This study aimed to assess the medicinal properties of Breynia retusa, a plant rich in phytocompounds predominantly used as an ethnomedicinal agent in Western Ghats, which appeared to be promising for therapeutic use, especially in the treatment of ovarian cancer. Herein, its cytotoxic potential on ovarian cancer cell lines SKOV-3, neurotoxicity, antioxidant activity, and molecular docking was determined to aid in explaining the mechanisms of interactions with proteins related to ovarian cancer. B . retusa methanolic extract demonstrated exuberant antioxidant activity, with 81.91% scavenging ability of DPPH radicals and efficient reduction of phosphomolybdenum (22.98 mg ascorbic acid equivalents antioxidant capacity/g extract). The extract proved to be an important anti-inflammatory agent through membrane stabilization inhibition of 83%. The cytotoxicity study against the SKOV-3 cell line indicated an IC50 value of 34.01 µg/mL and a very negligible neurotoxicity in SH-SY5Y cell lines. The GC-MS and HPLC profiling indicated many anticancer compounds in the extract such as secalciferol, methyl gallate, ricinoleic acid, gallic acid, and naringenin. The docking study showed significant interactions of secalciferol molecules with the key ovarian cancer proteins, which include IGF1 (-6.758 kcal/mol) and c-ERBB2 (-4.281 kcal/mol). Fatty acid derivatives and methyl gallate showed efficient dock scores (< -5.0 kcal/mol) with antioxidant (catalase and superoxide dismutase) enzymes and inflammatory cytokines (IL-6 and COX-1), respectively, as evidences of antioxidant and anti-inflammatory potentials. The bio-accessibility of phenolics and their antioxidant activity ranged above 90%, indicating the promising bioavailability of phytochemicals expected in vivo. Hence the current study emphasizes the anticancer potential of B. retusa phytocompounds that appeared to interact very strongly with ovarian cancer targets and confirms the dose-dependent cytotoxic and antioxidant activities of B. retusa methanolic extract.

The online version contains supplementary material available at 10.1007/s13205-025-04276-8.

Vitamin D deficiency (VDD) is a widespread situation, linked to patients' dietary habits and/or geographical origins. On the other hand, hypervitaminosis D (VDO) is also a worldwide problem, mainly associated with uncontrolled self-administration. In this study, we investigated the effects of VDD and VDO on sex steroid production and ovarian histology in mice. In addition to addressing the rarely explored situation of VDO, the originality of our approach is to disconnect VDD/VDO situations from the well-known calciotrophic effect of vitamin D (VitD). Our data indicate that VDD led to a significant decrease in serum LH and FSH levels, independently of serum calcium levels. VDD was also associated with increased testosterone and reduced oestradiol levels. VDO animals showed increased LH and reduced testosterone levels. Hormonal changes in the VDO animal groups were correlated with a lower accumulation of transcripts of steroidogenic genes such as CYP11A1 and 3ß-HSD, whereas these transcripts were higher in the VDD groups. CYP19A1 transcripts were lower in VDD animals than in controls. This study highlights the complex interaction between vitamin D status, the regulation of reproductive hormones and, consequently, reproductive performance. It underlines the need for caution when oral vitamin D supplementation is chosen as a therapeutic action to boost female reproductive performance, as VDO can be as detrimental as VDD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the abnormal lipid deposition in hepatocytes. The prevalence of MASLD is significantly increased in the elderly population, suggesting that aging may be related to the occurrence of MASLD. Emerging evidences suggest that vitamin D receptor (VDR) may be implicated in the progression of MASLD. Therefore, additional researches are warranted to elucidate whether VDR plays a role in aging-related MASLD.

To investigate the relationship between aging and MASLD and explore the role and related mechanisms of VDR in aging-related MASLD.

Cellular senescence models were established, and the senescence phenotype of telomerase RNA component knockout mice was validated. These mice were then used as a senescence model for subsequent studies. Changes in VDR expression in the livers of aging mice were examined. VDR knockdown models, including cell knockdown models and hepatic-specific VDR knockout mice, were constructed, and MASLD was established in these models. Additionally, vitamin D (VD)-supplemented models, including senescent liver cell lines and senescent mice, were constructed.

The steatosis in senescent liver cells was more severe than in normal cells (P < 0.05). Moreover, hepatic steatosis was significantly more pronounced in senescence model mice compared to control group when the MASLD model was successfully induced (P < 0.05). Therefore, we concluded that aging aggravated hepatic steatosis. The hepatic expression of VDR increased after aging. VDR knockdown in senescent liver cells and senescent mice alleviated hepatic steatosis (P < 0.05). When senescent liver cells were stimulated with VD, cellular steatosis was aggravated (P < 0.05). However, VD supplementation had no effect on aging mice.

Aging can lead to increased hepatic steatosis, and the hepatic-specific knockdown of VDR alleviated aging-related MASLD. VDR could serve as a potential molecular target for aging-related MASLD.

Autism spectrum disorder (ASD) is associated with various symptoms, including repetitive behaviors, restricted interests, and deficits in proper communication. Earlier studies have linked these symptoms to abnormalities in the balance between excitatory (glutamatergic signaling) and inhibitory (GABAergic signaling) neurotransmission. The present study aimed to analyze the levels of different biomarkers in children with ASD compared to neurotypical (NT) controls. The study included 80 children, of whom 40 were cases (children with ASD) and 40 were age- and sex-matched NT controls. Serum levels of GABAA, and GABAB receptors, glutamate, zinc, potassium, and calcium were measured in both groups. ASD diagnosis was verified using the Childhood Autism Rating Scale (CARS) and Autism Diagnostic Interview-Revised (ADI-R). There was a significant decrease (P < 0.001) in the median serum levels of GABAA (0.6) and GABAB receptors (2.03) in children with ASD compared to controls. Additionally, a significant increase in median serum glutamate levels was observed in ASD children (102, P < 0.001) compared to controls. Children with ASD also showed a significant reduction (P < 0.001) in median levels of all studied blood minerals compared to controls, including potassium (3.8 vs. 4.6), calcium (9.0 vs. 9.7), and zinc (57.0 vs. 92.0). The roles of GABAB and zinc as potential pathological biomarkers were investigated due to their highly significant inverse correlations with stereotypic and repetitive behaviors (ADI-R domain), with rho = -0.393 (P = 0.012) and rho = -0.488 (P = 0.001), respectively. Further analysis of pathways regulating these biomarkers may provide deeper insights into the etiology and pathophysiology of ASD, paving the way for potential therapeutic interventions.

Information about the association of antimicrobial peptides with hypovitaminosis D in hospitalized foals is lacking.

