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Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury

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Neural Regeneration Research 2023年第6期18卷 1339-1346页

作者： Chen Chen Huiyuan Ji Nan Jiang Yingjie Wang Yue Zhou Zhenjie Zhu Yuming Hu Yongjun Wang Aihong Li Aisong Guo Department of Rehabilitation Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina Department of Rehabilitation Medicine The Second Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Department of Neurology Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina Department of Traditional Chinese Medicine Affiliated Hospital of Nantong UniversityNantongJiangsu ProvinceChina

Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

关键词： 25-hydroxycholesterol astrocyte chemotaxis cholesterol metabolism cholesterol-25-hydroxylase lipid homeostasis macrophage par1 spinal cord injury thrombin

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

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Cellular & Molecular Immunology 2020年第1期17卷 50-63页

作者： Atsushi Takahashi-Kanemitsu Christopher T.Knight Masanori Hatakeyama Department of Microbiology Graduate School of MedicineThe University of TokyoTokyoJapan

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretion system.Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala(EPIYA)motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners.Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks:sustained proliferation,evasion of growth suppressors,invasiveness,resistance to cell death,and genomic instability.Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation.The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation.Since Helicobacter pylori infection triggers a proinflammatory response in host cells,a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa.Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions,the multistep nature of gastric cancer development should include a“hit-and-run”process of CagA action.Thus,acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the“hit-and-run”process of gastric carcinogenesis.

关键词： cagA/CagA Helicobacter pylori SHP2 par1 inflammation “hit-and-run”carcinogenesis

Interactions between HLH and bHLH Factors Modulate Light-Regulated Plant Development

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Molecular Plant 2012年第3期5卷 688-697页

作者： Yaqi Hao Eunkyoo Oh GUtsu Choi Zongsuo Liang Zhi-Yong Wang College of Life Science Northwest A＆F University Yangling Shaanxi 712100 China Department of Plant Biology Carnegie Institution of Washington Stanford CA 94305 USA Department of Biological Sciences KAIST Daejeon 305-701 Korea

Phytochromes （Phy） and phytochrome-interacting factor （PIF） transcription factors constitute a major signal- ing module that controls plant development in response to red and far-red light. A low red：far-red ratio is interpreted as shading by neighbor plants and induces cell elongation--a phenomenon called shade-avoidance syndrome （SAS）. par1 and its closest homolog par2 are negative regulators of SAS; they belong to the HLH transcription factor family that lacks a typical basic domain required for DNA binding, and they are believed to regulate gene expressions through DNA binding transcription factors that are yet to be identified. Here, we show that light signal stabilizes par1 protein and par1 interacts with PIF4 and inhibits PIF4-mediated gene activation. DNA pull-down and chromatin immunoprecipitation （CHIP） assays showed that par1 inhibits PIF4 DNA binding in vitro and in vivo. Transgenic plants overexpressing par1 （parIOX） are insensitive to gibberellin （GA） or high temperature in hypocotyl elongation, similarly to the pifq mutant. In addition to PIF4, par1 also interacts with PRE1, a HLH transcription factor activated by brassinosteroid （BR） and GA. Overexpression of PRE1 largely suppressed the dwarf phenotype of parIOX. These results indicate that par1-PRE1 and par1-PIF4 het- erodimers form a complex HLH/bHLH network regulating cell elongation and plant development in response to light and hormones.

关键词： par1 PIF4 PRE1 bHLH DNA binding

A novel protease-activated receptor 1 inhibitor from the leech Whitmania pigra

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Chinese Journal of Natural Medicines 2019年第8期17卷 591-599页

作者： REN Shen-Hong LIU Zhao-Jun CAO Yuan HUA Yi CHEN Cong GUO Wei KONG Yi School of Life Science & Technology China Pharmaceutical University Nanjing 210009 China School of Life Science China Pharmaceutical University Nanjing 210009 China Jiangsu Province Hospital of Chinese Medicine Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing 210029 China

Whitmania pigra has been used as a traditional Chinese medicine(TCM) for promoting blood circulation, alleviating blood coagulation, activating meridians and relieving stasis for several hundred years. However, the therapeutic components of this species, especially proteins and peptides were poorly exploited. Until now only a few of them were obtained by using chromatographic isolation and purification. In recent decade, transcriptome techniques were rapidly developed, and have been used to fully reveal the functional components of many animal venoms. In the present study, the c DNA of the salivary gland of Whitmania pigra was sequenced by illumina and the transcriptome was assembled by using Trinity. The proteome were analysed by LC-MS/MS. Based on the data of the transcriptome and the proteome, a potential antiplatelet protein named pigrin was found. Pigrin was cloned and expressed using P. pastoris GS115. The antiplatelet and antithrombotic bioactivities of pigrin were tested by using aggregometer and the rat arterio-venous shunt thrombosis model, respectively. The bleeding time of pigrin was measured by a mice tail cutting method. The docking of pigrin and protease-activated receptor 1(par1) or collagen were conducted using the ZDOCK Server. Pigrin was able to selectively inhibit platelet aggregation stimulated by par1 agonist and collagen. Pigrin attenuated thrombotic formation in vivo in rat, while did not prolong bleeding time at its effective dosage. There are significant differences in the key residues participating in binding of Pigrin-Collagen complex from Pigrin-par1 complex. In conclusion, a novel par1 inhibitor pigrin was found from the leech Whitmania pigra. This study helped to elucidate the mechanism of the leech for the treatment of cardiovascular disorder.

