Dataset Information

Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

ABSTRACT: Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the development of a hMC1R-targeted photoprotection strategy, we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most of the existing analogs of the physiological tridecapeptide α-melanocortin because of their small size and high hMC1R selectivity. Testing on primary cultures of human melanocytes showed that these peptides are highly potent with prolonged stimulation of melanogenesis, enhanced repair of UV-induced DNA photoproducts, and reduced apoptosis. One of the tripeptides, designated as LK-514 (5), with a molecular weight of 660 Da, has unprecedented (>100,000) hMC1R selectivity when compared with the other melanocortin receptors hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured, three-dimensional skin model. These new analogs should be efficacious in preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions.

SUBMITTER: Koikov L

PROVIDER: S-EPMC9009400 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

Koikov Leonid L Starner Renny J RJ Swope Viki B VB Upadhyay Parth P Hashimoto Yuki Y Freeman Katie T KT Knittel James J JJ Haskell-Luevano Carrie C Abdel-Malek Zalfa A ZA

The Journal of investigative dermatology 20210218 7

Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the development of a hMC1R-targeted photoprotection strategy, we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most o ...[more]

PMID: 33609553

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Project description:Sunless (chemical) tanning is widely regarded as a safe alternative to solar UV-induced skin tanning known to be associated with epidermal genotoxic stress, but the cutaneous biology impacted by chemical tanning remains largely unexplored. Chemical tanning is based on the formation of melanin-mimetic cutaneous pigments ('melanoidins') from spontaneous amino-carbonyl ('glycation') reactions between epidermal amino acid/protein components and reactive sugars including the glycolytic ketose dihydroxyacetone (DHA). Here, we have examined the cutaneous effects of acute DHA-exposure on cultured human HaCaT keratinocytes and epidermal reconstructs, profiled by gene expression array analysis and immunodetection. In keratinocytes, DHA-exposure performed at low millimolar concentrations did not impair viability while causing a pronounced cellular stress response as obvious from rapid activation of phospho-protein signal transduction [p-p38, p-Hsp27(S15/S78), p-eIF2α] and gene expression changes (HSPA6, HMOX1, CRYAB, CCL3), not observable upon exposure to the non-ketose, tanning-inactive DHA-control glycerol. Formation of advanced glycation end products (AGEs) from posttranslational protein-adduction was confirmed by quantitative mass spectrometric detection of N-ε-(carboxyethyl)-l-lysine (CEL) and N7-carboxyethyl-l-arginine, and skin cells with CRISPR-Cas9-based elimination of the carbonyl stress response gene GLO1 (encoding glyoxalase 1) displayed hypersensitivity to DHA-cytotoxicity. In human epidermal reconstructs a topical use-relevant DHA-dose regimen elicited a comparable stress response as revealed by gene expression array (HSPA1A, HSPA6, HSPD1, IL6, DDIT3, EGR1) and immunohistochemical analysis (CEL, HO-1, p-Hsp27-S78). In DHA-treated SKH-1 hairless mouse skin IHC-detection revealed epidermal occurrence of CEL- and p-Hsp27-epitopes. For comparison, stress response gene expression array analysis was performed in epidermis exposed to a supra-erythemal dose of solar simulated UV (2 MEDs), identifying genes equally or differentially sensitive to either one of these cutaneous stimuli [DHA ('sunless tanning') versus solar UV ('sun-induced tanning')]. Given the worldwide use of chemical tanners in consumer products, these prototype data documenting a DHA-induced specific cutaneous stress response deserve further molecular exploration in living human skin.

