The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging.

While primarily produced in the pineal gland, melatonin's influence goes beyond its well-known role in regulating sleep, nighttime metabolism, and circadian rhythms, in the field of chronobiology. A plethora of new data demonstrates melatonin to be a very powerful molecule, being a potent ROS/RNS scavenger with anti-inflammatory, immunoregulatory, and oncostatic properties. Melatonin and its metabolites exert multiple beneficial effects in cutaneous and systemic aging. This review is focused on the neuroprotective role of melatonin during aging. Melatonin has an anti-aging capacity, retarding the rate of healthy brain aging and the development of age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, etc. Melatonin, as well as its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), can reduce oxidative brain damage by shielding mitochondria from dysfunction during the aging process. Melatonin could also be implicated in the treatment of neurodegenerative conditions, by modifying their characteristic low-grade neuroinflammation. It can either prevent the initiation of inflammatory responses or attenuate the ongoing inflammation. Drawing on the current knowledge, this review discusses the potential benefits of melatonin supplementation in preventing and managing cognitive impairment and neurodegenerative diseases.

Environmental Air Pollutants Affecting Skin Functions with Systemic Implications.

The increase in air pollution worldwide represents an environmental risk factor that has global implications for the health of humans worldwide. The skin of billions of people is exposed to a mixture of harmful air pollutants, which can affect its physiology and are responsible for cutaneous damage. Some polycyclic aromatic hydrocarbons are photoreactive and could be activated by ultraviolet radiation (UVR). Therefore, such UVR exposure would enhance their deleterious effects on the skin. Air pollution also affects vitamin D synthesis by reducing UVB radiation, which is essential for the production of vitamin D3, tachysterol, and lumisterol derivatives. Ambient air pollutants, photopollution, blue-light pollution, and cigarette smoke compromise cutaneous structural integrity, can interact with human skin microbiota, and trigger or exacerbate a range of skin diseases through various mechanisms. Generally, air pollution elicits an oxidative stress response on the skin that can activate the inflammatory responses. The aryl hydrocarbon receptor (AhR) can act as a sensor for small molecules such as air pollutants and plays a crucial role in responses to (photo)pollution. On the other hand, targeting AhR/Nrf2 is emerging as a novel treatment option for air pollutants that induce or exacerbate inflammatory skin diseases. Therefore, AhR with downstream regulatory pathways would represent a crucial signaling system regulating the skin phenotype in a Yin and Yang fashion defined by the chemical nature of the activating factor and the cellular and tissue context.

Attenuation of Hypothyroidism-Induced Cognitive Impairment by Modulating Serotonin Mediation.

Thyroid hormones play an important role in the modeling of neural networks in the brain. Besides its metabolic effects, thyroid dysfunction, and hypothyroidism in particular, is frequently associated with cognitive decline and depressive-like behavior. The current study aimed to examine the changes in behavior, cognition, and memory in rats with propylthiouracil-induced overt hypothyroidism. The behavior and cognition were assessed using the open field test, T-maze, and novel object recognition test. We found significant differences in the behavioral patterns of the hypothyroid animals showing a reduction in locomotor activity, frequency of rearing, and impaired memory function compared to the euthyroid controls. As serotonin is an essential biomarker regulating cognition and mood, we tried to modulate the serotonin mediation in hypothyroid animals through tryptophan administration. Treatment with 5-hydroxy-tryptophan (5-OH-TRP) intraperitoneally for 10 days or directly into the hippocampus as a single injection led to attenuation of the hypothyroidism-induced cognitive and memory decline. A staggering amount of research is suggesting that the common denominators in the pathophysiology of depression and the behavior changes in hypothyroidism are the hippocampal complex and the distorted serotonin metabolism. In our study, it was observed a significant alleviation of cognitive impairment and an improvement of memory performance in hypothyroid rats after 5-OH-TRP administration. Current results are promising and may serve as groundwork for further investigation of functional and structural changes in the hippocampus during a hypothyroid state, and in particular, the effects of serotonin mediation in hypothyroid-associated depressive-like behavior.

Protective Role of Melatonin and Its Metabolites in Skin Aging.

