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Role of protein kinase c α and cyclin D1 in the proliferation of airway smooth muscle in asthmatic rats

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chinese Medical Journal 2008年第20期121卷 2070-2076页

作者： QIAO Li-fen XU Yong-jian LIU Xian-sheng XIE Jun-gang WANG Jin DU chun-ling ZHANG Jian NI Wang cHEN Shi-xin Department of Respiratory Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China Department of Emergency Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background Airway smooth muscle （ASM） is suspected to be a determining factor in the structural change of asthma. However, the role of protein kinase c α （PKcα） and cyclin D1 involved in the dysfunction of ASM leading to asthmatic symptoms is not clear. In this study, the central role of PKcα and cyclin D1 in ASM proliferation in asthmatic rats was explored. Methods Thirty-six pathogen-free male Brown Norway （BN） rats were randomly divided into 2 groups： control groups （group N1, N2 and N3） and asthmatic groups （group A1, A2, and A3）. Groups A1, A2 and A3 were challenged with ovalbumin （OA） for 2 weeks, 4 weeks and 8 weeks respectively. control animals were exposed to an aerosolized sterile phosphate buffered saline （PBS）. The ASM mass and nucleus numbers were studied to estimate the degree of airway remodeling by the hematoxylin-eosin staining method. PKcα and cyclin D1 expression in the ASM cells was detected by reverse transcription polymerase chain reaction （RT-PcR） and immunohistochemistry. The relation between PKcα and cyclin D1 was assessed by linear regression analysis. PKc agonist phorbol 12-myristate 13-acetate （PMA）, PKc inhibitor Ro31-8220 and an antisense oligonucleotide against cyclin D1 （ASOND） were used to treat ASM cells （ASMcs） obtained from the 2 weeks asthmatic rats. The cyclin D1 protein expression level was detected by Western blotting.Results compared with the control group, the PKcα and cyclin D1 mRNA levels were increased in the asthmatic group. Similar to RT-PcR results, immunohistochemistry analysis for PKcα and cyclin D1 expression revealed an increased production in ASMcs after allergen treatment for 2, 4 and 8 weeks compared with the respective control groups. No difference in expression of PKcα and cyclin D1 in ASM were found in the 2, 4 or 8 weeks asthmatic rats. There were significant positive correlations between PKcα and cyclin D1 expression, both transcriptionally （r=0.944, P 〈0.01） and translationally （r=0.826, P 〈0.01）, in A

关键词： asthma bronchial diseases muscle smooth protein kinase c cyclin D1 cell proliferation

Isoform-selective modulators for metabotropic glutamate receptors and protein kinase c:Synthesis and biological evaluation

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chinese Journal of chemistry 1998年第4期16卷 292-302页

作者：马大为 Shanghai Institute of Organic chemistry Chinese Academy of SciencesShangha 200032China

The synthetic studies for some known modulators of metabotropic glutamate receptors (mGluRs) such as (S)-αM4cPG, (1S,3R)-AcPD, L-ccG-I are described. Based on the structure of αM4cPG several new conformationally constrained analogues are design ed and synthesized. Among them APIcA is a selective antagonist for group II mGluRs. Also, a new benzolactam-V8 analogue is found to have better isoform-selectivity for protein kine c family. Three different protocols for synthesizing benzolactam-VS analogues are developed to meet the requirement for delivering more analogues to test.

关键词： Asymmetric synthesis metabotropic glutamate receptor protein kinase c

Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase c pathway

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Acta Pharmacologica Sinica 2005年第2期26卷 171-176页

作者： Sun ZHANG~2,Ying HUANG~2,Yi-chun ZHU~2,Tai YAO~(2,3,4)~2Department of Physiology and Pathophysiology ~3State Key Laboratory for Medical Neurobiology,Shanghai Medical college of FudanUniversity,Shanghai 200032,china Department of Physiology and Pathophysiology Shanghai Medical College of Fudan University Shanghai China State Key Laboratory for Medical Neurobiology Shanghai Medical College of Fudan University Shanghai China

Aim:To investigate the mechanism of the action of estrogen,which stimulates therelease of secreted amyloid precursor protein α(sAPPα)and decreases the gen-eration of amyloid-β protein(Aβ),a dominant component in senile plaques in thebrains of Alzheimer's disease ***:Experiments were carried out inprimary rat cortical neurons,and Western blot was used to detect sAPPα in aculture medium and the total amount of cellular amyloid precursor protein(APP)***:17β-Estradiol(but not 17α-estradiol)and β-estradiol 6-(O-carboxymethyl)oxime:BSA increased the secretion of sAPPα and this effect wasblocked by protein kinase c(PKc)inhibitor calphostin c,but not by the classicalestrogen receptor antagonist IcI 182,***,17β-estradiol did not alterthe synthesis of cellular ***:The effect of 17β-estradiol on sAPPαsecretion is likely mediated through the membrane binding sites,and needs mo-lecular configuration specificity of the ***,the action of the PKc-dependent pathway might be involved in estrogen-induced sAPPα secretion.

