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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 23309

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Dr. Nipith Charoenngam

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Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA 02138, USA
Interests: vitamin D; endocrinology; bone and calcium metabolism

Special Issue Information

Dear Colleagues,

Vitamin D is a steroid hormone known to regulate calcium and phosphate homeostasis. It also has a multitude of non-skeletal biological activities due to the presence of the vitamin D receptor in most tissues and cells, including the skin, skeletal muscle, adipose tissue, endocrine pancreas, immune cells, blood vessels, brain, breast, many cancer cells and placenta. Activation of the vitamin D receptor by 1,25-dihydroxyvitamin D (i.e., the active form of vitamin D) results in changes in the transcription of thousands of genes, directly via its interaction with vitamin D responsive element in the target genes and indirectly via the modulation of calcium and phosphate homeostasis. Given its wide range of biological activity, vitamin D deficiency—indicated by low levels of circulating serum 25-hydroxyvitamin D concentration—has been shown in multiple observational studies to be associated with several clinical outcomes, including but not limited to osteoporosis, fracture, autoimmune diseases, cardio-metabolic disorders, malignancies, infections and all-cause mortality. Nevertheless, the clinical benefits of vitamin D supplementation on skeletal and non-skeletal outcomes are less accepted given the discrepancies in the results across several clinical trials, which could be due not only to differences in study protocols and participant characteristics but also the possibility that some individuals may respond to vitamin D differently than others. Further investigations are needed to further explain these discrepancies. This Special Issue provides insight into the evolving field of vitamin D regarding its mechanisms of action, consequences of vitamin D deficiency, genomics of vitamin D, novel markers for determining vitamin D status and novel approaches for the treatment and prevention of vitamin D deficiency.

Dr. Nipith Charoenngam
Guest Editor

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Keywords

vitamin D
25-hydroxyvitamin D
1,25-dihydroxyvitamin D
vitamin D receptor
health
disease
vitamin D deficiency
vitamin D supplementation

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Published Papers (9 papers)

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16 pages, 2105 KiB

Open AccessArticle

Analysis of Potential Vitamin D Molecule Biomarkers: Association of Calcitriol and Its Hydroxylation Efficiency Ratio with Cardiovascular Disease Risk in Rheumatoid Arthritis Patients

by Melissa Rivera-Escoto, Bertha Campos-López, Karen Pesqueda-Cendejas, Adolfo I. Ruiz-Ballesteros, Paulina E. Mora-García, Mónica R. Meza-Meza, Isela Parra-Rojas, Edith Oregon-Romero, Sergio Cerpa-Cruz and Ulises De la Cruz-Mosso

Biomedicines 2024, 12(2), 273; https://doi.org/10.3390/biomedicines12020273 - 25 Jan 2024

Viewed by 1371

Abstract

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which hypovitaminosis D by calcidiol quantification has been associated with disease severity. However, other vitamin D molecules could be implicated in RA pathophysiology and its comorbidities such as cardiovascular disease (CVD), which impacts the severity and mortality of RA patients. This study aimed to assess the relationship between calcidiol, calcitriol, its hydroxylation efficiency ratio, and the soluble vitamin D receptor (sVDR) and clinical and CVD risk variables to propose potential vitamin D molecule biomarkers for RA. A cross-sectional study of females was conducted on 154 RA patients and 201 healthy subjects (HS). Calcidiol, calcitriol, and the sVDR were measured in blood serum, and vitamin D hydroxylation efficiency was estimated using the calcitriol/calcidiol ratio score. CVD risk was calculated by the high-sensitivity C-reactive protein (hs-CRP) cutoff values. Disease activity was evaluated with the Disease Activity Score for 28 standard joints (DAS28-CRP). Results: The hydroxylation efficiency ratio and calcitriol serum levels were higher in RA patients with hypovitaminosis D (p < 0.001). Moreover, RA patients had a higher probability of a high hydroxylation efficiency ratio (OR = 2.02; p = 0.02), calcitriol serum levels (OR = 2.95; p < 0.001), and sVDR serum levels (OR = 5.57; p < 0.001) than HS. This same pattern was also observed in RA patients with high CVD risk using CRP serum levels; they showed a higher hydroxylation efficiency ratio (OR = 4.51; p = 0.04) and higher calcitriol levels (OR = 5.6; p < 0.01). Calcitriol correlates positively with the sVDR (r = 0.21, p = 0.03), CRP (r = 0.28, p < 0.001), and cardiometabolic indexes (p < 0.001) also showed discrimination capacity for CVD risk in RA patients with CRP ≥ 3 mg/L (AUC = 0.72, p < 0.01). In conclusion, hypovitaminosis D in RA patients was characterized by a pattern of a higher hydroxylation efficiency ratio and higher calcitriol and sVDR serum levels. Notably, higher calcitriol serum levels and a higher vitamin D hydroxylation efficiency ratio were associated with higher CVD risk in RA patients. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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10 pages, 876 KiB

