International Journal of Molecular Sciences

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16 pages, 3306 KiB

Open AccessArticle

Perinatal Vitamin D Deficiency Enhances Brown Adipose Tissue Thermogenesis in Weanling Rats

by Matheus L. Moro, Natany G. Reis, Aline Z. Schavinski, João B. Camargo Neto, Ana Paula Assis, Jonathas R. Santos, Luciane C. Albericci, Isis C. Kettelhut and Luiz C. C. Navegantes

Int. J. Mol. Sci. 2025, 26(10), 4534; https://doi.org/10.3390/ijms26104534 - 9 May 2025

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Abstract

Perinatal vitamin D (Vit. D) deficiency (VDD) disrupts the development of key tissues involved in metabolic regulation, including the endocrine pancreas, white adipose tissue, and skeletal muscle. Brown adipose tissue (BAT), essential for thermoregulation and energy homeostasis, may also be affected, but the [...] Read more.

Perinatal vitamin D (Vit. D) deficiency (VDD) disrupts the development of key tissues involved in metabolic regulation, including the endocrine pancreas, white adipose tissue, and skeletal muscle. Brown adipose tissue (BAT), essential for thermoregulation and energy homeostasis, may also be affected, but the impact of perinatal VDD on BAT physiology remains unclear. In this study, forty female Wistar rats were fed either a standard AIN93G diet (1000 IU Vit. D₃/kg; control group, CT) (n = 20) or a modified AIN93G diet lacking Vit. D (VDD group) (n = 20) for six weeks prior to conception and throughout gestation and lactation. Male offspring were evaluated at weaning (PN21) and adulthood (PN180) after Vit. D status was normalized through a standard diet. We found that perinatal VDD reduced total lipid droplet area, increased oxygen consumption, and upregulated thermogenic gene expression in BAT at weaning. Correspondingly, VDD offspring exhibited greater cold tolerance and enhanced BAT recruitment upon cold exposure (4 °C). Notably, normalization of Vit. D status by adulthood fully reversed these changes, indicating that while perinatal VDD transiently enhances BAT thermogenic activity during early life, it does not produce lasting effects into adulthood. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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17 pages, 3065 KiB

Open AccessArticle

In Vitro Study of Vitamin D Effects on Immune, Endothelial, and Vascular Smooth Muscle Cells in Chronic Kidney Disease

by Kajal Kamboj, Vivek Kumar and Ashok Kumar Yadav

Int. J. Mol. Sci. 2025, 26(9), 3967; https://doi.org/10.3390/ijms26093967 - 23 Apr 2025

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Abstract

Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin [...] Read more.

Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin D effects on endothelial and vascular function markers in human aortic endothelial cells (HAECs) and in human aortic smooth muscle cells (HASMCs), respectively. We studied endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinase 38 (p38 Map kinase), protein kinase B (Akt), and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in HAECs and α-smooth muscle actin (α-SMA), smooth muscle calponin (SM-Calponin), smooth muscle myosin heavy chain (SM-MHC), and calcium-sensing receptor (CaSR) in HASMCs. Vitamin D receptors (VDRs) and CYP27B1 were studied in both cell types. In cultured PBMCs isolated from CKD subjects, the percentage of T helper 1(TH1) cells significantly decreased while that of T helper 2 (TH2) cells increased after cholecalciferol treatment. No significant change in intracellular and surface markers of T helper 17 (TH17) and T regulatory (Treg) cells was observed. In vitro treatment of HASMCs and HAECs with cholecalciferol led to significant and favorable alterations in mRNA expression of markers of vascular smooth muscle cells, i.e., α-SMA, SM-Calponin, and SM-MHC. Regarding endothelial cell markers, mRNA encoding eNOS, p38 Map kinase, protein kinase B (Akt), NADPH oxidase, VDR, and CYP27B1 were also significantly changed. Finally, the expression levels of the following proteins were notably altered: NADPH oxidase and protein kinase B (Akt) (in HAECs); SM-MHC and SM-Calponin (in HASMCs). In vitro treatment of PBMCs with cholecalciferol led to a favorable change in T-cell population, decreasing TH1 and increasing TH2 cell percentage, along with beneficial alterations in mRNA expression of HASMCs and HAECs’ cell markers. This study provides evidence that cholecalciferol can influence immune and vascular function in CKD. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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16 pages, 1646 KiB

