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1.
Phys Chem Chem Phys ; 21(36): 19944-19950, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31475699

RESUMO

In this manuscript the ability of closo-carboranes to establish CHπ and BHπ interactions with several aromatic moieties exhibiting different electronic natures has been evaluated at the PBE0-D3/def2-TZVP level of theory. We have used the three closo isomers (ortho-, meta-, and para-) and benzene, trifluorobenzene and hexafluorobenzene as aromatic systems. Furthermore, we have used Bader's theory of "atoms in molecules" to further describe and characterize the noncovalent interactions described herein from a charge-density perspective. Finally, several biological examples retrieved from the PDB are also included, highlighting the impact of these interactions in the binding affinity of boron tracedrugs.


Assuntos
Compostos de Boro/química , Modelos Químicos , Cristalização , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismo , Vitamina D/química , Vitamina D/metabolismo , Raios X
2.
Anticancer Res ; 39(9): 4627-4635, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519560

RESUMO

In the clinical setting, administration of high daily or bolus doses of vitamin D is often solely based on 25-hydroxyvitamin D [25(OH)D] testing. This review summarizes the evidence of the effect of vitamin D on cardiovascular disease (CVD). Meta-analyses of randomized controlled trials (RCTs) have demonstrated that CVD risk markers, such as lipid parameters, inflammation markers, blood pressure, and arterial stiffness, are largely unaffected by vitamin D supplementation. Similar results have been obtained regarding CVD events and mortality from (meta)-analyses of RCTs, even in subgroups with 25(OH)D concentrations <50 nmol/l. Likewise, Mendelian randomization studies have indicated that the genetic reduction of the 25(OH)D concentration does not increase CVD risk. Some studies do not exclude the possibility of adverse vitamin D effects, such as elevated plasma calcium concentration and an increased CVD risk at a 25(OH)D concentration >125 nmol/l. Based on a conservative benefit-risk management approach, vitamin D doses beyond the nutritionally recommended amounts of 600 to 800 IE daily currently cannot be advised for the prevention of CVD events.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Vitamina D/metabolismo , Animais , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Suplementos Nutricionais/efeitos adversos , Overdose de Drogas/complicações , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Vitamina D/administração & dosagem , Vitamina D/efeitos adversos , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/diagnóstico
3.
Chem Pharm Bull (Tokyo) ; 67(7): 609-619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257315

RESUMO

To develop potent ligands for the vitamin D receptor (VDR), we designed and synthesized a series of vitamin D analogues with and without 22-alkyl substituents. These analogues exhibited agonistic, partial agonistic, or antagonistic activity. To elucidate the mechanism of action of the analogues, we conducted crystal structure analyses of the ligand-binding domain (LBD) of VDR complexed with the analogues. The VDR-LBD/agonist complex exhibited precise interactions, which clearly explained VDR agonism. The VDR-LBD/partial agonist complex showed two conformers (agonist and antagonist binding conformers) in a single crystal, demonstrating that partial agonism could be explained by the sum of the agonistic and antagonistic activities. Antagonist binding to the VDR-LBD structure was elucidated using both crystal structure analysis and in-solution structural analyses with the small-angle X-ray scattering (SAXS)-molecular dynamics (MD) and hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) methods. Several antagonist-binding structures were detected. We found that the antagonist binding structures differed depending on the structure of the antagonist itself, and those structures clearly explained the VDR antagonism. Furthermore, the apo VDR-LBD structure without the ligand in the ligand-binding pocket was revealed and found to have an entrance to accommodate the ligand. Thus we elucidated the mechanisms of action of agonists, partial agonists, and antagonists based on structural changes (differences) in the receptor protein induced by ligand binding.


Assuntos
Ligantes , Receptores de Calcitriol/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inibidores , Vitamina D/análogos & derivados , Vitamina D/metabolismo
4.
Cell Biochem Funct ; 37(6): 408-423, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31328813

RESUMO

Current understanding of vitamin D tends to be focussed on the measurement of the major circulating form 25-hydroxyvitamin D3 (25OHD3) and its conversion to the active hormonal form, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3) via the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1). However, whilst these metabolites form the endocrine backbone of vitamin D physiology, it is important to recognise that there are other metabolic and catabolic pathways that are now recognised as being crucially important to vitamin D function. These pathways include C3-epimerization, CYP24A1 hydroxylase, CYP11A1 alternative metabolism of vitamin D3, and phase II metabolism. Endogenous metabolites beyond 25OHD3 are usually present at low endogenous levels and may only be functional in specific target tissues rather than in the general circulation. However, the technologies available to measure these metabolites have also improved, so that measurement of alternative vitamin D metabolic pathways may become more routine in the near future. The aim of this review is to provide a comprehensive overview of the various pathways of vitamin D metabolism, as well as describe the analytical techniques currently available to measure these vitamin D metabolites.


