International Journal of Molecular Sciences

Editorial

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6 pages, 192 KiB

Open AccessEditorial

Vitamin D and Human Health

by Michal A. Zmijewski

Int. J. Mol. Sci. 2019, 20(1), 145; https://doi.org/10.3390/ijms20010145 - 3 Jan 2019

Cited by 103 | Viewed by 13040

Abstract

Vitamin D is currently one of the hottest topics in research and clinics, as well as in everyday life. Over the past decades, scientists gathered overwhelming evidence indicating that the observed global vitamin D deficiency not only has a negative impact on human [...] Read more.

Vitamin D is currently one of the hottest topics in research and clinics, as well as in everyday life. Over the past decades, scientists gathered overwhelming evidence indicating that the observed global vitamin D deficiency not only has a negative impact on human skeletal system, but also facilitates development and progression of multiple disease of civilization, including cardiovascular diseases, diabetes, autoimmune disease, and cancer. This Special Issue, entitled “Vitamin D and Human Health”, summarizes recent advances in our understanding of pleiotropic activity of vitamin D in the form of eight comprehensive reviews. Furthermore, eight research papers provide new insight into vitamin D research and highlight new directions. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

Research

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35 pages, 5839 KiB

Open AccessArticle

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

by Andrzej T. Slominski, Tae-Kang Kim, Zorica Janjetovic, Anna A. Brożyna, Michal A. Żmijewski, Hui Xu, Thomas R. Sutter, Robert C. Tuckey, Anton M. Jetten and David K. Crossman

Int. J. Mol. Sci. 2018, 19(10), 3072; https://doi.org/10.3390/ijms19103072 - 8 Oct 2018

Cited by 107 | Viewed by 6565

Abstract

A novel pathway of vitamin D activation by CYP11A has previously been elucidated. To define the mechanism of action of its major dihydroxy-products, we tested the divergence and overlap between the gene expression profiles of human epidermal keratinocytes treated with either CYP11A1-derived 20,23(OH) [...] Read more.

A novel pathway of vitamin D activation by CYP11A has previously been elucidated. To define the mechanism of action of its major dihydroxy-products, we tested the divergence and overlap between the gene expression profiles of human epidermal keratinocytes treated with either CYP11A1-derived 20,23(OH)₂D3 or classical 1,25(OH)₂D3. Both secosteroids have significant chemical similarity with the only differences being the positions of the hydroxyl groups. mRNA was isolated and examined by microarray analysis using Illumina’s HumanWG-6 chip/arrays and subsequent bioinformatics analyses. Marked differences in the up- and downregulated genes were observed between 1,25(OH)₂D3- and 20,23(OH)₂D3-treated cells. Hierarchical clustering identified both distinct, opposite and common (overlapping) gene expression patterns. CYP24A1 was a common gene strongly activated by both compounds, a finding confirmed by qPCR. Ingenuity pathway analysis identified VDR/RXR signaling as the top canonical pathway induced by 1,25(OH)₂D3. In contrast, the top canonical pathway induced by 20,23(OH)₂D3 was AhR, with VDR/RXR being the second nuclear receptor signaling pathway identified. QPCR analyses validated the former finding by revealing that 20,23(OH)₂D3 stimulated CYP1A1 and CYP1B1 gene expression, effects located downstream of AhR. Similar stimulation was observed with 20(OH)D3, the precursor to 20,23(OH)₂D3, as well as with its downstream metabolite, 17,20,23(OH)₃D3. Using a Human AhR Reporter Assay System we showed marked activation of AhR activity by 20,23(OH)₂D3, with weaker stimulation by 20(OH)D3. Finally, molecular modeling using an AhR LBD model predicted vitamin D3 hydroxyderivatives to be good ligands for this receptor. Thus, our microarray, qPCR, functional studies and molecular modeling indicate that AhR is the major receptor target for 20,23(OH)₂D3, opening an exciting area of investigation on the interaction of different vitamin D3-hydroxyderivatives with AhR and the subsequent downstream activation of signal transduction pathways in a cell-type-dependent manner. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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16 pages, 2376 KiB

Open AccessArticle

Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

by Tomasz Wasiewicz, Anna Piotrowska, Justyna Wierzbicka, Andrzej T. Slominski and Michal A. Zmijewski

Int. J. Mol. Sci. 2018, 19(9), 2583; https://doi.org/10.3390/ijms19092583 - 31 Aug 2018

Cited by 28 | Viewed by 4240

Abstract

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic [...] Read more.