Open AccessArticle

Impact of Liver and Kidney Function on Vitamin D3 Metabolism in Female and Male Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation

by Laura Weich, Christina Brummer, Sakhila Ghimire, Katrin Peter, Michael Althammer, Nathalie Babl, Florian Voll, Christina Bruss, Marcus Hoering, Stefan Wallner, Peter J. Siska, Ernst Holler, Wolfgang Herr, Heiko Bruns, Iris M. Heid, Klaus Stark, Marina Kreutz and Carina Matos

Int. J. Mol. Sci. 2025, 26(7), 2866; https://doi.org/10.3390/ijms26072866 - 21 Mar 2025

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Abstract

We previously described that elevated levels of the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during the early phase of allogeneic hematopoietic stem-cell transplantation (HSCT) can predict one-year transplant-related mortality (1y-TRM). Given that the liver and kidneys are the primary organs responsible for [...] Read more.

We previously described that elevated levels of the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during the early phase of allogeneic hematopoietic stem-cell transplantation (HSCT) can predict one-year transplant-related mortality (1y-TRM). Given that the liver and kidneys are the primary organs responsible for the effective conversion of vitamin D3, we investigated whether liver and/or kidney function, inflammation, or patient sex might influence vitamin D3 metabolism and, consequently, patient outcomes during transplantation. We found that female patients exhibited higher levels of 1,25(OH)2D3 at the time of transplantation compared with male patients. However, 1,25(OH)2D3 levels were associated with 1y-TRM in both sexes. No correlation was found between liver-associated markers, such as bilirubin, or the inflammation marker C-reactive protein (CRP) and serum levels of vitamin D3 metabolites in either female or male patients. However, serum levels of 1,25(OH)2D3, but not 25(OH)D3 correlated with the creatinine-based estimated glomerular filtration rate (eGFR), indicating that 1,25(OH)2D3 levels are associated with kidney function in HSCT patients. However, a Cox regression analysis, adjusted for baseline risk factors, demonstrated that high peri-transplant levels of 1,25(OH)2D3 (measured from days −2 to 7) remained a significant predictor of patient survival, even when eGFR was taken into account (hazard ratio = 0.99; p = 0.004). These findings suggest that optimal serum levels of 1,25(OH)2D3 may not be achievable in some HSCT patients and that kidney function alone cannot explain why some patients fail to reach the optimal 1,25(OH)2D3 threshold. These data support the potential use of 1,25(OH)2D3 as a prophylactic agent, particularly in patients with pre-existing kidney disease. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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13 pages, 570 KiB

Open AccessArticle

Search for Disease-Specific Genetic Markers Originated from the Vitamin D Binding Protein Gene Polymorphisms in the Multiple Sclerosis Cohort in the Latvian Population

by Jolanta Kalnina, Ilva Trapina, Samanta Plavina, Elina Leonova, Jegors Paramonovs, Nikolajs Sjakste and Natalia Paramonova

Int. J. Mol. Sci. 2025, 26(6), 2555; https://doi.org/10.3390/ijms26062555 - 12 Mar 2025

Cited by 1 | Viewed by 477

Abstract

Vitamin D is crucial for immune regulation, and its deficiency is linked to multiple sclerosis (MS). The GC gene encodes Vitamin D Binding Protein (VDBP), which regulates vitamin D transport and bioavailability. This study examines the association of GC polymorphisms (rs7041, rs4588) with [...] Read more.

Vitamin D is crucial for immune regulation, and its deficiency is linked to multiple sclerosis (MS). The GC gene encodes Vitamin D Binding Protein (VDBP), which regulates vitamin D transport and bioavailability. This study examines the association of GC polymorphisms (rs7041, rs4588) with MS susceptibility and their impact on 25-hydroxyvitamin D [25(OH)D] levels in a Latvian cohort. This case–control study included 296 MS patients and 253 healthy controls. Genotyping of rs7041 and rs4588 was conducted using restriction fragment length polymorphism analysis and validated by Sanger sequencing. Plasma 25(OH)D levels were measured in 131 MS patients using an enzyme-linked immunosorbent assay. Statistical analysis included Hardy–Weinberg equilibrium testing, Fisher’s exact test, allelic and genotypic frequency comparisons to assess MS risk, and the Kruskal–Wallis test for 25(OH)D level differences among genotypes. Our findings indicate that the rare rs7041-T and rs4588-A alleles, along with their corresponding haplotypes, exhibit a protective effect against MS (p < 0.001; OR = 0.65 for rs4588-A; p < 0.01; OR = 0.70 for rs7041-T). Conversely, the common rs7041-G and rs4588-C alleles were associated with an increased MS risk (p < 0.05). Individuals with the Gc1F/1F isotype had the highest average 25(OH)D levels (29.31 ng/mL), while Gc1S/2 carriers had the lowest (21.53 ng/mL). Our results indicate that GC polymorphisms may influence the susceptibility of Latvians to MS and vitamin D status. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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14 pages, 1484 KiB