Open AccessArticle

Vitamin D and Mitosis Evaluation in Endometriosis: A Step toward Discovering the Connection?

by Daniela Roxana Matasariu, Cristina Elena Mandici, Alexandra Ursache, Alexandra Irma Gabriela Bausic, Iuliana Elena Bujor, Alexandra Elena Cristofor, Lucian Vasile Boiculese, Mihaela Grigore, Elvira Bratila and Ludmila Lozneanu

Biomedicines 2023, 11(8), 2102; https://doi.org/10.3390/biomedicines11082102 - 26 Jul 2023

Cited by 3 | Viewed by 1524

Abstract

(1) Background: The effects of serum vitamin D levels, the vitamin D receptor (VDR), and phosphohistone H3 (PHH3) in endometriosis were investigated in two cohorts of women with this pathology: those receiving hormonal treatment and those without treatment. (2) Methods: In 60 cases of women with endometriosis (26 with progestin treatment and 34 without), paraffin-embedded endometriosis tissue samples retrieved after surgery were immunohistochemically (IHC) analyzed to determine the expression statuses of VDR and PHH3. In addition, serum levels of 25(OH) vitamin D were assessed for each patient. (3) Results: The serum 25(OH) vitamin D evaluations revealed higher levels of 25(OH) vitamin D in women with treatment compared with those without. The positive IHC indexes of VDR and PHH3 in these two groups were compared. Vitamin D receptor levels were positively correlated with PHH3 levels, both being increased in patients without treatment. (4) Conclusions: Serum 25(OH) vitamin D levels and IHC analysis of VDR and PHH3 can be used as additional tools for risk stratification and prognostic assessment in patients with endometriosis. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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12 pages, 749 KiB

Open AccessEditor’s ChoiceArticle

Vitamin D Supplementation and Adherence to World Cancer Research Fund (WCRF) Diet Recommendations for Colorectal Cancer Prevention: A Nested Prospective Cohort Study of a Phase II Randomized Trial

by Davide Serrano, Federica Bellerba, Harriet Johansson, Debora Macis, Valentina Aristarco, Chiara A. Accornero, Aliana Guerrieri-Gonzaga, Cristina M. Trovato, Maria Giulia Zampino, Emanuela Omodeo Salè, Bernardo Bonanni, Sara Gandini and Patrizia Gnagnarella

Biomedicines 2023, 11(6), 1766; https://doi.org/10.3390/biomedicines11061766 - 20 Jun 2023