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D—21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)₂D₃ and 25(OH)D₃, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)₂D₃ and became VDR^−/−CYP27B1^−/−). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog—21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)₂D₃, 25(OH)D₃ and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR^−/−. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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15 pages, 5672 KiB

Open AccessArticle

Calcitriol and Calcidiol Can Sensitize Melanoma Cells to Low–LET Proton Beam Irradiation

by Ewa Podgorska, Agnieszka Drzal, Zenon Matuszak, Jan Swakon, Andrzej Slominski, Martyna Elas and Krystyna Urbanska

Int. J. Mol. Sci. 2018, 19(8), 2236; https://doi.org/10.3390/ijms19082236 - 31 Jul 2018

Cited by 17 | Viewed by 3642

Abstract

Proton beam irradiation promises therapeutic utility in the management of uveal melanoma. Calcitriol (1,25(OH)₂D₃)—the biologically active metabolite of vitamin D₃—and its precursor, calcidiol (25(OH)D₃), exert pleiotropic effects on melanoma cells. The aim of the study [...] Read more.

Proton beam irradiation promises therapeutic utility in the management of uveal melanoma. Calcitriol (1,25(OH)₂D₃)—the biologically active metabolite of vitamin D₃—and its precursor, calcidiol (25(OH)D₃), exert pleiotropic effects on melanoma cells. The aim of the study was to evaluate the effect of both calcitriol and calcidiol on melanoma cell proliferation and their response to proton beam irradiation. Three melanoma cell lines (human SKMEL-188 and hamster BHM Ma and BHM Ab), pre-treated with 1,25(OH)₂D₃ or 25(OH)D₃ at graded concentrations (0, 10, 100 nM), were irradiated with 0–5 Gy and then cultured in vitro. Growth curves were determined by counting the cell number every 24 h up to 120 h, which was used to calculate surviving fractions. The obtained survival curves were analysed using two standard models: linear-quadratic and multi-target single hit. Calcitriol inhibited human melanoma proliferation at 10 nM, while only calcidiol inhibited proliferation of hamster lines at 10 and 100 nM doses. Treatment with either 1,25(OH)₂D₃ or 25(OH)D₃ radio sensitized melanoma cells to low doses of proton beam radiation. The strength of the effect increased with the concentration of vitamin D₃. Our data suggest that vitamin D₃ may be an adjuvant that modifies proton beam efficiency during melanoma therapy. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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23 pages, 2730 KiB

Open AccessArticle

Calcitriol and Its Analogs Establish the Immunosuppressive Microenvironment That Drives Metastasis in 4T1 Mouse Mammary Gland Cancer

by Agata Pawlik, Artur Anisiewicz, Beata Filip-Psurska, Marcin Nowak, Eliza Turlej, Justyna Trynda, Joanna Banach, Paweł Gretkierewicz and Joanna Wietrzyk

Int. J. Mol. Sci. 2018, 19(7), 2116; https://doi.org/10.3390/ijms19072116 - 20 Jul 2018

Cited by 26 | Viewed by 5826

Abstract

In our previous study, calcitriol and its analogs PRI-2191 and PRI-2205 stimulated 4T1 mouse mammary gland cancer metastasis. Therefore, we aimed to analyze the inflammatory response in 4T1-bearing mice treated with these compounds. Gene expression analysis of the splenocytes and regional lymph nodes [...] Read more.

