细胞外囊泡在心房颤动发病中的作用

细胞外囊泡(EVs)是循环和体液中从细胞膜上分泌或脱落的小泡,在细胞间通讯起着关键作用.EVs可为房颤(AF)诊断、危险分层和评估提供生物标志物,并可作为药物的输送载体为房颤的靶向治疗提供可能.     

革兰氏阳性菌细胞外囊泡研究进展

细胞外囊泡（EVs）是一种包括真核细胞和细菌在内的多种细胞分泌的具有脂质双层结构的囊泡。革兰氏阴性菌分泌的EVs已被广泛研究多年，但革兰氏阳性菌由于细胞壁的结构特征，一直被认为无法分泌EVs。然而近年来的研究发现，革兰氏阳性菌同样可以分泌EVs，其分泌的EVs携带了蛋白质、核酸、脂质以及代谢物等多种组分，在革兰氏阳性菌的生物膜形成、耐药性、水平基因转移（HGT）及对宿主细胞的免疫调节等方面发挥重要作用，在疫苗研发、疾病治疗和药物递送等领域具有重要的潜在应用价值。本文通过对近年来革兰氏阳性菌EVs的相关研究进行综述，以期为革兰氏阳性菌EVs的相关研究提供参考。     

胞外囊泡对血管生成影响的研究进展

正胞外囊泡(extracellular vesicles,EVs)是由不同细胞产生并释放到细胞外的囊泡。最初被认为是无生物学功能的细胞碎片,现在发现其在血管生成、免疫调节、组织修复等过程中发挥重要作用。EVs携带了许多表面受体、遗传物质、生物活性分子等,在细胞间传递信息,从而在血管生成过程中发挥了重要作用。本文就EVs对血管生成影响的研究进展综述如下。     

基于胞外囊泡治疗诊断学智能药物递送工具

胞外囊泡 （EVs） 作为细胞外的膜颗粒,在细胞间信号传导中起着至关重要的作用。研究表明,EVs有可能用作特定器官 （如内耳） 的生物标志物或药物递送系统。在压力与健康状态下,EVs释放的分子不同,这些活性分子能够识别机体的患病状态。研究表明,可以利用EVs将药物输送到难以到达的器官,如耳蜗感觉毛细胞和大脑,因为它们能够穿过血迷路和血脑屏障。在本综述中,我们总结了有关EVs的生物组成和发生、分离技术、表征手段、作为药物输送载体的潜在治疗应用、药物加载方法及在听觉系统内耳治疗的应用潜力。     

胞外囊泡在肿瘤发生发展中的研究进展

<正>胞外囊泡(extracellular vesicles,EVs)是释放到细胞外的膜性小囊泡,是传递细胞间信号的一种新方式,在生理或病理情况下发挥重要调节作用。几乎所有类型的细胞均可以产生并释放EVs,尤其是肿瘤细胞~([1-2])。越来越多的证据表明,在肿瘤的发生和发展过程中,肿瘤来源的胞外囊泡能够通过传递囊泡中的内容物来改变受体细胞的生物学功能,比如导致免疫抑制,诱导血管生成,甚至促进肿瘤转移~([3-4])。     

胞外囊泡在恶性肿瘤发生发展中的作用

通过胞外囊泡(extracellular vesicles,Evs)进行的细胞内信号转导是一种被低估的细胞间的沟通方式.EVs携带很多生物活性分子、表面受体以及基因信息,例如蛋白编码基因和miRNAs,lncRNAs以及mRNAs都可通过EVs在细胞间传递并且影响受体细胞的功能.本篇文章阐述了EVs,尤其是EVs相关的miRNAs如何影响恶性肿瘤的发生、侵袭、转移和复发.     

肝癌细胞来源LC3B阳性的细胞外囊泡诱导CD8 +T细胞耗竭的作用机制研究

目的:探讨肝癌细胞来源分泌型自噬体,即一群表达自噬标志LC3B的细胞外囊泡(LC3B + extracellular vesicles, LC3B +EVs)对CD8 +T细胞功能耗竭的影响及其作用机制。 方法:流式细胞术检测肝癌患者外周血和腹水中LC3B +E...     

