胞外囊泡在银屑病中的研究进展

银屑病是一种常见的慢性复发性炎症性皮肤病,以角质形成细胞过度增殖和分化异常及炎性细胞浸润为主要病理特点。胞外囊泡(extracellular vesicles, EVs)是由多种细胞分泌的一类脂质双层包裹的纳米级囊泡,可作为细胞间通讯和物质传输的载体,调控靶细胞的生理或病理反应。本文就EVs在银屑病的发病机制与应用中的研究进展进行综述。     

细胞外囊泡在真菌与宿主相互作用中的研究进展

真菌感染一直是严重的全球健康问题,随着发病率的逐年增加和耐药菌株的不断出现,对其致病机制和耐药机制的研究亟待深入。但人们对真菌如何在感染过程中与宿主相互作用,甚至对宿主进行操纵知之甚少。近年来,细胞外囊泡的功能研究成为热点。囊泡内运输的物质除保证其生存必需,可通过激活/抑制宿主细胞免疫应答,或其他作用于宿主细胞影响其内部微环境的方式改变感染进程和结果。该文对真菌细胞外囊泡的分类、形成、功能及其与宿主间相互作用加以综述,以期了解真菌如何利用细胞外囊泡改变宿主的免疫和非免疫反应,从而提高对真菌细胞间通讯的理解,有助于解析真菌与宿主之间相互交流的复杂性,从而针对性开发出对抗真菌感染的治疗策略。     

外泌体对毛囊周期调节作用的研究进展

细胞外囊泡（EV）是细胞旁分泌产生的脂质双分子层包绕的球状膜性囊泡,主要包括外泌体、凋亡小体、微囊泡和膜微粒等。自血浆中发现能加速血栓形成的可沉淀物质以来,各类细胞外囊泡不断被发现和命名。随着研究的深入,EV逐步被发现是载体而非细胞废弃物,发挥细胞间传递信号的功能。毛囊是皮肤附属器,具有上皮细胞成分和间充质细胞成分,其周期性再生包含休止、生长和退行阶段的循环。该文从毛囊的形态发生、生长周期和色素形成三方面,对近年外泌体研究的重要突破以及类外泌体纳米囊泡的研究进展作一综述。     

外泌体在感染性疾病免疫调控中的作用

外泌体是基于细胞内膜的双层囊泡小体,具有与生物学和病理学相关的各种组成成分。外泌体存在于多种体液当中,其内含有多种DNA和mRNA片段、非编码RNA分子、蛋白质和脂质等多种生物分子,在细胞信息传递中起重要作用,参与细胞凋亡、血管生成、免疫调节、肿瘤迁移等多种病理生理过程。本文综述了外泌体在感染性疾病免疫调节中的作用。     

外泌体与皮肤科相关疾病的研究进展

外泌体是一种可由大多数种类细胞分泌的纳米级(直径30~100 nm)囊泡。它不仅是细胞的代谢产物,而且具有在细胞间传递信息的生物学功能,可以通过内吞作用、微胞饮作用甚至直接与细胞膜脂质融合等机制被受体细胞摄取。目前有研究发现,外泌体与变态反应性疾病、黑素瘤、自身免疫性疾病及伤口愈合等皮肤相关的疾病有很大关系,在各种生理和病理过程中发挥着重要的生物学作用。该文对外泌体与皮肤科相关疾病的研究进展作一综述。     

非细胞治疗——干细胞来源细胞外囊泡在勃起功能障碍及损伤组织再生中的应用

细胞外囊泡(EVs)最初被认为是细胞碎片或活细胞的排泄废物,但随着人们对其来源和作用机制的深入了解,这类携带脂类、蛋白质和核酸等多种成分的囊泡样物质引起了广泛关注,尽管目前人们对于EVs形成和释放的刺激及驱动因素的了解才刚刚起步,但关于其在维持机体稳态方面发挥的重要作用已经形成共识,尤其在损伤修复领域,EVs被视作可能是干细胞治疗的合理替代途径。病理性勃起功能障碍(ED)亦同样涉及多种组织损伤类型,EVs可能是一种理想的治疗方式,本文着重回顾EVs在损伤组织修复中已发表的部分重要文献,对EVs及其在损伤组织修复和再生中发挥作用的相关机制做一介绍,为EVs在ED领域的治疗提供依据。     

