ABSTRACT
Skin inflammatory diseases are most commonly treated with corticosteroids, especially topical preparations, benefitting from high potency and unparalleled formulation flexibility. However, these benefits are limited due to side effects, especially under long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) which block the COX pathways have been used as safer alternatives to corticosteroids, and much effort and resources have been invested in developing COX inhibitors. However, synthetic NSAIDs are less potent than steroids, have limited formulation flexibility and have their own safety issues, thereby yielding unsatisfactory results, with some high-profile drugs (e.g., the COX-2 inhibitors Vioxx, Celebrex) being withdrawn from the market due to safety concerns. The potency and safety challenges of NSAIDs are related to inter-eicosanoid dynamics, pertaining to their pro-versus anti-inflammatory action, homeostatic functions and tissue-specific activities. Instead, the upstream control of phospholipase A2 (PLA2) enzymatic activity, which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production, has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions. Yet, PLA(2) inhibitors have hardly been tested for treating skin inflammatory/allergic conditions. In this article we review the involvement of PLA(2)s in skin physiology and pathology, and discuss the prospect of PLA(2) inhibition for the treatment of dermatological diseases.
Subject(s)
Phospholipases A2/metabolism , Skin Diseases/enzymology , Skin Physiological Phenomena , Skin/enzymology , Animals , Enzyme Inhibitors/pharmacology , Humans , Molecular Targeted Therapy , Phospholipase A2 Inhibitors , Skin/drug effects , Skin Diseases/drug therapy , Skin Diseases/etiology , Skin Physiological Phenomena/drug effectsABSTRACT
Topical application of acetylenic acetogenins (AAG) from avocado (0.01-1.0mg/ear), was effective in inhibiting both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, and in decreasing tissue myeloperoxidase activity (indicative of polymorphonuclear leukocyte influx). Maximum edema inhibition of 72% was achieved by AAG at lower concentration (0.6 mg/ear) than that of the anti-inflammatory drug indomethacin (2mg/ear). The maximum myeloperoxidase inhibition of 60% was obtained at AAG concentration 0.1mg/ear. Chemical reduction of unsaturated bonds in aliphatic chain of AAG molecules almost abrogated inhibition effect of AAG at high concentration. In vitro AAG administration reduced secretion of PGE(2) in TPA-induced keratinocytes, and inhibited total PLA(2) and sPLA(2) activities in HaCaT cells. The results indicate a topical anti-inflammatory effect of acetylenic acetogenins which is associated with inhibition of PLA(2) activity in skin.
Subject(s)
Acetogenins/chemistry , Acetogenins/pharmacology , Acetylene/chemistry , Dermatitis, Contact/drug therapy , Dermatitis, Contact/enzymology , Phospholipase A2 Inhibitors , Tetradecanoylphorbol Acetate/adverse effects , Acetogenins/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Cell Line , Dermatitis, Contact/etiology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Male , Mice , Phospholipases A2/metabolismABSTRACT
Exposing skin to ultraviolet (UV) radiation contributes to photoaging and to the development of skin cancer by DNA lesions and triggering inflammatory and other harmful cellular cascades. The present study tested the ability of unique lipid molecules, polyhydroxylated fatty alcohols (PFA), extracted from avocado, to reduce UVB-induced damage and inflammation in skin. Introducing PFA to keratinocytes prior to their exposure to UVB exerted a protective effect, increasing cell viability, decreasing the secretion of IL-6 and PGE(2), and enhancing DNA repair. In human skin explants, treating with PFA reduced significantly UV-induced cellular damage. These results support the idea that PFA can play an important role as a photo-protective agent in UV-induced skin damage.
Subject(s)
Fatty Alcohols/pharmacology , Keratinocytes/drug effects , Persea/chemistry , Skin/drug effects , Anti-Inflammatory Agents , Cell Survival/drug effects , Cells, Cultured , DNA Damage , DNA Repair , Dinoprostone/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Interleukin-6/metabolism , Keratinocytes/radiation effects , Organ Culture Techniques , Polymerase Chain Reaction , Pyrimidine Dimers/analysis , Skin/radiation effects , Ultraviolet RaysABSTRACT
Ascorbic acid (AA) and its derivatives participate in vitro in oxidative-reductive reactions both as antioxidants and as prooxidants. The physiological relevance of these prooxidant effects of AA and its derivatives remains unclear. There is little evidence that AA can initiate formation of reactive oxygen species (ROS) or lipid peroxidation in cells or tissue. In order to examine the effect of AA and its derivative palmitoyl ascorbate on in situ intracellular ROS production and lipid peroxidation, 2('),7(')-dichlorofluorescin diacetate (DCFH-DA) and cis-parinaric acid were used as fluorescent probes in cultural neonatal foreskin fibroblasts. The results demonstrated that the effect of AA depended on the in vitro growth conditions. AA induced augmentation of the intracellular ROS concentration in newly plated (24 hours) cells. However, in cells cultured for 72 hours, AA had a different effect: it moderately reduced intracellular ROS concentration but stimulated lipid peroxidation in the cytoplasmic membrane. Palmitoyl ascorbate demonstrated significant inhibition of intracellular DCFH-DA oxidation presumably caused by inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.
