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Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (15 February 2024) | Viewed by 26160

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Prof. Dr. Jun Sun

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Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
Interests: inflammation; cancer; VDR; microbiome; tight junctions

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Dear Colleagues,

Vitamin D has been described as a differentiative hormone, produced in its active form by many kinds of cells, and is effective over the whole life of a cell by means of different mechanisms, which lead to nuclear, non-genomic, and mitochondrial effects.

Over the past few decades, it has been demonstrated that vitamin D is essential for the proper function of the musculoskeletal, cardiovascular, nervous, and immune systems. Furthermore, vitamin D and its analogs were shown to regulate the proliferation and differentiation of keratinocytes, immune cells, and numerous cancer-derived cells, both in vivo and in vitro. On the other hand, population-based studies have provided evidence that global vitamin D deficiency is correlated with the occurrence and aggravation of symptoms of skeletal, cardiovascular, autoimmune, and skin diseases; infections; metabolic and cognitive disorders; multiple types of cancers; and overall mortality. Most importantly, proper vitamin D supplementation is known to have beneficial effects on health and is essential for the prevention and regression of multiple diseases of civilization. The therapeutic use of high doses of vitamin D, as well as its low calcemic analogs, is currently under intensive investigation. In order to fully understand the intracellular mechanisms activated by vitamin D and vitamin D receptors, as well the pleiotropic effects of vitamin D and its analogues on human health and disease, further investigation is needed.

The aim of this Special Issue is to provide a useful collection for the understanding of the biological effects and therapeutic methods of vitamin D and its analogues.

Prof. Dr. Jun Sun
Guest Editor

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Keywords

vitamin D
vitamin D receptor
vitamin D analogues
vitamin D deficiency
vitamin D supplementation
disease prevention
nutrition improvement
inflammation

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Published Papers (9 papers)

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Editorial

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4 pages, 167 KiB

Open AccessEditorial

Bringing Vitamin D and the Vitamin D Receptor into the Limelight

by Jun Sun

Biomolecules 2024, 14(9), 1094; https://doi.org/10.3390/biom14091094 - 31 Aug 2024

Viewed by 845

Abstract

Classically, vitamin D is known to regulate skeletal and mineral ion homeostasis [...] Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

Research

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11 pages, 2527 KiB

Open AccessArticle

4-Hydroxy-1α,25-Dihydroxyvitamin D₃: Synthesis and Structure–Function Study

by Carole Peluso-Iltis, Noé Pierrat, Daniela Rovito, Judit Osz, Daisuke Sawada, Atsushi Kittaka, Gilles Laverny and Natacha Rochel

Biomolecules 2024, 14(5), 551; https://doi.org/10.3390/biom14050551 - 3 May 2024

Cited by 2 | Viewed by 1218

Abstract

The active vitamin D metabolites, 25-hydroxyvitamin D₃ (25D₃) and 1,25-dihydroxyvitamin D₃ (1,25D₃), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of 25D₃ is a major one. This study aims to investigate the structure–activity relationships of 4-hydroxy derivatives of 1,25D₃. Structural analysis indicates that 1,4α,25(OH)₃D₃ and 1,4β,25(OH)₃D₃ maintain the anchoring hydrogen bonds of 1,25D₃ and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D₃ and 1,4β,25D₃ are as potent as 1,25D₃ in regulating the expression of VDR target genes in rat intestinal epithelial cells and in the mouse kidney. Moreover, these two 4-hydroxy derivatives promote hypercalcemia in mice at a dose similar to that of the parent compound. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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17 pages, 277 KiB

Open AccessArticle

The Association of Vitamin D Receptor Gene Polymorphisms with Vitamin D, Total IgE, and Blood Eosinophils in Patients with Atopy

by Daina Bastyte, Laura Tamasauskiene, Ieva Stakaitiene, Rasa Ugenskiene and Brigita Gradauskiene (Sitkauskiene)