关键词： Whitmania pigra Transcriptome and proteome par1 inhibitor Thrombosis

脑出血后脑组织内凝血酶受体1(par1)的表达及其病理意义

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中风与神经疾病杂志 2004年第2期21卷 100-103页

作者：姜亚军常诚张琳吴明华符为民吴灏昕南京中医药大学附属江苏省中医院脑病中心江苏南京210029 东南大学附属中大医院神经内科江苏南京210009 南京中医药大学基础医学院江苏南京210029

目的　探讨脑出血后脑组织内凝血酶受体 1(par1)的表达规律及其意义。方法　成年大鼠分为 3组 ,分别向大脑基底节区注入全血、全血加水蛭素、或生理盐水。于注射后 6 h、2 4 h、72 h和 7d,取脑组织 ,检测脑内par1表达 (免疫组织化学法 ... 详细信息

目的　探讨脑出血后脑组织内凝血酶受体 1(par1)的表达规律及其意义。方法　成年大鼠分为 3组 ,分别向大脑基底节区注入全血、全血加水蛭素、或生理盐水。于注射后 6 h、2 4 h、72 h和 7d,取脑组织 ,检测脑内par1表达 (免疫组织化学法 )。同时 ,观察神经细胞的凋亡情况 (Tunel法 )和脑组织水含量 (干燥法 )。结果　与生理盐水对照组比较 ,脑出血后血肿周围脑组织内 par1免疫阳性细胞数明显升高 (Ppar1表达上调开始于脑出血后 6 h,72 h达高峰 ,7d后下降。加用凝血酶抑制剂 -水蛭素者 ,出血周围组织内 par1表达明显抑制 ,同时脑组织水肿和神经凋亡显著减轻。结论　脑出血后脑组织 par1表达增加。 par1高表达可能介导了脑出血后神经损伤的过程。

关键词：脑出血后脑组织凝血酶受体 par1 组织表达病理分析

MK通过EPCR/par1通路促进乳腺癌MDA-MB-231细胞体外血管生成

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临床与实验病理学杂志 2015年第9期31卷 961-965页

作者：王庆苓刘冬梅韩正杰吴永平徐州医学院病理学教研室徐州221004

目的探讨中期因子(midkine,MK)在人乳腺癌MDA-MB-231细胞体外血管生成中的作用及其机制。方法采用shRNA干扰技术降低MDA-MB-231细胞MK表达,应用Western blot技术检测肿瘤细胞中内皮蛋白C受体(endothelial protein C receptor,EPCR)的表... 详细信息

目的探讨中期因子(midkine,MK)在人乳腺癌MDA-MB-231细胞体外血管生成中的作用及其机制。方法采用shRNA干扰技术降低MDA-MB-231细胞MK表达,应用Western blot技术检测肿瘤细胞中内皮蛋白C受体(endothelial protein C receptor,EPCR)的表达;干扰MK和EPCR表达或通过抗体阻断活化蛋白酶激活受体1(protease-activated receptor 1,par1)作用后,制备肿瘤条件培养基作用于人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs),通过CCK-8试剂盒检测HUVECs增殖、Transwell小室检测迁移以及Matrigel表面培养检测脉管形成能力。结果干扰MK表达后,EPCR表达随之降低。干扰MK和EPCR低表达后,HUVECs增殖、迁移及脉管形成能力均低于对照组(Ppar1作用后,HUVECs增殖、迁移及脉管形成能力低于对照组和EPCR干扰组(Ppar1通路促进乳腺癌MDA-MB-231细胞体外血管生成。

关键词：乳腺肿瘤 midkine EPCR par1 血管生成

par1与par4在肿瘤转移中作用的研究进展

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军事医学科学院院刊 2007年第6期31卷 586-588,598页

作者：于红阳于爱平吴祖泽军事医学科学院放射与辐射医学研究所北京100850

以往研究表明,凝血酶通过其细胞表面的受体——蛋白酶活化受体(protease-activated receptors,pars)影响肿瘤的转移。par1是介导凝血酶促肿瘤转移的主要受体,表达于血管内皮细胞上的par1通过影响肿瘤血管新生而促进肿瘤转移。近年来研... 详细信息

