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Antiaging efficacy of melatonin-based day and night creams: A randomized, split-face, assessor-blinded proof-of-concept trial

January 2018
Clinical, Cosmetic and Investigational Dermatology Volume 11:51-57

DOI:10.2147/CCID.S153905

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CC BY-NC 4.0

Authors:

Massimo Milani

Cantabria Labs Difa Cooper

Adele Sparavigna

Derming

Background Skin is a complete and independent melatoninergic system. At the skin level, melatonin (Mel) acts as a relevant antioxidant and cytoprotective substance. Topical application of Mel is considered meaningful, since it can easily penetrate the stratum corneum. Exogenous Mel can be expected to represent a potent antioxidative defense system against skin aging mechanisms. Day and night creams containing Mel, carried in lipospheres (Melatosphere™), have been developed (Nutriage SPF 30 day cream and Nutriage night cream). Study aim The aim of this study was to evaluate the efficacy of a Mel-based cream as antiaging treatment. Subjects and methods In a randomized, split-face, assessor-blinded, prospective 3-month study, 22 women (mean age 55 years) with moderate–severe skin aging were enrolled (clinical trial registration number: NCT03276897). Study products were applied in the morning (Nutriage day cream) and evening (Nutriage night cream) on the right or left side of the face. Primary outcomes were: 1) clinical evaluation of wrinkles’ grade (crow’s feet and nasolabial folds), surface microrelief, skin tonicity (resistance to pinching and traction, recovery after pinching) and skin dryness and 2) instrumental evaluation of skin roughness and 3D photographic documentation (Vectra H1 images system). Assessments of both clinical and instrumental evaluations were performed at baseline and after 1, 2 and 3 months of treatment by an investigator unaware of treatment allocation. Results All the subjects completed the study. Crow’s feet was reduced significantly (p=0.05) by −15% with the creams in comparison with the non-treated side after 3 months. At the end of the study, surface microrelief (−26.5%), skin profilometry (−13%), skin tonicity (+30%) and skin dryness (−59.5%) significantly improved with active treatment. Both products were well tolerated. Conclusion In women with skin aging, Mel-based creams improved significantly skin tonicity and skin hydration with a significant reduction in skin roughness, supporting the skin antiaging effect of this molecule applied topically.

Evolution of skin parameters and treatment. Notes: (A) Skin dryness evaluation (score from 0: very hydrated to 5: very dry; *p=0.001 in comparison with baseline, Wilcoxon test; **p=0.01 in comparison with the control side; Mann-Whitney U test). (B) Skin tonicity evaluation: resistance to traction (score from 0: very relevant to 4: very weak; *p=0.05 in comparison with baseline, Wilcoxon test; **p=0.05 in comparison with the control side, Mann-Whitney U test). (C) Skin tonicity evaluation: recovery after pinching (score from 0: very relevant to 4: very weak; *p=0.05 in comparison with baseline, Wilcoxon test; **p=0.05 in comparison with the control side, Mann-Whitney U test). Abbreviation: Mel, melatonin.

…

Evaluation of skin parameters. Notes: The Spidermig™ graph. Black line: baseline values; red line: one month application of melatonin (Mel)-products; green line: two-month application of Mel products; blue line: three-month application of Mel-products.

…

ectra 3D images. Notes: Subject 1: (A) baseline and (B) after 3 months of active treatment (active products were applied on the left side). Subject 2: (C) baseline and (D) after 3 months of active treatment (active products were applied on the right side).

…

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Clinical, Cosmetic and Investigational Dermatology 2018:11 51–57

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CLINICAL TRIAL REPORT

open access to scientiﬁc and medical research

Open Access Full Text Article

http://dx.doi.org/10.2147/CCID.S153905

Antiaging efcacy of melatonin-based day and

night creams: a randomized, split-face,

assessor-blinded proof-of-concept trial

Massimo Milani1

Adele Sparavigna2

1Medical Department, Cantabria Labs

Difa Cooper, Caronno Pertusella,

2Derming, Clinical Research and

Bioengineering Institute, Milan, Italy

Background: Skin is a complete and independent melatoninergic system. At the skin level,

melatonin (Mel) acts as a relevant antioxidant and cytoprotective substance. Topical application

of Mel is considered meaningful, since it can easily penetrate the stratum corneum. Exogenous

Mel can be expected to represent a potent antioxidative defense system against skin aging

mechanisms. Day and night creams containing Mel, carried in lipospheres (Melatosphere™),

have been developed (Nutriage SPF 30 day cream and Nutriage night cream).

Study aim: The aim of this study was to evaluate the efﬁcacy of a Mel-based cream as antiag-

ing treatment.

Subjects and methods: In a randomized, split-face, assessor-blinded, prospective 3-month

study, 22 women (mean age 55 years) with moderate–severe skin aging were enrolled (clinical trial

registration number: NCT03276897). Study products were applied in the morning (Nutriage day

cream) and evening (Nutriage night cream) on the right or left side of the face. Primary outcomes

were: 1) clinical evaluation of wrinkles’ grade (crow’s feet and nasolabial folds), surface microre-

lief, skin tonicity (resistance to pinching and traction, recovery after pinching) and skin dryness

and 2) instrumental evaluation of skin roughness and 3D photographic documentation (Vectra

H1 images system). Assessments of both clinical and instrumental evaluations were performed at

baseline and after 1, 2 and 3 months of treatment by an investigator unaware of treatment allocation.

