Beyond Circadian Rhythm: Melatonin as a Bio-Regulatory Molecule in Skin and Hair Aesthetics

Melatonin is a multifunctional hormone with diverse physiological roles, particularly in immune regulation and reproductive health. While primarily synthesized by the pineal gland in response to the circadian rhythm, melatonin is also produced in extrapineal tissues such as the placenta, gastrointestinal tract, and reproductive organs, highlighting its systemic significance. Beyond its role in sleep-wake cycle regulation, melatonin exhibits potent antioxidant, anti-inflammatory, and immunomodulatory properties, making it essential for maintaining cellular homeostasis and overall physiological stability. In the immune system, melatonin contributes to both innate and adaptive immunity by modulating cytokine production, reducing oxidative stress, and enhancing immune cell activity. It plays a protective role against infections and inflammatory diseases by suppressing pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) while promoting anti-inflammatory cytokines like interleukin-10 (IL-10). Additionally, melatonin influences immune tolerance, which is critical for preventing autoimmune responses and ensuring successful pregnancy. In females, melatonin improves oocyte quality, embryo development, and pregnancy outcomes by protecting ovarian follicles from oxidative damage, regulating steroidogenesis, and supporting placental function. Its role in fetal development is particularly significant, as it contributes to maternal-fetal circadian signaling, placental vascularization, and epigenetic modifications that influence gene expression. In men, melatonin contributes to spermatogenesis and improves sperm quality by boosting mitochondrial activity, decreasing oxidative stress, and safeguarding sperm DNA from damage. Additionally, it helps regulate hormone production in the testes, maintaining optimal reproductive health. Given its pleiotropic effects, melatonin holds substantial therapeutic potential for addressing immune dysfunction, reproductive disorders, and pregnancy complications. Future research should focus on clinical applications of melatonin supplementation in treating infertility, pregnancy-related complications, and immune-mediated diseases. Understanding the intricate relationship between melatonin, immunity, and reproduction may pave the way for innovative therapeutic strategies in both human and veterinary medicine. Melatonin is a multifunctional hormone with essential roles in immune regulation and reproductive health. Beyond its well-known function in circadian rhythm regulation, melatonin exerts potent antioxidant, anti-inflammatory, and immunomodulatory effects. It plays a critical role in maintaining immune homeostasis by reducing oxidative stress, modulating cytokine production, and enhancing immune cell function, thereby offering protection against infections and inflammatory disorders. In reproduction, melatonin influences key processes such as oocyte maturation, embryo development, and pregnancy maintenance. It supports fertility by improving ovarian function, regulating gonadotropin secretion, and protecting reproductive tissues from oxidative damage. Additionally, melatonin's involvement in placental function and fetal development highlights its significance in ensuring successful gestation. Given its widespread physiological effects, melatonin presents promising therapeutic potential for addressing immune-related and reproductive disorders. Future research exploring its clinical applications may lead to novel strategies for enhancing reproductive success and immune resilience in both human and veterinary medicine.

SummaryBackgroundSolar ultraviolet radiation (UVR) induces molecular and genetic changes in the skin, which result in skin cancer, photoageing and photosensitivity disorders. The use of sunscreens is advocated to prevent such photodamage; however, most formulations contain organic and inorganic UVR filters that are nonbiodegradable and can damage fragile marine ecosystems. Mycosporine‐like amino acids (MAAs) are natural UVR‐absorbing compounds that have evolved in marine species for protection against chronic UVR exposure in shallow‐water habitats.ObjectivesTo determine if palythine, a photostable model MAA, could offer protection against a range of UVR‐induced damage biomarkers that are important in skin cancer and photoageing.MethodsHaCaT human keratinocytes were used to assess the photoprotective potential of palythine using a number of end points including cell viability, DNA damage (nonspecific, cyclobutane pyrimidine dimers and oxidatively generated damage), gene expression changes (linked to inflammation, photoageing and oxidative stress) and oxidative stress. The antioxidant mechanism was investigated using chemical quenching and Nrf2 pathway activation assays.ResultsPalythine offered statistically significant protection (P < 0·005) against all end points tested even at extremely low concentrations (0·3% w/v). Additionally, palythine was found to be a potent antioxidant, reducing oxidatively generated stress, even when added after exposure.ConclusionsPalythine is an extremely effective multifunctional photoprotective molecule in vitro that has potential to be developed as a natural and biocompatible alternative to currently approved UVR filters.

