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2.
J Steroid Biochem Mol Biol ; 195: 105478, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31561003

RESUMO

The long-recognized role of the vitamin D endocrine system is to maintain stable serum calcium concentrations, which are ensured by a complex interplay between parathyroid gland, kidney, intestine, and bone. However, although VDR is expressed in osteoclastogenic cells, the contribution of VDR-mediated signaling to osteoclast differentiation and activity remains undefined. We therefore deleted Vdr expression efficiently and specifically in myeloid cells by use of M lysozyme-driven Cre expression, which targets granulocytes, monocytes, macrophages and osteoclasts (Vdrmyel- mice). Bone and calcium homeostasis were investigated under basal conditions and in conditions of increased bone remodeling, by feeding Vdrmyel- and Vdrmyel+ (wildtype) mice either a normal (1%) or a low (0.02%) calcium diet from weaning onwards. Vdrmyel- mice developed normally and were normocalcemic at the age of 8 weeks, both at the normal and the low calcium diet. No differences in trabecular or cortical bone mass were observed between Vdrmyel- mice and their wildtype littermates. Dietary calcium restriction resulted in a comparable reduction of trabecular bone mass (40%) and cortical thickness (48%) in Vdrmyel- and Vdrmyel+ mice, pointing to a massive transfer of calcium from the bone to the serum. In agreement with these results, osteoclastic differentiation of hematopoietic cells of Vdrmyel- mice, either induced by M-CSF and RANKL, or cocultured with osteoblasts, occurred as efficiently as osteoclastogenesis from Vdrmyel+ mice. In conclusion, our data do not support a role for osteoclastic Vdr signaling in the control of bone homeostasis.


Assuntos
Osso e Ossos/metabolismo , Osteoclastos/metabolismo , Receptores de Calcitriol/metabolismo , Animais , Cálcio/deficiência , Cálcio na Dieta , Células Cultivadas , Técnicas de Cocultura , Feminino , Homeostase , Macrófagos Peritoneais/metabolismo , Camundongos Transgênicos , Osteoblastos/metabolismo , Receptores de Calcitriol/genética
3.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 506-511, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484613

RESUMO

To investigate the expressions of mucosal barrier proteins in colon cell line DLD-1 under hypoxic environment in vitro and its mechanism. Methods After DLD-1 cells were treated separately with hypoxia(l% O2),vitamin D(100 nmol/L),or vitamin D plus hypoxia for 48 hours,the expressions of vitamin D receptor(VDR),tight junction proteins zonula occludens-1(ZO-1),occludin,Claudin-1,and adherent junction protein(E-cadherin)were determined by Western blot.Stable VDR knock-down(Sh-VDR)DLD-1 cell line and control DLD-1 cell line were established by lentivirus package technology and the protein expressions after hypoxia treatment were detected. Results Compared with control group,the expressions of occludin,Claudin-1,and VDR increased significantly after hypoxia treatment(all P<0.001).In addition to the protein expressions of occludin,Claudin-1 and VDR,the expressions of ZO-1 and E-cadherin were also obviously higher in vitamin D plus hypoxia group than in single vitamin D treatment group(all P<0.001).After hypoxia treatment,Sh-VDR cell line showed significantly decreased expressions of ZO-1(P<0.001),occludin(P<0.05),Claudin-1(P<0.01)and E-cadherin(P<0.001)when compared with untreated Sh-VDR cell line. Conclusion VDR acts as a regulator for the expressions of intestinal mucosal barrier proteins under hypoxia environment in DLD-1 colon cell line,indicating that VDR pathway may be another important protective mechanism for gut barrier in low-oxygen environment.