Results: All the subjects completed the study. Crow’s feet was reduced signiﬁcantly (p=0.05)

by –15% with the creams in comparison with the non-treated side after 3 months. At the end

of the study, surface microrelief (–26.5%), skin proﬁlometry (–13%), skin tonicity (+30%)

and skin dryness (–59.5%) signiﬁcantly improved with active treatment. Both products were

well tolerated.

Conclusion: In women with skin aging, Mel-based creams improved signiﬁcantly skin tonicity

and skin hydration with a signiﬁcant reduction in skin roughness, supporting the skin antiaging

effect of this molecule applied topically.

Keywords: melatonin, skin aging, assessor-blinded trial

Introduction

Skin is a complete and independent melatoninergic system.1,2 Skin can synthesize

melatonin (Mel), and skin cells express melatonin receptors MT1 and MT2.3,4 Mel is a

pleiotropic molecule.5 At the skin level, Mel acts as a relevant antioxidant and cytopro-

tective substance and plays a fundamental role in maintaining the homeostasis of the

skin.6 Skin Mel, and most of its metabolites, exerts a strong protection against oxidative

stress and ultraviolet radiation.2,7–9 Cutaneous melatoninergic and metabolic systems

can act as auto/paracrine protectors against environmentally induced damage.10 Skin

Correspondence: Massimo Milani

Medical Department, Cantabria Labs,

Difa Cooper, Via Milano 160, Caronno

Pertusella, VA, Italy

Email massimo.milani@difacooper.com

Journal name: Clinical, Cosmetic and Investigational Dermatology

Article Designation: CLINICAL TRIAL REPORT

Year: 2018

Volume: 11

Running head verso: Milani and Sparavigna

Running head recto: Antiaging efﬁcacy of melatonin-based day and night creams

DOI: http://dx.doi.org/10.2147/CCID.S153905

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Milani and Sparavigna

rapidly metabolizes Mel.11 Therefore, exogenous Mel can

be expected to represent one of the most potent antioxida-

tive defense systems against skin aging mechanisms.12 Oral

administration of Mel shows a prominent ﬁrst-pass effect

with very low systemic level.13,14 Topical administration

could circumvent this problem. Topical application of Mel

is considered meaningful, since it can penetrate the stratum

corneum due to its distinct lipophilic chemical structure.15

So far, no clinical data regarding the efﬁcacy of topical Mel

as an antiaging molecule has been reported. Recently, day

and night creams containing Mel, vehiculated in lipospheres

(Melatosphere™), have been developed (Nutriage day cream

and Nutriage night cream; Cantabria Labs, Difa Cooper,

Caronno Pertusella, VA, Italy). The liposphere carrier system

could further improve the penetration of the Mel molecules

through the skin layers.16

Study aim

The aim of this study was to assess the antiaging effect of

0.1% Mel-based creams (a day formulation and a night

formulation).

Subjects and methods

We planned a randomized, split-face, assessor-blinded, pro-

spective 3-month study.

Subjects

In all, 22 women (mean age 55 years) with moderate–severe

skin aging were enrolled after receiving their written informed

consent. The subjects also provided consent to the publica-

tion of any pictures. The inclusion criterion was women aged

≥45 years with moderate–severe facial skin aging (Glogau score

of 3 or 4). The exclusion criteria were any acute or chronic skin

conditions, which could interfere with the parameters of evalu-

ation and a positive history of allergic contact dermatitis to any

of the component of the creams. Study products were applied

one in the morning (Nutriage day cream) and one in the eve-

ning (Nutriage night cream) on the right or left side of the face

according to a randomization list. The randomization list was

generated using a dedicated software. The local institutional

review board (IRB; Independent Ethical Committee, c/o Derm-

ing Clinic, Milan, Italy) approved the trial protocol on March

10, 2017 (clinical trial registration Number: NCT03276897).

The study was conducted in accordance with the ethical prin-

ciples of the Declaration of Helsinki and consistent with the

Good Clinical Practice (GCP) regulatory requirements.17 Com-

pliance to the treatment was evaluated counting the returned

used cream blisters at visits during months 1, 2 and 3.

Study outcomes

Primary outcomes were: 1) clinical evaluation of wrinkles’

grade (crow’s feet and nasolabial folds), surface microrelief,

skin ﬁrmness/tonicity (resistance to pinching and traction,

recovery after pinching) and skin dryness and 2) instrumental

evaluation of skin roughness and 3D photographic documen-

tation (Vectra H1 images system). Assessments of both clini-

cal and instrumental evaluations were performed at baseline

and after 1, 2 and 3 months of treatment by an investigator

unaware of treatment allocation. Secondary outcome was the

local tolerability of the products evaluated. Sky dryness was

evaluated using a 6-point score scale (from 0: very hydrated

to 5: very dry). Resistance to traction, resistance to pinching

and recovery after pinching were evaluated using a 5-point

score scale (from 0: very strong to 4: very weak). Wrinkles’

grade and surface microrelief were scored visually on the base

of high-deﬁnition pictures using the Glogau18 (crow’s feet)

and Monheit et al19 (nasolabial) photographic 6-point scales.

