Melatonin is ubiquitously present in all animals and plants, where it exerts a variety of physiological activities thanks to its antioxidant properties and its key role as the first messenger of extracellular signaling functions. Most of the clinical studies on melatonin refer to its widespread oral use as a dietary supplement to improve sleep. A far smaller number of articles describe the clinical applications of topical melatonin to treat or prevent skin disorders by exploiting its antioxidant and anti-inflammatory activities. This review focuses on the clinical studies in which melatonin was applied on the skin as a photoprotective, anti-aging, or hair growth-promoting agent. The methodologies and results of such studies are discussed to provide an overall picture of the state of the art in this intriguing field of research. The clinical studies in which melatonin was applied on the skin before exposure to radiation (UV, sunlight, and high-energy beams) were all characterized by an appropriate design (randomized, double-blind, and placebo-controlled) and strongly support its clinical efficacy in preventing or reducing skin damage such as dermatitis, erythema, and sunburn. Most of the studies examined in this review do not provide a clear demonstration of the efficacy of topical melatonin as a skin anti-aging or as a hair growth-promoting agent owing to limitations in their design and/or to the use of melatonin combined with extra active ingredients, except for one trial that suggests a possible beneficial role of melatonin in treating some forms of alopecia in women. Further research efforts are required to reach definitive conclusions concerning the actual benefits of topical melatonin to counteract skin aging and hair loss.

The identification of natural remedies for the management of the skin aging process is an increasingly growing issue. In this context, ursolic acid (UA), a ubiquitous molecule, mainly contained in Annurca apple (AA) fruit, has demonstrated valuable cosmetic potential. To this end, in the current study, the AA oleolite (AAO, extract in sunflower oil containing 784.40 ± 7.579 µg/mL of UA) was evaluated to inhibit porcine elastase enzymatic reactions through a validated spectrophotometric method. AAO has shown a valuable capacity to contrast the elastase enzyme with a calculated IC₅₀ of 212.76 mg/mL, in comparison to UA (IC₅₀ of 135.24 μg/mL) pure molecules and quercetin (IC₅₀ of 72.47 μg/mL) which are used as positive controls. In this context and in view of the valuable antioxidant potential of AAO, its topical formulation with 2.5% (w/w) AAO was tested in a placebo-controlled, double-blind, two-arm clinical study on 40 volunteers. Our results indicated that after 28 days of treatment, a significant reduction of the nasolabial fold (−7.2 vs. baseline T0, p < 0.001) and forehead wrinkles (−5.3 vs. baseline T0, p < 0.001) were registered in combination with a valuable improvement of the viscoelastic skin parameters, where skin pliability/firmness (R₀) and gross elasticity (R₂) were significantly ameliorated (−13% vs. baseline T0, p < 0.001 for R₀ and +12% vs. baseline T0, p < 0.001 for R₂). Finally, considering the positive correlation between skin elasticity and hydration, the skin moisture was evaluated through the estimation of Trans epidermal water loss (TEWL) and skin conductance.

In recent years, there has been increasing interest in utilizing Traditional Chinese Medicine principles and natural bioactive compounds to combat age-related ailments and enhance longevity. A Cordyceps sinensis mycelium hydroethanolic extract (CsEx), which was standardized in cordycepin and adenosine using UHPLC-DAD, was investigated for its adaptogenic properties using in vitro assays and a double-blind, placebo-controlled clinical trial involving 40 subjects. The CsEx demonstrated activity at a concentration of 0.0006%, significantly increasing sirtuin expression (SirT1: +33%, SirT3: +10%, SirT6: +72%, vs. CTR, p < 0.05) and NAD+ synthesis in HaCat cells (+20% vs. CTR, p < 0.001). Moreover, the CsEx boosted ATP production by 68% in skin cells, correlating with higher skin energy values (+52.0% at D₂₈, p < 0.01) in the clinical trial. Additionally, CsEx notably reduced cytosolic reactive oxygen species (ROS) by 30% in HaCaT cells (p < 0.05) and enhanced collagen production both in vitro (+69% vs. CTR, p < 0.01) and in vivo (+10% vs. D0, p < 0.01), confirmed by ultrasound examination. Furthermore, CsEx’s stimulation of fibroblasts, coupled with its antioxidant and energizing properties, led to a significant reduction in wrinkles by 28.0% (D28, p < 0.001). This study underscores Cordyceps sinensis hydroethanolic extract’s potential in regulating skin cell energy metabolism and positively influencing the mechanisms associated with skin longevity control.