In our previous study, calcitriol and its analogs PRI-2191 and PRI-2205 stimulated 4T1 mouse mammary gland cancer metastasis. Therefore, we aimed to analyze the inflammatory response in 4T1-bearing mice treated with these compounds. Gene expression analysis of the splenocytes and regional lymph nodes demonstrated prevalence of the T helper lymphocytes (Th2) response with an increased activity of regulatory T (Treg) lymphocytes in mice treated with these compounds. We also observed an increased number of mature granulocytes and B lymphocytes and a decreased number of TCD4⁺, TCD4⁺CD25⁺, and TCD8⁺, as well as natural killer (NK) CD335⁺, cells in the blood of mice treated with calcitriol and its analogs. Among the splenocytes, we observed a significant decrease in NK CD335⁺ cells and an increase in TCD8⁺ cells. Calcitriol and its analogs decreased the levels of interleukin (IL)-1β and IL-10 and increased the level of interferon gamma (IFN-γ) in the plasma. In the tumor tissue, they caused an increase in the level of IL-10. Gene expression analysis of lung tissue demonstrated an increased level of osteopontin (Spp1) and transforming growth factor β (TGF-β) mRNA. The expression of Spp1 was also elevated in lymph nodes. Calcitriol and its analogs caused prevalence of tumor-conducive changes in the immune system of 4T1 tumor-bearing mice, despite the induction of some tumor-disadvantageous effects. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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13 pages, 3217 KiB

Open AccessArticle

Vitamin D’s Effect on the Proliferation and Inflammation of Human Intervertebral Disc Cells in Relation to the Functional Vitamin D Receptor Gene FokI Polymorphism

by Paola De Luca, Laura De Girolamo, Carlotta Perucca Orfei, Marco Viganò, Riccardo Cecchinato, Marco Brayda-Bruno and Alessandra Colombini

Int. J. Mol. Sci. 2018, 19(7), 2002; https://doi.org/10.3390/ijms19072002 - 9 Jul 2018

Cited by 13 | Viewed by 4214

Abstract

Vitamin D is known to have immunomodulatory effects, is involved in osteo-cartilaginous metabolism, and may have a role in human intervertebral disc pathophysiology. Although a link between vitamin D receptor (VDR) gene variants and disc degeneration-related pathologies has been observed, its functional contribution [...] Read more.

Vitamin D is known to have immunomodulatory effects, is involved in osteo-cartilaginous metabolism, and may have a role in human intervertebral disc pathophysiology. Although a link between vitamin D receptor (VDR) gene variants and disc degeneration-related pathologies has been observed, its functional contribution to pathologic processes has not been assessed yet. The aim of this study was to investigate the response of disc cells to vitamin D in terms of the regulation of proliferation, metabolism, and inflammatory processes, with a particular focus on the FokI VDR genotype. However, although it was found that vitamin D had a pro-apoptotic effect regardless of genotype, an up-regulation of IL-1Ra and downregulation of IL-6 was found to be evident only in Ff cells. Regarding the metabolic effects, in Ff cells, vitamin D promoted an upregulation of the aggrecan in inflammatory conditions but did not have an effect on the expression of collagen-related markers. Moreover, cells bearing the Ff genotype were the most responsive to vitamin D in the upregulation of catabolic markers. In addition, in contrast to the FF genotype, vitamin D downregulated the vitamin D-dependent signaling pathway in inflamed Ff cells, counteracting the inflammation-mediated catabolic effects. In conclusion, Ff cells were found to be more responsive to the anti-inflammatory and catabolic effects of vitamin D, which is likely to be related to matrix remodeling. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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11 pages, 287 KiB

Open AccessArticle

Single Nucleotide Polymorphisms in the Vitamin D Receptor Gene (VDR) May Have an Impact on Acute Pancreatitis (AP) Development: A Prospective Study in Populations of AP Patients and Alcohol-Abuse Controls

by Anna Cieślińska, Elżbieta Kostyra, Ewa Fiedorowicz, Jadwiga Snarska, Natalia Kordulewska, Krzysztof Kiper and Huub F. J. Savelkoul

Int. J. Mol. Sci. 2018, 19(7), 1919; https://doi.org/10.3390/ijms19071919 - 29 Jun 2018

Cited by 17 | Viewed by 5877

Abstract

Vitamin D imbalance is suggested to be associated with the development of pancreatitis. Single nucleotide polymorphisms (SNPs), Apa-1, Bsm-1, Fok-1, and Taq-1, in the vitamin D receptor gene (VDR) are known in various diseases, but not yet in pancreatitis. The aim [...] Read more.