We aimed to longitudinally determine the association of serum concentrations of vitamin D metabolites, vitamin D binding protein (DBP), and parathyroid hormone (PTH) with antimicrobial peptides (β-defensin-1 and cathelicidin-1) and the mRNA expression of the vitamin D receptor (VDR), 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), toll-like receptor-4 (TLR-4), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), disease severity, and mortality in hospitalized foals. We hypothesized that hypovitaminosis D would be associated with decreased serum concentrations of antimicrobial peptides, disease severity, and mortality in hospitalized foals.

One hundred nine foals ≤ 72 h of age divided into hospitalized (n = 83; 60 septic, 23 sick nonseptic [SNS]) and healthy (n = 26) foals.

Blood samples were collected on admission (0), and 24, 48, and 72 h after admission from healthy and hospitalized foals. Data were analyzed by repeated measure methods.

Serum 25(OH)D, 1,25(OH)2D, DBP, β-defensin-1, and cathlicidin-1 concentrations were significantly lower, whereas PTH concentrations were higher in hospitalized compared to healthy foals at different times during hospitalization (p < 0.05). Septic foals had lower VDR and CYP27B1, but higher TLR-4, TNF-α, and IL-1β mRNA expression than in healthy foals (p < 0.05). Decreased serum 25(OH)D, β-defensin-1, and cathelicidin-1, and high PTH concentrations were associated with higher odds of death in hospitalized foals (p < 0.05).

Decreased vitamin D metabolite concentrations and decreased antimicrobial peptide concentrations suggest that vitamin D has important immunomodulatory functions in newborn foals.

The importance of vitamin D for a well-functioning immune system is becoming increasingly evident. Nevertheless, the other fat-soluble vitamins A, E and K also seem to play a central role regarding the adequate function of immune cells and to counteract excessive immune reactions and inflammatory processes. However, recognizing hidden hunger, particularly micronutrient deficiencies in vulnerable groups like the elderly, is crucial because older adults often lack sufficient micronutrients for various reasons. This review summarizes the latest findings on the immune modulating functions of fat-soluble vitamins in a physiological and pathophysiological context, provides a graphical comparison of the Recommended Daily Allowances between Deutschland, Austria, Confoederatio Helvetica (D-A-CH; eng. GSA, Germany, Switzerland, Austria), Deutsche Gesellschaft für Ernährung (DGE; eng. German Nutrition Society) and National Institutes of Health (NIH) across all age groups and, in particular, addresses the question regarding the benefits of supplementation of the respective micronutrients for the aging population of industrialized nations to strengthen the immune system. The following review highlights the importance of fat-soluble vitamins A, D, E and K which play critical roles in maintaining immune system function and, in some cases, in preventing excessive immune activation. Therefore, a better understanding of the relevance of adequate blood levels and consequently potential supplementation strategies may contribute to the prevention and management of infectious diseases as well as better overall health of the elderly.

Owing to its promising advantages, including improved drug bioavailability and therapeutic efficiency at low doses and frequency, increased patient convenience and compliance, and prolonged storage life, nanomedicine has received heightened attention over conventional pharmaceuticals. Human serum albumin (HSA)-based nanoparticles have been used as drug carriers in injectable formulations, with great success and versatility. In this study, raloxifene and vitamin D3 were co-encapsulated in HSA-based nanoparticles (Ral/VitaD/HSA/PSS NPs) as an intravenously injected pharmaceutical formulation in order to enhance their availability in the body. The lyophilization-hydration method was utilized to develop the Ral/VitaD/HSA/PSS NPs. In addition, the characteristics and stability of the NP and the effect of the co-loading of vitamin D3 on raloxifene release in vitro and in vivo were discussed. The raloxifene and vitamin D3 molecules were successfully encapsulated and well dispersed in an amorphous state within Ral/VitaD/HSA/PSS NPs. The prepared Ral/VitaD/HSA/PSS NPs were lyophilized for long-term storage and were both biocompatible and hemocompatible, enhancing alkaline phosphtase activity in osteoblasts. Delivered via intravenous injection, Ral/VitaD/HSA/PSS NPs addressed the low bioavailability of raloxifene and vitamin D3 caused by oral administration, and improved their compatibility and residence time in the body. Overall, the established raloxifene-vitamin D3-co-loaded NPs may be a potential nanomedicine contender for treating postmenopausal osteoporosis.

The pancreatic ductal adenocarcinoma (PDAC) is among the deadliest tumor diseases worldwide. While treatment options have generally become more diverse, little progress has been made in the treatment of PDAC and the median survival time for patients with locally advanced PDAC is between 8.7 and 13.7 months despite treatment. The aim of this review was to explore the therapeutic potential of complementing standard therapy with natural or synthetic forms of vitamins A, C, and D. The therapeutic use of vitamins A, C, and D could be a promising addition to the treatment of PDAC. For all three vitamins and their derivatives, tumor cell-specific cytotoxicity and growth inhibition against PDAC cells has been demonstrated in vitro and in preclinical animal models. While the antitumor effect of vitamin C is probably mainly due to its pro-oxidative effect in supraphysiological concentrations, vitamin A and vitamin D exert their effect by activating nuclear receptors and influencing gene transcription. In addition, there is increasing evidence that vitamin A and vitamin D influence the tumor stroma, making the tumor tissue more accessible to other therapeutic agents. Based on these promising findings, there is a high urgency to investigate vitamins A, C, and D in a clinical context as a supplement to standard therapy in PDAC. Further studies are needed to better understand the exact mechanism of action of the individual compounds and to develop the best possible treatment regimen. This could contribute to the long-awaited progress in the treatment of this highly lethal tumor entity.

N-Phenyl ureidobenzensulfonates (PUB-SOs) are a novel family of dihydroorotate dehydrogenase (DHODH) inhibitors. Herein, we investigate the potential of PUB-SOs to induce acute myeloid leukemia (AML) cell differentiation and apoptosis. To that end, we screened our chemolibrary to select the most potent PUB-SOs based on their antiproliferative activity and their ability to arrest the cell progression of AML cells in the S phase. The most promising PUB-SOs show antiproliferative activity in the range of 0.13-23 µM against THP-1, MOLM-13 and HL-60 AML cells. Moreover, those PUB-SOs arrested the cell cycle progression in the S phase. In addition, molecular docking studies evidenced their potential to bind in the brequinar-binding site located on DHODH which was confirmed using the DHODH inhibition assay showing that PUB-SOs are potent DHODH inhibitors (half maximal inhibitory concentration (IC50) = 7.7-1000 nM). Our results also show that selected PUB-SOs induced the differentiation of THP-1 and HL-60 cells into cluster of differentiation (CD) 11b+/CD14+ phenotypes, up to 74 % and 50 %, respectively. They also promoted CD11b+ differentiation in MOLM-13 cells (up to 44 %). Additionally, the prototypical PUB-SOs SFOM-0046 induced lactate dehydrogenase (LDH) release, mitochondrial stress and mitochondrial membrane potential loss in MOLM-13 cell line. Furthermore, SFOM-0046 induced apoptosis in MOLM-13 cells, which was confirmed by the increase of annexin V/propidium iodide (PI) and caspase 3/7 positive cells. In summary, our results highlight PUB-SOs as a novel family of DHODH inhibitors inducing both cell differentiation and apoptosis in AML cells, underscoring their potential as therapeutic agents for AML treatment.

