蛋白激酶JNK、p38与皮肤病

c-Jun氨基末端激酶、p38是丝裂原活化蛋白激酶细胞信号转导通路中重要的蛋白激酶。在炎性细胞因子和应激环境的刺激下，可导致c-Jun氨基末端激酶通路与p38通路的激活．并进而改变细胞的生物学特性。近年来发现c-Jun氨基末端激酶、p38丝裂原活化蛋白激酶通路在多种皮肤病中高度激活，并提示与发病机制有一定关联，如单纯疱疹、HIV感染、HPV感染以及皮肤肿瘤等。     

蛋白激酶JNK、p38与皮肤病

c Jun氨基末端激酶、p38是丝裂原活化蛋白激酶细胞信号转导通路中重要的蛋白激酶。在炎性细胞因子和应激环境的刺激下 ,可导致c Jun氨基末端激酶通路与p38通路的激活 ,并进而改变细胞的生物学特性。近年来发现c Jun氨基末端激酶、p38丝裂原活化蛋白激酶通路在多种皮肤病中高度激活 ,并提示与发病机制有一定关联 ,如单纯疱疹、HIV感染、HPV感染以及皮肤肿瘤等。     

微小RNA与银屑病发病相关信号转导通路关联的研究

细胞通过细胞间各种信号分子的活化来完成信号传导,从而控制细胞的生长、分化和凋亡.细胞间信号转导的异常经常是疾病发生的原因.银屑病的发病与多个信号转导通路的异常有关,主要丝裂原活化蛋白激酶信号转导通路、非受体酪氨酸蛋白激酶Janus激酶/信号转导和转录激活因子通路、肿瘤坏死因子α信号转导通路、磷脂酰肌醇3-激酶/蛋白激酶B信号转导通路,而这些通路的异常通常又与细胞转录后调控因子微小RNA有关.     

Akt和mTOR在皮肤基底细胞癌中的表达

基底细胞癌(BCC)是较常见的皮肤肿瘤之一,尽管其生长缓慢,转移少见,但可造成局部组织破坏,造成感染及大出血,甚至毁损容貌.因此,其发病机制的研究具有重要的意义.Akt/mTOR信号通路普遍存在于各种细胞中,是参与细胞生长、增殖、分化调节的信号通路.其表达异常与人类多种恶性肿瘤的发生、发展密切相关.在乳腺癌、肺癌以及胶质瘤中均已发现Akt与mTOR的高表达[1-3].目前对Akt和mTOR在皮肤BCC中表达的研究报道不多,我们采用免疫组化法检测Akt和mTOR在BCC组织中的表达水平,旨在探讨Akt/mTOR信号通路在BCC发展过程中所起的作用.     

Akt和mTOR在皮肤基底细胞癌中的表达

基底细胞癌(BCC)是较常见的皮肤肿瘤之一,尽管其生长缓慢,转移少见,但可造成局部组织破坏,造成感染及大出血,甚至毁损容貌.因此,其发病机制的研究具有重要的意义.Akt/mTOR信号通路普遍存在于各种细胞中,是参与细胞生长、增殖、分化调节的信号通路.其表达异常与人类多种恶性肿瘤的发生、发展密切相关.在乳腺癌、肺癌以及胶质瘤中均已发现Akt与mTOR的高表达[1-3].目前对Akt和mTOR在皮肤BCC中表达的研究报道不多,我们采用免疫组化法检测Akt和mTOR在BCC组织中的表达水平,旨在探讨Akt/mTOR信号通路在BCC发展过程中所起的作用.     

恶性黑素瘤与磷脂酰肌醇3-激酶-Akt信号通路

磷脂酰肌醇3-激酶信号参与增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节.近年来发现,IA型磷脂酰肌醇3-激酶和其下游分子蛋白激酶B所组成的信号通路与人类恶性黑素瘤的发生发展密切相关.该通路调节黑素瘤细胞的增殖和存活,其活性异常不但能引起细胞恶性转化,而且与黑素瘤细胞的迁移、黏附、血管生成以及细胞外基质的降解等相关.目前以磷脂酰肌醇3-激酶-Akt信号通路关键分子为靶点的恶性黑素瘤治疗策略正在研究中.     

PI3K/AKT信号通路及其与SLE的关系

PI3K/AKT信号通路是细胞内重要的信号传导通路之一,通过影响下游多种效应分子的活化调节细胞的基本功能,包括生存、生长、增殖和代谢.近年研究发现,T、B淋巴细胞PI3K/AKT信号通路的异常活化与SLE自身免疫的发生发展密切相关.概述PI3K/AKT信号通路的组成与功能,其与SLE发病机制的关系及其抑制剂在SLE治疗中的研究进展.     

