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The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-lp transcription and processing in monocytes

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Cellular & Molecular Immunology 2016年第6期13卷 747-763页

作者： Ankita Singh Vishal Singh Rajiv L. Tiwari Tulika Chandra Ashutosh Kumar Madhu Dikshit Manoj K. Barthwal pharmacology Division CSIR-Central Drug Research Institute B.S. 10/1 Sector 10 Sitapur Road Jankipuram Extension Lucknow 226031 Uttar Pradesh India Department of Transfusion Medicine and Blood Bank King George's Medical University Lucknow Uttar Pradesh India Department of Pathology King George's Medical University Lucknow Uttar Pradesh India

In monocytic cells, Toll-like receptor 4 （TLR4）- and TLR2-induced reactive oxygen species （ROS） cause oxidative stress and inflammatory response; however, the mechanism is not well understood. The present study investigated the role of interleukin-1 receptor-associated kinase （IRAK）, extracellular signal-regulated kinase （ERK）, p67phox and Nox-2 in TLR4- and TLR2-induced ROS generation during interleukin-1 beta （IL-1β） transcription, processing, and secretion. An IRAK1/4 inhibitor, U0126, PD98059, an NADPH oxidase inhibitor （diphenyleneiodonium （DPI））, and a free radical scavenger （N-acetyl cysteine （NAC））-attenuated TLR4 （lipopolysaccharide （LPS））- and TLR2 （Pam3csk4）-induced ROS generation and IL-1β production in THP-1 and primary human monocytes. An IRAK1/4 inhibitor and siRNA-attenuated LPS- and Pam3csk4-induced ERK-IRAK1 association and ERK phosphorylation and activity. LPS and Pam3csk4 also induced IRAK1/4-, ERK- and ROS-dependent activation of activator protein-1 （AP-1）, IL-1β transcription, and IL-1β processing because significant inhibition in AP-1 activity, IL-lp transcription, Pro- and mature IL-p expression, and caspase-1 activity was observed with PD98059, U0126, DPI, NAC, an IRAK1/4 inhibitor, tanshinone Ila, and IRAK1 siRNA treatment. IRAK-dependent ERK-p67phox interaction, p67phox translocation, and p67phox-Nox-2 interaction were observed. Nox-2 siRNA significantly reduced secreted IL-lp, IL-1β transcript, pro- and mature IL-1β expression, and caspase-1 activity indicating a role for Nox-2 in LPS- and Pam3csk4-induced IL-1β production, transcription, and processing. In the present study, we demonstrate that the TLR4- and TLR2-induced IRAK-ERK pathway cross-talks with p67phox-Nox-2 for ROS generation, thus regulating IL-1β transcription and orocessin; in monocvtic cells.

关键词： IL-1β IRAK monocytes ROS TLR

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Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

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Neuroimmunology and Neuroinflammation 2018年第9期5卷 2-14页

作者： Cinzia Dello Russo Natalia Cappoli Institute of pharmacology UniversitàCattolica del S CuoreRome00168Italy Fondazione Policlinico Gemelli IRCCS 00168RomeItaly

Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, par-ticularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a specific pheno-type of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain parenchyma. Therefore, treatments that limit or prevent GAMs' recruitment at the tumor site or modulate their immune activa-tion promoting antitumor activities are expected to exert beneficial effects in glioblastoma. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function and are currently proposed as an alternative/additional option to current approved cytotoxic regimens.

关键词： Glioblastoma macrophages microglia metalloproteases pro-inflammatory activation pro-tumor func-tions glioma associated microglia/macrophages targeted therapies pharmacotherapy

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Transcriptomics and Proteomics in the Study of H1N1 2009

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Genomics, Proteomics & Bioinformatics 2010年第3期8卷 139-144页

作者： Lijun Zhang Xiaojun Zhang Qing Ma Fang Ma Honghao Zhou Department of Pharmacogenetics Institute of Clinical Pharmacology Central South University Changsha 410078 China Shanghai Public Health Clinical Center Fudan University Shanghai 201508 China Department of Neurosurgery Fuzhou General Hospital Fuzhou 350025 China School of Pharmacy and Pharmaceutical Sciences University at Buffalo NY 14260 USA.

Influenza A virus （H1N1） 2009, a new swine-origin influenza A virus, has been spread worldwidely and caused great public fear. High-throughput transcriptomics and proteomics methods are now being used to identify H1N1 and H1Nl-host interaction. This article reviews recent transcriptomics and proteomics research in H1N1 diagnosis, treatment, and H1N1 virus-host interaction, to offer some help for further understanding the infection mechanism and controlling H1N1 transmission.

关键词： H 1N 1 proteomics transcriptomics host

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BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2

BNIP3L/NIX-mediated mitophagy protects against ischemic brai...

