比特派官网网址安卓下载|pars
作者： 比特派官网网址安卓下载
2024-03-17 02:43:45
PARS中文(简体)翻译：剑桥词典
PARS中文(简体)翻译：剑桥词典
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pars 在英语-中文（简体）词典中的翻译
parsnoun [ C ]
medical
specialized uk
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/pɑːs/ us
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/pɑːrz/ plural partes
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a Latin word meaning "part", used in medical names and descriptions
（拉丁语，用于医学术语）部分
(pars在剑桥英语-中文（简体）词典的翻译 © Cambridge University Press)
C1
pars的翻译
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（拉丁語，用於醫學術語）部分…
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parricide
parrot
parrot-fashion
parry
pars
parse
Parsi
parsimonious
parsimoniously
“每日一词”
token
UK
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/ˈtəʊ.kən/
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/ˈtoʊ.kən/
something that you do, or a thing that you give someone, that expresses your feelings or intentions, although it might have little practical effect
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蛋白酶激活受体_百度百科
活受体_百度百科 网页新闻贴吧知道网盘图片视频地图文库资讯采购百科百度首页登录注册进入词条全站搜索帮助首页秒懂百科特色百科知识专题加入百科百科团队权威合作下载百科APP个人中心收藏查看我的收藏0有用+10蛋白酶激活受体播报讨论上传视频生物学术语本词条缺少概述图，补充相关内容使词条更完整，还能快速升级，赶紧来编辑吧！蛋白酶激活受体(protease activated receptors, PARS)属于G蛋白偶联受体家族成员，胞外信号调节激酶(extracellar signal-regulated kiase, ERK1/2)信号转道通路， 引起细胞核反应， 激活多种细胞转录因子。中文名蛋白酶激活受体外文名protease activated receptors简 写PARS学 科生物学性 质蛋白质位 置细胞表面特 点有七次膜跨越它是细胞表面的一种G蛋白偶联受体，同样具有单链七次跨膜的共性。发现有四个受体即PAR1 ,PAR2,PAR3,PAR4.除了PAR2是胰酶受体，其他的三个都是凝血酶受体。它区别于其他G蛋白偶联受体的地方在于：一般的G蛋白偶联受体都是在被细胞外配体结合剪掉片段结合后引发G蛋白的磷酸化，然后自身也被磷酸化后进入细胞，再被磷酸化后和配体分离，再次运到细胞表面，重新使用。但是绝大多数PARs-配体复合物在进入细胞后被溶酶体消化降解，不再重新使用。它的一些生理功能如下：人体内几乎所有细胞都有不同类型PARS的存在与表达, 其生理功能非常广泛, 包括诱发凝血反应、促进细胞分裂与增殖、释放炎症介质或细胞因子调控局部炎症反应、收缩子宫、胃肠道和气道平滑肌、调节血管张力等. 激活PAR能够刺激胞浆磷脂酶C、A 和D, 激活蛋白激酶C、有丝分裂原激活蛋白激酶(MAPK)和酪氨酸蛋白激酶, 暂时升高胞浆游离钙离子的浓度, 开放细胞膜离子通道, 并促进细胞生长。新手上路成长任务编辑入门编辑规则本人编辑我有疑问内容质疑在线客服官方贴吧意见反馈投诉建议举报不良信息未通过词条申诉投诉侵权信息封禁查询与解封©2024 Baidu 使用百度前必读 | 百科协议 | 隐私政策 | 百度百科合作平台 | 京ICP证030173号 京公网安备110000020000PARS/dsRNA-Seq
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TBD
Illumina COVIDSeq Test
This high-throughput NGS test detects SARS-CoV-2 in nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs
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TBD
Illumina COVIDSeq Test
This high-throughput NGS test detects SARS-CoV-2 in nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs
View Product
软件和分析
TBD
Illumina COVIDSeq Test
This high-throughput NGS test detects SARS-CoV-2 in nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs
View Product
访谈和新闻
TBD
Illumina COVIDSeq Test
This high-throughput NGS test detects SARS-CoV-2 in nasopharyngeal, oropharyngeal, and mid-turbinate nasal swabs
View Product
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/所有测序方法
/PARS/dsRNA-Seq
PARS/dsRNA-Seq
PARS/dsRNA-Seq
Parallel analysis of RNA structure (PARS-Seq) mapping gives information about the secondary and tertiary structure of RNA. In this method RNA is digested with RNases that are specific for double-stranded and single-stranded RNA, respectively. The resulting fragments are reverse-transcribed to cDNA. Deep sequencing of the cDNA provides high-resolution sequences of the RNA. The RNA structure can be deduced by comparing the digestion patterns of the various RNases.
Pros:
Provides RNA structural information
Distinguishes between paired and unpaired bases
Alternative to mass spectrometry, NMR, and crystallography
Cons:
Enzyme digestion can be nonspecific
Digestion conditions must be carefully controlled
RNA can be over-digested
PARS-Seq/dsRNA-Seq: Wan Y., Qu K., Ouyang Z. and Chang H. Y. (2013) Genome-wide mapping of RNA structure using nuclease digestion and high-throughput sequencing. Nat Protoc 8: 849-869
TruSeq Small RNA Library Preparation Kits
TruSeq Stranded total RNA library prep kit
TruSeq Nano DNA Library Prep Kit
TruSeq DNA PCR-Free Library Prep Kit
Sugimoto Y., Vigilante A., Darbo E., Zirra A., Militti C., et al. (2015) hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature 519: 491-494.
Wan Y, Qu K, Ouyang Z, Chang HY; (2013) Genome-wide mapping of RNA structure using nuclease digestion and high-throughput sequencing. Nat Protoc 8: 849-69
仅供研究使用。不得用于诊断。（除特殊标注外）
Not for import or sale to the Australian general public.
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科学网—RNA结构组学分析技术 - 孙学军的博文
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2015-7-24 08:30
|个人分类:自然科学|系统分类:海外观察
转发请注明：请关注本人氢气医学公众号 氢思语 （hydrogen_thinker）基因组、蛋白组和代谢组学研究已经成为常规生物学研究方法，但是对RNA分子进行组学研究依然属于少数实验室的专门技术，主要问题是分析技术的局限。2015年7月23日《自然》有文章专门对这个问题进行了介绍。国际上最早开展这样研究的实验室是用植物开始的，宾夕法尼亚州立大学化学家Philip Bevilacqua2014年在《自然》发表了第一篇RNA组学研究论文，开创了RNA组学研究技术。RNA是细胞功能重要调节分子，这些分子结构必然能提供关于功能的重要信息，但生化学家一般都检测和分析RNA单分子，Bevilacqua认为，理解RNA应该对细胞内所有RNA分子进行整体研究，Bevilacqua首先考虑用植物细胞开展研究，虽然他没有任何研究植物生理学的经历，这显得有他过于胆大妄为，但是科学家就应该有一种敢于应对挑战的精神。为了学习植物细胞知识，Bevilacqua首先恶补了植物解剖学的本科课程。为了解决RNA分析的技术瓶颈，Bevilacqua与植物分子生物学家Sarah Assmann合作，开发出一种能进行大规模RNA分析的技术。2013年11月，Bevilacqua小组率先在国际上描述了活细胞内数千种RNA形态研究技术，并对植物模式生物拟南芥细胞内RNA形态进行了研究。2013年12月，加州大学旧金山分校采用类似技术报道了酵母和人类细胞的研究结果。北卡罗莱纳大学教堂山分校生物学家Alain Laederach说，这些研究在大规模RNA结构分析方面取得了突破性进。RNA一直是科学家关注的分子，早期认为RNA只是在DNA和蛋白之间传递遗传信息的分子，生物学家现在知道，人类基因组85%能转录成RNA，但大部分RNA并不会翻译成蛋白质，而是拥有多种多样功能的调节分子，RNA不仅传递蛋白质合成的遗传信息，也是控制基因活性和调节其他RNA功能的重要因素。不过，科学家对RNA复杂多样的结构并不十分了解。DNA是能预测的双螺旋结构，RNA与DNA不同，是单链折叠成的隆起、假结、头样、发夹等多种多样的复杂三维循环结构。满足不同功能状态的需要，不同折叠能相互转化。科学家对RNA的这些信息了解非常肤浅。生物物理学家Jonathan Weissman说，这正是关于RNA功能研究中最薄弱的环节。最近几年，科学家开始对RNA结构研究发起挑战。Bevilacqua, Weissman等设计的技术能对细胞内大量RNA结构进行整体解析，初步研究结果发现，活细胞内RNA折叠方式与人工条件下的完全不同。他们提出了一些RNA折叠规则，这些规则可能对理解细胞功能和疾病有帮助。Laederach说，RNA折叠规则是生物进化中的基本问题，能有助于理解各种RNA表现和功能机制，这是让生物学家最希望了解的内容。北卡大学化学生物学家Kevin Weeks是RNA结构研究专家，他认为进化过程中，RNA是保守的分子，序列和结构进化过程中发生很少变化。不过他指的保守结构和序列的分子是转运RNA、核糖体RNA和核酸酶。Weeks说，稳定序列的RNA不过是海量RNA世界中的个别现象。加州大学欧文分校化学家Robert Spitale说，我们对大部分RNA的结构几乎一无所知，RNA分子通常有一个线性核苷酸链，但在细胞核内合成后，会通过自身核苷酸配对迅速折叠，然后进一步折叠成复杂三维结构，与蛋白和其他RNA分子发生相互作用时会改变形状。研究RNA结构的大部分技术利用核苷酸相互结合的特点，或者序列对某些酶的敏感性。计算机模拟技术也有助于整体结构的分析。但是这些方法非常繁琐，一次只能分析一个分子的一部分。五年前，加州大学基因组学家Howard Chang，联合以色列魏茨曼科学研究所计算生物学家Eran Segal开发了一种RNA结构的PARS技术。PARS技术利用RNA酶将RNA单链部分与双链部分切割。对目标RNA样本进行酶切，制造出两种RNA片段库，然后对两个RNA片段库分别进行序列分析，最后对这些片段进行对接分析，该技术的好处是可批量分析成千上万RNA。