Search Results (30)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the etiologic agent that causes the coronavirus disease (COVID-19) identified in Wuhan, in 2019. Men are more prone to developing severe manifestations than women, suggesting a possible crucial role of sex hormones. 17,β-Estradiol (E2) and 1,25 α dihydroxyvitamin D₃ (calcitriol) act upon gene pathways as immunomodulators in several infectious respiratory diseases. In this study, we aimed to evaluate the influence of E2 and calcitriol on the VSV-based pseudovirus SARS-CoV-2 and SARS-CoV-2 infection in vitro. We infected Vero E6 cells with the recombinant VSV-based pseudovirus SARS-CoV-2 and the SARS-CoV-2 viruses according to the pre-treatment and pre–post-treatment models. The Angiotensin-Converting Enzyme 2 (ACE2) and Vitamin D Receptor (VDR) gene expression did not change under different treatments. The VSV-based pseudovirus SARS-CoV-2 infection showed a significant decrease in the focus-forming unit count in the presence of E2 and calcitriol (either alone or in combination) in the pre-treatment model, while in the pre–post-treatment model, the infection was inhibited only in the presence of E2. Th SARS-CoV-2 infection highlighted a decrease in viral titres in the presence of E2 and calcitriol only in the pre–post-treatment model. 17,β-Estradiol and calcitriol can exert an inhibitory effect on SARS-CoV-2 infections, demonstrating their protective role against viral infections. Full article

Osteogenesis imperfecta (OI) is a rare bone dysplasia that occurs with a frequency of 1/15,000–20,000 live births. It is characterized by increased susceptibility of bone fractures, skeletal deformities, low stature, and low bone mass. It results in impaired production of type I collagen. About 90% of people with OI have heterozygous mutations in the COL1A1 and COL1A2 genes. Fibroblast growth factor 23 (FGF23) is a protein involved in the regulation of phosphate and 1,25-dihydroxyvitamin D₃ metabolism on a negative feedback basis. FGF23 is secreted by osteocytes in response to increased serum calcitriol and phosphorus. The purpose of this study was to evaluate the concentration of FGF23 among children with osteogenesis imperfecta and the differences in reference values in a healthy population of children and adolescents. Then, this study sought to evaluate how the course of osteogenesis imperfecta, including type of disease, number of bone fractures, and bone mineral density, are related to FGF23 concentration. The study included 47 children aged 3 to 17 years with a diagnosis of osteogenesis imperfecta, confirmed by genetic tests. The patients were hospitalized at the Department from August 2019 to September 2020 and were treated with intravenous infusions of sodium pamidronate. The course of the disease was analyzed, including the number of bone fractures, clinical symptoms, and anthropometric parameters, and bone densitometry was performed by dual X-ray absorptiometry (DXA) in Total Body Less Head (TBLH) and Spine options with Z-score evaluation. FGF23 concentration was determined by the ELISA method. The study was prospective in nature. Results: The mean level of FGF23 in the study group of patients was 645.09 pg/mL and was within the reference values for the developmental age population. There was no significant correlation between FGF23 concentration and anthropometric measurements: body weight (p = 0.267), height (p = 0.429), gender (p = 0.291), or pubertal stage (p = 0.223) in the study group of patients. FGF23 levels were not related to the number of fractures (p = 0.749), the number of sodium pamidronate cycles administered (p = 0.580), bone mineral density parameters (Z-score), the form of osteogenesis imperfecta (p = 0.156), or the genetic test result (p = 0.573). FGF23 levels decrease with age (r = −0.32, p = 0.030) and BMI (r = −0.34, p = 0.020). The level of FGF23 in patients with osteogenesis imperfecta is lower among older children and those having a higher BMI. This index cannot be a diagnostic tool in this group of patients, for no differences were found between the concentrations in patients with osteogenesis imperfecta and the developmental age population. Full article

There is evidence that calcitriol is the only biologically active vitamin D metabolite. This review summarizes data on the regulation of renal and extrarenal synthesis of calcitriol by nutritional, physiologic, mechanical, genetic, and disease-related factors. Relatively low circulating calcitriol due to low substrate availability, i.e., low circulating 25-hydroxyvitamin D, has been reported in nutritional rickets, osteomalacia, obesity, and preeclampsia. In these situations, vitamin D supplementation can increase circulating calcitriol and, together with calcium, prevent rickets/osteomalacia and reduce the risk of preeclampsia and obesity-related type 2 diabetes mellitus. However, the correction of low circulating calcitriol due to mechanical unloading/immobilization by vitamin D supplementation is not effective in preventing osteoporotic fractures. Circulating calcitriol is also low in diseases such as cardiac and renal failure. Both illnesses share some other similarities regarding dysregulated calcium/phosphate metabolism, including elevated parathyroid hormone and fibroblast growth factor-23, suggesting similar treatment strategies. Genetic disorders of vitamin D metabolism are rare and can affect circulating calcitriol differently. Calcitriol synthesis in immune cells is obviously not primarily dependent on circulating 25-hydroxyvitamin D, which challenges the use of vitamin D for infection prevention. Since various factors can differently influence calcitriol regulation, more personalized preventive/therapeutic strategies of targeting calcitriol synthesis are necessary. Full article