Assuntos
Metaboloma/fisiologia , Vitamina D/análise , Vitamina D/metabolismo , Animais , Humanos
5.
Int J Infect Dis ; 84: 80-88, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075507

RESUMO

BACKGROUND AND AIMS: It has been demonstrated that 1,25-hydroxyvitamin-D3-24-hydroxylase, encoded by CYP24A1 gene, is a key enzyme that neutralizes the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in response to hepatitis C virus (HCV) infection. This study aimed to investigate whether CYP24A1 genetic variation is associated with HCV infection outcomes. METHODS: 848 HCV chronically infected subjects, 507 natural clearance subjects, and 1017 uninfected controls were enrolled. Nine single nucleotide polymorphisms (SNPs) in theCYP24A1 gene were genotyped using the Sequenom MassARRAY platform. RESULTS: After adjusting for age, gender, and routes of infection, logistic regression analyses showed that rs6013897-A was associated with an elevated risk of HCV infection (P<0.05). In addition, this study has also demonstrated that rs6068816-T significantly reduced the risk of chronic HCV infection, while rs3787557-C, rs6022999-G, and rs2248359-T significantly increased the risk of chronic HCV infection (all P<0.05). Haplotype analysis suggested that, compared to the most frequent Trs6068816Trs3787557Ars6022999Crs2248359 haplotype, the CTGT haplotype (adjusted OR=1.376, 95% CI=1.092-1.735, P=0.007) and CCAC haplotype (adjusted OR=1.483, 95% CI=1.139-1.929, P=0.003) were associated with an increased risk of chronic HCV infection. CONCLUSION: These findings indicate that SNPs in CYP24A1 gene may contribute to the risk of HCV infection and chronic HCV infection among a high-risk Chinese population.


Assuntos
Hepatite C Crônica/etiologia , Polimorfismo de Nucleotídeo Único , Vitamina D3 24-Hidroxilase/genética , Vitamina D/metabolismo , Adulto , Feminino , Haplótipos , Hepatite C Crônica/genética , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Fatores de Risco
6.
Nat Commun ; 10(1): 2329, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133636

RESUMO

Variability in bacterial sterilization is a key feature of Mycobacterium tuberculosis (Mtb) disease. In a population of human macrophages, there are macrophages that restrict Mtb growth and those that do not. However, the sources of heterogeneity in macrophage state during Mtb infection are poorly understood. Here, we perform RNAseq on restrictive and permissive macrophages and reveal that the expression of genes involved in GM-CSF signaling discriminates between the two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more permissive of Mtb growth while addition of GM-CSF increases bacterial control. In parallel, we find that the loss of bacterial control that occurs in HIV-Mtb coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the natural variation in macrophage control of Mtb to identify a critical cytokine response for regulating Mtb survival and identify components of the antimicrobial response induced by GM-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Transdução de Sinais/imunologia , Tuberculose/imunologia , Buffy Coat/citologia , Células Cultivadas , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Análise de Sequência de RNA , Tuberculose/microbiologia , Vitamina D/imunologia , Vitamina D/metabolismo
7.
Actas dermo-sifiliogr. (Ed. impr.) ; 110(4): 262-272, mayo 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-180898

RESUMO

relación entre esta vitamina y algunas dermatosis ha supuesto la publicación de múltiples trabajos al respecto. Como dermatólogos, conocer sus principales fuentes, síntesis, niveles plasmáticos y algunos de los factores modificadores son varios de los aspectos a recordar. Asimismo, es preciso resaltar los últimos descubrimientos sobre el papel de la vitamina D en las diferentes enfermedades dermatológicas, como el lupus eritematoso, la ictiosis, la dermatitis atópica, la hidrosadenitis supurativa, el acné, la alopecia areata y androgenética, el melanoma y el cáncer cutáneo no melanoma, así como la relevancia como terapia adyuvante en pacientes en tratamiento crónico con corticoides. Acercamos al lector la información más relevante y reciente de la relación entre la vitamina D y las enfermedades de la piel, así como la importancia de conocer los niveles de esta vitamina