Open AccessArticle

Synthesis and Evaluation of Aromatic A-Ring 23-Oxavitamin D₃ Analogues as Hedgehog Pathway Inhibitors

by Wang Chen, Feifan Lai and Jianghe Xu

Int. J. Mol. Sci. 2025, 26(4), 1631; https://doi.org/10.3390/ijms26041631 - 14 Feb 2025

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Abstract

The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D₃ (VD₃) and its derivatives [...] Read more.

The Hedgehog (Hh) signaling pathway plays a crucial role in the initiation and progression of tumors, and Hh inhibitors have been used as potential chemotherapeutic agents for the treatment of basal cell carcinomas (BCCs). Vitamin D₃ (VD₃) and its derivatives have been identified as potent Hh inhibitors. However, the selectivity of VD₃ derivatives to vitamin D receptor (VDR) and the Hh signaling pathway still needs optimization. In this study, a series of aromatic A-ring mimics VD₃ analogues that contain a C-23 oxygen atom or incorporate C-25 hydroxyl on side chains were designed and synthesized. These compounds were tested in various cell lines for anti-Hh activity, with analogues 3j and 4i identified as potent inhibitors. Mechanism studies showed their anti-Hh effects are mainly due to targeting Smoothened (Smo) without binding to the cyclopamine site. Structure-activity relationship (SAR) studies revealed that VD₃-based inhibitors enhance anti-Hh activity by adding a hydroxyl group at C25 while reducing VDR activity by incorporating an oxygen atom into the side chain. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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16 pages, 5203 KiB

Open AccessArticle

Ligand-Independent Vitamin D Receptor Actions Essential for Keratinocyte Homeostasis in the Skin

by Satoko Kise, Shinichi Morita, Toshiyuki Sakaki, Hiroyuki Kimura, Seigo Kinuya and Kaori Yasuda

Int. J. Mol. Sci. 2025, 26(1), 422; https://doi.org/10.3390/ijms26010422 - 6 Jan 2025

Cited by 1 | Viewed by 1478

Abstract

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the [...] Read more.

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since Vdr-KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among Vdr-KO, Vdr-R270L/H301Q, and wild-type (WT) rats. While Vdr-R270L/H301Q rats exhibited normal skin formation similar to WT rats, Vdr-KO rats showed remarkable hyperkeratosis and trans-epidermal water loss in the skin. RNA sequencing and proteomic analysis revealed that the gene and protein expression patterns in Vdr-KO rats significantly differed from those in WT and Vdr-R270L/H301Q rats, with a marked decrease in the expression of factors involved in Shh, Wnt, and Bmp signaling pathways, a dramatic reduction in the expression of hair keratins, and a substantial increase in the expression of epidermal keratins. This study clearly demonstrated that non-liganded VDR is significantly involved in the differentiation, proliferation, and cell death of keratinocytes in hair follicles and the epidermis. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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17 pages, 2792 KiB

Open AccessArticle

Population Pharmacokinetic Model of Vitamin D₃ and Metabolites in Chronic Kidney Disease Patients with Vitamin D Insufficiency and Deficiency

by Stacey M. Tuey, Avisek Ghimire, Serge Guzy, Linda Prebehalla, Amandla-Atilano Roque, Gavriel Roda, Raymond E. West 3rd, Michel B. Chonchol, Nirav Shah, Thomas D. Nolin and Melanie S. Joy

Int. J. Mol. Sci. 2024, 25(22), 12279; https://doi.org/10.3390/ijms252212279 - 15 Nov 2024

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Abstract

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD₃) and its three major [...] Read more.