Assuntos
Colo/citologia , Receptores de Calcitriol/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Hipóxia Celular , Linhagem Celular , Claudina-1/metabolismo , Humanos , Ocludina/metabolismo , Junções Íntimas , Vitamina D/farmacologia , Proteína da Zônula de Oclusão-1/metabolismo
4.
Toxicol Lett ; 316: 109-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472180

RESUMO

Lithocholic acid (LCA) is both a secondary bile acid and a vitamin D receptor (VDR) ligand. The VDR is activated by 1,25-dihydroxy vitamin D3 and plays an important role in maintaining integrity of the intestinal mucosal barrier. LCA can also substitute for vitamin D to carry out the in vivo functions of vitamin D. However, it is unclear whether activation of the VDR by LCA affects mucosal barrier function. In the present study, we researched the protective effect of LCA on tumor necrosis factor-alpha (TNF-α)-induced intestinal epithelial barrier dysfunction in Caco-2 cells of the human epithelial intestinal adenocarcinoma cell line. Caco-2 cell monolayers were pretreated with LCA and then exposed to 100 ng/mL TNF-α. The results showed that LCA alleviated the decrease in transepithelial electrical resistance and the increase in FITC-Dextran flux induced by TNF-α. LCA ameliorated the TNF-α-induced decrease in protein expression and distribution of ZO-1, E-cadherin, Occludin, and Claudin-1, which are tight junction markers. Additionally, the LCA treatment effectively counteracted TNF-α-mediated downregulation of silent information regulator 1 (SIRT1), nuclear factor erythroid2-related factor 2 (Nrf2), and heme oxygenase-1, which are related to oxidative stress. Increases in NF-κB p-p65 and p-IκB-α induced by TNF-α were significantly inhibited by LCA. Considering all these, the present study indicates that LCA has a significant protective effect on TNF-α-induced injury of intestinal barrier function through the VDR and suggests that suppressing NF-κB signaling and activating the SIRT1/Nrf2 pathway might be one of the mechanisms underlying the protective effect of LCA.


Assuntos
Células Epiteliais/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Ácido Litocólico/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptores de Calcitriol/agonistas , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Células CACO-2 , Citoproteção , Impedância Elétrica , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Permeabilidade , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
6.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455010

RESUMO

1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs.


Assuntos
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Receptores de Calcitriol/metabolismo , Vitamina D/farmacologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Concentração Inibidora 50 , Cinética , Especificidade de Órgãos/efeitos dos fármacos , Ligação Proteica , Receptores de Calcitriol/agonistas , Vitamina D/análogos & derivados , Vitamina D/química
7.
Asian Pac J Cancer Prev ; 20(8): 2267-2273, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450894

RESUMO

Objective: The present study aimed to investigate the possible role of IL-6 and 1α,25-dihydroxyvitamin D3 (1,25D) signaling in epithelial-mesenchymal transition (EMT) and stemness in triple-negative breast cancer (TNBC) cell line. Methods: TNBC cell line, HCC 1806, was treated with IL-6 and 1,25D for three and six days. Also, the role of vitamin D receptor (VDR) was studied by transfection of TNBC cell line with VDR gene and transfection efficiency was assessed using Human VDR enzyme-linked immunosorbent assay (ELISA). Changes in E-cadherin gene expression were analyzed by quantitative real-time PCR (qRT-PCR). Also, changes in CD44+ cells were analyzed by flow cytometry. Finally, morphological changes were investigated by light microscopy after 6 days. Results: Treatment of HCC1806 cells with IL-6 has no significant effect either on E-cadherin gene expression or CD44+ cells, (p > 0.05). However, E-cadherin gene expression was significantly up-regulated after treatment with 1,25D for 6 days, (p < 0.05). Also, CD44+ cells were significantly reduced after treatment with 1,25D either for 3 or 6 days, (p < 0.05). Transfection of TNBC cell line with VDR gene significantly up-regulated VDR protein expression, (p < 0.05). In addition, overexpression of VDR in TNBC cells and treatment with 1,25D significantly up-regulated E-cadherin gene expression, (p < 0.05) and reduced CD44+ cells, (p < 0.05). Moreover, transfection with VDR and treatment with a combination of 1,25D and IL-6 significantly down-regulated E-cadherin gene expression and increased CD44+ cells compared with transfected cells with VDR treated with 1,25D alone, (p < 0.05). No significant morphological changes were observed in treated cells, 6 days post-treatment. Conclusion: The presence of IL-6 in the breast tumor microenvironment may impair the activity of vitamin D3 signaling, limiting its anti-tumor effects in TNBC.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Interleucina-6/administração & dosagem , Receptores de Calcitriol/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Vitamina D/análogos & derivados , Antígenos CD/genética , Caderinas/genética , Feminino , Humanos , Receptores de Calcitriol/genética , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Células Tumorais Cultivadas , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem
8.
Life Sci ; 234: 116755, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415769