Vitamin D imbalance is suggested to be associated with the development of pancreatitis. Single nucleotide polymorphisms (SNPs), Apa-1, Bsm-1, Fok-1, and Taq-1, in the vitamin D receptor gene (VDR) are known in various diseases, but not yet in pancreatitis. The aim of this study was to explore possible associations of the four SNPs in the VDR receptor gene in a population of acute pancreatitis patients and alcohol-abuse controls, and to investigate the association with acute pancreatitis (AP) susceptibility. The study population (n = 239) included acute pancreatitis patients (n = 129) and an alcohol-abuse control group (n = 110). All patients met the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria for alcohol dependence. DNA was extracted from peripheral leukocytes and analyzed for VDR polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. To date, we have found allele T in Taq-1 (OR = 2.61; 95% CI: 1.68–4.03; p < 0.0001) to be almost three times more frequent in the AP group compared to the alcohol-abuse control patients. Polymorphism Taq-1 occurring in the vitamin D receptor may have an impact on the development of acute pancreatitis due to the lack of the protective role of vitamin D. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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12 pages, 1268 KiB

Open AccessArticle

Vitamin D Receptor Is Necessary for Mitochondrial Function and Cell Health

by Chiara Ricca, Alessia Aillon, Loredana Bergandi, Daniela Alotto, Carlotta Castagnoli and Francesca Silvagno

Int. J. Mol. Sci. 2018, 19(6), 1672; https://doi.org/10.3390/ijms19061672 - 5 Jun 2018

Cited by 127 | Viewed by 9893

Abstract

Vitamin D receptor (VDR) mediates many genomic and non-genomic effects of vitamin D. Recently, the mitochondrial effects of vitamin D have been characterized in many cell types. In this article, we investigated the importance of VDR not only in mitochondrial activity and integrity [...] Read more.

Vitamin D receptor (VDR) mediates many genomic and non-genomic effects of vitamin D. Recently, the mitochondrial effects of vitamin D have been characterized in many cell types. In this article, we investigated the importance of VDR not only in mitochondrial activity and integrity but also in cell health. The silencing of the receptor in different healthy, non-transformed, and cancer cells initially decreased cell growth and modulated the cell cycle. We demonstrated that, in silenced cells, the increased respiratory activity was associated with elevated reactive oxygen species (ROS) production. In the long run, the absence of the receptor caused impairment of mitochondrial integrity and, finally, cell death. Our data reveal that VDR plays a central role in protecting cells from excessive respiration and production of ROS that leads to cell damage. Because we confirmed our observations in different models of both normal and cancer cells, we conclude that VDR is essential for the health of human tissues. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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16 pages, 1703 KiB

Open AccessArticle

Expression of TXNIP in Cancer Cells and Regulation by 1,25(OH)₂D₃: Is It Really the Vitamin D₃ Upregulated Protein?

by Mohamed A. Abu el Maaty, Fadi Almouhanna and Stefan Wölfl

Int. J. Mol. Sci. 2018, 19(3), 796; https://doi.org/10.3390/ijms19030796 - 10 Mar 2018

Cited by 15 | Viewed by 7825

Abstract

Thioredoxin-interacting protein (TXNIP) was originally identified in HL-60 cells as the vitamin D₃ upregulated protein 1, and is now known to be involved in diverse cellular processes, such as maintenance of glucose homeostasis, redox balance, and apoptosis. Besides the initial characterization, little [...] Read more.

Thioredoxin-interacting protein (TXNIP) was originally identified in HL-60 cells as the vitamin D₃ upregulated protein 1, and is now known to be involved in diverse cellular processes, such as maintenance of glucose homeostasis, redox balance, and apoptosis. Besides the initial characterization, little is known about if and how 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] induces TXNIP expression. We therefore screened multiple cancerous cell lines of different tissue origins, and observed induction, repression, or no change in TXNIP expression in response to 1,25(OH)₂D₃. In-depth analyses on HL-60 cells revealed a rapid and transient increase in TXNIP mRNA levels by 1,25(OH)₂D₃ (3–24 h), followed by a clear reduction at later time points. Furthermore, a strong induction in protein levels was observed only after 96 h of 1,25(OH)₂D₃ treatment. Induction of TXNIP expression by 1,25(OH)₂D₃ was found to be dependent on the availability of glucose in the culture medium, as well as the presence of a functional glucose transport system, indicating an inter-dependence of 1,25(OH)₂D₃ actions and glucose-sensing mechanisms. Moreover, the inhibition of de novo protein synthesis by cycloheximide reduced TXNIP half-life in 24 h, but not in 96 h-1,25(OH)₂D₃-treated HL-60 cells, demonstrating a possible influence of 1,25(OH)₂D₃ on TXNIP stability in long-term treatment. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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9 pages, 1403 KiB

