Oxidative stress and antioxidant strategies in dermatology

Abstract

Oxidative stress results from a prooxidant-antioxidant imbalance, leading to cellular damage. It is mediated by free radicals, such as reactive oxygen species or reactive nitrogen species, that are generated during physiological aerobic metabolism and pathological inflammatory processes. Skin serves as a protective organ that plays an important role in defending both external and internal toxic stimuli and maintaining homeostasis. It is becoming increasingly evident that oxidative stress is involved in numerous skin diseases and that antioxidative strategies can serve as effective and easy methods for improving these conditions. Herein, we review dysregulated antioxidant systems and antioxidative therapeutic strategies in dermatology.

Introduction

Reactive oxygen species (ROS) include superoxide anion $\left({\mathrm{O}}_2{}^{\circ }{}^{-}\right)$, peroxides, hydroxyl radical (OH°, and singlet oxygen ${(}^1{\mathrm{O}}_2)$.¹ These molecules activate proliferative and cell survival signaling and can damage DNA (DNA base damage, DNA single-strand and double-strand breaks, DNA and protein crosslinks, DNA and chromosomal aberration), lipid membranes, collagen structures, and mitochondrial function. ROS are produced by keratinocytes and virtually all types of skin cells in response to signals from cytokines, growth factors, airborne pollutants, UV radiation, food additives/preservatives, cosmetics, drugs, and physiologic stimuli. Antioxidants are generally classified as endogenous and exogenous. The skin has a vast antioxidant system, including enzymatic antioxidants, such as glutathione peroxidase (GPX), glutathione S-transferase, glutathione reductase, superoxide dismutase (SOD) and catalase, as well as non-enzymatic antioxidants, including ascorbic acid (vitamin C), glutathione (GSH), ubiquinol, uric acid, vitamin A, melanin, alpha-tocopherol (vitamin E), carotenoids (beta-carotene, lutein, zeaxanthin, and alpha-carotene) and sulfhydryls.^2,3 Flavonoids, coenzyme Q10, alpha-lipoic acid, selenium, pyruvate, and bilirubin are other examples of endogenous non-enzymatic antioxidants. We can also obtain antioxidants exogenously via food intake. Examples of this class of antioxidants, or foods that contain them, are lycopene, curcumin, green tea, Coffea arabica, silymarin, polypodium leucotomos, resveratrol, grape seed extract, pomegranate, pycnogenol, soy isoflavones, propolis, and squalene.⁴ In skin, the epidermis contains higher concentrations of antioxidants than the dermis. These antioxidants generally are distributed in a gradient fashion with increasing concentrations noted toward the deeper layer of the stratum corneum.⁵

Skin is the largest organ in body that is subjected to oxidative stress, and this stress is known to influence numerous cutaneous diseases (Fig. 1). In this review, we summarize current knowledge regarding oxidative stress and antioxidant strategies in several cutaneous diseases.

Figure 1.

Various cutaneous disorder related with oxidative stress and aberrant antioxidant system

Contact dermatitis

Irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) exhibit similar clinical, histological, and molecular features; however, these conditions exhibit different forms of pathogenesis. ICD is a non-immunologic inflammatory reaction in response to toxic materials, whereas ACD is an antigen-specific, memory T-cell-mediated delayed-type hypersensitivity reaction. ROS play a central role in the development of both forms of contact dermatitis.⁶ The response to irritants or allergens involves the synthesis and release of proinflammatory cytokines as well as the generation of signals to attract leukocytes, upregulate surface costimulatory molecules, activate matrix metalloproteinases (MMPs) and carbonylate proteins. ROS also directly activate or provide costimulatory signals for nuclear factor kappa B (NF-κB), thereby resulting in the regulation of the prostaglandin pathway and the expression of COX-2.⁷ Thioredoxin is induced by ROS and functions as a chemoattractant for polymorphonuclear leukocytes, monocytes, and T-lymphocytes in inflammatory tissues.⁸ ROS initially mediate extracellular matrix changes that facilitate ACD. Contact sensitizer-induced, hyaluronidase-mediated hyaluronic acid degradation and sensitization is completely prevented by antioxidants or pre-treatment with the hyaluronidase inhibitor, aristolochic acid.⁹ Th1 and Th2 response patterns in antigen-presenting cells are modulated by GSH.¹⁰

N-Acetylcysteine inhibits IL-1-induced mRNA upregulation and expression of E-selectin and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells and reduces NF-κB binding to the NF-κB binding site of the VCAM-1 gene.¹¹ N-Acetylcysteine, resveratrol, and tea polyphenols inhibit ROS-regulated expression of MMPs.¹² Although N-acetylcysteine, alpha-tocopherol and ascorbate inhibit the expression and functional activity of cutaneous lymphocyte-associated antigen (CLA) in isolated human T-lymphocytes,¹³ these antioxidants do not inhibit contact dermatitis when administered in topical form.¹⁴ In keratinocytes, cell-permeable SOD suppresses TNF-induced MMP-9; thus, SOD is thought to be an immunomodulatory agent in inflammatory skin diseases.¹⁵