原理类似于利用质谱分析小分子原子组成的技术。利用PARS技术，Chang和Segal对酿酒酵母3000多mRNA进行分析，并发现基因组中存在除非翻译区序列外更多复杂的奇怪结构成分。这些结构有重要生理意义，因为非翻译区通常需要与调节性蛋白相互作用。2014年，Yue Wan利用PARS技术对来自一家三口的血液细胞的20,000多个mRNA进行分析，发现大约1900个非编码单链变异区。2015年5月，Laederach小组报道，一种mRNA非翻译区变异和一种罕见眼部癌症视网膜母细胞瘤有关。健康人的该mRNA有三种结构，但视网膜母细胞瘤只有两种。mRNA核苷酸结构变异能让该分子形成单链结构。Laederach认为，这种mRNA核苷酸结构变异可能与某些疾病和身高差异有密切关系。PARS的主要缺陷是某些核酸内切酶不容易穿过细胞膜，因此只能将RNA从细胞内抽提出来，这将破坏细胞的天然结构。理论上RNA在细胞内和细胞外应该有大致相同的形状，但事实上这种操作会破坏结合RNA的蛋白，导致RNA在细胞内外结构上的差异。为研究活体RNA结构，许多科学家采用硫酸二甲酯方法，硫酸二甲酯能够结合未折叠的RNA链，不能结合折叠的RNA链。硫酸二甲酯也能进入细胞内，在细胞内与未折叠的RNA链中四种碱基中的腺嘌呤和胞嘧啶反应。然后将RNA逆转录成DNA并进行序列分析。那些结合硫酸二甲酯的核苷酸不能被逆转录，通过分析缩短的DNA序列确定未折叠RNA链。Weissman等将该方法应用于酵母和人类细胞全部mRNA分析，比较了活细胞和细胞破碎提取后再折叠RNA。参与该项目的Silvi Rouskin说，研究可对比活体和离体mRNA的差异，这非常有意思。许多科学家主观估计，细胞内RNA折叠更明显，因为细胞内有许多蛋白质能稳定RNA结构。Weissman的研究结果正好相反。他们分析可能是因为细胞内mRNA翻译成蛋白质时需要保持比较松散的结构。使用硫酸二甲酯技术，Bevilacqua和Assmann分析拟南芥细胞mRNA后获得了奇怪的结果。一些在干旱情况下被激活的应激反应基因的mRNA在细胞内折叠程度远低于理论模拟。相反，维持细胞稳定的管家基因折叠程度与计算机模拟更接近。Bevilacqua等认为，应激反应mRNA折叠少是为提高相关基因翻译效率，应对外界环境改变，而管家基因mRNA必须保持稳定的表达。硫酸二甲酯技术的只能确定一类核苷酸对，其余部分只能依靠计算机模拟填充。为获得细胞内RNA每一序列，Chang和Spitale使用改进的结构探针技术SHAPE6，对老鼠胚胎干细胞内19000个RNA结构进行整体分析（2015）。发现了的一种能促进mRNA分子伸展的常见化学修饰，对这些修饰部位分析可预测蛋白质结合和控制RNA形状的独特序列。一些研究人员已经考虑将这些技术用于更多细胞。Assmann 和 Bevilacqua正在用这些技术对大米细胞RNA进行分析，并计划对其他农作物开展类似研究。他们希望通过这种研究，寻找到能操作RNA形状的方法，以作为提高作物的抗逆能力和产品产量。Rouskin正在研究果蝇RNA结构对胚胎发育的影响。http://www.nature.com/news/a-cellular-puzzle-the-weird-and-wonderful-architecture-of-rna-1.18014
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PARS：预测儿童哮喘的更好工具
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By 赛欧团队
15 2019三月
已经创建并测试了基于计算机的工具来预测幼儿的哮喘
哮喘 影响全球 300 亿多人，是最常见的慢性病之一 疾病 给成本带来了沉重的负担。 哮喘是一种复杂的疾病，其中气道发生炎症，然后阻止足够的氧气转移到肺部，导致持续咳嗽、呼吸急促和胸闷等症状。 通过疗法进行哮喘护理已经很成熟，但良好的哮喘初级护理由于缺乏人员、知识、培训、资源等而受到限制。哮喘护理的全球成本估计每年高达数十亿英镑。
小儿哮喘风险评分 (PARS)：一种预测幼儿哮喘的工具
在发表的一项研究 过敏与临床免疫学杂志， 科学家设计并评估了一种称为小儿哮喘风险评分的决策工具（PARS) 可以准确预测幼儿哮喘1. 与既定工具不同，它由诸如人口统计数据和患者临床因素之类的标准组成。 与黄金标准哮喘预测评分 (API) 相比，被 PARS 评分标记为轻度至中度哮喘风险的儿童多出 43%。 这两种工具对具有高风险因素的儿童的预测相似。 根据需要识别轻度或中度风险的儿童很重要，并且可以更好地对哮喘预防策略做出反应。
PARS 工具是通过利用来自辛辛那提儿童过敏和空气污染队列研究预测哮喘发展的数据/因素设计的。 这项研究由大约 800 名婴儿组成，其中至少有一位父母有至少一种过敏症状。 这些儿童每年在 1、2、3、4 和 7 岁时接受皮肤测试，以确定是否发生过敏性疾病。 研究人员检查了 15 种空气过敏原（空气传播）和食物过敏原，包括猫、霉菌、牛奶、鸡蛋和蟑螂。 共有 589 名儿童在 7 岁时接受了哮喘发展测试，并通过肺功能的标准测量（如肺活量测试）进行诊断。 这些儿童中有 16% 患有哮喘，他们的父母被要求了解可能导致哮喘的各种风险因素。 使用 PARS 预测哮喘的变量是喘息、对 2 种或更多食物和/或空气传播的过敏原和非裔美国人的过敏原。 这些孩子的父母中至少有一位患有哮喘病，并且在很小的时候还患有其他疾病，如湿疹和过敏性鼻炎。
PARS 的新模型比黄金标准 API 的敏感度高 11%。 与用于预测哮喘发展的大约 30 个已建立的模型相比，PARS 也更好且侵入性小得多。 PARS 更容易实施，这项研究包括一个 PARS 表，其中包含决策工具和临床解释。 PARS 还有一个 Web 应用程序2，应用程序开发目前正在进行中。
与自 2000 年以来开发和使用的黄金标准哮喘预测评分 (API) 相比，PARS 评分将 43% 的儿童标记为轻度至中度哮喘风险，因为 API 仅提供“是”或“否”为风险。 这两种工具对具有高风险因素的儿童的预测相似。 识别轻度或中度风险的儿童至关重要，因为他们立即需要，并且可以在很小的时候通过早期干预对哮喘预防策略做出更好的反应。 这有助于在并发症开始前缓解哮喘。
与黄金标准 API 相比，PARS 的新模型在预测生命早期的哮喘方面的敏感性和准确性高 11%。 在英国进行的另一项不包括非裔美国人的研究证实了这一结果。 PARS 是一种更强大、更有效和更通用的工具，而且与 30 个已建立的模型相比，它是一种侵入性更小的方法。 预测 1-2 岁儿童的轻度至中度哮喘可以对控制这种疾病产生重大影响。 PARS 易于实施，本研究包括一张 PARS 表，其中包含决策工具和临床解释。 PARS 也有一个网络应用程序2 和应用程序可用于智能手机。
***
{您可以通过单击下面引用来源列表中给出的 DOI 链接来阅读原始研究论文}
来源（S）
1. Jocelyn M. 2019. 小儿哮喘风险评分可更好地预测幼儿哮喘的发展。 杂志过敏和临床免疫学. https://doi.org/10.1016/j.jaci.2018.09.0372. 小儿哮喘风险评分。 2019. 辛辛那提儿童。 https://pars.research.cchmc.org [10 年 2019 月 XNUMX 日访问]
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PARS中文(繁體)翻譯：劍橋詞典
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pars 在英語-中文（繁體）詞典中的翻譯
parsnoun [ C ]
medical
specialized uk
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/pɑːs/ us
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/pɑːrz/ plural partes
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a Latin word meaning "part", used in medical names and descriptions
（拉丁語，用於醫學術語）部分
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something that you do, or a thing that you give someone, that expresses your feelings or intentions, although it might have little practical effect
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pars是什么意思_pars怎么读_pars翻译_用法_发音_词组_同反义词_部_部分-新东方在线英语词典
pars是什么意思_pars怎么读_pars翻译_用法_发音_词组_同反义词_部_部分-新东方在线英语词典
英语词典 -
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首页 > 英语词典 > 字母单词表 > p开头的单词 > pars
pars
听听怎么读
英 [pɑ:z]
美 [pɑz]
是什么意思
n.部，部分；平均( par的名词复数 )；平价；同等（高尔夫球中的）标准杆数；
英英释义
par[ pɑ:z ]n.(golf) the standard number of strokes set for each hole on a golf course, or for the entire course"a par-5 hole"; "par for this course is 72"a state of being essentially equal or equivalent; equally balanced"on a par with the best"同义词：equalityequivalenceequationv.make a score (on a hole) equal to par
学习怎么用
词组短语
on a par同等on a par with与…同等；和…一样at par adv. 平价；依照票面价格；与票面价值相等 up to par达到标准par value面值；票面价值；平价above par在标准以上；超过票面价值under par低于或高于平值；（股票，证券等）在票面价值以上或下on par with与…同等水平par excellence出类拔萃的；最卓越的below par在票面价值以下；在标准以下over par超过票面价值no par value无票面价值；非平价above par value高于面值；高于票面价值；平价以上par value stock有面值的股票 更多收起词组短语
双语例句
As a writer she was on a par with the great novelists.她是与伟大小说家齐名的作家。At this school, only ten people passed the music examination this year. That may seem a small number but it's(about) par for the course.今年这所学校只有10人通过了音乐考试。人数看来太少了，但这却是意料之中的事。
权威例句
Flora Reipublicae Popularis Sinicae, Tomus 20, Pars. 2, Salicaceae by Wang-Zhan; Fang Chen-fuDeep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's diseaseDeep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease — NEJMVisual and oculomotor functions of monkey substantia nigra pars reticulata. II. Visual responses related to fixation of gazeVisual and oculomotor functions of monkey substantia nigra pars reticulata. III. Memory-contingent visual and saccade responses.Visual and oculomotor functions of monkey substantia nigra pars reticulata. IV. Relation of substantia nigra to superior colliculus.Visual and oculomotor functions of monkey substantia nigra pars reticulata. I. Relation of visual and auditory responses to saccadesA Primate Model of Parkinsonism: Selective Destruction of Dopaminergic Neurons in the Pars Compacta of the Substantia Nigra by N-met...Modification of saccadic eye movements by GABA-related substances. II. Effects of muscimol in monkey substantia nigra pars reticulata.Hikosaka, O. & Wurtz, R. H. Visual and oculomotor functions of monkey substantia nigra pars reticulata. II. Visual responses related...
