Vol 6, No 3 (2021)
Review article
Published online: 2021-09-14
Novel vitamin D3-hydroxyderivatives as candidates for the therapy against skin-aging and photo-aging: bioinformatical analysis
1, 2, 2, 2
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Med Res J 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.
Keywords: skin agingphoto-agingceramidemelanosisatopic dermatitisvitamin D3-hydroxyderivatives
References
- Van den Bossche J. A brake on inflammaging. Science Translational Medicine. 2020; 545.
- Bharath LP, Agrawal M, McCambridge G, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 2020; 32(1): 44–55.e6.
- Jetten AM, Takeda Y, Slominski A, et al. Retinoic acid-related Orphan Receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease. Curr Opin Toxicol. 2018; 8: 66–80.
- Carlberg C. Vitamin D Genomics: From In Vitro to In Vitro . Front Endocrinol (Lausanne). 2018; 9: 250.
- Slominski AT, Kim TK, Shehabi HZ, et al. In vivo evidence for a novel pathway of vitamin D₃ metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 2012; 26(9): 3901–3915.
- Slominski AT, Kim TK, Li W, et al. Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. Sci Rep. 2015; 5: 14875.
- Slominski AT, Li W, Kim TK, et al. Novel activities of CYP11A1 and their potential physiological significance. J Steroid Biochem Mol Biol. 2015; 151: 25–37.
- Zmijewski MA, Li W, Zjawiony JK, et al. Photo-conversion of two epimers (20R and 20S) of pregna-5,7-diene-3beta, 17alpha, 20-triol and their bioactivity in melanoma cells. Steroids. 2009; 74(2): 218–228.
- Tuckey RC, Slominski AT, Cheng CYS, et al. Lumisterol is metabolized by CYP11A1: discovery of a new pathway. Int J Biochem Cell Biol. 2014; 55: 24–34.
- Tuckey RC, Li W, Ma D, et al. CYP27A1 acts on the pre-vitamin D3 photoproduct, lumisterol, producing biologically active hydroxy-metabolites. J Steroid Biochem Mol Biol. 2018; 181: 1–10.
- Bikle DD. Vitamin D: newer concepts of its metabolism and function at the basic and clinical level. J Endocr Soc. 2020; 4(2): bvz038.
- Kim TK, Wang J, Janjetovic Z, et al. Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength. Mol Cell Endocrinol. 2012; 361(1-2): 143–152.
- Lin Z, Marepally SR, Goh ESY, et al. Investigation of 20S-hydroxyvitamin D analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities. Sci Rep. 2018; 8(1): 1478.
- Slominski AT, Kim TK, Takeda Y, et al. RORα and RORγ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J. 2014; 28(7): 2775–2789.
- Maestro MA, Molnár F, Carlberg C. Vitamin D and its synthetic analogs. J Med Chem. 2019; 62(15): 6854–6875.
- Ribone SR, Ferronato MJ, Vitale C, et al. Vitamin D receptor exhibits different pharmacodynamic features in tumoral and normal microenvironments: A molecular modeling study. J Steroid Biochem Mol Biol. 2020; 200: 105649.
- Rochel N, Wurtz JM, Mitschler A, et al. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000; 5(1): 173–179.
- Molnár F. Structural considerations of vitamin D signaling. Front Physiol. 2014; 5: 191.
- Molnár F, Peräkylä M, Carlberg C. Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket. J Biol Chem. 2006; 281(15): 10516–10526.
- Carlberg C. Molecular basis of the selective activity of vitamin D analogues. J Cell Biochem. 2003; 88(2): 274–281.
- Carlberg C. Molecular endocrinology of vitamin D on the epigenome level. Mol Cell Endocrinol. 2017; 453: 14–21.
- Wei Z, Yoshihara E, He N, et al. Vitamin D switches BAF complexes to protect β cells. Cell. 2018; 173(5): 1135–1149.e15.