Surface microrelief was evaluated using a 4-point scale (from

1: very regular to 4: very irregular). Instrumental evaluation

of wrinkles using proﬁlometry was performed at the crow’s

feet area using Primos compact portable device (GFMesste-

chinck, Konstanz; Germany). The Primos software is able to

elaborate 3D representations of skin wrinkles and to measure

skin principal proﬁlometric parameters. Pictures with the

Vectra device were performed in a standardized (distance

and illumination) manner with the subjects with open eyes

and relaxed face muscles. Finally, the Spiderming™ radial

graph was used to “visualize” the global antiaging effect of

the treatment.20 This graph (Derming S.r.l. Clinical Research

Institute, Milan, Italy) allows the results to be evaluated and

the effect of an antiaging cosmetic product to be visualized,

taking into account that a smaller area of the graph coincides

with a younger skin; the activity of the products in terms of

antiaging activity could be quantiﬁed.

Statistical analysis and sample size

calculation

Statistical analysis was performed using GraphPad Statisti-

cal Software (GraphPad Software, Inc., La Jolla, CA, USA).

Continuous variables were expressed as mean ± standard

deviation (SD). The primary outcomes of the study were to

evaluate scores of skin parameters at month 3 in comparison

with baseline values (intragroup evaluation) using paired

nonparametric test (Wilcoxon test) and to compare at month

3, the same skin parameters between treated and non-treated

sides (intergroup evaluation) using unpaired nonparametric

test (Mann–Whitney test). The secondary outcome was to

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Antiaging efcacy of melatonin-based day and night creams

evaluate the evolution of the skin variables during the study

at each visit (baseline, month 1, month 2 and month 3) using

analysis of variance (ANOVA) test for repeated measures.

Inferential statistical analysis was done based on intention-

to-treat principle. In view of the proof-of-concept nature of

the present trial, a formal sample size calculation was not per-

formed. We decided to enroll at least 20 evaluable subjects.

Results

The trial was conducted between March 2017 and September

2017 in an outpatient derma-esthetic clinic. All the subjects

completed the study. In comparison with baseline value, skin

dryness was signiﬁcantly (p=0.001; Wilcoxon test) reduced

by 59.5% (from 3.6±0.7 to 1.5±0.4) on the side treated with

Mel creams. Skin dryness score was signiﬁcantly lower in the

active-treated side in comparison with the non-treated side

(p=0.01; Mann–Whitney U test; 1.5±0.4 vs 3.5±0.6; Figure

1A). Skin tonicity (resistance to traction, resistance to pinch-

ing and recovery after pinching) signiﬁcantly improved by

33% in comparison with the baseline value on the side treated

with Mel creams only (from 3.0±0.5 to 2.1±0.4; Figure 1B

and C). Crow’s feet photographic severity score was reduced

signiﬁcantly (p=0.05) by -15% with the creams in compari-

son with both baseline value (2.3±0.2 vs. 2.7±0.3) and value

of the non-treated side after 3 months. Surface microrelief

photographic score was signiﬁcantly reduced by -26.5% at

the end of treatment in comparison with both baseline value

(2.4±0.5 vs. 3.4±0.6; p=0.001; Wilcoxon test) and value of

the control side at month 3 (2.4±0.5 vs. 3.3±0.6; p=0.001;

Mann–Whitney U test). Signiﬁcant improvements were also

observed starting from month 1 on the sides treated with the

active product (ANOVA test; data not shown). For all the skin

parameters evaluated, nonstatistical signiﬁcant modiﬁcations

have been observed in the control side comparing baseline

and 3-month values. Figure 2 shows the evolution of the

Spiderming graph with a signiﬁcant reduction in the total area

after active treatment in comparison with baseline and non-

treated sides. Skin proﬁlometry evaluation showed a -13%

Figure 1 Evolution of skin parameters and treatment.

Notes: (A) Skin dryness evaluation (score from 0: very hydrated to 5: very dry; *p=0.001 in comparison with baseline, Wilcoxon test; **p=0.01 in comparison with the

control side; Mann–Whitney U test). (B) Skin tonicity evaluation: resistance to traction (score from 0: very relevant to 4: very weak; *p=0.05 in comparison with baseline,

Wilcoxon test; **p=0.05 in comparison with the control side, Mann–Whitney U test). (C) Skin tonicity evaluation: recovery after pinching (score from 0: very relevant to 4:

very weak; *p=0.05 in comparison with baseline, Wilcoxon test; **p=0.05 in comparison with the control side, Mann–Whitney U test).

Abbreviation: Mel, melatonin.

Dryness severity score Skin tonicity: resistance to traction

Skin tonicity: recovery after pinching

Score

Mel cream Control

Baseline

Month 3

Baseline

Month 3

Baseline

Month 3

Mel cream Control

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Milani and Sparavigna

reduction in roughness proﬁle, –13% reduction in wrinkles’

maximum depth and –7.2% reduction in total wrinkles’ height

in comparison with baseline and control sides. However,

these reductions, although clinically relevant, did not reach a

statistical signiﬁcant difference. Figure 3 shows two subjects’

pictures performed with Vectra at baseline and after 3 months

of treatment. Both products (day and night creams) were well

tolerated. No side effects were reported. Compliance to the

treatment was >90% in all the enrolled subjects.

Discussion

Mel is considered as a strong antioxidant molecule, and it

is one of the most potent ·OH radical scavenger in nature.21

Experimental studies have shown that Mel is a stronger

radical scavenger than vitamins C and E.22 Extrapineal Mel

production has been demonstrated in bone marrow, cerebro-

spinal ﬂuid, ovary, eye, lymphocytes, gastric mucosa and

skin.23–25 Human skin and skin-derived cells can produce and

metabolize Mel, and Mel exerts many effects on cell growth

“Crow’s feet”

Resistance to traction

Recovery after pinching

Resistance to pinching

Vascular and pigmentary homogeneity

Skin dryness

Surface microrelief

Nasolabial folds

Figure 2 Evaluation of skin parameters.

