皮肤间充质干细胞在促进皮肤愈合中的作用

间充质干细胞(mesenchymal stem cells,MSCs)是当前干细胞研究的热点之一。目前,皮肤愈合正逐渐受到重视。现有的研究认为骨髓间充质干细胞(BM-MSCs)能从多个方面促进皮肤愈合,如促进表皮生长、促进真皮成纤维细胞的增生等。皮肤间充质干细胞(SMSCs)和BM-MSCs均为MSCs,具有很多的相似性,且SMSCs较BM-MSCs更容易得到。所以可从目前对BM-MSCs的研究预测到SMSCs在皮肤创伤愈合中的研究前景,且将来很可能会替代BM-MSCs。     

Nrf2激活剂防御紫外线致皮肤氧化应激损伤的研究

核因子E2相关因子2(Nrf2)激活剂作为一种新型的光保护剂,能有效抵御UV照射对皮肤的损伤。天然Nrf2激活剂可提取自茶多酚、姜黄素、莱菔硫烷、白藜芦醇、丹参酮、小白菊等,为以Nrf2信号通路为靶点治疗氧化应激损伤皮肤病提供了广阔前景。     

Controversial role of mast cells in skin cancers

Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumor initiation and progression. The stromal microenvironment can promote tumor development. Mast cells, widely distributed throughout all tissues, are a stromal component of many solid and haematologic tumors. Mast cells can be found in human and mouse models of skin cancers such as melanoma, basal and squamous cell carcinomas, primary cutaneous lymphomas, haemangiomas and Merkel cell carcinoma. However, human and animal studies addressing potential functions of mast cells and their mediators in skin cancers have provided conflicting results. In several studies, mast cells play a pro‐tumorigenic role, whereas in others, they play an anti‐tumorigenic role. Other studies have failed to demonstrate a clear role for tumor‐associated mast cells. Many unanswered questions need to be addressed before we understand whether tumor‐associated mast cells are adversaries, allies or simply innocent bystanders in different types and subtypes of skin cancers.     

Contact allergy: the role of skin chemistry and metabolism

Chemical reactivity plays the driving role in the biological processes that result in the induction of allergic contact dermatitis. This paper presents an overview of the chemical basis of allergic contact dermatitis, including the physicochemical parameters governing skin penetration, chemical reaction mechanisms associated with haptenation of skin proteins, (quantitative) structure-activity relationships (Q)SARs for contact allergens and prohaptens/skin metabolism of contact allergens. Despite the complexities and poor understanding of some of the metabolic processes leading to skin sensitization, it is possible to describe some of the relationships between chemical structures and the ability to form covalent conjugates with proteins. This knowledge, which relates chemical structure to a specific endpoint, can be programmed into an expert system. The Deductive Estimation of Risk from Existing Knowledge (DEREK) is one such expert system which is described in further detail.     

茶多酚诱导的Nrf2通路和自噬在痤疮发病机制中的作用

痤疮是一种常见的毛囊皮脂腺的慢性炎症性疾病,主要累及表皮和毛囊皮脂腺单位,引起局部皮肤炎性或非炎性病变。其发病机制主要包括雄激素刺激皮脂分泌亢进、皮脂排泄受阻、毛囊内痤疮丙酸杆菌的定植及炎性反应。茶多酚作为一种Nrf2激活剂,其有效成分表没食子儿茶素、没食子酸酯可激活Nrf2信号通路或自噬,通过抑制痤疮丙酸杆菌增殖、抑制炎症蔓延、减少皮脂分泌等途径治疗痤疮。本文研究了Nrf2信号通路和自噬在痤疮发病机制中的关系和作用,有助于为临床治疗痤疮开辟新方向。     

姜黄素对紫外线照射后HaCaT细胞内Nrf2核转位的激活作用

目的:明确姜黄素对急性紫外线损伤的HaCaT细胞内Nrf2核转位的影响。方法:1μM、2.5μM、5μM姜黄素与细胞共培养,UVA、UVB照射后Western blot法检测各实验组HaCaT细胞内Nrf2核转位情况。结果:姜黄素预处理后照射UVA和UVB,Nrf2胞质蛋白的浓度随姜黄素的浓度升高而下降,胞核蛋白浓度则随其升高而升高(P0.05)。结论:姜黄素对急性紫外线损伤的HaCaT细胞内Nrf2核转位有激活作用。     

Cinnamic compound metabolism in human skin and the role metabolism may play in determining relative sensitisation potency

BACKGROUND: trans-Cinnamaldehyde and trans-cinnamic alcohol cause allergic contact dermatitis (ACD) in humans; cinnamaldehyde is a more potent sensitiser than cinnamic alcohol. These two chemicals are principal constituents of the European Standard 'Fragrance Mix', as used in patch testing diagnostics of sensitisation to fragrances by clinical dermatologists. As contact sensitisers are usually protein reactive compounds, it is hypothesised that cinnamic alcohol (not protein-reactive) is a 'prohapten' that requires metabolic activation, presumably by cutaneous oxidoreductases, to the protein-reactive cinnamaldehyde (a 'hapten'). It is postulated that cinnamaldehyde can be detoxified by aldehyde dehydrogenase (ALDH) to cinnamic acid and/or by alcohol dehydrogenase (ADH) to cinnamic alcohol. Hence, a variety of metabolic pathways may contribute to the relative exposures and hence sensitising potencies of cinnamic alcohol and cinnamaldehyde. OBJECTIVE: To evaluate the extent of cinnamaldehyde and cinnamic alcohol metabolism in human skin and provide evidence for the role of cutaneous ADH and ALDH in such metabolism. METHODS: The extent of cinnamic alcohol and aldehyde metabolism was investigated in human skin homogenates and sub-cellular fractions. A high performance liquid chromatography method was used for analysis of skin sample extracts. Studies were conducted in the presence and absence of the ADH/cytochrome P450 inhibitor 4-methylpyrazole and the cytosolic ALDH inhibitor, disulfiram. RESULTS: Differential metabolism of cinnamic alcohol and cinnamaldehyde was observed in various subcellular fractions: skin cytosol was seen to be the major site of cinnamic compound metabolism. Significant metabolic inhibition was observed using 4-methylpyrazole and disulfiram in whole skin homogenates and cytosolic fractions only. CONCLUSIONS: This study has demonstrated that cutaneous ADH and ALDH activities, located within defined subcellular compartments, play important roles in the activation and detoxification of CAlc and CAld in skin. Such findings are important to the development of computational hazard prediction tools for sensitisation (e.g. the DEREK program) and also to dermatologists in understanding observed interindividual differences, cross-reactivities or co-sensitisation to different cinnamic compounds in the clinic.     

