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This study aimed to evaluate the effects of acute and chronic intake of different doses of vitamin D3 on seizure responses and cognitive impairment induced by pentylenetetrazole (PTZ) in immature male rats. Sixty-six immature male NMRI rats were divided into control (10), epileptic (10), and treatment groups (46). The stage 5 latency (S5L) and stage 5 duration (S5D) were assessed along with the shuttle box test. Levels of antioxidant enzymes and inflammatory factors along with genes involved in inflammation, oxidative damage, apoptosis, and mTORc1 were measured in the hippocampus tissue of the brain of controlled and treated rats. Serum levels of parathyroid hormone (PTH), vitamin D, calcium, and phosphorus were also assessed. The results showed that the ability to learn, memory consolidation, and memory retention in epileptic rats were reduced. In addition, S5D increased and S5L decreased in epileptic rats, while being effectively ameliorated by chronic and acute vitamin D intake. The results showed that vitamin D in different doses acutely and chronically decreased the levels of oxidative and inflammatory biomarkers in hippocampus tissue and inhibited the expression of genes involved in inflammation, oxidative damage, apoptosis, and mTORc1 in the hippocampus tissue of epileptic rats. The results showed that vitamin D in different doses acutely and chronically could improve cognitive impairments and convulsive responses in epileptic rats by improving neurotransmission, inflammation, apoptosis, and oxidative damage.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25D3), regulates a number of physiological and pathological processes, including cell proliferation and differentiation. Thousands of analogues of 1,25D3 have been developed with the aim of selective effects for medical use. Here we describe the synthesis of two new unconventional vitamin D analogues bearing A-ring modifications with ortho-carborane (dicarba-o-closo-1,2-dodecaborane) units. The ligands function as agonists for VDR with similar antiproliferative activities as 1,25D3. Whereas mice treated with the analogues 4 and 5 exhibited similar hypercalcemic activities as 1,25D3, only compound 4 and 1,25D3 induced the strong activation of CYP24A1 mRNA expression but not compound 5.

Vitamin D 3 (VD 3 ) participated widely in the nuclear factor-κB (NF-κB)-mediated inflammation, apoptosis, and autophagy through the vitamin D receptor (VDR). However, the molecular mechanisms remain not understood in teleost. The present study investigated the functions of VD 3 /VDR on intestinal inflammation, autophagy, and apoptosis of turbot in vivo and in vitro . Triple replicates of 30 fish were fed with each of three diets with graded levels of 32.0 (D 0 ), 1012.6 (D 1 ), and 3978.2 (D 2 ) IU/kg VD 3 . Obvious intestinal enteritis was observed in the D 0 group and followed with dysfunction of intestinal mucosal barriers. The intestinal inflammatory response induced by VD 3 deficiency was regulated by the NF-κB/inflammasome signalling. The promotion of intestinal apoptosis and suppression of intestinal autophagy were also observed in the D 0 group. Similarly, VD 3 deficiency in vitro induced more intense inflammation regulated by NF-κB/inflammasome signalling. The mutually exclusive apoptosis and autophagy were also observed in the group without 1,25(OH) 2 D 3 in vitro , accompanied by similar changes in apoptosis and autophagy increased apoptosis. The gene expression of VDRs was significantly increased with the increasing VD 3 supplementation both in vivo and in vitro . Moreover, VDR knockdown in turbot resulted in intestinal inflammation, and this process relied on the activation of inflammasome mediated by NF-κB signalling. Simultaneously, intestinal apoptosis was promoted, whereas intestinal autophagy was inhibited. In conclusion, VD 3 deficiency could induce intestinal inflammation via activation of the NF-κB/inflammasome pathway, intestinal apoptosis, and autophagy formed a mutually exclusive relation in teleost. And VDR is the critical molecule in those processes.

Renal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D3 through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25‐dihydroxyvitamin D3 analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25‐dihydroxyvitamin D3 (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ)‐diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose‐mediated down‐regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose‐induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co‐localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down‐regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ‐diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN.

Recently it has been shown that vitamin D3 acting via its cognate receptor (VDR) regulates the growth, differentiation and function of female reproductive tissues including ovary. The aim of the study was to examine the effect of testosterone (T) and its antagonist 2-hydroxyflutamide (HF) on VDR protein expression and function in porcine ovarian follicles. Medium size antral follicles expressing great amount of androgen receptors and represent high steroidogenic activity were used in this research. After 6 h incubation of whole follicles with T, HF or T+HF, immunohistochemical analysis of VDR revealed its nuclear localization in granulosa and theca interna cells in control and experimental groups. The expression of VDR protein was shown as a band of 48 kDa. There were no significant differences between either experimental group and the control. T influenced the function of VDR through decreased formation of VDR/RXR (retinoid X receptor) complexes (P<0.05) in both granulosa and theca interna cells, but HF abolished this effect only in granulosa cells (P<0.05). These results suggest that androgens regulate the response of follicular cells to vitamin D3 in pigs ovary via regulation of VDR transcriptional activity.

