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Special Issue "Vitamin D and Its Analogues 2019: New Insights on Biological Effects and Therapeutic Uses"

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

Deadline for manuscript submissions: closed (31 August 2019).

Special Issue Editors

Prof. Dr. George P. Studzinski
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Leading Guest Editor
Department of Pathology, Rutgers-New Jersey Medical School, Newark, Medical Science Building (MSB), 185 South Orange Avenue Room C543, Newark, NJ 07103, USA
Interests: vitamin D; vitamin D analogs; retinoids; semi-selective activities; cell differentiation; nuclear receptors
Special Issues and Collections in MDPI journals
Prof. Dr. Michael Danilenko
Website
Guest Editor
Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
Interests: acute myeloid leukemia; cell differentiation; vitamin D; vitamin D analogs; plant-derived bioactive compounds; redox signaling and regulation; calcium signaling; cell cycle regulation, apoptosis
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The proven importance of vitamin D for human health has stimulated extensive efforts, not only to understand the variety of its biological actions, but also attempts by organic chemists to modify the vitamin D structure to produce analogs that can be more potent in its effects on various body systems other than the skeletal system. The earliest modification occurred in nature. Animals, including humans, synthesize the secosteroid known as vitamin D3 (cholecalciferol), while plants synthesize vitamin D2 (ergocalciferol) with an unsaturated side-chain. Both have similar biological functions in humans, and both are used to treat rickets, osteoporosis, and osteomalacia. In order to be active as regulators of gene transcription, they need to be metabolically activated in the human body. Vitamin D2 and its derivatives were found to be somewhat less potent, but also less toxic, compared to vitamin D3 compounds. Numerous analogues have been synthesized with the primary goal of overcoming the hypercalcemic toxicity of active natural vitamin D derivatives, which limits their clinical use. Several such analogues have demonstrated reduced calcemic effects in model systems and human studies. Nevertheless, more work is necessary to develop clinically effective analogues. The ability of vitamin D compounds to cooperate with conventional drugs and with agents that sensitize abnormal cells to these compounds may offer a complementary approach towards an improved vitamin D-based therapy of human diseases.

This Special Issue will cover a selection of recent research topics and current review articles in the field of vitamin D and its analogues for biological actions and therapy of human diseases.

Prof. Dr. Ewa Marcinkowska
Prof. Dr. George P. Studzinski
Prof. Dr. Michael Danilenko
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vitamin D
  • analogs of vitamin D
  • vitamin D receptor
  • vitamin D metabolism
  • calcium-phosphate homeostasis
  • differentiation
  • apoptosis
  • cell cycle
  • intracellular signaling
  • regulation of immune system

Published Papers (6 papers)

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Research

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Open AccessArticle
Synthesis, CYP24A1-Dependent Metabolism and Antiproliferative Potential against Colorectal Cancer Cells of 1,25-Dihydroxyvitamin D2 Derivatives Modified at the Side Chain and the A-Ring
Int. J. Mol. Sci. 2020, 21(2), 642; https://doi.org/10.3390/ijms21020642 - 18 Jan 2020
Abstract
Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the [...] Read more.
Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion. Full article
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Open AccessArticle
Hormone Receptor Expression in Multicentric/Multifocal versus Unifocal Breast Cancer: Especially the VDR Determines the Outcome Related to Focality
Int. J. Mol. Sci. 2019, 20(22), 5740; https://doi.org/10.3390/ijms20225740 - 15 Nov 2019
Cited by 1
Abstract
The aim of this study was to evaluate the prognostic impact that hormone receptor (HR) expressions have on the two different breast cancer (BC) entities—multifocal versus unifocal BC. As the prognosis determining aspects, we investigated the overall survival (OS) and disease-free survival (DFS) [...] Read more.
The aim of this study was to evaluate the prognostic impact that hormone receptor (HR) expressions have on the two different breast cancer (BC) entities—multifocal versus unifocal BC. As the prognosis determining aspects, we investigated the overall survival (OS) and disease-free survival (DFS) by univariate and multivariate analysis. To underline the study’s conclusions, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging. A retrospective analysis was performed on survival-related events in a series of 320 breast cancer patients treated at the Department of Gynecology and Obstetrics at the Ludwig Maximillian University in Munich between 2000 and 2002. All three steroid receptors analyzed by immunohistochemistry, namely, the estrogen receptor (ER), the progesterone receptor (PR), and the vitamin D receptor (VDR), showed a significantly positive influence on the course of the disease, but only for the unifocal breast tumor patients. The prognosis of patients with multifocal breast cancer was either not affected by estrogen and/or progesterone receptor expression or even involved a worse etiopathology for the vitamin D receptor-positive patients. The estrogen receptor in unifocal breast cancer and the vitamin D receptor in multifocal breast cancer were especially identified as an independent prognostic marker for overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of the hormone receptors in breast cancer and understand why they have different effects on each focality type. Moreover, the studies for an adopted vitamin D supplementation due to breast cancer focality type must be enlarged to fully comprehend the remarkable and interesting role played by the vitamin D receptor. Full article
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Open AccessArticle
Investigating the Role of VDR and Megalin in Semi-Selectivity of Side-Chain Modified 19-nor Analogs of Vitamin D
Int. J. Mol. Sci. 2019, 20(17), 4183; https://doi.org/10.3390/ijms20174183 - 26 Aug 2019
Cited by 2
Abstract
1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should [...] Read more.
1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs. Full article
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Open AccessArticle
25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism
Int. J. Mol. Sci. 2019, 20(9), 2367; https://doi.org/10.3390/ijms20092367 - 13 May 2019
Cited by 1
Abstract
Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced [...] Read more.
Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced in vitamin D3-treated Huh7.5 cells. In this study, we aimed to explore the mechanism of vitamin D3 anti-hepatitis C virus effect. We show that vitamin D3 activity is not mediated by its metabolic conversion to calcitriol, but may be due to its primary metabolic product 25(OH)D3. This is inferred from the findings that 25(OH)D3 could inhibit hepatitis C virus production in our system, and that adequate concentrations needed to exert this effect are produced in Huh7.5 cells treated with vitamin D3. Using the CRISPR-Cas9 editing technology to knockout the vitamin D receptor, we found that the antiviral activity of vitamin D3 and 25(OH)D3 was not impaired in the vitamin D receptor knockout cells. This result indicates that 25(OH)D3 anti-hepatitis C virus effect is exerted by a vitamin D receptor-independent mode of action. The possibility that vitamin D3 and 25(OH)D3, being 3β-hydroxysteroids, affect hepatitis C virus production by direct inhibition of the Hedgehog pathway in a vitamin D receptor-independent manner was ruled out. Taken together, this study proposes a novel mode of action for the anti-hepatitis C virus activity of vitamin D3 that is mediated by 25(OH)D3 in a vitamin D receptor-independent mechanism. Full article
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Review