RESUMO

AIMS: Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully elucidated. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase-derived metabolites of arachidonic acid, protecting against diabetes and DN. Herein, we hypothesized that activation of VDR attenuated high glucose-induced cellular injury in renal tubular epithelial cells partially through up-regulating CYP2J5 expression. MAIN METHODS: Streptozotocin (STZ) was injected to induce diabetic in wild type and Vdr-/- mice. The effects of VDR knockout and an activator of VDR, paricalcitol, on the renal injury were detected. In vitro, a murine kidney proximal tubule epithelial cell line BU.MPT induced by high glucose were treated with or without paricalcitol (30 mM) for 12 h or 24 h. KEY FINDINGS: The expression of CYP2J5 was significantly decreased both in wild type and Vdr-/- diabetic mice induced by STZ. The STZ-induced kidney architecture damage and apoptosis rate in Vdr-/- mice were more severe. In vitro, high glucose treatment strongly reduced the CYP2J5 expression and the synthesis of 14,15-EET in BU.MPT cells. Supplement of 14,15-EET significantly reduced the lactate dehydrogenase (LDH) release induced by high glucose in BU.MPT cells. Furthermore, treatment with paricalcitol attenuated cellular injury and restored the expression of CYP2J5 reduced by high glucose in BU.MPT cells. SIGNIFICANCE: We conclude that activation of VDR attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cells and paricalcitol may represent a potential therapy for DN.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Ergocalciferóis/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Receptores de Calcitriol/agonistas , Animais , Linhagem Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Ergocalciferóis/uso terapêutico , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo
9.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31387330

RESUMO

Vitamin D is a major steroid hormone that is gaining attention as a therapeutic molecule. Due to the general awareness of its importance for the overall well-being, vitamin D deficiency (VDD) is now recognized as a major health issue. The main reason for VDD is minimal exposure to sunlight. The vitamin D receptor (VDR) is a member of the steroid hormone receptors that induces a cascade of cell signaling to maintain healthy Ca2+ levels that serve to regulate several biological functions. However, the roles of vitamin D and its metabolism in maintaining gastric homeostasis have not yet been completely elucidated. Currently, there is a need to increase the vitamin D status in individuals worldwide as it has been shown to improve musculoskeletal health and reduce the risk of chronic illnesses, including some cancers, autoimmune and infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and general mortality. The role of vitamin D in gastric homeostasis is crucial and unexplored. This review attempts to elucidate the central role of vitamin D in preserving and maintaining the overall health and homeostasis of the stomach tissue.


Assuntos
Receptores de Calcitriol/metabolismo , Estômago/fisiologia , Vitamina D/metabolismo , Animais , Transporte Biológico , Biomarcadores , Cálcio/metabolismo , Homeostase , Humanos , Ligantes , Fosfatos/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Vitamina D/química
10.
Curr Protein Pept Sci ; 20(10): 984-995, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389312

RESUMO

Vitamin D, as a natural medicine, is known to regulate calcium and phosphate homeostasis. But abundant research has shown that vitamin D also plays a regulatory role in autoimmunity, inflammation, angiogenesis and vascular cell activity. Since the vitamin D receptor (VDR) is widely distributed in vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes, the role of vitamin D and VDR in hypertension has received extensive attention. Hypertension is a disease with high incidence and high cardiovascular risk. In recent years, both clinical trials and animal experiments have shown that vitamin D plays a regulatory role in decreasing blood pressure (BP) through inhibiting renin-angiotensin-aldosterone system activity, modulating function of vascular wall and reducing vascular oxidative stress. A growing body of data suggest that vitamin D deficiency is associated with increased cardiovascular disease risk in hypertension, even short-term vitamin D deficiency may directly raise BP and promote target organ damage. Due to the high correlation between vitamin D and hypertension, vitamin D supplementation therapy may be a new insight in the treatment of hypertension. The aim of this review will explore the mechanisms of the vitamin D and VDR in regulating the BP and protecting against the target organ damage.


