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1.
J Steroid Biochem Mol Biol ; 204: 105771, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33065275

RESUMO

Vitamin D may be a central biological determinant of COVID-19 outcomes. The objective of this quasi-experimental study was to determine whether bolus vitamin D3 supplementation taken during or just before COVID-19 was effective in improving survival among frail elderly nursing-home residents with COVID-19. Sixty-six residents with COVID-19 from a French nursing-home were included in this quasi-experimental study. The "Intervention group" was defined as those having received bolus vitamin D3 supplementation during COVID-19 or in the preceding month, and the "Comparator group" corresponded to all other participants. The primary and secondary outcomes were COVID-19 mortality and Ordinal Scale for Clinical Improvement (OSCI) score in acute phase, respectively. Age, gender, number of drugs daily taken, functional abilities, albuminemia, use of corticosteroids and/or hydroxychloroquine and/or antibiotics (i.e., azithromycin or rovamycin), and hospitalization for COVID-19 were used as potential confounders. The Intervention (n = 57; mean ± SD, 87.7 ± 9.3years; 79 %women) and Comparator (n = 9; mean, 87.4 ± 7.2years; 67 %women) groups were comparable at baseline, as were the COVID-19 severity and the use of dedicated COVID-19 drugs. The mean follow-up time was 36 ± 17 days. 82.5 % of participants in the Intervention group survived COVID-19, compared to only 44.4 % in the Comparator group (P = 0.023). The full-adjusted hazard ratio for mortality according to vitamin D3 supplementation was HR = 0.11 [95 %CI:0.03;0.48], P = 0.003. Kaplan-Meier distributions showed that Intervention group had longer survival time than Comparator group (log-rank P = 0.002). Finally, vitamin D3 supplementation was inversely associated with OSCI score for COVID-19 (ß=-3.84 [95 %CI:-6.07;-1.62], P = 0.001). In conclusion, bolus vitamin D3 supplementation during or just before COVID-19 was associated in frail elderly with less severe COVID-19 and better survival rate.


Assuntos
Colecalciferol/administração & dosagem , Infecções por Coronavirus/genética , Pneumonia Viral/genética , Vitamina D/genética , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Vitamina D/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(40): 24986-24997, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958661

RESUMO

It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.


Assuntos
Inflamação/genética , Receptores de Calcitriol/genética , Linfócitos T/imunologia , Animais , Regulação da Expressão Gênica/genética , Humanos , Inflamação/imunologia , Camundongos , Polimorfismo Genético , Linfócitos T/metabolismo , Vitamina D/genética , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/imunologia
3.
Am J Physiol Cell Physiol ; 319(2): C345-C358, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520608

RESUMO

The maturity of osteoblasts by proliferation and differentiation in preosteoblasts is essential for maintaining bone homeostasis. The beneficial effects of vitamin D on bone homeostasis in mammals have been demonstrated experimentally and clinically. However, the direct actions of vitamin D on preosteoblasts remain to be fully elucidated. In this study, we found that the functional activity of intermediate-conductance Ca2+-activated K+ channels (KCa3.1) positively regulated cell proliferation in MC3T3-E1 cells derived from mouse preosteoblasts by enhancing intracellular Ca2+ signaling. We examined the effects of treatment with vitamin D receptor (VDR) agonist on the expression and activity of KCa3.1 by real-time PCR examination, Western blotting, Ca2+ imaging, and patch clamp analyses in mouse MC3T3-E1 cells. Following the downregulation of KCa3.1 transcriptional modulators such as Fra-1 and HDAC2, KCa3.1 activity was suppressed in MC3T3-E1 cells treated with VDR agonists. Furthermore, application of the KCa3.1 activator DCEBIO attenuated the VDR agonist-evoked suppression of cell proliferation rate. These findings suggest that a decrease in KCa3.1 activity is involved in the suppression of cell proliferation rate in VDR agonist-treated preosteoblasts. Therefore, KCa3.1 plays an important role in bone formation by promoting osteoblastic proliferation under physiological conditions.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Osteoblastos/metabolismo , Receptores de Calcitriol/genética , Vitamina D/genética , Células 3T3 , Animais , Benzimidazóis/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/genética , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Histona Desacetilase 2/genética , Humanos , Camundongos , Osteoblastos/citologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/genética , Receptores de Calcitriol/agonistas , Transdução de Sinais/efeitos dos fármacos
4.
Sci Rep ; 10(1): 5677, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32231239

