水通道的生理功能及与疾病的关系

水通道是哺乳动物细胞膜上转运水的特异孔道。第一个水通道蛋白即原型分子水通道（２８ｋＤ通道构成整合膜蛋白）的ｃＤＮＡ序列是在１９９１年完成鉴定的。目前从哺乳动物组织中已鉴定出至少六种水通道蛋白，统称水蛋白。越来越多的研究证实这类蛋白质对维持机体的正常状态至关重要，且与水平衡紊乱所致的临床症状密切相关。对水通道功能及调节的研究，将会为临床多种疾病的治疗提供新的途径。     

水通道蛋白与脑

在哺乳动物内已发现有十种水通道蛋白(AQP0～AQP9)分布于水代谢活跃的器官.每种水通道蛋白都具有组织分布特异性,不同水通道蛋白之间的结构相似,均以四聚体形式存在,每一单体构成一个功能单位(水通道),具有转运水的功能.脑组织中的水通道蛋白主要为AQP4和AQP1,其分子结构与功能在基因水平存在动态调节.深入研究它们在脑内的分布与功能,尤其与脑水肿之间的关系,对指导脑水肿治疗和开发新药均具有重要意义.     

水通道蛋白3在人前列腺组织中的表达及意义

目的： 揭示水通道蛋白3（AQP3）在人前列腺移行区和外周区的表达及意义,为深入探讨AQP在人前列腺及疾病状态下的表达及生理作用奠定基础。方法: 取前列腺组织标本5例,采用RT-PCR方法检测AQP3 mRNA在前列腺组织的表达。同时应用Western blotting和免疫染色技术研究AQP3蛋白在前列腺组织的定位表达。结果: RT-PCR结果显示在前列腺的移行区和外周区均存在AQP3 mRNA表达。Western blotting结果显示人前列腺的移行区和外周区均特异表达AQP3蛋白,且移行区表达强于外周区。免疫组织化学和免疫荧光染色结果表明AQP3表达在前列腺移行区分泌细胞的细胞膜。结论: 前列腺移行区分泌细胞表达AQP3提示, AQP3在前列腺液分泌过程中可能发挥重要的生理作用。     

水通道蛋白1、5在星形细胞瘤中的表达变化

目的:观察水通道蛋白1、5(AQP1、5)在人不同病理级别星形细胞瘤组织中的表达差异,探讨星形细胞瘤增殖、生长的分子机制.方法:收集人各个病理级别星形细胞瘤标本55例,以肿瘤周围相对正常脑组织作为对照,采用H-E染色诊断分级,石蜡切片免疫组织化学、免疫印迹分析及逆转录聚合酶链式反应观察AQP1、5及其mRNA的表达变化.结果:与正常脑组织相比,人星形胶质瘤组织中AQP1及其mRNA表达上调,随着星形细胞瘤病理级别的升高,AQP1及其mRNA表达增强,胶质母细胞瘤组织表达最强烈;而AQP5及其mRNA仅在高恶性星形细胞瘤组织中表达增强.结论:AQP1在人星形细胞瘤组织中表达与其病理级别相关,而AQP5仅在人高恶性星形细胞瘤组织中表达增强,提示不同病理级别胶质瘤组织中AQP的表达规律不尽相同.     

肾脏神经的生理作用及病理意义

肾神经分为传出纤维及传入纤维。传出纤维进入肾脏后主要分布在肾小球入球小动脉、出球小动脉,近端肾小管,远端肾小管,髓袢的粗段升支以及球旁装置(1,2)。 由于肾神经在调节肾功能,维持机体的内环境稳定,调节心血管功能中有重要作用,因此引起了各国学者的广泛关注。本文就近年来有关肾神经的生理病理意义的研究作一综述。     

水通道蛋白4和8在人不同病理级别星形细胞瘤组织中的表达

目的: 观察水通道蛋白(AQP)4和AQP8在人不同病理级别星形细胞瘤组织中的表达变化,进一步阐明星形细胞瘤的发病机制。方法: 收集人各个病理级别星形细胞瘤标本55例。以肿瘤周围相对正常脑组织作为对照,采用石蜡切片HE染色行病理诊断和分级,Western blotting、RT-PCR以及免疫组织化学方法观察瘤组织中AQP4和AQP8的表达情况。结果: AQP4和AQP8主要分布在不同病理级别星形细胞瘤组织中瘤细胞的胞膜和胞浆内;和对照组比较,AQP4及其mRNA在低级别(Ⅰ~Ⅱ级)肿瘤组织中的表达降低,但在高级别(Ⅲ~Ⅳ级)星形细胞瘤组织中表达又上调;而AQP8及其mRNA在低级别肿瘤组织的表达增强,在高级别肿瘤组织中表达进一步增强;AQP4和AQP8分别在低级别之间、高级别之间比较,均没有显著差异(P>0.05)。结论: AQP4与AQP8在肿瘤组织中的表达是有差异的,两者在人星形细胞瘤组织中的表达变化与肿瘤恶性程度有关。     