Vitamin D is a sterol prohormone with no intrinsic biological activity. Calcitriol, the active form of vitamin D, is synthesized in the kidneys. It has well-known pleiotropic and cytoprotective properties. In addition to regulating parathyroid hormone secretion and enhancing gut calcium absorption, it exhibits antioxidant, anti-inflammatory, antiproliferative, and antineoplastic effects. However, the role of vitamin D in AKI is unclear, unlike in CKD. Thus, this review aimed to understand how dysregulated vitamin D homeostasis occurs in AKI, as well as to explore how vitamin D deficiency and excess influence AKI. A comprehensive literature search was conducted between January 2000 and June 2024 to uncover relevant works detailing vitamin D homeostasis in health as well as investigating the impact of vitamin D deficiency and excess in humans, animals, and in vitro cell models of AKI. According to the findings of this review, vitamin D appears to have a reciprocal relationship with AKI. Acute renal injury, among other factors, can cause hypo- or hypervitaminosis D. Conversely, AKI can also be caused by vitamin D deficiency and toxicity. Even though hypovitaminosis D is associated with AKI, it is uncertain how it impacts AKI outcomes in distinct clinical scenarios. Newer therapeutic options might emerge as a result of understanding these challenges. Vitamin D supplementation may ameliorate renal injury but needs further validation. Furthermore, hypervitaminosis D has also been implicated in AKI by causing hypercalcemia and hyperphosphatemia. It is crucial to avoid prolonged, uncontrolled, and unsupervised supraphysiological vitamin D administration, especially intramuscular injection. Full article

Vitamin D toxicosis poses a health threat to dogs, with cases often stemming from cholecalciferol rodenticide ingestion. This case report investigates two clinical cases of canine cholecalciferol toxicosis, shedding light on the persistent elevation of 25-hydroxyvitamin D (25(OH)D) and the adaptive response of 24,25-dihydroxyvitamin D (24,25(OH)₂D). Serum samples from affected dogs were analyzed over several months, revealing sustained increases in 25(OH)D concentrations. Notably, concurrent measurements of 24,25(OH)₂D unveiled a marked elevation, suggesting a compensatory mechanism to mitigate calcitriol excess and hypercalcemia. These findings highlight the potential role of upregulating 24-hydroxylase activity as a therapeutic target for managing cholecalciferol toxicosis. These cases underscore the importance of understanding vitamin D metabolism in canine toxicology and prompt further exploration into novel treatment strategies and other research areas. Full article

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. Full article

Clinical and preclinical studies have provided conflicting data on the postulated beneficial effects of vitamin D in patients with prostate cancer. In this opinion piece, we discuss reasons for discrepancies between preclinical and clinical vitamin D studies. Different criteria have been used as evidence for the key roles of vitamin D. Clinical studies report integrative cancer outcome criteria such as incidence and mortality in relation to vitamin D status over time. In contrast, preclinical vitamin D studies report molecular and cellular changes resulting from treatment with the biologically active vitamin D metabolite, 1,25-dihydroxyvitamin D₃ (calcitriol) in tissues. However, these reported changes in preclinical in vitro studies are often the result of treatment with biologically irrelevant high calcitriol concentrations. In typical experiments, the used calcitriol concentrations exceed the calcitriol concentrations in normal and malignant prostate tissue by 100 to 1000 times. This raises reasonable concerns regarding the postulated biological effects and mechanisms of these preclinical vitamin D approaches in relation to clinical relevance. This is not restricted to prostate cancer, as detailed data regarding the tissue-specific concentrations of vitamin D metabolites are currently lacking. The application of unnaturally high concentrations of calcitriol in preclinical studies appears to be a major reason why the results of preclinical in vitro studies hardly match up with outcomes of vitamin D-related clinical studies. Regarding future studies addressing these concerns, we suggest establishing reference ranges of tissue-specific vitamin D metabolites within various cancer entities, carrying out model studies on human cancer cells and patient-derived organoids with biologically relevant calcitriol concentrations, and lastly improving the design of vitamin D clinical trials where results from preclinical studies guide the protocols and endpoints within these trials. Full article

