Vol 6, No 3 (2021)
Review article
Published online: 2021-09-14

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Novel vitamin D3-hydroxyderivatives as candidates for the therapy against skin-aging and photo-aging: bioinformatical analysis

Joanna Stefan1, Przemyslaw Blawat2, Alicja Bartoszewska-Kubiak2, Małgorzata Szamocka2, Krzysztof Roszkowski2
Medical Research Journal 2021;6(3):254-269.

Abstract

Vitamin D3 acts through its most active form, calcitriol, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as agonist of one of the receptors involved in this ligand action, vitamin D receptor (VDR), which is also a transcription factor. Numerous modifications of calcitriol at its side-chain, C-ring, A-ring, triene system, alone or in combination, as well as nonsteroidal mimics provided new VDR agonists and some antagonists with biological activity and possible therapeutical potential. Some of the D3 metabolites, including 20,23(OH)2D3 and 20(OH)D3 are able to inhibit RORE-mediated transactivation, as well as the interaction between the RORα/γ ligand-binding domain (LBD) with an LXXLL coactivator peptide. Our analysis of recently reported microarray data on vitamin D3 (D3) induced changes in cultured human keratinocytes indicated that D3 hydroxyderivatives stimulate the expression of genes involved in anti-aging activities. Furthermore, we noted upregulation of the kallikrein gene family by 1,25(OH)2D3 after 24-hour treatment, including stimulation of KLK6, KLK13, KLK3, KLK9, KLK5, KLK7, and KLK10. Also, after 6-hour incubation with 1,25(OH)2D3, the upregulation of KLK6, KLK13, and KLK3 was seen.  Interestingly, ACEIs administered to hypertensive rats doubled the lifespan of these animals. In humans, ACEIs prevent hallmarks of aging, such as organ fibrosis and cardiac hypertrophy. We noted also that vitamin D3-hydroxyderivatives act against oxidative stress through upregulation of thioredoxin reductase (TXNRD1) and heme reductase-1 (HMOX-1) gene expression in keratinocytes treated for 24h. Another mechanism of anti-aging properties of inverse agonist RORa/γ is the resolution of inflammation caused by T helper (Th17) lymphocytes and switching the immune response into T regulatory (Treg) lymphocytes activation, with silencing of the inflammation state and reducing the inflammation process. The gene connected with inflammatory response, AKR1C3 (which encodes prostaglandin F synthase) is also strongly downregulated by 20,23(OH)2D3 in keratinocytes after incubation for 24 h. We suggest that vitamin D3 analogs, such as 20,23(OH)2D3, 1,25(OH)2D3, and 20(OH)D3 may have anti-aging properties through action on different pathways connected with DNA repair.

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