Current Drug Metabolism - Volume 11, Issue 5, 2010

If the First Volume of the Hot Topic Issue has covered mainly the vast and rapidly growing field of targeted “biological” drugs developed on purpose to specifically inhibit or even completely interrupt inflammatory pathways in the patients affected by chronic immune-mediated skin diseases, the Second Volume provides comprehensive reviews on the “re-discovery” of natural low molecular weight substances with potent anti-inflammatory, wound healing, and anti-photoaging properties. The idea of using “tender” drugs offered by “Mother-Nature” [1] is one of the most attractive health concepts nowadays. Numerous secondary metabolites produced by plants in order to protect themselves against hostile environment, competitors, infections, and physical damage, seem to be excellent candidates for the treatment of chronic diseases and esthetical defects of the skin. Hence a wealth of skin products based on botanicals or purified plant-derived substances are emerging yearly. A mountain of evidence suggests that, when topically applied, these products exert anti-inflammatory, photo-protective, cancer chemopreventive, wound healing, anti-aging, or whitening effects. It has been noticed that 12 out of 40 anti-inflammatory drugs approved between 1983 and 1994 worldwide were derived from or based on plant substances, mainly polyphenols [2]. A decade ago, the capacity of plant polyphenols to attenuate acute or/and chronic inflammation of the skin was ascribed to their antioxidant, free radical scavenging, and metal chelating properties. However, it is now evident that remarkable anti-inflammatory efficacy of plant polyphenols could be better explained by a multitude of effects. To our present knowledge, plant-derived molecules have a major impact on resident (keratinocytes and mast cells) and recruited (granulocytes, lymphocytes, and dendritic cells) cells involved in the inflammatory response in the skin. From the molecular point of view, these natural substances can inhibit both expression and activity of numerous pro-inflammatory enzymes, react with specific surface and nuclear receptors, modulate signal transduction pathways and cytokine production, and affect epigenetically the expression of genes involved in the inflammatory response [3]. The first brief introductory overview by Igor Afanas'ev, a pioneer of free radical research in chemistry and biology, describes the current concept on double biological roles of superoxide and nitric oxide radicals. The traditionally widely accepted philosophy on the exclusively damaging effects of free radicals towards biological molecules and cellular structures has been recently changed by the acknowledgment of their essential physiological functions. The author explains the prevalence of signalling events rather than deleterious biological effects of superoxide and nitric oxide by their low chemical reactivity under physiological conditions. Firstly, he concentrates on the chemistry of the astonishing and surprising phenomena of initiation and activation of enzymatic heterolytic reactions, such as hydrolysis, etherification, or phosphorylation mediated by superoxide and NO. The crucial aspect covered by the paper is how signaling and modulating actions of the free radicals may switch to the damaging one. The author discusses this topic in terms of concentration dependency. Indeed, low level free radicals control cellular homeostasis by signal transduction and enzyme activity modulation, whereas high level free radicals lack the controlling functions but, in turn, create breakdown of homeostasis with consequent irreversible damage. In the last part, a few examples of protective and curing effects of selected classical antioxidants and free radical scavengers in skin pathologies are provided. In keeping with this line, the paper by Vladimir Kostyuk et al. is dedicated to molecular free radical-dependent and free radical-independent aspects of anti-inflammatory action of plant polyphenols. Usually, the initial screening of natural substances/mixtures for antiinflammatory properties starts from the evaluation of their antioxidant and free radical scavenging activity in cell-free systems, weak antioxidants/scavengers being excluded from further analyses. Literature data collected by the authors provide clear evidence that pretty often redox-dependent properties do not correlate with anti-inflammatory effects revealed in vitro and in vivo. In other words, good antioxidant substances must not be necessarily promising anti-inflammatory drug and vice versa. The extremely complex cutaneous inflammatory process involves oxygen (ROS), nitrogen (RNS) and lipid reactive species, but it is also driven by other mechanisms highlighted in these recent years, related to the regulation of gene expression, and to metabolic and signalling pathways that are considered ROS/RNS-independent. Furthermore, bioavailability of plant-derived products in the skin is highly limited due to effective barrier properties of the skin and fast metabolism of these xenobiotics by specific metabolizing enzymes located in different skin compartments. According to the authors' opinion, (i) the screening of the enormous array of plant secondary metabolites for new effective and safe anti-inflammatory agents should be rather directed towards molecules targeting specific inflammatory pathways recognized to be centrally involved in skin inflammation, and (ii) proper vehicles should be used for targeted delivery of anti-inflammatory plant polyphenols....