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portion
percent
part
integral p开头的单词Pythagorean theorem
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pyruvate dehydrogenase
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puzzle out
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pars是什么意思_pars的翻译_音标_读音_用法_例句_爱词霸在线词典
是什么意思_pars的翻译_音标_读音_用法_例句_爱词霸在线词典首页翻译背单词写作校对词霸下载用户反馈专栏平台登录pars是什么意思_pars用英语怎么说_pars的翻译_pars翻译成_pars的中文意思_pars怎么读,pars的读音,pars的用法,pars的例句翻译人工翻译试试人工翻译翻译全文pars英 [pɑ:z]美 [pɑz]释义n.部，部分; 平均( par的名词复数 ); 平价; 同等; （高尔夫球中的）标准杆数大小写变形:PARSPaRSPARs点击 人工翻译，了解更多 人工释义实用场景例句全部In humans, the pars intermedia is a rudimentary region.人的脑垂体中间部是不发达的.辞典例句James Gregory gave in in his " Geometriae Pars Universalis " a method of rectifying curves.JamesGregory在他的《几何的通用部分 》 中给出了计算曲线长度的方法.辞典例句The dangerous type chronic otitis media occurs with pars flaccida and marginal perforations.慢性中耳炎的危险型可出现鼓膜松弛部的穿孔和鼓膜边缘性穿孔.辞典例句To investigate and analyze the epidemiology material of pars plana vitrectomy.目的调查玻璃体切割手术病人流行病学的状况.互联网Methods All patients with dislocated - lens underwent pars plana vitrectomy.方法:采用睫状体扁平部玻璃体切除术切除脱位的晶体.互联网All transmission devices are arranged inside the machine so as to keep pars clean.所有的传动装置均布置在机器内部,保持机件清洁.互联网In addition, there are some general guidelines to help you buy used pars in any situation.此外, 这里有一些指导性建议,对你在任何情况下买二手零件都有帮助.互联网Reject the player whose score is over 120 pars to enter into the course.本俱乐部禁止成绩120杆以上球员下场.互联网Objective To study the clinical value of treading after cataract posterior capsulotomy via pars plana.目的探讨经睫状体平坦部切口行晶状体后囊膜切开术治疗后发性白内障的临床价值.互联网Method 38 eyes with traumatic endophthalmitis were operated with pars plana closed vitrectomy.方法儿童外伤性眼内容炎38例(38眼)行经扁平部闭合式玻璃体切割术.互联网Objective To determine the efficacy and safety of self - sealing pars plana sclerotomies for vitrectomy.目的探讨自 闭式 巩膜隧道切口用于经睫状体平坦部玻璃体切除术的有效性和安全性.互联网Various part of brain substance was: medulla ( pars ventralis ), cortex ( pars dorsalis ), pia mater encephali.脑内组织依次为: 髓质 ( 被盖部 ) 、 皮质 ( 基底部 ) 、 软脑膜.互联网The fe of Sparta ng Menelaus ho as abducted by Pars and proved the Trojan ar.斯巴达王墨涅拉俄斯的王后,因被帕里斯拐去而引发特洛伊战争.互联网There are no previously published case reports of nonambulatory patients with pars interarticularis defects.之前未见有卧床病人发生峡部不连的病例报道.互联网The pars transversa provides lateral wall rigidity and can even be a dilatory muscle.鼻肌横部提供外侧壁硬度,甚至做为扩张肌.互联网收起实用场景例句行业词典医学〔NA〕部，部分：一个大区域、器官或结构的某一特殊部分的通称 法律当事人 释义实用场景例句行PARS在剑桥英语词典中的解释及翻译
PARS在剑桥英语词典中的解释及翻译
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pars 在英语中的意思
parsnoun [ C ]
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/pɑːs/ us
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a Latin word meaning "part", used in medical names and descriptions
(pars在剑桥高级学习词典和同义词词典中的解释 © Cambridge University Press)
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C1
pars的翻译
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（拉丁語，用於醫學術語）部分…
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（拉丁语，用于医学术语）部分…
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/ˈtoʊ.kən/
something that you do, or a thing that you give someone, that expresses your feelings or intentions, although it might have little practical effect
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Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases - PMC
Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases - PMC
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Thromb J
v.17; 2019
PMC6440139
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Thromb J
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Thromb J. 2019; 17: 4. Published online 2019 Mar 29. doi: 10.1186/s12959-019-0194-8PMCID: PMC6440139PMID: 30976204Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseasesDorothea M. Heuberger1,2 and Reto A. Schuepbach1Dorothea M. Heuberger1Institute of Intensive Care Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland 2Surgical Research Division, University Hospital Zurich, University of Zurich, Zurich, Switzerland Find articles by Dorothea M. HeubergerReto A. Schuepbach1Institute of Intensive Care Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland Find articles by Reto A. SchuepbachAuthor information Article notes Copyright and License information PMC Disclaimer1Institute of Intensive Care Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland 2Surgical Research Division, University Hospital Zurich, University of Zurich, Zurich, Switzerland Dorothea M. Heuberger, Email: hc.zsu@regrebueh.akinomaehtorod.Contributor Information.Corresponding author.Received 2018 Nov 20; Accepted 2019 Mar 8.Copyright © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been corrected. See Thromb J. 2019 November 6; 17: 22.Associated DataData Availability StatementData sharing not applicable to this article as no datasets were generated or analysed during the current study.AbstractInflammatory diseases have become increasingly prevalent with industrialization. To address this, numerous anti-inflammatory agents and molecular targets have been considered in clinical trials. Among molecular targets, protease-activated receptors (PARs) are abundantly recognized for their roles in the development of chronic inflammatory diseases. In particular, several inflammatory effects are directly mediated by the sensing of proteolytic activity by PARs.PARs belong to the seven transmembrane domain G protein-coupled receptor family, but are unique in their lack of physiologically soluble ligands. In contrast with classical receptors, PARs are activated by N-terminal proteolytic cleavage. Upon removal of specific N-terminal peptides, the resulting N-termini serve as tethered activation ligands that interact with the extracellular loop 2 domain and initiate receptor signaling. In the classical pathway, activated receptors mediate signaling by recruiting G proteins. However, activation of PARs alternatively lead to the transactivation of and signaling through receptors such as co-localized PARs, ion channels, and toll-like receptors.In this review we consider PARs and their modulators as potential therapeutic agents, and summarize the current understanding of PAR functions from clinical and in vitro studies of PAR-related inflammation.IntroductionThe four mammalian members of the protease-activated receptor (PAR) family PAR1, PAR2, PAR3, and PAR4 are encoded by the genes F2R [1], F2RL1 [2], F2RL2 [3], and F2RL3 [4], respectively. Human PAR1 was discovered in 1991 as a key thrombin receptor on platelets [5, 6]. Although human and mouse PAR2 genes are homologous to PAR1 genes, PAR2 is not responsive to thrombin [2, 7, 8]. Unexpected responses of platelets to thrombin in PAR1 knockout mice lead to the discovery of the thrombin receptors PAR3 and PAR4 [4, 9, 10]. PAR regulation varies between species and tissues, with differing expression levels, protease cleaving activities, dimerization with other receptors, compartimentalization, trafficking, posttranslational modifications, and co-localization with co-receptors, as shown in Fig. 1.Open in a separate windowFig. 1Mechanisms of PAR activation. PAR activation is regulated by a direct proteolytic cleavage at the N-terminus, b homo- or heterodimerization with other PARs and transactivation through the cleaved tethered ligand, c compartmentalization on the cell surface, d degradation or recycling by endosomal trafficking, e posttranslational modifications such as glycosylation, phosphorylation, and ubiquitination, and f co-localization with other receptors and cofactorsStudies of PAR activation under physiological conditions are crucial for the understanding of the pathophysiological roles of PARs, such as those in inflammatory disorders.Cleavage and activation of PARs and signal transductionPARs are specifically cleaved and irreversibly activated by various endogenous proteases, and by exogenous proteases from bacteria, plants, fungi, and insects. Proteases, soluble or cell membrane associated (bound to co-receptors or specific membrane compartments), cleave specific N-terminal peptides of PARs, resulting in exposure of new N-terminal peptides that serve as tethered activation ligands, which bind a conserved region on extracellular loop 2 (ECL2) [5, 11]. This interaction initiates conformational changes and alters affinity for intracellular G proteins [12]. Various N-terminal cleavage sites have been described, and these have various active conformations with specific G protein preferences. Multiple cleavage site-specific cellular responses are generally referred to as biased signaling, and the ensuing models describe how distinct proteases with distinct cleavage sites induce protease-specific responses via the same PAR [13, 14].In contrast with PAR-activating proteases, other proteases cleave PARs at cleavage sites that are not related to signaling. Under these conditions, shedding of the PAR1 terminus, which removes the thrombin activation site, was first recognized as a mechanism for rendering platelets irresponsive to thrombin [15]. These truncated PARs can no longer be proteolyticaly activated, but remain activated by ligands from adjacent PARs [16]. Alternatively, truncated PARs bind soluble peptides with affinity for ECL2 by mimicking the tethered ligand. Both mechanisms result in receptor activation [17, 18]. Multiple ECL2-binding agonist peptides have been described and shown to induce signaling from truncated and uncleaved PARs (see agonist peptides in Tables 5, ,6,6, ,77).Table 5PAR1 signaling modulatorsClassAgonist/ AntagonistNameReceptor/Cell/Tissue typeCellular responsePeptideAgonistSFLLRN/−NH2HumanInduces platelet activation [6, 138, 265, 278, 279]TFLLRN/−NH2HumanInduces platelet activation, enhances endothelial barrier permeability [137, 138, 265]NPNDKYEPF/−NH2HumanInduces cytoprotective signaling [28, 187]PRSFLLRN/−NH2HumanInduces platelet activation [86]HumanInduces ERK1/2 activation [280]AntagonistYFLLRNHumanCompets with thrombin and PAR1-AP and prevents platelet activation [278, 279]PeptidomimeticAntagonistRWJ-56110HumanBlunts thrombin and PAR1-AP effects on platelets and vascular endothelial cells [264, 281, 282]HumanBlocks MMP-1 activaiton in SMCs [87]RWJ-58259Guinea pigBlocks thrombin and PAR1-AP platelet activation [215, 283]RatBlocks thrombin induced calcium release in AoSMC Inhibits intimal thickening [111, 215, 264, 273]MousePrevents destruction of intestinal barrier [62, 284]Non-peptide small moleculeAntagonistFR17113HumanBlocks PAR1-AP induced platelet activation [285, 286]HumanInhibits thrombin and PAR1-AP induced ERK1/2 activation [287]{"type":"entrez-nucleotide","attrs":{"text":"ER129614","term_id":"128975082","term_text":"ER129614"}}ER129614–06HumanBlocks thrombin and PAR1-AP induced platelet activation [288]Guinea pigShows antithrombotic effects [289]{"type":"entrez-nucleotide","attrs":{"text":"F16357","term_id":"1132624","term_text":"F16357"}}F16357, {"type":"entrez-nucleotide","attrs":{"text":"F16618","term_id":"1132885","term_text":"F16618"}}F16618HumanBlocks PAR1-AP induced platelet activation [290]RatShows antithrombotic effects [291]{"type":"entrez-protein","attrs":{"text":"SCH79797","term_id":"1052762130","term_text":"SCH79797"}}SCH79797HumanBlocks thrombin and PAR1-AP induced calcium release and platelet activation [292]Human, MouseInduces NETs formation and increases bacterial killing capacity [293]SCH203009HumanBlocks thrombin and PAR1-AP induced platelet activation [292]SCH530348 (vorapaxar)Human, MonkeyBlocks thrombin and PAR1-AP induced platelet activation [266]E5555 (atopaxar)HumanBlocks thrombin and PAR1-AP induced platelet activation and inhibits thrombus formation [267]Guinea pigBleeding time not affected [267, 294]Q94HumanBlocks thrombin induced calcium release [295]MouseBlocks thrombin induced ERK1/2 activation [296]PepducinAntagonistP1pal-12HumanBlocks thrombin induced platelet activation [268]HumanBlocks platelet activation [86]HumanBlocks MMP-1 induced endothelial damage [297]MouseReduces lung vascular damage and sepsis lethality [297, 298]P1-pal7(PZ-128)HumanBlocks MMP-1 induced Akt signaling in cancer cells [150]HumanBlocks platelet activation [86]MouseInhibits tumor growth [280]Guinea pigPrevents from systemic platelet activation [86]ParmodulinAntagonistML161 (Parmodulin-2)HumanBlocks thrombin and PAR1-AP induced platelet activation [299]HumanBlocks thrombin induced inflammatory signaling on endothelial cells [269]MouseBlocks thrombus formation [300]AntibioticAntagonistDoxycyclineHumanInhibits thrombin induced cancer cell migration [301, 302]HumanBlocks MMP-1 cleavage [303]AntibodyAntagonistATAP-2WEDEHumanBlocks thrombin cleavage of PAR1 and thrombin induced calcium release [147]Open in a separate windowTable 6PAR2 signaling modulatorsClassAgonist/ AntagonistNameReceptor/Cell/Tissue typeCellular responsePeptideAgonistSLIGRL/−NH2Human, RatInduces calcium release [2, 8, 136, 139]SLIGKV/−NH2HumanInduces calcium release [136]2f-LIGRLO/−NH2Human, RatInduces calcium release [140]AntagonistFSLLRY-NH2HumanBlocks trypsin, not SLIGRL activation, reduces proinflammatory IL-8 and TNFα [82]RatInhibits neuropathic pain [304]LSIGRL-NH2HumanBlocks trypsin, not SLIGRL induced calcium release [305]PeptidomimeticAntagonistK14585,K12940HumanReduces SLIGKV induced calcium release [306]HumanInhibits SLIGRL induced NFkB activation [307]C391aHuman, MouseBlocks calcium release and MAPK activation [308]Non-peptide small moleculeAgonistGB110HumanInduces calcium release [309]AC-5541,AC-264613HumanInduces calcium release [310]RatInduces edema and hyperalgesia [310]AntagonistENMD-1068HumanBlocks p.acnes induced calcium release and induction of IL-1a, IL-8 and TNFα [92]HumanInhibited FVIIa induced cancer cell migration [311]MouseReduces joint inflammation [260]MouseBlocks calcium release and reduces liver fibrosis [312]GB83HumanInhibits trypsin and PAR2-AP calcium release [313]GB88HumanBlocks PAR2 induced calcium release [309]RatReduces acute paw edema, inhibits PAR2-AP induced inflammation [309, 314]AZ8838AZ3451HumanBlocks PAR2-AP induced calcium release and β-arrestin recruitment [315]PepducinAntagonistP2pal-18SHumanBlocks PAR2 induced calcium release [316]MouseDecreases risk for developing severe biliary pancreatitis [317]P2pal-14GQHumanBlocks PAR2 induced calcium release [316]AntibioticAntagonistTetracyclines(Tetracycline,Doxycycline,Minocycline)HumanInhibits SLIGRL induced IL-8 release [318]MouseTopical application of tetracycline decreases PAR2 induced skin inflammation [319]RatSubantimicrobial doses of doxycycline inhibit PAR2 induced inflammation [320]AntibodySAM-11MouseReduces joint inflammation [260]MousePrevents allergic inflammation [124]B5MouseReduces joint inflammation [260]MouseInhibits allergic airway inflammation [124]MAB3949HumanBlocks trypsin induced PAR2 activation [315]Open in a separate windowTable 7PAR4 signaling modulatorsClassAgonist/ AntagonistNameReceptor/Cell/Tissue typeCellular responsePeptideAgonistGYPGQV/−NH2Human, RatInduces platelet activation [144]GYPGKF/−NH2Human, RatInduces platelet activation [144]AYPGKF/−NH2Human, MouseInduces platelet activation [145]PeptidomimeticAntagonisttc-YGPKFRatBlocks thrombin and PAR4-AP induced platelets aggregation [321]Non-peptide small moleculeAntagonistYD-3HumanBlocks thrombin induced platelet activation [282, 322–325]Mouse, Rat, RabbitBlocks thrombin and PAR4-AP induced platelets activation [323–325]ML-354HumanBlocks PAR4-AP induced platelet activation [326–328]BMS-986120HumanBlocks PAR4-AP induced calcium release and platelet activation [329]HumanBlocks thrombus formation at high shear stress [277]MonkeyBlocks platelet activation [329]PepducinAntagonistP4pal-10Human, MouseBlocks thrombin and PAR4-AP induced platelet activation [268]RatBlocks thrombin and PAR4-AP induced platelets activation [330]P4pal-i1HumanBlocks PAR4 induced platelets activation [150]Open in a separate windowPAR activation by proteolytical cleavagePAR-cleaving proteases are a focus of many current studies. Whereas some PAR-cleaving proteases produce N-terminal components with regulatory roles, others render the receptors irresponsive to further protease exposure as shown in Fig. 2 and summarized in Tables 1, ,2,2, ,33 and and4.4. Important proteases are discussed below.Open in a separate windowFig. 2Proteolytic PAR cleavage. a N-terminal sequences of human PARs (PAR1–4) containing potential cleavage sites. b Proteolytic cleavage of PARs by soluble exogenous proteases exposes new N-terminal sequences that serve as tethered ligands for G protein dependent activation of receptors. Alternatively, proteolytic cleavage at other sites destroys the function of the receptor to prevent intracellular signal transductionTable 1PAR1 cleaving proteasesProteaseMajor cleavage siteAdditional cleavage sitesMammalian proteasesThrombinR41S42aPCR46N47R41S42FVIIaunknownFXaR41S42TrypsinR41S42ChymaseunknownMMP-1D39P40, L44L45, F87I88N47P48, R70L71,K82Q83MMP-2L38D39MMP-3,-8,-9R41S42MMP-12unknownMMP-13S42F43L38T39, mouseCathepsin GR41S42, F55W56, Y69R70Neutrophil elastaseA36T37, V72S73, A86F87Proteinase-3A36T37, P48N49, V72S73, A92S93PlasminK32A33, R41S42, R70 L71, K76 S77, K82 Q83Kallikrein-4,-5,-6unknownKallikrein-14R46N47Granzyme A,B, KunknownCalpain-1K32A33, S76K77Non-mammalian proteasesPA-BJR41S42, R46N47ThrombocytinR41S42, R46N47DerP1unknownGingipain RR41S42SpeBL44L45LepAunknownS.pneumoniae proteasesunknownThermolysinF43L44, L44L45penCR41S42Open in a separate windowTable 2PAR2 cleaving proteasesProteaseMajor cleavage siteAdditional cleavage sitesMammalian proteasesThrombinR36S37aPCunknownFXaR36S37TrypsinR36S37K34G35, K51G52, K72L73TryptaseR36S37ChymaseG35R36L38I39, mouseMatriptaseR36S37Cathepsin GF65S66F59S60, F64S65Cathepsin SG40K41E56P57, mouseNeutrophil elastaseA66S67, S67V68V42D43,V48T49,V53T54,V58T59,T74T75,V76F77Proteinase-3D62E63V48T49,V55E56,T57V58 V61D62,K72L73,T74T75,T75V76,V76F77PlasminR36S37K34G35TestisinunknownKallikrein-4,unknownKallikrein-5,-6,-14R36S37Calpain-2unknownNon-mammalian proteasesDer-P1,-P2,-P3,-P9unknownCockroach E1-E3R36S37Gingipain RunknownLepAunknownEPaS37L38S38L39, ratS.pneumoniae proteasesunknownThermolysinunknownSerralysinunknownP.acnes proteasesunknownaPAunknownBromelainunknownFicinunknownPapainunknownpenCR36S37Open in a separate windowTable 3PAR3 cleaving proteasesProteaseMajor cleavage siteAdditional cleavage sitesMammalian proteasesThrombinK38T39mouse PAR3 at K37S38aPCR41G42FXaR41G42TrypsinunknownOpen in a separate windowTable 4PAR4 cleaving proteasesProteaseMajor cleavage siteAdditional cleavage sitesMammalian proteasesThrombinR47G48TrypsinR47G48Cathepsin GR47G48Kallikrein-14unknownNon-mammalian proteasesPA-BJR47G48ThrombocytinR47G48Der-P3unknownGingipain RR47G48LepAunknownS.pneumoniae proteasesunknownBromelainunknownFicinunknownPapainunknownOpen in a separate windowMammalian proteasesSerine proteases Thrombin, the key protease of coagulation, is generated by proteolytic cleavage of zymogen prothrombin. Although thrombin production predominantly occurs on platelets and subendothelial vascular walls, extravascular thrombin has been detected in synovial fluid [19] and around tumors [20]. Thrombin has long been known to activate platelets, and the discovery of PAR1 initiated research into the underlying molecular mechanisms. PAR1 contains a hirudin-like domain, which has a high affinity thrombin binding site and recruits thrombin via exosite I. This interaction enables thrombin to specifically and efficiently activate PAR1 [6]. Similarly, PAR3 contains a hirudin-like thrombin recruitment site, which results in cleavage [9, 21]. In other studies, mouse PAR3 maintained thrombin recruitment activity but lost its receptor function, as discussed above [22–24]. Thrombin also cleaves and activates PAR4, which, in