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD₃) and its three major metabolites, 25-hydroxyvitamin D₃ (25D₃), 1,25-dihydroxyvitamin D₃ (1,25D₃), and 24,25-dihydroxyvitamin D₃ (24,25D₃), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD₃ (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD₃ and its metabolites. The simultaneous fit of a two-compartment model for VitD₃ and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD₃ and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD₃ and metabolites. This is the first reported population pharmacokinetic modeling of VitD₃ and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D₃ concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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15 pages, 2981 KiB

Open AccessArticle

Anticancer Activity of Vitamin D, Lumisterol and Selected Derivatives against Human Malignant Melanoma Cell Lines

by Paweł Domżalski, Anna Piotrowska, Robert C. Tuckey and Michał A. Zmijewski

Int. J. Mol. Sci. 2024, 25(20), 10914; https://doi.org/10.3390/ijms252010914 - 10 Oct 2024

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Abstract

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D₃ and lumisterol (L₃) exert [...] Read more.

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D₃ and lumisterol (L₃) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D₃ and L₃ in comparison to 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL₃ showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L₃ failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)₃D₃ and 1,25(OH)₂D₃ were similar in both cell types. 1,25(OH)₂D₃ showed higher potency than 1,24,25(OH)₃D₃ in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)₂D₃, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)₃D₃ markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)₃D₃, which has undergone the first step in 1,25(OH)₂D₃ inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)₂D₃ in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L₃, (25R)-27(OH)L₃ effectively inhibits proliferation and migration of the human malignant melanoma cell line A375. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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16 pages, 2656 KiB

Open AccessArticle

Vitamin D and Sulforaphane Decrease Inflammatory Oxidative Stress and Restore the Markers of Epithelial Integrity in an In Vitro Model of Age-Related Macular Degeneration

by Loredana Bergandi, Giulia Palladino, Alessandro Meduri, Laura De Luca and Francesca Silvagno

Int. J. Mol. Sci. 2024, 25(12), 6404; https://doi.org/10.3390/ijms25126404 - 10 Jun 2024

Cited by 4 | Viewed by 2476

Abstract

Age-related macular degeneration (AMD) is strictly linked to chronic oxidative stress, inflammation, loss of epithelial barrier integrity, and often with abnormal new blood vessel development. In this study, the retinal epithelial cell line ARPE-19 was treated with pro-inflammatory transforming growth factor-beta (TGF-β) to [...] Read more.

Age-related macular degeneration (AMD) is strictly linked to chronic oxidative stress, inflammation, loss of epithelial barrier integrity, and often with abnormal new blood vessel development. In this study, the retinal epithelial cell line ARPE-19 was treated with pro-inflammatory transforming growth factor-beta (TGF-β) to investigate the activity of vitamin D (VD) and sulforaphane (SF) in abating the consequences of oxidative stress and inflammation. The administration of VD and SF lowered reactive oxygen species (ROS) levels, and abated the related expression of the pro-inflammatory cytokines interleukin-6 and interleukin-8 induced by TGF-β. We evaluated mitochondrial respiration as a source of ROS production, and we discovered that the increased transcription of respiratory elements triggered by TGF-β was prevented by VD and SF. In this model of inflamed epithelium, the treatment with VD and SF also reduced the secretion of VEGF, a key angiogenic factor, and restored the markers of epithelial integrity. Remarkably, all the observed biological effects were potentiated by the co-stimulation with the two compounds and were not mediated by VD receptor expression but rather by the ERK 1/2 pathway. Altogether, the results of this study reveal the powerful synergistic anti-inflammatory activity of SF and VD and lay the foundation for future clinical assessment of their efficacy in AMD. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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Review

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30 pages, 2436 KiB

Open AccessReview

Vitamin D in the Prevention and Treatment of Inflammatory Skin Diseases

by Zrinka Bukvić Mokos, Lucija Tomić Krsnik, Kristijan Harak, Danijela Marojević Tomić, Deša Tešanović Perković and Marija Vukojević

Int. J. Mol. Sci. 2025, 26(11), 5005; https://doi.org/10.3390/ijms26115005 - 22 May 2025

Abstract

Vitamin D, a hormone synthesized in the skin through ultraviolet B radiation (UVB), plays a crucial role not only in calcium and phosphate homeostasis but also in regulating skin homeostasis and modulating immune responses. In keratinocytes, vitamin D is converted to its active [...] Read more.

