Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo

Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent.     

Aging‐like skin changes in metabolic syndrome model mice are mediated by mineralocorticoid receptor signaling

Aging is accelerated, at least in part, by pathological condition such as metabolic syndrome (MetS), and various molecular pathways such as oxidative stress are common mediators of aging and MetS. We previously developed the aging‐like skin model by single ultraviolet (UV) irradiation on the MetS model mice. Recent studies revealed that mineralocorticoid receptor (MR) signaling plays a pivotal role for various tissue inflammation and damages in MetS. Although previous studies reported that MR is expressed in the skin and that overexpression of MR in the skin resulted in the skin atrophy, the physiological or pathological functions of MR in the skin are not fully elucidated. Here, we show the involvement of MR signaling in the aging‐like skin changes in our own model. Elevations of oxidative stress and inflammation markers were observed in the MetS mice, and the UV‐evoked aging‐like skin damages were attenuated by topical antioxidant. MR expression was higher in the MetS mouse skin, and notably, expression of its effecter gene Sgk1 was significantly upregulated in the aging‐like skin in the UV‐irradiated MetS mice. Furthermore, topical application of MR antagonist spironolactone suppressed Sgk1 expression, oxidative stress, inflammation, and the aging‐like changes in the skin. The 2‐week UV onto the non‐MetS mice, the more usual photoaging model, resulted in the skin damages mostly equivalent to the MetS mice with single UV, but they were not associated with upregulation of MR signaling. Our studies suggested an unexpected role of MR signaling in the skin aging in MetS status.     

Photoprotection by antioxidants against UVB-radiation-induced damage in pig skin organ culture

Topically applied antioxidants constitute an important group of protective agents against skin damage induced by ultraviolet radiation. The current study was performed to investigate whether a recently developed ex vivo pig skin model was suitable for short-term studies of the mechanism(s) of UVB-radiation-induced skin damage; the protective effect of topical application of alpha-tocopherol, l-ascorbic acid, alpha-lipoic acid, glutathione ethylester and N-acetylcysteine was tested. Increasing doses of the antioxidants were applied topically on ex vivo pig skin explants and allowed to penetrate for 60 min. Epidermal antioxidant bioavailability was measured before and 60 min after exposure to an ultraviolet B (UVB) radiation of 7.5 kJ/m2. Cell viability (trypan blue dye exclusion) and apoptosis were measured 48 h later in isolated keratinocytes. UVB-radiation-induced epidermal lipid peroxidation was determined immediately after exposure of the skin to a UVB dose of 28 kJ/m2. All antioxidants tested became bioavailable in pig skin epidermis, and none of them were depleted after UVB-radiation exposure. Increasing doses of the antioxidants tested decreased UVB-radiation-induced cell death and apoptosis. The highest doses of antioxidants prevented UVB-radiation-induced lipid peroxidation; alpha-lipoic acid only tended to decrease lipid peroxidation. In conclusion, a single topical dose of the above antioxidants on ex vivo pig skin can reduce UVB-radiation-induced oxidative stress and lipid peroxidation and thereby reduce apoptotic stimuli and cell death. Furthermore, the ex vivo pig skin model was a useful tool for testing compounds for their antioxidant activity.     

Bioactive compounds from natural resources against skin aging

Skin aging involves degradation of extracellular matrix (ECM) in both the epidermal and dermal layers, it leaves visible signs on the surface of skin and the physical properties of the skin are modified. Chronological aging is due to passage of time, whereas premature aging occurred due to some environmental factors on skin produces visible signs such as irregular dryness, dark/light pigmentation, sallowness, severe atrophy, telangiectases, premalignant lesions, laxity, leathery appearance and deep wrinkling. There are several synthetic skincare cosmetics existing in the market to treat premature aging and the most common adverse reactions of those include allergic contact dermatitis, irritant contact dermatitis, phototoxic and photo-allergic reactions. Recent trends in anti-aging research projected the use of natural products derived from ancient era after scientific validation. Ample varieties of phytomolecules such as aloin, ginsenoside, curcumin, epicatechin, asiaticoside, ziyuglycoside I, magnolol, gallic acid, hydroxychavicol, hydroxycinnamic acids, hydroxybenzoic acids, etc. scavenges free radicals from skin cells, prevent trans-epidermal water loss, include a sun protection factor (SPF) of 15 or higher contribute to protect skin from wrinkles, leading to glowing and healthy younger skin. Present era of treating aging skin has become technologically more invasive; but herbal products including botanicals are still relevant and combining them with molecular techniques outlined throughout this review will help to maximize the results and maintain the desired anti-skin aging benefits.     

