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Melatonin and Vitamin D: Molecular Mechanisms and Biological Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 35143

Special Issue Editors


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Guest Editor
Department of Dermatology, University of Münster, 48149 Münster, Germany
Interests: dermato-endocrinology; melanoma; melanogenesis; human skin; photobiology; cutaneous cells; mitochondria; oxidative stress
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Special Issue Information

Dear Colleagues,

Recently, numerous studies have provided new insights into the new biological capacities and health-related or clinical applications for melatonin, vitamin D as well as its metabolites. Namely, both substances have been widely documented as differentiative ones with beneficial impact such as the biological regulation of circadian rhythms, sleep, mood, reproduction, tumor growth, immune response, and neurodegenerative processes for melatonin or being a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, phosphate, and many other biological effects for vitamin D.

The Special Issue on “Melatonin and Vitamin D: Molecular Mechanisms and Biological Function” will include manuscripts collecting the latest scientific findings in terms of molecular mechanisms of action and biological function of melatonin and vitamin D as well as their metabolites or homologues. Papers aim to improve our understanding of the biological meaningful of these substances as well as involved signalling pathways. Original experimental research, review articles, and commentary articles on this and related topics are invited.

Dr. Konrad Kleszczyński
Prof. Dr. Andrzej Slominski
Guest Editors

Manuscript Submission Information

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Keywords

  • Melatonin
  • Metabolites of melatonin
  • Vitamin D
  • Vitamins
  • Melanoma
  • Skin Diseases
  • Cell Signalling
  • Mitochondria
  • Dermatoendocrinology
  • Skin Therapy

Published Papers (7 papers)