Assuntos
Anti-Hipertensivos , Hipertensão/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Humanos , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inibidores , Sistema Renina-Angiotensina/efeitos dos fármacos
11.
Nutrients ; 11(8)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382666

RESUMO

The active form of vitamin D (calcitriol) exerts its biological effects by binding to nuclear vitamin D receptors (VDRs), which are found in most human extraskeletal cells, including skeletal muscles. Vitamin D deficiency may cause deficits in strength, and lead to fatty degeneration of type II muscle fibers, which has been found to negatively correlate with physical performance. Vitamin D supplementation has been shown to improve vitamin D status and can positively affect skeletal muscles. The purpose of this study is to summarize the current evidence of the relationship between vitamin D, skeletal muscle function and physical performance in athletes. Additionally, we will discuss the effect of vitamin D supplementation on athletic performance in players. Further studies are necessary to fully characterize the underlying mechanisms of calcitriol action in the human skeletal muscle tissue, and to understand how these actions impact the athletic performance in athletes.


Assuntos
Atletas , Desempenho Atlético , Calcitriol/administração & dosagem , Suplementos Nutricionais , Contração Muscular/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estado Nutricional , Deficiência de Vitamina D/tratamento farmacológico , Animais , Calcitriol/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/fisiopatologia
12.
J Steroid Biochem Mol Biol ; 193: 105431, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31326626

RESUMO

Vitamin D reveals antiproliferative activity against many types of cancer cells. Calcitriol (1,25D3), the most active form of vitamin D3, acts mainly through the vitamin D receptor, regulating the expression of target genes. Cells with reasonable expression of VDR are considered to be sensitive to antiproliferative activity of 1,25D3. However, a few alleles of the VDR gene are correlated with higher or lower response to 1,25D3 treatment. The goal of our study was to establish if cells differing in EGFR, KRAS, p53 mutation status and VDR polymorphism were sensitive to antiproliferative activity of selected vitamin D derivatives (VDDs). In our search for the lead VDD against human lung cancer cells, we selected, for this study, low calcemic analogs of active forms of vitamin D2 and D3 that had previously shown anticancer potential. The selected cell lines revealed differential response to VDDs. The highest proliferation inhibition was observed for EGFR mutant cells while a weaker response was observed for KRAS and/or p53 mutant cells. 24,24-Dihomo-1,25D3 (PRI-1890) showed the highest activity on the VDD-sensitive cell lines (A549, HCC827, NCI-H1299, and NCI-H1703). Therefore, PRI-1890 was selected as the lead VDD for further structure optimization. None of the VDDs used in this study showed antiproliferative activity against A-427 and Calu-3. VDR polymorphisms correlated inversely with sensitivity to the antiproliferative activity of VDDs since we observed less transcriptionally active form of VDR in HCC827 cells sensitive to VDD, while more transcriptionally active form was observed in NCI-H358 cells that were stimulated by VDDs to proliferate. Lack of KRAS and p53 mutations in HCC827 cells may be, therefore, responsible for the higher antiproliferative activity of VDDs, while the presence of KRAS and/or p53 mutations in other cell lines might prevent antiproliferative activity even though the VDDs were transcriptionally active as assessed on increased CYP24A1 expression. VDR gene polymorphism is not directly responsible for the sensitivity of tested cells to VDDs.