The human genome is exposed to many different kinds of DNA-damaging agents. While most damage is detected and repaired through complex damage recognition and repair machineries, some damage has the potential to escape these mechanisms. Unrepaired DNA damage can give rise to alterations and mutations in the genome in an individual cell, which can result in malignant transformation, especially when critical genes are deregulated. In this study, we investigated gene expression changes in response to oxidative stress, gamma (gamma) radiation, and ultraviolet (UV) radiation and their potential implications in cancer development. Doses were selected for each of the three treatments, based on their ability to cause a similar G(1) checkpoint induction and slow down in early S-phase progression, as reflected by a comparable reduction in cyclin E-associated kinase activity of at least 75% in logarithmically growing human dermal diploid fibroblasts. To investigate gene expression changes, logarithmically growing dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 microM of tert-butyl hydroperoxide (t-butyl-OOH)), or UV radiation (UVC) (7.5 J/m(2)) and RNA was harvested 6 h after treatment. Gene expression was analyzed using the NIEHS Human ToxChip 2.0 with approximately 1901 cDNA clones representing known genes and expressed sequence tags (ESTs). We were able to identify common and distinct responses in dermal diploid fibroblasts to the three different stimuli used. Within our analysis, gene expression profiles in response to gamma radiation and oxidative stress appeared to be more similar than profiles expressed after UV radiation. Interestingly, equivalent cyclin E-associated kinase activity reduction with all the three treatments was associated with greater transcriptional changes after UV radiation than after gamma radiation and oxidative stress. While samples treated with UV radiation displayed modulations of their mitogen activated protein kinase (MAPK) pathway, gamma radiation had its major influence on cell-cycle progression in S-phase and mitosis. In addition, cell cultures from different individuals displayed significant differences in their gene expression responses to DNA damage.

The skin represents the body’s first barrier against the external environment and is therefore constantly exposed to potentially harmful agents such as pollution, ultraviolet radiation, microorganisms, and even physical damage (Woodby et al., 2020). Maintaining skin homeostasis is essential to support the overall homeostasis of the organism (Dehkordi et al., 2019). This organ, the largest in the human body, is composed of two principal layers: the epidermis (outer) and the dermis (inner). The epidermis can be further subdivided into five strata, arranged from the innermost to the outermost: basal layer, spinous layer, granular layer, lucid layer (present only in thick skin), and corneal layer. The epidermal cells are predominantly epithelial cells, or keratinocytes, except in the outermost layer, where they are referred to as corneocytes. This stratification reflects the progressive differentiation of keratinocytes until they reach the stratum corneum. The basal layer is characterized by intense mitotic activity, giving rise to new keratinocytes. The granular layer contains keratinocytes rich in keratohyalin granules, which are essential for maintaining the structural integrity, resilience, and hydration of the skin. The stratum corneum, composed of corneocytes, is distinguished by the absence of nuclei and organelles, consisting instead of keratin-rich cells. The dermis is composed of connective tissue and contains nerve endings and blood vessels that provide nutrition and oxygen to the overlying epithelial cells. It also harbors skin appendages, including glands and follicles (Junqueira &amp; Carneiro, 2022). It is now well established that inflammation and oxidative stress are interdependent processes, mutually reinforcing each other. Reactive species generated by oxidative stress trigger inflammatory responses, while inflammatory mediators can exacerbate oxidative stress. This feedback loop is referred to as oxi-inflammation (Farris et al., 2022; Valacchi et al., 2018). Oxi- inflammation promotes the formation of Advanced Glycation End-products (AGEs) (Sruthi &amp; Raghu, 2021). AGEs are molecules generated through non-enzymatic reactions in which glucose reacts with proteins, lipids, or nucleic acids—a process known as glycation (Singh, 2001). Glycation is harmful because it occurs spontaneously and uncontrollably, altering the structure of biomolecules and leading to multiple cellular impairments, including protein dysfunction, apoptosis, cellular senescence, mitochondrial disturbances, inflammation, and oxidative stress (Ansari &amp; Dash, 2012). Among the compounds capable of inducing oxidative stress and inflammatory processes, methylglyoxal (MGO) is of particular importance (Desai et al., 2010). MGO is an endogenous aldehyde present in all mammals, produced as a byproduct of glucose metabolism (Thornalley, 1996). Under physiological conditions, MGO is detoxified by the glyoxalase system, an enzymatic pathway responsible for its clearance. However, when cellular homeostasis is disrupted and this pathway becomes impaired, MGO can accumulate (Polykretis et al., 2020). The danger lies in its high reactivity, as MGO readily interacts with proteins, lipids, and nucleic acids, acting as a precursor of AGEs (Lo et al., 1994; Rabbani &amp; Thornalley, 2008). For this reason, MGO is frequently employed in laboratory models to induce cellular stress. For example, in order to evaluate the efficacy of antioxidant compounds, it is first necessary to induce oxidative stress in cells or tissues. Once stressed, the application of candidate compounds allows the assessment of their potential antioxidant and anti- inflammatory effects. In recent years, the search for natural compounds capable of modulating inflammation and oxidative stress has gained increasing attention. One such plant used in Brazilian folk medicine is Commiphora leptophloeos, commonly known as Imburana. This species is endemic to the Caatinga biome in northeastern Brazil (De Melo Alcântara et al., 2023). Extracts prepared from its leaves and bark can be tested for biological activity in models of inflamed or stressed tissues (Dantas- Medeiros et al., 2021). To reduce or replace the use of animal models or direct human subjects in clinical testing, ex vivo approaches have emerged as valuable alternatives. These involve the study of tissues removed from the body and maintained under controlled laboratory conditions while preserving much of their original physiological properties (Neil et al., 2022). In this study, ex vivo experiments were conducted using skin explants obtained from patients undergoing elective plastic surgery in Viçosa. The objective of this dissertation was twofold: first, to investigate the effects of methylglyoxal on skin tissue and establish a working concentration for laboratory use; second, to employ this concentration as a stress- inducing agent in order to evaluate the anti-inflammatory and antioxidant properties of Imburana leaf and bark extracts in an ex vivo skin model. Accordingly, the dissertation is divided into two chapters corresponding to separate articles. The first presents the experiments and results regarding methylglyoxal as a stress-inducing agent, while the second reports the effects of Imburana extracts on inflamed and stressed skin tissue using the concentration established in the first study. The articles are presented in different formats due to the publication requirements of the journals to which they were submitted. Keywords: oxiinflammation; skin; ex vivo; methylglyoxal; Commiphora leptophloeos