The skin, being the largest organ in the human body, is exposed to the environment and suffers from both intrinsic and extrinsic aging factors. The skin aging process is characterized by several clinical features such as wrinkling, loss of elasticity, and rough-textured appearance. This complex process is accompanied with phenotypic and functional changes in cutaneous and immune cells, as well as structural and functional disturbances in extracellular matrix components such as collagens and elastin. Because skin health is considered one of the principal factors representing overall "well-being" and the perception of "health" in humans, several anti-aging strategies have recently been developed. Thus, while the fundamental mechanisms regarding skin aging are known, new substances should be considered for introduction into dermatological treatments. Herein, we describe melatonin and its metabolites as potential "aging neutralizers". Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. It regulates circadian rhythmicity and also exerts anti-oxidative, anti-inflammatory, immunomodulatory, and anti-tumor capacities. The intention of this review is to summarize changes within skin aging, research advances on the molecular mechanisms leading to these changes, and the impact of the melatoninergic anti-oxidative system controlled by melatonin and its metabolites, targeting the prevention or reversal of skin aging.

Immunopathogenesis and management of polymorphic light eruption.

Polymorphic light eruption (PLE) is the most common immunologically mediated photodermatosis, demonstrating many abnormalities caused by critical failure of ultraviolet (UV)-induced immunosuppression. The unique expression of antimicrobial peptides in PLE, which is most likely determined by alteration of microbiome components upon UV exposure, implicates their possible triggering role and pathogenic significance in the eruption. The review aims to clarify current knowledge regarding the immunological disturbances correlated with PLE that serve a base for better understanding of molecular pathogenesis of the disease and the development of new therapeutic strategies. Preventive treatment with broad-spectrum suncreens and sunscreens containing DNA repair enzymes, as well as natural photohardening with graduate exposure to sunlight in early spring could be sufficient in milder cases. Antioxidants and topical calcipotriol are promising approach for adjuvant prevention. Phototherapy, mainly with narrow band UVB rays, is more appropriate method in severe cases of the disease. The established treatment options for PLE include local and systemic glucocorticoids, systemic nonsedative antihistamines for itch relief, and rarely, immunosuppressive drugs in the refractory cases. Like medical photohardening, afamelanotide has the potential of photoprotection by inducing a melanization of the skin. Afamelanotide is believed to be a possible new treatment option for very severe and refractory cases of PLE. Targeting the main pruritogenic cytokine, IL-31, opens a new road for the development of novel therapeutic approaches to combat moderate and severe itching in cases of PLE with intense pruritus.

The Impact of Vitamin D on Skin Aging.

The active metabolites of vitamin D3 (D3) and lumisterol (L3) exert a variety of antiaging and photoprotective effects on the skin. These are achieved through immunomodulation and include anti-inflammatory actions, regulation of keratinocytes proliferation, and differentiation programs to build the epidermal barrier necessary for maintaining skin homeostasis. In addition, they induce antioxidative responses, inhibit DNA damage and induce DNA repair mechanisms to attenuate premature skin aging and cancerogenesis. The mechanism of action would involve interaction with multiple nuclear receptors including VDR, AhR, LXR, reverse agonism on RORα and -γ, and nongenomic actions through 1,25D3-MARRS receptor and interaction with the nongenomic binding site of the VDR. Therefore, active forms of vitamin D3 including its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 derivatives as well as L3 derivatives are promising agents for the prevention, attenuation, or treatment of premature skin aging. They could be administrated orally and/or topically. Other forms of parenteral application of vitamin D3 precursor should be considered to avoid its predominant metabolism to 25(OH)D3 that is not recognized by CYP11A1 enzyme. The efficacy of topically applied vitamin D3 and L3 derivatives needs further clinical evaluation in future trials.

Immunological Aspects of Skin Aging in Atopic Dermatitis.

The cutaneous immune response is important for the regulation of skin aging well as for the development of immune-mediated skin diseases. Aging of the human skin undergoes immunosenescence with immunological alterations and can be affected by environmental stressors and internal factors, thus leading to various epidermal barrier abnormalities. The dysfunctional epidermal barrier, immune dysregulation, and skin dysbiosis in the advanced age, together with the genetic factors, facilitate the late onset of atopic dermatitis (AD) in the elderly, whose cases have recently been on the rise. Controversial to the healthy aged skin, where overproduction of many cytokines is found, the levels of Th2/Th22 related cytokines inversely correlated with age in the skin of older AD patients. As opposed to an endogenously aged skin, the expression of the terminal differentiation markers significantly increases with age in AD. Despite the atenuated barrier disturbances in older AD patients, the aged skin carries an impairment associated with the aging process, which reflects the persistence of AD. The chronicity of AD in older patients might not directly affect skin aging but does not allow spontaneous remission. Thus, adult- and elderly subtypes of AD are considered as a lifelong disease.