- Carlberg C, Campbell MJ. Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids. 2013; 78(2): 127–136.
- Slominski AT, Kim TK, Hobrath JV, et al. Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR and inverse agonists on RORα and RORγ. J Steroid Biochem Mol Biol. 2017; 173: 42–56.
- Jetten AM. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal. 2009; 7: e003.
- Giguère V, Tini M, Flock G, et al. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994; 8(5): 538–553.
- Sun Z, Unutmaz D, Zou YR, et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science. 2000; 288(5475): 2369–2373.
- Kurebayashi S, Ueda E, Sakaue M, et al. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A. 2000; 97(18): 10132–10137.
- Hirose T, Smith RJ, Jetten AM. ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem Biophys Res Commun. 1994; 205(3): 1976–1983.
- Kang HS, Angers M, Beak JuY, et al. Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics. 2007; 31(2): 281–294.
- Schmidt SF, Madsen JG, Frafjord KØ, et al. Integrative genomics outlines a biphasic glucose response and a ChREBP-RORγ axis regulating proliferation in β cells. Cell Rep. 2016; 16(9): 2359–2372.
- Slominski AT, Kim TK, Takeda Y, et al. RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J. 2014; 28(7): 2775–2789.
- Aguiar SL, Miranda MC, Guimarães MA, et al. High-salt diet induces IL-17-dependent gut inflammation and exacerbates colitis in mice. Front Immunol. 2017; 8: 1969.
- Santori FR, Huang P, van de Pavert SA, et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 2015; 21(2): 286–298.
- Zhao CN, Wang P, Mao YM, et al. Potential role of melatonin in autoimmune diseases. Cytokine Growth Factor Rev. 2019; 48: 1–10.
- Takeda Y, Kang HS, Freudenberg J, et al. Retinoic acid-related orphan receptor γ (RORγ): a novel participant in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. PLoS Genet. 2014; 10(5): e1004331.
- Cook DN, Kang HS, Jetten AM. Retinoic acid-related Orphan Receptors (RORs): regulatory functions in immunity, development, circadian rhythm, and metabolism. Nucl Receptor Res. 2015; 2.
- Slominski AT, Kim TK, Janjetovic Z, et al. Differential and overlapping effects of 20,23(OH)₂D3 and 1,25(OH)₂D3 on gene expression in human epidermal keratinocytes: identification of AhR as an alternative receptor for 20,23(OH)₂D3. Int J Mol Sci. 2018; 19(10).
- Shirvani A, Kalajian TA, Song A, et al. Disassociation of vitamin D's calcemic activity and non-calcemic genomic activity and individual responsiveness: A randomized controlled double-blind clinical trial. Sci Rep. 2019; 9(1): 17685.
- Mia S, Kane MS, Latimer MN, et al. Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption. Am J Physiol Heart Circ Physiol. 2020; 318(6): H1487–H1508.
- Stormo C, Kringen MK, Lyle R, et al. RNA-sequencing analysis of HepG2 cells treated with atorvastatin. PLoS One. 2014; 9(8): e105836.
- Rauber S, Luber M, Weber S, et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat Med. 2017; 23(8): 938–944.
- Roediger B, Weninger W. Resolving a chronic inflammation mystery. Nat Med. 2017; 23(8): 914–916.
- Ruderman NB, Xu XJ, Nelson L, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010; 298(4): E751–E760.
- Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012; 11(2): 230–241.
- Edrey YH, Casper D, Huchon D, et al. Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity. Aging Cell. 2012; 11(2): 213–222.
- Luizon MR, Eckalbar WL, Wang Y, et al. Genomic characterization of metformin hepatic response. PLoS Genet. 2016; 12(11): e1006449.
- Martínez-Revelles S, García-Redondo AB, Avendaño MS, et al. Lysyl oxidase induces vascular oxidative stress and contributes to arterial stiffness and abnormal elastin structure in hypertension: role of p38MAPK. Antioxid Redox Signal. 2017; 27(7): 379–397.