contrast with PAR1, lacks a hirudin-like domain. Thus, higher concentrations of thrombin activate PAR4 and initiate intracellular signaling [10]. PAR2 is considered the only PAR that resists cleavage or activation by thrombin [4, 25], although emerging evidence suggests that at very high concentrations (100–500 nM), thrombin may directly cleave and activate PAR2 [26, 27].In contrast with thrombin, the anticoagulant protease activated protein C (aPC) binds to the co-receptor endothelial protein C receptor (EPCR) to promote the cleavage and activation of co-localized PAR1 [28, 29] and induce anti-apoptotic and protective effects on endothelial barrier permeability [29–33]. Compartmentalization of PAR1 and co-localization with EPCR in calveolae is crucial for efficient cleavage by aPC [13]. Moreover, aPC cleaves PAR3 in humans and mice [21, 34, 35] and acts as a PAR3 shedding protease that prevents thrombin-induced barrier disruption [21]. However, the dependency of aPC cleavage of PAR3 on EPCR remains controversial [21, 35]. Similar to aPC, coagulation factor Xa binds EPCR and mediates proteolytic activation of PAR1 and PAR3 [21, 28, 36–39]. In addition, EPCR-bound factor Xa reportedly cleaves PAR2 and initiates inflammatory signaling [40]. PAR2 was also shown to be activated by tissue factor (TF)-bound coagulation factor VIIa [40–42]. Yet recent studies suggest that the TF-VIIa complex does not directly activate PAR2, and rather activates matriptase, which cleaves and activates PAR2 [42–44]. Anti-inflammatory signaling was also previously related to PAR1 cleavage by EPCR-bound VIIa [45, 46]. Taken together, these studies indicate that TF-Xa–VIIa complexes activate PAR1 and PAR2 [47].Trypsins are PAR-activating proteases with roles as major digestive enzymes in the duodenum [48]. Trypsin is also secreted by epithelial cells, nervous system cells [49], and tumor cells [50, 51]. Trypsins may also be involved in cell growth and coagulation, as suggested by secretion from human vascular endothelial cells [52]. Trypsin cleaves human PAR1 and PAR4 at putative protease cleavage sites, and thereby prevents thrombin signaling in endothelial cells and platelets [4, 53]. Trypsin is the major PAR2 cleaving protease that initiates inflammatory signaling [2, 7].Tryptase is the main protease of mast cells, and activates PAR2 by proteolytic cleavage to induce calcium signaling and proliferation [54–57]. The source tissue of tryptase reportedly plays an important role in the cleavage and induction of tryptase-activated PAR signaling, reflecting differences in posttranslational modifications, such as glycosylation and sialic acid modifications [54, 58]. Tryptase induces calcium signaling via PAR1 when PAR2 is co-expressed, but cannot activate human platelets, suggesting that tryptase does not directly cleave PAR1 [54–57]. Chymase is a mast cell serine protease that also cleaves PAR1 in human keratinocytes and fibroblasts, and thus prevents thrombin sensitivity [59]. Moreover, the epithelial serine protease matriptase cleaves and initiates inflammatory responses in human and mouse keratinocytes and in Xenopus oocytes overexpressing human PAR2 [44, 60–63].PARs have been identified as substrates of kallikreins, which are serine proteases that have been related to various inflammatory and tumorigenic processes [64]. Kallikrein-4 increases intracellular calcium levels via PAR1 and PAR2, but activates PAR1 most efficiently [65]. Kallikrein-14 induces calcium signaling via PAR1, PAR2, and PAR4, but can also shed PAR1 to prevent signaling. Rat platelets are activated by kallikrein-14 via the proteolytic cleavage of PAR4, but are not activated by kallikrein-5 and kallikrein-6 [66]. Instead, neurotoxic effects of kallikrein-6 were inhibited by blocking PAR1 and PAR2, indicating a direct proteolytic role in PAR activation [67].Neutrophils are mobilized to sites of inflammation and infection, where they modulate inflammatory signaling, in part by secreting PAR-cleaving proteases. The neutrophil serine protease cathepsin G prevents thrombin-induced effects by cleaving PAR1 into non-functional parts [68, 69]. In contrast, cathepsin G reportedly induced chemoattractant signaling via PAR1, further supporting the role of cathepsin G in PAR1 activation [70]. Another unexpected observation of cathepsin G was that cleavage sites differ between recombinant and native human PAR2 [26, 71, 72]. These discrepancies may reflect the influence of cell types and posttranslational modifications on PAR cleavage. Studies in mice and humans show that platelet activation by cathepsin G is dependent on PAR3 and PAR4 [71, 73, 74]. Cathepsin G also cleaves and activates PAR4 on endothelial cells [75]. The neutrophil proteases elastase and proteinase-3 cleave recombinant PAR1 and PAR2 at various sites [26, 72]. Recently, rat elastase was shown to cleave and activate PAR1, although sequences of rat and human PAR1 have low homology [76]. In contradiction with neutrophil proteases that prevent PAR signaling at sites of inflammation, monocytes secret the protease cathepsin S, which initiates inflammatory signaling by cleaving PAR2 [72, 77, 78]. Low concentrations of the fibrinolytic protease plasmin prevent platelet activation by cleaving PAR1, whereas high concentrations of plasmin lead to the cleavage and activation of PAR1 [79]. Plasmin also cleaves PAR2 and prevents subsequent activation by trypsin [26, 80].The serine proteases granzyme A and granzyme B induce intracellular signaling pathways that lead to neuronal death via PAR1 [81, 82]. Recently, granzyme K was also shown to activate PAR1 and promote inflammatory endothelial signaling [83, 84]. Few studies show activation of PAR1 by proteases of the granzyme family, and the details of this interaction remain poorly characterized.Cysteine proteases Calpain-1 is a calcium-dependent cysteine protease that has been associated with inflammatory disorders, and initiates calcium signaling pathways by activating PAR1 [26]. At very high concentrations, calpain-2 was also shown to cleave PAR2, and the authors suggested that this cleavage event inactivated PAR2 [26]. Recently, calpain-1 was shown to be induced by thrombin-activated PAR1, and subsequently regulated the internalization of PAR1 [85].Metalloproteases Matrix metalloproteases (MMPs) are known to be involved in various inflammatory- and cancer-related conditions. MMP-1 cleaves human PAR1 and initiates platelet activation [86–89]. MMP-1 also regulates cancer cell activities depending on PAR1 availability [90]. Similarly, MMP-2 cleaves human PAR1 and enhances platelet activation [91], and MMP-3, MMP-8, and MMP-9 were shown to induce platelet activation via PAR1 [92]. Whether these three MMPs cleave PAR2 is not clear, although PAR2 activation by trypsin induced secretion of MMP-9 in human airways, suggesting that MMP-9 is a PAR2-activating protease [93]. In mice, PAR1 expression was regulated by MMP-12, and activated PAR1 increased MMP-12 secretion [94, 95]. A similar feedback loop involving MMP-12 and PAR2 has been reported in mice [96]. Moreover, MMP-13 was shown to activate PAR1 and induce intracellular signaling [87], and thrombin-induced activation of PAR1 and PAR3 was associated with increased levels of MMP-13 in human chondrocytes [24].In addition to coagulation and inflammation, PAR activation may play roles in human germ cells, where the serine protease testisin activates PAR2 and induces calcium signaling and ERK1/2 activation. This interaction may play roles in the regulation of ovarian and testicular cancer, as suggested previously [97, 98].Non-mammalian proteasesExogenous proteases from various species that modulate PAR activation are disscues in the following section and are summarized in Fig. 3.Open in a separate windowFig. 3Non-mammalian exogenous proteases induce PAR-driven pathological effects. Various proteases are secreted from bacteria, amoebae, insects, plants, fungi, and snakes, and can cleave PARs and modulate signal transduction, leading to inflammation, thrombosis, or painBacterial proteases Endogenous mammalian proteases are not the only regulators of PAR activation. Indeed, both pathogenic and commensal bacteria secret various proteases that cleave PARs and act as inflammatory modulators [99]. In this section, we describe bacterial proteases that either activate PARs, and thus allow bacteria to penetrate host barriers, or inactivate PARs to prevent inflammatory signaling by the host.The human pathogen Pseudomonas aeruginosa secrets two PAR-cleaving proteases with contrasting effects. The exoprotease LepA cleaves and activates PAR1, PAR2, and PAR4, and subsequently induces nuclear factor kappa B (NFκB) promoter activity [100], whereas cleavage by elastase EPa inactivates PAR2 to prevent inflammation in lungs [101].The streptococcal pyrogenic exotoxin B (SpeB) of Group A Streptococcus also inactivates PAR1 by cleaving it, and thereby renders human platelets unresponsive to thrombin [102]. In mice, proteases of Streptococcus pneumoniae cleaved PAR2 and facilitated the spread of the pathogen from the airways into the blood stream [103]. PAR1 has also been associated with S. pneumonia-mediated sepsis in mice, although direct cleavage of PAR1 was not shown [104, 105]. Pulmonary inflammation from S. pneumoniae infections is reduced in PAR4 knockout mice [106], further supporting this causal link.Inflammation-associated periodontal diseases are predominantly induced by the Porphyromonas gingivalis cysteine protease gingipain R, which activates PAR2 [107, 108]. Subsequently, gingipain R activates PAR1 and PAR4, and thereby, human platelets [109–111]. This mechanism may also explain associations between periodontitis and cardiovascular events [112].In addition, supernatants from Propionibacterium acnes cultures initiated inflammatory signaling in human keratinocytes