RESUMO

Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 25-hydroxyvitamin D3 (25(OH)D3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH)2D3 with an affinity equivalent to that for 25(OH)D3, were also generated. Although Cyp27b1-knockout (KO), Vdr-KO, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH)2D3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system.


Assuntos
Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Animais , Calcifediol/genética , Calcifediol/metabolismo , Calcitriol/farmacologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Raquitismo/metabolismo , Vitamina D/análogos & derivados , Vitamina D/genética , Vitamina D3 24-Hidroxilase/genética
5.
PLoS One ; 15(3): e0230426, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32231377

RESUMO

OBJECTIVE: Postnatal vitamin D supplementation is standard of care in neonates and preterm infants. Despite routine supplementation of vitamin D, a wide range of complications related to vitamin D deficiency has been described in the literature. Since standard vitamin D supplementation might be not sufficient in preterm infants with a genetic predisposition for vitamin D deficiency, we investigated the outcome of preterm infants with regard to their genetic estimated vitamin D levels. METHODS: Preterm infants with a birth weight below 1500 grams were included in the German Neonatal Network at the time of their birth and tested at the age of five. The vitamin D level was genetically calculated based on three single nucleotide polymorphisms (SNPs: rs12794714, rs7944926 and rs2282679) which alter vitamin D synthesis pathways. Specific alleles of these polymorphisms are validated markers for low plasma vitamin D levels. Outcome data were based on baseline data at the time of birth, typical complications of prematurity, body measurements at the age of five and occurrence of bone fractures. T-test and Fisher's exact test were used for statistical comparison. RESULTS: According to their genetic predisposition, 1,924 preterm infants were divided into groups of low (gsVitD < 20. Percentile), intermediate and high vitamin D level estimates. Low genetic vitamin D level estimates could not be shown to be associated with any adverse outcome measures examined. The analyses covered data on aforementioned determinants. CONCLUSION: Low genetic vitamin D level estimates could not be shown to be associated with previously described adverse outcome in preterm infants.


Assuntos
Predisposição Genética para Doença , Recém-Nascido de muito Baixo Peso/metabolismo , Deficiência de Vitamina D/genética , Vitamina D/metabolismo , Peso ao Nascer/fisiologia , Estudos de Coortes , Suplementos Nutricionais , Feminino , Fraturas Ósseas , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/metabolismo , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Masculino , Vitamina D/genética , Deficiência de Vitamina D/metabolismo
6.
Am J Physiol Cell Physiol ; 318(5): C836-C847, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159363