Notes: The Spidermig™ graph. Black line: baseline values; red line: one month application of melatonin (Mel)-products; green line: two-month application of Mel products;

blue line: three-month application of Mel-products.

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Antiaging efcacy of melatonin-based day and night creams

regulation and skin tissue homeostasis via Mel receptors

MT1 and MT2.26 Skin can produce large amount of Mel.27,28

The protective effects of Mel against ultraviolet (UV) solar

skin damage are mediated through direct and indirect radical

scavenging and antioxidative enzyme-stimulating actions.29

Several data support the concept that at the skin level. Mel and

its metabolites serve as protectors against physicochemical

(oxidative damage, ultraviolet radiation [UVR], chemicals)

and biological stressors. The antioxidant action of Mel has

also genomic inﬂuences, regulating the expression of several

genes.30 Mel stimulates both antioxidant enzyme activity and

cellular mRNA levels for these enzymes.31 Mel could also

protect DNA from oxidative damage.32 Mel can maintain

mitochondrial membrane potential in UVR-exposed kera-

tinocytes.33,34 Therefore, Mel is a good cytoprotective and

antiaging molecule.35 As stated by Fischer et al,36 for applica-

tion in clinical dermatology, exogenous Mel should be used

topically rather than orally, since orally administered Mel

appears in rather low levels in the blood due to prominent

ﬁrst-pass degradation in the liver, thus limiting skin access.

Topical administration circumvents this problem. Therefore,

in contrast with oral administration, topical application of Mel

Figure 3 Vectra 3D images.

Notes: Subject 1: (A) baseline and (B) after 3 months of active treatment (active products were applied on the left side). Subject 2: (C) baseline and (D) after 3 months of

active treatment (active products were applied on the right side).

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Milani and Sparavigna

is considered meaningful, since it can penetrate the stratum

corneum due to its distinct lipophilic chemical structure. In

the present study, the tested products contain Mel molecules

incorporated in lipospheres (Melatosphere) with the aim to

further increase the skin penetration of the molecule. So far,

no clinical data regarding the efﬁcacy of topical Mel as an

antiaging molecule has been reported. In our study, we evalu-

ated for the ﬁrst time, the efﬁcacy of two Mel-based products

in women with skin aging. The results we observed show that

in comparison with the non-treated control side, these topical

Mel formulations improve skin hydration and skin tonicity

with a clinical improvement in the aspect of wrinkles. Some

limitations should be taken into account in evaluating our

results. First, this is a proof-of-concept study. Future trials with

larger sample size are warranted to evaluate the real clinical

effects of these products in the treatment of skin aging. A

second limitation of this study is that this is not a double-blind

trial. However, to increase the internal validity of our results,

we adopted a split face, assessor-blinded study design.

Conclusion

In women with skin aging, Mel-based creams improved sig-

niﬁcantly skin tonicity and skin hydration with a signiﬁcant

reduction in skin roughness, supporting the skin antiaging

effect of this molecule applied topically.

Acknowledgment

Difa Cooper Spa, IFC Group, supported this trial with an

unrestricted grant.

Author contributions

AS conducted the trial performing visits and instrumental

evaluations. MM was involved in study protocol design.

Both authors contributed toward data analysis, drafting and

critically revising the paper and agree to be accountable for

all aspects of the work.

Disclosure

MM is an employee of Cantabria Lab, Difa Cooper. The other

author reports no conﬂicts of interest in this work.

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Benefits and adverse events of melatonin use in the elderly (Review)

Article

Full-text available

Jan 2022
Exp Ther Med

Melatonin is a hormone secreted by the pineal gland in accordance with the circadian rhythm when the light level decreases. Reduction of melatonin secretion with age may be associated with physiological aging in neurode-generative diseases by affecting the suprachiasmatic nucleus or of the neuronal pathways of transmission to the pineal gland. A significant decrease in melatonin synthesis has been reported in various disorders and diseases, including cardiovascular diseases, metabolic disorders (particularly diabetes type 2), cancer and endocrine diseases. In addition to the fact, that melatonin is a sleep inducer, it also exerts cytoprotective properties as an antioxidant and free radical scavenger. The therapeutic role of melatonin has been demonstrated in sleep disorders, eye damage and cardiovascular disease. The association between melatonin and β-blockers has had a positive impact on sleep disorders in clinical trials. Previous studies have reported the anti-inflammatory effect of melatonin by adjusting levels of pro-inflammatory cytokines, including interleukin (IL)-6, IL-1β and tumor necrosis factor-α. Melatonin treatment has been demonstrated to decrease IL-6 and IL-10 expression levels and efficiently attenuate T-cell proliferation. Currently, there is an inconsistency of scientific data regarding the lowest optimal dose and safety of melatonin for long-term use. The aim of the present review was to summarize the evidence on the role of melatonin in various clinical conditions and highlight the future research in this area.