Vitamin D deficiency (VDD) is a widespread global health issue, affecting nearly a billion individuals worldwide, and mounting evidence links it to an increased risk of cardiovascular diseases like hypertension, atherosclerosis, and heart failure. The discovery of vitamin D receptors and metabolizing enzymes in cardiac and vascular cells, coupled with experimental studies, underscores the complex relationship between vitamin D and cardiovascular health. This review aims to synthesize and critically evaluate the preclinical evidence elucidating the role of vitamin D in cardiovascular health. We examined diverse preclinical in vitro (cardiomyocyte cell line) models and in vivo models, including knockout mice, diet-induced deficiency, and disease-specific animal models (hypertension, hypertrophy and myocardial infarction). These studies reveal that vitamin D modulates vascular tone, and prevents fibrosis and hypertrophy through effects on major signal transduction pathways (NF-kB, Nrf2, PI3K/AKT/mTOR, Calcineurin/NFAT, TGF-β/Smad, AMPK) and influences epigenetic mechanisms governing inflammation, oxidative stress, and pathological remodeling. In vitro studies elucidate vitamin D's capacity to promote cardiomyocyte differentiation and inhibit pathological remodeling. In vivo studies further uncovered detrimental cardiac effects of VDD, while supplementation with vitamin D in cardiovascular disease (CVD) models demonstrated its protective effects by decreasing inflammation, attenuating hypertrophy, reduction in plaque formation, and improving cardiac function. Hence, this comprehensive review emphasizes the critical role of vitamin D in cardiovascular health and its potential as a preventive/therapeutic strategy in CVDs. However, further research is needed to translate these findings into clinical applications as there are discrepancies between preclinical and clinical studies.

Active vitamin D insufficiency accelerates the development of osteoporosis, with senescent bone cells and the senescence-associated secretory phenotype (SASP) playing crucial roles. This study aimed to investigate whether the senolytic agent ABT263 could correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent cells.

Bone marrow mesenchymal stem cells (BM-MSCs) from young and aged mice were treated with ABT263 in vitro, and 1,25(OH)2D-insufficient (Cyp27b1+/-) mice were administered ABT263 in vivo. Cellular, molecular, imaging, and histopathological analyses were performed to compare treated cells and mice with control groups.

ABT263 induced apoptosis in senescent BM-MSCs by downregulating Bcl2 and upregulating Bax expression. It also induced apoptosis in senescent BM-MSCs from 1,25(OH)2D-insufficient mice. ABT263 administration corrected bone loss caused by 1,25(OH)2D insufficiency by increasing bone density, bone volume, trabecular number, trabecular thickness, and collagen synthesis. It also enhanced osteoblastic bone formation and reduced osteoclastic bone resorption in vivo. ABT263 treatment corrected the impaired osteogenic action of BM-MSCs by promoting their proliferation and osteogenic differentiation. Furthermore, it corrected oxidative stress and DNA damage caused by 1,25(OH)2D insufficiency by increasing SOD-2 and decreasing γ-H2A.X expression. Finally, ABT263 corrected bone cell senescence and SASP caused by 1,25(OH)2D insufficiency by reducing the expression of senescence and SASP-related genes and proteins.

ABT263 can correct osteoporosis caused by active vitamin D insufficiency by selectively clearing senescent skeletal cells, reducing oxidative stress, DNA damage, and SASP, and promoting bone formation while inhibiting bone resorption. These findings provide new insights into the potential therapeutic application of senolytic agents in the treatment of osteoporosis associated with active vitamin D insufficiency.

This study highlights the therapeutic potential of ABT263, a senolytic compound, in treating osteoporosis caused by active vitamin D insufficiency. By selectively eliminating senescent bone cells and their associated SASP, ABT263 intervention demonstrates the ability to restore bone homeostasis, prevent further bone loss, and promote bone formation. These findings contribute to the growing body of research supporting the use of senolytic therapies for the prevention and treatment of age-related bone disorders. The translational potential of this study lies in the development of novel therapeutic strategies targeting cellular senescence to combat osteoporosis, particularly in cases where vitamin D insufficiency is a contributing factor. Further clinical studies are warranted to validate the efficacy and safety of ABT263 and other senolytic agents in the treatment of osteoporosis in humans.

Experimental and observational studies suggest that circulating micronutrients, including vitamin D (VD), may increase COVID-19 risk and its associated outcomes. Mendelian randomization (MR) studies provide valuable insight into the causal relationship between an exposure and disease outcomes.

The aim was to conduct a systematic review and meta-analysis of causal inference studies that apply MR approaches to assess the role of these micronutrients, particularly VD, in COVID-19 risk, infection severity, and related inflammatory markers.

Searches (up to July 2023) were conducted in 4 databases.

The quality of the studies was evaluated based on the MR-STROBE guidelines. Random-effects meta-analyses were conducted where possible.

There were 28 studies (2 overlapped) including 12 on micronutrients (8 on VD) and COVID-19, 4 on micronutrients (all on VD) and inflammation, and 12 on inflammatory markers and COVID-19. Some of these studies reported significant causal associations between VD or other micronutrients (vitamin C, vitamin B6, iron, zinc, copper, selenium, and magnesium) and COVID-19 outcomes. Associations in terms of causality were also nonsignificant with regard to inflammation-related markers, except for VD levels below 25 nmol/L and C-reactive protein (CRP). Some studies reported causal associations between cytokines, angiotensin-converting enzyme 2 (ACE2), and other inflammatory markers and COVID-19. Pooled MR estimates showed that VD was not significantly associated with COVID-19 outcomes, whereas ACE2 increased COVID-19 risk (MR odds ratio = 1.10; 95% CI: 1.01-1.19) but did not affect hospitalization or severity of the disease. The methodological quality of the studies was high in 13 studies, despite the majority (n = 24) utilizing 2-sample MR and evaluated pleiotropy.

MR studies exhibited diversity in their approaches but do not support a causal link between VD/micronutrients and COVID-19 outcomes. Whether inflammation mediates the VD-COVID-19 relationship remains uncertain, and highlights the need to address this aspect in future MR studies exploring micronutrient associations with COVID-19 outcomes.

PROSPERO registration no. CRD42022328224.

The relationship between vitamin D and depression has garnered significant attention in recent years. However, the efficacy of vitamin D in ameliorating depression among specific subgroups of older patients remains controversial. This study aimed to assess the impact of vitamin D supplementation on depressive symptoms and the prevalence of depression in older adults. Additionally, the study sought to examine potential moderating factors, including differences among population subgroups and various supplementation strategies.