Vitamin D, a hormone synthesized in the skin through ultraviolet B radiation (UVB), plays a crucial role not only in calcium and phosphate homeostasis but also in regulating skin homeostasis and modulating immune responses. In keratinocytes, vitamin D is converted to its active form, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D), which interacts with the vitamin D receptor (VDR) to regulate gene expression involved in proliferation, differentiation, and antimicrobial defense. Dysregulation of this pathway has been implicated in inflammatory skin diseases such as psoriasis, atopic dermatitis, acne vulgaris, and hidradenitis suppurativa. These conditions are associated with altered epidermal differentiation, immune imbalance, and microbial interactions, where vitamin D plays a modulatory role by suppressing proinflammatory cytokines, enhancing antimicrobial peptide synthesis, and restoring skin barrier integrity. Topical vitamin D analogues have shown therapeutic benefits in psoriasis, while emerging evidence supports the adjunctive role of vitamin D supplementation in acne, hidradenitis suppurativa, and atopic dermatitis. Despite promising associations between low serum vitamin D levels and disease severity, a causal relationship remains uncertain. This review integrates molecular mechanisms with clinical findings, emphasizing the role of vitamin D in cutaneous physiology and pathology, and highlights the need for further research into targeted supplementation strategies in dermatological disorders. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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19 pages, 700 KiB

Open AccessReview

Current Knowledge of the Impact of Vitamin D in Coronary Artery Disease

by Freja Esager Jespersen, Daniela Grimm, Marcus Krüger and Markus Wehland

Int. J. Mol. Sci. 2025, 26(11), 5002; https://doi.org/10.3390/ijms26115002 - 22 May 2025

Abstract

Coronary artery disease and vitamin D deficiency are both widespread conditions with a high incidence worldwide. Coronary artery disease is a complex illness with variable manifestation and pathogenesis. It often involves the development of atherosclerosis, and it frequently has serious or even fatal [...] Read more.

Coronary artery disease and vitamin D deficiency are both widespread conditions with a high incidence worldwide. Coronary artery disease is a complex illness with variable manifestation and pathogenesis. It often involves the development of atherosclerosis, and it frequently has serious or even fatal consequences for the patient. Vitamin D receptor expression is found in many tissues throughout the body, which results in a broad effect of the vitamin. Studies have found correlations between vitamin D deficiency and the development of coronary artery disease as well as other cardiovascular diseases, such as hypertension. This review will discuss randomized controlled trials conducted from 2020 forward, aiming to elucidate whether vitamin D supplements have the potential to be used as an add-on treatment for coronary artery disease. The randomized controlled trials all used vitamin D as intervention and tested a population suffering from coronary artery disease or the risk of developing it. Even though animal studies found evidence that vitamin D can regulate inflammation, lipid profile, foam cell formation, vessel reactivity, and blood pressure, which are all mediators in the development of atherosclerosis, the results from the randomized controlled trials were ambiguous. The general older population did not seem to benefit from the treatment, but different subgroups such as patients with type 2 diabetes and patients with more developed coronary artery disease exhibited some positive effects from the treatment. Furthermore, vitamin D showed cardioprotective effects following coronary artery bypass surgery, which make it a possible add-on treatment before invasive coronary intervention. The question in focus still needs further research and a more focused approach on subgroups that may benefit from treatment. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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18 pages, 1185 KiB

Open AccessReview

Type 1 Diabetes Mellitus and Vitamin D

by Teodoro Durá-Travé and Fidel Gallinas-Victoriano

Int. J. Mol. Sci. 2025, 26(10), 4593; https://doi.org/10.3390/ijms26104593 - 11 May 2025

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Abstract

Type 1 diabetes mellitus (T1DM) is a multifactorial disease in which environmental factors and genetic predisposition interact to induce an autoimmune response against pancreatic β-cells. Vitamin D promotes immune tolerance through immunomodulatory and anti-inflammatory functions. The aim of this study is to provide [...] Read more.