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Research

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15 pages, 1876 KiB  
Article
Modulation by 17,20S(OH)2pD of Fibrosis-Related Mediators in Dermal Fibroblast Lines from Healthy Donors and from Patients with Systemic Sclerosis
by Monica L. Brown Lobbins, Andrzej T. Slominski, Karen A. Hasty, Sicheng Zhang, Duane D. Miller, Wei Li, Tae-Kang Kim, Zorica Janjetovic, Robert C. Tuckey, Imara-Safi O. Scott, Linda K. Myers and Arnold E. Postlethwaite
Int. J. Mol. Sci. 2022, 23(1), 367; https://doi.org/10.3390/ijms23010367 - 29 Dec 2021
Cited by 7 | Viewed by 1756
Abstract
We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH)2pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma [...] Read more.
We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH)2pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma (SSc)) and assessed the effects of 17,20S(OH)2pD on fibrosis-related mediators. Dermal fibroblast lines were established from skin biopsies from patients with SSc and healthy controls. Fibroblasts were cultured with either 17,20S(OH)2pD or 1,25(OH)2D3 (positive control) with/without TGF-β1 stimulation and extracted for protein and/or mRNA for collagen synthesis and mediators of fibrosis (MMP-1, TIMP-1, PAI-1, BMP-7, PGES, GLI1, and GLI2). 1 7,20S(OH)2pD (similar to 1,25(OH)2D3) significantly suppressed net total collagen production in TGF-β1-stimulated normal donor fibroblast cultures and in cultures of SSc dermal fibroblasts. 17,20S(OH)2pD (similar to 1,25(OH)2D3) also increased MMP-1, BMP-7, and PGES and decreased TIMP-1 and PAI1 expression in SSc fibroblasts. Although 17,20S(OH)2pD had no effect on Gli1 or Gli2 in SSc fibroblasts, it increased Gli2 expression when cultured with TGF-β1 in normal fibroblasts. These studies demonstrated that 17,20S(OH)2pD modulates mediators of fibrosis to favor the reduction of fibrosis and may offer new noncalcemic secosteroidal therapeutic approaches for treating SSc and fibrosis. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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14 pages, 1554 KiB  
Article
1,25-Dihydroxyvitamin D3 and 20-Hydroxyvitamin D3 Upregulate LAIR-1 and Attenuate Collagen Induced Arthritis
by Linda K. Myers, Michael Winstead, John D. Kee, Jeoungeun J. Park, Sicheng Zhang, Wei Li, Ae-Kyung Yi, John M. Stuart, Edward F. Rosloniec, David D. Brand, Robert C. Tuckey, Andrzej T. Slominski, Arnold E. Postlethwaite and Andrew H. Kang
Int. J. Mol. Sci. 2021, 22(24), 13342; https://doi.org/10.3390/ijms222413342 - 12 Dec 2021
Cited by 9 | Viewed by 2739
Abstract
Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) [...] Read more.
Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) model to analyze the efficacy of the noncalcemic analog of vitamin D, 20S-hydroxyvitamin D3 [20S(OH)D3], as well as 1,25(OH)2D3, to attenuate arthritis and explore a potential mechanism of action. Mice fed a diet deficient in vitamin D developed a more severe arthritis characterized by enhanced secretion of T cell inflammatory cytokines, compared to mice fed a normal diet. The T cell inflammatory cytokines were effectively suppressed, however, by culture of the cells with 20S(OH)D3. Interestingly, one of the consequences of culture with 1,25(OH)2D3 or 20S(OH)D3, was upregulation of the natural inhibitory receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1 or CD305). Polyclonal antibodies which activate LAIR-1 were also capable of attenuating arthritis. Moreover, oral therapy with active forms of vitamin D suppressed arthritis in LAIR-1 sufficient DR1 mice, but were ineffective in LAIR-1−/− deficient mice. Taken together, these data show that the effect of vitamin D on inflammation is at least, in part, mediated by LAIR-1 and that non-calcemic 20S(OH)D3 may be a promising therapeutic agent for the treatment of autoimmune diseases such as Rheumatoid Arthritis. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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16 pages, 2508 KiB  
Article
1,25(OH)2D3 Inhibited Ferroptosis in Zebrafish Liver Cells (ZFL) by Regulating Keap1-Nrf2-GPx4 and NF-κB-hepcidin Axis
by Ke Cheng, Yanqing Huang and Chunfang Wang
Int. J. Mol. Sci. 2021, 22(21), 11334; https://doi.org/10.3390/ijms222111334 - 20 Oct 2021
Cited by 40 | Viewed by 5973
Abstract
Ferroptosis is a kind of iron-dependent programed cell death. Vitamin D has been shown to be an antioxidant and a regulator of iron metabolism, but the relationship between vitamin D and ferroptosis is poorly studied in fish. This study used zebrafish liver cells [...] Read more.