A systematic literature search was conducted in the databases PubMed, EMBASE, Web of Science, and the Cochrane Library up to March 2024. The RevMan 5.3 software was utilized to calculate the standardized mean difference (SMD) and to evaluate the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The objective was to determine the efficacy of vitamin D supplementation in alleviating depressive symptoms or treating depression in older adults.

This meta-analysis encompassed eleven studies, comprising a total of 21,561 participants. The findings did not indicate a statistically significant therapeutic benefit of vitamin D supplementation for depression in older patients [SMD: -0.10; 95% CI: (-1.19, 0.00); p = 0.05]. Subgroup analyses revealed that the efficacy of vitamin D intervention in geriatric depression correlated with several factors, including baseline serum 25(OH)D levels, the dosage of the intervention, gender, and the initial presence of depressive symptoms or a diagnosis of depression.

The current evidence is insufficient to conclusively establish the significant efficacy of vitamin D supplementation in alleviating depressive symptoms among older patients. Consequently, additional randomized controlled trials are warranted to further validate the relationship between vitamin D supplementation and depression in the older adults.

Vitamin D is a steroid hormone that is naturally produced in the body or obtained through dietary sources, primarily under the influence of UVB radiation. This essential nutrient has a vital role in numerous physiological processes, encompassing immune function, cell growth, differentiation, insulin regulation, and cardiovascular well-being, along with its pivotal role in sustaining the delicate equilibrium of calcium and phosphate concentrations in the body. Moreover, vitamin D reinforces mucosal defense and bolsters the immune system through immunomodulation, making it a critical component of overall health. Numerous studies have unveiled the profound connection between vitamin D and the predisposition to respiratory tract infections, including well-known viruses such as influenza and the novel severe acute respiratory syndrome coronavirus 2. Vitamin D deficiency has been consistently linked to increased severity of coronavirus disease 2019 (COVID-19) and a heightened risk of mortality among afflicted individuals. Retrospective observational studies have further substantiated these findings, indicating that levels of vitamin D are linked with both the occurrence and severity of COVID-19 cases. Vitamin D has its influence on viral infections through a multitude of mechanisms, such as promoting the release of antimicrobial peptides and fine-tuning the responses of the immune system. Additionally, vitamin D is intertwined with the intricate network of the renin-angiotensin system, suggesting a potential impact on the development of complications related to COVID-19. While further clinical trials and extensive research are warranted, the existing body of evidence strongly hints at the possible use of vitamin D as a valuable tool in the prophylaxis and management of COVID-19 and other viral infectious diseases.

Vitamin D3 (25-hydroxyvitamin D3 (VD)) and vitamin E (VE) have proven to have immunomodulatory and antioxidant functions along with capacities to improve the reproductive function in chickens. Coccidiosis in laying hens at different stages of growth has been shown to negatively affect performance, immune response, and oxidative status, thus increasing the cost of production. A study was conducted to evaluate the influence of dietary VD or VE on performance, gut health, immune response, and oxidative status of laying hens at peak production. Laying hens (23 wk-of-age, n = 225) were randomly allocated into 5 treatment groups (n = 9 hens/replicate) with 5 replicate groups each: 1) unchallenged control (UC), 2) pair-fed control (PF), 3) challenged control (CC), 4) challenged control top-dressed with 5,000 IU of 25-hydroxyvitamin D3 (VD) per kg of diet, and 5) challenged control top-dressed with 100 IU of DL-α-tocopherol (VE). At 25 wk-of-age, hens grouped in CC, VD, and VE were challenged with mixed Eimeria spp. to induce coccidiosis. VD or VE supplemented hens did not impact bird body weight; however, egg production increased by 10.36% and 13.77%, respectively (P < 0.0001). Furthermore, the gut health of the hens was improved with either VD or VE supplementation, as indicated by lowered gut permeability and intestinal lesion scores (P < 0.05). VE significantly reduced the heterophil count (P = 0.0490) alongside numerically increasing the peripheral CD4+ and CD8+ T cells and monocyte counts (P > 0.05). Both VD or VE increased the TAC at 14 DPI compared to UC (P<0.05). Preliminary findings suggest that dietary VD or VE supplementation has the potential to improve gut health, modulate the immune response, and increase egg production in coccidiosis-infected laying hens.

Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is estimated to be >50% in women aged >45 years. Fibroids represent a considerable health burden. It is time to acquire a deeper mechanistic understanding of uterine fibroid-related etiology and pathogenesis, which may help pinpoint new strategies and an individualized approach. There is a need to gather prospective data and conduct studies to compare alternative approaches and assess long-term outcomes with respect to quality of life, recurrence of symptoms (bleeding and bulk symptoms), fertility, and even complications The goal of this review was to evaluate the widely accepted pathogenesis and identify risks factors and future directions for clinical and basic research into fibroids.

Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D2 [ercalcitriol, 1,25(OH)2D2] and 1α,25-dihydroxyvitamin D3 [calcitriol, 1,25(OH)2D3], which act as classical steroid hormones. 1,25(OH)2D3 exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)2D3 cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)2D3 and 1,25(OH)2D2 have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies.

Background and Objectives: A deficiency in serum 25-hydroxyvitamin D levels is associated with a number of cardiovascular situations, such as high blood pressure, heart failure, atherosclerotic heart disease, and peripheral artery disease. The frontal QRS-T angle has recently been proposed as a marker of ventricular repolarization. A wider frontal QRS-T angle has been positively correlated with adverse cardiac events. The objective of our study was to examine the association between serum 25-hydroxyvitamin D level and the frontal QRS-T angle. Materials and Methods: A total of 173 consecutive patients aged 18-60 years undergoing routine cardiology check-up evaluation, and not receiving concurrent vitamin D treatment were included in the study. Patients were classified in three groups, depending on their vitamin D levels, and categorized as follows: Group 1-deficient (<20 ng/mL), Group 2-insufficient (20-29 ng/mL), or Group 3-optimal (≥30 ng/mL). The frontal QRS-T angle was determined using the automated reports generated by the electrocardiography machine. Results: The average age of participants was 45.8 (±12.2) years, and 55.5% of participants were female (p < 0.001). Individuals with low vitamin D concentrations exhibited a wider frontal QRS-T angle. It was determined that vitamin D level is an independent predictive factor for the frontal QRS-T angle. Conclusions: As the levels of 25-hydroxyvitamin D decrease, repolarization time assessed by frontal QRS-T angle is widened. Our findings indicate that lower concentrations of vitamin D may increase the susceptibility to ventricular arrhythmia.