RESUMO

Prostate cancer (PCa) is a leading cause of cancer death in men. Despite the antiproliferative effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on PCa, accumulating evidence indicates that 1,25(OH)2D3 promotes cancer progression by increasing genome plasticity. Our investigation of epigenetic changes associated with vitamin D insensitivity found that 1,25(OH)2D3 treatment reduced the expression levels and activities of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively). In silico analysis and reporter assay confirmed that 1,25(OH)2D3 downregulated transcriptional activation of the DNMT3B promoter and upregulated microRNAs targeting the 3'-untranslated regions of DNMT3B. We then profiled DNA methylation in the vitamin D-resistant PC-3 cells and a resistant PCa cell model generated by long-term 1,25(OH)2D3 exposure. Several candidate genes were found to be hypomethylated and overexpressed in vitamin D-resistant PCa cells compared with vitamin D-sensitive cells. Most of the identified genes were associated with mammalian target of rapamycin (mTOR) signaling activation, which is known to promote cancer progression. Among them, we found that inhibition of ribosomal protein S6 kinase A1 (RPS6KA1) promoted vitamin D sensitivity in PC-3 cells. Furthermore, The Cancer Genome Atlas (TCGA) prostate cancer data set demonstrated that midline 1 (MID1) expression is positively correlated with tumor stage. Overall, our study reveals an inhibitory mechanism of 1,25(OH)2D3 on DNMT3B, which may contribute to vitamin D resistance in PCa.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , Neoplasias da Próstata/genética , Vitamina D/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Serina-Treonina Quinases TOR/genética , Ubiquitina-Proteína Ligases/genética , Vitamina D/análogos & derivados , Vitamina D/genética , Vitamina D/farmacologia
7.
Sci Rep ; 10(1): 2359, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047189

RESUMO

The effects of vitamin A and/or vitamin D deficiency were studied in an Arf-/- BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4+ splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH)2VD3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G0/G1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Vitamina A/metabolismo , Vitamina D/metabolismo , Animais , Apoptose , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores X Retinoide/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Vitamina A/genética , Vitamina A/farmacologia , Vitamina D/genética , Vitamina D/farmacologia
8.
J Steroid Biochem Mol Biol ; 199: 105616, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32027935

RESUMO

To evaluate the measured free 25-hydroxyvitamin D [25(OH)D] levels in patients with hyperparathyroidism (PHPT) and healthy controls. Eighty patients with PHPT(n = 40) and age and BMI matched controls (n = 40) were examined. Serum levels of total or free 25(OH)D, vitamin D binding protein (DBP), intact parathyroid hormone (iPTH) and calcium were measured. There was no significant difference in age (61.2 ± 11.9 vs 60.2 ± 7.0 years) and BMI (30.0 ± 6.1 vs 30.0 ± 2.2 kg/m2) between PHPT patients and healthy subjects. Levels of total 25(OH)D were about 20 % lower in PHPT patients (26.4 ± 7.7 ng/mL) compared to controls (31.0 ± 7.8 ng/mL, P < 0.05). There were no significant differences in calculated or measured free 25(OH)D levels between PHPT patients (4.9 ± 1.8 or 4.9 ± 1.6 pg/mL, respectively) and control subjects (5.1 ± 1.2 or 5.3 ± 1.6 pg/mL, respectively). Levels of free 25(OH)D were positively associated with levels of total 25(OH)D (r = 0.28, P < 0.05) but negatively correlated with iPTH and calcium levels (r=-0.22 and -0.23 respectively, P < 0.05). Serum total 25(OH)D levels were lower but the calculated or measured free 25(OH)D levels in patients with PHPT did not differ from healthy subjects. We suggest that total 25(OH)D levels may not reflect true vitamin D nutritional status in patients with PHPT.


Assuntos
Calcifediol/administração & dosagem , Hiperparatireoidismo Primário/sangue , Vitamina D/análogos & derivados , Vitamina D/genética , Idoso , Índice de Massa Corporal , Cálcio/sangue , Cálcio na Dieta/administração & dosagem , Feminino , Humanos , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/patologia , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Hormônio Paratireóideo/sangue , Vitamina D/sangue
9.
J Steroid Biochem Mol Biol ; 199: 105613, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32007564