Stat1与某些免疫相关性皮肤病

细胞信号传递Jak-Stat途径可与酪氨酸磷酸化信号通路偶联,是细胞生长、分化乃至机体免疫反应等一系列生理反应的关键环节.Stat1作为Stats成员,可被干扰素、IL-6 、IL-10等多种细胞因子活化.Stat1的异常活化可引起细胞因子的异常表达,在许多免疫性皮肤病的发生发展中占有重要的地位.本文将Stat1的结构、功能及其与自身免疫性皮肤病的相关性研究进展作一综述.     

C-Jun和Jun-B与银屑病

Jun-B和c-Jun作为AP-1(activator protein-1)的重要组成成员,主要参与调控细胞的增殖、分化、转化和凋亡过程,二者在细胞增殖、分化以及AP-1依赖性靶基因表达上的作用相反。Jun-B和c-Jun之间的平衡决定细胞进入细胞周期或走向凋亡,这种平衡在表皮中表现尤为突出。打破平衡将导致表皮细胞异常增殖和分化,从而促使银屑病、扁平苔藓、湿疹等皮肤病的发生。通过对AP-1亚基调控角质形成细胞(keratinocyte,KC)生长及其在银屑病小鼠模型中的研究进展,探讨Jun-B和c-Jun与银屑病的关系。     

磷酸化c-Jun氨基末端激酶和P38丝裂原活化蛋白激酶在寻常性银屑病皮损中的表达

目的 探讨磷酸化c-Jun氨基末端激酶（p-JNK）和P38丝裂原活化蛋白激酶（p-P38MAPK）在寻常性银屑病皮损中的表达。 方法 收集30例确诊的寻常性银屑病患者皮损,同时收集30例健康人皮肤组织作为对照组。采用免疫组化及Western印迹法分别检测p-JNK和p-P38MAPK蛋白在寻常性银屑病皮损组织和正常人皮肤中的表达情况。 结果 免疫组化结果显示,寻常性银屑病皮损组织p-JNK和p-P38MAPK表达的平均吸光度（AOD）值分别为0.663 ± 0.016和0.436 ± 0.011,均明显高于对照组（0.333 ± 0.009和0.306 ± 0.010）,差异有统计学意义（t = 44.869、21.913,均P < 0.001）。Western印迹法同样显示,寻常性银屑病皮损p-JNK和p-P38MAPK蛋白相对表达量均显著高于对照组,差异均有统计学意义（t值分别为20.477和165.084,均P < 0.05）。结论 JNK和P38MAPK的活化可能参与了寻常性银屑病表皮细胞的过度增殖。     

Notch signaling: its role in epidermal homeostasis and in the pathogenesis of skin diseases

Skin undergoes self-renewal throughout life. Terminally differentiated keratinocytes, namely the corneocytes, are continually shed from the surface of the skin, whereas immature cells produce progeny that proceed through the differentiation process. Notch signaling controls a number of cellular processes including cell fate decision, proliferation, differentiation and survival/apoptosis. Hence, Notch and its ligands are expressed in multiple tissues including the skin, where they are abundantly expressed in the epidermis. Notch activation results in the promotion of growth arrest and the onset of differentiation, therefore suggesting that specific Notch activation may regulate skin homeostasis by balancing these processes, i.e. Notch signaling functions as a molecular switch that controls the transition of cells between skin layers during the epidermal differentiation process. Recent advances in the study of Notch signaling have confirmed that there is cross-talk between the Notch signaling pathway and a variety of other signaling molecules including Sonic hedgehog (Shh), beta-catenin and the p53 family member, p63. The absence of Notch activity allows Wnt and Shh signaling to persist in a tissue where they are normally repressed. In addition, Notch counteracts the action of p63 to maintain immature cell characteristics. However, aberrant Notch signaling results in the development of psoriasis and skin cancers such as squamous cell carcinoma, basal cell carcinoma and malignant melanoma. Future efforts to further define how Notch controls cell proliferation and differentiation may lead to the application of Notch in new therapies for various skin diseases.     

Notch信号通路在皮肤病的研究进展

Notch信号通路是一条进化上十分保守的信号转导系统.Notch受体与相邻细胞的配体相互作用转导细胞信号,从而影响细胞的增殖、分化和凋亡.较多文献表明,Notch信号通路在维持皮肤正常生理功能以及炎症性皮肤病、自身免疫性皮肤病、皮肤肿瘤、色素性皮肤病等多种皮肤病中发挥重要作用.尽管目前临床应用尚不成熟,Notch信号抑制剂和激活剂有希望为皮肤病的治疗提供新思路.     