Secondary osteoporosis is frequently due to the use of high-dose glucocorticoids (GCs). The existing strategy for managing glucocorticoid-induced osteoporosis (GIOP) is considered insufficient and remains in a state of ongoing evolution. Therefore, it is crucial to develop more precise and effective agents for the treatment of GIOP. The constituents of Reynoutria multiflora (Thunb.) Moldenke, specifically Polygonum multiflorum (PM) Thunb, have previously shown promise in mitigating osteopenia. This study aimed to investigate the therapeutic effects of an ethanolic PM extract (PMR30) against GIOP in male rats. Prednisone (6 mg/kg/day, GC) was continuously administered to rats to induce GIOP, and they were subjected to treatment with or without ethanolic PMR30 for a duration of 120 days. Serum was collected for biochemical marker analysis. Bone histomorphometric, histological, and TUNEL analyses were performed on tibia samples. The protein expressions of LC3, Agt5, and Beclin 1 in the femur underwent examination through western blotting. Prolonged and excessive GC treatment significantly impeded bone formation, concomitant with reduced bone mass and body weight. It also suppressed OCN and OPG/RANKL in serum, and decreased Beclin 1 and LC3 in bone. Simultaneously, there was an elevation in bone resorption markers and apoptosis. Treatments with both high dose and low dose of PMR30 alleviated GIOP, stimulated bone formation, and upregulated OCN and OPG/RANKL, while suppressing TRACP-5b, CTX-I, and apoptosis. The impact of PMR30 possibly involves the enhancement of autophagy proteins (LC3, Agt5, and Beclin 1) and the inhibition of apoptosis within the bone. PMR30 holds promise as a prospective therapeutic agent for preventing and treating GIOP.

Introduction Vitamin D deficiency (VDD) is considered one of the leading causes of poor bone quality. It may also be related to severe muscular weakness, especially in the elderly, which leads to frequent falls. Thus, VDD might be associated with fragility fractures of the hip, wrist, and spine in this age category. In this cross-sectional study, our goal was to present vitamin D levels in an elderly Mediterranean population with hip fractures and to assess whether its levels are related to the incidence or prevention of such injuries. Methods Between January and December 2021, 140 patients aged 65 years or older were hospitalized in our department with a fracture involving the hip joint. Serum calcium and vitamin D level control was performed upon admission, as well as recording whether anti-osteoporosis medication had been prescribed. Only patients with low-energy fractures were included, whereas oncologic patients and those with high-energy trauma were excluded. Results Thirty-eight men and 102 women, with a mean age of 83.12 and 84.88 years, respectively, participated in our study. Intertrochanteric fractures were the most common injuries (50.72%). Low vitamin D levels (<30 ng/mL) were observed in 132 patients (94.28%). A bone density scan during the last year had been conducted by only seven patients (5%), whereas in 136 patients (97.14%), no anti-osteoporotic medication was given. Conclusion There is an excessive percentage of aged patients with hip fractures in Greece, demonstrating a significant vitamin D insufficiency despite the high annual frequency of sunny days in this Mediterranean region. Presumably, most of these patients neither perform the routine bone density scan nor do they take any kind of preventive pharmaceutical treatment, which might reveal devaluation of osteoporosis from this age group due to contingent comorbidities.

Avian coccidiosis, despite advancements in management, nutrition, genetics, and immunology, still remains the most impactful disease, imposing substantial economic losses to the poultry industry. Coccidiosis may strike any avian species, and it may be mild to severe, depending on the pathogenicity of Eimeria spp. and the number of oocysts ingested by the bird. Unlike broilers, low emphasis has been given to laying hens. Coccidiosis in laying hens damages the gastrointestinal tract and causes physiological changes, including oxidative stress, immunosuppression, and inflammatory changes, leading to reduced feed intake and a drastic drop in egg production. Several countries around the world have large numbers of hens raised in cage-free/free-range facilities, and coccidiosis has already become one of the many problems that producers have to face in the future. However, limited research has been conducted on egg-laying hens, and our understanding of the physiological changes following coccidiosis in hens relies heavily on studies conducted on broilers. The aim of this review is to summarize the effect of coccidiosis in laying hens to an extent and correlate it with the physiological changes that occur in broilers following coccidiosis. Additionally, this review tries to explore the nutritional strategies successfully used in broilers to mitigate the negative effects of coccidiosis in improving the gut health and performance of broilers and if they can be used in laying hens.

Close correlation between vitamin D (VitD) deficiency and Parkinson's Disease (PD) risk, VitD as an adjuvant treatment promising to improve PD progression. However, VitD excessive intake could induce hypercalcemia and renal damage. Therefore, upregulation of vitD receptor (VDR) is considered a compensatory strategy to overcome VitD insufficiency and alleviate PD symptoms. In this study, we discovered that VDR played antioxidative roles in dopaminergic neurons by decreasing reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. Further, we newly identified VDR downstream events in C. elegans, including glutathione S-transferase (gst) and forkhead box transcription factor class O (daf-16) mediated oxidative stress resistance. VDR upregulation also mitigated microglial activation through inhibition of NLRP3/caspase-1-mediated inflammation and membrane permeabilization. These findings highlight the multifaceted protective effects of VDR in both neurons and microglia against the development of PD. Importantly, we discovered a novel deubiquitinase DUB3, whose N-terminal catalytic domain interacted with the C-terminal ligand-binding domain of VDR to reduce VDR ubiquitination. Identification of DUB3 as an essential player in the deubiquitinating mechanism of VDR provides valuable insights into VDR regulation and its potential as a therapeutic target for PD.

Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)-the most common variant of CTCL-often presents with skin lesions around the abdomen and buttocks ("bathing suit" distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL.

Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.

Vitamin D deficiency has reached epidemic proportions globally. Observational data link low vitamin D status to diabetes, dyslipidemia, and metabolic syndrome, but interventional trials on the effects of supplementation are limited.

We investigated associations between serum 25-hydroxyvitamin D (25(OH)D) levels and metabolic markers in Saudi adults.

This retrospective cross-sectional study analyzed the clinical records of 476 patients from Saudi Arabia, aged 15-78 years. According to 25(OH)D levels, participants were stratified as vitamin D-sufficient (≥30 ng/mL), -insufficient (21-29 ng/mL), or -deficient (≤20 ng/mL). The outcomes were diabetic status (fasting glucose, HbA1c) and lipid panel results.

Higher diabetes prevalence was significantly associated with lower 25(OH)D levels (10.1% in the sufficient group, 11.6% in the insufficient group, and 18.3% in the deficient group). Similarly, worse lipid profiles were associated with more severe hypovitaminosis D, including a total cholesterol level of ≥240 mg/dL (5.3% in participants with normal vitamin D levels vs. 18.9% in those with deficient levels) and LDL ≥ 160 mg/dL (6.9% in participants with normal vitamin D levels vs. 13.2% in those with deficient levels). Vitamin D deficiency disproportionately affected women and adults > 45 years old.

Vitamin D deficiency is endemic in Saudi Arabia and strongly linked to worsened metabolic markers. Optimizing vitamin D status through screening and correcting the deficiency may provide a cost-effective approach to confronting the regional diabetes epidemic and reducing cardiovascular disease risk.