Emerging role of E4BP4/NFIL3 in metabolic homeostasis.

Cardiac Metallothionein Synthesis in Streptozotocin-Induced Diabetic Mice, and Its Protection against Diabetes-Induced Cardiac Injury

BackgroundGlioblastoma (GBM) is the most aggressive and common form of malignant brain tumor in adults, characterized by poor prognosis and limited treatment options. The molecular mechanisms underlying GBM pathogenesis and progression remain incompletely understood. Recent studies have suggested potential links between anesthesia-related genes and cancer progression, as well as the influence of circadian rhythm disruptions on tumor biology.MethodsIn this study, we conducted a comprehensive analysis using public databases to identify genes that are both related to anesthesia and circadian rhythms, and their association with GBM. We performed an analysis to identify differentially expressed genes (DEGs) in GBM compared to normal brain tissues. NFIL3, a gene implicated in both anesthesia response and circadian rhythm regulation, was identified among the DEGs. We further validated the differential expression of NFIL3 in GBM using RT-qPCR, western blotting, and immunohistochemistry.ResultsThirteen genes were found to be common between anesthesia-related and circadian rhythm gene datasets, with NFIL3 showing significant differential expression in GBM tissues. Our analysis revealed that higher expression of NFIL3 was significantly associated with worse overall survival in GBM patients. Experimental validation confirmed the overexpression of NFIL3 at both mRNA and protein levels in GBM samples compared to normal brain tissues.ConclusionsOur findings highlight NFIL3 as a potential biomarker and therapeutic target in GBM. The dual role of NFIL3 in anesthesia-related pathways and circadian rhythm regulation may provide new insights into its role in GBM pathogenesis and its impact on patient prognosis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12672-025-04271-8.

There is good epidemiological evidence that melanin in the skin protects against sunburn and skin cancer resulting from excessive ultraviolet radiation (UVR) exposure. Melanin is synthesized in a multistep biochemical pathway within specialized cell types in human skin called melanocytes situated in the epidermis. UV light causes an increase in melanocyte‐stimulating hormone (α‐MSH) receptor activity on cutaneous melanocytes (MC1‐R) that results in an increase of eumelanin within the epidermal melanocytes. Melanotan is a synthetic analogue of α‐MSH with potent melanogenic activity in animals and humans. We have recently completed a double‐blind, randomized controlled study in 80 healthy Caucasian adult subjects. A fixed dose of Melanotan (0.16 mg/kg/day) or placebo in a 3 : 1 ratio was given as three cycles of daily subcutaneous injections over 10 days each month for three consecutive months. Changes in skin pigmentation were quantified by serial skin reflectance measurements and UVR injury, as determined by ×3 MED exposure to broadband UVR, was assessed by measurement of apoptosis (sunburn cells). Results demonstrated that a highly significant increase in skin melanin was attained in all subjects on active treatment compared with placebo, and this was especially pronounced in subjects with lighter skin types (Fitzpatrick I and II; P &lt; 0.0001). In these latter subjects, significant sunburn protection was also determined. The ability of Melanotan to stimulate melanin production without the associated UV‐induced skin damage may prove a useful adjunct to current photoprotective strategies to stem the marked rise in skin cancer incidence. Currently, we are studying the therapeutic efficacy of a slow‐release implant of Melanotan in skin disorders such as polymorphic light eruption and psoriasis.