Assuntos
Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Vitaminas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/metabolismo , Mutação , Polimorfismo Genético , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo
13.
Biomed Res Int ; 2019: 9013904, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275989

RESUMO

Background: It has been documented that vitamin D supplementation showed an improvement of symptoms of diabetic nephropathy; however, the underlying mechanisms remain unknown. We here tested the hypothesis that active vitamin D is able to up-regulate AKT/UCP2 signaling to alleviate oxidative stress of renal tubular cell line HK2. Methods: There are eight groups in the present study: normal glucose, osmotic control (5.5 mmol/L D-glucose+24.5 mmol/L D-mannitol), NAC control (30 mmol/L D-glucose + 1.0 mmol/L N-Methylcysteine), high glucose, high glucose+VD, high glucose (HG)+VD+siVDR, HG+VD+AKT inhibitor (AI), and high glucose+VD+UCP2 inhibitor (Gelipin). Concentration of superoxide dismutase (SOD) and malondialdehyde (MDA) was analyzed by ELISA. Reactive oxygen species (ROS), mitochondrial membrane potential and apoptosis were measured by flow cytometry. JC-1 was evaluated by flow cytometry. The presence of VDR, AKT, and UCP2 in HK cells was assessed using RT-PCR and western blot analyses. Results: VD administration significantly upregulated the SOD activation and downregulated MDA levels compared to HG group. siVDR, AKT inhibitor, and UCP2 inhibitor significantly suppressed the activation of SOD and increased the expression of MDA compared to VD group. ROS generation and apoptosis of HK2 cells in HG+VD group were significantly lower than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. ΔΨm in HG+VD group was obviously higher than those in HG, HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group. Decreased mRNA and protein levels of VDR, p-AKT, and UCP2 were observed in HG+VD+siVDR, HG+VD+AI, and HG+VD+Gelipin group compared to those in HG+VD group. Conclusions: siVDR, AKT inhibitor, and UCP2 inhibitor elevated the ROS and apoptosis of HK2 cells while attenuating the mitochondrial membrane potential, suggesting that vitamin D protects renal tubular cell from high glucose by AKT/UCP2 signaling pathway.


Assuntos
Glucose/toxicidade , Túbulos Renais/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Proteína Desacopladora 2/metabolismo , Vitamina D/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
14.
Biomed Pharmacother ; 117: 109170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261027

RESUMO

Vitamin D deficiency is identified as a risk factor for gestational diabetes mellitus (GDM). Forkhead box class O1 (FoxO1) is closely related to GDM; however, the role of vitamin D deficiency and the underlying pathogenesis of GDM has not been elucidated. Serum vitamin D level was detected using chemiluminescence immunoassay. FOXO1 expression was examined using Real-time polymerase chain reaction (PCR), western blot and immunocytochemistry analysis. Apoptosis of cells was assessed by flow cytometry. Mitochondrial function was assessed via reactive oxygen species (ROS) generation and changes in the mitochondrial membrane potential (ΔΨm). Our study demonstrated that vitamin D levels were significantly lower in 40 GDM patients. The silencing of the vitamin D receptor (VDR) decreased cell survival and increased both FoxO1 mRNA and protein expression. Overexpression of FoxO1 could cause the mitochondrial dysfunction (including production of ROS and decrease of mitochondrial membrane potential (ΔΨm)) and cell apoptosis. However, Overexpression of VDR and vitamin D treatment could induce the cell survival and alleviate the FoxO1-induced cell apoptosis, furthermore, vitamin D treatment or silencing of FoxO1 gene could reverse the ROS-induced cell apoptosis. Therefore, our results support that vitamin D may protect FoxO1-induced pancreatic beta cell apoptosis, which suggests that vitamin D may have beneficial effects in preventing and treating GDM.


Assuntos
Apoptose , Citoproteção , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Receptores de Calcitriol/metabolismo , Adulto , Sobrevivência Celular , Diabetes Gestacional/sangue , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Gravidez , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Vitamina D/sangue
15.
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
16.
J Steroid Biochem Mol Biol ; 193: 105434, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351131