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro. Full article

Sphingolipids (SLs) are structural, bioactive molecules with several key cellular roles, whereas 1,25-dihydroxyvitamin D (1,25(OH)D), the active form of vitamin D, is considered the major regulator of calcium homeostasis, although it also exerts other extraskeletal effects. Many studies reported the physiological connection between vitamin D and SLs, highlighting not only the effects of vitamin D on SL metabolism and signaling but also the influence of SLs on vitamin D levels and function, thus strongly suggesting a crosstalk between these molecules. After a brief description of 1,25(OH)D and SL metabolism, this review aims to discuss the preclinical and clinical evidence on the crosstalk between SLs and 1,25(OH)D, with a special focus on cardiometabolic diseases. Full article

Both 25-autoimmunity and(25(OH)D: calcifediol) and its active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D: calcitriol), play critical roles in protecting humans from invasive pathogens, reducing risks of autoimmunity, and maintaining health. Conversely, low 25(OH)D status increases susceptibility to infections and developing autoimmunity. This systematic review examines vitamin D’s mechanisms and effects on enhancing innate and acquired immunity against microbes and preventing autoimmunity. The study evaluated the quality of evidence regarding biology, physiology, and aspects of human health on vitamin D related to infections and autoimmunity in peer-reviewed journal articles published in English. The search and analyses followed PRISMA guidelines. Data strongly suggested that maintaining serum 25(OH)D concentrations of more than 50 ng/mL is associated with significant risk reduction from viral and bacterial infections, sepsis, and autoimmunity. Most adequately powered, well-designed, randomized controlled trials with sufficient duration supported substantial benefits of vitamin D. Virtually all studies that failed to conclude benefits or were ambiguous had major study design errors. Treatment of vitamin D deficiency costs less than 0.01% of the cost of investigation of worsening comorbidities associated with hypovitaminosis D. Despite cost-benefits, the prevalence of vitamin D deficiency remains high worldwide. This was clear among those who died from COVID-19 in 2020/21—most had severe vitamin D deficiency. Yet, the lack of direction from health agencies and insurance companies on using vitamin D as an adjunct therapy is astonishing. Data confirmed that keeping an individual’s serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) (and above 40 ng/mL in the population) reduces risks from community outbreaks, sepsis, and autoimmune disorders. Maintaining such concentrations in 97.5% of people is achievable through daily safe sun exposure (except in countries far from the equator during winter) or taking between 5000 and 8000 IU vitamin D supplements daily (average dose, for non-obese adults, ~70 to 90 IU/kg body weight). Those with gastrointestinal malabsorption, obesity, or on medications that increase the catabolism of vitamin D and a few other specific disorders require much higher intake. This systematic review evaluates non-classical actions of vitamin D, with particular emphasis on infection and autoimmunity related to the immune system. Full article

In previous publications, we pointed out the importance of mannosylation of fibrinogen for the development of cardiovascular complications and fucosylation as a predictor of peritoneal membrane dysfunction in patients on peritoneal dialysis (PD). After a follow-up period of 30 months from the onset of the COVID-19 pandemic, we evaluated the significance of 1,25-dihydroxyvitamin D₃ (calcitriol) therapy, primary disease, biochemical and hematologic analyzes, and previously performed glycan analysis by lectin-based microarray as predictors of mortality in this patient group. After univariate Cox regression analysis, diabetes mellitus (DM) and calcitriol therapy were found to be potential predictors of mortality. Additional multivariate Cox regression analysis confirmed that only DM was a predictor of mortality. Nevertheless, the use of calcitriol in therapy significantly reduced mortality in this patient group, as shown by the Kaplan–Meier survival curve. The presence of DM as a concomitant disease proved to be a strong predictor of fatal outcome in PD patients infected with SARS-CoV-2. This is the first study to indicate the importance and beneficial effect of calcitriol therapy on survival in PD patients with COVID-19 infection. In addition, this study points to the possibility that adverse thrombogenic events observed in PD patients during the pandemic may be caused by aberrant fibrinogen glycosylation. Full article