化疗诱导的衰老细胞胞外囊泡的分离及相关特性研究

目的:探讨化疗诱导的衰老肿瘤细胞分泌的胞外囊泡(EVs)特性及其对肿瘤细胞与巨噬细胞的影响。方法:化疗药物阿霉素、顺铂及极光激酶抑制剂MLN8237作用神经母细胞瘤细胞系,分析细胞衰老及细胞周期阻滞情况,建立化疗诱导的细胞衰老模型。分离衰老细胞培养上清中的EVs,Western blot及Nanosight分析EVs纯度、粒径大小与浓度。分别用肿瘤细胞及巨噬细胞孵育EVs,Western blot与RT-qPCR检测胞内蛋白与细胞因子表达。结果:低浓度MLN8237作用IMR32细胞成功诱导细胞衰老;衰老细胞分泌的EVs(SAEs)数量低于未处理细胞,但大小在30～150 nm的外泌体组分含量偏高;与EVs孵育组相比,SAEs孵育的IMR32细胞BRD4与C-MYC表达水平明显下调;EVs与SAEs孵育的THP-1细胞均发生形态改变:贴壁并伸出伪足,呈现极化状态;但THP-1细胞内细胞因子表达水平明显不同:在EVs与SAEs组,IL-4与TNF-α水平明显比未处理组低;与EVs组相比,SAEs组IL-1β、IL-10与TGF-β水平明显降低。结论:SAEs能够抑制肿瘤细胞BRD4表达并下调巨噬细胞分泌IL-10与TGF-β水平,有利于肿瘤预后,但具体机制还需要进一步研究。     

周细胞在慢性肾脏病中缺氧与纤维化相互关系中的作用

肾间质纤维化、肾小管损伤和炎性细胞浸润是慢性肾脏病的重要标志.组织缺氧是肾间质损伤发生的重要机制之一.肾周毛细血管损伤导致的间质血流减少为肾间质纤维化的重要病因.纤维化时,周细胞从肾小管周围毛细血管分离并生成ECM,毛细血管稀疏介导了肾小管间质损伤、缺氧和纤维化间错综复杂的相互关系.理清上述三者之间的关系,以及周细胞在其中所起到的作用,有助于肾纤维化的治疗,延缓慢性肾脏病的进展.     

小鼠囊胚胞外囊泡对子宫内膜上皮细胞E-cadherin和vimentin表达的影响

目的：探讨小鼠囊胚细胞外囊泡（EVs）对小鼠子宫内膜上皮细胞（mEECs）上皮钙黏素（E-cadherin和波形蛋白（vimentin）表达的影响。方法：以孕4.5 d的BABL/c小鼠囊胚为材料，利用超高速离心分离纯化小鼠囊胚EVs，粒度仪分析粒径，透射电子显微镜观察形态，Western blot分析Tsg101和CD63的表达；酶消化结合差速贴壁筛选法制备原代mEECs，流式细胞术分析细胞角蛋白8(CK8)的阳性率鉴定mEECs纯度。建立囊胚EVs与mEECs共培养模型，共聚焦显微镜观察PKH26标记的囊胚EVs进入mEECs的形态过程，Western blot和细胞免疫化学法分析共培养中mEECs中E-cadherin和vimentin表达的变化。结果：（1）小鼠囊胚EVs平均粒径（226.6±3.8） nm，表现囊泡超微形态，表达Tsg101和CD63蛋白标志物。（2）原代mEECs形态均匀，CK8阳性细胞率80%以上。（3）与0 h相比，mEECs与囊胚EVs共培养48和96 h时E-cadherin表达水平显著降低（P<0.01）,vimentin表达水平显著升高（P...     

