倍扎罗汀及其在皮肤科的应用

倍扎罗汀是一种合成的维A酸X受体激动剂,与维A酸X受体高度特异性结合,主要通过影响与维A酸X受体形成异二聚体的多种细胞核受体发挥调节细胞生长、增殖与分化的作用。近年来,随着系统和局部应用适应证的不断扩大,其作用机制的研究也日益深入。     

维A酸结合蛋白的作用及其调节

随着维A酸类药物在临床上的广泛应用,对维A酸作用机制及其分子机制的探讨也越来越深入。近些年的研究表明维A酸结合蛋白在维A酸代谢和胞内信号转导等一系列过程中发挥着重要作用,而且维A酸结合蛋白与维A酸及其他因素之间均存在复杂的调控关系,他们之间的相互作用调节着细胞的生长和分化。     

倍扎罗汀及其在皮肤科的应用

倍扎罗汀是一种合成的维A酸X受体激动剂，与维A酸X受体高度特异性结合，主要通过影响与维A酸X受体形成异二聚体的多种细胞核受体发挥调节细胞生长、增殖与分化的作用。近年来，随着系统和局部应用适应证的不断扩大，其作用机制的研究也日益深入。     

维A酸结合蛋白的作用及其调节

随着维A酸类药物在临床上的广泛应用，对维A酸作用机制及其分子机制的探讨也越来越深入。近些年的研究表明维A酸结合蛋白在维A酸代谢和胞内信号转导等一系列过程中发挥着重要作用，而且维A酸结合蛋白与维A酸及其他因素之间均存在复杂的调控关系，他们之间的相互作用调节着细胞的生长和分化。     

维A酸类药物的分类及药理作用

正维A酸类药物包括维生素A及一些结构或功能与维生素A相类似的人工合成的药物。维生素A及其代谢物是细胞活性强有力的自然调节因子,在胚胎发生、生殖、炎症调节、细胞生长和分化过程中发挥了广泛的生理作用。目前临床应用的维A酸类药物主要是人工合成的,通过与维A酸受体(RARs)和维A酸X受体(RXRs)结合,可发挥对角质形成细胞的增殖、表皮的分化、调节免疫和抑制炎症等药理作用,广泛用于皮肤病的治疗,是皮肤病治疗发展史     

维A酸在皮肤科领域的研究新进展

维A酸在皮肤科领域有着广泛的用途及进一步开发应用的前景。一般认为在体内维A酸主要是通过两类维A酸核受体共 6种亚型发挥作用的 ,在此方面已进行了大量的研究 ,受体选择性维A酸的出现并应用于临床就是此方面研究的成果。另一方面 ,近期的研究证明维A酸对某些疾病的治疗作用至少有一部分是通过非受体依赖途径实现的。因此 ,维A酸在体内作用的具体机制尚待进一步的研究。     

维A酸在皮肤科领域的研究新进展

维A酸在皮肤科领域有着广泛的用途及进一步开发应用的前景。一般认为在体内维A酸主要是通过两类维A酸核受体共6种亚型发挥作用的，在此方面已进行了大量的研究，受体选择性维A酸的出现并应用于临床就是此方面研究的成果。另一方面，近期的研究证明维A酸对某些疾病的治疗作用至少有一部分是通过非受体依赖途径实现的。因此，维A酸在体内作用的具体机制尚待进一步的研究。     

维A酸类药物治疗皮肤T细胞淋巴瘤的研究进展

维A酸类药物是一类维生素A衍生物,具有调节细胞增殖、分化,促进凋亡的作用并能影响人体免疫应答,其应用于皮肤T细胞淋巴瘤的治疗已有多年,疗效确切.维A酸类药物生物学作用机制主要是通过与维A酸受体和维A酸X受体结合,转录辅助活化因子和转录抑制因子参与,诱导基因转录.维A酸受体选择剂和维A酸X受体选择剂治疗皮肤T细胞淋巴瘤均有效,但联合治疗疗效更明显.维A酸类药物常与光疗、干扰素及其他免疫抑制剂联合,其联合疗法已成为其在皮肤T细胞淋巴瘤中应用的主要方式.维A酸类药物的不良反应主要表现在对肝功能、血脂、甲状腺激素水平、白细胞及生殖系统的影响,外用主要表现为皮肤刺激反应.     

