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Acta Pharmacologica Sinica 2006年第5期27卷 549-554页

作者： Yi ZHU Zhen-lun GU Zhong-qin LIANG Hui-lin ZHANG zheng-hong qin~2 department of pharmacology,soochow university school of medicine,suzhou 215123,China departmentofpharmacology SoochowUniversitySchoolofMedicineSuzhou215123China

Aim:In our previous studies we found that cyclopentenane prostaglandin A1(PGA1) had neuroprotective effects in a rodent ischemic *** the presentstudy we aimed to investigate the inhibitory effect of PGA1 on platelet ***:The rate of aggregation of human platelets was measured by *** rate of adhesion of platelets to cultured endothelial cells wasdetermined by using [~3H]-adenine labeled platelets.5-Hydroxytryptamine releasefrom platelets was measured with O-phthaldialdehyde *** levels of TXB2,a stable metabolite of TXA2,were determined by *** in platelet morphology were observed using an electronmicroscope,and the intraplatelet free calcium concentrations were measured withFluo-3/AM FCM ***:PGA1 significantly inhibited thrombin-,col-lagen-and ADP-induced aggregation and adhesion of *** morphologi-cal changes of platelets induced by thrombin were blocked by ***1inhibited the release of 5-hydroxytyptamine from dense granules and the synthe-sis of ***:PGA1 inhibits the activation of platelets probablythrough blocking increases in intracellular calcium concentration and TXA2synthesis.

关键词： prostaglandin A1 platelet aggregation calcium TXA2

Neuroprotective effects of pioglitazone is associated with PPARγ-mediated inhibition of NF-kB signaling pathway in rat model of permanent focal cerebral ischemia

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Neuroprotective effects of pioglitazone is associated with P...

Quality Control System of the Endoplasmic Reticulum and Related Diseases

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Chao WEI,Hui-Ling ZHANG,zheng-hong qin department of pharmacology,soochow university school of medicine,suzhou 215123,China

＜正＞Objective To investigate the neuroprotective actions of pioliotazone（Piog） and the effects of Piog-mediated PPARγ activation on NF-B signaling pathway in rat model of permanent focal cerebral *** Permanent middle cerebral artery occlusion（pMCAO） model was induced by using intraluminal filament technique in ***（0.5, 1 and 2 mg/kg） was administrated intraperitoneally（i.p.） twice at 24 h before and at the time of ischemia,or administrated intraperitoneally（i.p.） only once 10 min after the onset of *** neuroprotection of Piog was analyzed by scoring neurological deficits,assessing brain infarction volume with 2,3,5-triphenyltetrazolium chloride（TTC） and determining the brain water content at 24 h after ischemia.A selective PPARγ antagonist GW9662 150,300 and 600 nmol/kg was administrated intracerebral ventricularly（i.c.v.） 30 min before *** then Piog（1 mg/kg） was administrated intraperitoneally （i.p.） 10 min after the onset of *** volume was assessed with 2,3,5-triphenyltetrazolium chloride （TTC） at 24 h after *** blot analysis was employed to determine alterations in IκBy,p-ERK in ischemic striatum at the indicated *** sections were immunostained for NF-kB p65 in ischemic ***-PCR was used to measure p53 mRNA levels in ischemic *** Piog（0.5,1 and 2 mg/kg） reduced infarction volume in a dose-dependent manner（P＜0.05,P＜0.01） when administered twice at 24 h before and at the time of ischemia,or only once at 10 min after the onset of *** 0.5,1 and 2 mg/kg also significantly ameliorated motor behavior deficits,diminished the increase in brain water content（P＜0.01）.Pretreatment with the irreversible PPARγantagonist GW9662 300 and 600nmol/kg abolished piog’s neuroprotection against ischemia（P＜0.01）.Western blot analysis revealed that Piog（0.5,1 and 2 mg/kg） markedly up-regulated the levels of IκBγin ischemic striatum at 12 h after ischemia（P＜0.01）.GW9662 significantly decr

关键词： pioglitazone PPARγ GW9662 cerebral ischemia neuroprotection apoptosis NF-κB signal transduction

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Acta Biochimica et Biophysica Sinica 2006年第4期38卷 219-226页

作者： Jun-Chao WU Zhong-qin LIANG zheng-hong qin* department of pharmacology,school of medicine,soochow university,suzhou 215123,China departmentofpharmacology SchoolofMedicineSoochowUniversitySuzhou215123China

The quality control (QC) system of the endoplasmic reticulum (ER) is an important monitoringmechanism in the protein maturation process,which ensures export of properly folded proteins from the *** or incompletely folded proteins are retained in the ER for refolding or degradation by the ER-residing *** calnexin/calreticulin cycle and ER-associated degradation are the key elements *** two mechanisms work together to allow incorrectly folded proteins have additional opportunitiesto achieve their native *** QC dysfunction is involved in many diseases caused by mutantproteins,many of which are causes of neurodegenerative disorders.A better understanding of molecularregulation in the QC system will uncover the molecular pathogenic mechanisms of many diseases caused byprotein misfolding and help discover novel strategies for preventing or treating these diseases.