以往研究表明,凝血酶通过其细胞表面的受体——蛋白酶活化受体(protease-activated receptors,pars)影响肿瘤的转移。par1是介导凝血酶促肿瘤转移的主要受体,表达于血管内皮细胞上的par1通过影响肿瘤血管新生而促进肿瘤转移。近年来研究发现,par1表达于多数肿瘤细胞表面,其表达水平往往预示着该细胞侵袭能力的强弱。par4在肿瘤转移中的作用报道较少,仅有的几篇报道提示,par4在血管内皮细胞中有表达且在血管发育中起作用,但其是否通过影响肿瘤血管新生而参与肿瘤转移还未见报道。同时,par4在肿瘤细胞上的表达仅见于肺癌组织,且其表达水平与肺癌患者的生存直接相关,提示par4可能是介导凝血酶影响肿瘤转移的另一重要受体。

关键词：凝血酶 par1 par4 肿瘤转移内皮,血管肺肿瘤

亚低温对脑出血后par1、AIF表达影响的实验性研究

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亚低温对脑出血后PAR1、AIF表达影响的实验性研究

作者：李晓玲兰州大学

学位级别：硕士

目的观察亚低温治疗对脑出血后凝血酶受体1(par1)、凋亡诱导因子(AIF)表达的影响,探讨其变化规律,试图揭示亚低温脑保护的机制。方法54只雄性SD大鼠,随机分为生理盐水组、脑出血组和亚低温+脑出血组。采用自体血注入法建立脑出血模型,... 详细信息

目的观察亚低温治疗对脑出血后凝血酶受体1(par1)、凋亡诱导因子(AIF)表达的影响,探讨其变化规律,试图揭示亚低温脑保护的机制。方法54只雄性SD大鼠,随机分为生理盐水组、脑出血组和亚低温+脑出血组。采用自体血注入法建立脑出血模型,检测三个组血肿周围组织中par1、AIF在出血后24h、72h、7d三个时间点的表达(免疫组化法)。同时,干湿重法测定脑出血组和亚低温+脑出血组的脑水含量。结果①脑出血后24h血肿周围组织中par1、AIF的表达开始增加,于72h达高峰,7d后下降(P＜0.05),三个时间点两者的表达均高于生理盐水组(P＜0.05);②亚低温组par1、AIF在24h、72h、7d三个时间点的表达均低于脑出血组;③脑出血组的脑水含量于出血后24h开始增加,72h达高峰,7d时开始下降(P＜0.01);④亚低温组脑水含量在三个时间点与脑出血组比较明显下降(P＜0.01);⑤脑出血后par1随时间变化规律与脑水含量一致。结论1脑出血后血肿周围组织中par1、AIF的表达增加,二者可能参与了脑出血后脑损伤,分别在出血后脑水肿的形成和神经元凋亡方面起了重要的作用;2亚低温治疗能抑制脑出血后血肿周围组织中par1、AIF的表达,在减轻脑水肿和神经元凋亡的同时发挥了其脑保护作用。

关键词：亚低温脑出血 par1 AIF 脑水肿凋亡

aFGF、bFGF和EGF对小鼠皮肤成纤维细胞生长及蛋白酶活化受体1的影响

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中国生化药物杂志 2011年第3期32卷 180-182,186页

作者：靳波徐盈斌刘旭盛唐锦明曹鹏飞中山大学附属第一医院烧伤科广东广州510080

目的比较酸性成纤维细胞生长因子（aFGF）、碱性成纤维细胞生长因子（bFGF）和表皮生长因子（EGF）对小鼠皮肤成纤维细胞增殖的作用以及对蛋白酶活化受体1（par1）的影响,探讨par1与促进成纤维细胞增殖的关系。方法取出生3周体质量为15-... 详细信息

目的比较酸性成纤维细胞生长因子（aFGF）、碱性成纤维细胞生长因子（bFGF）和表皮生长因子（EGF）对小鼠皮肤成纤维细胞增殖的作用以及对蛋白酶活化受体1（par1）的影响,探讨par1与促进成纤维细胞增殖的关系。方法取出生3周体质量为15-20 g的NIH小鼠皮肤进行成纤维细胞培养,采用MTT法测定细胞数和活度,免疫细胞学XTT法检测aFGF、bFGF和EGF对小鼠皮肤成纤维细胞生长的影响,RT-PCR法检测小鼠皮肤成纤维细胞中par1 mRNA的表达。结果小鼠皮肤成纤维细胞健康生长,aFGF、bFGF和EGF对小鼠皮肤成纤维细胞生长的促进作用在实验组与对照组间有显著性差异（P〈0.05）,其对成纤维细胞作用浓度梯度较为明显;小鼠皮肤成纤维细胞存在par1 mRNA的表达,且三种生长因子对其表达的影响有差异,以aFGF组表达最显著。结论aFGF、bFGF和EGF均能促进成纤维细胞增殖,以aFGF的促进作用最强,par1可能参与成纤维细胞的增殖。

关键词： aFGF bFGF 表皮生长因子成纤维细胞 par1