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中国神经科学学会第十二届全国学术会议

作者： Xiaoli Wu Yang Yuan Yanrong Zheng Xiangnan Zhang Zhong Chen Department of pharmacology Key Laboratory of Medical Neurobiology of The Ministry of Health of China College of Pharmaceutical Sciences Zhejiang University

Objective: Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared and thus attenuates brain injury by mitophagy. Here, we identified the involvement of BNIP3 L/NIX in cerebral ischemia-reperfusion(I-R)-induced mitophagy. Methods:(1) Transient middle cerebral artery occlusion mouse models;(2) OxygenGlucose Deprivation for primary cortical neuronal culture. Results: Bnip3 l knockout(Bnip3l

关键词： Cerebral ischemia Mitophagy PARK2 BNIP3L Neuroprotection

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Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

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World Journal of Gastroenterology 2007年第42期13卷 5618-5628页

作者： Quan Zhou Xiao-Feng Yan Zhong-Miao Zhang Wen-Sheng Pan Su Zeng Department of Clinical pharmacology & Clinical Pharmacy the 2^nd AffiliatedHospital School of Medicine Zhejiang University Hangzhou310009 Zhej iang Province China Department of Gastroenterology the 2^nd Affiliated Hospital School of Medicine Zhejiang UniversityHangzhou 310009 Zhejiang Province China Department of Pharmaceutical Analysis & Drug Metabolism College of Pharmaceutical Sciences ZhejiangUniversity Hangzhou 310058 Zhejiang Province China

AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical ***:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to ***:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole *** showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above ***:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of *** relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

关键词： Cytochrome P450 Pharmacokinetics Drugmetabolism Genotype Polymorphism Drug interaction Pharmacotherapy Gastrointestinal diseases

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Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine

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Engineering 2019年第1期5卷 32-39页

作者： Jigang Wang Chengchao Xu Yin Kwan Wong Yujie Li Fulong Liao Tingliang Jiang Youyou Tu Research Center China Academy of Chinese Medical Sciences Beijing 100700 China Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences Beijing 100700 China Department of pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore 117600 Singapore Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Singapore 117597 Singapore

Artemisinin and its derivatives represent the most important and influential class of drugs in the fight against malaria. Since the discovery of artemisinin in the early 1970s, the global community has made great strides in characterizing and understanding this remarkable phytochemical and its unique chemical and pharmacological properties. Today, even as artemisinin continues to serve as the foundation for antimalarial therapy, numerous challenges have surfaced in the continued application and development of this family of drugs. These challenges include the emergence of delayed treatment responses to artemisinins in malaria and efforts to apply artemisinins for non-malarial indications. Here, we provide an overview of the story of artemisinin in terms of its past, present, and future. In particular, we comment on the current understanding of the mechanism of action (MOA) of artemisinins, and emphasize the importance of relating mechanistic studies to therapeutic outcomes, both in malarial and non-malarial contexts.

关键词： Artemisinin Mechanism of action Malaria Anti-cancer

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Possible role of polyamines in gastric mucus synthesis inhibited by cigarette smoke exposure and its extracts

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Acta Pharmacologica Sinica 1999年第7期 92-92页

作者：马莉周业金曹之宪 China Department of pharmacology Faculty of Medicine The University of Hong Kong

AIM: Cigarette smoking was shown to delay gastric ulcer healingand reduce mucus synthesis, which is important for gastricmucosal protection and healing. Since polyamines had beenshown to accelerate ulcer healing, we hypothesized that cigarettesmoking reduced mucus synthesis through its interference with thepolyamine pathway. METHODS: In vitro, mucus synthesis

关键词： Possible role of polyamines in gastric mucus synthesis inhibited by cigarette smoke exposure and its extracts

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Serum Bcl-2 concentrations in overweight-obese subjects with nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2011年第48期17卷 5280-5288页

作者： Giovanni Tarantino Francesco Scopacasa Annamaria Colao Domenico Capone Marianna Tarantino Ernesto Grimaldi Silvia Savastano Department of Clinical and Experimental Medicine Federico Ⅱ University Medical School of Naples Department of Biochemistry and Medical Biotechnology Federico Ⅱ University Medical School of Naples Department of Molecular and Clinical Endocrinology and Oncology Endocrinology UnitFederico Ⅱ University Medical School of Naples Department of Neurosciences Unit of Clinical Pharmacology Federico Ⅱ University Medical School of Naples Department of Biomorphological and Functional Sciences Federico Ⅱ University Medical School of Naples