Ischemic stroke is one of the major causes of death and permanent disability worldwide. The only efficient treatment to date is anticoagulant therapy and thrombectomy, which enable restitution of blood flow to ischemic tissues. Numerous promising neuroprotectants have failed in clinical trials. Given the complex pathomechanism of stroke, a multitarget pharmacotherapy seems a more rational approach in stroke prevention and treatment than drugs acting on single molecular targets. Recently, vitamin D3 has emerged as a potential treatment adjunct for ischemic stroke, as it interferes with the key prosurvival pathways and shows neuroprotective, anti-inflammatory, regenerative and anti-aging properties in both neuronal and vascular tissue. Moreover, the stimulatory effect of vitamin D3 on brain-derived neurotrophic factor (BDNF) signaling and neuroplasticity may play a role not only in the recovery of neurological functions, but also in ameliorating post-stroke depression and anxiety. This narrative review presents advances in research on the biochemical mechanisms of stroke-related brain damage, and the genomic and non-genomic effects of vitamin D3 which may interfere with diverse cell death signaling pathways. Next, we discuss the results of in vitro and in vivo experimental studies on the neuroprotective potential of 1alpha,25-dihydroxyvitamin D3 (calcitriol) in brain ischemia models. Finally, the outcomes of clinical trials on vitamin D3 efficiency in ischemic stroke patients are briefly reviewed. Despite the mixed results of the clinical trials, it appears that vitamin D3 still holds promise in preventing or ameliorating neurological and psychiatric consequences of ischemic stroke and certainly deserves further study. Full article

Vitamin D intervenes in calcium and phosphate metabolism and bone homeostasis. Experimental studies have shown that 1,25-dihydroxyvitamin D (calcitriol) generates immunologic activities on the innate and adaptive immune system and endothelial membrane stability. Low levels of serum 25-hydroxyvitamin D (25(OH)D) are associated with an increased risk of developing immune-related diseases such as psoriasis, type 1 diabetes, multiple sclerosis, and autoimmune diseases. Various clinical trials describe the efficacy of supplementation of vitamin D and its metabolites for treating these diseases that result in variable outcomes. Different disease outcomes are observed in treatment with vitamin D as high inter-individual difference is present with complex gene expression in human peripheral blood mononuclear cells. However, it is still not fully known what level of serum 25(OH)D is needed. The current recommendation is to increase vitamin D intake and have enough sunlight exposure to have serum 25(OH)D at a level of 30 ng/mL (75 nmol/L) and better at 40–60 ng/mL (100–150 nmol/L) to obtain the optimal health benefits of vitamin D. Full article

The association between vitamin D deficiency and especially critical shortage of active vitamin D (1,25-dihydroxyvitamin D, calcitriol) with the development of secondary hyperparathyroidism (sHPT) is a well-known fact in patients with chronic kidney disease (CKD). The association between sHPT and important clinical outcomes, such as kidney disease progression, fractures, cardiovascular events, and mortality, has turned the prevention and the control of HPT into a core issue of patients with CKD and on dialysis. However, vitamin D therapy entails the risk of unwanted side effects, such as hypercalcemia and hyperphosphatemia. This review summarizes the developments of vitamin D therapies in CKD patients of the last decades, from calcitriol substitution to extended-release calcifediol. In view of the study situation for vitamin D insufficiency and sHPT in CKD patients, we conclude that the nephrology community has to solve three core issues: (1) What is the optimal parathyroid hormone (PTH) target level for CKD and dialysis patients? (2) What is the optimal vitamin D level to support optimal PTH titration? (3) How can sHPT treatment support reduction in the occurrence of hard renal and cardiovascular events in CKD and dialysis patients? Full article

Pathogenic mutations of CYP24A1 lead to an impaired catabolism of vitamin D metabolites and should be considered in the differential diagnosis of hypercalcemia with low parathyroid hormone concentrations. Diagnosis is based on a reduced 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D ratio and confirmed by genetic analyses. Pregnancy is associated with an upregulation of the active vitamin D hormone calcitriol and may thus particularly trigger hypercalcemia in affected patients. We present a case report and a narrative review of pregnant women with CYP24A1 mutations (13 women with 29 pregnancies) outlining the laboratory and clinical characteristics during pregnancy and postpartum and the applied treatment approaches. In general, pregnancy triggered hypercalcemia in the affected women and obstetric complications were frequently reported. Conclusions on drugs to treat hypercalcemia during pregnancy are extremely limited and do not show clear evidence of efficacy. Strictly avoiding vitamin D supplementation seems to be effective in preventing or reducing the degree of hypercalcemia. Our case of a 24-year-old woman who presented with hypercalcemia in the 24th gestational week delivered a healthy baby and hypercalcemia resolved while breastfeeding. Pathogenic mutations of CYP24A1 mutations are rare but should be considered in the context of vitamin D supplementation during pregnancy. Full article