Type 1 diabetes mellitus (T1DM) is a multifactorial disease in which environmental factors and genetic predisposition interact to induce an autoimmune response against pancreatic β-cells. Vitamin D promotes immune tolerance through immunomodulatory and anti-inflammatory functions. The aim of this study is to provide a narrative review about the association between vitamin D status in the pathogenesis of T1DM and the role of vitamin D supplementation in the prevention and treatment of T1DM. Although vitamin D deficiency is more prevalent in children/adolescents with new-onset T1DM than in healthy individuals, there does not appear to be an association between vitamin D status before diagnosis and the onset of T1DMD later in life. The results of vitamin D as adjuvant therapy have, at best, a positive short-term effect in newly diagnosed T1DM patients. Intervention studies have been conducted in the clinical phase of T1DM, but it would be desirable to do so in the early stages of the autoimmune process (pre-diabetes). Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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16 pages, 1233 KiB

Open AccessFeature PaperReview

Vitamin D and Immune Checkpoint Inhibitors in Lung Cancer: A Synergistic Approach to Enhancing Treatment Efficacy

by Yu Zhang, Yan Xu, Wei Zhong, Jing Zhao, Xiaoyan Liu, Xiaoxing Gao, Minjiang Chen and Mengzhao Wang

Int. J. Mol. Sci. 2025, 26(10), 4511; https://doi.org/10.3390/ijms26104511 - 9 May 2025

Viewed by 223

Abstract

Lung cancer, a malignant neoplasm that is globally prevalent and characterized by high incidence and mortality rates, has seen the rise of immune checkpoint inhibitors (ICIs) as a crucial systemic treatment. However, a subset of patients exhibits suboptimal responses to ICIs. Recently, studies [...] Read more.

Lung cancer, a malignant neoplasm that is globally prevalent and characterized by high incidence and mortality rates, has seen the rise of immune checkpoint inhibitors (ICIs) as a crucial systemic treatment. However, a subset of patients exhibits suboptimal responses to ICIs. Recently, studies revealed the role of vitamin D in inflammation modulation, cell differentiation, and cancer prevention. Vitamin D precisely modulates immune responses and inflammatory states within the tumor microenvironment (TME) by targeting both innate and adaptive immunity. These effects may reduce immune tolerance to ICIs and synergistically enhance their therapeutic efficacy. Here, we review vitamin D metabolism in lung cancer patients, as well as its anti-tumor mechanisms, immune regulation, and the significant promise of vitamin D in lung cancer immunotherapy and adjuvant therapeutic strategies. Further research is imperative to surmount these challenges and fully realize vitamin D’s potential in improving lung cancer immunotherapy outcomes. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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56 pages, 11868 KiB

Open AccessReview

Modifiable Nutritional Biomarkers in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis of Vitamin D, B₁₂, and Homocysteine Exposure Spanning Prenatal Development Through Late Adolescence

by Oana-Elisabeta Avram, Elena-Alexandra Bratu, Cecilia Curis, Lavinia-Alexandra Moroianu and Eduard Drima

Int. J. Mol. Sci. 2025, 26(9), 4410; https://doi.org/10.3390/ijms26094410 - 6 May 2025

Viewed by 514

Abstract

Autism Spectrum Disorder (ASD) has been associated with disruptions in one-carbon metabolism and vitamin D pathways. Nutritional exposures—particularly vitamin D, vitamin B₁₂, and homocysteine—may influence neurodevelopmental outcomes. However, a comprehensive, lifespan-spanning synthesis of these modifiable nutritional biomarkers has not been conducted. [...] Read more.