- Molez AM, do Nascimento EH, Haiter Neto F, et al. Effect of resveratrol on the progression of experimental periodontitis in an ovariectomized rat model of osteoporosis: Morphometric, immune-enzymatic, and gene expression analysis. J Periodontal Res. 2020; 55(6): 840–849.
- Ulaszewska M, Garcia-Aloy M, Vázquez-Manjarrez N, et al. Food intake biomarkers for berries and grapes. Genes Nutr. 2020; 15(1): 17.
- Lokhande KB, Ballav S, Yadav RS, et al. Probing intermolecular interactions and binding stability of kaempferol, quercetin and resveratrol derivatives with PPAR-γ: docking, molecular dynamics and MM/GBSA approach to reveal potent PPAR- γ agonist against cancer. J Biomol Struct Dyn. 2020 [Epub ahead of print]: 1–11.
- Rybchyn MS, De Silva WG, Sequeira VB, et al. Enhanced repair of UV-induced DNA damage by 1,25-dihydroxyvitamin D in skin is linked to pathways that control cellular energy. J Invest Dermatol. 2018; 138(5): 1146–1156.
- Bikle D, Christakos S. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nat Rev Endocrinol. 2020; 16(4): 234–252.
- Christakos S, Li S, De La Cruz J, et al. New developments in our understanding of vitamin metabolism, action and treatment. Metabolism. 2019; 98: 112–120.
- Tuckey RC, Cheng CYS, Slominski AT. The serum vitamin D metabolome: What we know and what is still to discover. J Steroid Biochem Mol Biol. 2019; 186: 4–21.
- Slominski AT, Chaiprasongsuk A, Janjetovic Z, et al. Photoprotective properties of vitamin D and lumisterol hydroxyderivatives. Cell Biochem Biophys. 2020; 78(2): 165–180.
- Wang Q, Zhou X, Zhang P, et al. 25-hydroxyvitamin D3 positively regulates periodontal inflammaging via SOCS3/STAT signaling in diabetic mice. Steroids. 2020; 156: 108570.
- Fiala M. Re-balancing of inflammation and abeta immunity as a therapeutic for Alzheimer's disease-view from the bedside. CNS Neurol Disord Drug Targets. 2010; 9(2): 192–196.
- Kawano T, Shimamura M, Nakagami H, et al. Therapeutic vaccine against S100A9 (S100 calcium-binding protein A9) inhibits thrombosis without increasing the risk of bleeding in ischemic stroke in mice. Hypertension. 2018; 72(6): 1355–1364.
- Pawar H, Srikanth SM, Kashyap MK, et al. Downregulation of S100 calcium binding protein A9 in esophageal squamous cell carcinoma. ScientificWorldJournal. 2015; 2015: 325721.
- Lee TH, Jang AS, Park JS, et al. Elevation of S100 calcium binding protein A9 in sputum of neutrophilic inflammation in severe uncontrolled asthma. Ann Allergy Asthma Immunol. 2013; 111(4): 268–275.e1.
- Sales JM, Resurreccion AVA. Resveratrol in peanuts. Crit Rev Food Sci Nutr. 2014; 54(6): 734–770.
- Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors. 2018; 44(1): 36–49.
- Li YR, Li S, Lin CC. Effect of resveratrol and pterostilbene on aging and longevity. Biofactors. 2018; 44(1): 69–82.
- Varoni EM, Lo Faro AF, Sharifi-Rad J, et al. Anticancer molecular mechanisms of resveratrol. Front Nutr. 2016; 3: 8.
- Kim CW, Hwang KA, Choi KC. Anti-metastatic potential of resveratrol and its metabolites by the inhibition of epithelial-mesenchymal transition, migration, and invasion of malignant cancer cells. Phytomedicine. 2016; 23(14): 1787–1796.
- Lephart ED, Andrus MB. Human skin gene expression: Natural (trans) resveratrol versus five resveratrol analogs for dermal applications. Exp Biol Med (Maywood). 2017; 242(15): 1482–1489.