via PAR2 [92]. The virulence of P. acnes was also reduced in PAR2 knockout mice [113], further suggesting that PAR2 is involved in bacterial infections.Serralysin is a matrix metalloprotease expressed by Serratia marcescens, and induced inflammation in human airway cells via PAR2 in vitro [114].Finally, Bacillus thermoproteolyticus rokko secretes the metalloprotease thermolysin, which cleaves and inactivates PAR1 to prevent thrombin-induced signaling in rat astrocytes [115, 116]. The in vitro effects of PAR2-cleavage by thermolysin, however, vary between cell lines [116].Amoeba proteases In acanthamoebic keratitis, PAR2 triggers inflammation following secretion of the plasminogen activator (aPA) by Acanthamoeba strains, leading to induction of IL-8 in human corneal epithelial cells [117].Reptile proteases Following snakebites, coagulation disorders in humans and mice occur due to the presence of venom proteases. In Proatheris superciliaris bites, venom proteases activate platelets by activating PAR1 and PAR4 [118]. Bothrops atrox and B. jararaca are snake species of the family viperidae. These snakes secrete the serine proteases PA-BJ and thrombocytin, which activate human platelets via PAR1 and PAR4 [119].Insect proteases Several cysteine and serine proteases from insects induce inflammation-associated diseases such as asthma. For example, dust mite allergens contain the serine proteases DerP2, DerP3, and DerP9 [120] and the cysteine protease DerP1. DerP1 induces PAR2-dependent signaling, whereas thrombin-induced PAR1-signaling is prevented by these proteases in human epithelial cells [121]. DerP3 was also recently shown to activate PAR4, and this process was associated with allergies to dust mites [122].Similar to proteases from house dust mites, three serine proteases (E1–E3) from cockroach extracts activate PAR2 and induce inflammatory signaling in mice and humans [123–125].Fungal proteases Pen C is a serine protease from Penicillium citrinum that induces IL-8 in human airway cells by activating PAR1 and PAR2 [126]. Proteases from Aspergillus fumigatus have also been shown to prevent PAR2-dependent inflammation [127]. Moreover, serine proteases from Alternaria alternate induced calcium signaling in human bronchial cells and induced inflammation in mice by secreting IL-33 following PAR2 activation [128–130].Plant proteases Bromelain is a mixture of cysteine proteases that is extracted from pineapple which is used as a PAR-independent anti-inflammatory agent [131]. Bromelain cleaves PAR2 and thereby prevents the associated inflammatory signaling [132]. In another study, however, bromelain, ficin, and papain activated PAR2 and PAR4 by proteolytic cleavage, leading to increased intracellular calcium levels [133]. Thus, further studies are required to further clarify the modes of action of pineapple proteases.Cleavage-independent PAR activation by agonist peptidesIndependent of proteolytic cleavage, PARs can be activated by synthetic soluble ligands corresponding with cleaved N-terminal sequences, or can be transactivated by cleavage-generated N-terminal regions of homo- or heterodimer partners.Synthetic peptides that mimic the first six amino acids of tethered N-terminal ligands can act as agonist peptides that activate PARs in the absence of cleavage events [11, 18, 134]. Specific activation of PARs by a soluble agonist peptide was first shown for human PAR1 with the peptide SFLLRN [6, 18]. However, this peptide also activated PAR2 [135–137] and therefore various peptides were tested for specific PAR1 activation. Yet, PAR1 was the most specifically and efficiently activated by TFLLRN [138]. In addition to thrombin agonist peptides, other PAR1 agonist peptides have been identified. In particular, the peptide NPNDKYEPF reproduced the effects of aPC [28], and PRSFFLRN corresponds with the N-terminal peptide generated by MMP-1 [86]. SLIGKV corresponds with the trypsin cleaved N-terminal region of human PAR2. However, the corresponding rat N-terminus SLIGRL is a more specific and efficient PAR2 agonist in rodents and humans [136, 139], and only the synthetic peptide LIGRLO achieved this effect more efficiently than SLIGRL in humans [140]. The roles of ECL-2 in specific PAR activation have been shown using labeled PAR2 agonist peptides [141, 142]. Because the thrombin generated PAR3 peptide does not activate the G protein autonomously, no such agonist peptides have been identified to date [9, 143]. GYPGKF corresponds with the thrombin-cleaved human PAR4 and has weak activity as an agonist [144]. But replacement of the first amino acid glycine (G) with alanine (A) induced PAR4 by 10-fold. This peptide may be suitable as a platelet activator in humans and mice [145].Several models of PAR–PAR interactions have been proposed and extensively studied based on PAR transactivation by agonist peptides [146]. When PAR1 is blocked on endothelial cells, however, thrombin, and not the PAR1-specific agonist peptide TFLLRN, induces signaling, reportedly by facilitating the heterodimerization of PAR1 and PAR2 [147]. Thrombin activation of the PAR1–PAR2 heterodimer leads to constitutive internalization and activation of β-arrestin by the PAR1 C-tail [146]. Accordingly, the required co-localization of PAR1 and PAR2 was shown in a human overexpression system, in mice studies of sepsis, and in PAR1–PAR2-driven cancer growth in a xenograft mouse model [148, 149]. In other studies, stable heterodimerization of human PAR1 and PAR4 was shown in platelet cells, and thrombin accelerated platelet activation under these conditions [150, 151]. Similar studies of mouse platelets showed efficient activation of platelets by thrombin in the presence of PAR3–PAR4 heterodimers [143]. Consistent with the thrombin-cleaved PAR3 peptide, which is not self-activating, PAR3 signaling was observed in the presence of PAR1 or PAR2 [22, 23, 34, 152]. Yet, heterodimerization influenced signal transduction and PAR membrane delivery due to enhanced glycosylation [153].In addition to activation by heterodimerization, PARs interact with other receptors, such as ion channels, other G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), receptor serine/threonine kinases (RSTKs), NOD-like receptors, and TLRs [154]. In particular, PAR2 initiated inflammatory signaling pathways, resulting in pain due to transactivation of the ion channels TRPV1 and TRPV4 in humans and mice [155–159]. Similar inflammatory effects follow transactivation of the RTKs EGFR and VEGFR by PAR2 and PAR4 [160–163]. Bacterial interactions with PARs suggest important roles of PARs in infectious disease. In agreement, TLRs recognize bacteria-derived molecules and contribute to innate immunity [164, 165]. Moreover, direct interactions of PAR2 with TLR3 and TLR4 were necessary for inflammatory responses to LPS in human cell lines and knockout mice and rats [166–171].PAR signalingActivation pathwaysPARs belong to a large family of GPCRs and induce multiple signaling pathways after coupling with heterodimeric G proteins. Activation of the Gα-subunit due to the exchange of a guanine from GDP to GTP results in dissociation of the Gβγ-dimer and activation of downstream pathways [172, 173].Following proteolytic cleavage or induction of agonist peptides, the engaged signaling pathways vary between tissues, cell lines, and the availability of co-receptors for transactivation. Depending on the ligand, specific α-subunits are activated, and these regulate subsequent cellular functions as summarized in Fig. 4. For example, thrombin-stimulated PAR1 activates the small GTPase protein RhoA via ERK1/2 kinases, but not via Rac1, whereas aPC-stimulated PAR1 induces Rac1 via Akt kinase, but not via RhoA [13, 174–176]. Moreover, in accordance with PAR1 cleavage sites, aPC prevents thrombin-induced RhoA signaling [16]. However, in contrast with thrombin-induced RhoA activation on platelets and endothelial cells, PAR1-agonist peptides and thrombin activated the inhibitory G protein Gi which leads to the inhibition of adenylyl cyclase in human fibroblasts [177, 178]. Other studies indicate that PAR2 activation is less tissue specific than PAR1 activation, and trypsin and VIIa cleaved PAR2 and activated Gαq and Gi, resulting in calcium influx, MAPK activation, and inflammatory signaling [8, 179].Open in a separate windowFig. 4G protein-coupled signaling induced by PAR activation. Depending on the tethered ligand, activated PAR couples with G protein α-subtypes. Gαq activates phospholipase Cβ (PLCβ), which mobilizes calcium. This further activates MAPKs (ERK1/2) and induces Ras signaling. Primarily, Gα12/12 and Gaq activate the Rho pathway. Gαi inhibits the activation of adenylyl cyclase, which leads to reduced production of cAMP. In contrast, the βγ-subunit functions as a negative regulator when bound to the α-subunit. After receptor activation, subunits separate, and the βγ-subunit interacts with other proteins, thereby activating or inhibiting signalingSignaling by tethered ligands can differ from that generated by corresponding soluble agonist peptides. For example, thrombin-cleaved PAR1 activated Gα12/13 and Gαq and induced Rho and Ca2+ signaling, whereas the PAR1-agonist peptide activated only Ga12/13 and downstream RhoA-dependent pathways that affected endothelial barrier permeability [180]. Similar observations of human platelets suggested that platelet activation followed coupling of thrombin-activated PAR1 with multiple heterotrimeric G protein subtypes, including Gα12/13 and Gαq [181–183]. Moreover, trypsin and the PAR2-agonist peptide induced ERK1/2 signaling and inflammation by activating PAR2 [29, 180, 184–186]. β-arrestins also play major roles in PAR-induced signaling independently of G protein activation. For instance, aPC-activated PAR1 induces cytoprotective effects by recruiting β-arrestin in endothelial cells. Thus, aPC cleavage fails to protect β-arrestin deficient cells from the effects of thrombin [187, 188]. In addition, multiple studies show that activated PAR2 co-localizes with β-arrestin-1 and arrestin-2 and induces ERK1/2 signaling [77, 189–191].Desensitization and terminationPAR activation is regulated by internalization and proteolytic desensitization, which limits the duration of signaling. For instance, PAR1 is constitutively internalized and recycled or agonist-induced internalized and degraded as described in [192, 193] and shown in the scheme of Fig. 5. As discussed above, some PAR-cleaving proteases abolish receptor responses by removing (shedding) or destroying the tethered ligands. For example, PAR1 is inactivated following cleavage by cathepsin G, and thrombin activation is hence prevented, allowing the formation of clotting under inflammatory conditions.Open in a separate windowFig. 