维A酸在皮肤科临床应用的现状与进展

目前将维A 酸类药物按其结构分为3 类.维A 酸一般是通过其受体发挥药理作用,但也存在非受体机制.其参与调控表皮细胞增殖、分化、凋亡,免疫调节,抑制皮脂腺分泌等生物学效应.维A 酸用于银屑病、痤疮、皮肤T 淋巴细胞瘤、皮肤光老化、角化性皮肤病及表皮肿瘤等多种皮肤病的治疗.维A 酸的主要不良反应是致畸和胚胎毒性,儿童长期...     

维A酸治疗皮肤肿瘤机制的进展

维A酸在调节细胞的增殖、分化和调亡以及对于部分肿瘤的治疗上有着重要意义. 1 维A酸及其受体 维A酸类药物结构中有3个基本组成部分:羧基末端、多烯侧链和环状结构.这三部分结构被不同基团取代,可得到生物活性不同的化合物.目前维A酸类化合物根据结构不同分为三代.第三代维A酸引入多芳香环状结构,使其具有受体选择性,药物作用的针对性提高,并减少不良反应.     

Immunolocalization of enzymes, binding proteins, and receptors sufficient for retinoic acid synthesis and signaling during the hair cycle

Retinoic acid (RA) is essential for maintenance of most epithelial tissues. One RA biosynthesis pathway consists of cellular retinol-binding protein (Crbp), retinol dehydrogenase (Dhrs9/eRoldh), retinal dehydrogenase 1-3 (Aldh1a1-3), and cellular RA-binding protein 2 (Crabp2). Previously, we localized Aldh1a2 and Aldh1a3 to both epithelial and mesenchymal cells within the hair follicle throughout the hair cycle. This study expands that observation by examining the complete pathway of RA biosynthesis and signaling via RA receptors alpha, beta, and gamma by immunohistochemistry in C57BL/6J mice wax-stripped to initiate and synchronize the cycle. This pathway of RA biosynthesis and signaling localized to the majority of layers of the hair follicle, sebaceous gland, and interfollicular epidermis in a hair cycle-dependent manner, suggesting that RA biosynthesis within the hair follicle is regulated in both a spatial and temporal manner. This localization pattern also revealed insights into epithelial-mesenchymal interactions and differentiation state differences within the RA biosynthesis and signaling pathway, as well as novel observations on nuclear versus cytoplasmic localization of Crabp2 and RA receptors. This complex pattern of RA biosynthesis and signaling identified by immunolocalization suggests that endogenous RA regulates specific aspects of hair follicle growth, differentiation, and cycling.     

Cutaneous Mixed Tumor Containing Ossification,Hair Matrix,and Sebaceous Ductal Differentiation

A 58-year-old Japanese male presented with a cutaneous mixed tumor containing ossification and hair matrix differentiation on the left side of the chin. Histologically, the tumor consisted almost exclusively of apocrine-type epithelial ductal structures and chondroid stroma. Strands and aggregation of basaloid cells which contained keratinous cystic structures with a column of shadow cells arising from basophilic basaloid cells, sebaceous duct-like structures, and ossification in the stroma were also evident. These findings suggest that cutaneous mixed tumors with ossification and hair matrix differentiation are related to both the whole hair follicle and the sweat aparatus.     