RESUMO

Intracellular calcium (Ca) levels play pivotal roles in aldosterone biosynthesis. Several somatic mutations of ion channels associated with aldosterone over-production were reported to result in over-inflow of Ca ion. Recently, the main regulators of extracellular Ca including VDR, CaSR and PTH1R were also reported to regulate steroidogenesis including aldosterone production. Therefore, not only intracellular but also extracellular Ca levels could regulate aldosterone biosynthesis. In addition, primary aldosteronism (PA) is clinically associated with not only more frequent cardiovascular events but also secondary metabolic disorders including abnormal calcium metabolism, osteoporosis and others. However, the details of Ca metabolic abnormalities associated with, including the potential correlation between those abnormalities and aldosterone overproduction, have remained virtually unknown. Therefore, in this study, we first immunolocalized Ca metabolism-related receptors (CaSR, VDR and PTH1R) in normal adrenal glands (NAs), aldosterone-producing adenomas (APAs) and cortisol-producing adenoma (CPA). We then compared the findings with clinicopathological parameters of these patients and the patterns of KCNJ5 somatic mutation of the tumors among APA patients. In vitro study was also performed to further explore the potential effects of extracellular Ca, PTH, Vitamin D and ionophore on aldosterone production. Ca metabolism-related receptors were predominantly localized in aldosterone-producing cells (ZG and APA) in both immunohistochemistry and qRT-PCR analysis. CYP11B2 mRNA was significantly increased by CaCl2 treatment and further by adding ionophore. All the key enzymes related to aldosterone and cortisol biosynthesis including CYP11B2, CYP17A1 and CYP11B1 were upregulated by PTH treatment in this model and PTH could serve as a co-stimulator of ANG II to increase CYP11B2 expression. VDR mRNA levels were positively correlated with those of CYP11B2, CYP17A1 and CYP11B1 in APA tumor tissues and significantly higher in KCNJ5 mutated APAs than wild type. CYP11B1 levels were also significantly increased by VitD treatment. PTH1R mRNA levels were positively correlated with those of CYP17A1 and CYP11B1, both involved in cortisol production. In addition, the status of VDR was correlated with TRACP-5b levels, and that of PTH1R with serum Ca levels as well as urinary Ca excretion, respectively. Results of our present study did firstly demonstrate that aldosterone-producing cells were more sensitive to the fluctuations of extracellular Ca levels and Ca metabolism could directly influence steroidogenesis, especially "neoplastic" co-secretion of aldosterone and cortisol in APA patients.


Assuntos
Glândulas Suprarrenais/metabolismo , Aldosterona/metabolismo , Cálcio/metabolismo , Hiperaldosteronismo/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Feminino , Humanos , Hiperaldosteronismo/genética , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptores de Calcitriol/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Adulto Jovem
17.
Breast Cancer Res ; 21(1): 84, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358030

RESUMO

BACKGROUND: Vitamin D has been suggested to prevent and improve the prognosis of several cancers, including breast cancer. We have previously shown a U-shaped association between pre-diagnostic serum levels of vitamin D and risk of breast cancer-related death, with poor survival in patients with the lowest and the highest levels respectively, as compared to the intermediate group. Vitamin D exerts its functions through the vitamin D receptor (VDR), and the aim of the current study was to investigate if the expression of VDR in invasive breast tumors is associated with breast cancer prognosis. METHODS: VDR expression was evaluated in a tissue microarray of 718 invasive breast tumors. Covariation between VDR expression and established prognostic factors for breast cancer was analyzed, as well as associations between VDR expression and breast cancer mortality. RESULTS: We found that positive VDR expression in the nuclei and cytoplasm of breast cancer cells was associated with favorable tumor characteristics such as smaller size, lower grade, estrogen receptor positivity and progesterone receptor positivity, and lower expression of Ki67. In addition, both intranuclear and cytoplasmic VDR expression were associated with a low risk of breast cancer mortality, hazard ratios 0.56 (95% CI 0.34-0.91) and 0.59 (0.30-1.16) respectively. CONCLUSIONS: This study found that high expression of VDR in invasive breast tumors is associated with favorable prognostic factors and a low risk of breast cancer death. Hence, a high VDR expression is a positive prognostic factor.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Expressão Gênica , Receptores de Calcitriol/genética , Idoso , Biomarcadores , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptores de Calcitriol/metabolismo , Suécia/epidemiologia
18.
Nutrients ; 11(7)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252594

RESUMO

The vitamin D receptor is expressed in multiple cells of the body (other than osteoblasts), including beta cells and cells involved in immune modulation (such as mononuclear cells, and activated T and B lymphocytes), and most organs in the body including the brain, heart, skin, gonads, prostate, breast, and gut. Consequently, the extra-skeletal impact of vitamin D deficiency has been an active area of research. While epidemiological and case-control studies have often suggested a link between vitamin D deficiency and conditions such as type 1 and type 2 diabetes, connective tissue disorders, inflammatory bowel disorders, chronic hepatitis, food allergies, asthma and respiratory infections, and cancer, interventional studies for the most part have failed to confirm a causative link. This review examines available evidence to date for the extra-skeletal effects of vitamin D deficiency, with a focus on randomized controlled trials and meta-analyses.