肿瘤微环境代谢重编程调控耗竭性CD8+T细胞研究进展

G蛋白偶联受体 (G-Protein-Coupled Receptors,GPCRs) 广泛表达于不同的细胞类型,参与众多细胞生物学功能的调控。研究显示,GPCRs介导的相关通路在维持肾脏发育、调节肾脏生理功能及在肾脏疾病发生发展中发挥重要作用。 本综述简要阐述了GPCRs相关通路特点,并重点介绍黏附类GPCRs(adhesion GPCRs,aGPCRs)、大麻素受体 (Cannabinoid Receptors,CB)、溶血磷脂酸受体 (Lysophosphatidic Acid Receptor,LPAR) 在肾脏疾病领域的最新研究进展,以期加深对 GPCRs功能的认识,并为多种肾脏疾病治疗药物的开发提供思路。     

Unsung renal receptors: orphan G‐protein‐coupled receptors play essential roles in renal development and homeostasis

Recent studies have shown that orphan GPCRs of the GPR family are utilized as specialized chemosensors in various tissues to detect metabolites, and in turn to activate downstream pathways which regulate systemic homeostasis. These studies often find that such metabolites are generated by well‐known metabolic pathways, implying that known metabolites and chemicals may perform novel functions. In this review, we summarize recent findings highlighting the role of deorphanized GPRs in renal development and function. Understanding the role of these receptors is critical in gaining insights into mechanisms that regulate renal function both in health and in disease.     

Antibodies against Angiotensin II Type 1 and Endothelin A Receptors: Relevance and pathogenicity

Antibodies against two G-protein coupled receptors (GPCRs), angiotensin II type 1 receptor (AT1R) and endothelin A receptor (ETAR) are among a growing number of autoantibodies that are found to be associated with allograft dysfunction. AT1R antibodies (AT1Rabs) and ETAR antibodies (ETARabs) have been shown to activate their target receptors and affect signaling pathways. Multiple single center reports have shown an association between presence of these antibodies and acute or chronic rejection and graft loss in kidney, heart, liver, lung and composite tissue transplantations. However, the characteristics of patients that are most likely to develop adverse outcomes, the phenotypes associated with graft damage solely due to these antibodies, and the antibody titer required to cause dysfunction are areas that remain controversial. This review compiles existing knowledge on the effect of antibodies against GPCRs in other diseases in order to bridge the gap in knowledge within transplantation biology. Future areas for research are highlighted and include the need for functional assays and treatment protocols for transplant patients who present with AT1Rabs and ETARabs. Understanding how antibodies that activate GPCRs influence transplantation outcome will have direct clinical implications for preemptive evaluation of transplant candidates as well as the post-transplant care of organ recipients.     

G-protein-coupled receptor expression, function, and signaling in macrophages

G-protein-coupled receptors (GPCRs) are widely targeted in drug discovery. As macrophages are key cellular mediators of acute and chronic inflammation, we review here the role of GPCRs in regulating macrophage function, with a focus on contribution to disease pathology and potential therapeutic applications. Within this analysis, we highlight novel GPCRs with a macrophage-restricted expression profile, which provide avenues for further exploration. We also review an emerging literature, which documents novel roles for GPCR signaling components in GPCR-independent signaling in macrophages. In particular, we examine the crosstalk between GPCR and TLR signaling pathways and highlight GPCR signaling molecules which are likely to have uncharacterized functions in this cell lineage.     

Peroxisome proliferator-activated receptor agonists in a battle against the aging kidney

As aging is a complex phenomenon characterized by intraindividual and interindividual diversities in the maintenance of the homeostatic condition of cells and tissues, changes in renal function are not uniform and depend on associated diseases and environmental factors. Multiple studies have investigated the possible underlying mechanisms of age-related decline in kidney function. Evolutionary, molecular, cellular and systemic theories have been postulated to explain the primary disease independent age-related changes and adaptive responses. As peroxisome proliferator-activated receptors (PPARs) are involved in a broad spectrum of biological processes, PPAR activation might have an effect on the prevention of cell senescence. In this review, we will focus on the experimental and clinical evidence of PPAR agonists in a battle against the aging kidney.     