In recent years, the growing interest in the role played by vitamin D in skin disease has given rise to the publication of many studies of the relationship between this vitamin and certain skin conditions. As dermatologists, we need to understand, among other aspects, how vitamin D is synthesized and the main sources in humans, as well as plasma levels and the factors that can modify them. Of particular interest are the latest discoveries about the role of vitamin D in skin diseases such as lupus erythematosus, ichthyosis, atopic dermatitis, hidradenitis suppurativa, acne, alopecia areata, androgenetic alopecia, melanoma, and nonmelanoma skin cancer. Also of interest is the importance of vitamin D as adjuvant therapy in patients on long-term treatment with corticosteroids. In this review, we provide an overview of the most important and most recent information regarding the relationship between vitamin D and skin disease and discuss the importance of assessing individual vitamin D status and correcting deficiencies


Assuntos
Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Vitamina D/biossíntese , Vitamina D/metabolismo , Lúpus Eritematoso Cutâneo/etiologia , Ictiose/tratamento farmacológico , Psoríase/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Acne Vulgar/tratamento farmacológico , Hidradenite/tratamento farmacológico , Vitiligo/tratamento farmacológico , Transtornos de Fotossensibilidade , Alopecia em Áreas , Neoplasias Cutâneas
8.
Graefes Arch Clin Exp Ophthalmol ; 257(6): 1191-1198, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937534

RESUMO

PURPOSE: To compare serum and aqueous humor (AH) vitamin D levels between the patients with diabetic macular edema (DME) and controls. METHODS: A total of 65 subjects (30 DME, 35 control) were included. One-third of the control group had hypertension, dyslipidemia, or diabetes mellitus without diabetic retinopathy as underlying diseases. Serum and AH levels of 25-hydroxyvitamin D were measured in each subject. Multiple linear regression analysis was performed to investigate factors associated with serum and AH vitamin D levels. RESULTS: There were no significant differences in serum vitamin D levels between the DME (14.3 ± 9.1 ng/mL) and control (16.2 ± 8.0 ng/mL) groups (P = 0.374). However, eyes with DME (41.6 ± 8.0 ng/mL) had a higher AH level of vitamin D than control eyes (25.5 ± 4.1 ng/mL, P < 0.001). AH vitamin D level was significantly associated with the presence of DME (ß = 0.775, P < 0.001). Serum and AH levels of vitamin D were not significantly correlated (r = - 0.157, P = 0.211). CONCLUSION: Serum vitamin D levels did not significantly differ between the DME and control groups. Localized vitamin D level in the eye was independent from systemic vitamin D level and it might be another indicator of DME severity.


Assuntos
Humor Aquoso/metabolismo , Retinopatia Diabética/complicações , Edema Macular/metabolismo , Acuidade Visual , Vitamina D/análogos & derivados , Biomarcadores/metabolismo , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/metabolismo , Feminino , Angiofluoresceinografia/métodos , Fundo de Olho , Humanos , Edema Macular/diagnóstico , Edema Macular/etiologia , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Vitamina D/metabolismo
9.
Oncol Rep ; 41(6): 3393-3403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002352

RESUMO

Scientific evidence linking vitamin D with various cancer types is growing, but the effects of vitamin D on ovarian cancer stem cell­like cells (CSCs) are largely unknown. The present study aimed to examine whether vitamin D was able to restrain the stemness of ovarian cancer. A side population (SP) from malignant ovarian surface epithelial cells was identified as CSCs, in vitro and in vivo. Furthermore, 1α,25­dihydroxyvitamin D3 [1α,25(OH)2D3] treatment inhibited the self­renewal capacity of SP cells by decreasing the sphere formation rate and by suppressing the mRNA expression levels of cluster of differentiation CD44, NANOG, OCT4, SOX2, Krüppel­like factor 4 and adenosine triphosphate binding cassette subfamily G member 2. Additionally, 1α,25(OH)2D3 treatment decreased the expression of Cyclin D1, whereas it increased the expression of ß­catenin and vitamin D receptor (VDR). Notably, immunofluorescence staining verified that 1α,25(OH)2D3 promoted the expression of ß­catenin in the cytoplasm. Furthermore, vitamin D3 delayed the onset of tumor formation derived from injection of ovarian CSCs to nude mice, by reducing CD44 and enhancing ß­catenin expressions in vivo. In conclusion, 1α,25(OH)2D3 restrains the stem cell­like properties of ovarian cancer cells by enhancing the expression of VDR, by promoting the expression of ß­catenin in the cytoplasm, and by suppressing the expression of CD44. These findings provide a novel insight into the functions of vitamin D in diminishing the stemness of cancer CSCs.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Vitamina D/genética , Autorrenovação Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/genética , Fatores de Transcrição Kruppel-Like/genética , Proteína Homeobox Nanog/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição SOXB1/genética , Vitamina D/metabolismo , Vitamina D/farmacologia , beta Catenina/genética
10.
BMC Res Notes ; 12(1): 216, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961641