Autism Spectrum Disorder (ASD) has been associated with disruptions in one-carbon metabolism and vitamin D pathways. Nutritional exposures—particularly vitamin D, vitamin B₁₂, and homocysteine—may influence neurodevelopmental outcomes. However, a comprehensive, lifespan-spanning synthesis of these modifiable nutritional biomarkers has not been conducted. This systematic review and stratified meta-analysis critically synthesized data on vitamin D, vitamin B₁₂, and homocysteine to elucidate their relationships with ASD risk and symptomatology. Our central question was: How do levels of vitamin D, vitamin B₁₂, and homocysteine—measured before and after birth—affect the risk, severity, and potential treatment outcomes for ASD? We conducted a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) compliant systematic review and stratified meta-analysis (2015–2025) of 35 studies (11 randomized controlled trials, 24 observational), examining prenatal, neonatal, and postnatal biomarker levels. Eligibility criteria were defined using the PICOS (Population, Intervention, Comparator, Outcome, and Study Design) framework to ensure scientific rigor and clinical relevance, including studies involving human participants aged 0–18 years with a formal Autism Spectrum Disorder (ASD) diagnosis or prenatal exposures potentially linked to later ASD onset, while excluding animal studies, adult-only ASD populations, and studies lacking ASD cohorts or biomarker data. The search strategy, developed according to PRISMA, and Cochrane best practices, encompassed five major databases (PubMed/MEDLINE, Cochrane Library, Google Scholar, ClinicalTrials.gov, and ProQuest) alongside manual searches of key references, grey literature, and clinical trial registries to ensure comprehensive retrieval of both published and unpublished studies. Study quality was assessed using version 2 of the Cochrane risk-of-bias tool for RCTs (RoB2) and the Newcastle–Ottawa Scale (NOS) for observational studies; certainty of evidence was graded via GRADE (Grading of Recommendations Assessment, Development and Evaluation). Random-effects meta-analyses were stratified by biomarker and study design. Heterogeneity, small-study effects, and publication bias were evaluated using Cochran’s Q, I², Egger’s test, and trim-and-fill. Prenatal vitamin D deficiency was associated with approximately two-fold increased odds of Autism Spectrum Disorder (ASD) in offspring (pooled OR ≈ 2.0; p < 0.05), while excessively elevated maternal B₁₂ concentrations, often co-occurring with folate excess, were similarly linked to increased ASD risk. Meta-analytic comparisons revealed significantly lower circulating vitamin D (SMD ≈ −1.0; p < 0.001) and B₁₂ levels (SMD ≈ −0.7; p < 0.001), alongside elevated homocysteine (SMD ≈ 0.7; p < 0.001), in children with ASD versus neurotypical controls. Early-life vitamin D/B₁₂ insufficiency and elevated homocysteine are important, modifiable correlates of ASD risk and severity. Adequate maternal and child nutritional status could have risk-reducing and symptom-mitigating effects, although causality remains to be confirmed. This evidence supports tailored nutritional interventions as a component of ASD risk reduction and management strategies, within the bounds of overall developmental healthcare. The article processing charges (APC) were supported by “Dunărea de Jos” University of Galati, Romania. No external funding was received for the execution of the research. The review was not prospectively registered in PROSPERO or any other systematic review registry. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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14 pages, 812 KiB

Open AccessReview

The Role of Vitamin D in Gastrointestinal Homeostasis and Gut Inflammation

by Varun Vemulapalli and Anusha Shirwaikar Thomas

Int. J. Mol. Sci. 2025, 26(7), 3020; https://doi.org/10.3390/ijms26073020 - 26 Mar 2025

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Abstract

Gastrointestinal homeostasis describes a delicate state of equilibrium in which various systems cooperate to maintain digestive health, support microbial activity, and regulate immune responses. There is growing evidence that Vitamin D is one of the many factors that influences gastrointestinal homeostasis through its [...] Read more.

Gastrointestinal homeostasis describes a delicate state of equilibrium in which various systems cooperate to maintain digestive health, support microbial activity, and regulate immune responses. There is growing evidence that Vitamin D is one of the many factors that influences gastrointestinal homeostasis through its effects on gut barrier integrity, regulating microbial diversity and modulating immune responses. Given these effects of Vitamin D, there may be potential for it as both a preventative and a therapeutic intervention for a variety of conditions, but especially for inflammatory conditions of the gastrointestinal tract. This article will summarize the role of Vitamin D in a state of equilibrium, as well as its role in a pro-inflammatory state in the gastrointestinal tract. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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28 pages, 1956 KiB

Open AccessReview

Vitamin D and Type 2 Diabetes Mellitus: Molecular Mechanisms and Clinical Implications—A Narrative Review

by Héctor Fuentes-Barría, Raúl Aguilera-Eguía, Cherie Flores-Fernández, Lissé Angarita-Davila, Diana Rojas-Gómez, Miguel Alarcón-Rivera, Olga López-Soto and Juan Maureira-Sánchez

Int. J. Mol. Sci. 2025, 26(5), 2153; https://doi.org/10.3390/ijms26052153 - 27 Feb 2025

Viewed by 1498

Abstract

Vitamin D has been widely studied for its implications on type 2 diabetes mellitus, a chronic condition characterized by insulin resistance, inflammation, and metabolic dysfunction. This review explores the molecular mechanisms underpinning vitamin D’s effects on glucose metabolism, inflammation, and adipogenesis, while assessing [...] Read more.