与紫外线致皮肤损伤相关的部分信号通路研究进展

紫外线照射可使皮肤损伤,导致皮肤光老化或皮肤肿瘤.多个信号通路如Nrf2-Keap1-ARE、核因子κB、丝裂原活化蛋白激酶(MAPK)、磷脂酰肌醇-3激酶-丝氨酸/苏氨酸激酶-西罗莫司靶蛋白(PI3K-AKt-mTOR)信号通路等参与皮肤光老化和(或)皮肤肿瘤的发病.Nrf2信号通路在氧化应激状态下开启,有维持氧化还原平衡和参与细胞新陈代谢等作用.核因子κB信号通路的激活引起基质金属蛋白酶等水平上调,与皮肤老化和非黑素性皮肤癌有关.MAPK信号通路参与皮肤老化和皮肤肿瘤的进展.PI3K-AKt-mTOR信号通路主要与皮肤肿瘤相关.紫外线照射可诱导上述通路的活化,参与皮肤光老化或皮肤肿瘤的发生发展.对上述通路的进一步研究有望为抵御皮肤的光老化和皮肤肿瘤提供新的方法.     

Bone morphogenetic proteins and their antagonists in skin and hair follicle biology

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta superfamily regulating a large variety of biologic responses in many different cells and tissues during embryonic development and postnatal life. BMP exert their biologic effects via binding to two types of serine/threonine kinase BMP receptors, activation of which leads to phosphorylation and translocation into the nucleus of intracellular signaling molecules, including Smad1, Smad5, and Smad8 ("canonical" BMP signaling pathway). BMP effects are also mediated by activation of the mitogen-activated protein (MAP) kinase pathway ("noncanonical" BMP Signaling pathway). BMP activity is regulated by diffusible BMP antagonists that prevent BMP interactions with BMP receptors thus modulating BMP effects in tissues. During skin development, BMPs its receptors and antagonists show stringent spatiotemporal expressions patterns to achieve proper regulation of cell proliferation and differentiation in the epidermis and in the hair follicle. In normal postnatal skin, BMP are involved in the control of epidermal homeostasis, hair follicle growth, and melanogenesis. Furthermore, BMP are implicated in a variety of pathobiologic processes in skin, including wound healing, psoriasis, and carcinogenesis. Therefore, BMPs represent new important players in the molecular network regulating homeostasis in normal and diseased skin. Pharmacologic modulation of BMP signaling may be used as a new approach for managing skin and hair disorders.     

Janus激酶抑制剂在皮肤病治疗中的应用前景

【摘要】 Janus激酶（JAK）和信号转导和转录激活因子（STAT）所构成的JAK-STAT信号通路是一条重要的细胞内信号通路，参与许多炎症性疾病的发病。JAK抑制剂阻断该通路已经成为治疗某些疾病的有效方法，例如类风湿关节炎、溃疡性结肠炎。然而，目前JAK抑制剂尚未被批准应用于皮肤病治疗。本文就JAK抑制剂在皮肤疾病中的应用前景进行综述。     

Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARalpha and PPARgamma is decreased. This observation suggests the possibility that PPARalpha and PPARgamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARgamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARalpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARdelta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARdelta. PPARdelta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARalpha and PPARgamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARgamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARalpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARalpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.     

Notch信号通路在遗传性色素障碍性皮肤病的研究进展

色素障碍性皮肤病主要由黑素细胞功能障碍或数目异常所致,严重影响皮肤外观.近期一系列研究报道,Notch信号通路组成部分功能的异常或缺失与人类遗传性色素障碍性皮肤疾病发病相关.Notch信号通路是一条高度保守的调控细胞分化增殖凋亡的信号传导途径,但其如何导致色素异常的致病机制尚不明确.探讨Notch信号通路在遗传性色素障碍性皮肤病的研究进展,为理解遗传因素在黑素细胞生长发育和功能中发挥的作用提供了新视野.     

Galectin-3 and the skin

Galectin-3 is highly expressed in epithelial cells including keratinocytes and is involved in the pathogenesis of inflammatory skin diseases by affecting the functions of immune cells. For example, galectin-3 can contribute to atopic dermatitis (AD) by promoting polarization toward a Th2 immune response by regulating dendritic cell (DC) and T cell functions. In addition, galectin-3 may be involved in the development of contact hypersensitivity by regulating the migratory capacity of antigen presenting cells. Galectin-3 may act as a regulator of epithelial tumor progression and development through various signaling pathways, such as inhibiting keratinocyte apoptosis through regulation of the activation status of extracellular signal-regulated kinase (ERK) and activated protein kinase B (AKT). Galectin-3 is detected at different stages of melanoma development. In contrast, a marked decrease in the expression of galectin-3 is observed in non-melanoma skin cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Galectin-3 may play an important role in tumor cell growth, apoptosis, cell motility, invasion, and metastasis. Galectin-3 may be a novel therapeutic target for a variety of skin diseases.