乳房外佩吉特病中囊泡病液体蛋白15的表达及其意义

目的：分析乳房外佩吉特（Paget）病中囊泡病液体蛋白（GCDFP）-15的表达及其意义。方法：应用免疫组化方法对20例乳房外Paget病患者的GCDFP-15和细胞角蛋白20（CK20）进行检测。结果：20例患者CK20均为阴性，8例呈侵袭性生长的患者GCDFP-15表达为强阳性或阳性，12例呈原位生长的患者GCDFP-15表达为弱阳性或阴性。结论：GCDFP-15的表达对于判断乳房外Paget病是否呈侵袭性生长有一定意义。     

中性粒细胞胞外诱捕网与嗜中性皮病

中性粒细胞胞外诱捕网成分复杂,包括DNA和组蛋白及各种抗菌肽等,发挥的作用不仅限于宿主防御,还包括癌症、血管疾病、自身免疫性疾病等疾病.近年来,越来越多的研究发现,中性粒细胞胞外诱捕网的产生与嗜中性皮病的发生发展密切相关.本文主要围绕中性粒细胞胞外诱捕网的成分及作用、形成方式及参与嗜中性皮病的病理过程展开论述.     

外泌体在炎症性皮肤疾病中的作用研究进展

外泌体是包含蛋白质、脂质、核酸等物质的直径为30～150 nm的细胞外囊泡,它是参与皮肤免疫稳态和病理改变的关键因子,在炎症性皮肤疾病的发生发展中发挥调控作用。本文就外泌体在相关炎症性皮肤疾病发病机制中的作用做一综述,探讨外泌体在炎症性皮肤疾病治疗中的价值。     

酪氨酸酶等黑素小体相关蛋白胞内分选及投送的分子基础

内质网内新生酪氨酸酶肽链在钙连蛋白的作用下正确折叠并获得主要为N键寡糖的糖基化修饰。高尔基体外侧网络（TGN）上网格蛋白包被囊泡形成转运囊泡。其中AF3在特异性识别TYR等黑素小体相关蛋白中的双亮氨酸分选基序同时与网格蛋白结合。正确分选后的蛋白质在胞浆尾内含双亮氨酸基序，它能够指引被膜囊泡将TYR等分子投送到后期内涵体（Ⅰ期黑素小体）。当囊泡接触到靶膜后．v-SNARE和t-SNARE相结合，Rab蛋白水解GTP释能，将囊泡锁定在靶膜区域并发生融合。     

Interleukin‐17A affects extracellular vesicles release and cargo in human keratinocytes

Psoriasis is a chronic inflammatory systemic disease caused by deregulation of the interleukin‐23/‐17 axis that allows the activation of Th17 lymphocytes and the reprogramming of keratinocytes proliferative response, thereby inducing the secretion of cyto‐/chemokines and antimicrobial peptides. Beside cell‐to‐cell contacts and release of cytokines, hormones and second messengers, cells communicate each other through the release of extracellular vesicles containing DNA, RNA, microRNAs and proteins. It has been reported the alteration of extracellular vesicles trafficking in several diseases, but there is scarce evidence of the involvement of extracellular vesicles trafficking in the pathogenesis of psoriasis. The main goal of the study was to characterize the release, the cargo content and the capacity to transfer bioactive molecules of extracellular vesicles produced by keratinocytes following recombinant IL‐17A treatment if compared to untreated keratinocytes. A combined approach of standard ultracentrifugation, RNA isolation and real‐time RT‐PCR techniques was used to characterize extracellular vesicles cargo. Flow cytometry was used to quantitatively and qualitatively analyse extracellular vesicles and to evaluate cell‐to‐cell extracellular vesicles transfer. We report that the treatment of human keratinocytes with IL‐17A significantly modifies the extracellular vesicles cargo and release. Vesicles from IL‐17A‐treated cells display a specific pattern of mRNA which is undid by IL‐17A neutralization. Extracellular vesicles are taken up by acceptor cells irrespective of their content but only those derived from IL‐17A‐treated cells enable recipient cells to express psoriasis‐associated mRNA. The results imply a role of extracellular vesicles in amplifying the pro‐inflammatory cascade induced in keratinocyte by pro‐psoriatic cytokines.     