Marine algae as attractive source to skin care

As the largest organ in the human body, the skin has multiple functions of which one of the most important is the protection against various harmful stressors. The keratinised stratified epidermis and an underlying thick layer of collagen-rich dermal connective tissues are important components of the skin. The environmental stressors such as ultraviolet radiation (UVR) and pollution increase the levels of reactive oxygen species (ROS), contributing to clinical manifestations such as wrinkle formation and skin aging. Skin aging is related to the reduction of collagen production and decrease of several enzymatic activities including matrix metalloproteinases (MMPs), which degrade collagen structure in the dermis; and tissue inhibitor of metalloproteinases (TIMPs), which inhibit the action of MMPs. In addition to alterations of DNA, signal transduction pathways, immunology, UVR, and pollution activate cell surface receptors of keratinocytes and fibroblasts in the skin. This action leads to a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis. Therefore, an efficient antioxidants strategy is of major importance in dermis and epidermis layers. Marine resources have been recognised for their biologically active substances. Among these, marine algae are rich-sources of metabolites, which can be used to fight against oxidative stress and hence skin aging. These metabolites include, among others, mycosporine-like amino acids (MAAs), polysaccharides, sulphated polysaccharides, glucosyl glycerols, pigments, and polyphenols. This paper reviews the role of oxidative processes in skin damage and the action of the compounds from algae on the physiological processes to maintain skin health.     

Small molecular antioxidants effectively protect from PUVA-induced oxidative stress responses underlying fibroblast senescence and photoaging

Exposure of human fibroblasts to 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA) results in stress-induced cellular senescence in fibroblasts. We here studied the role of the antioxidant defense system in the accumulation of reactive oxygen species (ROS) and the effect of the antioxidants alpha-tocopherol, N-acetylcysteine, and alpha-lipoic acid on PUVA-induced cellular senescence. PUVA treatment induced an immediate and increasing generation of intracellular ROS. Supplementation of PUVA-treated fibroblasts with alpha-tocopherol (alpha-Toc), N-acetylcysteine (NAC), or alpha-lipoic acid (alpha-LA) abrogated the increased ROS generation and rescued fibroblasts from the ROS-dependent changes into the cellular senescence phenotype, such as cytoplasmic enlargement, enhanced expression of senescence-associated-beta-galactosidase and matrix-metalloproteinase-1, hallmarks of photoaging and intrinsic aging. PUVA treatment disrupted the integrity of cellular membranes and impaired homeostasis and function of the cellular antioxidant system with a significant decrease in glutathione and hydrogen peroxide-detoxifying enzymes activities. Supplementation with NAC, alpha-LA, and alpha-Toc counteracted these changes. Our data provide causal evidence that (i) oxidative stress due to an imbalance in the overall cellular antioxidant capacity contributes to the induction and maintenance of the PUVA-induced fibroblast senescence and that (ii) low molecular antioxidants protect effectively against these deleterious alterations.     

Antiaging Action of Caloric Restriction: Endocrine and Metabolic Aspects

Restricting the energy intake of mice and rats slows the rate of actuarial aging, delays or prevents most age-associated disease processes, and maintains physiological processes in a youthful state at advanced ages. This manipulation is effective when initiated in young animals or in adult life. Although body fat is decreased by this reduction in energy intake, the reduction in body fat is not causally related to the antiaging action. Nor does this reduction in energy intake slow the aging processes by decreasing the metabolic rate, but it may do so by altering the characteristics of fuel use. Another possible mechanism underlying the antiaging action is the general protection restriction of energy intake provides against harmful agents, an action which may be the result of an alteration in adrenal glucocorticoid physiology.     

