皮肤的神经-内分泌-免疫功能及药物调节

摘要：皮肤是人体重要的保护屏障,其拥有自我调节机制。查阅文献及书籍,发现皮肤存在类似机体的神经-内分泌-免疫系统皮肤细胞可分泌神经递质、激素及炎症因子,可与机体的相互作用,共同达到治疗疾病的目的。皮肤为药物外用最重要的接收器但因中药制剂透皮吸收部分较微,多通过皮肤局部稳态的调整。本文分析其相互作用及药物调节作用,有利于外用药物机制更加明晰,为外治提供新思路。     

神经肽Y效应器系统：用于药物开发的前景

神经肽Ｙ广泛分布于中枢和外周神经元，可产生多种生物学效应。例如，神经肽Ｙ与刺激食物和水的摄取、心境的控制及中枢自主神经功能的调节有关。外周交感神经中，神经肽Ｙ是作为血管加压剂和血管收缩剂发挥作用的。神经肽Ｙ至少作用于三类不同的受体，称为Ｙ１、Ｙ２和Ｙ３。某些疾病可能涉及神经肽Ｙ依赖机制。神经肽Ｙ受体有希望成为药物作用的靶点。     

皮肤细胞色素P450酶的研究进展

皮肤是肝外药物代谢的主要器官之一，有多种代谢酶表达。细胞色素P450酶（CYP）是一组含亚铁血红素的超家族基因编码的同工酶，皮肤CYP参与了多种内源性物质和外源性物质的代谢，在维持皮肤的正常生理功能和保护内环境稳定方面发挥重要作用。对皮肤CYP的研究有助于了解它在药物代谢和皮肤疾病中的作用，对提高药物疗效、开发经皮给药新制剂、防止药物和毒性物质对皮肤的侵害等，具有重要意义。     

辣椒素脱敏作用研究进展

辣椒素对感觉神经具有选择性作用，能耗竭神经素端的神经肽类物质，减少对化学物质的敏感性，抑制神经元炎，对人和动物鼻粘膜产生脱敏作用，并能缓解及治疗变应性鼻炎等变应性疾病，是一种有前途的抗变应性药物。本文就辣椒素与感觉神经、神经肽的关系，脱敏作用和用于变应性鼻炎的治疗效果进行了综述。     

组织工程化皮肤在药物经皮吸收研究中的应用

目的：介绍组织工程化皮肤在药物经皮吸收研究中的应用。方法：查阅文献，简要综述组织工程化皮肤的特征及其在药物经皮吸收研究中的应用情况，结果：组织工程化皮肤已用于药物经皮吸收的研究。结论：组织工程化皮肤作为药物经皮吸收研究的模型值得进一步推广。     

P物质与成瘾相关研究进展

<正>常见滥用药物有阿片类、可卡因、酒精、尼古丁等,这些药物长期使用会导致成瘾。在美国,每年大概花费7000亿美元以上用于社会上药物滥用的管理~([1])。药物成瘾与多巴胺和谷氨酸等神经递质相关。神经激肽属于肽类神经递质,与药物滥用也有着密切的联系~([2]),但是有关神经肽系统在成瘾中的作用机制还不十分清楚。     

多巴胺受体信号传递及机能调节

从发现多巴胺（DA）成为脑内一种神经递质到现在，已经历了50年。50年来，对DA的认识也逐渐在深入。现在可以这样认为，DA作为中枢神经系统最主要的神经递质之一，几乎与脑内重要功能的各个方面均密切相关。DA通过DA受体起作用，后属于G-蛋白偶联受体（GPCR），目前，已经克隆了5种DA受体，包括D1类（D1、D5），D2类（D2、D3、D4）。前与Gs蛋白偶联．后与Gi／o蛋白偶联。近年来，有关DA受体功能的调节机制的研究进展迅速，一些新的信号通道被发现，一些新的调节机制被认知。而这些新的调节机制和信号通道在DA机能活动，DA有关的疾病病理发展中可能起着重要作用。因此，这些新的通道和调节机制也有可能成为药物研究的新靶点。     

神经肽与皮肤病

神经肽(NP)是一组由氨基酸组成并具有生物活性的肽类或蛋白,属神经内分泌系统的内源性信息物质。近年来研究表明,神经肽还广泛的存在于免疫系统,而且在免疫系统中同样属内源性物质,并可接受神经系统难以感受到的刺激,而引起相关的免疫应答。皮肤是一个免疫场所,其中存在有多种NP,其与皮肤免疫、炎症的关系及在皮肤病发病中的作用,日益受到人们的关注。     

中缝背核5-HT在创伤后应激障碍发病机制中的研究

中缝背核是位于脑干正中缝两侧的中缝核细胞群中的一员,其存在多种神经递质和神经肽,参与多种生理活动。本文主要叙述中缝背核中的5-羟色胺及其相关的神经递质和神经肽在中缝背核神经精神调节中的主要作用机制,及在创伤后应激障碍发病机制中的作用。     