For many years the formation of reactive oxygen and nitrogen species (ROS) and (RNS) in living organisms has been considered to be dangerous phenomenon due to their damaging action on biomolecules. However, present studies demonstrated another important activity of ROS and RNS: their signaling functions in physiological and pathological processes. In this work we discuss the new data concerning a role of ROS and RNS in many enzymatic/gene cascades causing damaging changes during the development of skin diseases and pathological disorders (skin cancer, the toxic effects of irradiation on the skin, and skin wounding). It has been suggested that the enhancement of ROS formation in tumor cells through the inactivation of mitochondrial MnSOD or the activation of NADPH oxidase leads to apoptosis and might be applied for developing a new cancer therapy. On the other hand ROS overproduction might stimulate malignant transformation of melanoma. Role of ROS signaling is also considered in the damaging action of UVA, UVB, and IRA irradiation on the skin and the processes of wound healing. In the last part of review the possibility of the right choice of antioxidants and free radical scavengers for the treatment of skin disease is discussed.

Inflammation is a key event in the skin normally occurring in response to the constant exposure to environmental and endogenous stimuli as well as to accidental damage. It also plays a central role in the pathogenesis of major cutaneous pathologies, ultimately resulting in skin carcinogenesis. As the acute mild inflammatory process is mainly adaptive in nature, chronic inflammation is a multifactorial and complex noxious process, extremely difficult to combat. The wealth of data documenting the involvement of redoxdependent regulatory and damaging processes in the skin inflammation has prompted research on a steadily growing number of plantderived active substances, mainly polyphenols, and selected principally on the basis of their free radical scavenging and antioxidant properties. In spite of the wide recognition of their anti-inflammatory efficacy in vitro, the clinical use for the prevention and treatment of major skin inflammatory conditions is in most cases yet to be conclusively proven. The complex nature of the cutaneous inflammatory process involves oxygen (ROS), nitrogen (RNS) and lipid reactive species, but is also driven by other mechanisms highlighted in these recent years, related to the regulation of gene expression, and to metabolic and signaling pathways that are ROS/RNS-independent. The screening of the enormous array of plant secondary metabolites, first of all polyphenols, for new effective and safe anti-inflammatory agents should be rather directed towards molecules targeting specific inflammatory pathways recognized to be active in the peculiar skin compartment.

Rottlerin is a natural polyphenolic compound, which was initially indicated and marketed as a PKC δ inhibitor and recently proposed and patented as an anti-hypertensive drug. In vitro results from our Laboratory and data from the literature suggest a potential use of Rottlerin in the treatment/control of psoriasis, a skin disease characterized by abnormal cellular proliferation, abnormal angiogenesis and inflammation. Rottlerin, indeed, is an antioxidant and a potent inhibitor of the transcription factor NFκB, a key mediator of immune responses and a crucial regulator of cell cycle and apoptosis in immune cells, endothelial cells and keratinocytes. Herein, we will review the multiple activities of Rottlerin (antioxidant, antiproliferative, antiangiogenic and anti-inflammatory) that give to the drug the potential to be used as a new therapeutic approach against psoriasis.

The skin photoaging is an inevitable process that occurs in daily life. It is characterized by acceralated keratinocyte proliferation and degradation of collagen fibers, causing skin wrinkling and laxity, and melanocyte proliferation that leads to pigmentation. Ultraviolet (UV) is considered to be a major cause of such skin changes. It is well established that nuclear factor κ B (NF-κB) is activated upon UV irradiation and induces various genes including interleukin-1 (IL-1), tumor necrosis factor α (TNFα), and matrix metalloprotease- 1 (MMP-1). It is also known that production of basic fibroblast growth factor (bFGF) is induced in skin tissues by UV irradiation and it promotes the proliferation of skin keratinocytes and melanocytes. We found that either UVB, IL-1 or TNFα could induce NF-κB by activating its signal transduction pathway. The activated NF-κB produces MMP-1 and bFGF in skin fibroblasts and human keratinocyte cell line HaCaT. In this experiment, we examined whether parthenolide and magnolol, NF-κB inhibitors, could block such UVB-mediated skin changes. We found that either parthenolide or magnolol could effectively inhibit the gene expression mediated by NF-κB and the production of bFGF and MMP-1 from cells overexpressing p65, a major subunit of NF-κB. We also found that these NF-κB inhibitors could inhibit the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin. These findings suggest that NF- κB inhibitors are useful in preventing the skin photoaging.