Employing extracellular vesicles for non-invasive renal monitoring:A captivating prospect

Extracellular vesicles(EVs) are fascinating nano-sized subjects extensively studied over the recent years across several disparate disciplines. EVs are endlessly secreted into the extracellular microenvironment by most cell types under physiological and pathological conditions. EVs encompass a variety of molecular constituents from their cell of origin, such as lipids, cell specific proteins and RNAs, thus constituting an informative resource for studying molecular events at the cellular level. There are three main classes of EVs classified based on their size, content, biogenesis and biological functions: exosomes, shedding microvesicles and apoptotic bodies. Besides cell culture supernatants, biological fluids have also been shown to contain different types of EVs. Amongst the various body fluids, the study of urinary extracellular vesicles(u EVs) as a source of candidate biomarkers gained much attention, since:(1) urine can be non-invasively collected in large amounts; and(2) the isolated u EVs are stable for a relatively long period of time. Here, we review the important aspects of urinary extracellular vesicles which are fast gaining attention as a promising future tool for the non-invasive monitoring of urinary tract. Recent advancements in the purification and analysis of u EVs and collection of their constituents in rapidly developing public databases, allow their better exploitation in molecular diagnostics. As a result, a growing number of studies have shown that changes in expression profile at the RNA and/or protein levels of u EVs reveal the molecular architectures of underlying key pathophysiological events of different clinically important diseases with kidney involvement.     

Characteristics and roles of extracellular vesicles released by epidermal keratinocytes

Keratinocytes, which constitute 90% of the cells in the epidermis of the skin, have been demonstrated to communicate with other skin cells such as fibroblasts, melanocytes and immune cells through extracellular vesicles (EVs). This communication is facilitated by the enriched EV biomolecular cargo which regulates multiple biological processes within skin tissue, including cell proliferation, cell migration, anti‐apoptosis, pigmentation transfer and extracellular matrix remodelling. This review will provide an overview of the current literature and advances in the field of keratinocyte‐derived EV research with particular regard to the interactions and communication between keratinocytes and other skin cells, mediated by EVs and EV components. Importantly, this information may shed some light on the potential for keratinocyte‐derived EVs in future biomedical studies.     

外泌体免疫作用机制在自身免疫性疾病中的研究进展

外泌体属于囊泡的一种,是由磷脂双分子层构成,经多种细胞释放,存在于生物体液中的一类亚细胞结构,其包含蛋白、脂质以及核酸.研究发现,外泌体介导细胞间的信息交流,并参与许多机体反应,包括炎症、免疫信号传导、血管再生、应激反应、衰老、细胞增殖、细胞分化等.随着相关研究的不断深入,越来越多的证据表明,外泌体不仅参与自身免疫过程的建立、维持与调节,在癌症和心血管疾病的发病中也具有重要作用.     

The extracellular matrix of the dermis: flexible structures with dynamic functions

The current understanding of the role of extracellular matrix proteins is mainly based on their structural properties and their assembly into complex networks. The multiplicity of interactions between cells, cytokines and growth factors within the networks determines functional units dictating the biophysical properties of tissues. This review focuses on the understanding how alterations in the genes, modifying enzymes or biological functions of extracellular matrix molecules, lead to inborn or acquired skin disorders. Analysis of the disease mechanisms provides the basis for the emerging concept that not solely structural defects of single extracellular matrix proteins are at fault, but rather that the functional unit as a whole is not working properly, causing similar clinical symptoms although the causative genes are entirely different. The understanding of these disease-causing pathways has already led to surprising new therapeutic developments applied to rare inborn disorders. They now permit to design new concepts for the treatment of more common diseases associated with the accumulation of connective tissue and alterations of the biomechanical properties of the extracellular matrix.     