Cited by 2 | Viewed by 1696

Abstract

Vitamin D and a healthy diet, based on World Cancer Research Fund (WCRF) recommendations, are considered key elements for colorectal cancer (CRC) prevention. In a CRC case-control study, we observed that CRC cases were often significantly Vitamin D deficient while subjects following WCRF recommendations significantly decreased their risk of developing CRC. We conducted a randomized phase-II trial (EudraCT number-2015-000467-14) where 74 CRC patients showed differences in response to Vitamin D supplementation, 2000 IU in average per day, according to gender and microbiota. The aim of this nested study is to correlate Vitamin D (supplementation, serum level and receptor polymorphisms), circulating biomarkers, and events (polyp/adenoma, CRC relapse and other cancers) in concomitant to WCRF recommendation adherence. Vitamin D supplementation did not modulate circulating biomarkers or follow-up events. FokI and TaqI VDR were associated with 25-hydroxyvitamin D (25OHD) levels. Patients following the WCRF recommendations had significantly lower leptin, significantly lower IL-6 (only in females), and significantly lower risk of events (HR = 0.41, 95%CI: 0.18–0.92; p = 0.03; median follow-up 2.6 years). Interestingly, no WCRF adherents had significantly more events if they were in the placebo (p < 0.0001), whereas no influence of WCRF was observed in the Vitamin D arm. While one-year Vitamin D supplementation might be too short to show significant preventive activity, a healthy diet and lifestyle should be the first step for preventive programs. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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20 pages, 10903 KiB

Open AccessArticle

25-Hydroxycholecalciferol Inhibits Cell Growth and Induces Apoptosis in SiHa Cervical Cells via Autocrine Vitamin D Metabolism

by Rivak Punchoo, Greta Dreyer and Tahir S. Pillay

Biomedicines 2023, 11(3), 871; https://doi.org/10.3390/biomedicines11030871 - 13 Mar 2023

Cited by 4 | Viewed by 2365

Abstract

Preclinical studies show that the anticancer actions of vitamin D metabolites are mediated by apoptosis, inhibition of cell proliferation and induction of cell cycle arrest. Cervical cancer cells express an autocrine vitamin D metabolising system (VDMS) comprised of a vitamin D receptor, vitamin D catabolic enzyme (CYP24A1), and the activating enzyme of 25-hydroxycholecalciferol (25(OH)D3), CYP27B1. We assessed the anticancer effects of 25(OH)D3 at clinically relevant concentrations on a cervical squamous cell cancer cell line, SiHa. We evaluated cell health parameters (cell count, viability, and cell cycle), cell death modes (apoptosis, autophagic-dependent death, and necrosis by flow cytometry and transmission electron microscopy), and autocrine VDMS gene and protein expression by qPCR and Western blot, respectively. Our study demonstrates that physiological and supraphysiological doses of 25(OH)D3 inhibit cell growth and viability and induce biochemical and morphological apoptosis in SiHa cells. These growth effects are mediated by alteration in the VDMS gene and protein expression, with prominent negative feedback at supraphysiological treatment dose. These data identify promising therapeutic potential of 25(OH)D3 in cervical cancer, which warrants further clinical translational investigations. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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14 pages, 3140 KiB

Open AccessArticle

Oral Administration of Vitamin D3 Prevents Corneal Damage in a Knock-Out Mouse Model of Sjögren’s Syndrome

by Maria Consiglia Trotta, Hildegard Herman, Cornel Balta, Marcel Rosu, Alina Ciceu, Bianca Mladin, Carlo Gesualdo, Caterina Claudia Lepre, Marina Russo, Francesco Petrillo, Gorizio Pieretti, Francesca Simonelli, Settimio Rossi, Michele D’Amico and Anca Hermenean

Biomedicines 2023, 11(2), 616; https://doi.org/10.3390/biomedicines11020616 - 18 Feb 2023