Although edible flowers have been historically principally used due to their visual appeal and smell, the world is discovering their value as innovative and natural sources of bioactive compounds. Cucurbita pepo L. (CpL), a plant from the Cucurbitaceae family, is widely cultivated for its edible fruits and flowers, which are rich in polyphenols and carotenoids—compounds known for their potent antioxidant and anti-inflammatory properties. Despite their potential, the use of CpL flowers for skin-related applications remains underexplored. This study aimed to comprehensively analyze CpL flower extract (CpLfe), focusing on its polyphenolic and carotenoid content using, for the first time, advanced UHPLC-Q-Orbitrap HRMS and HPLC-DAD analysis. CpLfe highlighted remarkable antioxidant activity according to the DPPH, ABTS, and FRAP tests. CpLfe showed significantly reduced intracellular ROS in HaCaT (23%, p < 0.05) and protected against UVB-induced damage by lowering MMP-1 expression. CpLfe also upregulated genes crucial for skin hydration (AQP3) and barrier function (CerS2, CerS4, and CerS6). A placebo-controlled, randomized clinical trial further validated CpLfe efficacy, demonstrating marked improvements in moisture retention, wrinkle reduction, and collagen production in women aged 35–55. These findings suggested that CpL flowers could be a source of bioactive compounds recovered from edible flowers able to improve the major skin aging and photoaging features.

This study explores the potential of Arbutus unedo L. pomace, a by-product of the food industry, as a natural ingredient for skincare applications. In Portugal, A. unedo L. fruits are traditionally used to produce “Aguardente de Medronho”, a spirit with a protected geographical indication. The distillation process generates pomace, comprising skins, pulp remnants, seeds, and residual alcohol rich in phenolic compounds, whose levels are significantly increased during distillation. In addition to their documented high antioxidant content, these residues also display notable antimicrobial properties. However, their potential benefits for skin health have not yet been explored. The methodology entailed the preparation of the pomace extract and a comprehensive analysis of its polyphenolic content and antioxidant capacity under laboratory conditions and in preclinical cellular models. The by-products demonstrated a high polyphenol content and potent antioxidant activity, comparable to vitamin C. Bioscreening on human skin models (i.e., dermal fibroblasts and keratinocytes) revealed their ability to reduce reactive oxygen species (ROS) formation under oxidative stress in skin cells, highlighting their potential to mitigate skin aging and damage caused by environmental pollutants. Moreover, bioscreens in vitro revealed a high safety profile, without any interference with cell viability at concentrations up to 100 µg/mL. These findings support the use of A. unedo L. pomace extract as a sustainable ingredient for the development of antioxidant-rich and eco-friendly cosmetic or dermatologic products.

Metabolites resulting from the bacterial fermentation of dietary fibers, such as short-chain fatty acids, especially butyrate, play important roles in maintaining gut health and regulating various biological effects in the skin. However, butyrate is underutilized due to its unpleasant odor. To circumvent this organoleptic unfavorable property, phenylalanine butyramide (PBA), a butyrate precursor, has been synthesized and is currently available on the market. We evaluated the inhibition of mushroom tyrosinase by butyrate and PBA through in vitro assays, finding IC₅₀ values of 34.7 mM and 120.3 mM, respectively. Docking calculations using a homology model of human tyrosinase identified a putative binding mode of PBA into the catalytic site. The anti-aging and anti-spot efficacy of topical PBA was evaluated in a randomized, double-blind, parallel-arm, placebo-controlled clinical trial involving 43 women affected by photo-damage. The results of this study showed that PBA significantly improved skin conditions compared to the placebo and was well tolerated. Specifically, PBA demonstrated strong skin depigmenting activity on both UV and brown spots (UV: −12.7% and −9.9%, Bs: −20.8% and −17.7% after 15 and 30 days, respectively, p < 0.001). Moreover, PBA brightened and lightened the skin (ITA°: +12% and 13% after 15 and 30 days, respectively, p < 0.001). Finally, PBA significantly improved skin elasticity (Ua/Uf: +12.4% and +32.3% after 15 and 30 days, respectively, p < 0.001) and firmness (Uf: −3.2% and −14.9% after 15 and 30 days, respectively, p < 0.01).