Open AccessArticle

Vitamin D Status and the Relationship with Bone Fragility Fractures in HIV-Infected Patients: A Case Control Study

by Marco Atteritano, Luigi Mirarchi, Emmanuele Venanzi-Rullo, Domenico Santoro, Chiara Iaria, Antonino Catalano, Antonino Lasco, Vincenzo Arcoraci, Alberto Lo Gullo, Alessandra Bitto, Francesco Squadrito and Antonio Cascio

Int. J. Mol. Sci. 2018, 19(1), 119; https://doi.org/10.3390/ijms19010119 - 2 Jan 2018

Cited by 30 | Viewed by 5502

Abstract

HIV-infected patients show high risk of fracture. The aims of our study were to determine the prevalence of vertebral fractures (VFs) and their associations with vitamin D in HIV patients. 100 patients with HIV infection and 100 healthy age- and sex-matched controls were [...] Read more.

HIV-infected patients show high risk of fracture. The aims of our study were to determine the prevalence of vertebral fractures (VFs) and their associations with vitamin D in HIV patients. 100 patients with HIV infection and 100 healthy age- and sex-matched controls were studied. Bone mineral density was measured by quantitative ultrasound at the non-dominant heel. Serum osteocalcin and C-terminal telopeptide of collagen type 1 served as bone turnover markers. Bone ultrasound measurements were significantly lower in patients compared with controls (Stiffness Index (SI): 80.58 ± 19.95% vs. 93.80 ± 7.10%, respectively, p < 0.001). VFs were found in 16 patients and in 2 controls. HIV patients with vertebral fractures showed lower stiffness index (SI) (70.75 ± 10.63 vs. 83.36 ± 16.19, respectively, p = 0.045) and lower vitamin D levels (16.20 ± 5.62 vs. 28.14 ± 11.94, respectively, p < 0.02). The majority of VFs (87.5%) were observed in HIV-infected patients with vitamin D insufficiency, and regression analysis showed that vitamin D insufficiency was significantly associated with vertebral fractures (OR 9.15; 95% CI 0.18–0.52, p < 0.04). VFs and are a frequent occurrence in HIV-infected patients and may be associated with vitamin D insufficiency. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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Review

Jump to: Editorial, Research

16 pages, 862 KiB

Open AccessReview

The Anti-Inflammatory Effects of Vitamin D in Tumorigenesis

by Wei Liu, Lei Zhang, Hui-Jing Xu, Yan Li, Chuan-Min Hu, Jing-Yan Yang and Mei-Yan Sun

Int. J. Mol. Sci. 2018, 19(9), 2736; https://doi.org/10.3390/ijms19092736 - 13 Sep 2018

Cited by 142 | Viewed by 13972

Abstract

In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally [...] Read more.

In conjunction with the classical functions of regulating intestinal, bone, and kidney calcium and phosphorus absorption, as well as bone mineralization of vitamin D, the population-based association between low vitamin D status and increased cancer risk is now generally accepted. Inflammation is causally related to oncogenesis. It is widely thought that vitamin D plays an important role in the modulation of the inflammation system by regulating the production of inflammatory cytokines and immune cells, which are crucial for the pathogenesis of many immune-related diseases. Mechanistic studies have shown that vitamin D influences inflammatory processes involved in cancer progression, including cytokines, prostaglandins, MAP kinase phosphatase 5 (MKP5), the nuclear factor kappa B (NF-κB) pathway, and immune cells. Multiple studies have shown that vitamin D has the potential to inhibit tumor development by interfering with the inflammation system. The present review summarizes recent studies of the mechanisms of vitamin D on regulating the inflammation system, which contributes to its potential for cancer prevention and therapy. This review helps answer whether inflammation mediates a causal relationship between vitamin D and tumorigenesis. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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25 pages, 1093 KiB