关键词： protein folding quality control calnexin/calreticulin cycle endoplasmic reticulum-associated degradation protein misfolding disease

Huntingtin processing in pathogenesis of Huntington disease

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Acta Pharmacologica Sinica 2004年第10期 3-9页

作者： zheng-hong qin, Zhen-lun GUdepartment of pharmacology, soochow university school of medicine, suzhou 215 007, China Laboratory of Cellular Neurobiology, department of Neurology, Massachusetts General Hospital and Harvard Medical school, MA 02129, USA

Huntington's disease (HD) is caused by an expansion of the polyglutamine tract in the protein named huntingtin. The expansion of polyglutamine tract induces selective degeneration of striatal projection neurons and cortical pyramidal neurons. The bio-hallmark of HD is the formation of intranuclear inclusions and cytoplasmic aggregates in association with other cellular proteins in vulnerable neurons. Accumulation of N-terminal mutant huntingtin in HD brains is prominent. These pathological features are related to protein misfolding and impairments in protein processing and degradation in neurons. This review focused on the role of proteases in huntingtin cleavage and degradation and the contribution of altered processing of mutant huntingtin to HD pathogenesis.

关键词： Huntington disease huntingtin caspase calpain proteasome protein aggregation autophagy neurodegeneration

Huntingtin Cleavage Induced by Thrombin In Vitro

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Acta Biochimica et Biophysica Sinica 2007年第1期39卷 15-18页

作者： Fang LIN Junchao WU Yan WANG and zhenghong qin department of pharmacology,Laboratory of Aging and Nervous Diseases,soochow university school of medicine,suzhou 215123,China department of pharmacology Laboratory of Aging and Nervous DiseasesSoochowUniversity School of MedicineSuzhou 215123China

Huntingtin (Htt) mutation causes Huntington's *** analysis of Htt revealed apossible thrombin cleavage site in the N-terminal region of *** order to investigate if thrombin can eleaveHtt,we expressed the N-terminal fragment (1-969) of wild-type (wt) Htt (Htt 1-969) in MCF-7 cells andstudied its cleavage pattern by thrombin in *** expression plasmid pcDNA3-Htt-18Q-969 was used totransfect MCF-cells and Htt 1-969 expression was confirmed with *** lysates wereincubated with thrombin (1 U/ml, 10 U/ml,and 30 U/ml) for 1 h in the presence or absence of hirudin,athrombin *** fragments were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis(SDS-PAGE) and detected with anti-Htt antibodies. An Htt fragment with molecular mass of approximately80 kDa was produced after incubation with *** size of this Htt fragment was anticipated bymolecular mass generated from thrombin-mediated cleavage at the amino acid 183 in the *** ofan 80 kDa fragment was inhibited by hirudin. This study provides the first evidence that Htt is cleaved bythrombin in vitro at amino acid *** endogenous thrombin cleaves Htt in vivo,the physiological significanceof thrombin-mediated cleavage of Htt should be further investigated.

关键词： thrombin huntingtin(Htt) cleavage hirudin

Animal models of Huntington's disease: implications in uncovering pathogenic mechanisms and developing therapies

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Acta Pharmacologica Sinica 2006年第10期27卷 1287-1302页

作者： Lin-hui WANG~2 zheng-hong qin~(3,4) departments of ~2Physiology and ~3pharmacology,soochow university school of medicine,suzhou 215123,China departmentsofPhysiologysoochowuniversityschoolofmedicine Suzhou215123China departmentsofpharmacology SoochowUniversitySchoolofMedicineSuzhou215123China

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder,which is caused by an abnormal expansion of Cytosine Adenine Guanine (CAG)trinucleotide repeat in the gene making huntingtin (Htt).Despite intensiveresearch efforts devoted to investigate molecular mechanisms of pathogenesis,effective therapy for this devastating disease is still not available at *** of various animal models of HD has offered alternative approachesin the study of HD molecular *** HD models,including chemical-induced models and genetic models,mimic some aspects of HD symptoms *** date,however,there is no ideal model which replicates all of theessential features of neuropathology and progressive motor and cognitive impair-ments of human *** a result,our understanding of molecular mechanisms ofpathogenesis in HD is still limited.A new model is needed in order to uncover thepathogenesis and to develop novel therapies for *** this review we discussedusefulness and limitations of various animal and cellular models of HD in uncov-ering molecular mechanisms of pathogenesis and developing novel therapies forHD.