RESUMO

OBJECTIVE: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin's lymphoma (HL), a malignant pathology of B cell origin, in vitro. RESULTS: Immunofluorescence staining showed the expression of VDR by primary Hodgkin's (H) and Reed-Sternberg (RS)-HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, and L428. One-way analysis of variance (ANOVA) on data obtained from water-soluble tetrazolium 1 (WST-1) cell proliferation assay showed decreased cell growth in HDLM2 and L428, 72 h after treatment with 10 µM of either VD3 of VDAs. Western blot analyses showed that treatment of L428 cells with the VDAs (calcipotriol and EB1089) resulted in modest increases in nuclear accumulation of VDR (nuVDR) compared to either dimethyl sulfoxide (DMSO) or VD3 treatments. nuVDR for DMSO control and VD3 was comparable. These results suggest that VD3 or VDAs may affect growth of HL.


Assuntos
Calcitriol/análogos & derivados , Colecalciferol/farmacologia , Regulação Neoplásica da Expressão Gênica , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Calcitriol/metabolismo , Calcitriol/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colecalciferol/metabolismo , Dimetil Sulfóxido/farmacologia , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia
11.
Microb Pathog ; 131: 158-163, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953746

RESUMO

Mycobacterium tuberculosis (Mtb) has the extraordinary ability to persist for decades within granulomas in the human host. These histopathological structures involved in both protection and pathogenesis, are subject to various influences from the host systemically and through micro-niche environments. Despite the fact that vitamin D (VD) has a key role in macrophage activation and mycobacterial clearance in the early stages of Mtb infection, the overall role of VD in granuloma maintenance or functionality has been scarcely studied. VD deficiency has long time been known to influence on gut microbiota composition, and recent studies have shown that it can also impact on respiratory microbiome. The human microbiota plays an important role in pathogen colonization resistance, and it has been proposed to play a potential role in TB pathogenesis. In this article, we have reviewed current knowledge on the interaction between VD, the lung microbiome and TB, and propose mechanisms by which the tuberculous granuloma's outcome could be modulated by these two factors. The determinants of the final fate of lung granulomas are still unclear, and deciphering the underlying drivers of Mtb infection outcome within those structures is of critical importance.


Assuntos
Microbioma Gastrointestinal/fisiologia , Granuloma/imunologia , Pulmão/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Vitamina D/metabolismo , Disbiose , Microbioma Gastrointestinal/imunologia , Granuloma/patologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/patologia , Ativação de Macrófagos , Tuberculose/patologia , Vitamina D/imunologia , Deficiência de Vitamina D/complicações
12.
J Dairy Sci ; 102(6): 5706-5712, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954263

