Vitamin D in Disease Prevention and Cure-Part I: An Update on Molecular Mechanism and Significance on Human Health.

Vitamin D, a versatile secosteroid hormone, continues to captivate scientific interest due to its multifaceted influence on human health. This comprehensive review, part 1 of a series, provides an up-to-date exploration of the molecular mechanisms governing Vitamin D’s impact on various aspects of health. Focusing on its pivotal role in the central nervous system (CNS), neurodevelopmental disorders, and neurodegenerative diseases, the review also delves into its intriguing correslations with oral, prostate, breast, and colon cancers. Beyond these domains, Vitamin D’s reach extends to viral infections and reproductive health, affecting fertility in both males and females and playing a crucial role throughout pregnancy. The article offers an in-depth examination of the complex molecular pathways and signaling cascades through which Vitamin D exerts its physiological effects. Importantly, it provides a detailed overview of Vitamin D’s involvement in a spectrum of diseases, laying the foundation for the upcoming second part of the article. This forthcoming article (part II) will expand on the role of Vitamin D in additional diseases, contributing to a more comprehensive understanding of its therapeutic potential. In summary, this article serves as a valuable resource for researchers and healthcare professionals, offering insights into the diverse roles of Vitamin D and setting the stage for further exploration in part II.

Vitamin D, Schizophrenia, Pregnancy, Cancers, Inflammation, Immunity, Viral diseases, Infertility

Vitamins are required for numerous biochemical and physiological processes in the body. It is common knowledge that most vitamins cannot be synthesized in the body, making their supplementation in the diet essential. On the basis of their solubility, vitamins are categorized as water-soluble (C and B complexes) and fat-soluble (A, D, E, K) [1]. Vitamin D is synthesized in the epidermis through a photolytic process acting on 7-dehydrocholesterol, subsequently isomerizing to form active Vitamin D. Few vitamins have received as much attention in the realms of nutrition and wellness as Vitamin D. Vitamin D, sometimes known as the “sunshine vitamin,” is unique in that it may be generated by the skin through sunlight exposure, but it also plays an important role in our food intake. In addition to its traditional association with bone health, recent investigations have unveiled that this crucial vitamin executes an extensive array of physiological functions. Table 1 provides a summary of human and animal studies that have established its involvement in diverse diseases. Table 1. | Study | Type of study | Findings | References | |---|---|---|---| | Vitamin D receptor deficiency impairs inner ear development in zebrafish | Animal study | Mutation in the vitamin D receptor in mice is associated with cochlear neural degeneration, sensorineural hearing loss, and impairments in muscular and motor functions, indicating a potential correlation between vitamin D and vestibular performance. Further investigation is needed to assess vestibular function in these mice | [2] | | Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation | Animal Study | The study found that prenatal exposure to maternal immune activation (MIA) caused social, behavioral, and cognitive deficits in juvenile offspring, similar to effects seen in adults. However, administering 1,25-dihydroxyvitamin D (1,25OHD) during pregnancy prevented these deficits without altering pro-inflammatory cytokine levels, suggesting the protective effects are not due to anti-inflammatory properties | [3] | | Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort | Observational cohort study | The study found that low maternal and neonatal 25OHD levels are associated with higher odds of ASD. Specifically, maternal 25OHD insufficiency in Nordic-born mothers and neonatal 25OHD levels below 25 nmol/L both increased ASD risk. Children with both low maternal and neonatal 25OHD had even higher odds of ASD. These findings support the idea that early-life vitamin D levels may influence the risk of neurodevelopmental disorders like ASD | [4] | | Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring | Observational cohort study | Women with ASD have lower quantities of 25OHD during the first trimester compared to a control group, suggesting a relationship between prenatal vitamin D levels and the risk of developing ASD. Prenatal vitamin D insufficiency may contribute to various neurodevelopmental outcomes, including ASD | [5] | | Developmental Vitamin D Deficiency in the Rat Impairs Recognition Memory, but Has No Effect on Social Approach or Hedonia | Animal Study | Investigated the effects of vitamin D deficiency during gestation on neurodevelopment in animal models, demonstrating a retardation of cerebral maturation and aberrant cellular mechanisms, with alterations in cellular dynamics and gene expression related to cell cycle progression | [6] | | In Vitro Inhibitory Effect of Vitamin D on Cell Proliferation and Neurite Formation | In Vitro Study | Vitamin D deficiency during development is linked to neuropsychiatric disorders like schizophrenia. Studies show it affects brain shape, ventricle size, neurotrophic factors, and behavior in animal models, suggesting vitamin D is crucial for brain development and a potential risk factor for these disorders | [7] | | Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study | Birth Cohort Study | Explored the potential correlation between maternal vitamin D supplementation during infancy and susceptibility to schizophrenia in male offspring based on a birth cohort study in Finland, highlighting the need for further investigation into long-term effects of vitamin D supplementation | [8] | | Vitamin D and parkinson’s disease (PD) | Literature review | Investigated the potential correlation between vitamin D, its receptor (VDR), and Parkinson’s disease (PD). Studies suggest variations in VDR gene may impact Parkinson Disease susceptibility, with VDR observed in substantia nigra neurons implicated in Parkinson Disease. However, post-mortem investigation found no vitamin D3 presence in specific brain regions | [9] | | Influence of Vitamin D on neural stem cells and catecholamine production | Laboratory study | Explored vitamin D’s ability to enhance neural stem cell proliferation, differentiation into neurons/oligodendrocytes, and regulatory control over catecholamine production, potentially impacting stress responses and neuroprotection in Parkinson Disease | [10] | | Neuroprotective and Immunomodulatory Effects of Vitamin D | Experimental studies | Investigated vitamin D’s role in safeguarding dopaminergic neurons, increasing intracellular glutathione levels, and influencing astrocyte detoxification pathways, nerve growth factor (NGF) concentration, and iNOS production, regulating CNS immunological responses in Parkinson Disease | [11] | | Correlation between Vitamin D levels and parkinson’s disease symptoms | Observational studies | Explored potential associations between vitamin D deficiency and Parkinson Disease symptoms like postural instability and freezing of gait. Uncertainty remains regarding the correlation between vitamin D levels and Parkinson Disease severity | [12] | | Vitamin D in multiple sclerosis—lessons from animal studies | Experimental study | Examined the antioxidative effects of vitamin D supplementation in a multiple sclerosis (MS) animal model, showing a reduction in oxidative stress and inflammation, key factors in Multiple Sclerosis progression. Researchers suggest vitamin D’s antioxidative properties may slow MS progression by mitigating cellular damage | [13] | | Functional genomics analysis of vitamin D effects on CD4 + T cells in vivo in experimental autoimmune encephalomyelitis | Animal model | Vitamin D supplementation protects against experimental autoimmune encephalomyelitis (EAE) by reducing harmful T cell proliferation and altering key signaling and epigenetic pathways. It decreases Th1 and Th17 cells, impacting gene expression related to multiple sclerosis (MS) risk, indicating its potential in modulating MS development | [14] | | The health effects of vitamin D supplementation: evidence from human studies | Human study | Vitamin D may reduce multiple sclerosis (MS) risk by influencing vitamin D production in myeloid cells and increasing CTLA-4 expression in T-cells, which helps regulate immune activity in the central nervous system. Studies suggest that CTLA-4, when regulated by vitamin D, acts as an immunological checkpoint in MS mitigation | [15] | | Oral squamous cell carcinomas: state of the field and emerging directions | Human Study | Vitamin D supplementation reduced treatment-related toxicities in head and neck cancer patients | [16] | | Dietary vitamin D and cancers of the oral cavity and esophagus | Human Study | VDR gene polymorphism associated with elevated risk of oral squamous cell carcinoma (OSCC) | [17] | | Decreased VDR Expression as Predictor of Tumor Recurrence and Prognosis in Oral Cancer | Prognostic Study | Decreased VDR expression linked to tumor recurrence and poor prognosis in oral cancer | [18] | | Role of vitamin D and vitamin D receptor (VDR) in oral cancer | Experimental Study | Correlation found between blood vitamin D levels and apoptosis induction in oral precancerous lesions | [18] | | Dietary vitamin D and cancers of the oral cavity and esophagus | Epidemiological Study | Inverse relationships observed between oral cancer risk and dietary vitamin D intake in heavy smokers | [17] | | Cancer incidence and mortality and vitamin D in black and white male health professionals | Clinical Study | Vitamin D deficiencies and oxidant-antioxidant imbalance more prevalent in oral cancer patients | [19] | | Vitamin D Insufficiency (< 25 ng/mL) Associated with Increased Risk of Oral Squamous Cell Cancer (OSCC) | Clinical Study (Human Study) | Vitamin D insufficiency, particularly at levels below 25 ng/mL, associated with increased risk of oral squamous cell cancer (OSCC) | [20] | | Parameters of Oxidative Stress, Vitamin D, Osteopontin, and Melatonin in Patients with Lip, Oral Cavity, and Pharyngeal Cancer | Clinical Study (Human Study) | Vitamin D medication helps head and neck cancer patients retain normal immunological reactivity | [21]] | | VDR FokI Polymorphism and Lower Incidence of Oral Cancer | Genetic Study | VDR FokI polymorphism significantly lowers the incidence of oral cancer and may serve as a prognostic marker | [22] | | No Discernible Difference in Serum Vitamin D Levels Between Oral Squamous Cell Carcinoma (OSCC) Cases and Controls | Literature Review | No significant variation in serum vitamin D levels found between cases and controls with oral squamous cell carcinoma (OSCC) | [23] | | Vitamin D, a Regulator of Androgen Levels, Is Not Correlated to PSA Serum Levels in a Cohort of the Middle Italy Region Participating to a Prostate Cancer Screening Campaign | Animal Model | Animal models demonstrate the potential for IL-6 inhibition to enhance the response of prostate cancer to radiation therapy. Inhibiting IL-6 increased responsiveness of prostate cancer cells to radiation and studies resulted in delayed tumor growth and smaller tumor size. Reduction in IL-6 levels was associated with decreased cellular proliferation and changes in epithelial-mesenchymal transition features in irradiated tumors. Investigated the complex interplay between IL-6, immune microenvironment, and tumor characteristics in radiation therapy | [24] | | Vitamin D levels and the risk of prostate cancer and prostate cancer mortality | Clinical Studies | Explored the biologic effects of vitamin D compound administration before prostatectomy. Gee et al. studied doxercalciferol versus placebo, examining serum and tissue markers including vitamin D metabolites, PSA, growth factors, and histology. Wagner et al. evaluated vitamin D3 administration on vitamin D metabolite levels, proliferation markers, and serum levels of PTH and PSA. Examined tissue expression of VDR and vitamin D hydroxylases | [25, 26] | | Vitamin D deficiency aggravates growth and metastasis of prostate cancer through promoting EMT in two β-catenin-related mechanisms | Clinical Studies | Investigated the clinical efficacy of vitamin D compounds (calcitriol, doxercalciferol, paricalcitol) as standalone treatments in prostate cancer patients. Limited evidence of noteworthy clinical efficacy observed when administered independently. Challenges in assessing calcitriol response rate due to concurrent glucocorticoid use. Highlighted the need for further study to clarify the effectiveness of vitamin D compounds as standalone medicines in prostate cancer treatment | [27] | | Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized prostate cancer and high-grade pin | Nested Case–Control Study | Examined genetic polymorphisms in the vitamin D pathway and their association with prostate cancer risk in a cohort of 2,333 male participants. Identified varying relationships based on racial groups and treatment cohorts (finasteride vs. placebo). Highlighted the complex interplay of hereditary factors, therapeutic interventions, and prostate cancer susceptibility, underscoring the need for additional research | [28] | | Efficacy of Calcitriol and Analogues in Breast Cancer Xenograft Models | In vivo Studies | Investigated the efficacy of calcitriol and its analogues in inhibiting human breast cancer xenograft tumors and preventing the development of breast tumors induced by carcinogens using animal models | [29] | | Role of Vitamin D Receptor (VDR) in Mammary Gland Development and Carcinogenesis | Pre-clinical Studies | Recognized the presence of VDR in mammary glands and breast cancer cells since the early 1980s. Demonstrated modulation of mammary gland development and carcinogenesis by VDR ligand 1,25D through pre-clinical studies | [30] | | Vitamin D Deficiency in Breast Cancer Patients and its Impact on Disease Development | Clinical Observations | Common occurrence of vitamin D deficiency in breast cancer patients. Suggested association between low vitamin D status and increased risk of disease development or progression | [31] | | Tumor Expression of Vitamin D Receptor and Breast Cancer Histopathological Characteristics and Prognosis | Clinical and Molecular Studies | Limited and inconclusive clinical data on VDR responsiveness of established breast tumors. Emphasized the importance of analyzing VDR actions in specific molecular subtypes of breast cancer to resolve conflicting data | [32] | | Impact of VDR Ablation on Mammary Gland Development and Susceptibility to Carcinogens | Genetic Studies | Demonstrated heightened mammary gland development, increased responsiveness to hormones, and delayed involution process in VDR-deficient mice. Showed increased susceptibility to carcinogen-induced skin cancers in mice lacking VDR compared to wild-type mice | [29] | | Vitamin D Intake and the Risk of Colorectal Cancer: An Updated Meta-Analysis and Systematic Review of Case–Control and Prospective Cohort Studies | Literature Review | Previous studies indicate uncertainty regarding the influence of active vitamin D and the vitamin D receptor (VDR) on preventing intestinal carcinogenesis. Evidence from rat and mouse models suggests that VDR absence may not directly impact carcinogenesis when calcium levels are normal | [33] | | Could vitamin D sufficiency improve the survival of colorectal cancer patients? | Observational Studies | Studies show a complex relationship between vitamin D levels and colorectal cancer (CRC) risk. Individuals with CRC often have inadequate vitamin D levels. Research emphasizes the importance of maintaining optimal 25(OH)D levels (30–80 ng/mL) and highlights associations between higher levels and reduced CRC occurrence and mortality | [34] | | How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases? | Meta-Analysis | Meta-analysis shows a statistically significant decrease in CRC risk with higher serum vitamin D levels in the Asian population. Provides evidence of a protective effect of vitamin D against CRC development | [35] | | Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women | Case control study | Individuals with 25(OH)D levels above 29 ng/mL experienced the most significant decrease in colorectal cancer (CRC) occurrence and mortality | [34] | | Vitamin D and Immunity: A comprehensive review of its impact on autoimmunity, allergy suppression, antimicrobial defense, and cancer inhibition | Cohort study | Study involving 17 cohorts, determining that the optimal 25(OH)D concentration for reducing CRC risk is between 75 and 100 nmol/L | [36] | | How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases? | Metaanalysis | Investigating the impact of serum vitamin D levels on CRC patients in the Asian population. They found a statistically significant 21% decrease in CRC risk for every 16 ng/mL increase in vitamin D levels | [37] | Vitamin D appears to play a crucial part in the rich tapestry of human health, from supporting the central nervous system to impacting illnesses such as multiple sclerosis, autism, schizophrenia, and Parkinson’s disease [3]. Vitamin D’s importance to the body goes much beyond what has already been proven, such as in ensuring healthy bones and teeth. Numerous trials have been carried out, as outlined in Table 2, to investigate its involvement in various physiological processes and functions. Its possible effect on the brain and spinal cord is one of the most fascinating aspects of this function. Multiple sclerosis, autism spectrum disorder, schizophrenia, and Parkinson’s disease are only some of the neurological illnesses that have been linked to Vitamin D deficiency in recent years. This article explores the complex web of relationships between Vitamin D and various diseases, illuminating potential new therapy approaches [2]. Vitamin D exhibits multifaceted involvement within the intricate domain of the central nervous system (CNS), yielding significant ramifications for a range of illnesses including autism, multiple sclerosis, Parkinson’s disease, diverse malignancies, viral infections, fertility, and pregnancy. The intricate mechanics and therapeutic potential of this subject serve as catalysts for continued scientific study, leading to the advancement of research and healthcare. Table 2. | S.no | Clinical trial number date of registration | Project title | Conditions/phase | Interventions | No. of participants | Outcome | |---|---|---|---|---|---|---| | 1 | NCT01490502 September 28, 2022 | A randomized controlled trial of Vitamin D supplementation in multiple sclerosis | Relapsing remitting multiple sclerosis (Phase 3) | Drug: Vitamin D3 | 172 | Primary Outcome Measure: Proportion of Subjects That Experience a Relapse: Confirmed relapse characterized by new or worsening central nervous system symptoms lasting ≥ 24 h, occurring at least 30 days after the prior attack, accompanied by EDSS worsening (≥ 0.5 points) or Functional Systems scales (2 points on at least one or 1 point on ≥ two FS scales) | | 2 | NCT01198132 December 14, 2017 | A Multicentre Study of the Efficacy and Safety of Supplementary Treatment With Cholecalciferol in Patients With Relapsing Multiple Sclerosis Treated With Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly | Multiple sclerosis (Phase 2) | Dietary Supplement: Cholecalciferol (Vitamin D3) Dietary Supplement: Placebo Drug: Rebif | 129 | Primary Outcome Measures: Annualized Relapse Rate -The annualized relapse rate was calculated for each treatment group as follows: the number of relapses observed during the study period divided by the time spent in the study (in years) | | 3 | NCT01285401 November 28, 2016 | Supplementation of VigantOL® Oil Versus Placebo as Add-on in Patients With Relapsing Remitting Multiple Sclerosis Receiving Rebif® Treatment | Relapsing–remitting multiple sclerosis (Phase 2) | Drug: VigantOL oil plus interferon beta-1a (Rebif); Drug: Placebo plus interferon beta-1a (Rebif); Biological: Interferon beta-1a (Rebif®) alone | 260 | Primary Outcome Measures: Percentage of Subjects With Disease Activity Free Status up to Week 48. Disease activity free status was defined as absence of any of the clinical and imaging parameters related to the assessment of disease activity; no relapses, no expanded disability status scale (EDSS) progression and no new