Human hair shape is programmed from the bulb

BACKGROUND: Few biological data on curly hair follicles have been reported in the literature. OBJECTIVES: To investigate the growth and morphology of curly hair follicles. METHODS: Follicles were dissected from scalp skin samples from African, Guyanese and caucasian volunteers and were observed macroscopically, in culture in William's E medium, and by immunohistochemistry. RESULTS: Macroscopic study of scalp biopsies obtained from African volunteers showed that the dermal implantation of follicles was curved with a retrocurvature at the level of the bulb, as opposed to a straight shape in caucasian follicles. The bulb itself was bent, in the shape of a golf club, while both the outer root sheath (ORS) and the connective tissue sheath were dissymmetrical along the follicle. In vitro growth of curly hair follicles was slightly slower than that of caucasian follicles but, more importantly, the curvature was maintained in the hair shaft produced in vitro. As shown by immunohistochemistry, the proliferative matrix compartment of curly hair follicles was asymmetrical, Ki-67-labelled cells being more numerous on the convex side and extending above the Auber line. On the convex part of the follicle, the ORS was thinner and the differentiation programmes of the inner root sheath and hair shaft were delayed. Furthermore, some ORS cells expressed alpha-smooth muscle actin protein on the concave side of the curvature, reflecting a mechanical stress. CONCLUSIONS: Hair curliness is programmed from the bulb and is linked to asymmetry in differentiation programmes.     

Electron microscopic study on cell differentiation in anagen hair follicles in mice

The dorsal and sinus hair follicles from 7-day-old mice of several strains were ultrastructurally examined to study their cell differentiation. The findings were compared with those in human anagen hair follicles. The keratinized cells in the Henle's and Huxley's layers gradually lost their cell volume and finally became thin and lamellar in mice. The outer root sheath (ORS) was composed of two cell layers in the mouse hair bulb. The cells in the outer layer gradually increased in number upwards; the completed outer layer consisted of 2-3, and over 10 cell layers in the mouse dorsal and sinus hair follicles, respectively. These cells produced many membrane-limited, highly electron-dense granules or cementsomes, and finally underwent a keratinization toward the hair canal. The innermost cell (IMC) layer of the ORS formed a unique single-cell layer in mice as well as in humans, although the mouse IMC were much thinner and contained fewer tonofilaments. Accumulation of tonofilaments in the inner side of the cytoplasm and keratohyalin production, but no cementsome production occurred in the mouse IMC. The mouse IMC started to keratinize after the degeneration of the keratinized inner root sheath (IRS) cells. These findings suggest that the lower hair follicle is composed of the IRS layers, the IMC layer, and the outer layer of the ORS in either mice or humans, although there are some morphological differences in cell differentiation in each layer between the two species.     

On the regulation of hair keratin expression: lessons from studies in pilomatricomas

Human hair follicles exhibit a complex pattern of sequential hair keratin expression in the hair matrix, cuticle, and cortex. In pilomatricomas, that is, benign skin tumors thought to arise from germinative matrix cells of the hair follicle and retaining morphological signs of cortical differentiation, this differential hair keratin pattern has been shown to be faithfully preserved in the lower and upper transitional cell compartments of the tumors. Here we show that also the co-expression of hair keratin hHa5 with its regulatory nuclear homeoprotein HOXC13 in matrix cells of the hair follicle is maintained in lower transitional cells of pilomatricomas. In contrast, the nuclear co-expression of LEF1 and beta-catenin, which in the hair follicle has been postulated to initiate cortex cell differentiation through the induction of hair keratin hHa1 expression (Merill et al, Genes Dev 15:1688-1705, 2001), is not preserved in upper transitional cells of pilomatricomas. Although these cells correctly express hHa1, they are completely devoid of LEF1 and nuclear LEF1/beta-catenin co-expression is shifted to a subpopulation of hair keratin-free basaloid cells of the tumors. These data imply that unlike the normal hair follicle, cortical differentiation in pilomatricomas is not under the control of the canonical Wnt signaling pathway.     

Cytokeratins 16 and 10 bind to retinoic acid covalently in skin tissue of mice

Background Retinoic acid (RA) has various biological effects in mammalian cells and tissues. In epidermal cells, RA is an inhibitor of differentiation to the squamous phenotype. The molecular mechanisms underlying the effects of RA on epidermal cells and other cell types are mediated by RA nuclear receptors and retinoylation (acylation by RA) of proteins. Objectives To understand the components responsible for RA effects via RA nuclear receptors and retinoylation. Methods We examined for the first time RA‐binding proteins in mouse skin in vivo by immunoblotting using anti‐RA monoclonal antibodies and identified by matrix‐assisted laser desorption ionization–time of flight mass spectrometry. Results We identified eight RA‐binding proteins in the skin of hairless mice that were increased by topical RA treatment. Three of these proteins were identified as cytokeratin 10, cytokeratin 16 and serum albumin. Conclusion These results raise the possibility that RA binding to cytokeratins in vivo may be involved in the effect of RA on keratinocytes in mouse skin.     