G蛋白偶联受体激酶在心血管疾病中的作用

G-protein-coupled receptors (GPCRs) are hitherto the largest family of membrane receptors. They activate associated heterotrimeric G-proteins and participate in the regulation of intracellular signaling pathways, which are accomplished via ligand binding to them. G-protein-coupled receptor kinases (GRKs) are key modulators of GPCR signaling. GRKs, in concert with β-arrestins, classically lead to desensitization and internalization of GPCR, thus preventing hyperactivation of GPCR second messenger cascades. Changes in the GRKs expression and regulation have featured prominently in many cardiovascular diseases, including heart failure, myocardial infarction, cardiac hypertrophy, and hypertension. Intensively studying the role of GRKs in cardiovascular diseases contributes to expounding the mechanism of correlated diseases. Herein, we review the role of GRKs in cardiovascular pathophysiology.     

Emerging roles for the BAI1 protein family in the regulation of phagocytosis,synaptogenesis, neurovasculature,and tumor development

While G-protein-coupled receptors (GPCRs) have received considerable attention for their biological activity in a diversity of physiological functions and have become targets for therapeutic intervention in many diseases, the function of the cell adhesion subfamily of GPCRs remains poorly understood. Within this group, the family of brain angiogenesis inhibitor molecules (BAI1-3) has become increasingly appreciated for their diverse roles in biology and disease. In particular, recent findings suggest emerging roles for BAI1 in the regulation of phenomena including phagocytosis, synaptogenesis, and the inhibition of tumor growth and angiogenesis via the processing of its extracellular domain into secreted vasculostatins. Here we summarize the known biological features of the BAI proteins, including their structure, proteolysis events, and interacting partners, and their recently identified ability to regulate certain signaling pathways. Finally, we discuss the potential of the BAIs as therapeutics or targets for diseases as varied as cancer, stroke, and schizophrenia.     

G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis

Introduction

G protein-coupled receptors (GPCRs) are transmembrane receptor proteins, which allow the transfer of signals across the membrane. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response. GPCRs signaling pathways play a significant role in inflammatory and immune response processes including RA.

Findings

In this review, we have focused on the advances in GPCRs signaling pathway implicating the inflammatory and immune response of RA. The signaling pathways of GPCRs–adenylyl cyclase (AC)–cyclic adenosine 3′, 5′-monophosphate (cAMP) include β₂ adrenergic receptors (β₂-ARs)–AC–cAMP signaling pathways, E-prostanoid2/4 (EP2/4)–AC–cAMP signaling pathways and so on. Regulatory proteins, such as G protein-coupled receptor kinases (GRKs) and β-arrestins, play important modulatory roles in GPCRs signaling pathway. GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.

Conclusion

GPCRs–AC–cAMP signal pathways involve in the inflammatory and immune response of RA. Different signaling pathways are mediated by different receptors, such as β₂-AR, PGE2 receptor, chemokines receptor, and adenosine receptor. GRKs and β-arrestins are crucial proteins in the regulation of GPCRs signaling pathways. The potential therapeutic targets as well as strategies to modulate GPCRs signaling pathway are new development trends.

     

Molecular targets for treatment of kidney fibrosis

Renal fibrosis is the culmination of processes driven by signaling pathways involving transforming growth factor-β family of cytokines, connective-tissue growth factor, nuclear factor κB, Wnt/β-catenin, Notch, and other growth factors. Many studies in experimental animal models have directly targeted these pathways and demonstrated efficacy in mitigating renal fibrosis. However, only a small fraction of these approaches have been attempted in human and even fewer have been successfully translated to clinical use for patient with kidney diseases. Drugs with proven efficacy for treatment of kidney diseases and tissue fibrosis exert some of their effects by interfering with components of these pathways. This review considers key molecular mediators of renal fibrosis and their potential as targets for treatment of renal fibrosis.     

Costimulatory Pathways in Kidney Transplantation: Pathogenetic Role,Clinical Significance and New Therapeutic Opportunities

Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.