gadolinium (Gd)-enhancing or relaxation time 2 (T2) magnetic resonance imaging (MRI) lesions | | 4 | NCT01119131 March 7, 2016 | Effects of Vitamin D in Parkinson’s Disease (PD) | Parkinson Disease Accidental Falls | Drug: Vitamin D3 Dietary Supplement: calcium Other: Placebo | 101 | Primary Outcome Measures: 1 Change in Static Balance as Recorded Using Dynamic Posturography With the Sensory Organization Test (SOT 1–3) 2. Change in Ambulatory Balance Measured by Instrumented Timed up and go (iTUG) Turn Duration 3. Change in Strength as Recorded by Measuring Knee Flexion Using Biodex (Total Work) 4. Change in Dynamic Balance as Recorded Using Dynamic Posturography With the Sensory Organization Test (SOT 4–6) 5. Change in Strength as Recorded by Measuring Knee Extension Using Biodex (Total Work) | | 5 | NCT01366885 June 14, 2016 | Study of Vitamin D to Prevent Autism in Newborn Siblings (Phase 2) | Autistic Disorder | Drug: Vitamin D3 | 20 | Primary Outcome Measures: Number of Children Who Developed Autism The child will be screened by an Modified Checklist for Autism in Toddlers (MCHAT) interview at 18 months of age, and by a questionnaire, the Pervasive Developmental Disorder Behavioral Inventory (PDDBI) at 3 years of age to determine whether the child has developed autism or not | | 6 | NCT01004354 February 10, 2012 | Effect of Vitamin D Supplementation on the Metabolic Abnormalities of Second Generation Antipsychotics in Children and Adolescents | Obesity, Vitamin D Deficiency, Psychosis, Schizophrenia,,Schizoaffective Disorder | Drug: Ergocalciferols | 12 | Primary Outcome Measures:Change in Weight | | 7 | NCT00953849 December 21, 2016 | Vitamin D Plus Celecoxib Therapy to Stimulate Intratumoral Immune Reactivity | Mouth Neoplasms | Drug: Celecoxib; Drug: Calcitriol; Drug: Celecoxib plus Calcitriol | 21 | Study evaluated the change in GM-CSF stimulatory cytokine levels within tumor tissue of head and neck squamous cell carcinoma patients across different treatment arms (Celecoxib, Calcitriol, Celecoxib Plus Calcitriol, No Treatment). The statistical analysis showed significant differences in GM-CSF levels between certain treatment groups | | 8 | NCT02726113 December 3, 2019 | Vitamin D and Prostate Cancer: A Clinical Study Enrolling Subjects Undergoing Prostatectomy | Prostate Cancer | Drug: cholecalciferol: Other: placebo | 50 | Baseline vitamin D3 levels will be obtained at enrollment and approximately two months later during the surgical procedure (prostatectomy). These D3 levels will be evaluated for the 27 participants who had genomic analysis and compared by race (Caucasian and AA) | | 9 | NCT03103152 March 29, 2023 | A Study to Examine the Effectiveness of Aspirin and/or Vitamin D3 to Prevent Prostate Cancer Progression (PROVENT) (Phase 2) (Phase 3) | Prostate Cancer | Drug: High dose Aspirin & Vitamin D; Drug: High dose Aspirin, Vitamin D placeboDrug: Low dose Aspirin, Vitamin D; Drug: Low dose Aspirin, Vitamin D; placeboDrug: Aspirin Placebo, Vitamin D; Drug: Aspirin placebo, Vitamin D placebo | 104 | Rate of Patient Recruitment to a Randomised Chemoprevention Study in Men Enrolled on an Active Surveillance Programme for Prostate Cancer. Number Accrued Per Month. [ Time Frame: 12 months]. The proportion of eligible patients that join the trial over the 12-month trial recruitment period | | 10 | NCT00524680 November 1, 2015 | Vitamin D in Treating Patients With Prostate Cancer (Phase 2) | Prostate Cancer | Dietary Supplement: cholecalciferol | 148 | Pattern of Response of Serum 25(OH) D3 Levels [ Time Frame: Baseline, at 1, 3, 6 months]. Change from Baseline in Serum 25(OH) D3 Levels at 1, 3, and 6 Months at dose levels 4000, 6000, 8000 and 10,000 IU. Statistical analysis was done using one sample t-test | | 11 | NCT00953225 April 6, 2015 | Vitamin D Supplementation in Veterans With Early-Stage Prostate Cancer (vit D & PCa) (Phase 2) | Prostate Cancer | Drug: vitamin D3Drug: Placebo daily for one year | 83 | PSA Slope (Trajectory) or the Change in PSA Level Over Time [ Time Frame: 1 year (visits # 1–8)]. Change in PSA (ng/mL) from baseline to 1 year visit, which include the baseline through 1 year follow-up | | 12 | NCT01325311 August 3, 2016 | Cholecalciferol and Genistein Before Surgery in Treating Patients With Early Stage Prostate Cancer | Prostate Adenocarcnoma | Prostate Adenocarcinoma | 15 | Detectability of Calcitriol Levels in Tissue Between the Placebo and Cholecalciferol/Genistein Arms Hide.To identify the amount of Calcitriol that is found in the tissue comparing Placebo and Cholecalciferol/Genistein | | Stage I Prostate Cancer | Stage I Prostate Cancer | ||||| | Stage IIA Prostate Cancer | Stage IIA Prostate Cancer | ||||| | Stage IIB Prostate Cancer | Stage IIB Prostate Cancer | ||||| | 13 | NCT00499408 February 17, 2014 | Vitamin D and Soy Supplements in Treating Patients With Recurrent Prostate Cancer (Phase 2) | Prostate Cancer | Dietary Supplement: Vitamin D | 26 | Number of Participants Showing a 50% Reduction in Serum Prostate Specific Antigen(PSA) During Treatment [ Time Frame: up to one year] | | Dietary Supplement: soy | |||||| | 14 | NCT00585637 April 1, 2015 | Vitamin D for Chemoprevention (Phase 1) | Gastrointestinal Cancers Prostate Cancer Hypertension | Drug: Vitamin D | 328 | Levels of Plasma 25(OH)D at Baseline, 3 Months and 6 Months. [Time Frame: Baseline, 3 months, 6 months]. Among Blacks, identify a dose of oral vitamin D supplementation that will result in levels of plasma 25(OH)D that would be predicted to reduce colorectal cancer incidence. Community-based African Americans drawn from the Open Doors to Health, which is a colorectal cancer prevention study in 1554 subjects from 12 public-housing communities and community- and faith-based organizations in Boston | | Dietary Supplement: Placebo | |||||| | 15 | NCT00365105 November 10, 2014 | Zoledronate, Vitamin D, and Calcium with or without Strontium 89 or Samarium 153 in Preventing or Delaying Bone Problems in Patients With Bone Metastases From Prostate Cancer, Lung Cancer, or Breast Cancer (Phase 3) | Breast Cancer | Dietary Supplement: Calcium | 261 | Median time to development of a malignant skeletal related event (SRE), which is defined as a pathological bone fracture, spinal cord compression, surgery to bone or radiation to bone is estimated using Kaplan–Meier method. The time of failure was measured from date of randomization to the date of a documented SRE. The analysis was planned to occur after 257 SRE have been observed, unless the criteria for early stopping are met | | Lung Cancer | Dietary Supplement: Vitamin | ||||| | Metastatic Cancer Pain | D Drug: zoledronic acid | ||||| | Prostate Cancer | Drug: Sm-153Radiation: Sr-89 | ||||| | 16 | NCT01074216 February 22, 2010 | Vitamin D Levels in Stage IV Colorectal Cancer Patients | Colorectal Cancer (Phase 2) | Drug: vitamin D repletion with Cholecalciferol (vitamin D3 50,000 International Units) | 45 | To determine the ability of achieving the target serum 25-hydroxy vitamin D level of 40 ng/ml within 6 weeks of beginning vitamin D supplements in patients with metastatic colon cancer. A response is defined as achieving serum vitamin D levels ≥ 40 ng/ml at least once at any point during the first 6 weeks | | 17 | NCT01516216 January 13, 2012 | Study of Vitamin D in Untreated Metastatic Colorectal Cancer | Metastatic Colorectal Cancer (Phase 2) | Drug: FOLFOX + bevacizumab, Dietary Supplement: Vitamin D | 139 | Median Progression-free Survival (PFS): Progression-free survival based on the Kaplan–Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients who discontinued treatment to pursue potentially curative resection were censored for progression-free survival at the time of surgery. Patients who had not experienced cancer progression or died were censored at their last known follow-up date. Disease was evaluated every 4 cycles on treatment and off treatment every 8–16 weeks until PD or non-protocol therapy start if discontinued for reason other than PD. Participants were observed up to 28.5 months with maximum follow-up of 56.7 months | | 18 | NCT04449718 | Effect of a Single High-Dose Vitamin D3 on the Length of Hospital Stay of Severely 25-Hydroxyvitamin D-Deficient Patients with COVID-19 | COVID-19 (Phase 2) | Drug: High-Dose Vitamin D3 (200,000 IU) vs. Placebo | 32 | No significant difference in the median length of hospital stay between the vitamin D3 group (6.0 [4.0–18.0] days) and the placebo group (9.5 [6.3–15.5] days). Vitamin D3 significantly increased serum 25-hydroxyvitamin D levels in the vitamin D3 group compared to the placebo group | | 19 | NCT04449718 2020–06-02 | Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19 | COVID-19 (Phase 2) | Drug: 200,000 IU Vitamin D3 vs. Placebo | 240 participants | A single dose of 200,000 IU of vitamin D3 did not significantly reduce hospital length of stay or improve other clinically relevant outcomes compared to placebo | | 20 | ISRCTN46539495 17 November 2020 | Effect of early vitamin D supplementation on the incidence of preeclampsia in primigravid women | Preeclampsia / Phase not specified | Vitamin D supplementation (cholecalciferol, 60,000 IU monthly) | 1300 | Significant reduction in preeclampsia incidence, preterm delivery, low birth weight, and caesarean section rate. Improved APGAR scores and newborn size | | 21 | IRCT2017010131695N1 | Effects of Vitamin D Supplement on Prevention of Recurrence of Preeclampsia in Pregnant Women with a History of Preeclampsia | Preeclampsia (Not Phase-specific) | 50,000 IU vitamin D3 once every two weeks vs. Placebo | 142 participants | Significant reduction in recurrence of preeclampsia, lower risk of preeclampsia in the intervention group | | 22 | ACTRN12611000402943 / April 2011 | Monthly high-dose vitamin D supplementation does not increase kidney stone risk or serum calcium: results from a randomized controlled trial | Kidney stones, hypercalcemia / Phase not specified | Monthly high-dose vitamin D supplementation (100,000 IU) | 5110 | No significant increase in kidney stone risk or serum calcium levels over a median follow-up of 3.3 years | | 23 | https://doi.org/10.2215/CJN.11331111 / May 2012 | Effect of Vitamin D Repletion on Urinary Calcium Excretion among Kidney Stone Formers | Kidney Stones / Phase not specified | Oral ergocalciferol (50,000 IU/week for 8 weeks) | 29 | No significant change in mean 24-h urinary calcium excretion after vitamin D repletion. A subset of participants experienced an increase in urinary calcium excretion ≥ 20 mg/d, but no adverse effects or hypercalcemia were observed | | 24 | IRCT20151128025274N4 / 28 March 2018 | The effects of Vitamin D3 supplementation on Spermatogram and endocrine factors in asthenozoospermia infertile men | Asthenozoospermia / Phase not specified | Daily 4000 IU Vitamin D3 for 3 months | 86 | VD3 supplementation significantly increased serum 25(OH)VD3, PTH, phosphorus, and seminal and serum calcium; T/LH ratio; and total and progressive sperm motilities in infertile men with asthenozoospermia. No significant effects on reproductive hormones were found | | 25 | NCT01304927 / February 28, 2011 | Effects of Vitamin D Supplementation on Semen Quality, Reproductive Hormones, and Live Birth Rate: A Randomized Clinical Trial | Male factor infertility / Not specified | Cholecalciferol 300,000 IU initially, then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days; placebo | 330 | Vitamin D supplementation did not improve semen quality in vitamin D-insufficient infertile men. However, vitamin D treatment in oligozoospermic men increased the chance for a live birth (35.6% vs 18.3%) | Dietary Sources Vitamin D, denoted as D2, D3, or a combination of both, is a secosterol compound that is endogenously synthesized in the skin upon exposure to sunlight or can be obtained from dietary sources such as cod liver oil, salmon, mackerel, and tuna and mushrooms that are subjected to ultraviolet (UV) radiation [3]. Food products that have been fortified with vitamin D. Milk, morning cereals, and margarine exemplify fortified food products. Enriched orange juice has just become accessible in the United States [4]. Fish, including non-fatty varieties, egg yolk, and organ meats such as liver, are highly beneficial sources of vitamin D3. Meat exhibits a comparatively low content of vitamin D3. Furthermore, it is plausible that certain species of wild mushrooms may possess substantial amounts of vitamin D2 [5]. There were differences in the consumption of vitamin D-rich foods between South Asians and Caucasians. Flour, cereals, and starches were discovered to constitute 21.8%–33.0% of vitamin D intake among South Asians. Individuals of Caucasian heritage, on the other hand, obtained roughly 24.2%–26.6% of their recommended daily vitamin D intake from items such as wheat, cereals, and carbs [6]. Vitamin D: Role in CNS Vitamin D has emerged as a subject of considerable interest in the context of neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. While some studies have raised concerns about reverse causality, suggesting that low vitamin D levels might be a consequence of disease-induced behavioural changes rather than a direct cause, numerous clinical supplementation trials have been initiated to explore its potential benefits. Vitamin D: Role in Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). Multiple sclerosis is characterized by central nervous system (CNS) inflammation, degeneration, loss of axons or neurons, and astrocytic gliosis. The disease can manifest in a variety of ways and progress in a variety of ways. Common symptoms include vision loss, double vision, muscle paralysis, spasticity, ataxia, trembling, loss of or problems with the senses, sphincter issues, and cognitive difficulties. Vitamin D may be one of many factors that contribute to your safety. Numerous investigations have revealed that people with multiple sclerosis are more likely to have elevated vitamin D levels. Low levels of serum 25 Hydroxy Vitamin D (approximately 50 nmol/L) are associated with an increased prevalence of multiple sclerosis [7]. Studies Based on Animal Models in Multiple Sclerosis Vitamin D supplementation shows antioxidative benefits in animal models simulating multiple sclerosis (MS), reducing oxidative stress and inflammation which are critical in the disease’s progression. Researchers believe that Vitamin D’s antioxidative properties might slow MS progression by protecting cells from damage. Studies support this by linking higher Vitamin D levels to reduced severity and slower progression of MS. Additionally, lower blood levels of 25 Hydroxy vitamin D, particularly around 50 nmol/L, are associated with a higher risk of MS. This suggests that Vitamin D deficiency could worsen the disease, possibly due to increased oxidative stress from excessive reactive oxygen species (ROS), which leads to demyelination and axonal damage [8]. In the context of exploring the role of Vitamin D in managing Multiple Sclerosis (MS), various clinical trials have been undertaken to assess its efficacy when combined with standard MS therapies. Two clinical trials explored the role of Vitamin D3 supplementation in managing Relapsing Remitting Multiple Sclerosis (RRMS). The Phase 3 trial (NCT01490502) focused on the proportion of patients experiencing clinical relapses, examining Vitamin D3’s potential in immune modulation or neuroprotection in MS. A Phase 2 study (NCT01198132) investigated the effects of combining Cholecalciferol (Vitamin D3) with Interferon Beta-1a, aiming to determine the annualized relapse rate and explore its synergistic effects in enhancing MS therapy efficacy. Additionally, a study (NCT01285401) tested VigantOL® Oil, a form of Vitamin D3, versus placebo in patients also treated with Interferon Beta-1a, focusing on achieving disease activity-free status through clinical and MRI assessments up to week 48. Mechanism Vitamin D administration has been found to reduce Major Histocompatibility Complex II (MHCII) expression in rats with Experimental Autoimmune Encephalomyelitis (EAE), suggesting a dose-dependent effect on demyelination and inflammation in the central nervous system. Studies in 2020 revealed that Vitamin D downregulates pro-inflammatory genes and impacts the pathophysiology of EAE, potentially altering the disease’s course in humans [9]. Vitamin D’s protective role is also evident in its reduction of CD4 + T-cell proliferation and pathogenic T-helper 17 cells, affecting crucial T-cell activation and differentiation pathways, including the Jak/Stat, Erk/Mapk, and PI3K/Akt/mTOR pathways. It also modifies myelin-reactive T-cell expression patterns, supporting its use in managing autoimmune diseases broadly. Additionally, Vitamin D might reduce multiple sclerosis (MS) risk by affecting vitamin D production in myeloid cells and enhancing CTLA-4 expression in CNS-invading T-cells. Genetic studies suggest that CTLA-4, influenced by vitamin D, acts as an immunological checkpoint that could mitigate MS [10]. Vitamin D: Therapy and Treatment in Multiple Sclerosis Research on vitamin D supplementation for multiple sclerosis (MS) has yielded mixed results, with some studies showing benefits in reducing disease severity and others showing no significant effects. High doses up to 40,000 IU per day have been tested and are considered safe for short periods under medical supervision, though the long-term effects are still uncertain. There’s also interest in vitamin D’s potential to alleviate MS-related fatigue, but the optimal dosage remains undetermined. Further research is needed to establish effective dosages and treatment durations for individuals with low initial vitamin D levels. [11]. Clinical trials have evaluated the safety of vitamin D supplementation at doses ranging from 10,000 to 40,000 IU/day when used as an adjunct therapy. In 2018, a meta-analysis conducted by a Chinese research team assessed the effectiveness of vitamin D in individuals with multiple sclerosis (MS), but found no improvements in annualized relapse rate (ARR) or Expanded Disability Status Scale [12]. This analysis included six studies, which had small sample sizes and varied methodologies, complicating direct comparisons. Subsequently, another meta-analysis involving 13 high-quality studies showed that vitamin D supplementation led to a modest reduction in relapse rates and radiographic activity, although its impact on disability progression remained uncertain. In 2019, a separate meta-analysis of six trials investigated vitamin D’s effect on the progression of the Expanded Disability Status Scale, concluding that vitamin D did not significantly affect disability progression [13]. Vitamin D: Role in Autism ASD is an intellectual disability with multiple risk factors that are both environmental and genetic. Recent research indicates that vitamin D deficiency during pregnancy or early childhood may be an environmental risk factor for autism spectrum disorder. Exciting findings from molecular and animal experiments point to potential causes of this menace [14]. Previous studies have provided evidence supporting the notion that calcitriol exerts a suppressive effect on the synthesis of inflammatory cytokines inside the central nervous system. This finding holds particular importance due to the established association between these cytokines and the pathogenesis of autism. There exists a correlation between the consumption of fish high in vitamin D during pregnancy and a reduction in the severity of symptoms associated with autism in offspring [15]. The study conducted by researchers revealed a significant disparity in the levels of 25-hydroxyvitamin D between autistic youngsters and their non-autistic counterparts. These studies may classify individuals as “Vitamin D deficient,” so providing evidence to support the hypothesis that autism may be attributed to insufficient Vitamin D intake [16]. Study Based on Animal Models and Human in Autism Research indicates a potential link between vitamin D deficiency and impaired vestibular system function, with vitamin D receptors found in the semicircular canal ducts critical to this system. Mice with a mutation in the vitamin D receptor exhibit cochlear neural degeneration and sensorineural hearing loss, suggesting possible vestibular impacts. These mice also show muscular and motor function impairments, supporting the idea of a correlation between vitamin D and vestibular performance. Further studies are needed to investigate vestibular physiology in