RESUMO

Antimicrobial peptides are a common defense against bacterial infections in many species and a significant part of the innate immune response of the bovine mammary gland. The objective of this study was to investigate the influence of epigenetic factors on vitamin D and toll-like receptor-mediated induction of ß-defensins in mammary epithelial cells. Primary bovine mammary epithelial cells were treated with lipopolysaccharide (LPS, 0 or 100 ng/mL), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0 or 10 nM], and 5-aza-2'-deoxycytidine (5-Aza, inhibitor of DNA methyltransferase, 0 or 5 µM) or trichostatin A (TSA, inhibitor of histone deacetylase, 0 or 80 nM) in a factorial arrangement. Effects of treatments on ß-defensin gene expression along with genes for cytokines and enzymes known to be induced by LPS or 1,25(OH)2D3 were evaluated by quantitative PCR. The LPS treatment induced expression of ß-defensin (DEFB)3, DEFB5, DEFB7, DEFB10, enteric ß-defensin (EBD), lingual antimicrobial peptide (LAP), and tracheal antimicrobial peptide (TAP); whereas, the 1,25(OH)2D3 treatment increased DEFB5 and DEFB7 expression and decreased LAP. The 5-Aza treatment increased expression of DEFB3, DEFB5, DEFB10, EBD, LAP, and TAP in the presence and absence of LPS. The TSA treatment increased expression of DEFB3, DEFB4, DEFB5, DEFB7, and DEFB10 in the absence of LPS but decreased LPS-induced expression of and LAP and TAP. Together these results indicate that ß-defensin expression in bovine mammary epithelial cells is likely influenced by DNA methylation and histone acetylation. Investigation of environmental and nutritional factors that influence epigenetic control of ß-defensins in the mammary gland may be beneficial for improving resistance to intramammary infections.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Histona Desacetilases/metabolismo , Lipopolissacarídeos/metabolismo , Glândulas Mamárias Animais/metabolismo , Metiltransferases/metabolismo , Vitamina D/análogos & derivados , beta-Defensinas/genética , Animais , Bovinos/genética , Metilação de DNA , Feminino , Histona Desacetilases/genética , Glândulas Mamárias Animais/citologia , Metiltransferases/genética , Vitamina D/metabolismo , beta-Defensinas/metabolismo
13.
Cell Commun Signal ; 17(1): 18, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813930

RESUMO

BACKGROUND: Oral lichen planus (OLP) is known as a chronic inflammatory disease. Our recent studies have suggested that vitamin D/vitamin D receptor (VDR) signaling exerts its protective effects on oral keratinocyte apoptosis by regulating microRNA-802 and p53-upregulated modulator of apoptosis (PUMA), but its roles in oral epithelial inflammatory responses in OLP are still unknown. Herein, we identify lipopolysaccharide (LPS) is able to enhance interferon gamma (IFNγ) and interleukin-1 beta (IL-1ß) productions in human oral keratinocytes (HOKs) dependent on hypoxia-inducible factor-1α (HIF-1α). METHODS: HIF-1α and cytokines levels in HOKs were investigated by real-time PCR and western blotting after LPS challenge. The effects of 1,25(OH)2D3 on LPS-induced HIF-1α and cytokines were tested by real-time PCR, western blotting, siRNA-interference and plasmids transfection techniques. The roles of 1,25(OH)2D3 in regulating HIF-1α levels were investigated using western blotting, siRNA-interference, plasmids transfection and Chromatin Immunoprecipitation (ChIP) assays. Finally, HIF-1α, IFNγ and IL-1ß expressions in oral epithelia derived from mice and individuals were measured by real-time PCR, western blotting and immunohistochemical staining. RESULTS: As a critical regulator, vitamin D suppresses LPS-induced HIF-1α to block IFNγ and IL-1ß productions. Mechanistically, vitamin D inactivates nuclear factor-κB (NF-κB) pathway and up-regulates von Hippel-Lindau (VHL) levels, leading to HIF-1α reduction. Moreover, HIF-1α status of oral epithelia is elevated in VDR-/- mie as well as in VDR-deficient human biopsies, accompanied with increased IFNγ and IL-1ß. CONCLUSION: Collectively, this study uncovers an unrecognized roles of vitamin D/VDR signaling in regulating cytokines in oral keratinocytes and reveals the molecular basis of it.


Assuntos
Epitélio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Vitamina D/metabolismo , Animais , Sequência de Bases , Calcitriol/farmacologia , Linhagem Celular , Epitélio/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Líquen Plano Bucal/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Boca/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
14.
Pharmacol Rep ; 71(2): 282-288, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826568

RESUMO

BACKGROUND: After the onset of type 1 diabetes mellitus (T1DM), preservation of the residual ß-cell function can help good metabolic control. The aim of this study was to evaluate the effect of vitamin D and its receptor gene polymorphisms on residual ß-cells function. METHODS: One hundred and one children with T1DM (new cases) older than 5 years were selected. Vitamin D receptor (VDR) gene polymorphisms, vitamin D (VD), fasting and stimulated C-peptide (FCP and SCP) levels were measured within 1.5 and 4.5 month after the diagnosis of disease. Kruskal-Wallis and Mann-whitney U test were used for comparing the study groups. Generalized estimating equation (GEE) model was used for the estimation of association between VD and VDR gene polymorphisms with FCP and SCP after adjustment for comorbid variables. RESULTS: The most frequent genotypes and alleles in TaqI, FokI, BsmI and ApaI polymorphisms were TT (50%) and allele T (68.88%), FF (59.2%) and allele F (77.04%), Bb (41.8%) and allele b (61.73%), and Aa (53.1%) and allele A (63.29%) respectively. In children with higher VD levels, the C-peptide (CP) levels were elevated. Also we observed: the tt genotype associated with increasing SCP levels compared with TT genotype; the bb and Bb genotypes were associated with increasing both FCP and SCP in comparison to BB; and the aa and Aa genotypes were associated with decreasing FCP in comparison to the AA genotype. CONCLUSIONS: Sufficient levels of VD (more than 30 ng/ml) can preserve residual ß-cells and insulin secretion.