Biomolecules 2024, 14(2), 212; https://doi.org/10.3390/biom14020212 - 11 Feb 2024

Cited by 3 | Viewed by 1795

Abstract

Background: In order to improve the control of atopic diseases, it is important to clarify the pathogenesis of atopy and identify its various triggers. Single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene (VDR) may impact atopy. The aim of this study was to investigate the possible associations between VDR SNPs and vitamin D, total IgE, and eosinophils in atopy. Methods: In total, 203 adults, including 122 patients with atopic diseases (45 with atopic dermatitis, 77 with allergic asthma) and 81 healthy controls, were involved in the study. The blood eosinophil count was determined with an automated hematology analyzer. Vitamin D and total immunoglobulin E (IgE) levels were evaluated using the ELISA method. Polymorphisms in the VDR gene were analyzed with real-time PCR using TaqMan probes. Results: We analyzed six VDR single nucleotide polymorphisms and found a significant association between VDR rs731236 GG genotype and normal vitamin D levels in atopic patients and healthy subjects (OR 11.33; 95% CI: 1.049–122.388 and OR 4.04; 95% CI: 1.117–14.588, respectively, p < 0.05). Additionally, the study results revealed a significant relationship between the VDR rs2228570 GG genotype and normal vitamin D levels in patients with atopy and healthy subjects (OR 3.80; 95% CI: 1.190–12.134 and OR 2.09; 95% CI: 1.044–4.194, respectively, p < 0.05). The rs2228570 allele A was associated with decreased vitamin D levels in patients with atopy and healthy subjects (OR 0.28; 95% CI: 0.098–0.804 and OR 0.229; 95% CI: 0.069–0.761, respectively, p < 0.05). The VDR rs3847987 genotypes AA and AC were significantly associated with normal vitamin D levels in healthy subjects (OR 35.99; 95% CI: 6.401–202.446 and OR 4.72; 95% CI: 1.489–15.007, respectively, p < 0.05). In addition, a decreased amount of vitamin D was associated with atopic diseases such as atopic dermatitis and allergic asthma (OR 0.49; 95% CI: 0.439–1.308 and OR 0.58; 95% CI: 0.372–0.908, respectively, p < 0.05). The rs11168293 allele T was associated with the normal range of total IgE in atopy (OR 2.366; 95% CI: 1.133–5.027; p < 0.05). Significant associations were found between VDR rs731263 allele G, rs11168293 allele G, and increased blood eosinophil levels in patients with atopy (OR 0.319; 95% CI: 0.163–0.934 and OR 0.323; 95% CI: 0.112–0.935, respectively, p < 0.05). Conclusions: A decreased vitamin D level showed a significant relationship with atopic diseases (atopic dermatitis and allergic asthma). The association between the VDR gene polymorphisms rs2228570, rs731236, and rs11168293 and vitamin D, total IgE, and blood eosinophils in patients with atopy suggested that VDR polymorphisms and the vitamin D level should be considered when examining the factors associated with atopy. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

15 pages, 606 KiB

Open AccessArticle

Total 25-Hydroxyvitamin D Is an Independent Marker of Left Ventricular Ejection Fraction in Heart Failure with Reduced and Mildly Reduced Ejection Fraction

by Timea Magdolna Szabo, Előd Ernő Nagy, Ádám Kirchmaier, Erhard Heidenhoffer, Hunor-László Gábor-Kelemen, Marius Frăsineanu, Judit Cseke, Márta Germán-Salló and Attila Frigy

Biomolecules 2023, 13(11), 1578; https://doi.org/10.3390/biom13111578 - 26 Oct 2023