Natural phenolics in the prevention of UV-induced skin damage. A review

UV skin exposure induces extensive generation of reactive oxygen species (ROS). These can react with DNA, proteins, fatty acids and saccharides causing oxidative damage. Such injuries result in a number of harmful effects: disturbed cell metabolism, morphological and ultrastructural changes, attack on the regulation pathways and, alterations in the differentiation, proliferation and apoptosis of skin cells. These processes can lead to photoaging and skin cancer development. One approach to protecting human skin against the harmful effects of UV irradiation is to use antioxidants as photoprotectives. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. In this review, we strive to summarize the findings of studies performed to date, regarding the photoprotective effects of plant phenolics on the skin damage induced by UV radiation.     

Unveiling the mystery of Riehl's melanosis: An update from pathogenesis,diagnosis to treatment

Riehl's melanosis is a hyperpigmentation disorder that has a significant psychological and social impact on individuals. In the past 10 years, new categories have been developed, raising questions about how to classify Riehl's melanosis. The mechanism of this disease remains unclear, although the type IV hypersensitivity response caused by allergic sensitization, as well as genetic, ultraviolet radiation, and autoimmune factors, is to blame. Clinical manifestation, dermoscopy, reflectance confocal microscopy, patch/photopatch testing, histopathology, and a novel multimodality skin imaging system have been used for the diagnosis. A variety of therapies including topical skin-lightening agents, oral tranexamic acid, glycyrrhizin compound, chemical peels, and lasers and light therapies (intense pulsed light, 1064-nm Q-Switched Nd: YAG laser, 755-nm PicoWay laser, nonablative 1927-nm fractional thulium fiber laser, new pulsed-type microneedling radiofrequency), with improved effectiveness. The latest findings on possible biomarkers and their relationship to other autoimmune diseases were also summarized.     

Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes

Ultraviolet (UV) irradiation rapidly increases tyrosine phosphorylation (i.e. activates) of epidermal growth factor receptors (EGFR) in human skin. EGFR-dependent signaling pathways drive increased expression of matrix metalloproteinases, whose actions fragment collagen and elastin fibers, the primary structural protein components in skin connective tissue. Connective tissue fragmentation, which results from chronic exposure to solar UV irradiation, is a major determinant of premature skin aging (photoaging). UV irradiation generates reactive oxygen species, which readily react with conserved cysteine residues in the active site of protein-tyrosine phosphatases (PTP). We report here that EGFR activation by UV irradiation results from oxidative inhibition of receptor type PTP-kappa (RPTP-kappa). RPTP-kappa directly counters intrinsic EGFR tyrosine kinase activity, thereby maintaining EGFR in an inactive state. Reversible, oxidative inactivation of RPTP-kappa activity by UV irradiation shifts the kinase-phosphatase balance in favor of EGFR activation. These data delineate a novel mechanism of EGFR regulation and identify RPTP-kappa as a key molecular target for antioxidant protection against skin aging.     

Skin aging caused by intrinsic or extrinsic processes characterized with functional proteomics

The skin provides protection against environmental stress. However, intrinsic and extrinsic aging causes significant alteration to skin structure and components, which subsequently impairs molecular characteristics and biochemical processes. Here, we have conducted an immunohistological investigation and established the proteome profiles on nude mice skin to verify the specific responses during aging caused by different factors. Our results showed that UVB‐elicited aging results in upregulation of proliferating cell nuclear antigen and strong oxidative damage in DNA, whereas chronological aging abolished epidermal cell growth and increased the expression of caspase‐14, as well as protein carbonylation. Network analysis indicated that the programmed skin aging activated the ubiquitin system and triggered obvious downregulation of 14‐3‐3 sigma, which might accelerate the loss of cell growth capacity. On the other hand, UVB stimulation enhanced inflammation and the risk of skin carcinogenesis. Collectively, functional proteomics could provide large‐scale investigation of the potent proteins and molecules that play important roles in skin subjected to both intrinsic and extrinsic aging.     