Cited by 4 | Viewed by 2257

Abstract

Background: Vitamin D deficiency has been associated with dry eye development during Sjögren’s syndrome (SS). Here, we investigated whether repeated oral vitamin D3 supplementation could prevent the corneal epithelium damage in an SS mouse model. Methods: 30 female mouse knock-out for the thrombospondin 1 gene were randomized (six per group) in untreated mice euthanized at 6 weeks as negative control (C−) or at 12 weeks as the positive control for dry eye (C+). Other mice were sacrificed after 6 weeks of oral vitamin D3 supplementation in the drinking water (1000, 8000, and 20,000 IU/kg/week, respectively). Results: The C+ mice showed alterations in their corneal epithelial morphologies and thicknesses (p < 0.01 vs. C−), while the mice receiving 8000 (M) and 20,000 (H) IU/kg/week of vitamin D3 showed preservation of the corneal epithelium morphology and thickness (p < 0.01 vs. C+). Moreover, while the C+ mice exhibited high levels and activity of corneal tumor necrosis factor alpha converting enzyme (TACE), neovascularization and fibrosis markers; these were all reduced in the M and H mice. Conclusions: Oral vitamin D3 supplementation appeared to counteract the negative effect of TACE on corneal epithelium in a mouse model of SS-associated dry eye. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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8 pages, 975 KiB

Open AccessArticle

Inadequacy of Vitamin D Does Not Interfere with Body Weight Loss in Women of Reproductive Age after Roux-en-Y Gastric Bypass

by Sabrina Cruz, Andrea Cardoso de Matos, Suelem Pereira da Cruz, Silvia Pereira, Carlos Saboya and Andrea Ramalho

Biomedicines 2023, 11(1), 86; https://doi.org/10.3390/biomedicines11010086 - 29 Dec 2022

Cited by 1 | Viewed by 1518

Abstract

Objective: To assess the influence of vitamin D on body weight loss in women who had previously undergone Roux-en-Y gastric bypass (RYGB). Methodology: This is an analytical, longitudinal and retrospective study comprising 40 women of reproductive age who had previously undergone RYGB. To investigate the influence of the serum concentrations of vitamin D on body weight reduction, the variables were analyzed in the pre-operative period (T0), in the first (T1) and in the second postoperative year (T2) and were stratified according to the BMI measured in T1 and T2. In addition, in the pre-operative period, participants were subdivided into groups based on adequacy (G1), deficiency (G2) and insufficiency (G3), according to their serum concentrations of vitamin D. Results: Although weight loss occurred in a substantial way in T1, it continued to decrease in T2 (p = 0.017). The women who reached normal weight within two years of surgery showed the lowest vitamin D concentrations preoperatively when compared to those who were overweight (p = 0.011). Women with preoperative vitamin D deficiency showed increased concentrations in the assessed times (p < 0.001), while the opposite (p = 0.001) occurred in women with adequacy. Conclusion: The study showed that inadequacy of vitamin D does not interfere with weight loss in the two-year-follow-up after RYGB and highlights that vitamin D can present a differentiated response postoperatively, to the detriment of the pre-operative period. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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Review

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40 pages, 566 KiB

Open AccessReview

Evidence That Increasing Serum 25(OH)D Concentrations to 30 ng/mL in the Kingdom of Saudi Arabia and the United Arab Emirates Could Greatly Improve Health Outcomes

by William B. Grant, Fatme Al Anouti, Barbara J. Boucher, Hana M. A. Fakhoury, Meis Moukayed, Stefan Pilz and Nasser M. Al-Daghri

Biomedicines 2023, 11(4), 994; https://doi.org/10.3390/biomedicines11040994 - 23 Mar 2023

Cited by 4 | Viewed by 6674

Abstract

Accumulating evidence supports the potential protective effects of vitamin D against chronic diseases such as Alzheimer’s disease, autoimmune diseases, cancers, cardiovascular disease (ischaemic heart disease and stroke), type 2 diabetes, hypertension, chronic kidney disease, stroke, and infectious diseases such as acute respiratory tract diseases, COVID-19, influenza, and pneumonia, as well as adverse pregnancy outcomes. The respective evidence is based on ecological and observational studies, randomized controlled trials, mechanistic studies, and Mendelian randomization studies. However, randomized controlled trials on vitamin D supplementation have largely failed to show benefits, probably due to poor design and analysis. In this work, we aim to use the best available evidence on the potential beneficial effects of vitamin D to estimate the expected reduction in incidence and mortality rates of vitamin D-related diseases in the Kingdom of Saudi Arabia and the United Arab Emirates if minimum serum 25(OH)D concentrations were to be raised to 30 ng/mL. Estimated reductions by 25% for myocardial infarction incidence, 35% for stroke incidence, 20 to 35% for cardiovascular disease mortality, and 35% for cancer mortality rates depicted a promising potential for raising serum 25(OH)D. Methods to increase serum 25(OH)D concentrations at the population level could include food fortification with vitamin D₃, vitamin D supplementation, improved dietary vitamin D intake, and sensible sun exposure. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

