词： Alcohol-associated liver disease(ALD) Liver injury Mechanistic target of rapamycin(mTOR) Adipose atrophy Adipokine Liver-adipose tissue crosstalk

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

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Military Medical Research 2022年第5期9卷 628-636页

作者： Zaid Sirhan Anita Thyagarajan Ravi P.Sahu Department of Pharmacology and Toxicology Boonshoft School of Medicine Wright State UniversityDaytonOH45435USA

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.

关键词： HER2-positive(HER2^(+)) Breast cancer Targeted therapy Tucatinib Immunotherapy

Regulation of macrophage activation in the liver after acute injury: Role of the fibrinolytic system

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World Journal of Gastroenterology 2020年第16期26卷 1879-1887页

作者： Katherine Roth Jenna Strickland Bryan L Copple Department of Pharmacology and Toxicology Institute for Integrative ToxicologyMichigan State UniversityEast LansingMI 48824United States

The liver functions,in part,to prevent exposure of the body to potentially harmful substances ingested in the diet.While it is highly efficient at accomplishing this,it is frequently prone to liver injury due to the biotransformation of xenobiotics into toxic metabolites.To counter this injury,the liver has evolved a unique capacity to rapidly and efficiently repair itself.Successful resolution of acute liver injury relies on hepatic macrophage populations that orchestrate the reparative response.After injury,Kupffer cells,the resident macrophages of the liver,become activated and secrete proinflammatory cytokines.These cytokines recruit other immune cells,including monocyte-derived macrophages,to the liver where they contribute to the repair process.Monocyte-derived macrophages traffic into the necrotic foci where they rapidly phagocytose dead cell debris.Simultaneous with this process,these cells change phenotype from a proinflammatory macrophage to a prorestorative macrophage that produce pro-mitogenic growth factors and antiinflammatory cytokines.Ultimately this process triggers resolution of inflammation,and along with proliferation of other hepatic cells,restores the liver architecture and function.While the mechanisms regulating specific macrophage functions during repair remain to be elucidated,recent studies indicate a key role for the fibrinolytic system in coordinating macrophage function during repair.In this review,we will highlight the function and role of hepatic macrophages in repair after acute liver injury,and will discuss the role of the fibrinolytic enzyme,plasmin,in regulation of these various processes.

关键词： Macrophage Plasmin Acetaminophen Liver injury Liver repair

PBPK modeling and simulation in drug research and development

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Acta Pharmaceutica Sinica B 2016年第5期6卷 430-440页

作者： Xiaomei Zhuang Chuang Lu State Key Laboratory of toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology department of DMPK BiogenInc.

Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment.PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and development.In this mini-review,the concept and methodology of PBPK modeling are briefly introduced.Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development.These case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical trials.The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

关键词： PBPK PK prediction Absorption Metabolism Drug–drug interaction Special population