animals with developmental vitamin D deficiency [17]. Additionally, empirical evidence supports the notion that maternal vitamin D supplementation may help prevent certain autism spectrum disorder (ASD) deficiencies, particularly in social interaction, stereotyped behavior, and emotional learning and memory. However, further studies on maternal and fetal inflammatory markers indicate that these benefits are not primarily due to anti-inflammatory effects [18]. There are numerous research using human models that support the link between vitamin D and autism spectrum disorder (ASD). One such study looked at non-genetic risk factors for autism spectrum disorders (ASD), such as exposures during pregnancy and the first few years of life to infections, obstetric challenges, and toxins or poor nutrition [19]. Fernell et al. conducted a study to compare the neonatal vitamin D levels in children diagnosed with autism spectrum disorder (ASD) with those of their unaffected siblings. The study findings revealed that the ASD cases had lower concentrations of 25-Hydroxyvitamin D compared to their unaffected siblings. The researchers were motivated by previous birth cohort studies that had demonstrated links between prenatal vitamin D deficiency and brain-related outcomes, such as language and cognitive development [20]. Chen et al. conducted a case–control study in China to compare first trimester maternal 25 Hydroxy Vitamin D levels between women with autism spectrum disorder (ASD) offspring and a control group. The findings indicated that the ASD cases had lower levels of 25 Hydroxy Vitamin D compared to the control group. This study contributes to the understanding of a potential link between prenatal vitamin D deficiency and the risk of ASD. The authors suggest that prenatal vitamin D levels might correlate with neurodevelopmental outcomes, including ASD, but emphasized the need for further research to establish clear causal relationships [21]. Secondly, trial NCT01366885, which began on June 14, 2016, explored the preventive potential of Vitamin D3 against the development of Autistic Disorder in newborn siblings of children already diagnosed with autism. This Phase 2 study’s primary outcome was the number of children who developed autism, assessed through early screening tools such as the Modified Checklist for Autism in Toddlers (MCHAT) at 18 months and the Pervasive Developmental Disorder Behavioral Inventory (PDDBI) at 3 years of age. The research sought to assess whether early Vitamin D3 supplementation could reduce the incidence of autism in this high-risk group. Vitamin D: Therapy and Treatment in Autism Research suggests that the effectiveness of vitamin D supplementation for autism spectrum disorder (ASD) may depend on factors such as the patient’s age and timing of treatment. It appears particularly beneficial for younger children, especially those under three years old. Prenatal vitamin D supplements may also offer protective effects against ASD, although results vary regarding their impact on inflammation biomarkers and neurotrophins due to factors like dosage and duration of treatment. Generally, vitamin D supplementation is considered safe for individuals with ASD, with minimal side effects and is beneficial in maintaining adequate blood vitamin D levels [22]. Recommendations indicate that individuals with ASD should maintain a minimum serum vitamin D level of 40 ng/mL, and levels up to 88 ng/mL are safe. However, the link between maternal vitamin D levels and ASD risk remains unclear, with some studies suggesting a risk increase associated with maternal vitamin D levels below 50 nmol/L, a threshold indicative of vitamin D insufficiency [23]. Vitamin D: Role in Schizophrenia Schizophrenia, a severe mental illness characterized by both positive (e.g., hallucinations, delusions) and negative (e.g., lack of motivation, speech problems) symptoms, affects about 1% of the population equally across genders. It typically emerges between ages 16 and 30, with men experiencing onset about five years earlier than women. Risk factors such as birth month, migration status, and residency latitude might relate to vitamin D deficiency [24]. People with higher melanin levels have lower vitamin D synthesis compared to those with less melanin, particularly noticeable at higher latitudes due to increased UVB ray absorption enhancing vitamin D synthesis. Research has linked low vitamin D levels in infants to increased schizophrenia risk later in life. A study found that vitamin D supplementation during the first year of life significantly reduced schizophrenia risk in males, but not in females [25]. Schizophrenia is also associated with elevated levels of immune markers like TNF and IL-6, indicating an immune system shift from a type 1 to a type 2 reaction [28]. Furthermore, vitamin D deficiency in schizophrenia patients may be linked to obesity, insulin resistance, diabetes, hyperlipidemia, and cardiovascular disease, suggesting that future research should explore the benefits of vitamin D supplementation for improving both the physical health and psychiatric symptoms of schizophrenia patients [26]. Study Based on Animal Models and Human in Schizophrenia. Vitamin D plays a critical role in regulating cellular systems and brain development. Deficiencies during pregnancy, as shown in animal studies, can delay cerebral maturation and disrupt cellular functions. These deficiencies impact cellular differentiation, proliferation, and apoptosis. In rat models with Developmental Vitamin D Deficiency (DVD), researchers have observed increased cellular proliferation and reduced cell elimination during neurodevelopment, leading to abnormal developmental processes. This is linked to altered expression of key cell cycle genes like cyclin-dependent kinase p21, p27, and cyclin D1, and increased proliferation of neuroprogenitor cells in the ventricular zone of DVD-deficient offspring [27]. Research indicates that mice lacking the CYP27B1 gene, essential for converting vitamin D into its active form, exhibit increased neuronal proliferation within the dentate gyrus. This supports the role of vitamin D in inhibiting cell proliferation and promoting neurite formation during brain development, as observed in vitro with 1,25(OH)2D. However, the effects of vitamin D deficiency can vary across different animals. For instance, animals with Developmental Vitamin D Deficiency (DVD) show specific brain phenotypes during development, such as reduced lateral ventricles at embryonic stages [28]. Furthermore, vitamin D plays a crucial role in brain myelination processes. Studies show that cholecalciferol supplementation in chemically demyelinated adult rats stimulates neural stem cell proliferation and differentiation in the subventricular zone, leading to myelin formation by oligodendrocytes migrating towards the corpus callosum [29]. The examination of the potential impact of maternal vitamin D supplementation in reducing the susceptibility to schizophrenia in offspring is a subject that has garnered significant scholarly interest. The results of a birth cohort study conducted in Finland revealed a possible correlation between the absence of vitamin D supplementation during the first year of life and an increased vulnerability to schizophrenia in male infants [30]. However, conducting randomized clinical trials to test the effects of maternal vitamin D supplementation on schizophrenia prevalence in offspring is challenging due to ethical and logistical issues. Moreover, there’s ongoing research on the broader impacts of maternal vitamin D supplementation on health outcomes, which could provide insights into its effectiveness against psychiatric disorders like schizophrenia, ADHD, or autism in the future. Mechanism The enzyme CYP27B1 is critical for converting Vitamin D into its active form and is found mainly in the kidney but also in specific brain regions like the cerebral cortex and nucleus accumbens. Only one of the seven identified CYP27B1 isoforms are present in the brain, and no significant links have been found between its brain expression and genetic variations at the SNP level. Similarly, CYP24A1, responsible for degrading active Vitamin D, shows limited expression in the brain, with higher levels in the kidney. This enzyme has several isoforms with varying tissue distributions, and SNPs in CYP24A1 can affect its transcription in different brain parts, such as the amygdala and frontal cortex. Overall, both CYP27B1 and CYP24A1 are essential for Vitamin D metabolism in the brain, although their expression there is less than in the kidney. The complexity of Vitamin D metabolism in the brain suggests significant implications for brain health and function [31]. Vitamin D: Therapy and Treatment in Schizophrenia Multiple interventional studies have examined the effects of vitamin D supplementation in individuals with schizophrenia. These studies have found that administering vitamin D supplementation at a minimum dosage of 2000 IU per day to male individuals during their first year of life led to a notable decrease of 77% in the risk of developing schizophrenia. However, the study conducted by McGrath et al. did not yield any data supporting the existence of this protective effect among female participants [32]. Dealberto et al. conducted a trial in which an immigrant population receiving continuous antipsychotic medication was supplemented with a daily dose of 1000 IU/day of vitamin D. Nevertheless, the researchers observed no statistically significant changes in schizophrenia symptoms following vitamin D supplementation [33]. Vitamin D: Role in Parkinson’s Disease Parkinson’s disease (PD) is a common neurodegenerative disorder marked by motor symptoms such as tremor, rigidity, and bradykinesia, with issues like freezing of gait and postural instabilities developing as the disease progresses. Non-motor symptoms (NMSs) like autonomic dysfunction, sleep disturbances, and cognitive impairments can emerge well before the motor symptoms. Vitamin D, crucial for bone metabolism and brain function, has been linked to PD, with studies from about twenty years ago indicating a higher prevalence of vitamin D deficiency in PD patients than in controls, suggesting its neuroprotective potential through the activation of neurotrophic factors and regulation of nerve growth. Research shows that low vitamin D levels are associated with worse motor symptoms in PD, as measured by scales like the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr scale, and may also increase the risk of falls. However, the impact of vitamin D on NMSs is less understood, highlighting the need for further research to explore its influence on these symptoms in PD [34]. Study Based on Animal Models and Human in Parkinson’s Disease Research suggests a potential link between vitamin D, its receptor (VDR), and Parkinson’s disease (PD). Studies indicate that variations in the VDR gene may influence PD susceptibility, especially in populations with significant ultraviolet radiation exposure. VDR has been identified in neurons within the substantia nigra, a brain area implicated in PD. However, a specific post-mortem study did not detect vitamin D3 in certain brain regions [35]. Multiple studies have elucidated the potential methods through which vitamin D may exert its influence on Parkinson’s disease (PD). For example, previous studies have demonstrated that vitamin D has the ability to augment the proliferation of neural stem cells and facilitate their differentiation into neurons and oligodendrocytes when tested in a laboratory setting. Additionally, it seems to exert regulatory control over the production of catecholamines, hence potentially facilitating stress responses [36]. Research links Vitamin D deficiency with structural and functional brain changes. It’s suggested that 1,25OH2D3, a form of Vitamin D, may protect dopaminergic neurons by increasing intracellular glutathione levels and influencing the detoxification pathways of astrocytes, nerve growth factor concentration, and inhibition of iNOS production, thereby regulating specific immunological responses in the central nervous system. Studies also explore the relationship between Vitamin D levels and Parkinson’s disease, noting that a deficiency might correlate with symptoms like postural instability and freezing of gait. However, the impact of Vitamin D on the severity of Parkinson’s disease remains unclear [37]. One study, trial NCT01119131 which began on March 7, 2016, focused on the effects of Vitamin D3 supplementation in PD patients, particularly in relation to reducing accidental falls. The study assessed changes in balance and muscle strength using Dynamic Posturography with the Sensory Organization Test, the instrumented Timed Up and Go (iTUG) test, and Biodex measurements of knee flexion and extension, aiming to determine if Vitamin D3 could improve balance and strength, thereby decreasing fall risk in PD patients. Mechanism Oxidative stress plays a significant role in Parkinson’s disease (PD), and vitamin D’s anti-inflammatory and antioxidant properties may help mitigate this. Vitamin D promotes neuroprotection by enhancing neurotrophin secretion, producing proteins like parvalbumin, and regulating inflammatory processes and calcium channels. Notably, high levels of the vitamin D receptor (VDR) and 1-hydroxylase in the substantia nigra suggest that vitamin D activation could influence dopaminergic neuron degeneration in PD. Genetic variations in the VDR may also correlate with PD severity. While low vitamin D levels are linked to increased PD susceptibility and higher levels may improve motor symptoms, the relationship between vitamin D and PD progression remains unclear, necessitating further research to define its therapeutic potential and impact on disease progression [38]. Vitamin D: Therapy and Treatment in Parkinson’s Disease The effectiveness of vitamin D supplementation in managing Parkinson’s disease (PD) is still under investigation, with some clinical trials indicating potential benefits. In one study involving 114 PD patients, half received 1200 IU of vitamin D3 daily while the other half took a placebo over a year. Results showed a protective effect against PD symptom progression, especially in individuals with the FokI TT genetic variant. Another trial by Sato et al. involved 86 PD patients, where half received 1 µg of 1alpha-Hydroxyvitamin D3 daily for a year, significantly reducing the risk of fractures, thus suggesting benefits for bone health and overall well-being. These studies highlight the potential of vitamin D3 supplementation as a supportive treatment for PD, with genetic factors influencing outcomes [39]. Vitamin D: Role in Cancers and Inflammation Cancer is often associated with immune modulation and chronic inflammation, which can increase the risk of malignancies such as liver, bladder, lung, colorectal, and gastric cancers. Inflammation plays a role in nearly every aspect of tumor development, including cell growth, angiogenesis, and tumor spread, as well as how tumors interact with the immune system and respond to treatments. Chronic inflammation, characterized by a prolonged, low-grade inflammatory response, releases reactive oxygen species (ROS) and cytokines, leading to tissue degeneration and regeneration. This process is increasingly recognized as a key factor in the initiation of cancer. Research indicates that vitamin D can potentially reduce inflammation through at least four different mechanisms. [40–43]. Occupational and environmental exposures are significant factors in the pathogenesis of inflammation and the initiation and progression of cancer. The influence of these exposures on cellular processes and immunological responses may lead to the development of chronic inflammation, which is recognised as a significant component in the initiation and progression of cancer. The comprehension and alleviation of these exposures play a vital role in the prevention and management of inflammation-related malignancies across several contexts [44]. Calcitriol, the active form of vitamin D, significantly reduces inflammation by modulating various biochemical pathways. It decreases COX-2 expression and prostaglandin (PG) synthesis, notably by enhancing the degradation of PGE2 in prostate cancer cells and reducing PGE2 and COX-2 mRNA in breast cancer cells. A negative correlation exists between Vitamin D receptor (VDR) expression and COX-2 in ovarian and breast cancer cells, emphasizing the calcitriol-VDR axis in inhibiting these inflammatory markers. Furthermore, calcitriol suppresses pro-inflammatory cytokine production by upregulating MAPK phosphatase-5 (MKP-5), which inhibits the p38 MAPK signaling pathway, reducing IL-6 and TNF in prostate and monocyte cells. It also blocks the NF-κB pathway in various ways, including inhibiting AKT phosphorylation in macrophages and enhancing IκB stability in fibroblasts, preventing NF-κB activation. Additionally, vitamin D regulates interactions between cancer cells and immune cells, reducing cytokine secretion in the tumor microenvironment. This effect is evident in experiments with colon cancer cells and peripheral blood mononuclear cells (PBMCs), where it reduces pro-inflammatory cytokines like TNF, IL-6, and IL-10. These findings highlight vitamin D’s potential as a therapeutic agent in managing inflammation and cancer progression [45]. Study Based on Animal Models in Cancer Promising findings from animal research suggest that vitamin D can inhibit tumor growth. Murine models demonstrate that vitamin D administration reduces tumor growth rates, diminishes tumor sizes, and suppresses tumor progression. The mechanisms are hypothesized to involve modulation of cell signaling pathways, facilitation of cancer cell death, suppression of angiogenesis, and regulation of the immune response to cancer cells. The effectiveness of vitamin D in these trials depends on dosage and timing, which researchers are optimizing for the best anti-cancer outcomes. However, translating these results to humans is challenging, necessitating human clinical trials to confirm vitamin D’s therapeutic potential for cancer. Ongoing research aims to identify the cancer types most responsive to vitamin D treatment. In summary, while animal studies provide compelling data on vitamin D’s anti-tumor properties, further research and clinical trials are essential to determine its effectiveness and safety in cancer prevention and treatment for humans. [46]. Animal studies show a correlation between vitamin D and reduced tumor growth. In these studies, mice were divided into two groups: one received vitamin D supplementation, and the other did not. The findings revealed that tumor growth in the vitamin D group was notably slower compared to the control group. Vitamin D supplementation inhibited cancer cell growth and gradually reduced tumor sizes by regulating cellular signaling pathways, promoting apoptosis, and suppressing angiogenesis, thereby limiting the tumor’s blood supply. Additionally, vitamin D’s immunomodulatory properties enhance the immune system’s ability to combat malignant cells by improving immune cell activation and targeting cancer cells. While this study focused on prostate cancer, similar results have been observed in other cancer types across various animal models. These outcomes suggest that vitamin D intake may slow tumor growth and extend treatment timelines. ssHowever, clinical trials involving human subjects are essential to validate these findings and determine optimal dosages and treatment protocols. [47]. Mechanism Calcitriol, also known as bioactive vitamin D, plays a crucial role in the regulation of multiple metabolic pathways. Vitamin D exhibits many mechanisms that could potentially safeguard somatic stem cells, such as DNA damage repair and defense against oxidative stress. Additionally, it may impede the proliferation of cancer stem cells through mechanisms like cell cycle arrest and induction of cell death (68).The anticancer effects of vitamin D have been comprehensively explained by in vitro research, revealing numerous essential processes. Initially, it exerts regulatory control on the progression of the cell cycle by inducing cell cycle arrest specifically in the G0/G1 phase, thereby inhibiting the proliferation of cancerous cells. The regulation of this activity is facilitated through the modification of cyclin-dependent kinase inhibitors, specifically p21 and p27. This modulation ultimately