Vitamin D deficiency is currently a significant public health issue closely linked to numerous diseases, such as breast cancer. This study aims to determine the estimated optimal serum levels of vitamin D to have a protective effect against breast cancer, in addition to exploring the biological mechanisms and risk factors involved. A literature search of articles published in the last 5 years was conducted, and simple statistical analyses using mean and standard deviation were performed to calculate the average concentration of vitamin D from different available studies. It has been observed that serum levels of vitamin D ≥ 40.26 ng/mL ± 14.19 ng/mL could exert a protective effect against breast cancer. Additionally, various biological mechanisms, such as those related to the immune system, and risk factors like diet implicated in this relationship were elucidated. Consequently, it can be concluded that proper serum levels of vitamin D may have a protective effect against breast cancer, and dietary supplementation may be an appropriate procedure to achieve these optimal vitamin D concentrations.

The aim of this study was to gain a better understanding of the key structural factors and intermolecular interactions underlying the formation, functionality, and in vitro gastrointestinal behaviour of the liposomal form of nutraceuticals coated with whey proteins (WPI) and chitosan (CHIT). Phosphatidylcholine (PC) liposomes were used to encapsulate a combination of hydrophobic and hydrophilic nutraceuticals. The hydrophobic constituents were long-chain (LC) n-3 PUFAs (DHA and EPA) from fish oil (FO), vitamin D3, and clove essential oil (CEO), while the hydrophilic component was γ-aminobutyric acid (GABA). A combination of physicochemical methods was used to achieve this goal, including electron paramagnetic resonance spectroscopy (EPRS), laser light scattering in dynamic, static, and electrophoretic modes, transmission electron microscopy, spectrophotometry and tensiometry. The efficiency of encapsulating the nutraceuticals in PC liposomes simultaneously was as follows: 100 ± 1% for both FO triglycerides and CEO, 82 ± 2% for vitamin D3, and 50 ± 1% for GABA. According to EPRS data, encapsulating LC PUFA reduced microviscosity at a depth of 20 Å in the PC bilayer. The co-encapsulation of other nutraceuticals in PC liposomes at selected concentrations did not alter this effect. The upper part (8 Å) of PC liposome bilayers showed an increase in rigidity parameter S, indicating the presence of D3, CEO, and partially GABA. The liposome layer-by-layer encapsulation efficiency (EE%) was achieved by using WPI to form the binary complex [WPI-(PC-FO-D3-GABA-CEO)] (EE = 50% at pH 7.0 and I = 0.001 M), followed by coating with chitosan to form the ternary complex [WPI-(PC-FO-D3-GABA-CEO)]-CHIT (EE = 80% at pH 5.1 and I = 0.001 M). The biopolymer-coated liposomes displayed high water solubility owing to their submicron sizes, thermodynamic affinity for the aqueous medium, and 20 mV ζ-potential values. The chitosan shell regulated the release of liposomes from the ternary complex during in vitro gastrointestinal digestion. In the stomach, the hydrolysis of chitosan by pepsin resulted in a 40% release of liposomes. In the small intestine, chitosan was separated from the WPI-liposome core, facilitatig its hydrolysis and resulting in a 60% release of liposomes. The bioavailability of nutraceuticals encapsulated in PC liposomes in the small intestine may be enhanced by the interactions of both non-hydrolysed and hydrolysed liposomes with bile salts and mucin.

(1) Vitamin D deficiency is associated with mortality in the general population and has been observed in one rheumatoid arthritis (RA) cohort. Here, we investigate the relationship between 25-hydroxyvitamin D (25(OH)D) levels before methotrexate (MTX) therapy initiation in patients with RA and the subsequent all-cause mortality in a national Veterans Affairs (VA) cohort. (2) This is a retrospective study on RA patients time-oriented around the initial MTX prescription and 25(OH)D levels before starting MTX. We examined survival in patients with 25(OH)D levels > 50 nmol/L and ≤50 nmol/L using the Cox Proportional Hazard Model and fully adjusted for risk factors. (3) In total, 15,109 RA patients were included in the nationwide cohort. RA patients with 25(OH)D levels > 50 nmol/L before starting MTX had a 28% reduced risk of mortality when compared to those with levels ≤ 50 nmol/L (HR: 0.72, CI: 0.64-0.80, p < 0.001) after adjusting for traditional risk factors. (4) In this national RA cohort receiving standard-of-care MTX, patients with 25(OH)D levels > 50 nmol/L have a lower subsequent mortality when compared to those with 25(OH)D levels ≤ 50 nmol/L. It remains to be determined whether increasing Vitamin D levels in RA patients initially found to be Vitamin D deficient impacts their all-cause mortality.

Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.

In the last few years, vitamin D functions have been studied progressively, and along with their main role in regulating calcium homeostasis, the potential function in the nervous system and the link between different psychiatric disorders and vitamin D deficiency have been revealed. The discovery of vitamin D receptors in multiple brain structures, like the hippocampus, led to the hypothesis that vitamin D deficiency could be responsible for treatment resistance in psychiatric diseases. The aim of this study was to analyze the current knowledge in the literature regarding vitamin D deficiency among individuals afflicted with psychiatric disorders and assess the potential therapeutic benefits of vitamin D supplementation. A systematic search was conducted on the PubMed database for articles published in the last five years (2016-2022) in English, focusing on human subjects. Results show that vitamin D deficiency has implications for numerous psychiatric disorders, affecting mood and behavior through its influence on neurotransmitter release, neurotrophic factors, and neuroprotection. It also plays a role in modulating inflammation, which is often elevated in psychiatric disorders. In conclusion, vitamin D deficiency is prevalent and has far-reaching implications for mental health. This review underscores the importance of exploring the therapeutic potential of vitamin D supplementation in individuals with psychiatric disorders and highlights the need for further research in this complex field.

The global prevalence of dental caries in deciduous teeth remains a significant health concern, affecting almost 70% of children by the age of six in specific regions. This systematic review aspired to methodically investigate the association between vitamin D levels and susceptibility to caries in children's deciduous teeth. A detailed search, guided by the PRISMA and PROSPERO guidelines, was conducted across three prominent electronic databases: PubMed, Web of Science, and Scopus, culminating in August 2023. The search integrated various keywords related to vitamin D and dental caries in primary dentition, yielding an initial pool of 1678 articles. After meticulous scrutiny, seven studies with a total of 7655 participants were deemed suitable for inclusion. The studies represented diverse geographical regions, showcasing varied vitamin D levels and sun exposure. Patient habits like brushing frequency, dental visits, and vitamin consumption also varied across studies. The analysis pinpointed vitamin D deficiency as a potential risk factor in some of the studies, with Odds Ratios (OR) ranging from 0.68 to 2.15. Statistically significant associations between vitamin D deficiency and caries susceptibility were documented in three studies (ORs of 2.15, 1.98, and 1.70). This comprehensive review elucidates the complex relationship between vitamin D levels and dental caries in children's deciduous teeth. While some studies spotlight vitamin D's pivotal role in dental health, inconsistencies across studies and regional differences necessitate more in-depth, globally representative investigations. Ensuring optimal vitamin D levels may play an integral role in dental health strategies. However, it is important to highlight that the roles of these studied factors might differ in deciduous teeth compared to permanent teeth.