关键词： Alzheimer disease estrogen amyloid precursor protein estrogen receptors protein kinase c

cigarette smoke extract promotes human pulmonary artery smooth muscle cells proliferation through protein kinase c alpha-dependent induction of cyclin D1

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chinese Medical Journal 2010年第24期123卷 3663-3670页

作者： XIANG Min XU Yong-jian LIU Xian-sheng ZENG Da-xiong Department of Respiratory Medicine Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 Chin Department of Respiratory Medicine Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background Exposure to cigarette smoke stimulates the proliferation of human pulmonary artery smooth muscle cells （HPASMcs） in vivo and in vitro. However, the molecular mechanism remains unclear. This study aimed at investigating the role of signaling pathways involving protein kinase c alpha （PKcα） and cyclin D1 in the cigarette smoke extract （cSE）-induced HPASMcs *** Synchronized HPASMcs were treated with different concentrations of cSE. cell proliferation was evaluated by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyttetrazolium bromide （MTT） assay and cell counting. cell cycle was analyzed by flow cytometry with propidium iodide staining. Activation of PKcα was measured by detecting the expression of PKcαprotein in the cytosolic and membrane fractions using Western blotting analysis. Small interfering RNA （siRNA） was used to knockdown PKcα and cyclin D1. The cyclin D1 mRNA was assessed by real-time RT-PcR. The PKcα and cyclin D1protein levels were detected by Western *** Low concentrations of cSE （1%-10%） stimulated proliferation of HPASMcs, with its maximal effect at 5%.cSE （5%） led to PKcα activation. Inhibition of PKcα activity using G（o） 6976 or siRNA-mediated knockdown of PKcα significantly attenuated cSE-induced cell proliferation and G1/S transition. cyclin D1, one of key regulators of G1/S transition, was found to be upregulated by 5% cSE at both the mRNA and protein levels. cSE-stimulated cellproliferation and G1/S transition was abolished by cyclin D1 siRNA. Moreover, G（o） 6976 or PKcα siRNA significantlysuppressed cSE-induced upregulation of cyclin D1 at both the mRNA and protein *** PKcα-cyclin D1 pathway at least partially mediates the cSE-induced proliferation in HPASMcs.

关键词： cell proliferation cell cycle protein kinase c cyclin D1

calycosin improves cognitive function in a transgenic mouse model of Alzheimer's disease by activating the protein kinase c pathway

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Neural Regeneration Research 2017年第11期12卷 1870-1876页

作者： Lei Song Xiaoping Li Xiao-xue Bai Jian Gao chun-yan Wang Department of Respiratory Medicine First Hospital of Jilin UniversityChangchunJilin ProvinceChina Department of Pediatrics First Hospital of Jilin UniversityChangchunJilin ProvinceChina cadre's Ward First Hospital of Jilin UniversityChangchunJilin provinceChina Department of Neurosurgery China-Japan Union Hospital of Jilin UniversityChangchunJilin ProvinceChina

The major pathological changes in Alzheimer＇s disease are beta amyloid deposits and cognitive impairment. calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produce estrogen-like effects. Radix astragali calycosin has been shown to relieve cognitive impairment induced by diabetes mellitus, suggesting calycosin may improve the cognitive function of Alzhei- mer＇s disease patients. The protein kinase c pathway is upstream of the mitogen-activated protein kinase pathway and exerts a neuropro- tective effect by regulating Alzheimer＇s disease-related beta amyloid degradation. We hypothesized that calycosin improves the cognitive function of a transgenic mouse model of Alzheimer＇s disease by activating the protein kinase c pathway. Various doses of calycosin （10, 20 and 40 mg/kg） were intraperitoneally injected into APP/PS1 transgenic mice that model Alzheimer＇s disease. calycosin diminished hippocampal beta amyloid, Tau protein, interleukin-lbeta, tumor necrosis factor-alpha, acetylcholinesterase and malondialdehyde levels in a dose-dependent manner, and increased acetylcholine and glutathione activities. The administration of a protein kinase c inhibitor, cal- phostin c, abolished the neuroprotective effects of calycosin including improving cognitive ability, and anti-oxidative and anti-inflammato- ry effects. Our data demonstrated that calycosin mitigated oxidative stress and inflammatory responses in the hippocampus of Alzheimer＇s disease model mice by activating the protein kinase c pathway, and thereby improving cognitive function.