results in the arrest of the cell cycle, particularly in the S phase, within specific cancer cell lines. Additionally, it has been observed that vitamin D can trigger apoptosis, a process of programmed cell death, in cancer cells. This is achieved by upregulating the expression of pro-apoptotic molecules such as Bax and Bad, while downregulating the expression of anti-apoptotic molecules such as Bcl-2. Moreover, it has been observed that vitamin D has a pivotal role in the activation of caspase 3, an essential protein involved in the cellular process of apoptosis. Moreover, it is worth noting that vitamin D has the capacity to initiate autophagy, a fundamental cellular mechanism that plays a crucial role in eliminating impaired cells and cellular constituents. Consequently, this phenomenon significantly aids in impeding the proliferation of malignant cells. Finally, vitamin D plays a regulatory role in inflammation, which is widely recognised as a contributing factor to the development of cancer, through its modulation of cytokine and prostaglandin synthesis. Furthermore, it hinders the NF-kB signalling pathway, which is involved in the development of inflammation-related cancer, while also impacting immune cells and the cytokine environment within the tumour microenvironment. The results obtained from in vitro investigations underscore the diverse and encouraging potential of vitamin D in the prevention and treatment of cancer [49]. Vitamin D: Therapy and Treatment in Cancer The daily cost of vitamin D3 supplementation at 1000 IU is less than five cents, minimal compared to the high societal and economic costs of cancers due to vitamin D deficiency. Optimal action often follows the public health community’s guidance. Vitamin D levels are typically assessed by measuring 25(OH)D in the bloodstream, with individuals categorized based on established criteria into sufficient (30–100 ng/ml), insufficient (21–29 ng/ml), or deficient (20 ng/ml or less) [50]. The daily cost of vitamin D3 supplementation at 1000 IU is under five cents, relatively minimal when compared to the extensive societal and economic impacts of cancers related to vitamin D deficiency. Public health leadership provides crucial guidance for timely interventions. Vitamin D levels are typically assessed by measuring 25(OH)D in the bloodstream, and individuals are categorized into three levels based on established criteria: sufficient (30–100 ng/ml), insufficient (21–29 ng/ml), and deficient (20 ng/ml or less) [51]. The role of vitamin D in the immune systems of cancer patients has been extensively studied. For example, prostate transcriptome analysis revealed that administering 4000 IU of vitamin D daily for two months before a prostatectomy altered gene expression related to inflammation. High doses of vitamin D (10,000 IU/day) have been shown to reduce levels of 27-Hydroxycholesterol (27HC), a metabolite acting as an estrogen receptor modulator that promotes breast cancer growth [52]. Another study monitored cancer patients with low vitamin D who received either standard chemotherapy or chemotherapy with an additional 2000 IU of vitamin D daily for two years, observing them for around four years [53]. Vitamin D: Role in Oral Cancer ([Premalignant Lesions and Oral Squamous Cell Carcinoma (OSCC) The etiology of oral squamous cell carcinoma (OSCC) is an intricate and multidimensional phenomenon that impacts the fundamental cellular pathways involved in tumorigenesis and cellular proliferation. A wide range of both external and internal triggers have been shown to trigger a complex series of molecular changes that actively contribute to the progression of cancer [54]. Research on the relationship between serum vitamin D levels and its receptor (VDR) is promising for enhancing treatments for precancerous tumors and oral squamous cell carcinoma (OSCC). Vitamin D, particularly when activating apoptosis in VDR-positive tumors and lesions like oral lichen planus or leukoplakia, could serve as an effective chemopreventive or therapeutic agent. A study by Grimm et al. investigated the impact of calcitriol and its analogs on oral tissues, discovering a potential link between reduced VDR expression and OSCC tumor regression. Although the mechanisms of VDR function remain unclear, utilizing calcitriol or similar drugs could improve cancer management by targeting residual tumor cells [55]. The study by Lipworth et al. found a negative correlation between dietary vitamin D intake and the incidence of squamous cell carcinoma of the esophagus (SCCE), as well as oral and pharyngeal cancers. This correlation was particularly significant among heavy smokers and excessive alcohol users [56]. Study Based on Animal Models and Human in Oral Cancer Research underscores the link between vitamin D and oral cancer. Vitamin D supplementation is shown to lessen treatment-related side effects in head and neck cancers (Anand et al.), while VDR gene polymorphism has been linked to an increased risk of oral squamous cell carcinoma (OSCC). Studies by Giovannucci et al. and Grimm et al. indicate that lower vitamin D levels and decreased VDR expression are associated with higher cancer risks and poorer prognoses, with specific impacts on apoptosis in precancerous lesions [57]. According to Nuszkiewicz et al., furthermore, deficiencies in vitamin D and an imbalance between oxidants and antioxidants were shown to be more prevalent in patients with oral cancer [58]. Udeabor et al. found that vitamin D insufficiency, particularly at levels below 25 ng/mL, is associated with an increased risk of oral squamous cell cancer (OSCC) [59]. Vitamin D medication was reported to help patients with head and neck malignancies retain normal immunological reactivity [60]. According to Zeljic et al. (2012), the VDR FokI polymorphism significantly lowers the incidence of oral cancer and may serve as a stand-alone prognostic marker [61]. Finally, Zhang et al. (2015) found no discernible variation in serum vitamin D levels between cases and controls with OSCC [62]. In the clinical trial NCT00953849, initiated on December 21, 2016, the effects of combining Vitamin D (Calcitriol) with Celecoxib were investigated in patients with mouth neoplasms, specifically head and neck squamous cell carcinoma. The study measured changes in GM-CSF, a cytokine that stimulates immune response, within tumor tissues. Results indicated significant variations in GM-CSF levels across different treatment groups, highlighting the potential of this drug combination to modulate tumor-associated immune activity. Mechanism Vitamin D has a diverse variety of functions in relation to oral cancer, presenting possible advantages in terms of both prevention and treatment through several complex pathways. One of the principal processes is the capacity to impede the multiplication of oral cancer cells, hence decelerating the progression of tumors. Vitamin D exerts its effects through the regulation of the cell cycle and facilitation of apoptosis, a controlled mechanism of cell death that plays a crucial role in the regulation of malignant tissue growth. Moreover, vitamin D demonstrates anti-inflammatory characteristics, which play a crucial role in the progression of cancer. The presence of persistent inflammation in the oral cavity has been identified as an established risk factor for the onset and progression of oral cancer. Vitamin D has the potential to have a role in the prevention of mouth cancer by mitigating inflammation and modifying the immune response. Additionally, vitamin D plays a crucial function in the regulation of the immune system. It has the potential to augment the functionality of immune cells, specifically T-cells, which play a pivotal role in the identification and eradication of malignant cells. The observed immune-enhancing effect has the potential to enhance the body’s natural defense systems against oral cancer. Furthermore, vitamin D can impede angiogenesis, which is the physiological process responsible for the synthesis of blood vessels, in addition to its effects on immunological function. Tumors necessitate a consistent provision of nutrients and oxygen to proliferate and flourish. The inhibition of angiogenesis by vitamin D has the potential to restrict the vascularization of oral cancers, hence inhibiting their growth and progression. Moreover, there is a correlation between vitamin D and the regulation of cellular adhesion and invasion. These activities play a crucial role in the movement of cancer cells and their ability to metastasize. Vitamin D has the potential to limit the dissemination of mouth cancer to adjacent structures and remote locations within the body by modulating cell adhesion and invasion. Moreover, vitamin D plays a crucial function in facilitating DNA repair pathways and sustaining genomic stability. This phenomenon decreases the probability of genetic mutations that can contribute to the progression of mouth cancer. Additionally, vitamin D has the capacity to impact the regulation of genes implicated in the progression of cancer. The potential mechanism of action for its anticancer activities involves the upregulation of tumor suppressor genes and the downregulation of oncogenes. Finally, it is worth noting that vitamin D has the potential to interact with hormonal pathways that are pertinent to the development and progression of cancer. This relationship could potentially have ramifications in the development and progression of hormone-related oral malignancies. Although these processes propose a potential involvement of vitamin D in the prevention and treatment of oral cancer, it is crucial to underscore that vitamin D supplementation should not be regarded as a sole therapy for oral cancer. The integration of this method into a comprehensive treatment strategy is crucial in conjunction with conventional modalities including surgery, radiation therapy, chemotherapy, and targeted medicines. Furthermore, it is recommended that the administration of vitamin D supplements be carried out with the supervision of healthcare specialists in order to guarantee its safety and efficacy in the realm of cancer treatment. Further investigation is required to comprehensively clarify the underlying mechanisms and determine the most effective dosages and treatment protocols for vitamin D in the context of oral cancer [63]. The influence of VDD on the process of tooth mineralization has been thoroughly examined in prior scholarly works. The fundamental basis of biology is established on the premise that a significant deficiency in vitamin D (VDD), characterized by levels below 10 ng/mL, leads to a reduction in calcium levels (hypocalcemia) and phosphorus levels (hypophosphatemia). Consequently, this deficiency induces secondary hyperparathyroidism because of the hypocalcemia. Hyperparathyroidism is a pathological state characterized by the upregulation of calcium (Ca2+) absorption in the intestines and the synthesis of 1 α,25-dihydroxyvitamin D (1,25[OH]2D) in the kidneys. As a consequence, there is an elevation in bone remodelling, leading to augmented calcium (Ca2+) concentrations in the circulatory system and reduced levels of inorganic phosphate (Pi) [64]. The original condition of hypophosphatemia is subsequently aggravated to a severe extent. The inadequate quantities of calcium ions (Ca2+) and phosphate ions in tooth cells, resulting from impaired vitamin D signalling pathways, inhibit the proper mineralization process of teeth. Consequently, this disruption leads to the development of mineralization abnormalities [65]. To summarize, the presence of severe vitamin D deficiency (VDD), which is characterized by markedly low levels of vitamin D, can exert a notable influence on the process of tooth mineralization. The primary cause of this phenomenon can be attributed to the sequential occurrence of events initiated by VDD, which encompasses the development of hypocalcemia (characterized by reduced calcium levels) and hypophosphatemia (characterized by diminished phosphorus levels), ultimately resulting in the manifestation of secondary hyperparathyroidism. Hyperparathyroidism, in turn, induces the facilitation of calcium absorption in the intestines and the synthesis of active vitamin D in the kidneys. The heightened bone turnover leads to elevated concentrations of calcium in the bloodstream and reduced amounts of inorganic phosphate, hence worsening the condition of hypophosphatemia. In the cellular context of teeth, the perturbations observed in vitamin D signalling pathways, which manifest as inadequate levels of calcium and phosphate ions, impede the appropriate mineralization mechanism of teeth, ultimately resulting in irregularities in mineralization. Hence, it is imperative to ensure enough vitamin D to facilitate the proper mineralization of teeth, underscoring the significance of managing vitamin D deficiency (VDD) to promote dental health. Vitamin D: Therapy and Treatment in Oral Cancer The potential of vitamin D as a viable approach to mitigate the morbidity and mortality associated with oral cancer has been acknowledged. Vitamin D is an essential fat-soluble vitamin that plays a critical role in managing calcium and phosphorus levels, which are vital components for maintaining excellent bone and dental health. Vitamin D can be acquired by using dietary supplements, the consumption of food sources, or the process of manufacture in the skin subsequent to exposure to sunshine. Aside from its role in regulating calcium and phosphorus levels within the human body, vitamin D plays a crucial role in facilitating cellular growth, moderating inflammatory responses, facilitating the production of prostaglandins, beginning programmed cell death, and impeding the proliferation of cancerous cells. These effects are achieved by many processes that impact the action of growth factors. The available preclinical evidence provides robust support for the cancer-preventative advantages of vitamin D. Studies have demonstrated its ability to induce programmed cell death, inhibit cell growth, and delay angiogenesis in several types of cancer cells. The utilization of vitamin D in therapeutic protocols for oral cancer has been found to potentially alleviate the adverse effects of chemotherapy and radiotherapy, while simultaneously enhancing the overall well-being and health of patients. Through a thorough examination, a strong association has been discovered between hypovitaminosis D and decreased rates of survival, increased likelihood of post-operative recurrence, and heightened occurrence of adverse reactions to chemotherapy in individuals diagnosed with oral cancer. The current body of literature exhibits a dearth of sufficiently robust randomized controlled trials that examine the efficacy of vitamin D administration in the prevention of oral cancer [66].The therapeutic efficacy of vitamin D supplementation has been investigated in the context of oral cancer, with specific research suggesting that it may confer advantageous outcomes through modulating inflammatory indicators associated with the condition. The examination of VDR gene polymorphisms and expression holds promise in identifying gene therapy targets linked to vitamin D and oral cancer. Numerous research has investigated the correlation between cigarette use and excessive alcohol use, which are widely acknowledged as prominent risk factors for oral cancer, and their effects on vitamin D levels and genetic characteristics associated with the disease. The importance of doing subgroup analysis is emphasized by the potential interplay of many variables, including alcohol consumption, tobacco usage, and gender, and their influence on vitamin D levels. These factors, in turn, may have implications for the risk and outcomes associated with oral cancer [67]. Vitamin D: Role in Prostate Cancer Throughout the years, there has been considerable discourse surrounding the association between vitamin D levels and the likelihood of developing prostate cancer. The varying levels of solar radiation in the Nordic countries have sparked considerable interest in investigating the potential association between vitamin D and prostate cancer. This is due to the high prevalence of prostate cancer in that region [68]. The study observed that plasma calcitriol levels in patients with prostate cancer were comparatively lower than those in a control group that was carefully matched. Additionally, it was shown that males with elevated plasma vitamin D levels had a greater likelihood of developing aggressive Prostrate cancer, as indicated by prostatectomy specimens. Nevertheless, there was a correlation between decreased vitamin D levels in the bloodstream and an elevated likelihood of developing aggressive prostate cancer. Multiple studies have indicated the significance of considering both the VDR gene and UV exposure in determining an individual’s susceptibility to prostate cancer. The study findings indicate that individuals of the male gender exposed to significant amounts of sunlight and possessed protective VDR genotypes exhibited a reduced risk of developing skin cancer, ranging from 33 to 54%, compared to their counterparts who had little sun exposure and lacked protective genotypes. Further investigation is warranted on the examination of study groups of sufficient size to identify statistically significant interactions. [69]. Several investigations, however, were unable to establish a clear association between vitamin D levels and the prevalence of prostate cancer [70]. In this study, we examined the suppressive impact of the biologically active variant of vitamin D (1,25-D) on the proliferation of human prostate epithelial and stromal cells under chemically specified conditions, both in the presence and absence of dihydrotestosterone (DHT). The results of this study indicate that vitamin D could potentially serve as a viable antiproliferative treatment for prostate cancer therapy, based on in vivo experiments conducted on the normal rat prostate [71]. Study Based on Animal Models and Humans in Prostrate Cancer Animal models have provided valuable insights into the potential for IL-6 inhibition to improve the response of prostate cancer to radiation therapy. Studies utilizing immunocompromised mouse models demonstrated that inhibiting IL-6 led to increased responsiveness of prostate cancer cells to radiation, supporting earlier in vitro findings. Additional research with immunocompetent mice showed suppressing IL-6 expression resulted in delayed tumor growth and smaller tumor size following radiation therapy. This highlights the key role IL-6 plays in the radiation response. Further investigations revealed reducing IL-6 levels was associated with decreased cellular proliferation and changes in epithelial-mesenchymal transition features in irradiated tumors. The complex interplay between IL-6, the immune microenvironment, and tumor characteristics in the setting of radiation therapy was also explored. Inhibiting IL-6 was found to reduce the recruitment of immunosuppressive myeloid-derived suppressor cells and increase T cell infiltration into irradiated tumours. Taken together, these animal model studies provide critical insights into the intricate relationships between IL-6, immune system response, and prostate cancer behaviours in the context of radiation treatment. The findings suggest inhibiting IL-6 may hold promise as a strategy to improve prostate cancer radiation therapy outcomes in patients [72]. Several studies have been conducted to explore the biologic effect of the administration of vitamin D compounds in the preoperative period before prostatectomy to evaluate potential biologic changes. This study design has considerable merit in allowing exploration of clinically relevant dose and biologic response relationships in human tissues. Gee and colleagues studied doxercalciferol in similar patients randomized to doxercalciferol (10 mcg QD × 28 days) versus placebo for 28 days prior to radical prostatectomy [73]. Serum markers examined included vitamin D metabolites, TGF-β 1/2, free/total PSA, insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF); tissue markers studied included histology, MIB-1 and TUNEL staining, microvessel density and factor VIII, staining, androgen receptor and PSA, VDR expression and nuclear morphometry. TGF-β2 was the only biomarker significantly altered by doxercalciferol supplementation (~ 2–fourfold). The meaning of this change has not been further studied. Wagner and colleagues