A hallmark of inherited retinal degenerative diseases such as retinitis pigmentosa (RP) is progressive structural and functional remodeling of the remaining retinal cells as photoreceptors degenerate. Extensive remodeling of the retina stands as a barrier for the successful implementation of strategies to restore vision. To understand the molecular basis of remodeling, we performed analyses of single-cell transcriptome data from adult zebrafish retina of wild type AB strain (WT) and a P23H mutant rhodopsin transgenic model of RP with continuous degeneration and regeneration. Retinas from both female and male fish were pooled to generate each library, combining data from both sexes. We provide a benchmark atlas of retinal cell type transcriptomes in zebrafish and insight into how each retinal cell type is affected in the P23H model. Oxidative stress is found throughout the retina, with increases in reliance on oxidative metabolism and glycolysis in the affected rods as well as cones, bipolar cells, and retinal ganglion cells. There is also transcriptional evidence for widespread synaptic remodeling and enhancement of glutamatergic transmission in the inner retina. Notably, changes in circadian rhythm regulation are detected in cones, bipolar cells, and retinal pigmented epithelium. We also identify the transcriptomic signatures of retinal progenitor cells and newly formed rods essential for the regenerative process. This comprehensive transcriptomic analysis provides a molecular road map to understand how the retina remodels in the context of chronic retinal degeneration with ongoing regeneration.

The present study aimed to investigate whether excessive oxidative stress production or reduction of antioxidative stress potential may occur following portal vein embolization (PVE) in an experimental animal nonalcoholic steatohepatitis (NASH) model. A NASH rabbit model (n=11) was established by feeding of a fat diet for 4 weeks, and a normal diet rabbit model (n=11) was prepared as a control. The oxidative status of NASH was examined by measuring derivatives of reactive oxygen metabolites (d-ROM) for oxidative stress and biological antioxidative potential (BAP) for antioxidative potential in the NASH model and normal group. Additionally, oxidative status of PVE after 2 weeks was assessed by measuring d-ROM and BAP in the NASH and normal liver models. Oxidative status in a PVE+NASH model was also detected. In the process of NASH creation (fat diet for 4 weeks), total cholesterol was increased in the NASH group (P<0.0001). In the NASH group, PVE induced an increase in serum aspartate transaminase (P=0.0318). At 4 weeks after initiation of the fat diet, a decrease in BAP was determined as statistically significant (P<0.0001). In normal liver, d-ROM production was stimulated in the Sham group after 2 weeks (P=0.0152), but BAP was not altered (P=0.6119). In NASH liver, d-ROM production was stimulated in PVE and Sham groups (P<0.0001 and P=0.0189, respectively), but BAP did not change (P>0.05). In conclusion, decrease of antioxidant potential may promote NASH progression. Additionally, PVE appeared to cause a surge in oxidative stress in NASH liver.

We describe highly reproducible methods for quantifying the erythema response of precisely selected areas (spots) of human skin to graded doses of ultraviolet radiation (UVR). These methods have permitted evaluation of the efficacy of protectors, such as sulforaphane from crucifers, that defend cells through induction of cytoprotective (phase 2) genes. Spots on the back were precisely located by opaque, adhesive, vinyl templates provided with 16 circular, 2.0 cm diameter occludable windows. Doses (100-800 mJ/cm(2)) of narrow-band (311 nm) UVR were administered, and the erythema index (a(*)) was measured with a chromometer on treated and control areas, before and after radiation. Daily variations in basal a(*) values of each spot were much smaller than the differences of a(*) values among spots of one individual, or those of corresponding spots among different individuals. The increments in erythema responses to UVR (Delta a(*)) were similar despite large variations of basal a(*) of spots. The most appropriate measure of UVR-evoked erythema is therefore the Delta a(*) value for each spot, which is an independent observational entity. Delta a(*) was proportional to UVR dose, and independent of spot location. To evaluate effectiveness of protectors against UVR damage we paired horizontally adjacent spots for treatment and controls. Vertical or random spot pairing did not provide significantly higher consistency. Protective efficacy against UVR erythema is appropriately expressed as percent reduction in Delta a(*) values upon treatment with inducers. The protection of skin against UVR damage can be quantified precisely from changes in erythema index (Delta a(*)) obtained with a chromometer.

