| Autor: |
Stefan J; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Department of Oncology, Nicolaus Copernicus University Medical College, Romanowskiej Str. 2, 85-796 Bydgoszcz, Poland., Kim TK; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Schedel F; Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany., Janjetovic Z; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Crossman DK; Department of Genetics, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Steinbrink K; Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany., Slominski RM; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Zmijewski J; Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA., Tulic MK; Team 12, Centre Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 06200 Nice, France., Reiter RJ; Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX 78229, USA., Kleszczyński K; Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany., Slominski AT; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL 35294, USA. |
| Abstrakt: |
We investigated the effects of melatonin and its selected metabolites, i.e., N 1 -Acetyl- N 2 -formyl-5-methoxykynurenamine (AFMK) and 6-hydroxymelatonin (6(OH)Mel), on cultured human epidermal keratinocytes (HEKs) to assess their homeostatic activities with potential therapeutic implications. RNA seq analysis revealed a significant number of genes with distinct and overlapping patterns, resulting in common regulation of top diseases and disorders. Gene Set Enrichment Analysis (GSEA), Reactome FIViZ, and Ingenuity Pathway Analysis (IPA) showed overrepresentation of the p53-dependent G1 DNA damage response gene set, activation of p53 signaling, and NRF2-mediated antioxidative pathways. Additionally, GSEA exhibited an overrepresentation of circadian clock and antiaging signaling gene sets by melatonin derivatives and upregulation of extension of telomere signaling in HEKs, which was subsequently confirmed by increased telomerase activity in keratinocytes, indicating possible antiaging properties of metabolites of melatonin. Furthermore, Gene Ontology (GO) showed the activation of a keratinocyte differentiation program by melatonin, and GSEA indicated antitumor and antilipidemic potential of melatonin and its metabolites. IPA also indicated the role of Protein Kinase R (PKR) in interferon induction and antiviral response. In addition, the test compounds decreased lactate dehydrogenase A ( LDHA ) and lactate dehydrogenase C ( LDHC ) gene expression. These results were validated by qPCR and by Seahorse metabolic assay with significantly decreased glycolysis and lactate production under influence of AFMK or 6(OH)Mel in cells with a low oxygen consumption rate. In summary, melatonin and its metabolites affect keratinocytes' functions via signaling pathways that overlap for each tested molecule with some distinctions. |