猪不同部位皮肤与人体皮肤对药物渗透性的比较

以苯甲酸、水杨酸、甲硝唑为模型药物，对猪耳和猪腹部皮肤进行体外药物渗透实验，在相同条件下与正常人体皮肤进行了渗透性差别的比较研究。结果表明：猪耳和猪腹部皮肤与人体皮肤对药物渗透性具有相似性，特别是猪耳皮肤对药物体外透皮实验是个有价值的动物模型。     

Therapeutic targeting of Toll-like receptors in cutaneous disorders

Introduction: The role of skin, as a part of the immune system has long been elucidated. Toll-like receptors (TLRs), a group of pattern recognition receptors, are involved in the recognition of invading pathogens, initiation of immune responses and regulation of both innate and adaptive immune systems. There is a growing body of evidence supporting the role of TLRs in the pathophysiology of several skin conditions, which mandates the development and study of therapeutic strategies that target TLRs.

Areas covered: With regards to the role of TLRs in pathogenesis of diverse cutaneous conditions, recent advances, as well as the future prospects of therapeutic implications of TLRs in cutaneous disorders is reviewed in this article.

Expert opinion: Although non-specific therapeutic strategies seem to reduce the symptoms in majority of patients, a considerable proportion remain untreated or have to deal with inevitable adverse effects of such therapies. Since TLRs regulate many patholophysiological processes, they could be good candidates for more specific therapeutic approaches. TLR targeting as the first recipient of invading pathogens is a growing concept in this field.     

皮肤中转运蛋白的作用研究进展

本文综述了目前在皮肤中发现的转运蛋白的种类,及其在透皮给药、皮肤免疫系统、内源性化合物代谢和皮肤病等方面的作用。     

Upcoming therapeutic targets in cutaneous lupus erythematous

Novel insights into molecular mechanisms have altered our understanding of the pathogenesis of autoimmune skin disorders. Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by auto-aggressive skin inflammation which histologically presents with interface dermatitis. This inflammation is driven by interferon (IFN)-regulated proinflammatory cytokines that orchestrate the B- and T-cell mediated lesional inflammation. During the last years, therapeutic strategies have focused on these players: biologicals targeting type I IFNs and their receptors as well as anti-B-cell drugs have been investigated in clinical trials with variable success. Very recently, CLE gene expression analyses revealed lesional activation of several pathways of the immune system, thus providing potential new therapeutic targets. In this article, we review the current knowledge concerning pathways and key mediators involved in the pathogenesis of cutaneous lupus erythematosus (including TLR-dependent and TLR–independent immune activation, NfkB, TBK1, PI3K, MAPK, JAK/STAT-pathway) and their inhibitors (e.g. chloroquine, bufalin, duvelisib, rapamycin, R788, KN-93, amlexanox, tofacitinib, ruxolitinib, baricitinib), and discuss emerging strategies for the treatment of CLE and related diseases.     

Metabolic and redox barriers in the skin exposed to drugs and xenobiotics

Introduction: Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised.

Areas covered: Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo)

Expert opinion: Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.     

Clinical and experimental aspects of cutaneous neurogenic inflammation

The aim of this paper is to present the state of knowledge on cutaneous neurogenic inflammation. Peripheral effector functions served by afferent sensory neurons underlie the so-called neurogenic inflammation. The mechanism of cutaneous neurogenic inflammation is connected with the release of neuropeptides from the sensory endings. They also exert a number of functions within the immune system. The activity of neuropeptides in the inflammation of the skin can be observed in the form of erythema, edema, hyperthermia and pruritus. Beside these peptides and their receptors, inflammatory skin response, is regulated by tryptase and proteinase-activated receptor 2 (PAR-2). Capsaicin decreases effects of inflammation-induced sensory neuropeptides, which was used in the treatment of diseases caused by inflammation. The activity of transient receptor potential vanilloid receptor 1 (TRP-V1) is associated with the neurogenic inflammation. In inflammatory processes, the neuro-immuno-cutaneous system undergoes activation, which is responsible for triggering and maintaining the inflammatory conditions, both in the healthy skin as well as in the pathological conditions, like psoriasis. Skin exposure to UV radiation influences the neuro-immuno-cutaneous system and causes the release of neuropeptides, thereby eliciting inflammatory response in photodermatosis. In conclusion, understanding the mechanisms and the factors controlling neurotransmitters and their receptors will lead to the identification of novel therapeutic targets for the treatment of cutaneous diseases e.g. pruritus, psoriasis, alopecia areata.     