The suprachiasmatic nucleus (SCN) in the anterior hypothalamus is the major circadian pacemaker in humans. Melatonin is a key hormone secreted by the pineal gland in response to darkness. Light-induced stimuli are transmitted along the retinohypothalamic tract to the SCN. Activation of the SCN inhibits the production of melatonin by the pineal gland through a complex neural pathway passing through the superior cervical ganglion. Accordingly, when light is unavailable, the pineal gland secretes melatonin. The circadian rhythm modulates sleep-wake cycles as well as many physiological functions of the endocrine system, including core body temperature, pulse rate, oxygen consumption, hormone levels, metabolism, and gastrointestinal function. In neurodegenerative disorders, the sleep-wake cycle is disrupted and circadian regulation is altered, which accelerates disease progression, further disrupting circadian regulation and setting up a vicious cycle. Melatonin plays a critical role in the regulation of circadian rhythms and is a multifunctional pleiotropic agent with broad neuroprotective effects in neurodegenerative disorders, viral or autoimmune diseases, and cancer. In this review, I discuss the neuroprotective functions of melatonin in circadian regulation and its roles in promoting anti-inflammatory activity, enhancing immune system functions, and preventing alterations in glucose metabolism and mitochondrial dysfunction in neurodegenerative disorders and autoimmune central nervous system diseases.

Melatonin, a hormone primarily synthesized by the pineal gland, is traditionally associated with the regulation of circadian rhythms. However, recent research has unveiled its broad spectrum of biological effects, positioning it as a valuable therapeutic agent in diverse health contexts. Known for its potent antioxidant and anti-inflammatory properties, melatonin plays a crucial role in maintaining homeostasis and protecting cellular integrity. This review explores melatonin’s therapeutic applications across multiple medical domains, including muscle health, metabolic disorders, chronic pain management, and cardiovascular health. In muscle health, melatonin facilitates muscle hypertrophy and regeneration by mitigating oxidative stress and enhancing the activity of satellite cells responsible for muscle repair. This action is particularly beneficial for individuals undergoing intense physical exertion, recovering from injuries, or combating age-related muscle. In metabolic disorders, such as type 2 diabetes, melatonin improves insulin sensitivity and reduces cellular oxidative damage, which supports beta-cell function and glucose regulation, potentially minimizing diabetes-related complications. Furthermore, in fibromyalgia - a condition marked by widespread pain and sleep disturbances - melatonin has demonstrated efficacy in alleviating pain and improving sleep quality, thus enhancing the overall quality of life for patients. In cardiovascular health, melatonin has shown promise in preventing and managing heart failure by reducing oxidative damage, modulating inflammatory pathways, and supporting endothelial function, which collectively contribute to improved cardiac health and reduced disease progression. This comprehensive review underscores melatonin’s emerging role as an integrative therapeutic agent in modern medicine.

Green tea is one of the most popular drinks consumed in the world. Important components contained in green tea and having antioxidant and anticarcinogenic properties are catechins - organic substances belonging to the class of polyphenolic compounds. Green tea contains 4 main catechins: (-)-epicatechin, (-)-epicatechin-3-gallate, (-)-epigallocatechin and (-)-epigallocatechin-3-gallate. This review summarizes the results of key studies, predominantly performed over the last 5 years, which provide evidence that catechins in green tea protect against ultraviolet radiation, can improve the quality of life of patients suffering from cancer, cardiovascular, neurodegenerative, viral, infectious diseases, obesity and a number of other pathologies, as well as serve as a measure for the prevention of these diseases in healthy individuals. The most potent catechin found in green tea has been shown to be (-)-epigallocatechin-3-gallate. The anticarcinogenic effects of (-)-epigallocatechin-3-gallate in the case of prostate cancer, breast cancer, colorectal cancer are presented. The powerful antioxidant activity of catechins can form the basis for the prevention of the development of infectious and viral diseases, as well as improve the quality of life of patients with metabolic syndrome and obesity. Thus, green tea is not only a tonic drink, but also an important tool for the prevention and treatment of human diseases, in the pathogenesis of which free radical oxidation and oxidative stress play an important role. The areas of practical application of green tea catechins can be the treatment of malignant tumors (during a course of chemotherapy or radiation therapy), the treatment of viral, infectious and cardiovascular diseases, skin protection from ultraviolet rays, etc.

Chapter 78 - Green Tea Polyphenols and Skin Protection: An Overview