The aim of this study was to investigate the combined effects of vitamin D3 supplementation and aerobic training on regulating the autophagy process in rats with type 2 diabetic induced by a high-fat diet and streptozotocin. A total of 40 Wistar rats were divided into five groups: normal control (NC), diabetic control (DC), diabetic + aerobic training (DAT), diabetic + vitamin D3 (DVD), and diabetic + aerobic training + vitamin D3 (DVDAT). The rats underwent eight weeks of aerobic training with an intensity of 60% maximum running speed for one hour, along with weekly subcutaneous injections of 10,000 units of vitamin D3. The protein levels of different autophagy markers were assessed in the left ventricular heart tissue. The results showed that the protein levels of AMPK, pAMPK, mTOR, and pmTOR were significantly lower in the DC group compared to the NC group. Conversely, the levels of ULK, Beclin-1, LC3II, Fyco, and Cathepsin D proteins were significantly higher in the DC group. However, the interventions of aerobic training and vitamin D3 supplementation, either individually or in combination, led to increased levels of AMPK, pAMPK, mTOR, and pmTOR, and decreased levels of ULK, Beclin-1, LC3II, Fyco, and Cathepsin D (p < 0.05). Additionally, the aerobic capacity in the DAT and DVDAT groups was significantly higher compared to the NC, DC, and DVD groups (p < 0.05). These findings suggest that type 2 diabetes is associated with excessive autophagy in the left ventricle. However, after eight weeks of vitamin D3 supplementation and aerobic training, a significant reduction in excessive autophagy was observed in rats with type 2 diabetes.

Novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2, for which there is no effective treatment except employing prevention strategies, has already instituted significant number of deaths. In this review, we provide a scientific view on the potential role of vitamin D in SARS-CoV-2 virus/COVID-19 disease. Vitamin D is well-known to play a significant role in maintaining the immune health of an individual. Moreover, it induces antimicrobial peptide expression that can decrease viral replication and regulate the levels of pro-inflammatory/anti-inflammatory cytokines. Therefore, supplementation of vitamin D has the potential to reduce the incidence, severity and the risk of death from pneumonia resulting from the cytokine storm of many viral infections including COVID-19. We suggest that supplementation of subjects at high risk of COVID-19 with vitamin D (1.000 to 3.000 IU) to maintain its optimum serum concentrations may be of significant benefit for both in the prevention and treatment of the COVID-19.

Background: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH) 2 D 3 -generating 25-hydroxyvitamin D 3 1-alpha-hydroxylase (Cyp27b1) by FGF23. Conversely, 1,25(OH) 2 D 3 stimulates, by activating the vitamin D 3 receptor (Vdr), the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH) 2 D 3 and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. Methods: mRNA levels were determined utilizing quantitative RT-PCR in human embryonic kidney cells (HEK293) or in renal tissues from mice without or with prior mineralocorticoid (aldosterone or DOCA) and/or spironolactone treatment. In HEK293 cells, protein levels were determined by western blotting. The experiments in HEK293 cells were performed without or with silencing of CYP27B1, of vitamin D 3 receptor (VDR) or of mineralocorticoid receptor (NR3C2). Results: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours) and mice (8 hours or 5 days). Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours). Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. Conclusion: Besides blocking the effects of aldosterone, spironolactone upregulates KLOTHO gene expression by upregulation of 25-hydroxyvitamin D 3 1-alpha-hydroxylase with subsequent activation of the vitamin D 3 receptor by 1,25(OH) 2 D 3 , an effect possibly independent from the mineralocorticoid receptor.

Exposure to sunlight is the major source of vitamin D and the main environmental cause of non-melanocytic skin cancers. Vitamin D, partly mediated through the vitamin D receptor (VDR), has potential therapeutic applications in skin cancer. The aim of this study was to investigate the association of BsmI and ApaI VDR polymorphisms among patients with non-melanoma cancers and controls. An observational case-control study was conducted in a sample of 154 subjects. We observed no significant effects between these polymorphisms and skin cancer risk. When stratified for gender, GG and AG BsmI polymorphisms significantly increased the risk of basal cell carcinomas in males. In relation to ApaI, all three polymorphisms significantly increased the risk of basal cell carcinoma in males. When stratified for age, we found that being 70 years of age or younger was a protective factor against both skin cancers. Being a female and 70 years old or younger was a protective factor for basal cell carcinoma. A comparison of the frequencies of the VDR genotypes in patients older than 70 years vs. 70 years or younger also revealed age-dependent variations in patients with non-melanoma skin cancer. Our study suggests a role for VDR polymorphisms in non-melanoma skin cancer development.

INTRODUCTION: CD28/T-cell receptor (TCR)/cytotoxic T-lymphocyte antigen 4 (CTLA4) complex controls T-cell tolerance and autoimmunity in Hashimoto’s thyroiditis (HT). In addition, CD45 protein tyrosine phosphatase (PTPase) and vitamin D receptor (VDR) cooperatively interact with the TCR complex to affect autoimmune processes central to the pathogenesis of HT. Nevertheless, their role in HT aetiology has been less well established. In this study, we aimed to explore mRNA expression levels of CTLA4, CD28, CD45, and VDR in T-cells, across different outcomes of HT. MATERIAL AND METHODS: The study included 45 HT patients and 13 euthyroid, healthy controls. T-lymphocytes were isolated from peripheral blood mononuclear cells, total mRNA was extracted from T-cells, and gene expression was studied by reverse transcription-polymerase chain reaction (RT-PCR) and ImageQuant method relative to glyceraldehyde-3-phosphate dehydrogenase RT-PCR products. RESULTS: Nominally higher expression levels of VDR, CTLA4, CD28, and CD45RAB mRNA were found in unsorted T-lymphocytes of healthy controls when compared to the HT patients. No difference was observed between hypothyroid/untreated, spontaneously euthyroid and LT4-treated HT patients. VDR mRNA expression was linked to both T3 levels and CTLA4 gene expression, whilst CD45RB mRNA expression coincided with CTLA4 and CD28 transcript levels. Conversely, older age and lower T3 levels were associated with increased abundance of CD45R0 isoform in HT patients. CONCLUSIONS: The results suggest a cross talk between endocrine and immune functions in HT pathology: an altered peripheral T cell mRNA profile with reduced VDR, CTLA4, CD28, and CD45RAB transcript levels is accompanied by age-related shift from naive to memory/late-differentiated T cell CD45R mRNA signature and associated with thyroid hormone status in the HT patients.