Ferroptosis is a kind of iron-dependent programed cell death. Vitamin D has been shown to be an antioxidant and a regulator of iron metabolism, but the relationship between vitamin D and ferroptosis is poorly studied in fish. This study used zebrafish liver cells (ZFL) to establish a ferroptosis model to explore the effect of 1,25(OH)2D3 on cell ferroptosis and its mechanism of action. The results showed that different incubation patterns of 1,25(OH)2D3 improved the survival rate of ZFL, mitigated mitochondrial damage, enhanced total glutathione peroxidase (GPx) activity, and reduced intracellular reactive oxygen species (ROS), lipid peroxidation (LPO), and malondialdehyde (MDA), as well as iron ion levels, with the best effect at 200 pM 1,25(OH)2D3 preincubation for 72 h. Preincubation of ZFL at 200 pM 1,25(OH)2D3 for 72 h downgraded keap1 and ptgs2 gene expression, increased nrf2, ho-1, fth1, gpx4a,b expression, and lowered the expression of the nf-κb p65,il-6,il-1β gene, thus reducing the expression of hamp1. The above results indicate that different incubation patterns of 1,25(OH)2D3 have protective effects on ferroptosis of ZFL induced by ferroptosis activator RSL3 and 1,25(OH)2D3 can inhibit ferroptosis of ZFL by regulating Keap1–Nrf2–GPx4 and NF-κB–hepcidin axis. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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11 pages, 2697 KiB  
Article
17,20S(OH)2pD Can Prevent the Development of Skin Fibrosis in the Bleomycin-Induced Scleroderma Mouse Model
by Monica L. Brown Lobbins, Imara-Safi O. Scott, Andrzej T. Slominski, Karen A. Hasty, Sicheng Zhang, Duane D. Miller, Wei Li, Tae-Kang Kim, Zorica Janjetovic, Tejesh S. Patel, Linda K. Myers and Arnold E. Postlethwaite
Int. J. Mol. Sci. 2021, 22(16), 8926; https://doi.org/10.3390/ijms22168926 - 19 Aug 2021
Cited by 10 | Viewed by 2479
Abstract
Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses [...] Read more.
Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-β1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 μg/100 μL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 μg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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13 pages, 6582 KiB  
Article
Evaluation of Polymeric Matrix Loaded with Melatonin for Wound Dressing
by Beata Kaczmarek-Szczepańska, Justyna Ostrowska, Justyna Kozłowska, Zofia Szota, Anna A. Brożyna, Rita Dreier, Russel J. Reiter, Andrzej T. Slominski, Kerstin Steinbrink and Konrad Kleszczyński
Int. J. Mol. Sci. 2021, 22(11), 5658; https://doi.org/10.3390/ijms22115658 - 26 May 2021
Cited by 10 | Viewed by 3163
Abstract
The development of scaffolds mimicking the extracellular matrix containing bioactive substances has great potential in tissue engineering and wound healing applications. This study investigates melatonin—a methoxyindole present in almost all biological systems. Melatonin is a bioregulator in terms of its potential clinical importance [...] Read more.
The development of scaffolds mimicking the extracellular matrix containing bioactive substances has great potential in tissue engineering and wound healing applications. This study investigates melatonin—a methoxyindole present in almost all biological systems. Melatonin is a bioregulator in terms of its potential clinical importance for future therapies of cutaneous diseases. Mammalian skin is not only a prominent melatonin target, but also produces and rapidly metabolizes the multifunctional methoxyindole to biologically active metabolites. In our methodology, chitosan/collagen (CTS/Coll)-contained biomaterials are blended with melatonin at different doses to fabricate biomimetic hybrid scaffolds. We use rat tail tendon- and Salmo salar fish skin-derived collagens to assess biophysical and cellular properties by (i) Fourier transform infrared spectroscopy—attenuated total reflectance (FTIR–ATR), (ii) thermogravimetric analysis (TG), (iii) scanning electron microscope (SEM), and (iv) proliferation ratio of cutaneous cells in vitro. Our results indicate that melatonin itself does not negatively affect biophysical properties of melatonin-immobilized hybrid scaffolds, but it induces a pronounced elevation of cell viability within human epidermal keratinocytes (NHEK), dermal fibroblasts (NHDF), and reference melanoma cells. These results demonstrate that this indoleamine accelerates re-epithelialization. This delivery is a promising technique for additional explorations in future dermatotherapy and protective skin medicine. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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Review

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30 pages, 631 KiB  
Review
Melatonin and the Programming of Stem Cells
by Rüdiger Hardeland
Int. J. Mol. Sci. 2022, 23(4), 1971; https://doi.org/10.3390/ijms23041971 - 10 Feb 2022
Cited by 12 | Viewed by 4533
Abstract
Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly [...] Read more.
Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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23 pages, 1660 KiB  
Review
Protective Role of Melatonin and Its Metabolites in Skin Aging
by Georgeta Bocheva, Radomir M. Slominski, Zorica Janjetovic, Tae-Kang Kim, Markus Böhm, Kerstin Steinbrink, Russel J. Reiter, Konrad Kleszczyński and Andrzej T. Slominski
Int. J. Mol. Sci. 2022, 23(3), 1238; https://doi.org/10.3390/ijms23031238 - 22 Jan 2022
Cited by 54 | Viewed by 13487
Abstract
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue Melatonin and Vitamin D: Molecular Mechanisms and Biological Function)
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