19 pages, 1138 KiB

Open AccessReview

Genetic Variations of the Vitamin D Metabolic Pathway and COVID-19 Susceptibility and Severity: Current Understanding and Existing Evidence

by Nipith Charoenngam, Aunchalee Jaroenlapnopparat, Sofia K. Mettler and Ashna Grover

Biomedicines 2023, 11(2), 400; https://doi.org/10.3390/biomedicines11020400 - 29 Jan 2023

Cited by 11 | Viewed by 3017

Abstract

The immunomodulatory and metabolic effects of vitamin D receptor (VDR) activation have been considered beneficial in mitigating the susceptibility and severity of COVID-19 infection. Furthermore, vitamin D-binding protein (DBP) has pleiotropic effects on the immune system that may influence inflammation associated with COVID-19. Multiple observational studies have demonstrated an association between low levels of serum 25-hydroxyvitamin D and risk and the severity of COVID-19 infection. However, the impact of vitamin D supplementation as an adjunctive treatment for COVID-19 based on evidence from randomized clinical trials is unclear. Equally important is that certain variations of the genes involved in the vitamin D metabolic pathway have been shown to affect immune function and linked with various clinical outcomes, including cardio-metabolic disorders, autoimmune diseases, infections, and cancers. This indicates inter-individual difference in body response to vitamin D. There is also emerging evidence that common polymorphisms of these genes may influence the susceptibility and severity of COVID-19, although the confidence of these findings is limited by a small number of studies and participants. Further studies are needed to address the potential role of VDR activation and DBP in the pathophysiology of COVID-19 which take into account the genetic variations of vitamin D metabolic pathway. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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Other

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30 pages, 1647 KiB

Open AccessConcept Paper

A Mathematical Model for Determining the Body’s Fluctuating Need for and Synthesis of Active Vitamin D

by Sean R. Maloney

Biomedicines 2023, 11(2), 324; https://doi.org/10.3390/biomedicines11020324 - 24 Jan 2023

Viewed by 1577

Abstract

The process by which 1,25(OH)₂D₃ is synthesized and degraded and how it is transported out of the cell and body is described. The changing demand for the synthesis of 1-25(OH)₂D₃ during different conditions experienced by the body is reviewed. A method of determining 1,25(OH)₂D₃ synthesis and demand, and the percent utilization of 25(OH)D₃ to make 1,25(OH)₂D₃ is presented based on the measurement of the end metabolites of 1,25(OH)₂D₃ and of its immediate precursor, 25(OH)D₃. A mathematical model has been developed to allow the calculation of 1,25(OH)₂ D synthesis, and demand, and the percent utilization of 25(OH)D₃. Simple algebraic equations have been derived which allow the calculation of these new parameters using the concentrations of the end metabolites of 1,25(OH)₂D₃ and its immediate precursor, 25(OH)D₃ in the serum and urine. Vitamin D plays an important role in combating invading bacteria and viruses and in subduing the body’s associated inflammatory response. This new approach to evaluating vitamin D status may help clinicians determine 25(OH)D₃ and 1,25(OH)₂D₃ levels needed to suppress bacterial infections, viral replication during new viral infections and the reactivation of latent viruses, and to downregulate the inflammatory responses caused by bacteria and viruses. Full article

(This article belongs to the Special Issue Recent Advances in Vitamin D)

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