Phase separation liquid-liquid extraction for the quantification of 8-iso-Prostaglandin F2 Alpha in human plasma by LC-MS/MS.

BACKGROUND: Reactive oxygen species (ROS) are produced in the body during normal metabolism by means of enzymes and non-enzymatic chemical reduction of molecular oxygen. In case of the prevalence of ROS formation over their elimination, highly reactive free radicals can be accumulated and can cause multiple damages to the biomolecules and cells. Determination of isoprostanes in biological matrices is most often used to register free radical damage and requires selective, sensitive and specific techniques. METHODS: This study presents the development and validation of the LC-MS/MS method for the determination of 8-iso-Prostaglandin F2α in human plasma utilising a modified liquid-liquid extraction procedure with phase separation. RESULTS: Modified sample preparation procedure assured higher extraction yield, clear separation of organic layer from the plasma water phase and protein precipitates, and better-purified product for instrumental analysis. Linearity was validated in the range 0.1-5.0 µg/L with R2 > 0.996; normalised matrix varied between 86.0% and 108.3%, accuracy ranged from 90.4 % to 113.9% and precision both within runs and between runs was less than 7%. With a run time of 10 min, a throughput of over 50 samples per working day could be performed. CONCLUSIONS: The method meets all the current industrial validation criteria and allows the accurate and precise determination of 8-iso-PGF2α in human plasma at diagnostically significant concentration range.

Noncalcemic Vitamin D Hydroxyderivatives Inhibit Human Oral Squamous Cell Carcinoma and Down-regulate Hedgehog and WNT/ß-Catenin Pathways.

BACKGROUND/AIM: The hormonally-active form of vitamin D, 1,25(OH)2D3, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D3 and 1,20(OH)2D3, have overlapping beneficial effects with 1,25(OH)2D3 without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D3 and 1,20(OH)2D3 exhibit antitumor effects against OSCC comparable to those of 1,25(OH)2D3 and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/ß-catenin signaling pathways. MATERIALS AND METHODS: Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting. RESULTS: 20(OH)D3 and 1,20(OH)2D3 inhibited the growth of CAL-27 and demonstrated inhibition of WNT/ß-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and ß-catenin. CONCLUSION: Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)2D3 Their activities against SHH and the WNT/ß-catenin pathways provide insight for a possible target for OSCC treatment.

Neuroendocrine Aspects of Skin Aging.

Skin aging is accompanied by a gradual loss of function, physiological integrity and the ability to cope with internal and external stressors. This is secondary to a combination of complex biological processes influenced by constitutive and environmental factors or by local and systemic pathologies. Skin aging and its phenotypic presentation are dependent on constitutive (genetic) and systemic factors. It can be accelerated by environmental stressors, such as ultraviolet radiation, pollutants and microbial insults. The skin's functions and its abilities to cope with external stressors are regulated by the cutaneous neuroendocrine systems encompassing the regulated and coordinated production of neuropeptides, neurohormones, neurotransmitters and hormones, including steroids and secosteroids. These will induce/stimulate downstream signaling through activation of corresponding receptors. These pathways and corresponding coordinated responses to the stressors decay with age or undergo pathological malfunctions. This affects the overall skin phenotype and epidermal, dermal, hypodermal and adnexal functions. We propose that skin aging can be attenuated or its phenotypic presentation reversed by the topical use of selected factors with local neurohormonal activities targeting specific receptors or enzymes. Some of our favorite factors include melatonin and its metabolites, noncalcemic secosteroids and lumisterol derivatives, because of their low toxicity and their desirable local phenotypic effects.

Does hypothyroidism augment sun-induced skin damage?