Dietary restriction and longevity extension as a manifestation of Hormesis

Restricting the food intake of rats and mice to 60% of ad libitum intake has been shown to significantly slow their aging processes and markedly extend length of life. Evidence is presented that indicates the antiaging action of this dietary restriction is a manifestation of hormesis and acts by enabling the animal to cope with stressors, including the low‐intensity, long‐term intrinsic and extrinsic stressors conjectured to cause aging. A hypothesis is offered for the evolutionarily adaptive basis of the antiaging action of dietary restriction: It proposes that this antiaging action is a byproduct of the evolution of mechanisms that enabled animals living in the wild to survive unpredictable and relatively brief periods of food scarcity. Likely proximate mechanisms of antiaging action of dietary restriction are considered. Enhancement of the stress response genes, particularly the heat shock protein genes, appears to be importantly involved. Evidence indicates that moderate hyperadrenocorticism also plays a significant role. These proximate mechanisms may well be major players in other examples of hormesis.     

Protein, lipid, and DNA radicals to measure skin UVA damage and modulation by melanin

Afro-Caribbeans have a lower incidence of skin cancer than Caucasians, but the effectiveness of melanin as a photoprotective pigment is debated. We investigated the UVA and solar irradiation of ex vivo human skin and DMPO using electron spin resonance spectroscopy, to determine whether pigmented skin is protected by melanin against free radical damage. Initial ascorbate radicals in Caucasian skin were superseded by lipid and/or protein radical adducts with isotropic (a(H)=1.8 mT) and anisotropic spectra comparable to spectra in irradiated pig fat (a(H)=1.9 mT) and BSA. DNA carbon-centered radical adducts (a(H)=2.3 mT) and a broad singlet were detected in genomic DNA/melanin but were not distinguishable in irradiated Caucasian skin. Protein and lipid radicals (n=6 in Caucasian skin) were minimal in Afro-Caribbean skin (n=4) and intermediate skin pigmentations were variable (n=3). In irradiated Afro-Caribbean skin a shoulder to the melanin radical (also in UVA-irradiated pigmented melanoma cells and genomic DNA/melanin and intrinsic to pheomelanin) was detected. In this sample group, protein (but not lipid) radical adducts decreased directly with pigmentation. ESR/spin trapping methodology has potential for screening skin susceptibility to aging and cancer-related radical damage and for measuring protection afforded by melanin, sunscreens, and antiaging creams.     

Gene expression‐based drug repurposing to target aging

Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.     

Facial resurfacing in xeroderma pigmentosum with chemical peeling

We describe our experience with two patients with xeroderma pigmentosum who underwent multiple trichloroacetic acid chemical peels. Trichloroacetic acid and phenol were used in one case. Until now numerous treatment modalities have been reported. Deep chemical peeling has not been reported before in patients with xeroderma pigmentosum. Chemical peeling is a simple procedure with less associated morbidity.     

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin

The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.     

Melasma--updated treatments

Melasma is a common, acquired facial skin disorder, mostly involving sun-exposed areas like cheeks, forehead and upper lip. Melasma occurs in both sexes, although almost 90 percent of the affected are women. It is more common in darker skin types (Fitzpatrick skin types IV to VI) especially Hispanics/Latinos, Asians and African-Americans. The onset of the melasma is at puberty or later, with exception of darker skin types, who tend to develop this problem in the first decade of life. The etiology is still unknown, although there are a number of triggering factors related to the onset of melasma. The most important are sun-exposure and genetic factors in both sexes, while hormonal activity has more important role in females. In addition, stress and some cosmetic products and drugs containing phototoxic agents can cause outbreaks of this condition. Melasma should be treated using monotherapies or combination of therapy, mainly fixed triple or dual combinations containing hydroquinone, tretinoin, corticosteroids or azelaic acid. Modified Kligman's formula is also very effective. Above mentioned therapy regimens in combination with UVA and UVB blocking sunscreens are mostly effective in epidermal melasma. Discontinuation of the use of birth control pills, scented cosmetic products, and phototoxic drugs coupled with UV protection are also benefitial in clearing of melasma. Alternative treatment including chemical peels and glicolic acid, seem to have the best result as a second line treatment after bleaching creams. Laser treatments show limited efficacy and should rarely be used in the treatment of melasma. Combining topical agents like hydroquinone, tretinoin and a corticosteroid in addition to sun avoidance, regular use of sunscreen throughout the year and patient education is the best treatment in this difficult to treat condition.