evaluated the biologic effect of vitamin D3 (cholecalciferol) administration prior to prostatectomy on intraprostatic concentrations of vitamin D metabolites as well as on markers of potential biologic importance. Sixty-three patients completed the administration of either 400 IU, 10 000 IU, or 40 000 IU daily by mouth for up to 4 weeks prior to prostatectomy. In prostate tissue, vitamin D metabolite levels and Ki67 labelling were assessed and serum PTH and PSA were measured. This study demonstrated the safety of these dosing regimens and showed clearly that tissue and serum levels of vitamin D metabolites, including calcitriol, increased in a dose-dependent manner (P < 0.03). Vitamin D compound concentrations were highest in the 40 000 IU Day−1 group (P < 0.03). Tissue vitamin D metabolite levels were positively correlated with vitamin D serum levels (P < 0.0001). While Ki67 labelling indices were not different among the dosing groups, there was evidence that intraprostatic calcitriol level was inversely associated with the proliferation marker, Ki67 intensity and percent Ki67 “positive” nuclei in prostate cancer and benign tissue (P < 0.05). The two highest dose supplementation groups were combined in an analysis of the impact of dosing on PTH and PSA serum levels which indicated that high-dose D3 administration suppressed PTH and PSA levels (P < 0.02). This group conducted further exploratory analyses on the tissues available from this clinical trial. VDR was detected in both epithelial and stromal tissues, and vitamin D hydroxylases were present only in prostate stromal cells. VDR expression was suppressed in those tissues with the highest 1,25(OH)2D3 content. In specimens with the highest 1,25(OH)2D3 content, epithelial cell interleukin (IL)-6 was the highest and stromal cell COX-2 was the lowest. This group has also described in vitro studies in prostate stroma and found that the expression of miR-126-3p, miR-154-5p, and miR-21-5p was positively correlated with 1,25D3 prostate tissue content [74]. Multiple studies have been conducted in the field of human health to investigate the potential impact of Vitamin D on prostate cancer. The assessment of individual vitamin D compounds, such as calcitriol, doxercalciferol, and paricalcitol, in patients with prostate cancer demonstrates restricted evidence of noteworthy clinical efficacy when employed as independent treatments. Although certain studies have reported a reduction in prostate-specific antigen (PSA) levels, none of them offer convincing evidence of independent effectiveness. The assessment of calcitriol’s response rate presents a challenge due to its frequent administration in conjunction with glucocorticoids. This combination complicates the differentiation of calcitriol’s response rate from the expected response rate solely attributed to glucocorticoids. Glucocorticoids are recognized for their anticancer effect in prostate cancer. Research studies that have utilized the combination of calcitriol and dexamethasone have demonstrated a prostate-specific antigen (PSA) response rate of 19%. This finding poses a challenge in distinguishing this response rate from the expected response rate when dexamethasone is administered alone. This highlights the necessity for additional study to clarify the genuine and clinically significant effectiveness of vitamin D compounds as standalone medicines in the treatment of prostate cancer [75]. A nested case–control study, a cohort of 2,333 male participants from the Prostate Cancer Prevention Trial was examined to investigate potential connections between 21 single nucleotide polymorphisms (SNPs) in genes related to the vitamin D pathway and the risk of developing prostate cancer. Differences were noted among racial groups and treatment cohorts. Certain genes exhibited varying relationships depending on whether finasteride or a placebo was used. It is worth mentioning that two SNPs exhibited heightened risks in the placebo group but shown inverse relationships in the finasteride group. Although several genes were found to have an impact on serum 25(OH)D levels, the associations between these genes and prostate cancer remained uncertain. The research underscores the intricate interplay among hereditary factors, therapeutic interventions, and the susceptibility to prostate cancer, hence underscoring the imperative for additional inquiry [76]. Several clinical trials have explored the role of Vitamin D supplementation in prostate cancer management. The trial NCT02726113, started on December 3, 2019, assessed the impact of cholecalciferol on Vitamin D3 levels in patients undergoing prostatectomy, focusing on changes from baseline to surgical intervention and analyzing differences across racial groups. In another study, NCT03103152 (PROVENT), which began on March 29, 2023, researchers tested the effectiveness of aspirin combined with Vitamin D3 in preventing cancer progression in patients under active surveillance, measuring patient recruitment rates over 12 months. NCT00524680, initiated on November 1, 2015, examined the serum 25(OH) D3 response to various doses of cholecalciferol in prostate cancer patients, monitoring changes over several months. Additionally, NCT00953225, starting April 6, 2015, focused on the effects of Vitamin D3 on PSA levels over one year in veterans with early-stage prostate cancer. Lastly, NCT01325311, which commenced on August 3, 2016, explored the detectability of calcitriol in prostate tissues, comparing placebo with a cholecalciferol/genistein combination pre-surgery. These studies collectively contribute to understanding Vitamin D’s potential therapeutic benefits in prostate cancer treatment strategies. Mechanism Typically, cells possess a process by which they degrade β-catenin, a protein that serves a vital function in cellular adhesion and communication pathways. Nevertheless, in instances of vitamin D insufficiency, this process of breakdown may be impeded. Consequently, cellular levels of β-catenin may undergo accumulation. The accumulation of β-catenin within the cellular environment facilitates its translocation into the nucleus, so initiating the activation of the Wnt/β-catenin signalling pathway. The pathway has been identified as having a significant impact on a range of biological functions, such as cell proliferation, migration, and differentiation. The activation of this route in prostate cancer has the potential to facilitate the transition of cancer cells, hence augmenting their aggressiveness. Significantly, the stimulation of Wnt/β-catenin signalling is associated with the facilitation of epithelial-mesenchymal transition (EMT). The biological phenomenon known as Epithelial-Mesenchymal Transition (EMT) involves the loss of distinctive epithelial features and the acquisition of mesenchymal qualities by cancer cells. This shift is correlated with heightened invasiveness and the ability to metastasize. Within the framework of the article, the lack of vitamin D serves to intensify the process of epithelial-mesenchymal transition (EMT) by facilitating the accumulation of β-catenin and subsequent activation of this signalling pathway. Furthermore, β-catenin can directly engage with certain transcription factors associated with epithelial-mesenchymal transition (EMT), in addition to its involvement in Wnt signalling. Transcription factors, namely Snail, Slug, and Twist, assume a pivotal function in coordinating the molecular alterations that transpire during the process of epithelial-mesenchymal transition (EMT). β-catenin functions as a co-activator when it interacts with transcription factors related to epithelial-mesenchymal transition (EMT), hence promoting the transcription of genes that are implicated in EMT. These genes are involved in inhibiting epithelial characteristics and facilitating the acquisition of mesenchymal qualities in cancer cells. These characteristics, namely enhanced cell motility, invasiveness, and the capacity for distant metastasis, are recognized as defining attributes of metastatic cancer [77]. Vitamin D: Therapy and Treatment in Prostrate Cancer The regulating function of vitamin D signaling in prostate cancer cells has been observed. This presents an opportunity to explore the potential of vitamin D as a therapeutic target in the context of prostate cancer. Clinical trials have the ability to investigate the utilization of vitamin D analogs or supplements in order to control its effects and potentially impede the growth of cancer.The comprehension of the impact of vitamin D receptor signaling on ERAD and androgen receptor signaling has the potential to facilitate the identification of patients exhibiting distinct vitamin D receptor profiles by healthcare professionals. Tailored treatment strategies have the potential to be devised for these individuals, which may result in more efficacious outcomes [72]. The investigation of treatment techniques that augment endoplasmic reticulum-associated degradation (ERAD) may be warranted, as it has been observed that vitamin D signaling exerts a negative regulatory effect on ERAD. This may entail the advancement of pharmaceuticals or therapies that facilitate the breakdown of misfolded or impaired proteins, hence potentially diminishing the viability and propagation of cancer cells. The growth of prostate cancer frequently relies on the androgen receptor pathway. The comprehension of the detrimental effects of vitamin D on this system indicates the possibility of novel therapeutic strategies. The combination of drugs that specifically target the androgen receptor, along with approaches aimed at modulating vitamin D signalling, has the potential to enhance the effectiveness of treatment. The potential exploration of combination therapy arises from the combined influence of vitamin D signalling on ERAD and androgen receptor signalling. The integration of therapeutic interventions that simultaneously address both routes may yield synergistic outcomes, so offering a more holistic strategy for the management of prostate cancer. The present study aims to elucidate the molecular pathways that underlie the growth of prostate cancer. This understanding has the potential to contribute to future research endeavors and facilitate the advancement of targeted medicines. This research has the potential to uncover distinct biomarkers associated with the status of the vitamin D receptor. These biomarkers have the potential to assist doctors in the identification of patients who are more likely to exhibit positive responses to specific treatments or possess an elevated susceptibility to disease development. The investigation of therapeutic approaches that directly manipulate the signaling of the vitamin D receptor may be a subject of interest for researchers. One potential avenue of exploration entails the synthesis of vitamin D analogs with augmented anticancer effects, or the development of pharmaceutical agents that selectively target this pathway. The outcomes of many studies indicate that the integration of medicines aimed at modulating vitamin D signaling with established treatments for prostate cancer holds significant potential as a viable strategy. This method has the potential to improve treatment outcomes by concurrently tackling various facets of cancer biology. Research findings indicate prospective strategies for tailored and combined therapy, provide insights into the molecular mechanisms underlying the advancement of prostate cancer, and present the opportunity to develop innovative treatments that specifically target the signaling of the vitamin D receptor. The validation and translation of these implications into successful treatments for prostate cancer patients will require additional clinical research and trials [78]. Calcitriol was observed to decrease the expression of IL-6 and induce abnormalities in epithelial-mesenchymal transition (EMT) in cancer cells following exposure to radiation. Following radiation therapy, the administration of calcitriol resulted in an increase in the population of cytotoxic T lymphocytes at the tumor site in animals with tumors. This effect was achieved by reducing the recruitment of myeloid-derived suppressor cells (MDSCs). Moreover, vitamin D3 possesses several anti-inflammatory characteristics, including its ability to inhibit p38 stress kinase signaling and the resultant secretion of proinflammatory cytokines in various malignancies. This likely explains the observed favorable effects of vitamin D3 [79]. Vitamin D: Role in Breast Cancer Over the course of the last five decades, researchers have devoted significant efforts to the comprehensive examination of breast cancer, with current emphasis placed on investigating its intricate biological mechanisms [80–82].The overall concentration of 25-Hydroxyvitamin D in the bloodstream appears to be the primary determinant in the synthesis of the biologically active form of vitamin D within various organs. 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesized within the local vicinity has the capability to interact with vitamin D receptors (VDRs) present in the breast epithelium, thereby exerting regulatory control over gene expression by modulating the activation and repression of specific genes. Furthermore, it should be noted that breast cells possess the enzyme 24-hydroxylase (CYP24), which facilitates the conversion of 1,25(OH)2D into metabolites that exhibit lower levels of activity, such as 24,25-dihydrohydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3 [83].Consequently, breast cells possess all the necessary constituents of a vitamin D signalling pathway, which facilitates the regulation of local 1,25(OH)2D synthesis and metabolism, as well as the transmission of signals through vitamin D receptors (VDRs). As the understanding of Vitamin D’s role in cancer therapy deepens, emerging technologies in cancer diagnostics present new avenues for research and application. Single cell omics technologies, particularly in the context of breast cancer, offer profound insights into tumor heterogeneity and the molecular characterization of cancer cells. These advancements in single cell analysis can significantly enhance the diagnostic precision, allowing for more tailored therapeutic approaches. The integration of such technologies could be pivotal in refining the strategies for Vitamin D-based interventions in breast cancer, potentially improving both prognostic assessments and treatment outcomes [81]. Calcitriol exerts tissue-specific effects on aromatase expression. Calcitriol, functioning as a Selective Aromatase Modulator (SAM), diminishes the expression of aromatase in breast cancer (BCa) cells and the adipose tissue surrounding BCa, while concurrently augmenting aromatase expression in cells derived from bone. The down-regulatory impact of calcitriol on breast cancer (BCa) aromatase expression can be attributed to two main factors. Firstly, calcitriol directly represses aromatase transcription by targeting promoter II through the vitamin D response elements (VDREs) found within this promoter. Secondly, calcitriol indirectly affects aromatase expression by suppressing cyclooxygenase-2 (COX-2) and up-regulating 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which collectively reduce the levels of prostaglandin E2 (PGE2). PGE2 is a significant stimulator of aromatase transcription via promoter II in Breast Cancer [84]. Study Based on Animal Models and Human in Breast Cancer The utilization of animal models in scientific research has shown to be a valuable tool for studying many biological processes and diseases. In vivo studies utilizing animal models have investigated the efficacy of calcitriol and its analogs in inhibiting the growth of human breast cancer xenograft tumors, as well as their potential to delay or prevent the development of breast tumors produced by carcinogens [85]. The presence of the vitamin D receptor in mammary gland and breast cancer has been recognized since the early 1980s, and multiple pre-clinical studies have demonstrated that its ligand 1,25D modulates normal mammary gland development and sensitivity to carcinogenesis [86]. Although studies have characterized many 1,25D responsive targets in normal mammary cells and in breast cancers, validation of relevant targets that regulate cell cycle, apoptosis, autophagy and differentiation, particularly in vivo, has been challenging. Vitamin D deficiency is common in breast cancer patients and some evidence suggests that low vitamin D status enhances the risk for disease development or progression [87]. Model systems of carcinogenesis have provided evidence that both VDR expression and 1,25D actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease is necessary to clarify the conflicting data. Genomic, proteomic and metabolomic analyses of in vitro and in vivo model systems is also warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer heterogeneity [88]. Reduced breast cancer risk was associated with increased sun exposure in the age-group 10–19 years, cod liver oil use and milk uptake. Vitamin D-related exposures, outdoor activities, use of sunscreen, dietary contributions were protective factors, as corroborated by further studies [89–91]. The expression of the VDR, a transcription factor that is dependent on ligands, has been observed in the mammary glands of humans, rabbits, and rodents. The expression of this particular entity is subject to dynamic regulation throughout the reproductive cycle, exhibiting its peak levels during the phases of pregnancy and breastfeeding. The vitamin D receptor (VDR) is expressed in several cellular populations within the glandular tissue and is involved in the process of cellular differentiation. The findings from organ culture experiments indicate that 1,25(OH)2D3 has an impact on calcium transport, casein expression, and branching morphogenesis in the mammary gland. It was shown that mice lacking the vitamin D receptor (VDR) experienced enhanced development of the mammary gland during puberty and heightened responsiveness to estrogen and progesterone. The absence of VDR had an impact on the development of the mammary gland during pregnancy and resulted in a delay in the process of post lactational involution. The mice lacking the VDR gene exhibited heightened sensitivity to the chemical carcinogen DMBA, resulting in increased proliferation of skin cells and the subsequent development of skin cancers. On the other hand, wild-type mice exhibited negligible levels of epidermal hyperplasia and remained devoid of any tumor formations. This research study presented empirical evidence that the ablation of the vitamin D receptor (VDR) leads to an increased susceptibility to the development of tumor [92]. Mechanism Calcitriol, also known as bioactive vitamin D, plays a crucial role in the regulation of multiple metabolic pathways. Vitamin D exhibits many mechanisms that could potentially safeguard somatic stem cells, such as DNA damage repair and defense against oxidative stress. Additionally, it may impede the proliferation of cancer stem cells through mechanisms like cell cycle arrest and induction of cell death. Vitamin D metabolic enzymes, namely CYP27B1 (25-hydroxyvitamin D 1α-hydroxylase) and CYP24A1 (25-hydroxyvitamin D 24-hydroxylase), have been identified in breast cancer cells. The cellular metabolism of vitamin D involves the participation of several enzymes [93]. Breast epithelial cells in their normal state exhibit the expression of both VDR (Vitamin D Receptor) and CYP27B1, rendering them responsive to the growth-inhibitory impacts of 25-hydroxyvitamin D (25D) at concentrations that are within the range of physiological levels. The sensitivity in question is modulated by the existence of VDR and CYP27B1 [92]. During the process of in vitro transformation of breast epithelial cells, it has been observed that the expression levels of both VDR and CYP27B1 are reduced. The observed downregulation leads to a reduction in sensitivity towards both 25D and 1,25D, suggesting that the transformation process has an effect on the metabolism of vitamin D [94]. A documented phenomenon in breast cancer cells involves the overexpression of CYP24A1, an enzyme responsible for the breakdown of vitamin D metabolites. It is anticipated that this increase will result in a decrease in cellular sensitivity to 1,25D. Several nuclear receptors, such as ERR (Estrogen-Related Receptor), PgR (Progesterone Receptor), PXR (Pregnane X Receptor), and CAR (Constitutive