- Arora D, Khurana B, Nanda S. Statistical development and evaluation of resveratrol-loaded topical gel containing deformable vesicles for a significant reduction in photo-induced skin aging and oxidative stress. Drug Dev Ind Pharm. 2020; 46(11): 1898–1910.
- Kumar S, Chang YC, Lai KH, et al. Resveratrol, a molecule with anti-inflammatory and anti-cancer activities: natural product to chemical synthesis. Curr Med Chem. 2021; 28(19): 3773–3786.
- Göbel A, Zinna VM, Dell'Endice S, et al. Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer. BMC Cancer. 2020; 20(1): 703.
- Hai-Na Z, Xu-Ben Yu, Cong-Rong T, et al. Atorvastatin ameliorates depressive behaviors and neuroinflammatory in streptozotocin-induced diabetic mice. Psychopharmacology (Berl). 2020; 237(3): 695–705.
- Zhu X, Shen J, Feng S, et al. Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis. Aging (Albany NY). 2020 [Epub ahead of print]; 12(18): 17845–17862.
- Zajda A, Huttunen KM, Sikora J, et al. Is metformin a geroprotector? A peek into the current clinical and experimental data. Mech Ageing Dev. 2020; 191: 111350.
- Abe S, Ezaki O, Suzuki M. Medium-chain triglycerides (8:0 and 10:0) increase mini-mental state examination (MMSE) score in frail elderly adults in a randomized controlled trial. J Nutr. 2020; 150(9): 2383–2390.
- Mehrabadi S, Sadr SS. Administration of Vitamin D and E supplements reduces neuronal loss and oxidative stress in a model of rats with Alzheimer's disease. Neurol Res. 2020; 42(10): 862–868.
- Lin CI, Chang YC, Kao NJ, et al. 1,25(OH)D alleviates Aβ(25-35)-induced tau hyperphosphorylation, excessive reactive oxygen species, and apoptosis through interplay with glial cell line-derived neurotrophic factor signaling in SH-SY5Y cells. Int J Mol Sci. 2020; 21(12).
- Alamro AA, Alsulami EA, Almutlaq M, et al. Therapeutic potential of Vitamin D and curcumin an in Vitro model of alzheimer disease. J Cent Nerv Syst Dis. 2020; 12: 1179573520924311.
- Saad El-Din S, Rashed L, Medhat E, et al. Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer's disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways. Steroids. 2020; 156: 108586.
- Lin FY, Lin YF, Lin YS, et al. Relative D3 vitamin deficiency and consequent cognitive impairment in an animal model of Alzheimer's disease: Potential involvement of collapsin response mediator protein-2. Neuropharmacology. 2020; 164: 107910.
- Pawlowska E, Wysokinski D, Blasiak J. Nucleotide excision repair and Vitamin D--relevance for skin cancer therapy. Int J Mol Sci. 2016; 17(4): 372.
- Oak ASW, Bocheva G, Kim TK, et al. Noncalcemic Vitamin D hydroxyderivatives inhibit human oral squamous cell carcinoma and down-regulate hedgehog and WNT/β-catenin pathways. Anticancer Res. 2020; 40(5): 2467–2474.
- Li W, Peregrina K, Houston M, et al. Vitamin D and the nutritional environment in functions of intestinal stem cells: Implications for tumorigenesis and prevention. J Steroid Biochem Mol Biol. 2020; 198: 105556.
- Leonaviciute D, Madsen Bo, Schmedes A, et al. Severe metformin poisoning successfully treated with simultaneous venovenous hemofiltration and prolonged intermittent hemodialysis. Case Rep Crit Care. 2018; 2018: 3868051.
- Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care. 2008; 12(6): R149.
- Cottart CH, Nivet-Antoine V, Beaudeux JL, et al. Resveratrol bioavailability and toxicity in humans. Mol Nutr Food Res. 2010; 54(1): 7–16.