Melatonin inhibits senescence-associated melanin pigmentation through the p53-TYR pathway in human primary melanocytes and the skin of C57BL/6J mice after UVB irradiation

Preprint

Full-text available

Oct 2022

Purpose UVB exposure accelerates skin aging and age-associated pigmentation, but their relationship remains unclear. UVB induces premature senescence and melanin production within melanocytes, along with the upregulation of p53 and cellular tyrosinase (TYR). As a tumor suppressor gene, p53 can keep the genome intact by modulating cell apoptosis and growth arrest during DNA injury. It is also associated with age-associated pigmentation, directly or indirectly regulating pigment-related gene expression. Melatonin effectively regulates tyrosinase activity and resists aging. In this study, we investigated the regulation of p53 on TYR to understand the association between premature senescence and senescence-associated pigmentation and determine the mechanism by which melatonin affects UVB-stimulated melanin production. Methods Primary melanocytes were extracted and identified from the male foreskin. The primary melanocytes were transduced using lentivirus pLKD-CMV-EGFP-2A-Puro-U6-TYR to knock down TYR expression. The melanin content was determined using the NaOH method, 3,4-Dihydroxy-L-phenylalanine (L-DOPA) was oxidized to dopachrome to determine TYR activity, and Western blotting was performed to detect the level of TYR protein. The primary melanocytes were pretreated with Nutlin-3 or PFT-α to upregulate or downregulate p53 levels or melatonin for 12 h and exposed to UVB irradiation at 80 mJ/cm². The senescence-associated beta-galactosidase (SA-β-gal) kit was used to analyze premature senescence. The levels of p53, p-p53, and TYR protein were detected by performing the automated capillary electrophoresis Western blotting analysis in melanocytes 72 h after UVB irradiation. Wild-type and TYR(–/–) or TYR(+/–) knockout C57BL/6J mice were used to determine the regulatory role of TYR on melanin synthesis in vivo. Additionally, the effect of melatonin on skin erythema and pigmentation induced by UVB irradiation was analyzed in vivo. Results Primary melanocytes turned deep black after L-DOPA staining, indicating higher TYR protein and mRNA expression. Tyrosinase activity and melanin levels induced by UVB irradiation decreased significantly after the primary melanocytes were infected with pLKD-CMV-EGFP-2A-Puro-U6-TYR (P < 0.05). Premature senescence, tyrosinase activity, and melanin levels increased after exposure to UVB irradiation. There was a dramatic increase in primary melanocytes following Nutlin-3 treatment but significant inhibition after treatment with PFT-α (P < 0.05). Melatonin inhibited UVB-induced premature senescence, associated with decreased p53 level and phosphorylation at the serine-15 position, decreased UVB-induced tyrosinase activity and melanin levels, and reduced TYR expression.The TYR(–/–) knockout mice were recognized through white hair, whiskers, and paws, and loss of pigments in the eyes. The tyrosinase activity and melanin levels in the whisker follicles of TYR(–/–) knockout mice also decreased significantly (P < 0.05) relative to that in the wild-type (WT) mice. Skin erythema and melanin pigmentation induced by UVB irradiation decreased in the dorsal and ear skin of C57BL/6J mice topically pretreated with 2.5% melatonin. Conclusion Melanin synthesis induced by UVB irradiation is partly dependent on TYR in primary melanocytes and the C57BL/6J mice. Moreover, p53 links the UVB irradiation-induced premature senescence and senescence-associated pigmentation in primary melanocytes. It also directly regulates TYR in primary melanocytes after UVB irradiation. After UVB irradiation, melatonin partly inhibits senescence-associated pigmentation through the p53-TYR pathway in the primary melanocytes. Melatonin prevents skin erythema and melanin pigmentation induced by UVB irradiation in the dorsal and ear skin of C57BL/6J mice.

Essential Oils and Melatonin as Functional Ingredients in Dogs

Article

Full-text available

Aug 2022

The use of nutraceuticals or functional ingredients is increasingly widespread in human food; their use is also widespread in animal feed. These natural compounds generally come from plant materials and comprise a wide range of substances of a very diverse chemical nature. In animals, these compounds, so-called phytogenics, are used to obtain improvements in feed production/stability and also as functional components with repercussions on animal health. Along with polyphenols, isoprenoid compounds represent a family of substances with wide applications in therapy and pet nutrition. Essential oils (EOs) are a group of complex substances with fat-soluble nature that are widely used. Melatonin is an indolic amine present in all living with amphiphilic nature. In this work, we present a review of the most relevant phytogenics (polyphenol, isoprenoid, and alkaloid compounds), their characteristics, and possible uses as nutraceuticals in dogs, with special emphasis on EOs and their regulatory aspects, applied in foods and topically. Additionally, a presentation of the importance of the use of melatonin in dogs is developed, giving physiological and practical aspects about its use in dog feeding and also in topical application, with examples and future projections. This review points to the combination of EOs and melatonin in food supplements and in the topical application as an innovative product and shows excellent perspectives aimed at addressing dysfunctions in pets, such as the treatment of stress and anxiety, sleep disorders, alopecia, and hair growth problems, among others.