Cited by 4 | Viewed by 1535

Abstract

Vitamin D emerged as an important prognostic biomarker in heart failure (HF), with currently highly debated therapeutic implications. Several trials on vitamin D supplementation in HF showed improvements in left ventricular (LV) remodeling and function and health-related quality of life (HRQoL), which did not translate into mid- to long-term beneficial effects regarding physical performance and mortality. We addressed total 25-hydroxyvitamin D (25(OH)D), serum albumin, and uric acid (UA) levels, focusing mainly on vitamin D deficiency, as potential markers of LV systolic dysfunction in HF with reduced and mildly reduced ejection fraction (HFrEF, HFmrEF). Seventy patients with LVEF < 50% were comprehensively evaluated using ECG, echocardiography, lung ultrasound (LUS), blood sampling, and the six-minute walk test (6MWT). HRQoL was also assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Statistically significant positive correlations were found between LVEF, 25(OH)D, serum UA, and albumin, respectively (p = 0.008, p = 0.009, and p = 0.001). Serum UA (7.4 ± 2.4 vs. 5.7 ± 2.1, p = 0.005), NT-proBNP levels (1090.4 (675.2–2664.9) vs. 759.0 (260.3–1474.8), p = 0.034), and MLHFQ scores (21.0 (14.0–47.0) vs. 14.5 (4.5–25.5), p = 0.012) were significantly higher, whereas 25(OH)D concentrations (17.6 (15.1–28.2) vs. 22.7 (19.5–33.8), p = 0.010) were lower in subjects with severely reduced LVEF. Also, 25(OH)D was independently associated with LVEF in univariate and multiple regression analysis, maintaining its significance even after adjusting for confounders such as age, NT-proBNP, the presence of chronic coronary syndrome, hypertension, and anemia. According to our current findings, 25(OH)D is closely associated with LVEF, further supporting the need to establish correct vitamin D supplementation schemes and dietary interventions in HF. The changes in LVEF, 25(OH)D, serum UA, and albumin levels in HFrEF and HFmrEF indicate a similar pathophysiological background. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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10 pages, 775 KiB

Open AccessArticle

The Effect of Narrow-Band Ultraviolet B Phototherapy on Free and Total Vitamin D Serum Levels in Mild to Severe Plaque Psoriasis

by Andrea Elmelid, Maria Siekkeri Vandikas, Martin Gillstedt, Amra Osmancevic and Mikael Alsterholm

Biomolecules 2023, 13(7), 1018; https://doi.org/10.3390/biom13071018 - 21 Jun 2023

Cited by 2 | Viewed by 2517

Abstract

Vitamin D plays an important role in skin inflammation in psoriasis. The beneficial effects of ultraviolet light B (UVB) phototherapy in psoriasis are partly attributed to UVB-induced increase of vitamin D levels. In clinical practice, total 25-hydroxy vitamin D (25(OH)D) levels are measured to assess sufficiency, but it might be more accurate to measure free 25(OH)D levels. The aim of this study was to measure free serum 25(OH)D levels in psoriasis patients before and after phototherapy and to investigate if free 25(OH)D correlates stronger to disease severity than total 25(OH)D. Twenty adults (>18 years) with psoriasis were included for treatment with narrow-band UVB (NB-UVB) phototherapy for 10–12 weeks. Psoriasis Area and Severity Index (PASI) and Visual Analogue Scale (VAS) were used to assess disease severity. Serum levels of total 25(OH)D, free 25(OH)D, and 1,25(OH)₂D were measured before and after NB-UVB. Total 25(OH)D, free 25(OH)D, 1,25(OH)₂D and the percentage of free 25(OH)D increased after NB-UVB, and PASI and VAS improved. The increase in total and free 25(OH)D remained significant when stratifying for vitamin D confounders. No correlations between disease severity and vitamin D levels were found. Total and free 25(OH)D levels were positively correlated before and after NB-UVB. NB-UVB is an effective treatment for mild to severe plaque psoriasis and increases not only total but also free 25(OH)D levels, as well as the percentage of free 25(OH)D, suggesting an increased bioavailability of skin-produced vitamin D. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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8 pages, 1573 KiB