Assuntos
Diabetes Mellitus Tipo 1/genética , Células Secretoras de Insulina/metabolismo , Receptores de Calcitriol/genética , Vitamina D/metabolismo , Adolescente , Alelos , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Genótipo , Humanos , Secreção de Insulina/genética , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Tempo
15.
N Engl J Med ; 380(12): 1150-1157, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30893535

RESUMO

A 58-year-old woman with debilitating ankylosing spondylitis who was born to consanguineous parents was found to have an apparent severe vitamin D deficiency that did not respond to supplementation. Liquid chromatography-tandem mass spectrometry showed the absence of circulating vitamin D-binding protein, and chromosomal microarray confirmed a homozygous deletion of the group-specific component (GC) gene that encodes the protein. Congenital absence of vitamin D-binding protein resulted in normocalcemia and a relatively mild disruption of bone metabolism, in this case complicated by severe autoimmune disease. (Funded by the National Institutes of Health and the University of Washington.).


Assuntos
Doenças Autoimunes/complicações , Deleção de Genes , Hidroxicolecalciferóis/sangue , Espondilite Anquilosante/genética , Deficiência de Vitamina D/genética , Proteína de Ligação a Vitamina D/genética , Cálcio/sangue , Cromatografia Líquida , Feminino , Fraturas Espontâneas/etiologia , Expressão Gênica , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Irmãos , Espondilite Anquilosante/complicações , Espectrometria de Massas em Tandem , Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/deficiência
16.
Subcell Biochem ; 91: 453-476, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888662

RESUMO

Osteoporosis is a "skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture" which, in light of demographic change, is becoming an increasing burden on health care worldwide. Increasing age and female gender are associated with the condition, although a wider range of clinical risk factors are being used increasingly to identify those at risk of osteoporosis and its most important sequelae, fracture.While osteoporosis and fracture have long been associated with women in the post-menopausal age, fracture incidence increases because of the ageing of our population. Interventions to abate the progression of osteoporosis and to prevent fractures must focus on the old and the very old. Evidence associating nutritional factors, particularly calcium and vitamin D are reviewed as are the association of falls risk with fracture and the potential for interventions to prevent falls. Finally, the assessment of frailty in the oldest old, associated sarcopenia and multi-morbidity are considered in the evaluation of fall and fracture risk and the management of osteoporosis in the ninth decade of life and beyond.


Assuntos
Envelhecimento/patologia , Osteoporose Pós-Menopausa/patologia , Acidentes por Quedas/prevenção & controle , Envelhecimento/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Cálcio/metabolismo , Cálcio/farmacologia , Feminino , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/prevenção & controle , Fatores de Risco , Vitamina D/metabolismo , Vitamina D/farmacologia
17.
Eur J Appl Physiol ; 119(4): 825-839, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30830277

RESUMO

PURPOSE: This review provides a current perspective on the mechanism of vitamin D on skeletal muscle function with the emphasis on oxidative stress, muscle anabolic state and muscle energy metabolism. It focuses on several aspects related to cellular and molecular physiology such as VDR as the trigger point of vitamin D action, oxidative stress as a consequence of vitamin D deficiency. METHOD: The interaction between vitamin D deficiency and mitochondrial function as well as skeletal muscle atrophy signalling pathways have been studied and clarified in the last years. To the best of our knowledge, we summarize key knowledge and knowledge gaps regarding the mechanism(s) of action of vitamin D in skeletal muscle. RESULT: Vitamin D deficiency is associated with oxidative stress in skeletal muscle that influences the mitochondrial function and affects the development of skeletal muscle atrophy. Namely, vitamin D deficiency decreases oxygen consumption rate and induces disruption of mitochondrial function. These deleterious consequences on muscle may be associated through the vitamin D receptor (VDR) action. Moreover, vitamin D deficiency may contribute to the development of muscle atrophy. The possible signalling pathway triggering the expression of Atrogin-1 involves Src-ERK1/2-Akt- FOXO causing protein degradation. CONCLUSION: Based on the current knowledge we propose that vitamin D deficiency results from the loss of VDR function and it could be partly responsible for the development of neurodegenerative diseases in human beings.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Vitamina D/farmacologia , Animais , Metabolismo Energético/fisiologia , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo
18.
Med Hypotheses ; 125: 5-7, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30902151