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Open AccessReview
Epimers of Vitamin D: A Review
Int. J. Mol. Sci. 2020, 21(2), 470; https://doi.org/10.3390/ijms21020470 - 11 Jan 2020
Abstract
In this review, we discuss the sources, formation, metabolism, function, biological activity, and potency of C3-epimers (epimers of vitamin D). We also determine the role of epimerase in vitamin D-binding protein (DBP) and vitamin D receptors (VDR) according to different subcellular localizations. The [...] Read more.
In this review, we discuss the sources, formation, metabolism, function, biological activity, and potency of C3-epimers (epimers of vitamin D). We also determine the role of epimerase in vitamin D-binding protein (DBP) and vitamin D receptors (VDR) according to different subcellular localizations. The importance of C3 epimerization and the metabolic pathway of vitamin D at the hydroxyl group have recently been recognized. Here, the hydroxyl group at the C3 position is orientated differently from the alpha to beta orientation in space. However, the details of this epimerization pathway are not yet clearly understood. Even the gene encoding for the enzyme involved in epimerization has not yet been identified. Many published research articles have illustrated the biological activity of C3 epimeric metabolites using an in vitro model, but the studies on in vivo models are substantially inadequate. The metabolic stability of 3-epi-1α,25(OH)2D3 has been demonstrated to be higher than its primary metabolites. 3-epi-1 alpha, 25 dihydroxyvitamin D3 (3-epi-1α,25(OH)2D3) is thought to have fewer calcemic effects than non-epimeric forms of vitamin D. Some researchers have observed a larger proportion of total vitamin D as C3-epimers in infants than in adults. Insufficient levels of vitamin D were found in mothers and their newborns when the epimers were not included in the measurement of vitamin D. Oral supplementation of vitamin D has also been found to potentially cause increased production of epimers in mice but not humans. Moreover, routine vitamin D blood tests for healthy adults will not be significantly affected by epimeric interference using LC–MS/MS assays. Recent genetic models also show that the genetic determinants and the potential factors of C3-epimers differ from those of non-C3-epimers.Most commercial immunoassays techniques can lead to inaccurate vitamin D results due to epimeric interference, especially in infants and pregnant women. It is also known that the LC–MS/MS technique can chromatographically separate epimeric and isobaric interference and detect vitamin D metabolites sensitively and accurately. Unfortunately, many labs around the world do not take into account the interference caused by epimers. In this review, various methods and techniques for the analysis of C3-epimers are also discussed. The authors believe that C3-epimers may have an important role to play in clinical research, and further research is warranted. Full article
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Open AccessReview
A Narrative Role of Vitamin D and Its Receptor: With Current Evidence on the Gastric Tissues
Int. J. Mol. Sci. 2019, 20(15), 3832; https://doi.org/10.3390/ijms20153832 - 05 Aug 2019
Cited by 3
Abstract
Vitamin D is a major steroid hormone that is gaining attention as a therapeutic molecule. Due to the general awareness of its importance for the overall well-being, vitamin D deficiency (VDD) is now recognized as a major health issue. The main reason for [...] Read more.
Vitamin D is a major steroid hormone that is gaining attention as a therapeutic molecule. Due to the general awareness of its importance for the overall well-being, vitamin D deficiency (VDD) is now recognized as a major health issue. The main reason for VDD is minimal exposure to sunlight. The vitamin D receptor (VDR) is a member of the steroid hormone receptors that induces a cascade of cell signaling to maintain healthy Ca2+ levels that serve to regulate several biological functions. However, the roles of vitamin D and its metabolism in maintaining gastric homeostasis have not yet been completely elucidated. Currently, there is a need to increase the vitamin D status in individuals worldwide as it has been shown to improve musculoskeletal health and reduce the risk of chronic illnesses, including some cancers, autoimmune and infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and general mortality. The role of vitamin D in gastric homeostasis is crucial and unexplored. This review attempts to elucidate the central role of vitamin D in preserving and maintaining the overall health and homeostasis of the stomach tissue. Full article
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