关键词： nerve regeneration neurodegeneration Alzheimer's disease calycosin hippocampus oxidative stress inflammation mice protein kinase c calphostin c glutathione malondialdehyde neural regeneration

Expression of protein kinase c isoforms in retinoic acid-induced differentiation of mouse embryonic stem cells into neuron-like cells

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chinese Medical Journal 2007年第18期120卷 1639-1642页

作者： GAO Qian-ying WU Jun-shu WANG Zhi-chong GE Jian HUANG Dan-ping State Key Laboratory of Ophthalmology Zhongshan OphthalmicCenter Sun Yat-sen University Guangzhou 510060 China

protein kinases c （PKcs）, a big family including 12 isoenzymes, are divided into three major groups according to the variability of their regulatory domains^1.2 The classical PKcs （cPKc） including PKcα, PKcβI, PKcβ2, and PKc7 need calcium, phosphatidylserine, and diacylglycerol or phorbol esters for full activation. The novel PKcs （nPKc） including PKcδ, PKcε, PKcη, PKcθ, and PKc, do not require calcium for their activation. The third group is the atypical PKcs （aPKc） including PKcζ, PKcλ and PKc~ whose activation depends on phosphatidylserine but not on diacylglycerol, calcium or phorbol esters. The differences in function of specific PKc isoforms are mainly due to their different subcellular localization, activation or inhibition by different stimuli, and transcriptional regulation.

关键词： embryo stem cells protein kinase c retinoic acid

Effect of cigarette smoke extract on proliferation of rat pulmonary artery smooth muscle cells and the relevant roles of protein kinase c

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chinese Medical Journal 2007年第17期120卷 1523-1528页

作者： HU Jing XU Yong-jian ZHANG Zhen-xiang TIAN Feng Department of Respiratory Medicine Tongji Hospital Affiliated toTongji Medical College Huazhong University of Science andTechnology Wuhan 430030 China

Background Increased proliferation of pulmonary vascular cells and muscularisation of pulmonary vessels are frequently observed in human smokers and in animals exposed to cigarette smoke. To elucidate the molecular mechanisms leading to these changes, we studied the in vitro effect of cigarette smoke extract （cSE） on proliferation of pulmonary artery smooth muscle cells （PASMcs） and activation of protein kinase c （PKc）, an important kinase implicated in cell proliferation. Methods PASMcs cultured from 12 normal Wistar rats were studied in the following conditions：（1） PASMcs were exposed to different concentrations of cSE for 24 hours, then MTT colorimetric assay was used for detection of cell proliferation. cell viability was assessed by trypan blue exclusion. （2） PASMcs were pre-incubated with phorbol 12-myristate 13-acetate （PMA） for 24 hours or Ro31-8220 for 30 minutes before exposure to 5% cSE for 24 hours. cell proliferation was examined by MTT colorimetric assay, cell cycle analysis and proliferating cell nuclear antigen （PcNA） immunocytochemical staining. （3） PASMcs were exposed to 5% cSE for 24 hours. Then PKc-a mRNA expression was detected by reverse transcription-polymerase chain reaction （RT- PcR） and protein expression by Western blotting, while PKc-α translocation was observed by immunofluorescence staining and confocal microscopy. （4） PASMcs were transfected with specific antisense oligodeoxynucleotides against PKc-a 6 hours before exposure to 5% cSE for 24 hours. PKc-α protein expression and cell proliferation were detected by methods described previously. Results （1） Low concentration of cSE （5%） increased proliferation of PASMcs, whereas high concentrations （20%, 30%） were inhibitory as a result of cytotoxicity. （2） The value of absorbance （Value A）, proliferation index （PI）, S-phase cell fraction （SPF） and average optical density of PcNA staining in PASMcs from 5% cSE exposure group （0.306 ± 0.033, 0.339 ± 0.033, 0.175 ± 0.021, 0.315 ± 0.038,

关键词： tobacco smoke pollution protein kinase c pulmonary artery muscle, smooth cell proliferation

Up-regulation and time course of protein kinase c immunoreactivity during persistent inflammation of the rat spinal cord