Enhancing the anti-psoriatic activity of vitamin D3 employing nanostructured archaeolipid carriers

Article

Jul 2022
J DRUG DELIV SCI TEC

Psoriasis (Ps) is a multifactorial autoimmune skin disease, where oxidative stress plays a key role in promoting a vicious producing cycle between keratinocytes and immune cells. Vitamin D3 (VD3) regulates the differentiation, apoptosis, and proliferation of keratinocytes, also displaying antioxidant and anti-inflammatory activities. Previous attempts of using topical VD3 as anti-psoriatic agent, failed because of its poor solubility, high hydrophobicity, structural lability, and low bioavailability. Specifically tailored nanoparticles for topical co-delivery of VD3 and antioxidants to activated keratinocytes and macrophages could make Ps treatments more efficient. In this work, structural features, and in vitro activity of nanostructured archaeolipid carriers (NAC) containing VD3 plus the antioxidant C50 dipolar carotenoid bacterioruberin (BR) (NAC-VD3), are presented. Ultra-small (70 nm), −39 mV ζ potential, ∼5 mg VD3/ml, 0.35 BR μg/ml NAC-VD3, with good storage stability (at least 6 month) consisted of a compritol and BR core, covered by a shell of sn 2,3 ether linked archaeolipids and Tween 80 (2: 2: 1.2: 3% w/w) were obtained. Raman, DSC and SAXS analysis showed that VD3 was trapped within the disordered compritol-BR core, impairing its fast release, and protecting VD3 against thermal degradation. NAC-VD3 were extensively captured and displayed high anti-proliferative (65%), anti-inflammatory (IL-8 release) and antioxidant activities (ROS reduction) on a psoriatic model made of CaCl2 differentiated-imiquimod stimulated HaCaT cells, and on lipopolysaccharide induced THP-1 macrophages. Interestingly, the BR extract alone displayed high anti-Staphylococcus aureus activity including anti-biofilm formation. Overall, the results suggest that NAC-VD3 protect the labile structure of VD3, while enhancing its anti-psoriatic activity and deserves further in vivo exploration.

Cosmeceutical Therapy: Engaging the Repercussions of UVR Photoaging on the Skin’s Circadian Rhythm

Article

Full-text available

Mar 2022
INT J MOL SCI

Sunlight is an important factor in regulating the central circadian rhythm, including the modulation of our sleep/wake cycles. Sunlight had also been discovered to have a prominent influence on our skin’s circadian rhythm. Overexposure or prolonged exposure to the sun can cause skin photodamage, such as the formation of irregular pigmentation, collagen degradation, DNA damage, and even skin cancer. Hence, this review will be looking into the detrimental effects of sunlight on our skin, not only at the aspect of photoaging but also at its impact on the skin’s circadian rhythm. The growing market trend of natural-product-based cosmeceuticals as also caused us to question their potential to modulate the skin’s circadian rhythm. Questions about how the skin’s circadian rhythm could counteract photodamage and how best to maximize its biopotential will be discussed in this article. These discoveries regarding the skin’s circadian rhythm have opened up a completely new level of understanding of our skin’s molecular mechanism and may very well aid cosmeceutical companies, in the near future, to develop better products that not only suppress photoaging but remain effective and relevant throughout the day.

Protective Role of Melatonin and Its Metabolites in Skin Aging

Article

Full-text available

Jan 2022

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.

Skin aging risk factors: A nationwide population study in Mongolia risk factors of skin aging

Article

Full-text available

Jan 2022
PLOS ONE

The world population is aging and no country is immune to the consequences. We are not aware of any country-specific skin aging risk factors data for the Mongolian people. Thus, we aimed to study the risk factors associated with skin aging in the Mongolian population. A population-based cross-sectional study of 2720 study participants 18 years of age and older was performed evaluating the severity of skin aging based on cutaneous microtopography. Questionnaire data and skin physiological measurements were obtained. The odds ratios for skin aging grades associated with risk factors were estimated using ordinal logistic regression. Study participant’s mean age was 45 years, ranging from 18 to 87. After adjustment for known risk factors, skin aging was associated with demographic risk factors such as increasing age (aOR = 1.19, 95% CI 1.18–1.20), living in an urban area (aOR = 1.31, 95% CI 1.12–1.55) and lifestyle factors including being a smoker (aOR = 1.32, 95% CI 1.09–1.61), having a higher body mass index (aOR = 1.04, 95% CI 1.02–1.06) and higher levels of sun exposure time (aOR = 1.03, 95% CI 1.00–1.06) were significantly associated with higher skin aging grades. Having dry (aOR = 1.94, 95% CI 1.45–2.59) and combination skin (aOR = 1.62, 95% CI 1.22–2.16) types were also independent risk factors associated with skin aging. Having very low skin surface moisture at the T-zone (aOR = 2.10, 95% CI 1.42–3.11) was significantly related to skin aging. Older age, urban living and toxic working conditions were independent demographic risk factors related to skin aging. Smoking, higher BMI, greater levels of sun exposure were significant lifestyle risk factors. Having a skin type other than normal was a physiologic risk factor for skin aging.

Concentration‐dependent stimulation of melanin production as well as melanocyte and keratinocyte proliferation by melatonin in human eyelid epidermis

Article

Jan 2023

It remains unclear how the multifunctional indoleamine neurohormone, melatonin, alters melanin production and melanocytes within intact human epidermis under physiologically relevant conditions. In the current pilot study, we aimed to clarify this in long‐term organ‐cultured, full‐thickness human eyelid skin, selected for its clinically recognized sensitivity to pigmentation‐modulatory hormones. Warthin‐Starry histochemistry showed that 100 μM melatonin significantly increased epidermal melanin content and melanocyte dendricity after 6 days of organ culture, even though tyrosinase activity in situ was inhibited, as assessed by quantitative immunohistomorphometry. While the higher melatonin dose tested here (200 μM) did not change epidermal melanization, but again inhibited tyrosinase activity, it increased the number and proliferation of both gp100+ epidermal melanocytes and keratinocytes as well as protein expression of the pre‐melanosomal marker, gp100, ex vivo. Contrary to most previous studies, these eyelid skin organ culture results suggest that long‐term melatonin application exerts overall stimulatory, dose‐dependent effects on the epidermal pigmentary unit within intact human skin, which appear surprisingly tyrosinase‐independent. While these provocative preliminary findings require further work‐up and independent confirmation, they encourage one to systematically explore whether prolonged melatonin therapy can (re‐)stimulate melanogenesis and increase the pool/activity of epidermal melanocytes in hypopigmented skin lesions.