Androstane Receptor), have been identified as potential regulators of CYP24A1 expression and activity. The aforementioned receptors have the ability to regulate the metabolic processes of vitamin D within breast cancer cells [95]. The influence of external factors, specifically alcohol consumption, has been investigated in relation to its impact on vitamin D metabolism in tumor-bearing mice. Findings from these studies suggest that alcohol intake may contribute to the catabolism (breakdown) of vitamin D, potentially influencing the metabolic processes of vitamin D within breast cancer cells. The expression of CYP24A1 in breast cancer cells can be increased at the translational level in response to an inflammatory milieu. The process of upregulation is facilitated by variables such as activated macrophages produced from monocytes, and it is characterized by the involvement of a pathway that is dependent on PI3K. The potential association between the carcinogenic pathway AKT-PI3K and the stimulation of vitamin D catabolism has been suggested. The many regulatory mechanisms involved in breast tumor development Numerous molecular routes have been discovered that modify the metabolism of vitamin D in breast cancer cells under laboratory conditions. However, the regulation of vitamin D metabolic enzymes in human breast cancers is likely influenced by other variables that necessitate further exploration [96]. Vitamin D: Therapy and Treatment Breast Cancer Vitamin D is widely recognized for its diverse range of health advantages, and recent studies indicate its potential significance in the prevention of breast cancer. It is widely hypothesized that the administration of vitamin D supplements can mitigate the likelihood of developing breast cancer by means of various mechanisms: Vitamin D plays a crucial role in the regulation of cellular development and differentiation. The compound has the ability to impede the growth and division of cells associated with breast cancer, hence potentially serving as a preventive measure against the formation of malignant tumours. Vitamin D possesses anti-inflammatory effects that could contribute to the mitigation of chronic inflammation in breast tissue, a recognized risk factor associated with the development of cancer. Vitamin D can regulate estrogen activity within the human body. Elevated concentrations of estrogen have been linked to an augmented susceptibility to breast cancer, whereas vitamin D has been suggested to potentially mitigate estrogen imbalances. Maintaining sufficient levels of vitamin D is crucial for the optimal functioning of the immune system. A resilient immune system possesses the ability to identify and eliminate malignant cells, hence diminishing the probability of tumor development. Vitamin D is involved in the facilitation of DNA repair mechanisms, hence mitigating the potential for the accumulation of genetic mutations that have the propensity to induce carcinogenesis. In general, the findings indicate that the administration of vitamin D supplements has the potential to reduce the likelihood of breast cancer by exerting an influence on many biological mechanisms implicated in the progression of cancer. The study revealed that the administration of 1,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol, a vitamin D analog, resulted in an increased efficacy of tamoxifen, an antiestrogenic agent, in the prevention of breast cancers. This observation implies that there may be a synergistic relationship between vitamin D compounds and antiestrogenic compounds in their ability to provide protection against breast cancer [97]. Vitamin D: Role in Colon Cancer Vitamin D and its analogs have been observed to restrict the growth of colon cancer xenografts and inhibit tumor formation in various hereditary models of intestinal cancer. In the context of rodents, who serve as a model for sporadic colon cancer, it has been demonstrated that the risk of developing colon cancer by dietary means can be mitigated by the administration of vitamin D3 and calcium. Epidemiological research has demonstrated a positive correlation between vitamin D insufficiency and the prevalence of colon cancer, as well as a detrimental effect on the survival rates of those diagnosed with colon cancer. The anticancer action of 1,25D3 may be attributed to its capacity to suppress Wnt signalling and mitigate inflammation [98]. Study Based on Animal Models and Human in Colon Cancer Research on vitamin D’s effect on intestinal carcinogenesis remains inconclusive. Studies on rats and ApcMin/ + mice lacking the vitamin D receptor (VDR) show no direct impact on tumor quantity with normal calcium levels, but decreased VDR may lead to larger tumors in animals with inadequate dietary calcium [99]. Evidence suggests that lower vitamin D levels might follow rather than precede tumor development in colon cancer, complicating the cause-and-effect relationship [100]. Recent findings highlight that individuals with colorectal cancer often have low 25-hydroxyvitamin D [25(OH)D] levels, with recommendations to maintain levels within 30–80 ng/ml and regular monitoring [101]. Significant vitamin D deficiency was noted among stage IV colorectal cancer patients, especially women and Black individuals, in the Intergroup Trial N9741. Research indicates that higher 25(OH)D levels correlate with lower colorectal cancer occurrence and mortality, with every 20 nmol/L increase in 25(OH)D reducing death risk by 12% from colorectal conditions and 7% overall [102]. Optimal 25(OH)D levels for minimizing colorectal cancer risk are suggested between 75 and 100 nmol/L [103]. However, the Women’s Health Initiative trial found that low-dose vitamin D supplementation (400 IU/day) did not significantly reduce colorectal cancer risk, underscoring the complex relationship between vitamin D levels and colorectal cancer outcomes across different populations and supplementation approaches [104]. Mechanism The regulation of intracellular calcitriol concentrations the influence of calcitriol on cancer cells is contingent upon both the presence of Vitamin D Receptors (VDR) and the concentration of intracellular calcitriol [105]. The levels of calcitriol within the cell are subject to several factors, such as the concentrations of circulating 25(OH)D and calcitriol, as well as the enzymatic activity of CYP27B1 and CYP24A1 within the intracellular environment. It is worth mentioning that whereas CYP27B1 and CYP24A1 were initially identified as enzymes present in the kidneys, they have since been discovered in extrarenal locations, such as the colon [92]. The expression of CYP27B1, the enzyme accountable for the synthesis of calcitriol, has a discernible pattern in cases of colorectal cancer. The expression of CYP27B1 is increased in well and moderately differentiated colorectal cancer, whereas it is decreased in poorly differentiated cases. Significantly, previous research has demonstrated that the expression levels of CYP27B1 mRNA in samples of colorectal cancer are comparable to those seen in healthy colons. However, these expression levels drop in the adjacent normal colon mucosa located at a distance of 10 cm from the tumour border. This observation implies that the tumour may have a regulatory effect on the expression of CYP27B1 in the nearby colon tissue, or proposes that reduced expression of CYP27B1 in the colon could potentially increase the chance of developing cancer. In addition, it has been observed through cell-based experiments that the cellular response to growth factors such as epidermal growth factor (EGF) or calcitriol varies depending on the differentiation state of the cells. Specifically, highly differentiated cells exhibit an upregulation of VDR and CYP27B1 expression, whereas less differentiated cells show a downregulation of these expressions after treatment with EGF or calcitriol [106]. Although there is limited in vivo data supporting the local synthesis of calcitriol in the colon, there are clues suggesting its potential existence [107]. The role of CYP24A1 in biological processes, the expression levels of CYP24A1, which plays a key role in establishing the biological half-life of calcitriol, exhibit heterogeneity across different stages of colorectal cancer. The presence of this substance is observed at low concentrations in the normal mucosa of the human colon and colorectal adenomas. However, its levels are significantly increased in the majority of adenocarcinomas, especially in those that are poorly differentiated and in advanced stages of cancer. Furthermore, previous research has demonstrated that the expression of CYP24A1 mRNA is notably increased following the administration of calcitriol in specific human colon cancer cell lines [56]. The upregulation of CYP24A1 expression in response to calcitriol administration has been found to mitigate the inhibitory effects of calcitriol on cell proliferation. Significantly, the concurrent administration of calcitriol alongside a CYP24A1 inhibitor led to a substantial decrease in cellular survival and proliferation. This finding serves to emphasize the potential of CYP24A1 inhibition as a viable approach to augment the anti-tumor properties of calcitriol. The expression patterns of Vitamin D Receptors (VDR), which serve as the primary mediators of calcitriol’s biological actions, demonstrate variability in colorectal cancer. The expression of VDR is observed to be elevated in adenomas and well or moderately differentiated tissues of colorectal cancer. However, it demonstrates a reduction in poorly differentiated tumors and becomes insignificant in metastatic lymph nodes (131). Interestingly, unique transcription factors, namely SNAI1 and SNAI2 (often referred to as snails), have been recognized as suppressors of VDR expression in particular cancer cells. Several factors have the potential to impede the anti-tumor effects of calcitriol analogs. Furthermore, it has been discovered that the RNA expression levels of SNAI1 and SNAI2 are increased in human colorectal tumors, and there is a negative connection with VDR mRNA expression. This finding implies that increased expression of SNAI1 and SNAI2 could potentially play a role in the downregulation of VDR and the emergence of vitamin D unresponsiveness in advanced colorectal cancer. Therefore, the efficacy of vitamin D treatment might be constrained in patients who have elevated levels of SNAI1 and SNAI2 [60]. In summary, the mechanisms associated with vitamin D in the context of colorectal cancer encompass the regulation of intracellular calcitriol concentrations, the role of CYP27B1 and CYP24A1 enzymes, and the expression of VDR. These mechanisms influence cancer cell differentiation, treatment responses, and potential therapeutic approaches. Vitamin D: Therapy and Treatment Colon Cancer Several studies have reported that the incorporation of VD into a composite aerogel, known as Aero1, has demonstrated improved efficacy in inhibiting cell growth. Additionally, this composite aerogel formulation has shown the potential to reduce the necessary dosage of VD, hence enhancing its bioavailability. In addition, the research findings indicated that the utilization of nanovehicles for encapsulating VD resulted in the induction of apoptosis, a process of programmed cell death, in human colon cancer cells through the activation of internal signaling pathways. Colorectal cancer (CRC) is a significant contributor to mortality associated with cancer, frequently characterized by increased activation of β-catenin signaling. The progressive development of colorectal cancer (CRC) can be attributed to mutations and epigenetic alterations occurring in colonic epithelial stem cells. It is worth noting that the majority of colorectal cancers (CRCs) typically exhibit genetic modifications that result in the augmentation of β-catenin signaling. The activation of β-catenin, together with TCF/LEF transcription factors, induces the upregulation of genes associated with the promotion of malignancy, including c-Myc, cyclin D, and other others. In the context of advanced colorectal cancer (CRC), mutations such as KRAS or BRAF have been observed to enhance the activity of β-catenin-driven c-Myc. This study aims to investigate the regulatory mechanisms of β-catenin and examine potential preventative interventions against colorectal cancer (CRC), such as dietary modifications, nutraceutical supplementation, and pharmacological agents. The aforementioned diverse strategies are designed to effectively inhibit β-catenin signaling in a safe manner, hence decreasing the occurrence of genetic mutations in the colon. These approaches hold promise in terms of providing possible means to prevent the development of this highly lethal form of cancer. The authors, Paulsen et al., conducted a study to investigate the potential impact of vitamin D consumption on the risk of developing colorectal cancer (CRC), with a particular focus on various segments of the colon. The findings of the study revealed a significant association between a moderate consumption of vitamin D (10–19 µg) and a notable reduction of 27% in the incidence of proximal colon cancer. Moreover, it is worth noting that a substantial intake of 20 µg/d or more showed a statistically significant reduction of 17% in the risk of colorectal cancer (CRC). Furthermore, it was shown that with each incremental increase of 5 µg in the daily intake of vitamin D, a statistically marginal 3% reduction in the risk of colorectal cancer (CRC) and a 4% reduction in the risk of colon cancer were seen. Nevertheless, there were no significant correlations observed between distal colon or rectal cancer. The findings bring attention to possible inequalities in colon cancer risk based on gender, age, and subsite, indicating the presence of various underlying causes. Additional investigation is required to substantiate these results and explore the fundamental mechanisms involved [108]. Vitamin D: Role in Immunity Early research on cod liver oil’s use in tuberculosis helped show how vitamin D affects the immune system. The formation of a complex with calcitriol, VDR, and retinoid X receptor enhances immune cell chemotaxis and phagocytosis, and quickly starts the production of antimicrobial peptides like defensin 2 and cathelicidin. Other cytokines, such as interferon and IL-4, and toll-like receptor signaling also impact CYP27B1 synthesis. Although neutrophils have VDR, they lack CYP27B1 activity, preventing them from converting 25(OH)D into a form that can activate cathelicidin gene expression [109]. Human cathelicidin (hCAP18), which becomes the antibacterial peptide LL-37, increases in response to infections, exhibiting antibacterial, antiviral, and antifungal properties. Low levels of calcitriol in those with end-stage renal disease correlate with higher infection-related mortality, while reduced serum 25-hydroxyvitamin D is linked to more frequent upper respiratory infections. Calcitriol and its analogues can keep dendritic cells (DCs) immature, characterized by reduced antigen presentation and altered cytokine production, which promotes immunological tolerance. Additionally, calcitriol inhibits toll-like receptor activation and cytokine synthesis in T cells, and high-dose supplementation reduces inflammatory cytokine IL6, potentially boosting regulatory T cell production. This aligns with findings that vitamin D influences immune cell function and promotes a tolerogenic state, with positive effects on immune function and autoimmunity regulation noted in studies, including a focus on type 1 diabetes mellitus [109]. In exploring the complex interplay between Vitamin D and inflammatory responses, it’s noteworthy to consider broader immunological research. For instance, studies examining chronic conditions like opium abuse have identified specific microRNAs, such as miR-155 and miR-187, and their association with inflammatory cytokines IL-6, IL-10, and TNF-α. Understanding these associations helps underline the potential of Vitamin D not only in managing disease-specific inflammation but also in broader immunomodulatory roles. This could inspire further investigations into whether Vitamin D supplementation might similarly influence microRNA and cytokine profiles in other inflammatory conditions [110]. The expression of the Vitamin D Receptor (VDR) in T and B cells increases notably after their activation, regulating about 500 genes important for cellular differentiation and development. Administering a daily dose of 1 g of vitamin D twice for a week significantly reduces IL6 production by peripheral mononuclear cells, likely enhancing regulatory T cell promotion, crucial for regulating immune responses and preventing autoimmunity. Moreover, calcitriol directly affects B cell homeostasis by inhibiting proliferation and facilitating apoptosis. Recent studies have shown that vitamin D regulates T cell activity through endocrine actions, intracrine conversion of 25-hydroxyvitamin D to calcitriol by T cells, paracrine effects following conversion by monocytes or dendritic cells, and modulation of antigen presentation, alongside inhibitory impacts on T helper cell proliferation and cytokine release [111]. Vitamin D compounds inhibit cytokines interleukin-9 (Th9) and interleukin-22 (Th22), while increasing Th2 cytokines like IL3, IL4, IL5, and IL10. They also affect IL17-secreting Th17 cells, reducing their activity, which may help treat autoimmune disorders as seen in non-obese diabetic (NOD) mice. Epidemiological studies link vitamin D deficiency with an increased risk of autoimmune diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Additionally, vitamin D signaling enhances Toll-like receptor 2 (TLR2) expression in keratinocytes and boosts the signaling of vitamin D through a positive feedback loop involving TLR2 and TLR4. This signaling also inhibits the mannose receptor in macrophages, reducing dengue virus infection, and depends on the enzyme BCAT1 for inducing autophagy in macrophages. Vitamin D also activates transcription of the pathogen-sensing protein NOD2/CARD15/IBD1 in monocytes and epithelial cells [112]. Vitamin D and Viral Infections The study investigates the detection of muramyl dipeptide (MDP), a degradation product of bacterial peptidoglycan found in lysosomes. It found that activation of 1,25D and MDP leads to the induction of DEFB4 and CAMP in cells with functional NOD2. This regulation is absent in individuals with Crohn’s disease (CD), a recurrent inflammatory bowel disease, who have inactive NOD2 mutations. The control of NOD2 1,25D may potentially help combat mycobacterial infections like M. tuberculosis. Vitamin D has been shown to protect against viral infections, including hepatitis viruses, HIV, and respiratory pathogens. Infection with human respiratory syncytial virus (RSV) can cause respiratory tract sickness and even death. The presence of 1,25D suppresses the expression of VDR and CYP24A, preventing viral replication. A recent study found that herbal medication EPs®7630 enhances the body’s immune response against RV by upregulating VDR in human bronchial epithelial cells [113] Vitamin D: Role in COVID-19 Acute respiratory tract infections are a major global health concern, causing millions of deaths. Low levels of 25-hydroxyvitamin D in the blood are linked to increased vulnerability to these infections. Vitamin D may protect against respiratory pathogens by stimulating antimicrobial peptide production and innate immune responses. Several randomized controlled trials are exploring vitamin D supplementation’s potential to reduce infections. The molecular aspects of COVID-19, including interactions between the virus and ACE2 receptor, are also explored [114]. Study Based on Animal Models in Covid 19 Studies have shown a positive association between vitamin D levels and COVID-19 infection incidence, but some studies have failed to establish a significant relationship. Meltzer et al. found heightened vulnerability in Africans with 25D levels below 40 ng/mL, but no significant relationships were found among Caucasian individuals [113]. In a cohort research found an association between COVID-19 patients and lower serum vitamin D levels, and a correlation between vitamin D deficiency and increased cytokine storms. The role of vitamin D in COVID-19 risk and protection remains complex and may be influenced by multiple factors [115]. A retrospective analysis of 185 COVID-19 patients found a significant link between low serum 25(OH)D levels