RESUMO

Vitamin D deficiency (VDD) during pregnancy is common and related to several maternal and fetal morbidities. Vitamin D (VD) plays a role in normal lung development and VDD causes abnormal airway, alveolar, and vascular growth in newborn rats. Here we use an unbiased transcriptomic approach to identify pathways altered in the lungs of offspring from VDD dams. The lungs of newborn offspring from VD replete and VDD dams were removed and RNA from these samples were analyzed using Affymetrix microarrays. Data were RMA normalized, differential gene expression was determined using Significance Analysis of Microarrays (5 % FDR) and pathway enrichment analysis was assessed. There were 2233 differentially expressed transcripts between the VDD and control lungs (1889 up, 344 down). Consistent with the suppression of lung growth in the VDD group, there were significant suppression of signal transduction pathways related to vascular biology and anabolic signaling pathways, e.g. the insulin-like growth factor-1 receptor (IGF-1R), fibroblast growth factor (FGF), cell cycle control. A major, enriched functional category was upregulation of pathways related to the innate immune system, including pathways for granulocyte and macrophage development, chemotaxis, and activation of cytokine signaling through Jak/Stat (e.g. resulting in higher IL1 α and ß). We conclude that VDD during fetal development alters multiple pathways beyond the predicted angiogeneic alterations. These changes either contribute to, or reflect, the abnormal airway, alveolar, and vascular growth seen in the neonatal lung resulting from maternal VDD. The pattern also suggests abnormal lung development caused by maternal VDD creates a proinflammatory milieu that could contribute to the suppression of lung growth and development.


Assuntos
Transcriptoma/genética , Deficiência de Vitamina D/genética , Vitamina D/genética , Animais , Animais Recém-Nascidos , Feminino , Gravidez , Ratos , Transdução de Sinais/genética , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologia
10.
J Steroid Biochem Mol Biol ; 199: 105588, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004705

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy frequently accompanied with skeletal co-morbidity. Vitamin D (1,25(OH)2D) is an important mediator of skeletal homeostasis that mediates its effect by binding to vitamin D receptor (VDR), a steroid family receptor and modulates various downstream pathways. Multiple polymorphisms have been determined in VDR gene that witnessed significant association with cancer development and progression. Therefore, in this maiden study, we recruited 75 newly diagnosed MM patients and 75 control subjects. 25-hydroxy vitamin D (25(OH)D) levels were measured in all recruited study subjects. Further, PCR-RFLP was performed in DNA samples of recruited study subjects. Results demonstrated significantly decreased 25(OH)D levels in MM patients compared to controls. Additionally, decreased 25(OH)D levels in MM patients inversely associated with disease severity. Further, single nucleotide polymorphism (SNP) analysis of VDR gene showed significantly higher risk of MM disease development in Ff + ff, Aa + aa, and Bb + bb genotypes. Additionally, FokI f, ApaI a and BsmI b alleles were significantly associated with MM occurrence. In conclusion, this study provided initial evidences of association between 25(OH)D insufficiency, VDR gene polymorphism and MM development. Thus, we suggest that a study involving assessment of 25(OH)D levels and VDR gene polymorphism in large patients' cohort might substantiate their role in MM development which would further provide impetus to give 25(OH)D supplementation along with conventional chemotherapeutic agents for myeloma treatment in future.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Receptores de Calcitriol/genética , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único/genética , Isoformas de Proteínas/genética , Vitamina D/análogos & derivados , Vitamina D/genética
11.
J Steroid Biochem Mol Biol ; 199: 105587, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004706