A topical PPAR-alpha activator induces antioxidant enzymes and reduces inflammation in irritant and ACD models.¹⁶

Alopecia areata

Plasma beta-carotene, vitamin E, selenium GPX activity and GSH in plasma and erythrocytes, levels are decreased, whereas thiobarbituric acid reactive substance (TBARS, a marker of lipid peroxidation) in plasma and erythrocytes is increased in alopecia areata (AA) patients.¹⁷ GPX and SOD in scalp tissue are increased.¹⁸ Given that oxidative stress is associated with cell apoptosis, hair follicle cell apoptosis may be related to oxidative stress in AA. Oxidative stress index (OSI) and total oxidant capacity (TOC) were increased, whereas total antioxidant capacity (TAC) was decreased in AA patients.¹⁹

Atopic dermatitis

SOD, catalase, GPX, GSH, and vitamins A, C, and E are decreased in blood of atopic dermatitis patients.²⁰ Urinary 8-hydroxy-2′-deoxyguanosine (a marker of oxidative DNA damage), acrolein-lysine adducts (a marker of lipid peroxidation), and bilirubin oxidative metabolites (a marker of antioxidant activity of bilirubin under oxidative stress) were higher in acute exacerbated atopic dermatitis.²¹

Seborrheic dermatitis

Serum total antioxidant status (TAS) values were significantly reduced in seborrheic dermatitis patients. However, patients exhibited significantly increased serum total oxidative status (TOS) and OSI values.²² SOD and catalase activities and MDA levels were significantly higher in in scraping samples of patients' scalp.²³

Lichen planus

In oral lichen planus, 8-oxo-7,8-dihydro-2′-deoxyguanosine (an indicator of oxidative DNA damage) and 8-nitroguanine (a marker of nitrative DNA damage) in oral epithelium were increased.²⁴ Anthocyanin therapy of oral lichen planus was equal to or better than clobetasol propionate/neomycin/nystatin cream, especially for erosive forms.²⁵

Scleroderma

Oxidative stress is hypothesized to play an important role in disease development. Serum 8-isoprostane (a marker of oxidative stress) was increased in scleroderma patients.²⁶ Similarly, serum TOS and OSI levels indicative of systemic sclerosis were increased and TAC was reduced. Furthermore, TAC may serve as a marker that predicts the risk of lung and gastrointestinal tract involvements.²⁷

Recently, N-acetylcysteine was shown to attenuate skin fibrosis in a bleomycin-induced mouse model of scleroderma; this antioxidant significantly reduced the MDA and protein carbonyl content in the skin of mice.²⁸

Pemphigus vulgaris and pemphigus foliaceus

Serum GPX, catalase and GSH in erythrocyte and plasma, plasma β-carotene, vitamin E, and vitamin A are decreased, whereas MDA in erythrocyte and plasma is increased, in pemphigus vulgaris (PV) patients.²⁹ Serum TOC and lipid hydroperoxide (LOOH) are increased in PV patients.³⁰ Plasma uric acid is reduced, whereas GPX, vitamin C, selenium, and bilirubin levels did not differ in PV patients compared with controls.³¹

MDA, conjugated dienes, catalase, and SOD activities are increased, whereas protein thiol levels are decreased, in the skin of pemphigus foliaceus (PF) patients.³²

Vitiligo

Various conflicting results have been reported with regard to oxidative stress in vitiligo. These differences may be attributed to variations in the innate levels in different tissue samples, disease duration, or disease activity.³³

Among ROS, hydrogen peroxide (H₂O₂) plays a pivotal role in the onset and progression of vitiligo.³⁴ Nuclear transcription factor Nrf2 is thought to mainly regulate heme oxygenase-1 expression, which is involved in protecting human melanocytes against H₂O₂-induced oxidative stress.³⁵ Nrf2 regulates the expression of various antioxidant enzymes, including catalase, GPX and SOD, via the use of GSH as a substrate. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2-ARE) pathway is important in protection against oxidative stress-induced cellular injury, and its dysfunction can lead to oxidative stress and melanocyte injury.³⁶ It was recently demonstrated that narrowband ultraviolet (UV) B phototherapy, the well-known treatment of vitiligo, reduces erythrocyte MDA levels and increases GPX levels in patients with vitiligo.³⁷

Acne

SOD and GPX activities are decreased in leukocytes, whereas serum TBARS and MDA are increased, in patients with acne.³⁸ SOD, catalase, GSH, MDA, and adenosine deaminase levels are increased in scrapings of acne tissues.³⁹ Plasma levels of vitamin A and E are decreased in patients with acne.⁴⁰ Levels of squalene peroxides, which diminish GSH, are increased, whereas vitamin D levels are decreased, in the sebum of acne. Plasma vitamin E, vitamin A, and zinc levels were significantly reduced in acne patients, and a negative correlation between acne severity and vitamin E and zinc levels was noted.⁴¹