and unfavorable outcomes, including invasive mechanical breathing or mortality. These findings suggest that while vitamin D has shown promise in immune regulation and viral defence, its role in COVID-19 risk and protection remains complex and may be influenced by multiple factors. Mechanism Vitamin D plays a crucial role in the immune system and the severity of COVID-19. It stimulates the vasorelaxant ACE2/Ang-(1–7)/Mas receptor axis, providing protection against lung damage and ARDS. Vitamin D also affects renin synthesis, a component of the renin–angiotensin–aldosterone system (RAAS), while enhancing ACE2 expression. Gender disparities may impact COVID-19 severity, with females showing a heightened immunological response due to oestrogen protection. Vitamin D activates the respiratory system, regulating antiviral responses and mitigating cytokine storms. It can also inhibit the activity of TMPRSS2, a protease essential for SARS-CoV-2 entry. The first trial, NCT04449718, initiated in 2020, found no significant difference in hospital stay duration between Vitamin D3 and placebo groups, but Vitamin D3 significantly increased serum 25-hydroxyvitamin D levels. found that a 200,000 IU dose of Vitamin D3 did not significantly shorten hospital stay for COVID-19 patients compared to a placebo, suggesting that Vitamin D3’s effectiveness in reducing hospital stays is limited. Vitamin D may have potential benefits in COVID-19, including immune response modulation, lung injury protection, viral entry impediment, and virus functioning interference. Further research is needed to fully understand these connections [116]. Vitamin D: Therapy and Treatment in Covid-19 A study in India found that vitamin D supplementation significantly enhanced inflammatory markers in COVID-19 patients. Patients who received a daily vitamin D supplement showed improvements in C-reactive protein, IL-6, ferritin, and neutrophil to lymphocyte ratios. A randomized controlled trial in Spain investigated the effects of combining hydroxychloroquine and azithromycin with oral calcifediol for COVID-19 treatment. A study in India found that a high dose of vitamin D (60,000 IU) led to a higher proportion of asymptomatic or mildly symptomatic patients achieving a therapeutic target of 25(OH)D > 50 ng/mL and testing negative for SARS-CoV-2 RNA by day 21. A randomized controlled trial in Brazil found no significant reduction in hospitalization duration or mortality compared to a placebo [117]. Vitamin D: Role in Female Fertility and Pregnancy Research on the relationship between light and reproduction has shown a correlation between vitamin D and fertility. Vitamin D levels fluctuate seasonally, with elevated levels during summer and autumn and decreased during winter and spring. In regions with pronounced brightness variations, such as northern countries, conception rates fall during dark winter months, while summer months have a peak, leading to maximum birth rates in spring. In northern nations with long dark winters, ovulation rates and endometrial receptivity decrease. This could be due to changes in the hypothalamic-pituitary axis and brain neurotransmitters like serotonin, dopamine, and endogenous opioids. Melatonin’s efficacy in achieving this goal has been extensively studied [118]. Melatonin’s effectiveness in achieving endometrial and oocyte development has been extensively studied, but no direct effects have been found. Variations in vitamin D levels may help explain this observation. Studies Based on Animal Models and Human in Female Fertility and Pregnancy Previous research has linked insufficient levels of vitamin D to adverse pregnancy outcomes, such as gestational diabetes, hypertension, preeclampsia, small for gestational age, and increased likelihood of caesarean delivery. Intervention trials have shown no significant increase in birth weight outcomes despite normalizing serum vitamin D concentrations during pregnancy. Calcium inadequacy, due to reduced intestinal absorption and transport, leads to hyperparathyroidism and osteomalacia. Calcium also impacts reproductive health, affecting oocyte maturation and development, sperm motility, fertilization, and preterm labor. A primate model study investigated the impact of vitamin D on follicular development and oocyte generation. Vitamin D levels and telomere biology are also linked, with increased telomerase activity in obese African-American patients and elongated telomeres in hemodialysis patients [119]. Vitamin D levels may influence the length of telomeres and telomerase activity in the ovary, potentially influencing aneuploidy and in vitro fertilization outcomes. Studies show that women with sufficient vitamin D levels (≥ 30 ng/ml) have better in-vitro fertilization outcomes. Vitamin D treatment improves endometriosis in a rat model and reduces the risk of endometriosis. It is recommended that women maintain a minimum vitamin D level of 30 ng/ml for in-vitro fertilization (150). A study by Pal et al. found that vitamin D and calcium supplements significantly reduced testosterone and androstenedione levels in women with polycystic ovary syndrome (PCOS). Women who consumed more calcium had lower levels of testosterone and androstenedione, while displaying higher HDL cholesterol. Vitamin D also influences female reproductive processes, with diet-induced vitamin D insufficiency causing a 75% decrease in fertility. Vitamin D can enhance ovarian steroidogenesis, increasing the transcription of dehydroepiandrosterone sulfotransferase and enhancing the expression of the FSH receptor gene. It may also influence oestrogen synthesis [120]. A study on mice with vitamin D deficiency during pregnancy found that maternal vitamin D deficiency decreases the expression of the placental 11β-HSD2 gene, which deactivates glucocorticoids, and activates the fetal head gene glucocorticoid-induced leucine zipper, which is regulated by glucocorticoids [121]. Studies show a link between vitamin D and female fertility, endometriosis, and in vitro fertilization outcomes. Vitamin D supplements have been shown to improve metabolic and reproductive dysfunctions in women with polycystic ovary syndrome (PCOS). However, a definitive causal relationship is not yet established, and the optimal dosage for promoting fertility is not yet determined. Further research is needed to determine the threshold effects of vitamin D supplementation on hormonal, metabolic, and reproductive outcomes in PCOS patients [122]. Mechanism Vitamin D plays a crucial role in female fertility by regulating the production of sex hormones, such as estrogen and progesterone, in reproductive tissues like the ovaries and uterus. It enhances transcription of genes associated with these hormones, thereby influencing the menstrual cycle and fertility. Vitamin D also facilitates regular ovulation, a crucial determinant of female fertility. Adequate levels of vitamin D promote the growth and maturation of ovarian follicles, enhancing the probability of successful fertilization and pregnancy. Vitamin D’s anti-inflammatory and antioxidant properties can help alleviate chronic inflammation and oxidative stress, thereby enhancing fertility outcomes. These properties help preserve reproductive organ health and functionality, thereby enhancing fertility outcomes. Thus, vitamin D’s anti-inflammatory and antioxidant properties can significantly contribute to female fertility [123]. Vitamin D: Therapy and Treatment in Female Fertility The Endocrine Society recommends a daily Vitamin D dosage for fertility enhancement. Adults aged 18–70 should consume 1500–2000 IU of vitamin D3 daily, maintaining a constant 25-hydroxyvitamin D concentration over 30 nanograms per millilitre. The upper limit for vitamin D intake is 10,000 IU per day. The International Organization for Migration recommends a minimum 25-hydroxyvitamin D level of 50 nmol/l (20 ng/ml) for bone health. For in-vitro fertilization, women should maintain a minimum vitamin D level of 30 ng/ml. Increased vitamin D intake may improve metabolic parameters in women with Polycystic Ovary Syndrome (PCOS) and reduce the risk of endometriosis [118]. Vitamin D: Role in Male Fertility Vitamin D is crucial for the male reproductive system, as hypovitaminosis D can affect sperm and hormone function. Vitamin D metabolizing enzymes are found in various cell types, including Sertoli, germ, Leydig, spermatozoa, and epithelial cells. These organs regulate vitamin D response, potentially impacting male fertility. The expression of VDR in the testis suggests that vitamin D may have autocrine and paracrine capabilities, potentially affecting testicular function [124]. Study Based on Animal Models and Human in Male Fertility Vitamin D plays a crucial role in regulating testosterone production in various animals, including rats, hens, and rodents. Studies have shown that vitamin D depletion and supplementation can lead to decreased testosterone levels, increased testicular aromatase production, and decreased fertility and pregnancy. In a mouse model, vitamin D-depleted hens had lower calbindinD28k expression, which affects testosterone production [125]. Moreover, a study was conducted to investigate the effects of vitamin D depletion and replacement on chickens. The results showed that although testosterone levels were similar between the two groups, the expression of calbindinD28k, a calcium-binding protein responsible for maintaining calcium balance, was significantly reduced in the vitamin D-depleted chickens. Both the upregulation of calbindin-D28k and the genetic induction of osteocalcin have been observed to have an impact on testosterone synthesis. Moreover, it has been observed that the production of aromatase in the testis, which is increased by vitamin D, is both directly and indirectly associated with the impacts on estrogen synthesis. Ultimately, it seems that vitamin D does not exert any influence on the regulation of AMH, INHB, or INSL3 levels. The occurrence of successful reproduction, as shown by the presence of sperm in the vaginal tract, exhibited a decrease of 45 percent in males with insufficient levels of vitamin D in comparison to those with adequate levels of vitamin D. In a similar vein, it was shown that rodents with a deficiency in vitamin D saw a notable decrease in both fertility and pregnancy rate [126]. Hypovitaminosis patients’ testicular histology showed a loss in Leydig cells and germinal epithelium degeneration, suggesting that vitamin D affects testicular function and may cause male infertility. However, estradiol reversed these abnormalities and calcium increased aromatase activity, reducing hypogonadism. Numerous studies have examined how vitamin D deficiency affects blood testicular hormone levels, with inconsistent results. Some studies have linked 25-hydroxyvitamin D3 levels to sex hormone binding globulin, while others have found no significant relationship between vitamin D and sperm count and morphology [127].The predominant body of research consisted of clinical observational studies that assessed the correlation between the state of vitamin D and the quality of sperm or the process of spermatogenesis. Clinical observational studies on vitamin D and sperm quality or spermatogenesis dominated the field. Vitamin D insufficiency lowered total and progressive sperm motility and motile spermatozoa counts in men, suggesting that vitamin D insufficiency and ionized calcium levels may affect sex hormones and sperm quality in infertile men. However, the relationship between vitamin D and sperm motility and morphology is also disputed [128]. Several studies have found no significant link between vitamin D levels and male infertility, with no significant correlation found between vitamin D levels and sperm motility, successful pregnancy continuation rates, or fertilized oocytes. Vitamin D supplementation led to an elevation of intracellular calcium levels in human spermatozoa, enhancing sperm motility and triggering the acrosome reaction. However, the administration of vitamin D did not significantly impact semen quality characteristics or the number of successful live births. Two clinical trials have examined the impact of Vitamin D3 supplementation on various reproductive outcomes, particularly in male infertility, particularly asthenozoospermia [129]. In addressing male infertility, particularly asthenozoospermia, two clinical trials have examined the impact of Vitamin D3 supplementation on various reproductive outcomes. The trial IRCT20151128025274N4, initiated on March 28, 2018, involved 86 men diagnosed with asthenozoospermia. Participants received daily doses of 4000 IU of Vitamin D3 for three months. Results indicated a significant increase in serum 25(OH)VD3, parathyroid hormone (PTH), phosphorus, seminal and serum calcium levels, and the testosterone to luteinizing hormone (T/LH) ratio. Notably, the treatment also enhanced both total and progressive sperm motilities, though it had no significant impact on other reproductive hormones. Another study, NCT01304927, which began on February 28, 2011, explored the effects of high initial doses of cholecalciferol (300,000 IU) followed by daily doses of 1400 IU and 500 mg of calcium for 150 days on 330 vitamin D-insufficient men facing male factor infertility. The supplementation did not yield improvements in overall semen quality. However, among oligozoospermic men, Vitamin D treatment significantly increased the likelihood of achieving a live birth, comparing 35.6% in the treatment group to 18.3% in the placebo group. This suggests that while Vitamin D3 might not universally enhance semen quality, it can improve reproductive outcomes in specific subgroups of infertile men. Most of these studies on the effects of vitamin D on sperm parameters pointed to a potential beneficial effect of vitamin D on male reproductive health, particularly through improved sperm motility. Mechanism The male reproductive system, including Sertoli cells, germ cells, Leydig cells, spermatozoa, and epithelial cells, expresses vitamin D receptors (VDR) and enzymes responsible for metabolizing vitamin D. This implies that reproductive organs can regulate local vitamin D responses independently of systemic metabolism. Testicular germ cells may synthesize and degrade vitamin D locally, suggesting the potential for autocrine and paracrine actions of vitamin D, possibly influencing testicular function and playing a role in male infertility. Studies conducted in animals and humans support these findings. VDR protein is found in the prostate, seminal vesicles, epididymis, and specific germ cell types. However, the expression of VDR protein in Leydig cells is disputed. In human spermatozoa, VDR exhibits a heterogeneous pattern of localization, found in regions such as the post acrosome region, neck, and mid-piece. Retinod X receptors (RXR) in rat testis, with various subtypes located in Leydig cells, Sertoli cells, and germ cells, remain unexplored. Vitamin D metabolizing enzymes, including 25-hydroxylase, 1α-hydroxylase, and 24-hydroxylase, have been found in the testis, prostate, seminal vesicles, epididymis, germ cells, Sertoli cells, and Leydig cells in animals. The study underscores the complex interplay of vitamin D, VDR, and metabolizing enzymes in the male reproductive system and their potential implications for testicular function and male infertility.[124]. Vitamin D: Therapy and Treatment in Male Infertility In a three-month study, supplementation with vitamin D3 increased sperm motility and pregnancy rates in males with oligo-asthenozoospermia. Blomberg Jensen et al. conducted a study which yielded inconclusive results regarding sperm parameters but hypothesized possible reproductive advantages, especially for males afflicted with oligozoospermia. The relationship between vitamin D and testosterone levels is still unknown [130]. Vitamin D: Role in Pregnancy Pregnancy is a crucial stage in the vitamin D lifecycle, as the developing fetus relies on it for healthy growth. Studies show a strong association between pregnant women’s vitamin D levels and their babies’ health outcomes [131]. Vitamin D: Role In Preeclampsia Pregnant women often experience pre-existing, long-term, and gestational hypertension, including preeclampsia with proteinuria. This condition can cause seizures. Preeclampsia can cause higher 25-hydroxyvitamin D levels than normal blood pressure women, but PE women have lower levels. Preeclampsia placentas convert vitamin D3 differently [132]. Study Based on Animal Models and Human in Preeclampsia. Many studies have examined the relationship between vitamin D and preeclampsia. Farzaneh found a link between genetic polymorphisms in the vitamin D receptor (VDR) gene in mothers and placental tissue and PE susceptibility in Southeast Iran. The study found that moms with the Fok1 rs2228570 Ff genotype may have a lower risk of preeclampsia. Additionally, certain VDR genetic haplotypes were more or less susceptible to PE. However, this research has significant limitations, including a small sample size and a geographically confined population. Thus, larger and more diverse cohort studies are needed to confirm these findings and further understand PE’s genetic drivers [133]. Animal models, particularly non-human primates (NHP), have been used to study preeclampsia’s long-term effects on cardiovascular health. These models help determine if preeclampsia increases women’s risk of cardiovascular disease due to shared risk factors or the disorder itself. Rats with experimental preeclampsia are more susceptible to hypertension and retinal artery damage. A mouse model created by viral overexpression of sFLT-1 showed vascular damage reactions. Animal models are important for studying preeclampsia and its effects on vitamin D. However, further research is needed to establish definitive findings [134]. Two recent preeclampsia clinical trials found that Vitamin D supplementation may aid primigravid and previously afflicted women. The first trial, ISRCTN46539495, began on November 17, 2020, with 1,300 primigravid women taking 60,000 IU of cholecalciferol monthly. In addition to preterm delivery, low birth weight, caesarean section, APGAR scores, and newborn size, preeclampsia rates decreased significantly. In another trial, IRCT2M017010131695N1, 142 preeclampsia patients received 50,000 IU of Vitamin D3 monthly or a placebo. The intervention group had a significantly lower risk of preeclampsia and fewer recurrences. These studies demonstrate that Vitamin D administration may reduce preeclampsia incidence and recurrence, improving maternal and newborn outcomes. Mechanism Vitamin D deficiency may cause pulmonary embolism (PE), with studies linking allelic variation in vitamin D metabolism genes to preeclampsia. Insufficient Vitamin D may cause early and severe PE, and supplementation may reduce PE risk in future pregnancies. Vitamin D regulates the immune system, affecting implantation, angiogenesis, endothelial function, immune response regulation, and calcium metabolism, potentially preventing anti-angiogenic chemicals and controlling hypertension [135]. Vitamin D: Therapy and Treatment in Preeclampsia Multiple studies have shown that blood 25(OH)D levels alone cannot predict preeclampsia. However, women with 25-hydroxyvitamin D (25(OH)D) levels below 30 ng/mL are at danger and must supplement to normalize their levels. Maternal 25(OH)D concentrations < 20 ng/mL are associated with worse infant outcomes and long-term child effects. Low levels of 25(OH)D and 1,25(OH)2D are linked to high blood pressure and proteinuria in pregnant women.Vitamin D3 supplementation helps treat pregnancy-related 25(OH)D deficiency. 