RESUMO

Chronic kidney disease (CKD) is associated with elevated circulating fibroblast growth factor 23 (FGF23), impaired renal biosynthesis of 1α,25-dihydroxyvitamin D (1α,25(OH)2D), low bone mass, and increased fracture risk. Our previous data with human mesenchymal stem cells (hMSCs) indicated that vitamin D metabolism in hMSCs is regulated as it is in the kidney and promotes osteoblastogenesis in an autocrine/paracrine manner. In this study, we tested the hypothesis that FGF23 inhibits vitamin D metabolism and action in hMSCs. hMSCs were isolated from discarded marrow during hip arthroplasty, including two subjects receiving hemodialysis and a series of 20 subjects (aged 49-83 years) with estimated glomerular filtration rate (eGFR) data. The direct in vitro effects of rhFGF23 on hMSCs were analyzed by RT-PCR, Western immunoblot, and biochemical assays. Ex vivo analyses showed positive correlations for both secreted and membrane-bound αKlotho gene expression in hMSCs with eGFR of the subjects from whom hMSCs were isolated. There was downregulated constitutive expression of αKlotho, but not FGFR1 in hMSCs obtained from two hemodialysis subjects. In vitro, rhFGF23 countered vitamin D-stimulated osteoblast differentiation of hMSCs by reducing the vitamin D receptor, CYP27B1/1α-hydroxylase, biosynthesis of 1α,25(OH)2D3, and signaling through BMP-7. These data demonstrate that dysregulated vitamin D metabolism in hMSCs may contribute to impaired osteoblastogenesis and altered bone and mineral metabolism in CKD subjects due to elevated FGF23. This supports the importance of intracellular vitamin D metabolism in autocrine/paracrine regulation of osteoblast differentiation in hMSCs.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Insuficiência Renal Crônica/genética , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Idoso , Idoso de 80 Anos ou mais , Proteína Morfogenética Óssea 7/genética , Diferenciação Celular/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Osteoblastos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Vitamina D/análogos & derivados , Vitamina D/biossíntese , Vitamina D/genética
12.
PLoS One ; 15(1): e0225402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31967989

RESUMO

BACKGROUND: The prevalence of vitamin D inadequacy and breast cancer are both high among women living in Karachi, Pakistan. METHODS: A matched case control study was conducted in two hospitals of Karachi, Pakistan to evaluate the association of vitamin D (serum 25-hydroxyvitamin D) concentrations, vitamin D supplementation and sun exposure with breast cancer among Pakistani women. A total of 411 newly diagnosed histologically confirmed primary breast cancer cases were enrolled and 784 controls, free of breast and any other cancers, were matched by age (year of birth ± 5 years), residence in the same geographic area and study site. Information was collected on sociodemographic history, history of vitamin D supplementation, past medical and obstetrical history, family history of breast cancer, sun exposure history, histopathology reports and anthropometric measurement and venous blood was collected to measure serum 25-hydroxyvitamin D (25(OH)D) concentration. RESULTS: Compared to patients with sufficient serum vitamin D (>30 ng/ml), women with serum vitamin D deficiency (<20ng/ml), had a higher risk of breast cancer (OR = 1.65, 95%CI: 1.10, 2.50). Women with history of vitamin D supplementation one year prior to enrollment, had significant protective effect against breast cancer (OR = 0.32, 95% CI: 0.24, 0.43). CONCLUSIONS AND RECOMMENDATION: Serum vitamin D deficiency was associated with increased risk of breast cancer, while vitamin D supplementation was associated with decreased risk of breast cancer. In Pakistani women, where vitamin D deficiency is common, raising and maintaining serum vitamin D at population level is a safe and affordable strategy. It may play a role in reducing the incidence of both vitamin D deficiency and breast cancer, particularly among poor women where the breast cancer mortality is highest due to limited resources for early detection, diagnosis, and treatment. The effects of vitamin D with regard to breast cancer risk in Karachi Pakistan should be further evaluated.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Deficiência de Vitamina D/genética , Vitamina D/genética , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Suplementos Nutricionais , Feminino , Humanos , Pessoa de Meia-Idade , Paquistão/epidemiologia , Luz Solar , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/patologia
13.
J Steroid Biochem Mol Biol ; 199: 105595, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31954766

RESUMO

From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.