Modulatory actions of steroid hormones and neuropeptides on electrical activity in brain

Electrophysiological studies over the past decades have shown that many compounds in addition to 'classical' neurotransmitters affect electrical activity in the brain. These compounds include neuropeptides synthesized in brain as well as compounds which are released from peripheral sources and subsequently enter the brain compartment, such as corticosteroid hormones from the adrenal gland. In the present review, this principle is illustrated by describing the effects of two substances, i.e. vasopressin and corticosterone. Neuropeptides and corticosteroid hormones add at least two essential aspects to information processing in the brain. First, they both act conditional, i.e. they modulate the actions of 'classical' neurotransmitters, rather than changing basal neuronal activity by themselves. Second, the time-frame in which modulation of electrical properties takes place differs from that generally seen with 'classical' neurotransmitters. Neuropeptides modulate electrical activity over a period of minutes, while effects of corticosteroid hormones usually become apparent after at least an hour but then last for hours. In this way, neuropeptides and steroid hormones expand the repertoire of responses through which the brain reacts to environmental challenges.     

Targeting CD44 in mast cell regulation

Importance of the field: Accumulating evidence suggests that mast cells are involved in a wide variety of immune responses including chronic inflammation, immune tolerance and tumor immunity. Mast cells originate from hematopoietic stem cells and undergo terminal differentiation in the tissues, in which they are ultimately resident. Heterogeneity of tissue mast cells is, therefore, one of the key concepts for a better understanding of various immune responses.

Areas covered in this review: This review describes the candidate genes involved in regulation of cutaneous mast cell differentiation, with a particular attention to CD44, which is the primary receptor for hyaluronan.

What the reader will gain: CD44 is involved in various aspects of cutaneous inflammation. Regarding mast cells, CD44 is upregulated upon differentiation and maturation of mast cells, and plays a critical role in regulation of cutaneous mast cell number. Since both degradation and decrease of hyaluronan are often observed upon chronic inflammation, CD44 might be involved in modulation of local immune responses through regulation of cutaneous mast cell functions.

Take home message: Understanding of cutaneous immune responses should require clarification of local mast cell functions, a part of which is regulated by extracellular matrix components and their membrane receptors.     

Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin

The pathophysiology of rosacea has undergone renewed interest over the past decade, with a large body of evidence supporting the role of an abnormal innate immune response in rosacea. Many mechanisms interact with the cutaneous innate immune system that may be operative. A variety of potential triggers stimulate this immune detection system which is upregulated and hyper-responsive in facial skin of patients with rosacea as compared to normal skin. Based on the most current data, two conclusions have been reached. First, the major presentations of rosacea appear to be inflammatory dermatoses. Second, the presence of a microbial organism is not a primary or mandatory component of the pathogenesis of rosacea. Available therapies for rosacea exhibit reported modes of action that appear to correlate with the inhibition of inflammatory processes involved in the pathophysiology of at least some presentations of rosacea.     

The imidazoquinolines and their place in the therapy of cutaneous disease

The imidazoquinolines arose from efforts to develop a nucleoside analogue. Although molecularly similar to nucleosides, the imidazoquinolines did not have nucleoside-like activity. However, the imidazoquinolines induced immune modulatory cytokines, in part, because of their ability to activate toll receptors (TLR)s. Imiquimod, the first FDA-approved imidazoquinoline, has been marketed as a 5% cream, which is approved for the therapy of genital warts. The advantage of imiquimod therapy over other therapies for genital warts is the decrease in recurrence rate with the establishment of an adaptive immunological response or immunological memory/surveillance response. As tumours and viral infections are handled similarly by the immune system, there has been great interest in the use of topical imiquimod for the treatment of cutaneous neoplasms, particularly non-melanoma skin cancers. Future efforts in imidazoquinoline research is focused around the development of analogues with modifications in the immunological profiles, potency and penetration parameters that better focus these new analogues for the therapy of specific intracellular infections and neoplasms, as well as the development of imidazoquinolines for conditions related either directly or indirectly to patterns of immune dysregulation.     

PEPTIDES AS NEUROTRANSMITTERS IN VASCULAR AUTONOMIC NEURONS

1. Neuropeptides are present in the majority of autonomic neurons projecting to blood vessels, where they are co-localized with non-peptide transmitters and sometimes with other peptides. 2. Neuropeptides are released from vasoconstrictor and vasodilator nerve terminals after high frequency stimulation (>2–5 Hz) with trains of impulses. 3. Neuropeptides can have potent post-synaptic effects on vascular tone, but often these effects are restricted to selected regions of the vasculature. 4. Post-synaptic effects of neuropeptides tend to be more slowly-developing and more long-lasting than those of non-peptide transmitters. 5. Autonomic vasoconstrictor and vasodilator responses often have multiple phases, with the faster phases being mediated by non-peptide transmitters and the slower phases mediated predominantly by one or more neuropeptides. 6. Some neuropeptides do not seem to have post-synaptic effects in a particular vascular bed, but can have presynaptic actions on neurotransmitter release. 7. Neuropeptides form an important component of the repertoire of neurotransmitters used by vascular autonomic neurons to regulate regional blood flow in response to a range of physiological stimuli.