Open AccessCommunication

The Impact of Maternal Probiotics on Intestinal Vitamin D Receptor Expression in Early Life

by Anita Sharma, Yueyue Yu, Jing Lu, Lei Lu, Yong-Guo Zhang, Yinglin Xia, Jun Sun and Erika C. Claud

Biomolecules 2023, 13(5), 847; https://doi.org/10.3390/biom13050847 - 16 May 2023

Cited by 2 | Viewed by 1920

Abstract

Vitamin D signaling via the Vitamin D Receptor (VDR) has been shown to protect against intestinal inflammation. Previous studies have also reported the mutual interactions of intestinal VDR and the microbiome, indicating a potential role of probiotics in modulating VDR expression. In preterm infants, although probiotics have been shown to reduce the incidence of necrotizing enterocolitis (NEC), they are not currently recommended by the FDA due to potential risks in this population. No previous studies have delved into the effect of maternally administered probiotics on intestinal VDR expression in early life. Using an infancy mouse model, we found that young mice exposed to maternally administered probiotics (SPF/LB) maintained higher colonic VDR expression than our unexposed mice (SPF) in the face of a systemic inflammatory stimulus. These findings indicate a potential role for microbiome-modulating therapies in preventing diseases such as NEC through the enhancement of VDR signaling. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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10 pages, 263 KiB

Open AccessArticle

The Impact of Cholecaciferol Supplementation on Bone Mineral Density in Long-Term Kidney Transplant Recipients

by Yuri Battaglia, Antonio Bellasi, Pasquale Esposito, Alessandra Bortoluzzi, Silverio Rotondi, Michele Andreucci, Fulvio Fiorini, Domenico Russo and Alda Storari

Biomolecules 2023, 13(4), 629; https://doi.org/10.3390/biom13040629 - 31 Mar 2023

Cited by 3 | Viewed by 1676

Abstract

Although reduced bone mineral density (BMD) is associated with a higher risk of fractures, morbidity, and mortality in kidney transplant patients (KTRs), there is no consensus on optimal treatment for the alterations of BMD in this population. This study aims at assessing the effect of cholecalciferol supplementation on BMD over a follow-up period of 2 years in a cohort of long-term KTRs. Patients with age ≥ 18 years were included and divided into two subgroups based on treatment with bisphosphonate and/or calcimimetics and/or active vitamin D sterols (KTRs-treated) or never treated with the above medications (KTRs-free). BMD was evaluated at lumbar vertebral bodies (LV) and right femoral neck (FN) with standard DEXA at the beginning and end of the study. According to World Health Organization (WHO) criteria, results were expressed as T-score and Z-score. Osteoporosis and osteopenia were defined as T score ≤ −2.5 SD and T score < −1 and >−2.5 SD, respectively. Cholecalciferol was supplemented at a dose of 25,000 IU/week over 12 weeks followed by 1500 IU/day. KTRs-free (n. 69) and KTRs-treated (n. 49) consecutive outpatients entered the study. KTRs-free were younger (p < 0.05), with a lower prevalence of diabetes (p < 0.05) and of osteopenia at FN (46.3 % vs. 61.2 %) compared to KTRs-treated. At the entry none of the study subjects had a sufficient level of cholecalciferol; Z-score and T-score at LV and FN were not different between groups. At the end of the study period, serum cholecalciferol concentration was significantly increased in both groups (p < 0.001); the KTRs-free group presented an improvement in both T-score and Z-score at LV (p < 0.05) as well as a lower prevalence of osteoporotic cases (21.7% vs. 15.9%); in contrast, no changes were recorded in KTR-treated individuals. In conclusion, supplementation with cholecalciferol ameliorated Z-score and T-score at LV in long-term KTRs who had been never treated with active or inactive vitamin D sterols, bisphosphonates, and calcimimetics. Future endeavours are needed to confirm these preliminary findings. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