Assuntos
Melatonina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Vitamina D/metabolismo , Animais , Apoptose/genética , Humanos , Melatonina/genética , Mitocôndrias/genética , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/genética , Estações do Ano , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismo , Transtornos do Sono do Ritmo Circadiano/patologia , Vitamina D/genética
14.
J Steroid Biochem Mol Biol ; 199: 105589, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31953167

RESUMO

Production of testosterone is under tight control by human chorion gonadotropin (hCG) during fetal life and luteinizing hormone (LH) in adulthood. Several animal and human studies have linked vitamin D status with sex steroid production although it is not clear whether there exist a direct or indirect involvement in androgen production. Few studies have investigated this crosslink in young healthy men and putative direct or synergistic effect of activated vitamin D (1,25(OH)2D3) and LH/hCG on sex steroid production in vitro. Here, we present cross-sectional data from 300 young men and 41 hCG-stimulated men with impaired Leydig cell function combined with data from an ex vivo culture of human testicular tissue exposed to 1,25(OH)2D3 alone or in combination with hCG. Serum 25-OHD was positively associated with SHBG (ß:0.002; p = 0.023) and testosterone/estradiol-ratio (ß:0.001; p = 0.039), and inversely associated with free testosterone (%) (free testosterone/total testosterone) (ß:-0.002; p = 0.016) in young men. Vitamin D deficient men had higher total and free estradiol concentrations than men with higher vitamin D status (19% and 18%, respectively; p < 0.01). Interestingly, men with impaired Leydig cell function and vitamin D deficiency had a significantly lower hCG-mediated increase in total and free testosterone compared with vitamin D sufficient men (p < 0.05). Accordingly, testicular tissue exposed to 100 nM 1,25(OH)2D3 had a 15% higher testosterone release into the media compared with vehicle treated specimens (p = 0.030). In conclusion, vitamin D deficiency is associated with lower testosterone/estradiol ratio in young men and lower Leydig cell sensitivity after hCG-stimulation in men with impaired gonadal function. The significant effect of 1,25(OH)2D3 on testosterone production in a human testis model supports that the stimulatory effect at least in part may be direct. Larger placebo-controlled studies are needed to determine whether vitamin D supplementation can influence testosterone production.


Assuntos
Hormônios Esteroides Gonadais/genética , Células Intersticiais do Testículo/metabolismo , Testosterona/biossíntese , Vitamina D/metabolismo , Adulto , Androgênios/biossíntese , Androgênios/genética , Animais , Gonadotropina Coriônica/genética , Estradiol/genética , Hormônios Esteroides Gonadais/biossíntese , Hormônios Esteroides Gonadais/metabolismo , Humanos , Células Intersticiais do Testículo/patologia , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Masculino , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Testosterona/genética , Vitamina D/genética , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologia , Adulto Jovem
15.
J Steroid Biochem Mol Biol ; 199: 105603, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31981799

RESUMO

Calcitriol, the active metabolite of vitamin D, has been widely studied for its preventive and therapeutic activity against several cancers including oral squamous cell carcinoma (OSCC). However, the impact of dietary vitamin D supplementation on initiation and progression of OSCC is unclear. To address this gap in knowledge, we conducted preclinical trials using the 4-nitroquinoline-1-oxide 4NQO carcinogen model of oral carcinogenesis. Female C57BL/6 mice were maintained on one of three vitamin D diets [25 IU, 100 IU, 10,000 IU] and exposed to 4NQO in drinking water for 16 weeks followed by regular water for 10 weeks. Body weight measurements obtained through the study duration did not reveal any differences between the three diets. Animals on 100 IU diet showed lower incidence of high-grade dysplasia/OSCC and higher CD3 + T cells compared to animals on 25 IU and 10,000 IU diets. Serum 25OHD3 levels were highest in animals on 10,000 IU diet at week 0 prior to carcinogen exposure but showed ∼50 % reduction at week 26. Histologic evaluation revealed highest incidence of OSCC in animals maintained on 10,000 IU diet. Animals on 100 IU and 10,000 IU diets showed higher vitamin D receptor VDR and CYP24A1 immunostaining in high-grade dysplastic lesions and OSCC compared to normal tongue. Validation studies performed in a 4NQO-derived OSCC model showed that short-term treatment of animals on a 25 IU diet with calcitriol significantly inhibited tumor growth compared to controls but did not affect tumor growth in animals on reference diet 1000 IU. Collectively, our results highlight the complex dynamics between vitamin D status and oral carcinogenesis. Our observations also suggest that therapeutic benefits of short-term calcitriol treatment may be more pronounced in vitamin D deficient hosts.