5PAR trafficking. Activation-independent constitutive or agonist-induced internalization regulates PAR1 signalingDepending upon proteolytic cleavage, PAR1 rapidly internalizes or accumulates on the cell surface [194, 195]. Activated PAR1 is internalized via clathrin- and dynamin-dependent mechanisms, and is sorted from early endosomes to lysosomes for degradation [196–199]. Although the mechanisms that terminate PAR1 signaling are not clearly understood, this process is known to involve phosphorylation, ubiquitination, and recruitment of β-arrestin [200–204]. In contrast with PAR1, activated PAR2 is not constitutively internalized [205]. Thus, to prevent persistent signaling upon activation, PAR2 is phosphorylated and ubiquitinated and then binds β-arrestin before being internalized and degraded [206–208]. Under these conditions, the activated and internalized PAR2 is not recycled and instead induces β-arrestin-dependent endosomal ERK1/2 signaling in the cytoplasm [189, 191, 209]. Thus, large cytoplasmic stores of newly generated PAR2 are required for rapid externalization and activation on cell membranes [210]. Although less is known about how PAR4 signaling is terminated, recent observations suggest that PAR4 internalization is independent of β-arrestin and slowly occurs via clathrin- and dynamin-dependent pathways [211]. In agreement, human platelets internalized PAR4 much slower than PAR1, and exhibited prolonged PAR4 signaling activity [212]. Moreover, growing evidence indicates that PAR–PAR heterodimerization is important for internalization, and that the underlying mechanisms include PAR2-dependent glycosylation of PAR4, thus affecting membrane transport [153]. Upon internalization, endosomal PAR4 dimerizes with the purinergic receptor P2Y12 and induces Akt signaling by recruiting β-arrestin within endosomes [213].Depending on stimuli, PAR expression patterns are regulated by complex combinations of cell surface presentation, endocytosis, vesicle born or recycled (i.e., re-exocytosed) receptors, and trafficking modes that are linked to posttranslational modifications of PAR.Role of PARs in inflammationWith the current increases in the prevalence of inflammatory diseases, published in in vitro and in vivo studies of the roles of PARs in inflammation have become more numerous. These are reviewed below.Systemic inflammation and inflammatory cells in the cardiovascular systemPARs are critical for the interplay between clotting proteases of platelets, endothelial cells, and vascular smooth muscle cells that regulate hemostasis, vascular barrier function, vascular tone, vascular homeostasis, cell adhesion, and inflammatory responses [150]. The roles of PARs in these processes vary significantly between species. Specifically, whereas functional PAR1 and PAR4 are expressed in human platelets [214], PAR1, PAR3, and PAR4 have been found in guinea pig platelets [215]. Whereas mouse and rat platelets lack PAR1, they are activated at low concentrations of thrombin, which is recruited by PAR3 onto the surface of platelets and then efficiently activates PAR4 [4]. Due to interspecies differences in PAR expression, mouse and rat studies of PARs are difficult to translate to humans. PARs in endothelial cells contribute positive regulatory signals for endothelial adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin [216, 217], all of which promote vascular barrier function. As a counterpart of intravascular cells, PAR4 induces leukocyte migration [75], and PAR2 expressed on macrophages promotes inflammatory modulators such as interleukin-8 (IL-8) [218]. These modes of signaling all contribute to a complex PAR-mediated interplay of endothelial cells that is orchestrated by intravascular cells and cytokine secretion. In addition, PARs, particularly PAR1, regulate vascular barrier function, and hence, extravasation of macromolecules such as complement proteins and antibodies. In addition, thrombin-mediated activation of PAR1 increases endothelial barrier permeability by activating mitogen-activated protein kinases (MAPKs) [219]. Although this effect is reversed by activated protein C (aPC)-mediated activation of PAR1 [28, 174, 175, 220]. Thrombin further promotes prostaglandin 2 (PGE2) secretion, and consequent endothelial barrier permeability [221]. Similarly, PAR1 activation increased vascular leakage in a murine model [222]. Inflammatory mediators, such as tumor necrosis factor alpha (TNFα), were shown to regulate the expression of endothelial PAR2, and the authors suggested that these data were indicative of barrier protective effects of PAR2 [223]. Several other studies show that PAR2 activation induces endothelium-dependent relaxation in blood vessels of mice and in arteries of rats [224–228]. In contrast, dual activities of PAR2 on blood vessels were reported in a study of rats [229]. In this line, thrombin-activated PAR1 induced the expression of vascular endothelial growth factor in smooth muscle cells [230], thus revealing the relationship between coagulation and vascular growth. Although the roles of PARs in the development of arteriosclerosis are yet to be elucidated, PAR2 and PAR4 were induced in human arteries under inflammatory conditions [223], suggesting important roles of PARs in vascular inflammation.Chronic inflammation of the gastrointestinal tractIn the gut lumen, human and bacterial proteases are both present at high concentrations. Similar to endothelial barriers, proteases regulate intestinal barrier permeability via PARs, all four of which are expressed by cells of the gastrointestinal tract [9, 224, 231, 232]. Trypsins and tryptases are prominent intestinal proteases, suggesting likely involvement of PAR2 as a major receptor of intestinal inflammation. In accordance, intestinal tight junctions are disrupted by PAR2-activating proteases, leading to inflammatory signaling in humans and rats [139, 206, 233, 234]. Although the roles of PARs in irritable bowel syndrome (IBS) and inflammatory bowel diseases remain unclear, roles of PARs in intestinal barrier function have been described. Specifically, PAR1 and PAR2 regulated permeability and chloride secretion, which are involved in diarrhea and constipation in IBS patients [234–236]. In addition, activated endosomal PAR2 caused persistent pain in a mouse model of IBS [209].Inflammatory diseases of the respiratory systemIt has long been suggested that PARs are involved in the pathophysiology of respiratory disorders, reflecting observations of elevated levels of PAR-activating proteases, such as thrombin and tryptase, in bronchoalveolar lavage fluid from patients with pulmonary inflammation [237, 238]. In a sheep asthma model and in asthmatic patients, tryptase inhibitors reduced inflammation [239, 240], further indicating important roles of PAR2 in respiratory disease. These roles of PARs are also suggested by the prominence of a variety of non-mammalian PAR-activating proteases, such as those of house dust mites and cockroaches [120, 123, 124]. Expression of PAR1, PAR2, and PAR4 on bronchial epithelial and smooth muscle cells induced inflammatory signaling in multiple studies [55, 121, 241–245]. PAR2 is also upregulated in epithelial cells of patients with asthma and chronic obstructive pulmonary syndrome (COPD) [246, 247]. Whether PAR2 activation results in bronchoconstriction or dilatation remains controversial, in part owing to interspecies differences and tissue dependencies [242, 248, 249]. In humans, however, PAR1-agonist peptides with thrombin, and a PAR2-agonist peptide with trypsin and tryptase, induced bronchoconstriction by inducing Ca2+ signaling in airway smooth muscle cells [241, 244]. Moreover, the long-term activation of PAR1 and PAR2 led to pulmonary fibrosis in mice models [250].Inflammatory skin diseasesHigh concentrations of exogenous proteases are present on the skin of various species, and these may activate PARs to regulate epidermal permeability and barrier function [251]. Indeed, epidermal inflammation has been linked to PAR1 and PAR2 activation in keratinocytes, which comprise the epidermal barrier with sub-epidermal skin fibroblasts [179, 252, 253]. Subsequent release of IL-8, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF) was also observed previously [254], potentially involving NFκB activation [255]. In addition, the inflammatory roles of PAR2 have been demonstrated in mice models of atopic dermatitis due to elevated tryptase and PAR2 expression levels [256, 257]. Similar to studies in mouse models, PAR2 was upregulated in patients with atopic dermatitis, and PAR2 agonists increased itch, causing irresponsiveness of sensory nerves to therapy with antihistamines [258].Rheumatic disease“Rheumatic disease” is a common term for autoimmune diseases that affect joints, bones, and muscles. Although rheumatic disorders are numerous, some of the common underlying symptoms include chronic joint inflammation, stiffness, and pain [259]. Currently, PAR2 is the only PAR that has been associated with the development of rheumatic diseases [260]. Direct roles of PAR2 in rheumatic diseases were first indicated in 2003 in a mouse study by Ferrell et al. [261]. In their study, a PAR2-agonist peptide induced strong inflammatory effects in wt mice, causing joint swelling and synovial hyperemia, whereas joint swelling was absent in PAR2 deficient mice [261]. Similarly, in patients with rheumatoid arthritis, PAR2 is upregulated in inflamed tissues [262]. Further increases in PAR2 expression were noted in monocytes, and the PAR2-agonist peptide upregulated IL-6. In contrast, PAR2 expression was decreased after treatments with antirheumatic drugs [263], further supporting the role of PAR2 in rheumatic disease.PAR modulators as targets for therapyThe complexity of PAR regulation is indicated by the culmination of specific proteolytic cleavage modes (inactivating or activating), protease inhibitors, and cofactors, and with the effects of PAR glycosylation and dimerization (Fig. (Fig.1).1). In this section we discuss classes of agonists and antagonists that have been tested as PAR modulators for use as therapeutic agents as summarized in Fig. 6 and Tables 5, ,66 and and77.Open in a separate windowFig. 