关键词： Huntington’s disease huntingtin neurodegeneration animal models

Caspase-1 inhibitor Ac-YVAD-CHO attenuates quinolinic acid-induced increases in p53 and apoptosis in rat striatum

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Acta Pharmacologica Sinica 2005年第2期26卷 150-154页

作者： Yi CAO Zhen-lun GU Fang LIN Rong HAN zheng-hong qin department of pharmacology,soochow university school of medicine,suzhou 215007,China department of pharmacology Soochow University School of Medicine Suzhou 215007 China

Aim:To study the effects of the caspase-1 inhibitor Ac-YVAD-CHO on quinolinicacid(QA)-induced ***:Rats were pre-treated with intrastriatalinfusion of Ac-YVAD-CHO(2-8μg)before intrastriatal injection of QA(60 nmol).Striatal total proteins,genomic DNA,and nuclear proteins were *** of Ac-YVAD-CHO on QA-induced caspase-1 activity,internucleosomalDNA fragmentation, IκB-α degradation,NF-κB,and AP-1 activation,and increasesin p53 protein levels were measured with enzyme assays,agarose gel electro-phoresis,electrophoresis mobility shift assays,and Western blot ***:Pre-treatment with Ac-YVAD-CHO inhibited QA-induced internucleo-somal DNA ***-YVAD-CHO inhibited QA-induced increases incaspase-1 activity and p53 protein levels,but had no effect on QA-induced IκB-αdegradation,NF-κB or AP-1 ***:Caspase-1 is involved inQA-induced p53 upregulation but not IκB-α *** of caspase-1attenuates QA-induced apoptosis in rat striatum.

关键词： caspase 1 Ac-YVAD-CHO Huntington disease protein p53 NF-kappaB inhibitor alpha apoptosis NF-kappaB

The contribution of autophagy-lysosomal pathway to neuronal death and its underlying mechanisms in the rat models of permanent focal cerebral ischemia

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The contribution of autophagy-lysosomal pathway to neuronal ...

Molecular mechanism and regulation of autophagy

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Ya-Dan WEN department of pharmacology,soochow university school of medicine,suzhou 215123,China

＜正＞Objective To investigate activation of autophagy by permanent focal cerebral ischemia,the effects of blocking autophagy-lysosomal pathway,and evaluate relationships between its neuroprotection and the expression of LC3 and cathepsin B and Bcl-2 in rat models of permanent focal cerebral *** Permanent middle cerebral artery occlusion（pMCAO） model was induced by using intraluminal filament technique in *** of autophagy in neurons in ischemic cortex was observed using electron microscopy.3-MA（150-600 nmol） or CBI（5-10μg） was injected intracerebroventricularly（i.c.v.） immediately after the onset of ***-four hours after the occlusion,the neuroprotections of 3-MA or CBI were analyzed by scoring neurological deficits,assessing brain infarction volume with 2,3,5-triphenyl tetrazolium chloride（TTC）,determining the brain water *** blot was employed to determine alternations in LC3/Beclin l/cathepsin B levels in ischemic cortex 0 h,1 h,3 h,6 h,12 h,and 24 h after the occlusion,and alternations in LC3/Beclin l/cathepsin B/Bcl-2 levels in ischemic 3 h cortex after given 3-MA or *** Permanent focal cerebral ischemia induced the robust formation of autophagosome and enhanced presence of secondary lysosomes, fragmented endoplasmic reticulum,swollen *** deficits,infract areas and brain water content were significantly reduced in rats treated with 3-MA（300-600 nmol） or CBI（7.5-10μg）;3-MA（600 nmol） or CBI（10μg） could significantly reduce infract volume and brain water *** expression of LC3/Beclin 1/cathepsin B was significantly increased and peak at 3hr after pMACO,but the expression of Bcl-2 was significantly decreased 3 hr after the occlusion. 3-MA（600 nmol） or CBI（10μg） supressed the ischemia-induced increase in LC3/Beclin 1/cathepsin B,and recovered Bcl-2 levels in the ischemic ***（1） Permanent focal cerebral ischemia increased the formation of autophagosomes and actived lysosome

关键词： cerebral ischemic stroke neuroprotection autophagy lysosome apoptosis LC3 cathepsinB 3-MA cathepsin B inhibitor Bcl-2

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Acta Pharmacologica Sinica 2005年第12期26卷 1421-1434页

作者： Ya-ping YANG~2 Zhong-qin LIANG~2 Zhen-lun GU~2 zheng-hong qin~(2,3) 2 department of pharmacology,soochow university school of medicine,suzhou 215007,China departmentofpharmacology SoochowUniversitySchoolofMedicineSuzhou215007China

Autophagy is a major cellular pathway for the degradation of long-lived pro-teins and cytoplasmic organelles in eukaryotic cells.A large number of intracellu-lar/extracellular stimuli,including amino acid starvation and invasion ofmicroorganisms,are able to induce the autophagic response in *** discov-ery of the ATG genes in yeast has greatly advanced our understanding of themolecular mechanisms participating in autophagy and the genes involved in regu-lating the autophagic *** yeast genes have mammalian homologs,suggesting that the basic machinery for autophagy has been evolutionarily con-served along the eukaryotic *** regulation of autophagy is a very com-plex *** signaling pathways,including target of rapamycin(TOR)ormammalian target of rapamycin(mTOR),phosphatidylinositol 3-kinase-I(PI3K-I)/PKB,GTPases,calcium and protein synthesis all play important roles in *** molecular mechanisms and regulation of autophagy are dis-cussed in this review.

关键词： autophagy phosphatidylinositol 3-kinase Atg protein mTOR protein protein degradation