水通道蛋白与肿瘤

水通道蛋白（AQPs）是一类小分子质量的、膜内嵌蛋白,它所介导的自由水快速被动的跨生物膜转运,是水进出细胞的主要途径。AQPs大量表达于不同组织来源的肿瘤细胞,特别是侵袭性肿瘤。AQPs高表达的肿瘤细胞在体外表现为较强的迁移能力,体内则表现为局部侵袭力增强,渗出增多以及转移灶增多。抑制AQPs的表达将有可能为肿瘤的治疗提供帮助。     

水通道蛋白在胶质细胞的表达及其意义

20世纪80年代,美国学者Peter Agre发现质膜上存在一类介导水快速跨膜转运的膜蛋白,这类膜蛋白被称作水通道蛋白.已有大量研究发现胶质细胞表达的水通道蛋白对神经系统疾病的发生有重要作用.本文综述水通道蛋白在胶质细胞的表达定位及其意义,为中枢和周围神经系统疾病的诊断和治疗提供新的靶点.     

瘦素与女性生理及病理

瘦素是一种新的激素 ,主要调节体重和能量的消耗 ,但越来越多的研究表明它与女性的生理与病理有密切的联系 ,是多种激素反馈环中的重要组成部分     

Dysplasia of gallbladder. Its pathological significance

Twenty-three cases of dysplasia of the gallbladder and 38 cases of carcinoma with surrounding dysplasia were investigated. The dysplasia did not show any remarkable lesion and consisted of atypical basophilic cells with oval or round nuclei. The ratio of nucleus to cytoplasm (N/C) ratio was usually larger than the normal epithelial cells. For the combined dysplasia, it has been considered that 1) the dysplasia arose as well-differentiated carcinoma, 2) appeared synchronously, 3) arose secondarily, and 4) appeared as a precancerous lesion. Intestinal metaplasia, dysplasia, and carcinoma showed similar characteristics as to location and mucin-chemistry. According to CEA stain by PAP method, the dysplasia and carcinoma showed similar characteristics. It may be considered that the sequence of intestinal metaplasia-dysplasia-carcinoma is important.     

Cdk5: multitasking between physiological and pathological conditions

Cyclin-dependent kinase 5 (Cdk5) is a peculiar proline-directed serine/threonine kinase. Unlike the other members of the Cdk family, Cdk5 is not directly involved in cell cycle regulation, being normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity. This kinase is present mainly in post-mitotic neurons and its activity is tightly regulated by the interaction with the specific activators, p35 and p39. Despite its pivotal role in CNS development, Cdk5 dysregulation has been implicated in different pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and, most recently, prion-related encephalopathies (PRE). In these neurodegenerative conditions, Cdk5 overactivation and relocalization occurs upon association with p25, a truncated form of the normal activator p35. This activator switching will cause a shift in the phosphorylative pattern of Cdk5, with an alteration both in targets and activity, ultimately leading to neuronal demise. In AD and PRE, two disorders that share clinical and neuropathological features, Cdk5 dysregulation is a linking event between the major neuropathological markers: amyloid plaques, tau hyperphosphorylation and synaptic and neuronal loss. Moreover, this kinase was shown to be involved in abortive cell cycle re-entry, a feature recently proposed as a possible step in the neuronal apoptosis mechanism of several neurological diseases. This review focuses on the role of Cdk5 in neurons, namely in the regulation of cytoskeletal dynamics, synaptic function and cell survival, both in physiological and in pathological conditions, highlighting the relevance of Cdk5 in the main mechanisms of neurodegeneration in Alzheimer's disease and other brain pathologies.     

Neuropilins in physiological and pathological angiogenesis

Neuropilin-1 (Np1) and neuropilin-2 (Np2) are transmembrane glycoproteins with large extracellular domains that interact with both class 3 semaphorins and vascular endothelial growth factor (VEGF), and are involved in the regulation of many physiological pathways, including angiogenesis. The neuropilins also interact directly with the classical receptors for VEGF, VEGF-R1 and -R2, mediating signal transduction. The heart, glomeruli and osteoblasts express both Np1 and Np2, but there is differential expression in the adult vasculature, with Np1 expressed mainly by arterial endothelium, whereas Np2 is only expressed by venous and lymphatic endothelium. Both neuropilins are commonly over-expressed in regions of physiological (wound-healing) and pathological (tumour) angiogenesis, but the signal transduction pathways, neuropilin-mediated gene expression and the definitive role of neuropilins in angiogenic processes are not fully characterized. This review details the current evidence for the role of neuropilins in angiogenesis, and suggests future research directions that may enhance our understanding of the mechanisms of action of this unique family of proteins.     