Assuntos
Carcinoma de Células Escamosas/dietoterapia , Neoplasias Bucais/dietoterapia , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , Vitamina D/genética , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Peso Corporal , Calcitriol/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Suplementos Nutricionais/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Neoplasias Bucais/sangue , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/patologia , Vitamina D/sangue , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/patologia
16.
J Steroid Biochem Mol Biol ; 199: 105593, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31945466

RESUMO

Recently, it was reported that 25(OH)D3 (25D3) has physiological bioactivity in certain tissues derived from Cyp27b1 knockout mice. To investigate the function of 25D3 in the kidney as an informational crossroad of various calciotropic substances, we employed the CRISPR-Cas9 system to knock out Cyp27b1 in the mouse renal distal tubular mDCT cell line. Unlike the previously reported mice in which Cyp27b1 was targeted systemically, Cyp27b1 knockout mDCT cells did not produce any measurable 1α,25(OH)2D3 (1,25D3) after 25D3 administration. As was seen with treatment of Cyp27b1 knockout mDCT cells with ≥10-8 M of 1,25D3, the administration of 10-7 M of 25D3 translocated the vitamin D3 receptor (VDR) into the nucleus and promoted the expression of the representative 1,25D3-responsive gene Cyp24a1. The exhaustive target gene profiles of 25D3 were similar to those of 1,25D3. Subsequently, we confirmed that 25D3 induced the expression of the calcium reabsorption-related gene calbindin-D9K, in a way similar to 1,25D3. We also found that 1,25D3 and 25D3 induced the expression of the megalin gene. A chromatin immunoprecipitation assay identified two vitamin D response elements in the upstream region of the megalin gene that seemed to contribute to its expression. Together, we surmise that the ability of 25D3 to stimulate VDR target genes may provide a novel perspective for its role in certain tissues.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Vitamina D/genética , Animais , Cálcio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Camundongos , Camundongos Knockout , Proteína G de Ligação ao Cálcio S100/genética , Proteína G de Ligação ao Cálcio S100/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitamina D3 24-Hidroxilase/genética
17.
J Steroid Biochem Mol Biol ; 199: 105600, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31958633

RESUMO

The vitamin D receptor (VDR) and its ligand 1,25(OH)2D3 (1,25D) impact differentiation and exert anti-tumor effects in many tissues, but its role in salivary gland has yet to be defined. Using immunohistochemistry (IHC), we have detected strong VDR expression in murine and human salivary gland ducts. Compared to normal gland, VDR protein expression was retained in differentiated human pleomorphic adenoma (PA) but was undetectable in undifferentiated PA and in carcinomas, suggesting deregulation of VDR during salivary cancer progression. To gain insight into the potential role of VDR in salivary cancer, we assessed the effects of vitamin D in vivo and in vitro. Despite the presence of VDR in salivary gland, chronic dietary vitamin D restriction did not alter morphology of the salivary epithelium in C57/Bl6 mice. The localization of VDR in ductal epithelium prompted us to examine the effects of 1,25D in an established cell line (mSGc) derived from normal murine submandibular gland (SMG). This previously characterized cell line consists of multiple stem, progenitor and differentiated cell types as determined by mutually exclusive cellular expression of basal, ductal and myoepithelial markers. We demonstrated VDR expression and regulation of VDR target genes Vdr and Postn by 1,25D in mSGc, indicating functional ligand-mediated transcriptional activity. The effect of VDR signaling on epithelial differentiation markers was assessed by qPCR and IHC in mSGc cells treated with 1,25D. We found that 1,25D reduced mRNA expression of the basal cell progenitor marker keratin 5 (K5) and increased expression of the differentiated ductal cell marker keratin 7 (K7). Further, we found that 1,25D significantly decreased the number of proliferating cells, including proliferating K5+ cells. Characterization of cell cycle by Muse cytometry indicated 1,25D treatment decreased cells in S, G2, and M phase. The inhibition of K5+ cell proliferation by 1,25D is of particular interest because K5+ basal cells contribute to a wide variety of salivary tumor types. Our studies suggest that 1,25D alters cancer-relevant progenitor and differentiation markers in the salivary gland.