Proliferation and differentiation of organoid hair follicle cells co-cultured with fat cells in collagen gel matrix culture

Using rat skin, we studied the influence of fat cells on the proliferation and differentiation of organoid hair follicle cells in a three-dimensional collagen gel matrix culture system. We cultured organoid hair follicles embedded in collagen gel under each of the following three conditions: cell-free collagen gel for control experiments (condition 1); co-culture with fat cells in close apposition (condition 2); and co-culture with fat cells in spatial separation (condition 3). Outgrowths of epithelial cells from the organoid hair follicles associated with perifollicular proliferation of fibroblasts were observed under conditions 1 and 3. Under condition 2, proliferation of both organoid hair follicle cells and fibroblasts was inhibited, but differentiation of the hair follicle cells appeared to be accelerated. Fat cells are considered to have an inhibitory effect on the proliferation of perifollicular fibroblasts, which might have resulted in the inhibition of hair follicle cell proliferation and also in the better maintenance of normal follicular structure and integrity, allowing for hair-type differentiation to proceed. A direct accelerating effect of fat cells on hair follicle differentiation may also have been responsible. In a physiological state (co-culture with keratinocytes on the collagen gel), similar results were observed under conditions 1 and 2. The different findings under conditions 2 and 3 may be due to either of two possibilities: either the concentration gradient of the soluble factors released from fat cells, acting on either the hair follicle cells or the perifollicular fibroblasts as an inhibitor of proliferation, caused the difference in the results, or direct contact between the organoid hair follicle cells and fat cells may have influenced the accelerating effect of fat cells on the differentiation of hair follicle cells.     

毛乳头细胞体外诱导毛囊上皮细胞分化的实验研究

目的:探讨间质细胞对毛囊上皮细胞分化的调节作用,研究毛囊上皮细胞的分化特性。方法:分别用团块状的毛乳头细胞、皮肤成纤维细胞制成间质细胞胶原凝胶,表面接种毛囊上皮细胞,进行气-液界面培养。结果:毛囊上皮细胞有向毛乳头细胞移动集结的趋势;团块状的毛乳头细胞诱导毛囊上皮细胞形成球形结构;皮肤成纤维细胞诱导毛囊上皮细胞形成表皮样层化结构。结论:(1)毛囊上皮细胞具有双向分化特性,它既能分化形成毛囊,也能分化形成表皮结构;(2)毛乳头细胞对毛囊上皮细胞有趋化作用;(3)间质细胞的种类及分布在毛囊上皮细胞分化的调节中起着重要的作用。     

Effects of long-term retinoic acid treatment on epidermal differentiation in vivo: specific modifications in the programme of terminal differentiation

Summary To investigate the effects of long-term all-trans-retinoic acid (RA) treatment on epidermal differentiation in vivo , rhino mice were treated topically with 0.005% RA, and their epidermis was analysed histologically and biochemically after 5, 13 and 26 weeks of treatment. Effects of RA were observed first in the living layers of the epidermis, and then in the non-viable stratum corneum. Five weeks of topical RA led to thickening of the spinous and granular compartments, induction of keratins K6, K16 and K17, and suppression of filaggrin expression. After 13 and 26 weeks of RA treatment, the number of anucleate cornified cell layers remained similar to controls, but additional changes in histology and protein expression were observed. The results showed that prolonged administration of topical RA induced epidermal hyperproliferation, but did not suppress differentiation, in contrast to results observed in keratinocyte cultures. However, the distinct histological and biochemical changes observed in the spinous, granular and cornified layers of RA-treated skin after 26 weeks of treatment, suggested that the progeny of RA-treated basal cells undergo a modified programme of terminal differentiation. Considering the present data together with results of previous in vivo studies, we propose that long-term topical RA treatment retards, or specifically modulates, the later stages in epidermal differentiation, or programmed cell death.