Melatonin: Translation of Ongoing Studies Into Possible Therapeutic Applications Outside Sleep Disorders

Article

Apr 2022
CLIN THER

Purpose Melatonin, a natural hormone mainly synthesized by the pineal gland, is regulated by circadian rhythm. Synthetic melatonin is not approved by the US Food and Drug Administration for any indication. However, melatonin receptor agonists such as ramelteon and tasimelteon are US Food and Drug Administration approved and are considered by the American Academy of Family Physicians for the treatment of insomnia. Due to the availability of over-the-counter products in some countries and the increasing use of melatonin, it is interesting to highlight knowledge regarding the potential benefits of melatonin outside sleep disorders. Methods This narrative review included published reports in EMBASE and MEDLINE databases between 1975 and 2021 relating to the therapeutic applications of melatonin. Findings: Based on the quality of the evidence published to date, the most promising non-insomnia indications are for treating ischemia/reperfusion injury, primary headache disorders, fibromyalgia, glucose control, and blood pressure control. Implications Most of the studies were preclinical and in in vivo and in vitro phases. More clinical trials are needed before recommending melatonin as a treatment in clinical practice.

Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective

Article

Feb 2022

The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin‐lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation‐related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from non‐human species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responses to melatonin are best interrogated in a physiological tissue context. Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis‐inhibitory effects of melatonin may occur via activation of Nrf2‐mediated PI3K/AKT signaling, estrogen receptor‐mediated and/or melanocortin‐1 receptor‐ and cAMP‐dependent signaling, and/or via melatonin‐regulated changes in peripheral clock genes that regulate human melanogenesis, namely Bmal1 and Per1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto‐ and senescence‐protective as well as anti‐oxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function. We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture‐based observations translate into melatonin‐induced pigmentary changes in a physiological tissue context, i.e., in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models. This article is protected by copyright. All rights reserved.

Melatonin, mitochondria, and the skin

Article

Full-text available

Nov 2017
CELL MOL LIFE SCI

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.

Metabolism of melatonin in the skin: Why is it important?

Article

Full-text available

Sep 2016
EXP DERMATOL

Melatonin is produced in almost all living taxa and is probably 2-3 billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non-enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O-demethylation or non-enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor-dependent and receptor-independent mechanisms, receptors for melatonin metabolites remain to be identified, while their receptor-independent activities are well documented. The human skin with its main cellular components including malignant cells can both produce and rapidly metabolize melatonin in cell-type and context-dependent fashion. The predominant metabolism in human skin occurs through indolic, CYP-mediated and kynuric pathways with main metabolites represented by 6-hydroxymelatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK), N¹-acetyl-5-methoxykynuramine (AMK), 5-methoxytryptamine, 5-methoxytryptophol and 2-hydroxymelatonin. AFMK, 6-hydroxymelatonin, 2-hydroxymelatonin and probably 4-hydroxymelatonin can potentially be produced in epidermis through UVB-induced non-enzymatic melatonin transformation. The skin metabolites are also the same as those produced in lower organisms and plants indicating phylogenetic conservation across diverse species and adaptation by skin of the primordial defense mechanism. As melatonin and its metabolites counteract or buffer environmental stresses to maintain its homeostasis through broad-spectrum activities, both melatoninergic and degradative pathways must be precisely regulated, because the nature of phenotypic regulations will depend on local concentration of melatonin and its metabolites. These can be receptor-mediated or represent non-receptor regulatory mechanisms.

Melatonin: A potent endogenous hydroxyl radical scavenger

Article

Full-text available

Jan 1993

Local Melatoninergic System as the Protector of Skin Integrity

Article

Full-text available

Oct 2014
INT J MOL SCI

The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a "guardian" of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging.

Evaluation of the Activity and Tolerability of a Cosmetic Treatment for the Periocular Area on the Aging Face: Controlled Clinical and Instrumental Evaluation vs. Placebo

Article

Full-text available

Jun 2014

The aim of this study was to evaluate clinically and by non invasive instrumental evaluations the efficacy and tolerability of a cosmetic treatment containing an innovative active ingredient, ethyl ximenynate, in the prevention of dark circles under the eyes and blemishes of skin aging on the eye profile. Evaluations were performed at baseline and after 2 and 4 weeks of treatment on 22 volunteers; the study was planned as a double blind half-face trial. Data showed a trend towards a lifting of the eyelid skin; all investigator scores (eye puffiness, skin smoothness, roughness and dryness) decreased. In addition, profilometric results confirmed the anti-wrinkles efficacy of the active product and its lifting action, while those related to spectrophotometry underlined the decongestant effect on dark circles that appeared, at the end of the study, to be less marked. The improvement of skin microcirculation and capillary resistance and vascular tone in the eye area underlines a general mitigation of all relevant skin imperfections and blemishes of skin aging on the eye profile. The active ingredient was shown to be effective for the cosmetic treatment of the periocular area.

Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells

Article

Full-text available

Apr 2013
FASEB J

Indolic and kynuric pathways of skin melatonin metabolism were monitored by liquid chromatography mass spectrometry in human keratinocytes, melanocytes, dermal fibroblasts, and melanoma cells. Production of 6-hydroxymelatonin [6(OH)M], N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and 5-methoxytryptamine (5-MT) was detected in a cell type-dependent fashion. The major metabolites, 6(OH)M and AFMK, were produced in all cells. Thus, in immortalized epidermal (HaCaT) keratinocytes, 6(OH)M was the major product with Vmax = 63.7 ng/10(6) cells and Km = 10.2 μM, with lower production of AFMK and 5-MT. Melanocytes, keratinocytes, and fibroblasts transformed melatonin primarily into 6(OH)M and AFMK. In melanoma cells, 6(OH)M and AFMK were produced endogenously, a process accelerated by exogenous melatonin in the case of AFMK. In addition, N-acetylserotonin was endogenously produced by normal and malignant melanocytes. Metabolites showed selective antiproliferative effects on human primary epidermal keratinocytes in vitro. In ex vivo human skin, both melatonin and AFMK-stimulated expression of involucrin and keratins-10 and keratins-14 in the epidermis, indicating their stimulatory role in building and maintaining the epidermal barrier. In summary, the metabolism of melatonin and its endogenous production is cell type-dependent and expressed in all three main cell populations of human skin. Furthermore, melatonin and its metabolite AFMK stimulate differentiation in human epidermis, indicating their key role in building the skin barrier.-Kim, T.-K., Kleszczyński, K., Janjetovic, Z., Sweatman, T., Lin, Z., Li, W., Reiter, R. J., Fischer, T. W., Slominski, A. T. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells.

Melatonin and human skin aging

Article

Full-text available

Jul 2012

Like the whole organism, skin follows the process of aging during life-time. Additional to internal factors, several environmental factors, such as solar radiation, considerably contribute to this process. While fundamental mechanisms regarding skin aging are known, new aspects of anti-aging agents such as melatonin are introduced. Melatonin is a hormone produced in the glandula pinealis that follows a circadian light-dependent rhythm of secretion. It has been experimentally implicated in skin functions such as hair cycling and fur pigmentation, and melatonin receptors are expressed in many skin cell types including normal and malignant keratinocytes, melanocytes and fibroblasts. It possesses a wide range of endocrine properties as well as strong antioxidative activity. Regarding UV-induced solar damage, melatonin distinctly counteracts massive generation of reactive oxygen species, mitochondrial and DNA damage. Thus, there is considerable evidence for melatonin to be an effective anti-skin aging compound, and its various properties in this context are described in this review.

Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro

Article

Aug 2014

Melatonin and its metabolites including 6-hydroxymelatonin (6(OH)M), N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and 5-methoxytryptamine (5MT) are endogenously produced in human epidermis. This production depends on race, gender and age. The highest melatonin levels are in young African-Americans [30-50 years old (yo)], old Caucasian males (60-90 yo) and Caucasian females. AFMK levels are the highest in Caucasians males, while 6(OH)M and 5MT levels are similar in all groups. Testing of their phenotypic effects in normal human melanocytes show that melatonin and its metabolites (10(-5) M) inhibit tyrosinase activity and cell growth, and inhibit DNA synthesis in a dose dependent manner with 10(-9) M being the lowest effective concentration. In melanoma cells, they inhibited cell growth but had no effect on melanogenesis, except for 5MT which enhanced L-tyrosine induced melanogenesis. In conclusion, melatonin and its metabolites [6(OH)M, AFMK and 5MT] are produced endogenously in human epidermis and can affect melanocyte and melanoma behavior.

Melatonin Membrane Receptors in Peripheral Tissues: Distribution and Functions

Article

Apr 2012

Many of melatonin's actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes.

Development and Validation of a 6-Point Grading Scale in Patients Undergoing Correction of Nasolabial Folds with a Collagen Implant

Article

Nov 2010
DERMATOL SURG

Various scoring techniques prone to subjective interpretation have been used to evaluate soft tissue augmentation of nasolabial folds (NLFs). To design and validate a reliable wrinkle assessment scoring scale. Six photographed wrinkles of varying severity were electronically copied onto the same facial image to become a 6-point grading scale (GGS). A pilot training program (13 investigators) determined reliability, and a 12-week multicenter survey study validated the GGS scoring method. Pilot study inter- and intrarater scoring reliability were high (weighted kappa scores of 0.85 and 0.86, respectively). Seventy-five percent of survey investigators and independent review panel (IRP) members considered a GGS score difference of 0.5 to be a minimally perceivable difference. Interrater weighted kappa scores were 0.91 for the IRP and 0.80 for investigators. Intrarater agreements after repeat testing were 0.91 and 0.89, respectively. The baseline "live" assessment GGS mean score was 3.34, and the baseline blinded photographic assessment GGS mean score was 2.00 for the IRP and 2.16 for the investigators. The GGS is a reproducible method of grading the severity of NLF wrinkles. Treatment effectiveness of a dermal filler can be reliably evaluated using the GGS by comparing "live" assessments with the standard GGS photographic panel.