25(OH)D levels rise 10 ng/mL for every 1000 IU of vitamin D3 taken daily. Higher doses of vitamin D3 (50,000 IU) every two weeks reduce the risk of preeclampsia, other pregnancy problems, and neonatal harm [136]. Vitamin D: Role in Kidney Stones Kidney stones, primarily composed of calcium oxalate, are linked to increased urinary calcium excretion, known as hypercalciuria. This condition, characterized by heightened intestinal absorption of calcium, is primarily driven by calcitriol, a vitamin D active form, which binds to the vitamin D receptor in enterocytes and inhibits parathyroid hormone synthesis, potentially leading to elevated urinary calcium excretion [137]. Study Based on Animal Models and Human in Kidney Stones Hereditary hypercalciuric stone-forming rats are excellent kidney stone development models. Inbreeding the most hypercalciuric Sprague–Dawley rats over generations produced this model. When fed a regular diet, the rats excrete more calcium in their urine than the control group. They also create calcium phosphate or calcium oxalate kidney stones with hydroxyproline in their diets. Similar to humans, hypercalciuria is polygenic. This rat model is essential for understanding hypercalciuria’s pathophysiology. GHS rats exhibit increased intestinal calcium absorption, bone resorption, and decreased renal tubular calcium reabsorption [138]. The study found that rats with vitamin D receptor (VDR) hypercalciuria were more likely to develop kidney stones due to increased calcium absorption and bone resorption. The study also suggested potential associations between calcitriol and VDR in bone demineralization, a condition often associated with kidney stone formation [139]. High-concentration calcium in drinking water does not cause kidney stones, but concurrent calcium and cholecalciferol administration can lead to sizable stones. Oral calcium use does not pose a risk, but may prevent kidney stones by reducing oxalate absorption. Concurrent calcium and cholecalciferol administration may promote kidney stone development, with studies showing a correlation between calcium excretion and 25-hydroxyvitamin D levels [140]. Numerous studies have failed to definitively link 25-hydroxyvitamin D levels with calcium excretion or kidney stone disease, despite consistent findings in both retrospective and large cross-sectional studies [141]. In health professional cohorts, prospective analyses have indicated that there is no statistically significant correlation between vitamin D intake and the incidence of kidney stones in certain categories. However, it is worth noting that in a separate group with notably higher vitamin D intake, there is a potential elevated risk of developing kidney stones. The significance of calcitriol, a biologically active form of vitamin D, has been underscored in research examining the regulatory hormones involved in calcium and phosphorus metabolism. Elevated levels of plasma calcitriol were found to be significantly correlated with a heightened susceptibility to symptomatic kidney stones, irrespective of other factors. The study found that individuals with kidney stones had significantly higher levels of 25-hydroxyvitamin D compared to the control group in both European and Asian cohorts. [142]. A meta-analysis found that individuals with a history of kidney stones had higher calcitriol levels and 25-hydroxyvitamin D levels compared to the control group. However, those with hypercalciuria who developed stones had higher concentrations of both calcitriol and 25-hydroxyvitamin D. Studies have linked vitamin D supplementation with calcium to increased kidney stone susceptibility. However, a meta-analysis found that vitamin D alterations in calcium metabolism did not increase kidney stone occurrences [143]. Mechanism Research explores factors causing high calcitriol levels in kidney stone-prone individuals, including decreased serum phosphate, mutations in the SLC34A1 gene, and inhibiting fibroblast growth factor-23, a hormone regulating phosphate levels, potentially benefiting patients with certain genetic issues. Urolithiasis, a condition causing kidney stones, is linked to diets and physiological conditions that increase calcitriol levels. Genetic defects in the CYP24A1 gene, which synthesizes 25-hydroxyvitamin D 24-hydroxylase, have been linked to high calcitriol levels in idiopathic infantile hypercalcemia. Kidney stone patients have higher blood calcitriol levels, possibly due to vitamin D metabolism disturbances. Further research is needed to confirm these findings [144]. Vitamin D: Therapy and Treatment in Kidney Stones Calcium is crucial for bone health, muscle function, and kidney function. However, high intake, particularly in individuals with idiopathic hypercalciuria, can increase urine calcium excretion and kidney stone risk. A balanced calcium diet, with an average intake of 1200 mg per day, can reduce urinary oxalate excretion and the risk of new stones by 50%. The risk of kidney stones from calcium supplementation is still debated, with some studies linking it to a higher risk. The relationship between vitamin D and kidney stones is complex and depends on stone type and urinary risk factors. Further research is needed to understand how vitamin D supplementation prevents kidney stones and consider hereditary factors [145]. Vitamin D: Role in Infant health Preterm neonates face an increased susceptibility to vitamin D deficiency (VDD) as a result of insufficient vitamin D transfer from their mothers and exposure to many risk factors, including prolonged parenteral nutrition, sensitivity to human milk fortifiers and formulas, and neonatal cholestasis. Unfortunately, unfortified human milk, parenteral nutrition, and many types of full-term infant formulae, such as amino acid-based and soy-based formulas, lack sufficient amounts of calcium and phosphorus to adequately fulfill the requirements for bone mineralization in preterm neonates [146]. Premature infants fed unfortified human milk have been found to have hypercalcemia due to low phosphorus levels, resulting in a surplus of calcium [147]. Vitamin D insufficiency affects all age groups, particularly infants due to sun exposure restrictions, low vitamin D levels in breast milk, and cultural ignorance about regular supplementation. Study Based on Human in Infectious Diseases in Infants Vitamin D supplementation can reduce the risk and severity of infectious illnesses, especially in those with severe vitamin D insufficiency. To reduce upper respiratory tract infections (URTIs) and seasonal influenza A, research suggests daily or weekly vitamin D supplementation rather than bolus dose, especially in groups with low baseline vitamin D levels. Studies in Japanese and Mongolian children showed that daily vitamin D supplementation reduced infection rates. Vitamin D supplementation reduces the risk of recurrent AOM in otitis-prone children. Vitamin D bolus doses, such as high-dose intermittent supplementation, has not consistently prevented infections. Vitamin D supplementation effectiveness depends on time and population. Supplementing vitamin D is crucial for overall health and immunological function, especially for deficient people. Vitamin D deficiency in pediatrics increases disease mortality and outcomes, especially in sepsis. Adequate vitamin D levels can lower infection rates and improve health. Infants, babies, toddlers, and adults can be deficient due to sun avoidance, breast milk issues, and cultural ignorance [148]. The ViDiPeC-2 trial in Canada investigates vitamin D supplementation’s impact on pediatric Crohn’s disease and asthma risk in preschoolers and schoolchildren. The DIVA study and Vit-D-Kids Asthma trial aim to determine its potential benefits in managing respiratory health in young populations [149]. The Vitality study in Australia investigates the impact of vitamin D supplementation on food allergies in infants, highlighting its importance in immune responses and allergic conditions in infancy, and aiming to improve pediatric healthcare strategies. A study examining the correlation between vitamin D levels and mortality rates in children with acute or critical diseases involved a systematic review and meta-analysis of 7434 patients [150]. The study found a significant 25 hydroxy vitamin D deficit in 47% of children, particularly those with sepsis, and a correlation between vitamin D deficiency and higher mortality rates. This aligns with a Canadian study that found no difference in serum levels between children with lower respiratory tract infections and the control group [151]. Mechanism Many studies have examined the relationship between vitamin D intake and blood 25(OH)D levels in preterm and full-term children. However, little is known about how 25(OH)D levels affect bone health and fracture rates in premature babies. Increased 25(OH)D levels may benefit bone mineralization, according to preliminary research. However, larger-scale trials and clinical results should confirm these findings. There is no evidence that daily doses of 400 IU of vitamin D or serum 25(OH)D levels increase the incidence of rickets or fractures in preterm and full-term children. The relationship between body weight and vitamin D dose–response in newborns, both preterm and full-term infants, remains difficult to understand. The age-related assumptions in vitamin D guidelines often ignore babies’ skin-generated vitamin D. Quantification is the main obstacle to measuring skin vitamin D conversion accurately. Sunblock and insufficient sunlight make this source unreliable for newborns. Newborns absorb calcium using two ways, whether premature or full term. Transcellular and paracellular vitamin D-dependent pathways exist. The timing and comparative significance of these mechanisms in neonates are unknown, but existing research shows that calcium absorption in premature and potentially full-term infants is predominantly paracellular and does not require vitamin D. Across diets and calcium intake levels, calcium absorption increases. Transitioning to vitamin D-dependent active calcium absorption may take 1–2 months. However, the timing of this transition is unknown, making thorough analysis difficult [152]. Vitamin D: Therapy and Treatment in Infants Vitamin D, a crucial nutrient for human health, is essential for infants’ growth and development. It is primarily obtained through maternal transfer during pregnancy, lactation, supplementation, and limited sun exposure. Vitamin D deficiency is a global risk, often linked to medical disorders like rickets, convulsions, and respiratory complications. Supplementation is the primary method for maintaining adequate vitamin D levels in babies, with suggested daily dosages ranging from 5 to 10 µg. Educational initiatives targeting parents have shown efficacy in enhancing vitamin D status. However, high-dose bolus supplementation is not commonly used as a public health strategy. Global organizations advocate for vitamin D supplementation within the first month after birth and maintain it until other dietary sources meet vitamin D requirements. There is a lack of evidence on the impact of vitamin D levels on bone health and fracture rates in preterm newborns. The correlation between body weight and vitamin D intake in newborns is complex, with recommendations often based on age-related assumptions. Calcium absorption in newborns occurs through two mechanisms: the transcellular vitamin D-dependent pathway and the paracellular vitamin D-independent system [153].

Vitamin D has emerged as an intriguing and multifaceted compound with diverse influences on human health and disease. In this initial review (Part I), we have selectively highlighted major diseases influenced by Vitamin D due to word limit constraints. The extensive and diverse role of Vitamin D necessitates a more comprehensive exploration, prompting the forthcoming release of Part 2. This subsequent review will expound upon additional diseases impacted by Vitamin D, providing a more detailed and nuanced examination of its multifaceted influence on human health. Vitamin D demonstrates involvement in a spectrum of biological processes through complex molecular signalling cascades and regulatory mechanisms. Its reach spans from the central nervous system to cancers to pregnancy and beyond—elucidating new facets of its physiology and therapeutic potential. Accumulating evidence from animal models and human studies has uncovered promising links between vitamin D levels and outcomes across neurological conditions, viral infections, autoimmune disorders, and malignancies. Suppressed vitamin D receptor expression in multiple sclerosis lesions provides clues to its role in regulating neuroinflammation. Genetic vitamin D pathway variants may correlate with schizophrenia risk and symptom severity. Meanwhile, mounting data point to its immunomodulatory effects in viral defence and conditions like asthma, food allergies, sepsis and Crohn’s disease. Vitamin D also exhibits anti-proliferative, pro-apoptotic, anti-estrogenic and anti-angiogenic properties in diverse cancer models—evidenced by reduced tumor growth rates, smaller tumor volumes, and inhibited metastasis. Thus, it is evident that vitamin D is involved in the development of various diseases from neurological to cancers which is summarized in Fig. 1. Moreover, Table 3 provides an overview and review of the investigated mechanism that vitamin D manifests in a variety of diseases. Table 3. | Disease | Mechanism of Vitamin D Action | Role of Vitamin D | References | |---|---|---|---| | Multiple Sclerosis (MS) | Vitamin D is of paramount importance in immune response, specifically in relation to T-cells, as it inhibits the expression of pro-inflammatory genes, downregulates myelin-reactive T-cells and CTLA-4 immunological checkpoints, and decreases MHCII expression in models of multiple sclerosis | Vitamin D can reduce T-helper 17 cell proliferation and increase protective factors against MS severity. Supplementation reduces oxidative stress and inflammation in MS models, potentially slowing progression. However, clinical trials show mixed results, necessitating further research to determine optimal dosing and treatment duration | [13, 43, 44] | | Autism Spectrum Disorder (ASD) | Vitamin D impacts brain function, development, neurotransmitter synthesis, genetic expression, and cellular processes. Its anti-inflammatory properties may modulate immune response and cytokine production, potentially contributing to ASD | Vitamin D deficiency during pregnancy or early childhood increases the risk of ASD development. Supplementation may reduce symptoms and decrease risk by ensuring adequate prenatal and early life levels, supported by brain chemistry and immune function regulation | [2, 3, 49, 50] [54] | | Schizophrenia | Vitamin D governs cellular systems and brain development, therefore deficits during pregnancy may harm the brain. It affects genetic expression and immunological function, which may affect schizophrenia neurodevelopment | Early vitamin D supplementation reduces schizophrenia risk. Studies suggest that Vitamin D may improve physical health and reduce schizophrenia symptoms via regulating brain chemistry and the immune system | [55, 56] [6, 7] | | Parkinson’s Disease | Vitamin D stimulates neurotrophic factors, controls nerve growth, and inhibits cytotoxicity. Neural stem cell differentiation and neurotransmitter synthesis are impaired. Vitamin D in the substantia nigra suggests dopaminergic pathways, which are significant in Parkinson’s. This affects oxidative stress and mitochondrial function gene expression | Vitamin D reduces Parkinson’s motor symptoms. It may help improve dopaminergic pathways and prevent against Parkinson’s degeneration. Higher Vitamin D levels may lower illness risk or postpone development, according to epidemiological research | [9, 10, 61] | | Breast Cancer | Vitamin D regulates cell cycle progression, induces apoptosis, and modulates VDR activity. It controls gene expression, inhibits inflammatory pathways, and affects estrogen synthesis, crucial in hormone-sensitive cancers like breast cancer | Vitamin D may lower breast cancer risk and development by altering tumour growth, size, and cell proliferation. Clinical research suggests high levels increase survival, recurrence risk, and treatment results | [95–97] | | Prostate Cancer | Vitamin D impacts cell growth, differentiation, and death by modulating VDR expression and interacting with androgen receptor pathways, which are crucial in prostate cancer development, and regulating immunological response and inflammation | Vitamin D reduces aggressive prostate cancer risk, according to research. Vitamin D may slow tumour development and improve survival. Clinical trials examine vitamin D supplementation as a supplemental treatment | [27, 28, 87] | | Colon Cancer | Vitamin D receptor (VDR) regulates gene expression, colon epithelial cell proliferation, differentiation, and death, affecting Wnt/β-catenin signaling, crucial for colon cancer development, and suppressing inflammatory pathways | Vitamin D is believed to reduce colon cancer risk and progression by inhibiting tumor growth and promoting apoptotic pathways. Studies suggest higher serum levels may improve survival rates. Its anti-inflammatory effects also contribute to its potential protective effects | [33, 34, 108] | | Cardiovascular Diseases | Vitamin D plays a crucial role in cardiovascular function by regulating endothelial and smooth muscle cell function, regulating inflammation, thrombosis, and blood pressure control, and preventing cardiovascular risk factors like hypertension and vascular stiffness, while also promoting calcium metabolism | Vitamin D is believed to protect cardiovascular health by reducing hypertension, heart disease, and stroke risk, improving overall cardiovascular function and reducing cardiovascular event prevalence | [160],[161] | | Diabetes | Vitamin D regulates insulin secretion and sensitivity by affecting glucose metabolism genes, enhancing pancreatic β-cell function, and regulating calcium and phosphorus metabolism, crucial for insulin action and glucose tolerance | Maintaining adequate Vitamin D levels in diabetes patients can improve glucose control and reduce the risk of complications like cardiovascular disease and kidney damage | [162],[163] | However, the translation of these research findings into clinical practice remains an evolving pursuit. The heterogeneity of responses to vitamin D supplementation across trials and disease states highlights the influence of individual factors like baseline status, genetics, demographics and combination therapy. Dosage and treatment protocols similarly lack consensus at present. Nevertheless, the prevailing safety and feasibility of vitamin D therapy provides impetus for this continued investigation. As researchers persist in unravelling the intricate biology underlying vitamin D’s diverse associations, the door opens for potential breakthroughs in therapeutic targets, preventatives, biomarkers and personalized medicine. The development of novel vitamin D analogues, receptor modulators and genotype-guided interventions may yet actualize the immense promise of this versatile nutrient. Vitamin D has captivated scientific intrigue for good reason—its mystery not yet fully solved and its utility still unfolding across the rich tapestry of human health. With further elucidation of its complex roles, vitamin D’s future in disease prevention and treatment shines bright, warranting rigorous efforts toward solutions it may tender. In conclusion, this comprehensive two-part review traces vitamin D from molecular player to clinical potential—spanning its influences on homeostasis, genetic expression, signalling pathways and cellular mechanisms that ultimately impact predilection, diagnosis and prognosis across disease states. While research continues to reveal its multifaceted biodynamics, what clearly emerges is vitamin D’s imperative to advance therapeutics, inspire personalized regimens, and ultimately optimize well-being across populations. Unlocking the intricacy of its biology is key to translating vitamin D into clinical solutions—efforts that hold promise for preventing and treating myriad conditions, from neurodegeneration to cancer and immunopathologies. Emerging advancements in molecular biotechnology provide promising avenues for enhancing the diagnostic accuracy and therapeutic efficacy of Vitamin D in oncology. The integration of molecular diagnostics can facilitate the development of precision medicine approaches. This enables the tailoring of Vitamin D therapy based on individual genetic profiles, potentially optimizing outcomes in the prevention and treatment of cancers where the role of Vitamin D has been substantiated [154]. As science persists in decoding vitamin D, this ubiquitous biomolecule may prove profoundly consequential to the future landscape of healthcare through tailored modalities that harness its critical roles in human drama. Declarations Conflict of interest All authors have declared there is no conflict of interest. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Shailendra Dwivedi and Vijay Singh both have equally contributed, so they share first authorship.

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