Surface trafficking of N-methyl-D-aspartate receptors: physiological and pathological perspectives

The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in shaping the strength of synaptic connections. Over the last decades, extensive studies have defined the cellular and molecular mechanisms by which synaptic NMDARs control the maturation and plasticity of synaptic transmission, and how altered synaptic NMDAR signaling is implicated in neurodegenerative and psychiatric disorders. It is now clear that activation of synaptic or extrasynaptic NMDARs produces different signaling cascades and thus neuronal functions. Our current understanding of NMDAR surface distribution and trafficking is only emerging. Exchange of NMDARs between synaptic and extrasynaptic areas through surface diffusion is a highly dynamic and regulated process. The aim of this review is to describe the identified mechanisms that regulate surface NMDAR behaviors and discuss the impact of this new trafficking pathway on the well-established NMDAR-dependent physiological and pathophysiological processes.     

Neutrophil trafficking to lymphoid tissues: physiological and pathological implications

Recent advances have provided evidence for the involvement of neutrophils in both innate and adaptive immunity, robustly challenging the old dogma that neutrophils are short-lived prototypical innate immune cells solely involved in acute responses to microbes and exerting collateral tissue damage. There is now ample evidence showing that neutrophils can migrate into different compartments of the lymphoid system where they contribute to the orchestration of the activation and/or suppression of lymphocyte effector functions in homeostasis and during chronic inflammation, such as autoimmune disorders and cancer. In support of this notion, neutrophils can generate a wide range of cytokines and other mediators capable of regulating the survival, proliferation and functions of both T and B cells. In addition, neutrophils can directly engage with lymphocytes and promote antigen presentation. Furthermore, there is emerging evidence of the existence of distinct and diverse neutrophil phenotypes with immunomodulatory functions that characterise different pathological conditions, including chronic and autoimmune inflammatory conditions. The aim of this review is to discuss the mechanisms implicated in neutrophil trafficking into the lymphoid system and to provide an overview of the immuno-regulatory functions of neutrophils in health and disease in the context of adaptive immunity. Copyright © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Identification of the novel platelet activation receptor CLEC-2 and Its pathological and physiological roles

We have identified a novel class of platelet activation receptor, CLEC-2, as a receptor for rhodocytin, a platelet-activating snake venom. CLEC-2 activation leads to tyrosine phosphorylation of the YITL motif in its cytoplasmic tail, the binding of Syk, initiation of downstream tyrosine phosphorylation events, and activation of phodpholipas Cgamma2, which result in platelet aggregation. We also identified podoplanin as an internal ligand for CLEC-2. Podoplanin is expressed on the surface of tumor cells and facilitates tumor metastasis by inducing platelet aggregation. We showed that an antibody that blocked the binding between CLEC-2 and podoplanin inhibited tumor metastasis using an experimental lung metastasis model in mice. Podoplanin is also expressed in lymphatic endothelial cells, but the physiological role of the interaction between CLEC-2 and podoplanin in lymphatic endothelial cells has not been elucidated. We generated CLEC-2-deficient mice, and found that these mice die in the embryonic/neonatal stages, associated with disorganized and blood-filled lymphatic vessels and severe edema. Moreover, through the transplantation of fetal liver cells from CLEC-2 +/+ or CLEC-2-/- embryos, we were able to demonstrate that CLEC-2 is involved in thrombus stabilization in vitro and in vivo, possibly through homophilic interactions without any apparent increase in the bleeding tendency. These findings revealed that CLEC-2 plays a crucial role in not only tumor metastasis, but also in lymphangiogenesis and thrombus stabilization. We propose that CLEC-2 could be an ideal novel target protein for an anti-platelet drug, which inhibits pathological thrombus formation but not physiological hemostasis, as well as a novel target protein for an anti-metastatic drug.     

Mammalian phospholipase D physiological and pathological roles

Phospholipase D (PLD), a superfamily of signalling enzymes that most commonly generate the lipid second messenger phosphatidic acid, is found in diverse organisms from bacteria to humans and functions in multiple cellular pathways. Since the early 1980s when mammalian PLD activities were first described, most of the important insights concerning PLD function have been gained from studies on cellular models. Reports on physiological and pathophysiological roles for members of the mammalian PLD superfamily are now starting to emerge from genetic models. In this review, we summarize recent findings on PLD functions in these model systems, highlighting newly appreciated connections of the superfamily to cancer, neuronal pathophysiology, cardiovascular topics, spermatogenesis and infectious diseases.     

Brown adipose tissue: function and physiological significance

The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogenesis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.