Open AccessReview

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications

by Mayte Medrano, Estrella Carrillo-Cruz, Isabel Montero and Jose A Perez-Simon

Int. J. Mol. Sci. 2018, 19(9), 2663; https://doi.org/10.3390/ijms19092663 - 8 Sep 2018

Cited by 129 | Viewed by 12369

Abstract

Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called “non-classical actions.” Among them, vitamin D regulates immune [...] Read more.

Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called “non-classical actions.” Among them, vitamin D regulates immune cells function and hematopoietic cells differentiation and proliferation. Based on these effects, it is currently being evaluated for the treatment of hematologic malignancies. In addition, vitamin D levels have been correlated with patients’ outcome after allogeneic stem cell transplantation, where it might regulate immune response and, accordingly, might influence the risk of graft-versus-host disease. Here, we present recent advances regarding its clinical applications both in the treatment of hematologic malignancies and in the transplant setting. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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25 pages, 1085 KiB

Open AccessReview

Vitamin D and Influenza—Prevention or Therapy?

by Beata M. Gruber-Bzura

Int. J. Mol. Sci. 2018, 19(8), 2419; https://doi.org/10.3390/ijms19082419 - 16 Aug 2018

Cited by 145 | Viewed by 22526

Abstract

Vitamin D generates many extraskeletal effects due to the vitamin D receptor (VDR) which is present in most tissues throughout the body. The possible role of vitamin D in infections is implied from its impact on the innate and adaptive immune responses. A [...] Read more.

Vitamin D generates many extraskeletal effects due to the vitamin D receptor (VDR) which is present in most tissues throughout the body. The possible role of vitamin D in infections is implied from its impact on the innate and adaptive immune responses. A significant effect is also the suppression of inflammatory processes. Because vitamin D could be acknowledged as a “seasonal stimulus”, as defined by R. Edgar Hope-Simpson, it would be crucial to prove it from a potential easy and cheap prophylaxis or therapy support perspective as far as influenza infections are concerned. The survey of the literature data generates some controversies and doubts about the possible role of vitamin D in the prevention of influenza virus. The most important point is to realise that the broad spectrum of this vitamin’s activity does not exclude such a possibility. According to most of the authors, more randomized controlled trials with effective, large populations are needed to explore the preventive effect of vitamin D supplementation on viral influenza infections. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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14 pages, 579 KiB

Open AccessReview

The Impact of Vitamin D on the Immunopathophysiology, Disease Activity, and Extra-Musculoskeletal Manifestations of Systemic Lupus Erythematosus

by Anselm Mak

Int. J. Mol. Sci. 2018, 19(8), 2355; https://doi.org/10.3390/ijms19082355 - 10 Aug 2018

Cited by 44 | Viewed by 6970

Abstract

Over the past two decades it has been increasingly recognized that vitamin D, aside from its crucial involvement in calcium and phosphate homeostasis and the dynamics of the musculoskeletal system, exerts its influential impact on the immune system. The mechanistic roles that vitamin [...] Read more.

Over the past two decades it has been increasingly recognized that vitamin D, aside from its crucial involvement in calcium and phosphate homeostasis and the dynamics of the musculoskeletal system, exerts its influential impact on the immune system. The mechanistic roles that vitamin D plays regarding immune activation for combating infection, as well as pathologically and mediating autoimmune conditions, have been progressively unraveled. In vitro and in vivo models have demonstrated that the action of vitamin D on various immunocytes is not unidirectional. Rather, how vitamin D affects immunocyte functions depends on the context of the immune response, in the way that its suppressive or stimulatory action offers physiologically appropriate and immunologically advantageous outcomes. In this review, the relationship between various aspects of vitamin D, starting from its adequacy in circulation to its immunological functions, as well as its autoimmune conditions, in particular systemic lupus erythematosus (SLE), a prototype autoimmune condition characterized by immune-complex mediated inflammation, will be discussed. Concurring with other groups of investigators, our group found that vitamin D deficiency is highly prevalent in patients with SLE. Furthermore, the circulating vitamin D levels appear to be correlated with a higher disease activity of SLE as well as extra-musculoskeletal complications of SLE such as fatigue, cardiovascular risk, and cognitive impairment. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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27 pages, 484 KiB

Open AccessReview

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

by Rita Moretti, Maria Elisa Morelli and Paola Caruso

Int. J. Mol. Sci. 2018, 19(8), 2245; https://doi.org/10.3390/ijms19082245 - 31 Jul 2018

Cited by 119 | Viewed by 14599

Abstract

It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and [...] Read more.