Vitamin D has been widely studied for its implications on type 2 diabetes mellitus, a chronic condition characterized by insulin resistance, inflammation, and metabolic dysfunction. This review explores the molecular mechanisms underpinning vitamin D’s effects on glucose metabolism, inflammation, and adipogenesis, while assessing its potential clinical applications in type 2 diabetes. In its 1,25-dihydroxyvitamin D3 form, vitamin D modulates various metabolic processes, affecting proinflammatory cytokines and activating the AMPK pathway, inhibiting mTOR signaling, and promoting adipocyte differentiation. These effects enhance insulin sensitivity and reduce chronic inflammation, key contributors to metabolic dysfunction. In this context, the progression of prediabetes has been linked to vitamin D, which limits pathological progression and increases the likelihood of restoring a normal metabolic state, crucial in diabetes progression. Moreover, vitamin D has been reported to reduce the likelihood of developing diabetes by 15%, particularly in doses higher than the traditional recommendations for bone health. Despite promising evidence, discrepancies in study designs, serum vitamin D measurements, and population-specific factors highlight the need for standardized methodologies and personalized approaches. In conclusion, vitamin D has complementary therapeutic potential in treating type 2 diabetes, revealing gaps in research, such as optimal dosing and long-term effects across populations. Future studies should integrate molecular insights into clinical practice to optimize vitamin D’s impact on metabolic health. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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14 pages, 826 KiB

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Autoimmune Thyroiditis and Vitamin D

by Teodoro Durá-Travé and Fidel Gallinas-Victoriano

Int. J. Mol. Sci. 2024, 25(6), 3154; https://doi.org/10.3390/ijms25063154 - 9 Mar 2024

Cited by 16 | Viewed by 5897

Abstract

Hashimoto’s thyroiditis (HT) is marked by self-tissue destruction as a consequence of an alteration in the adaptive immune response that entails the evasion of immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this [...] Read more.

Hashimoto’s thyroiditis (HT) is marked by self-tissue destruction as a consequence of an alteration in the adaptive immune response that entails the evasion of immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review of the relationship between vitamin D status and HT and the role of vitamin D supplementation in reducing HT risk by modulating the immune system. There is extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titers decreased significantly. Further knowledge of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases requires the execution of additional randomized, double-blind, placebo-controlled trials and longer follow-up periods. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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16 pages, 2018 KiB

Open AccessReview

Vitamin D/Bone Mineral Density and Triglyceride Paradoxes Seen in African Americans: A Cross-Sectional Study and Review of the Literature

by Christopher M. Stevens and Sushil K. Jain

Int. J. Mol. Sci. 2024, 25(2), 1305; https://doi.org/10.3390/ijms25021305 - 21 Jan 2024

Cited by 5 | Viewed by 2937

Abstract

Vitamin D is known to have a positive effect on bone health. Despite the greater frequency of vitamin D deficiency in African Americans (AA), they have a higher bone mineral density (BMD) compared to whites, demonstrating a disconnect between BMD and vitamin D [...] Read more.

Vitamin D is known to have a positive effect on bone health. Despite the greater frequency of vitamin D deficiency in African Americans (AA), they have a higher bone mineral density (BMD) compared to whites, demonstrating a disconnect between BMD and vitamin D levels in AA. Another intriguing relationship seen in AA is the triglyceride (TG) paradox, an unusual phenomenon in which a normal TG status is observed even when patients house conditions known to be characterized by high TG levels, such as Type II diabetes. To the best of our knowledge, no study has examined whether these two paradoxical relationships exist simultaneously in AA subjects with Type II diabetes. In this study, we compared levels of blood markers, including HbA1c, TG, and vitamin D, measured as serum 25-hydroxyvitamin D [25(OH)VD] µM/mL, [25(OH)VD]/TG, calcium, and BMD in AA (n = 56) and white (n = 26) subjects with Type II diabetes to see whether these relationships exist concurrently. We found that AA subjects had significantly lower TG and [25(OH)VD] levels and a significantly higher BMD status compared to white subjects, even when the ages, BMI, duration of diabetes, HbA1c, and calcium levels were similar between the two groups. This demonstrates that these two paradoxical relationships exist simultaneously in Type II diabetic AA subjects. In addition to these findings, we discuss the current hypotheses in the literature that attempt to explain why these two intriguing relationships exist. This review also discusses four novel hypotheses, such as altered circulating levels and the potential role of estrogen and hydrogen sulfide on BMD and HMG-CoA reductase as a possible contributor to the TG paradox in AA subjects. This manuscript demonstrates that there are still many unanswered questions regarding these two paradoxical relationships and further research is needed to determine why they exist and how they can be implemented to improve healthcare. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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