10 pages, 856 KiB

Open AccessArticle

Infant Vitamin D Supplements, Fecal Microbiota and Their Metabolites at 3 Months of Age in the CHILD Study Cohort

by Xin Zhao, Sarah L. Bridgman, Kelsea M. Drall, Hein M. Tun, Piush J. Mandhane, Theo J. Moraes, Elinor Simons, Stuart E. Turvey, Padmaja Subbarao, James A. Scott and Anita L. Kozyrskyj

Biomolecules 2023, 13(2), 200; https://doi.org/10.3390/biom13020200 - 19 Jan 2023

Cited by 2 | Viewed by 2455

Abstract

Infant vitamin D liquid formulations often contain non-medicinal excipients such as glycerin (ie. glycerol) and 1,2-propanediol (1,2-PD). We examined whether infant vitamin D supplementation is associated with fecal glycerol and 1,2-PD concentrations at 3 months of age and characterized associations between these two molecules, and gut microbiota and their metabolites. Fecal metabolites and microbiota were quantified using Nuclear Magnetic Resonance Spectroscopy and 16S rRNA sequencing, respectively, in 575 infants from the CHILD Study at 3 months of age. Vitamin D supplement use was determined using questionnaires. Vitamin D supplementation was associated with greater odds of high 1,2-PD (adjusted OR 1.65 95% CI: 1.06, 2.53) and with decreased odds of high fecal glycerol (adjusted OR: 0.62 95% CI: 0.42, 0.90) after adjustment for breastfeeding and other covariates. Our findings were confirmed in linear regression models; vitamin D supplementation was positively associated with fecal 1,2-PD and inversely associated with glycerol (aβ: 0.37, 95% CI 0.03, 0.71 & aβ: −0.23 95% CI −0.44, −0.03, respectively). Fecal 1,2-PD and glycerol concentrations were negatively correlated with each other. Positive correlations between fecal 1,2-PD, Bifidobacteriaceae, Lactobacillaceae, Enterobacteriaceae and acetate levels were observed. Our research demonstrates that infant vitamin D supplement administration may differentially and independently influence infant gut microbiota metabolites. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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Review

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24 pages, 840 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Suggesting a Relationship between Vitamin D and Erectile Dysfunction: An Overview

by Andrea Crafa, Rossella Cannarella, Federica Barbagallo, Claudia Leanza, Roberto Palazzolo, Hunter Ausley Flores, Sandro La Vignera, Rosita A. Condorelli and Aldo E. Calogero

Biomolecules 2023, 13(6), 930; https://doi.org/10.3390/biom13060930 - 1 Jun 2023

Cited by 11 | Viewed by 11074

Abstract

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that may relate VDD to ED. The main mechanism by which vitamin D might exert its action on sexual function appears to be through the regulation of endothelial function. Indeed, VDD correlates with several markers of endothelial function. The action of vitamin D on the endothelium would be exercised both indirectly through its intervention in inflammatory processes and through the production of oxygen free radicals, and directly through the regulation of vascular stiffness, the production of nitric oxide, and the regulation of vessel permeability. Furthermore, the ubiquitous distribution of the vitamin D receptor in the human body means that this hormone can also exert a beneficial effect on erectile function by interfering with those comorbidities significantly associated with ED, such as hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, and hypogonadism. In this review, we thoroughly and carefully presented the evidence and mechanisms that would appear to relate vitamin D levels to erectile function. Furthermore, we have summarized the meta-analytic evidence for and against this association to provide a true representation of this topic. Data published to date suggest that low levels of vitamin D could contribute to worsening erectile function through several mechanisms. Therefore, vitamin D levels should be measured in patients with ED and maintained at adequate levels by specific supplementation in case of deficiency. However, the low quality and heterogeneity of clinical trials evaluating the effects of vitamin D administration on erectile function and ED-associated comorbidities do not allow for a univocal conclusion, and indicate the need for further studies to analyze these aspects. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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