Among various antioxidants, the vitamin C precursor sodium ascorbyl phosphate, topical or oral zinc, and nicotinamide were proved effective for acne in several studies.⁴² Other antioxidants that demonstrated efficacy in acne include a multi-nutrient antioxidant capsule consisting of zinc, vitamin C, carotenoids, d-alpha-tocopherol acetate, chromium, selenium and vitamin E, as well as lactoferrin.⁴³

On the other hand, oral isotretinoin treatment for severe acne increases erythrocyte lipid peroxidation, GSH, and GPX and decreases serum paraoxonase-1 activity by increasing oxidative stress. This action was suggested to be a pathomechanism of the side effects of isotretinoin.⁴⁴

Rosacea

Inflammation is suggested to be associated with ROS produced by inflammatory cells, such as neutrophils in rosacea.⁴⁵ Serum peroxide and cutaneous ferritin levels are increased, whereas serum total antioxidative potential levels are decreased, in patients with rosacea.⁴⁶ Effective therapeutic agents for rosacea, including metronidazole, tetracyclines, azelaic acid and azithromycin, exhibit antioxidant activity.⁴⁷ Oral supplementation of zinc sulfate demonstrated conflicting results regarding the improvement of rosacea.⁴⁸

Chronic venous ulcer

Oxidative stress potentially results in disturbed wound healing.⁴⁹ Increases in the allantoin:uric acid percentage ratio (AUR) and 8-isoprostane levels are reported in chronic wounds.⁵⁰ Selenium, zinc, and iron levels as well as GPX activity are decreased, and ROS-elevated iron deposition and superoxide are increased.⁵¹ Increased activity of inducible cyclooxygenase-2 from macrophages and endothelial cells was noted.⁵² Total iron levels in chronic exudates are also increased,⁵³ along with the proteolytic activity of MMPs and serine proteases.⁵⁴ SOD, MDA, and NO levels are upregulated in valve tissues, thereby indicating increased oxidative stress.⁵⁵

UV-associated skin cancer and skin photoaging

ROS can cause DNA damage, which results in mutagenesis and carcinogenesis. Phytochemicals from plant compounds can prevent UV-induced carcinogenesis via their antioxidant function. These compounds also potentially modulate gene expression and signal transduction pathways. Black and green tea, grape seed proanthocyanidins, resveratrol, quercetin, apigenin, silymarin, curcumin, genistein, ascorbic acid and garlic derivatives inhibit or reduce tumorigenesis in murine models or cell lines.

UV induces the generation of ROS and lipid peroxidation products (TBARS) and the depletion of endogenous antioxidants. UV depletes GPX, ascorbate, GSH, SOD, catalase, alpha-tocopherol, and ubiquinol in the skin. Damage to antioxidant systems is more prominent in the epidermis than the dermis.⁵⁶ It is important to prevent damage to the skin with antioxidants before UV exposure. Antioxidants, including vitamin C, vitamin E, coenzyme Q10, lycopene, carotenoids, tretinoin, GSH, zinc, resveratrol, genistein, cocoa, selenium, and polypodium leucotomos, can exert photoprotective effects. Other antioxidants exhibiting photoprotective properties include melatonin, green tea, silymarin, soy isoflavones, lutein, and zeaxanthin.⁵⁷

Psoriasis

The imiquimod-induced mouse model of psoriasis exhibits an aberrant antioxidant system. Myeloperoxidase (MPO) and GSH/GSH disulfide (GSSG), one of oxidative stress marker levels are increased, and SOD activity and levels are decreased in mouse skin.⁵⁸ Cellular signaling pathways, such as mitogen-activated protein kinase/activator protein 1, NF-κB, and Janus kinase-signal transducers, as well as activators of transcription are redox sensitive and involved in the progression of psoriasis.⁵⁹ Dimethylfumarate upregulates GSH and NAD(P)H:quinone oxidoreductase 1 (NQO1) and activates the Nrf2 transcriptional pathway, thereby resulting in anti-inflammatory effects, such as the downregulation of cytokines and adhesion molecules.⁶⁰

Imiquimod-induced psoriatic dermatitis exhibits elevated levels of ROS; thus, properly elevated levels of ROS might prevent psoriasis through enhancing indoleamine 2,3-dioxygenase (IDO) expression and Treg function. Successful treatment of psoriasis via hyperbaric oxygen therapy and phototherapy could be attributed to the elevation of ROS levels, which enhances Treg function.⁶¹

Conclusion

Although it has been suggested that oxidative stress plays an important role in the development of numerous cutaneous diseases via various redox-sensitive pathways, conflicting results have been reported regarding the oxidant/antioxidant states in these diseases. This discordance can be explained by the following: (1) the innate levels in different tissue samples differ; (2) ROS can affect different complex signaling and biochemical pathways; and (3) oxidative stress can be the result of inflammation, not the cause. Conclusions supporting the efficacy of antioxidative treatments remain still elusive. But there have been many reports about effective antioxidant treatment for cutaneous disease, as well as conventional drugs that have antioxidant activity. Targeting oxidative stress may be an effective strategy for various skin diseases; thus, further studies are required to establish a framework for antioxidative therapeutic plans for each disease.

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