It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurological pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurology, as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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18 pages, 1364 KiB

Open AccessReview

Vitamin D and Uterine Fibroids—Review of the Literature and Novel Concepts

by Michał Ciebiera, Marta Włodarczyk, Magdalena Ciebiera, Kornelia Zaręba, Krzysztof Łukaszuk and Grzegorz Jakiel

Int. J. Mol. Sci. 2018, 19(7), 2051; https://doi.org/10.3390/ijms19072051 - 14 Jul 2018

Cited by 54 | Viewed by 13199

Abstract

This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed [...] Read more.

This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed using the following key words: “uterine fibroid” and “vitamin D”. The results of the available studies, published in English from January 2002 up to April 2018, have been discussed. Vitamin D is a group of steroid compounds with a powerful impact on many parts of the human body. This vitamin is believed to regulate cell proliferation and differentiation, inhibit angiogenesis, and stimulate apoptosis. Nowadays, hypovitaminosis D is believed to be a major risk factor in the development of UFs. In many studies vitamin D appears to be a powerful factor against UFs, resulting in inhibition of tumor cell division and a significant reduction in its size, however, the exact role of this compound and its receptor in the pathophysiology of UFs is not fully understood. According to available studies, vitamin D and its analogs seem to be promising, effective, and low-cost compounds in the management of UFs and their clinical symptoms, and the anti-tumor activities of vitamin D play an important role in UF biology. The synergy between vitamin D and selected anti-UF drugs is a very interesting issue which requires further research. Further studies about the biological effect of vitamin D on UF biology are essential. Vitamin D preparations (alone or as a co-drugs) could become new tools in the fight with UFs, with the additional beneficial pleiotropic effect. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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Open AccessReview

The Impact of Vitamin D in the Treatment of Essential Hypertension

by Christian Legarth, Daniela Grimm, Markus Wehland, Johann Bauer and Marcus Krüger

Int. J. Mol. Sci. 2018, 19(2), 455; https://doi.org/10.3390/ijms19020455 - 3 Feb 2018

Cited by 72 | Viewed by 16033

Abstract

The aim of this review is to investigate, whether there is a possible link between vitamin D supplementation and the reduction of blood pressure in hypertensive patients. The renin-angiotensin-aldosterone system is known for being deeply involved in cardiovascular tonus and blood pressure regulation. [...] Read more.

The aim of this review is to investigate, whether there is a possible link between vitamin D supplementation and the reduction of blood pressure in hypertensive patients. The renin-angiotensin-aldosterone system is known for being deeply involved in cardiovascular tonus and blood pressure regulation. Hence, many of the pharmaceutical antihypertensive drugs inhibit this system. Interestingly, experimental studies in mice have indicated that vitamin D supplementation significantly lowers renin synthesis and blood pressure. It is conceivable that similar mechanisms may be found in the human organism. Regarding this, large-scale cross-sectional studies suggest the serum 25(OH)D-level to be inversely correlated to the prevalence of hypertension. However, randomized controlled trials (RCTs) have not found a clear association between vitamin D supplementation and improvements in hypertension. Nevertheless, the missing association of vitamin D and hypertension in clinical trials can be due to suboptimal study designs. There are hints that restoration of serum 25(OH)D levels during vitamin D therapy is essential to achieve possible beneficial cardiovascular effects. It is important to perform long-term trials with a short dose interval and a high bioavailability of supplementation. Taken together, more RCTs are required to further investigate if vitamin D can be beneficial for the reduction of blood pressure. Full article

(This article belongs to the Special Issue Vitamin D and Human Health)

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