AIM： To shed some light on the relationship between anti-apoptotic serum Bcl-2 concentrations and metabolic status, anthropometric parameters, inflammation indi- ces, and non-alcoholic fatty liver disease severity were investigated in 43 young individuals with fatty liver （FL） and 41 with nonalcoholic steatohepatitis （NASH）. METHODS： Circulating levels of Bcl-2 were detected in 84 patients with ultrasonographic findings of ＂bright liver＂ and/or hyper-transaminasemia of unknown origin and/or increase in T-glutamyl-transpeptidase （T-GT） strictly in the absence of other acute or chronic liver disease, whose age was not advanced, who gave consent to liver biopsy and were then divided on the basis of the histological results into two groups （43 with FL and 41 with NASH）. Twenty lean subjects, apparently healthy and young, were chosen as ***： Serum Bcl-2 concentrations were significantly higher in the FL group than in the NASH group. Insulin resistance and γ-GT activity were significantly higher in NASH subjects. Apoptotic hepatocytes were significantly more numerous in NASH patients. NASH patients presented with larger spleens and augmented C-reactive protein （CRP） concentrations than healthy subjects. Steatosis grade at histology was similar in both NASH and FL populations. The number of apoptotic cells was significantly related to anti-apoptotic Bcl-2 protein values in FL patients. Bcl-2 serum levels positively correlated to body mass index （BMI） values （P ~ 0.0001） but not to age of the population. Triglycerides/HDL ratio correlated well to waist circumference in males （P = 0.0008）. γ-GT activity was associated with homeostatic metabolic assessment （HOMA）（P = 0.0003） and with serum ferritin （P = 0.02）. Bcl-2 concentrations were not related to either spleen size or CRP values. NASH patients pre- sented a weak negative correlation between Iobular inflammation and Bcl-2 levels. A prediction by low values of serum Bcl-2 towards a greater presence of metaboli

关键词： Bcl-2 Nonalcoholic fatty liver disease Meta-bolically unhealthy overweight/obese

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The time course of serotonin 2A receptor expression after spinal transection of rats:An immunohistochemical study

The time course of serotonin 2A receptor expression after sp...

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中国解剖学会2012年年会

作者： Jacob Wienecke Hans Hultborn Laboratory of Spinal Injury and Rehabilitation Chengde Medical College Department of Neuroscience and pharmacology University of CopenhagenCopenhagenDenmark

＜正＞Serotonin（5-HT） denervation supersensitivity is one of the mechanisms underlying this increased motoneuron *** this study,to examine whether the supersensitivity is caused by 5-HT receptor upregulation,we investigated changes in levels of 5-HT2A receptor immunoreactivity（5-HT2AR-IR） following a spinal transection in the sacral spinal cord of rats at seven different time

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Mouse metabonomics for the analysis and prediction of drug metabolism

Mouse metabonomics for the analysis and prediction of drug m...

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第十五届国际药理学大会

作者： Frank J.Gonzalez Kristopher W.Krausz Chi Chen Sarbani Giri Jeffrey R.Idle Laboratory of Metabolism NCIBethesdaMarylandUSA （FJGKWKCCSG） Institute of pharmacology Charles UniversityPragueCzech Rep （JRI） Laboratory of Metabolism NCIBethesdaMarylandUSA （FJGKWKCCSG） Institute of pharmacology Charles UniversityPragueCzech Rep （JRI） Laboratory of Metabolism NCIBethesdaMarylandUSA （FJGKWKCCSG） Institute of pharmacology Charles UniversityPragueCzech Rep （JRI） Laboratory of Metabolism NCIBethesdaMarylandUSA （FJGKWKCCSG） Institute of pharmacology Charles UniversityPragueCzech Rep （JRI） Laboratory of Metabolism NCIBethesdaMarylandUSA （FJGKWKCCSG） Institute of pharmacology Charles UniversityPragueCzech Rep （JRI）

＜正＞ Objective: To study the the metabolism of drags and other foreign compounds in vivo and to examine pharmaco- and toxicokinetics of drugs. Methods are being developed that predict human metabolism of drags and susceptibility to chemical ***: P450-null and P450-humanized mice were developed. UPLC-QTOFMS, LC/MS/MS and GC/MS were used as analytic tools to examine the metabolism of drags in these ***: Comparing P450-null with wild-type mice yields metabolic patterns that reflect the catalytic activities of specific P450 forms. The humanized mice determine the catalytic activities and regulation of P450 genes found in humans. To study metabolism, drugs or other xenobiotic chemicals were administered to mice and serum and urine examined for production of metabolites that are not found in untreated mice. These metabolites can be derived from the drag or from organ toxicities. Specific examples will be presented with dietary alkaloids and anti-cancer ***: By accurate mass determination using UPLC-QTOFMS, pathways of metabolism of drugs can be rapidly assessed and data extrapolated to humans.

关键词： drug metabolism metabonomics P450s UPLC-QTOEMS

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