The role of Smads in skin development

Smads are a group of signaling mediators and antagonists of the transforming growth factor-beta (TGF-beta) superfamily, responding but not limited to signaling from TGF-beta, Activin, and bone morphogenetic proteins (BMPs). As all of these three signaling pathways play important roles in skin development, we have been actively pursuing studies assessing the role of Smads in skin development. Our studies revealed that Smad-4 affects hair follicle differentiation primarily by mediating BMP signaling. Smad-7 significantly affects hair follicle development and differentiation by blocking the TGFbeta/Activin/BMP pathway and by inhibiting WNT/beta-catenin signaling via ubiquitin-mediated beta-catenin degradation. In contrast, other Smads may have redundant or dispensable functions in skin development. Here, we review the work that shows the emergence of Smad functions in skin development via traditional and novel signaling pathways.     

The role of microRNAs in skin fibrosis

Fibrotic skin disorders may be debilitating and impair quality of life. There are few effective treatment options for cutaneous fibrotic diseases. In this review, we discuss our current understanding of the role of microRNAs (miRNAs) in skin fibrosis. miRNAs are a class of small, non-coding RNAs involved in skin fibrosis. These small RNAs range from 18 to 25 nucleotides in length and modify gene expression by binding to target messenger RNA (mRNA), causing degradation of the target mRNA or inhibiting the translation into proteins. We present an overview of the biogenesis, maturation and function of miRNAs. We highlight miRNA’s role in key skin fibrotic processes including: transforming growth factor-beta signaling, extracellular matrix deposition, and fibroblast proliferation and differentiation. Some miRNAs are profibrotic and their upregulation favors these processes contributing to fibrosis, while anti-fibrotic miRNAs inhibit these processes and may be reduced in fibrosis. Finally, we describe the diagnostic and therapeutic significance of miRNAs in the management of skin fibrosis. The discovery that miRNAs are detectable in serum, plasma, and other bodily fluids, and are relatively stable, suggests that miRNAs may serve as valuable biomarkers to monitor disease progression and response to treatment. In the treatment of skin fibrosis, anti-fibrotic miRNAs may be upregulated using mimics and viral vectors. Conversely, profibrotic miRNAs may be downregulated by employing anti-miRNAs, sponges, erasers and masks. We believe that miRNA-based therapies hold promise as important treatments and may transform the management of fibrotic skin diseases by physicians.     

核因子E2相关因子2信号通路及其在紫外线致皮肤蛋白氧化应激损伤中的作用

紫外线照射产生活性氧及自由基,与皮肤光老化、皮肤癌等皮肤光损伤疾病的发生相关.活性氧及自由基不仅通过攻击氨基酸主侧链等方式氧化蛋白质,而且能够激活丝裂原活化蛋白激酶产生基质金属蛋白酶,降解皮肤结缔组织中的胶原蛋白等蛋白质,使皮肤发生光损伤.核因子E2相关因子2信号通路是细胞氧化应激反应的核心调控机构,在应激条件下,激活核因子E2相关因子2,通过调节抗氧化酶类和Ⅱ相解毒酶基因的表达,清除过多的核因子E2相关因子2和自由基,抑制基质金属蛋白酶的分泌,保护蛋白质,增强机体抗氧化应激的能力,对皮肤起到保护作用.核因子E2相关因子2信号通路及其调控机制与皮肤蛋白氧化应激损伤间关系的深入研究,将有利于寻找蛋白氧化应激损伤导致的相关皮肤光损伤疾病新的有效的治疗防御措施.     

Stem cells in the skin and their role in oncogenesis

Stem cells generate great interest because they hold the promise for treatment of various incurable diseases. Several distinct stem cell populations have been identified in each organ, including the skin. As the skin is the largest organ in the body and is easily accessible, cutaneous stem cells have raised significant hopes for being a rich source of easily available multipotent stem cells. Genetic alterations and mutations in stem cells are being proposed as initiation step in multiple cancers. Small populations of oncogenic stem cells termed as cancer stem cells or tumour‐initiating cells have been identified in multiple tumours, including squamous cell carcinomas, and melanomas that can sustain tumour growth, underlie its malignant behaviour and initiate distant metastases. These cells are controlled and regulated by the same pathways that are also responsible for maintenance and differentiation of normal stem cells. Developing a targeted therapy against the oncogenic stem cells and dysregulated members of the signalling pathways may be the key to understanding and treating skin cancers like melanomas, for which we still do not have an effective treatment.