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Neural Regeneration Research 2008年第4期3卷 349-353页

作者： Liping Yang Qingjun Li Department of Neurology the 263 Hospital of Chinese PLA Beijing 101149China Department of Pathophysiology Institute of Basic Medical Science Hebei Medical University Shijiazhuang 050017 Hebei Province China

BAcKGROUND： It has been reported that activation and/or translocation of protein kinase c （PKc） is related to hyperalgesia, and changes in PKc expression in the dorsal horn of spinal cord take place during inflammatory pain. OBJEcTIVE： To observe PKc changes in the dorsal horn of spinal cord using immunohistochemistry and to measure the time-course during persistent pain produced by chemical stimulation with a right hind-paw injection of formalin. DESIGN： Randomized controlled animal experiment. SETTING： Institute of Basic Medical Science, Hebei Medical University MATERIALS： The present experiment was performed at the Department of Pathophysiology, Institute of Basic Medical Science, Hebei Medical University between September 2000 and June 2002. Forty-two Sprague-Dawley rats, weighing 260-280 g, irrespective of gender, were provided by the center of Animal Experimentation at Hebei Medical University. PKc antibody was provided by Sigma, USA. Immunohistochemistry kits were purchased from Zhongshan Biotechnology company, Beijing. HPIAS-1000 definition multicolor system was provided by Qianping Wuxiang Project company of Tongji Medical University. Animal use during experimentation was consistent with the standards of Animal Ethics committee. METHODS： Sprague-Dawley rats were divided randomly into control （n = 6） and experimental groups （n = 36）. Experimental rats were given an intracutaneous injection of 5% formalin into the planta surface of the right hind-paw. Animals with inflammatory pain were anesthetized and sacrificed to obtain the L5 spinal region at 1, 3, 12 hours, 1, 3, and 7 days after formalin treatment, with 6 rats in each time group. The spinal cords at the L5 region were collected from the control group following sodium chloride injections into the planta surface of the right hind-paw, identical to the experimental group. MAIN OUTcOME MEASURES： Pain reaction of experimental rats after formalin treatment. PKc-positive neurons, and distribution of PKc-immun

关键词： pain protein kinase c dorsal horn of spinal cord immunohistochemistry formalin test

Nitric oxide induces heat shock protein 72 production and delayed protection against myocardial ischemia in rabbits via activating protein kinase c

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chinese Medical Journal 2008年第12期121卷 1109-1113页

作者： LI Wei-jie ZHAO Zhi-jing LIU Bing ZHANG Dian-xin LI Fei WANG Hai-chang GUO Wen-yi JIA Guo-liang Masafumi Kitakaze Masatsugu Hori Department of cardiology Xijing Hospital Fourth Military Medical University Xi'an Shaanxi 710033 China First Department of Medicine Osaka University School of Medicine Suita 565 Japan

Background Nitric oxide （NO） is a biologically active molecule which has been reported to protect the heart against ischemia and reperfusion injury in different species. This study aimed to test the hypothesis that nitric oxide may induce the expression of heat shock protein 72 （HSP72） which may protect the heart against ischemia.Methods Rabbits were given intravenous saline or S-nitroso-N-acetylpenicillamine （SNAP）, a nitric oxide donor, or Zaprinast, an inhibitor of cyclic guanosine monophosphate （GMP）-phosphodiesterase, which may increase myocardial cyclic GMP content. Twenty-four hours later, the rabbits were either sampled to measure HSP72, or induced with a 30-minute coronary occlusion followed by a 120-minute reperfusion, and then the infarct size was measured. Meanwhile, chelerythrine （cHE, an inhibitor of protein kinase c） was given intravenously 5 minutes before SNAP injection and the effect on HSP72 expression and infarct size was determined.Results Twenty-four hours after pretreatment, immunoblotting showed HSP72 expression increased in the SNAP group compared with control groups, and this was blocked by cHE. Myocardial infarct size in the SNAP group was smaller than that of the control group （（32.4±5.8）% vs （51.1±4.7）%, P 〈0.05）. Pretreated with cHE abolished the infarct size-limiting effect of SNAP （（46.0±5.1）%）. Pretreatment with Zaprinast neither induced HSP72 expression nor reduced infarct size （（55.4±5.4）%）.conclusion NO induced HSP72 expression and a delayed protection to the heart via the activities of protein kinase c by a cyclic GMP-independent pathway.

关键词： nitric oxide heat shock protein 72 protein kinase c myocardial infarction