Assuntos
Doenças não Transmissíveis/epidemiologia , Receptores de Calcitriol/metabolismo , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Pré-Escolar , Suplementos Nutricionais , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Doenças não Transmissíveis/prevenção & controle , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Transdução de Sinais , Vitamina D/uso terapêutico , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia , Adulto Jovem
19.
Chem Soc Rev ; 48(13): 3497-3512, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31214680

RESUMO

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.


Assuntos
Boranos/química , Animais , Boranos/farmacologia , Desenho de Drogas , Enzimas/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fator 1 Induzível por Hipóxia/metabolismo , Ligantes , Receptores Androgênicos/metabolismo , Receptores de Calcitriol/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Purinérgicos/metabolismo
20.
J Periodontal Res ; 54(6): 671-680, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31215652

RESUMO

BACKGROUND AND OBJECTIVES: Serum 25-hydroxyvitamin D3 (25(OH)D3 ), a newly emerged immune regulator, is considered to be involved in type 2 diabetic periodontitis (T2DCP). However, the risk factors and genes with altered expression that influence the progression and severity of T2DCP remain unknown. Accordingly, the aim of the present study was to elucidate the relationship between 25(OH)D3 deficiency and severity of T2DCP as well as the potential mechanisms. MATERIAL AND METHODS: A total of 182 subjects were divided into two groups: chronic periodontitis without diabetes (P group, n = 88) and type 2 diabetes mellitus with periodontitis (DM+P group, n = 94). Patients in both groups were further classified according to age as young (Y) and elderly (E) for a total of four groups: P/Y, P/E, DM+P/Y, and DM+P/E. Periodontal status was evaluated based on the probing depth (PD) and clinical attachment loss (CAL). The serum levels of human 25(OH)D3 , interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assays. Immunohistochemistry was used to measure the expression of protein tyrosine phosphatase non-receptor type 2 (PTPN2), vitamin D receptor (VDR), and JAK/STAT proteins in the gingival tissue. RESULTS: Serum 25(OH)D3 levels were lower in the DM+P group than those in the P group (P < 0.001). When the patients were subgrouped according to age, 25(OH)D3 deficiency was more commonly found in DM+P/E than in DM+P/Y (67% vs 51%), with a significant difference detected in the 25(OH)D3 quartile of 15-20 ng/mL (P = 0.007). The 25(OH)D3 level showed a significant negative correlation with fasting blood glucose (FBG) (r = -0.623), serum IL-1ß (r = -0.392), serum TNF-α (r = -0.218), PD (r = -0.269), and CAL (r = -0.305) in the DM+P group (all P < 0.05), but not with hemoglobin A1c (P = 0.123). Additionally, reduced VDR and PTPN2 expression levels were observed in DM+P patients, whereas JAK1 and p-STAT5 protein levels were increased in this group. CONCLUSIONS: Vitamin D3 deficiency is strongly associated with T2DCP, and age mediates this relationship. Abnormal FBG and IL-1ß levels should be considered as important potential risk factors for the progression and severity of T2DCP. Moreover, 25(OH)D3 deficiency may be related to the immune function of T2DCP by weakening PTPN2 signaling.


Assuntos
Periodontite Crônica/sangue , Diabetes Mellitus Tipo 2/complicações , Vitamina D/análogos & derivados , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Calcifediol , Periodontite Crônica/complicações , Estudos Transversais , Feminino , Gengiva/metabolismo , Humanos , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Receptores de Calcitriol/metabolismo , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue , Vitamina D/sangue , Adulto Jovem
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