While many botanicals have been used during thousands of years in various cultures for the treatment of several inflammatory conditions, wound healing or preserving skin beauty, their active ingredients and their mechanisms of action are less well characterized. It is known that throughout life, environmental conditions and dietary compounds influence gene expression. Only recently it has been observed that exposure to specific phytochemicals can affect gene expression via reversible epigenetic mechanisms and gets recorded in our “epigenome” through life. Epigenetics refers to heritable phenotypical differences or changes in gene expression that are not attributable to changes in DNA sequence, but rather depend on variations in DNA methylation, chromatin structure or microRNA profiles. As such, our dietary epigenetic imprint superposed on our genome may rewire gene expression patterns in the body and the host immune system, and protect against inflammatory disorders, cancer and ageing. This has recently launched reexploration of nutritional, botanical or phytopharmaceutical compounds for epigenetic effects to identify promising nutraceuticals or cosmeceuticals which could (re)program stem cell differentiation, wound healing, skin regeneration, tissue homeostasis, or “correct” epigenetic marks responsible for inflammatory skin disorders and ageing.

Vitiligo is a multifactorial disorder characterized by the appearance of white maculae that may spread over the entire body skin. Depigmentation arises from the loss of functioning melanocytes. Non segmental vitiligo (NSV) is the most common form of the disease: it is usually progressive and may be associated with familiarity and autoimmunity. Segmental vitiligo (SV) frequently stabilizes few years after its onset. Vitiligo etiology involves multiple pathogenetic factors, most of them working in concert. Impaired antioxidative defences lead to accumulation of reactive oxygen species (ROS), which affect melanocytes. Mitochondrial membrane lipid peroxidation may participate to ROS overproduction. A temporal sequence may connect oxidative stress and autoimmunity. Overall, a genetic predisposition renders vitiligo melanocytes more susceptible to precipitating factors than normal healthy melanocytes. The definition of isolated or superimposed manifestations of polygenic skin disorders has been proposed for SV and SV-NSV association. Keratinocytes and melanocytes are both affected and apoptosis, ageing or melanocythorragy are the ultimate effects of the complex deregulation in vitiligo skin. Pathogenetic therapies mainly act by inducing immunosuppression and stimulation of melanocyte proliferation and migration. Here the most popular hypotheses for the pathogenesis of vitiligo are summarized. Fundamental cellular, biochemical and molecular alterations accounting for melanocyte destruction in vitiligo are also described. Last, pathogenetic approaches in the treatment of such a complex disease are discussed, with particular consideration on the cellular and molecular targets of the current therapies.

This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I), 2,5- dimethoxy-4-methyl-beta-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-beta-phenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-beta-phenethylamine (2C-T-7), beta-keto designer drugs such as 2- methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (butylone, bk-MBDB), 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1- one (ethylone, bk-MDEA), 2-methylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (methylone, bk-MDMA), and 2-methylamino-1- p-tolylpropane-1-one (mephedrone, 4-methyl-methcathinone), pyrrolidinophenones such as 4-methyl-pyrrolidinobutyrophenone (MPBP) and alpha-pyrrolidinovalerophenone (PVP), phencyclidine-derived drugs such as N-(1-phenylcyclohexyl)-propanamine (PCPr), N-(1- phenyl-cyclohexyl)-2-ethoxyethanamine (PCEEA), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), and N-(1-phenylcyclohexyl)- 2-methoxyethanamine (PCMEA), tryptamines such as 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), and finally alpha- methylfentanyl (alpha-MF) and 3-methylfentanyl (3-MF). Papers have been considered and reviewed on the identification of in vivo or in vitro human or animal metabolites and the cytochrome P450 or monoamineoxidase isoenzyme-dependent metabolism.