Osteoporosis is a prevalent bone disorder characterized by low bone mineral density (BMD) and deteriorated bone microarchitecture, leading to an increased risk of fractures. Vitamin D (VD), an essential nutrient for skeletal health, plays a vital role in maintaining bone homeostasis. The biological effects of VD are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that regulates the transcription of target genes involved in calcium and phosphate metabolism, bone mineralization, and bone remodeling. In this review article, we conduct a thorough literature search of the PubMed and EMBASE databases, spanning from January 2000 to September 2023. Utilizing the keywords "vitamin D," "vitamin D receptor," "osteoporosis," and "therapy," we aim to provide an exhaustive overview of the role of the VD/VDR system in osteoporosis pathogenesis, highlighting the most recent findings in this field. We explore the molecular mechanisms underlying VDR's effects on bone cells, including osteoblasts and osteoclasts, and discuss the impact of VDR polymorphisms on BMD and fracture risk. Additionally, we examine the interplay between VDR and other factors, such as hormonal regulation, genetic variants, and epigenetic modifications, that contribute to osteoporosis susceptibility. The therapeutic implications of targeting the VDR pathway for osteoporosis management are also discussed. By bringing together these diverse aspects, this review enhances our understanding of the VD/VDR system's critical role in the pathogenesis of osteoporosis and highlights its significance as a potential therapeutic target.

We aimed to study the vitamin D status of the population of Arkhangelsk, a city in northwestern Russia.

A cross-sectional study was conducted to estimate serum 25(OH)D concentrations in Arkhangelsk residents, including 55 neonates and their mothers, 214 children <3 years, 191 schoolchildren (7-8 years), 403 adolescents (13-17 years), 260 university students (18-22 years) and 85 adults (24-60 years). The data were collected from March 2013 to November 2014 and from January 2016 to May 2016.

Normal levels of 25(OH)D (>30 ng/ml) were found in 5% of neonates, 43% of their mothers, 43% of children <3 years, 9% of schoolchildren, 1% of adolescents, 17% of students and 26% of adults. There was a moderate positive correlation (rs = 0.563, p = 0.001) between 25(OH)D levels in mother's blood and umbilical cord blood.

Vitamin D deficiency is highly prevalent in the population of Arkhangelsk, particularly in neonates, schoolchildren and adolescents.

Previous studies have documented vitamin D imbalance in dogs with acute pancreatitis (AP), but no studies have investigated serum vitamin D receptor (VDR) and vitamin D-binding protein (VDBP) concentrations.

Compare serum 25-hydroxyvitamin D (25[OH]D), VDR, and VDBP concentrations in healthy dogs and dogs with AP and identify correlations between these concentrations with ionized calcium, C-reactive protein (CRP), and canine-specific pancreatic lipase (Spec cPL) concentrations.

Twenty-two dogs with AP and 20 healthy control dogs.

Prospective cross-sectional study. Serum 25(OH)D concentrations were measured using a chemiluminescence immunoassay, and VDR and VDBP concentrations were measured using a ELISA kit designed for dogs.

Serum concentrations of 25(OH)D were lower in dogs with AP (mean ± SD, 66.1 ± 39.2 ng/mL) than in controls (96.8 ± 30.4 ng/mL; P = .01), and VDR concentrations were lower in dogs with AP (5.3 ± 3.5 ng/mL) than in controls (7.4 ± 2.5 ng/mL; P = .03). No difference was observed in serum VDBP concentrations between the groups. Serum VDR concentrations differed between survivors (median [interquartile range] = 6.6 [4.3-8.2] ng/mL) and nonsurvivors (2.7 [0.5-3.5] ng/mL; P = .01). Negative correlations were observed among serum VDR, CRP (rs  = -0.55), and Spec cPL (rs  = -0.47) concentrations in dogs with AP.

Dogs with AP had lower serum 25(OH)D and VDR concentrations than controls. Additionally, our study suggests a potential role of VDR expression in the inflammatory process of AP in dogs.

Vitamin D deficiency or insufficiency is prevalent in childhood cancer patients and survivors after chemotherapy; further studies are needed to investigate the underlying aetiology and effectiveness of vitamin D supplementation in preventing chemotherapy-induced bone loss. This study used a rat model of treatment with antimetabolite methotrexate to investigate whether methotrexate chemotherapy causes vitamin D deficiency and if vitamin D supplementation attenuates the resultant bone loss. Methotrexate treatment (five daily injections) decreased serum vitamin D levels (from 52 to <30 ng/mL), reduced body and bone lengthening and tibial trabecular bone volume, and altered intestinal vitamin D metabolism, which was associated with intestinal mucosal damage known to cause malabsorption of nutrients, including dietary vitamin D and calcium. During the early stage after chemotherapy, mRNA expression increased for vitamin D activation enzyme CYP27B1 and for calcium-binding protein TRPV6 in the intestine. During the intestinal healing stage, expression of vitamin D catabolism enzyme CYP24 increased, and that of TRPV6 was normalised. Furthermore, subcutaneous calcitriol supplementation diminished methotrexate-induced bone loss due to its effect suppressing methotrexate-induced increased bone resorption. Thus, in young rats, methotrexate chemotherapy causes vitamin D deficiency, growth impairments, bone loss, and altered intestinal vitamin D metabolism, which are associated with intestinal damage, and vitamin D supplementation inhibits methotrexate-induced bone loss.

Following two requests from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin D and to propose a conversion factor (CF) for calcidiol monohydrate into vitamin D3 for labelling purposes. Vitamin D refers to ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), and calcidiol monohydrate. Systematic reviews of the literature were conducted to assess the relative bioavailability of calcidiol monohydrate versus vitamin D3 on serum 25(OH)D concentrations, and for priority adverse health effects of excess vitamin D intake, namely persistent hypercalcaemia/hypercalciuria and endpoints related to musculoskeletal health (i.e. falls, bone fractures, bone mass/density and indices thereof). Based on the available evidence, the Panel proposes a CF for calcidiol monohydrates of 2.5 for labelling purposes. Persistent hypercalciuria, which may be an earlier sign of excess vitamin D than persistent hypercalcaemia, is selected as the critical endpoint on which to base the UL for vitamin D. A lowest-observed-adverse-effect-level (LOAEL) of 250 μg/day is identified from two randomised controlled trials in humans, to which an uncertainty factor of 2.5 is applied to account for the absence of a no-observed-adverse-effect-level (NOAEL). A UL of 100 μg vitamin D equivalents (VDE)/day is established for adults (including pregnant and lactating women) and for adolescents aged 11-17 years, as there is no reason to believe that adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults. For children aged 1-10 years, a UL of 50 μg VDE/day is established by considering their smaller body size. Based on available intake data, European populations are unlikely to exceed the UL, except for regular users of food supplements containing high doses of vitamin D.

Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. This review examines the role of the gut microbiome in IBD and discusses how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia as the primary clinical symptom. The production and accumulation of aggregated β-amyloid (Aβ) in patient brain tissues is one of the hallmarks of AD pathogenesis. Microglia, brain-resident macrophages, produce inflammatory cytokines in response to Aβ oligomers or fibrils exacerbating Aβ pathology in AD. HMO6 cells were treated with Aβ42 in the presence or absence of 1,25-dihydroxy vitamin D₃ (1,25(OH)₂D₃) to determine its potential immunomodulatory effects, and the expression of pro-/anti-inflammatory cytokines, M1/M2-associated markers, Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 2 (TREM2) was examined. 1,25(OH)₂D₃ was found to suppress Aβ-induced expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), M1 markers (CD86 and iNOS), and TLR2/4, whilst increasing the expression of anti-inflammatory cytokines (IL-4, IL-10, and CCL17) and M2 markers (CD206 and Arg-1). Furthermore, 1,25(OH)₂D₃ promoted TREM2 expression and Aβ uptake by HMO6 cells, and the enhancement of Aβ uptake and M2 polarization was revealed to be TREM2-dependent. The findings of this study suggest that 1,25(OH)₂D₃ facilitates M2 polarization and Aβ uptake in a TREM2-dependent manner.

1,25-Dihydroxyvitamin D3 (1,25(OH)₂D₃), the hormonally active form of vitamin D, activates the nuclear vitamin D receptor (VDR) to mediate the transcription of target genes involved in calcium homeostasis as well as in non-classical 1,25(OH)₂D₃ actions. In this study, CARM1, an arginine methyltransferase, was found to mediate coactivator synergy in the presence of GRIP1 (a primary coactivator) and to cooperate with G9a, a lysine methyltransferase, in 1,25(OH)₂D₃ induced transcription of Cyp24a1 (the gene involved in the metabolic inactivation of 1,25(OH)₂D₃). In mouse proximal renal tubule (MPCT) cells and in mouse kidney, chromatin immunoprecipitation analysis demonstrated that dimethylation of histone H3 at arginine 17, which is mediated by CARM1, occurs at Cyp24a1 vitamin D response elements in a 1,25(OH)₂D₃ dependent manner. Treatment with TBBD, an inhibitor of CARM1, repressed 1,25(OH)₂D₃ induced Cyp24a1 expression in MPCT cells, further suggesting that CARM1 is a significant coactivator of 1,25(OH)₂D₃ induction of renal Cyp24a1 expression. CARM1 was found to act as a repressor of second messenger-mediated induction of the transcription of CYP27B1 (involved in the synthesis of 1,25(OH)₂D₃), supporting the role of CARM1 as a dual function coregulator. Our findings indicate a key role for CARM1 in the regulation of the biological function of 1,25(OH)₂D₃.

Vitamin D signaling is important in regulating calcium homeostasis essential for bone health but also displays other functions in cells of several tissues. Disturbed vitamin D signaling is linked to a large number of diseases. The multiple cytochrome P450 (CYP) enzymes catalyzing the different hydroxylations in bioactivation of vitamin D₃ are crucial for vitamin D signaling and function. This review is focused on the progress achieved in identification of the bioactivating enzymes and their genes in production of 1α,25-dihydroxyvitamin D₃ and other active metabolites. Results obtained on species- and tissue-specific expression, catalytic reactions, substrate specificity, enzyme kinetics, and consequences of gene mutations are evaluated. Matters of incomplete understanding regarding the physiological roles of some vitamin D hydroxylases are critically discussed and the authors will give their view of the importance of each enzyme for vitamin D signaling. Roles of different vitamin D receptors and an alternative bioactivation pathway, leading to 20-hydroxylated vitamin D₃ metabolites, are also discussed. Considerable progress has been achieved in knowledge of the vitamin D₃ bioactivating enzymes. Nevertheless, several intriguing areas deserve further attention to understand the pleiotropic and diverse activities elicited by vitamin D signaling and the mechanisms of enzymatic activation necessary for vitamin D-induced responses.

Osteogenesis Imperfecta (OI) is a heterogeneous group of inherited skeletal dysplasias characterized by bone fragility. The study of bone metabolism, in these disease, is problematic in terms of clinical and genetic variability. The aims of our study were to evaluate the importance of Vitamin D levels in OI bone metabolism, reviewing studies performed on this topic and providing advice reflecting our experience using vitamin D supplementation. A comprehensive review on all English-language articles was conducted in order to analyze the influence of vitamin D in OI bone metabolism in pediatric patients. Reviewing the studies, contradictory data were found on the relationship between 25OH vitamin D levels and bone parameters in OI, and in several studies the baseline levels of 25OH D were below the threshold value of 75 nmol/L. In conclusion, according to the literature and to our experience, we highlight the importance of adequate vitamin D supplementation in children with OI.

Vitamin D, its importance in different processes taking place in the human body, the effects of abnormal levels of this hormone, either too low or too high, and the need for supplementation have been extensively researched thus far. Variances in exposure to sunlight can cause vitamin D levels to fluctuate. Indoor activity can be a factor for these fluctuations and can lead to a decrease in vitamin D levels. We conducted a systematic review and meta-analysis aiming to identify whether indoor compared to outdoor training has a significant influence on vitamin D levels; we also performed subgroup analyses and multivariate meta-regression. The type of training has an impact on vitamin D levels that is influenced by multiple cofounders. In a subgroup analysis not considering cofounders, the mean serum vitamin D was 3.73 ng/mL higher in outdoor athletes, a difference which barely fails to achieve significance (p = 0.052, a total sample size of 5150). The indoor-outdoor difference is only significant (clinically and statistically) when considering studies performed exclusively on Asian athletes (a mean difference of 9.85 ng/mL, p < 0.01, and a total sample size of 303). When performing the analyses within each season, no significant differences are observed between indoor and outdoor athletes. To control for multiple cofounders (the season, latitude, and Asian/Caucasian race) simultaneously, we constructed a multivariate meta-regression model, which estimated a serum vitamin D concentration lower by 4.446 ng/mL in indoor athletes. While a multivariate model suggests that outdoor training is associated with slightly higher vitamin D concentrations when controlling for the season, latitude, and Asian/Caucasian race, the type of training has a numerically and clinically small impact. This suggests that vitamin D levels and the need for supplementation should not be decided based on training type alone.