Assuntos
Receptores de Calcitriol/genética , Neoplasias das Glândulas Salivares/genética , Glândulas Salivares/metabolismo , Vitamina D/genética , Animais , Calcitriol/farmacologia , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Homeostase/genética , Humanos , Camundongos , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia , Transdução de Sinais/genética , Vitamina D/metabolismo
18.
J Alzheimers Dis ; 73(2): 609-618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31815694

RESUMO

Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer's disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Análise da Randomização Mendeliana , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/genética , Vitamina D/genética , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/psicologia , Bases de Dados Factuais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hidroxicolecalciferóis/sangue , Hidroxicolecalciferóis/genética , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Reino Unido/epidemiologia , Vitamina D/sangue
19.
Neurobiol Aging ; 87: 140.e1-140.e3, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31785838

RESUMO

We conducted a mendelian randomization study to investigate the association between serum 25-hydroxyvitamin D (S-25OHD) concentrations and amyotrophic lateral sclerosis (ALS). Summary-level data for genetic predictors of S-25OHD concentrations were acquired from 2 genome-wide association studies, comprising up to 79,366 individuals. The corresponding data for ALS were collected from 12,577 ALS cases and 23,475 controls. None of 7 single-nucleotide polymorphisms predicting S-25OHD concentrations was associated with ALS, and there was no overall association of genetic predisposition to higher S-25OHD concentrations with ALS. The odds ratio of ALS per genetically predicted one standard deviation increase of S-25OHD concentrations was 0.96 (95% confidence interval: 0.86-1.08; p = 0.52). We conclude that increasing S-25OHD concentrations will unlikely reduce ALS incidence.


Assuntos
Esclerose Amiotrófica Lateral/genética , Vitamina D/análogos & derivados , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Vitamina D/genética
20.
J Clin Lab Anal ; 34(1): e23039, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541492

RESUMO

BACKGROUND: Vitamin D (Vit D) function in asthma progression has been studied well. The effects of genetic variations in Vit D pathway molecules have been also studied, although the results are contradicted. In the present study, for the first time we examined the Vit D pathway molecules included serum Vit D and vitamin D-binding protein (VDBP) and also genetic variations in the vitamin D receptor (VDR) and VDBP in a Kurdish population with asthma. METHODS: An enzyme-linked immunosorbent assay (ELISA) method was used to measure the serum Vit D and VDBP. VDR rs1544410 and rs2228570 and VDBP rs7041 were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The serum level of Vit D significantly decreased in asthmatic patients versus controls (16.26 ± 6.76 vs 23.05 ± 10.57 ng/mL, P value = .001). We observed an indirect correlation between Vit D and clinical findings. We also found an increased level of serum VDBP in patients as compared to the controls (1044.6 ± 310.82 vs 545.95 ± 121.73 µg/mL, P value < .0001). Besides, the risk of asthma progression was increased in patients with the VDR rs2228570 CC and VDBP rs7041 GG genotypes (OR = 3.56, P = .0382 and OR = 2.58, P = .01, respectively). CONCLUSION: In summary, our results explain the influence of the genetic variations in VDR and VDBP in addition to Vit D and VDBP serum concentrations on asthma susceptibility in the Kurdish population.


Assuntos
Asma/genética , Predisposição Genética para Doença , Vitamina D/genética , Adulto , Asma/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Masculino , Vitamina D/sangue , Proteína de Ligação a Vitamina D/sangue
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