OBJECTIVES: We investigated the mutual effects of overt hypothyroidism and prolonged sunlight exposure on free radical accumulation and oxidative skin damage. METHODS: Free radical accumulation was evaluated by monitoring the transformation of 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) into MTT-formazan. The pro-oxidant enzymes xanthine oxidase (XO) and NADPH-diaphorase were measured in the skin. XO activity was estimated based on the yield of uric acid, while NADPH-diaphorase reactivity was monitored histochemically as an indirect marker of nitric oxide synthase and nitric oxide activity. Cellular damage was determined by malondialdehyde formation, a marker for lipid peroxidation. RESULTS: In the skin of both euthyroid and hypothyroid animals, solar simulated ultraviolet irradiance increased the activity of XO and the NADPHdiaphorase reactivity as a protective response to formation of free radicals, such as reactive oxygen or nitrogen species. These pro-oxidant enzymes diminished in hypothyroid rats. Accumulation of the same amount of free radicals led to similar peroxidation in both hypothyroid and irradiated euthyroid rats. Hypothyroid skin after UV-exposure showed even greater lipid peroxidation. DISCUSSION: The hypothyroid state could be a risk factor for enhanced oxidative skin damage in chronic photo-exposed skin due to oxidative stress. The lipid peroxidation is one of the major pathways by which photo-oxidative stress promotes photocarcinogenesis and photo-aging.

Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis.

Osteoporosis is a common age-related disorder and causes acute and long-term disability and economic cost. Many factors influence the accumulation of bone minerals, including heredity, diet, physical activity, gender, endocrine functions, and risk factors such as alcohol, drug abuse, some pharmacological drugs or cigarette smoking. The pathology of bone development during intrauterine life is a factor for osteoporosis. Moreover, the placental transfer of nutrients plays an important role in the building of bones of fetuses. The importance of maternal calcium intake and vitamin D status are highlighted in this review. Various environmental factors including nutrition state or maternal stress may affect the epigenetic state of a number of genes during fetal development of bones. Histone modifications as histone hypomethylation, histone hypermethylation, hypoacetylation, etc. are involved in chromatin remodeling, known to contribute to the epigenetic landscape of chromosomes, and play roles in both fetal bone development and osteoporosis. This review will give an overview of epigenetic modulation of bone development and placental transfer of nutrients. In addition, the data from animal and human studies support the role of epigenetic modulation of calcium and vitamin D in the pathogenesis of osteoporosis. We review the evidence suggesting that various genes are involved in regulation of osteoclast formation and differentiation by osteoblasts and stem cells. Epigenetic changes in growth factors as well as cytokines play a rol in fetal bone development. On balance, the data suggest that there is a link between epigenetic changes in placental transfer of nutrients, including calcium and vitamin D, abnormal intrauterine bone development and pathogenesis of osteoporosis.

Role of matriptase and proteinase-activated receptor-2 in nonmelanoma skin cancer.

Matriptase (membrane-type serine proteinase) was reported to play a role in nonmelanoma skin cancer progression. Moreover, it was shown to stimulate proteinase-activated receptor-2 (PAR(2)) in vitro. Hepatocyte growth factor activator inhibitor-1 (HAI-1), the matriptase inhibitor, is an important regulator of enzyme activity. Therefore, the aim of this study was to elucidate the putative role of matriptase, HAI-1, and PAR(2) in normal human skin, as well as in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). In normal human epidermis, PAR(2) colocalized with matriptase and HAI-1. Immunoreactivity of all proteins was found to be diminished in BCCs. Likewise, PAR(2) immunoreactivity was significantly decreased, whereas matriptase immunoreactivity was enhanced with SCC progression. We could also show that matriptase was complexed to HAI-1 in normal human skin, whereas in SCCs, the enzyme was present in an unassociated form. Both a specific peptide agonist for PAR(2) and the proteinase domain of matriptase were able to induce intracellular calcium mobilization and inhibition of proliferation in cultured HaCaT keratinocytes. In conclusion, our results suggest that PAR(2) is a substrate for matriptase in human skin in vivo. Deregulation of these proteins delineates SCC progression.

Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases.

Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR2 on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR2 in vitro. PAR2 cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR2 signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR2. We could also show the coexpression of KLK14 and PAR2 receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR2 activation in the epidermis and thereby in PAR2-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR2 activation in vivo remains to be elucidated.

Severe bacterial infections of the skin: uncommon presentations.

Although most bacterial infections of the skin prove to be minor in nature, a few such dermatologic entities are significant, to the point of even being fatal. Their course can be extremely rapid and can lead to dreadful complications. The mortality rate is usually up to 30% to 50% and depends upon the type of infection, underlying disease, and immune status. Patients suffering them usually need to be hospitalized, sometimes in intensive care or burn units. They should be treated systemically with appropriate antimicrobial therapy plus aggressive supportive care. The two life-threatening skin infections which are most commonly experienced are toxin-mediated staphylococcal and streptococcal disorders; one could overlap the other. Several other related entities will also be discussed.