6PAR modulators. Pharmacological substances, such as 1) peptides and peptidomimetics, 2) blocking antibodies, 3) small molecules, 4) pepducins, and 5) parmodulins are used as therapeutic agents that affect PAR activitiesPeptide agonists and antagonists are short synthetic peptides that mimick the PAR-tethered ligand that is liberated by proteolytic cleavage, as described above. These peptides either induce signal transduction or prevent cleavage-dependent signaling following PAR rapid internalization, and some C- or N-terminal modifications of soluble ligand sequences have resulted in increased activation efficiency [18]. Peptidomimetic antagonists are small protein-like chains that mimick the tethered ligands of PARs, and were recently used as PAR modulators for the first time [264].Soon after PARs were discovered, PAR1 blocking antibodies were reported [265], and these blocked protease binding and or the cleavage site of the receptor. Non-peptide small molecules, such as the PAR1 antagonists vorapaxar [266] and atopaxar [267], also interact with PARs, mainly via ECL2.Only two classes of intracellular PAR antagonists have been developed to date. Pepducins are cell penetrating palmitoylated peptides that were derived from the intracellular loop of PAR, and these interfere with G protein binding [268]. Parmodulins, in contrast, are small molecules that bind PARs at the G protein binding pocket of the C-tail to compete with Gαq subunits, but not with other Gα subunits [269].Examination of agonists and antagonists in vitro and in preclinical studies (Tables (Tables5,5, ,66 and and77)Clinical studiesDespite the importance of PARs in various pathophysiological conditions, few PAR modulating tools have been tested in clinical studies, and even fewer have been established for treatment. Since the identification of PAR1 as a platelet thrombin receptor, an abundance of research has been conducted to identify PAR1 antagonists that can block platelet activation and prevent thrombotic cardiovascular events. The first clinically approved PAR1 antagonist was the small-molecule antagonist vorapaxar [266]. Phase II clinical trials of this agent showed reduced risks for myocardial infarction in patients treated with vorapaxar in combination with standard antiplatelet therapy. Moreover, the risks of bleeding complications were not significantly increased [270]. Subsequently, two large-scale phase III multicenter, randomized, double-blind, placebo-controlled studies of vorapaxar (ZONTIVITY, SCH530348) were performed. In the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50; details at www.ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT00526474","term_id":"NCT00526474"}}NCT00526474) study, the rate of cardiovascular events at the second efficacy endpoint were significantly reduced by vorapaxar in combination with standard antiplatelet therapy [271]. Furthermore, in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER; details at www.ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT00527943","term_id":"NCT00527943"}}NCT00527943) study, vorapaxar reduced the hazard of first myocardial infarction of any type in patients who were treated within 24 h of having symptoms of a cardiovascular event. However, in the TRACER study, vorapaxar failed to prevent secondary ischemic events [272]. Because vorapaxar increased bleeding complications in the clinical setting, the alternative PAR1 antagonist atopaxar (E5555) [267] was tested in a phase II clinical trial called (Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT-ACS; details at www.ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT00548587","term_id":"NCT00548587"}}NCT00548587) study [273]. Atopaxar inhibited platelet aggregation in ACS patients in a dose-dependent manner, and caused no side effects of abnormal platelet activation, such as bleeding [274, 275]. Yet, patients receiving atopaxar had dose-dependent increases in liver abnormalities [273].To prevent the bleeding problems that arise from treatments with PAR1 antagonists, a new class of PAR1 antagonist was designed, and the member pepducin PZ-128 (P1-pal7) was tested in a phase I trial [276]. This study showed no reduction in platelet aggregation, but the platelet blocking effect of PZ-128 was reversible ex vivo in the presence of saturating concentrations of the PAR1 agonist peptide SFLLRN. Based on these promising findings, the new PAR1 blocking agent PZ-128 was considered in the coronary artery disease study Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention (TRIP-PCI). Data from this phase II trial are not yet available (details at www.ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT02561000","term_id":"NCT02561000"}}NCT02561000).As an alternative to PAR1 targeted antithrombotic drugs, the PAR4 small-peptide antagonist BMS-986120 reduced reversible thrombus formation ex vivo in a phase I trial [277]. Consequently, this promising anticoagulant PAR4 antagonist is currently being compared with a standard anticoagulant drug in a phase II study of stroke recurrence (details at www.ClinicalTrials.gov; {"type":"clinical-trial","attrs":{"text":"NCT02671461","term_id":"NCT02671461"}}NCT02671461).ConclusionSince the identification of PARs in the 1990s, studies of the complex mechanisms of PAR activation have been abundant, and these have clarified the roles of PARs in inflammatory disease. Various mammalian and non-mammalian proteases have also been recognized as PAR-mediated regulators of physiological and pathophysiological processes. Despite the development of various PAR modulators, few have been approved for therapeutic use. Obstacles to this therapeutic strategy include species differences in PAR expression and limited bioavailability of modulators in vivo and in clinical studies. Further research is needed to identify specific and efficient anti-inflammatory PAR modulators.AcknowledgementsWe would like to thank Hermenegild K. Heuberger for the drawing of the figures.We thank Enago (http://www.enago.com) for the english language review.FundingWe would like to express our sincere gratitude for the support given to RAS by the Swiss National Science Foundation grant #PZ00P3_136639 for the salary of DMH.Availability of data and materialsData sharing not applicable to this article as no datasets were generated or analysed during the current study.AbbreviationsACAdenylyl CyclaseAKTProtein kinase BaPCActivated Protein CCOPDChronic Obstructive Pulmonary SyndromeCOXCyclooxygenaseECLExtracellular LoopEGFREpidermal Growth Factor ReceptorEPCREndothelial Protein C ReceptorERKExtracellular Signal-regulated KinaseF2RCoagulation Factor 2 ReceptorF2RL1Coagulation Factor 2 Receptor-Like 1F2RL2Coagulation Factor 2 Receptor-Like 2F2RL3Coagulation Factor 2 Receptor-Like 3FVIIaActivated Coagulation Factor VIIFXaActivated Coagulation Factor XGM-CSFGranulocyte Macrophage Colony-stimulating FactorGPCRG Protein-Coupled ReceptorIBDInflammatory Bowel DiseaseIBSIrritable Bowel SyndromeICAMIntercellular Adhesion MoleculeILInterleukinLepAPseudomonas aeruginosa-Derived Large Extracellular ProteaseLPSLipopolysaccharidesMAPKMitogen-Activated Protein KinaseMMPMatrix MetalloproteaseNFκBNuclear Factor kappa BPARProtease-Activated ReceptorpenCPenicillium citrinum-Derived Alkaline Serine Protease CPGE2Prostaglandin E2PI3KPhosphatidylinositol-3-KinasePLCβPhospholipase C betaRac1Ras-Related C3 Botulinum Toxin Substrate 1RhoARas homolog gene family, member ARSTKReceptor Serine/Threonine KinaseRTKReceptor Tyrosine KinaseSpeBStreptococcal Pyrogenic Exotoxin BTFTissue FactorTLRToll-Like ReceptorTMThrombomodulinTRPVTransient Receptor Potential Channels Vanilloid SubtypeVCAMVascular Cell Adhesion MoleculeVEGFVascular Endothelial Growth FactorVEGFRVascular Endothelial Growth Factor ReceptorAuthors’ contributionsManuscript preparation by DMH and RAS. All authors read and approved the final manuscript.NotesEthics approval and consent to participateNot applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Contributor InformationDorothea M. Heuberger, Email: hc.zsu@regrebueh.akinomaehtorod.Reto A. Schuepbach, Phone: +41 44 255 1092, Email: hc.zsu@hcabpeuhcs.oter.References1. Bahou WF, Nierman WC, Durkin AS, Potter CL, Demetrick DJ. Chromosomal assignment of the human thrombin receptor gene: localization to region q13 of chromosome 5. Blood. 1993;82:1532–1537. [PubMed] [Google Scholar]2. Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A. 1994;91:9208–9212. doi: 10.1073/pnas.91.20.9208. [PMC free article] [PubMed] [CrossRef] [Google Scholar]3. 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