RESUMO

Osteoporosis and intervertebral disc degeneration (IDD) are both age-related diseases of the musculoskeletal system. With the average life expectancy longer than ever, the morbidity caused by these two diseases is increasing. Nowadays, treatment strategies for osteoporosis are mainly aimed at increasing the mineral density of the bone. Some of these therapies, including vitamin D, calcium, bisphosphonates, Wnt signal activators and parathyroid hormone regulators, have been suggested to be capable of causing calcification of the cartilage endplate in the intervertebral disc. This alteration could block nutrient and oxygen transportation to the center part of the disc, thus lead to intervertebral disc degeneration. Consequently, we hypothesize that osteoporosis therapies might be a potential risk for IDD. This assumption indicates that we should take the alterations of the cartilage endplate into consideration in further osteoporosis treatment to avoid IDD in the patient.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Cartilagem/patologia , Degeneração do Disco Intervertebral/patologia , Osteoporose/tratamento farmacológico , Anel Fibroso/fisiologia , Densidade Óssea , Calcinose , Cálcio/metabolismo , Difosfonatos/efeitos adversos , Humanos , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/prevenção & controle , Núcleo Pulposo/fisiologia , Osteoporose/complicações , Hormônio Paratireóideo/metabolismo , Risco , Vitamina D/metabolismo , Proteínas Wnt/metabolismo
19.
Expert Opin Pharmacother ; 20(7): 821-835, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897020

RESUMO

INTRODUCTION: Despite its frequency, recognition and therapy of vulvovaginal atrophy (VVA) remain suboptimal. Wet mount microscopy, or vaginal pH as a proxy, allows VVA diagnosis in menopause, but also in young contraception users, after breast cancer, or postpartum. Intravaginal low dose estrogen product is the main therapy. Ultra-low-dose vaginal estriol is safe and sufficient in most cases, even in breast cancer patients, while hyaluronic acid can help women who cannot or do not want to use hormones. AREAS COVERED: The authors provide an overview of the current pharmaceutical treatment for vulvovaginal atrophy and provide their expert opinions on its future treatment. EXPERT OPINION: The basis of good treatment is a correct and complete diagnosis, using a microscope to study the maturity index of the vaginal fluid. Minimal dose of estriol intravaginally with or without lactobacilli is elegant, cheap and can safely be used after breast cancer and history of thromboembolic disease. Laser therapy requires validation and safety data, as is can potentially cause vaginal fibrosis and stenosis, and safer and cheaper alternatives are available.


Assuntos
Atrofia/tratamento farmacológico , Vagina/patologia , Atrofia/diagnóstico , Atrofia/patologia , Estradiol/uso terapêutico , Estriol/uso terapêutico , Feminino , Humanos , Probióticos/uso terapêutico , Progestinas/uso terapêutico , Receptores Estrogênicos/metabolismo , Vitamina D/metabolismo
20.
Orthop Clin North Am ; 50(2): 259-267, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850083

RESUMO

Vitamin D deficiency affects nearly one-sixth of the world's population and is common in patients undergoing foot and ankle surgery. Vitamin D is critical for calcium homeostasis and plays an important role in the maintenance of bone health. Patients undergoing foot and ankle procedures can be evaluated preoperatively with vitamin D level testing, and deficiencies can be addressed with either preoperative or postoperative supplementation. Current data suggest that patients with adequate vitamin D levels may have better outcomes, but the details are not yet clear. Vitamin D supplementation is well tolerated with rare side effects.


Assuntos
Articulação do Tornozelo/cirurgia , Tornozelo/cirurgia , Pé/cirurgia , Deficiência de Vitamina D/complicações , Vitamina D/provisão & distribução , Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/diagnóstico por imagem , Procedimentos Cirúrgicos Eletivos/métodos , Pé/diagnóstico por imagem , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Vitamina D/administração & dosagem , Vitamina D/metabolismo
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