The expression and function of galectins in skin physiology and pathology

The galectin family comprises β‐galactoside–binding proteins widely expressed in many organisms. There are at least 16 family members, which can be classified into three groups based on their carbohydrate‐recognition domains. Pleiotropic functions of different galectins in physiological and pathological processes through extracellular or intracellular actions have been revealed. In the skin, galectins are expressed in a variety of cells, including keratinocytes, melanocytes, fibroblasts, dendritic cells, lymphocytes, macrophages and endothelial cells. Expression of specific galectins is reported to affect cell status, such as activation or death, and regulate the interaction between different cell types or between cells and the extracellular matrix. In vitro cellular studies, in vivo animal studies and studies of human clinical material have revealed the pathophysiologic roles of galectins in the skin. The pathogenesis of diverse non‐malignant skin disorders, such as atopic dermatitis, psoriasis, contact dermatitis and wound healing, as well as skin cancers, such as melanoma, squamous cell carcinoma, basal cell carcinoma and cutaneous haematologic malignancy can be regulated by different galectins. Revelation of biological roles of galectins in skin may pave the way to future development of galectin‐based therapeutic strategies for skin diseases.     

Immunostimulatory activity of murine keratinocyte‐derived exosomes

It has long been known that keratinocytes influence cutaneous immunity through secretion of soluble factors. Exosomes, small membrane vesicles of endocytotic origin, have been implicated in intercellular communication processes such as the transfer of tumor cell antigens and the activation of recipient dendritic cells (DC). However, little is known about immunomodulatory functions of keratinocyte‐derived exosomes. To address this question, we analysed exosome secretion of the murine keratinocyte cell line MPEK under steady state as well as inflammatory conditions (+/? IFNγ). These exosomes were readily taken up by bone marrow‐derived DC (BMDC) in vitro resulting in a matured phenotype, as evidenced by increased CD40 expression as well as by the production of large amounts of IL‐6, IL‐10 and IL‐12. When the transfer of antigen‐specific information through exosomes was investigated, it was found that keratinocytes took up antigen (ovalbumin) and transferred it to their exosomes. However, these antigen‐harbouring exosomes failed to induce antigen‐specific T cell responses via BMDC. Together, this novel biological function suggests that keratinocytes are able to direct unspecific immune processes but do not elicit specific immune responses.     

Matricryptins and matrikines: biologically active fragments of the extracellular matrix

Numerous extracellular proteins and glycosaminoglycans (GAGs) undergo limited enzymatic cleavage resulting in the release of fragments exerting biological activities, which are usually different from those of the full‐length molecules. In this review, we define matrikines and matricryptins, which are bioactive fragments released from the extracellular matrix proteins, proteoglycans and GAGs and report their major biological activities. These fragments regulate a number of physiopathological processes including angiogenesis, cancer, fibrosis, inflammation, neurodegenerative diseases and wound healing. The challenges to translate these fragments from molecules biologically active in vitro and in experimental models to potential drugs are discussed in the last part of the review.     

Collagen XVII/BP180: a collagenous transmembrane protein and component of the dermoepidermal anchoring complex

Collagen XVII, or BP180, is a collagenous transmembrane protein and a structural component of the dermoepidermal anchoring complex. Molecular studies reveal that it has a globular cytosolic amino-terminal domain and flexible-rod extracellular carboxyterminal domain. The extracellular portion of collagen XVII is constitutively shed from the cell surface by ADAMs (proteinases that contain adhesive and metalloprotease domains). Cell biological analyses suggest that collagen XVII functions as a cell-matrix adhesion molecule through stabilization of the hemidesmosome complex. This concept is supported by investigations into human diseases of the dermoepidermal junction, in which collagen XVII is either genetically defective or absent (as in some forms of nonlethal junctional epidermolysis bullosa). Autoantibodies against collagen XVII (BP180) are seen in bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA disease, lichen planus pemphigoides and pemphigoid nodularis. In vivo and in vitro studies provide evidence for a pathogenic role of these autoantibodies, and suggest that the serum level and epitope specificity of these antibodies influences disease severity and phenotype. This review summarizes the structural and biological features of collagen XVII and its role in diseases of the basement membrane zone.     

Prolyl and lysyl hydroxylases in collagen synthesis

Collagens are the most abundant proteins in the extracellular matrix. They provide a framework to build organs and tissues and give structural support to make them resistant to mechanical load and forces. Several intra‐ and extracellular modifications are needed to make functional collagen molecules, intracellular post‐translational modifications of proline and lysine residues having key roles in this. In this article, we provide a review on the enzymes responsible for the proline and lysine modifications, that is collagen prolyl 4‐hydroxylases, 3‐hydroxylases and lysyl hydroxylases, and discuss their biological functions and involvement in diseases.