Project description:ImportanceThe US Food and Drug Administration has classified tanning beds as carcinogenic. Most states have enacted legislation to prevent or create barriers for minors accessing tanning establishments. Determining tanning salon compliance with legislation would provide an indication of the influence of legislation at preventing exposure to the carcinogen in minors.ObjectivesTo investigate compliance rates in the 42 states and the District of Columbia with legislation restricting tanning bed use in minors and to identify differences in compliance based on population, regional location, salon ownership, age group being regulated, and time since the law was enacted.Design, setting, and participantsThis investigation was a cross-sectional telephone survey conducted between February 1, 2015, and April 30, 2016, by callers posing as minors attempting to schedule a tanning appointment. The setting was tanning salons in the 42 states and the District of Columbia that currently have legislation restricting tanning bed use in minors. Included in the study were 427 tanning salons, 10 randomly selected from each state or territory with tanning legislation.Main outcomes and measuresOverall compliance of tanning salons with state tanning legislation and differences in compliance based on community population, regional location, independent vs chain tanning salon, age group being regulated, and time since the law was enacted.ResultsOf the 427 tanning salons surveyed, overall noncompliance with state legislation was 37.2% (n = 159). There were more noncompliant tanning salons in rural locations (45.5%; 95% CI, 37.5%-53.7%; P = .009), southern regions of the United States (49.4%; 95% CI, 41.4%-57.4%; P = .001), independently owned salons (43.9%; 95% CI, 37.3%-50.6%; P = .003), states with younger age groups being regulated (53.5%; 95% CI, 45.7%-61.2%; P < .001), and states with more than one tanning regulation (50.0%; 95% CI, 42.0%-58.0%; P < .001). No difference was found based on time since the law was enacted.Conclusions and relevanceCompliance with state legislation aimed at limiting tanning bed use among US minors is unsatisfactory, indicating that additional efforts to enforce the laws and education of the harmful effects of UV tanning are necessary, especially in rural, independently owned, and tanning salons in southern regions, which have decreased compliance rates.

Project description:BackgroundRates of melanoma have increased dramatically in the United States over the past 25 years, and it has become among the most prevalent cancers for young adult women. Intentional skin tanning leads to a pattern of intense and intermittent UV radiation exposure that is associated with increased risk of melanoma. Frequent tanning is most common among young women and is linked to a variety of sociocultural pressures that negatively impact body image and drive appearance control behaviors. Unfortunately, there are no established interventions designed for frequent tanners. This intervention addresses this gap with unique content informed by body image and acceptance-based interventions. The intervention is delivered using Facebook secret groups, an approach designed to support behavior change and ensure scalability.ObjectiveThis study aims to describe the rationale and methodology of a randomized controlled trial of a melanoma prevention program targeting young women engaged in frequent indoor or outdoor UV tanning.MethodsParticipants are women aged 18-25 years who report high-risk tanning (ie, at least 10 indoor tanning sessions in the past 12 months or 10 outdoor sessions in the previous summer). After recruitment and screening, participants completed a baseline survey and were randomly assigned to receive the intervention or an attention-matched control condition. Both conditions were 8-week-long Facebook groups (approximately 25 members each) with daily posting of content. Follow-up surveys are administered at 3, 8, and 18 months after baseline. The primary trial outcome is the combined number of indoor and outdoor tanning sessions reported at the 8-month follow-up. Hypothesized intervention mediators are assessed at the 3-month follow-up.ResultsThis project was funded by a National Cancer Institute award (R01 CA218068), and the trial procedures were approved by the University of Kentucky Institutional Review Board in February 2020. Trial recruitment and enrollment occurred in 6 waves of data collection, which started in February 2022 and closed in May 2023. The study is closed to enrollment but remains open for follow-ups, and this protocol report was prepared before data analyses. As of February 2024, all participants have completed the 8-month follow-up assessment, and data collection is scheduled to close by the end of 2024 after the collection of the 18-month follow-up.ConclusionsThis trial will contribute unique knowledge to the field of skin cancer prevention, as no fully powered trials have examined the efficacy of an intervention designed for frequent indoor or outdoor tanning. The trial may also contribute evidence of the value in translating principles of body image and acceptance-based interventions into the field of skin cancer prevention and beyond. If successful, the use of the Facebook platform is intended to aid in dissemination as it provides a way to embed the intervention into individuals' everyday routines.Trial registrationClinicalTrials.gov NCT03441321; https://clinicaltrials.gov/study/NCT03441321.International registered report identifier (irrid)DERR1-10.2196/56562.

Dataset Information

Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

Publications

Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

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