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1.
Anticancer Res ; 41(11): 5453-5459, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732414

RESUMO

BACKGROUND: Zinc is a mineral that is essential for biological molecules, such as transcription factors, and is involved in the maintenance of intestinal homeostasis. Vitamin D signaling is mediated by vitamin D receptor (VDR) activated by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and is also important in intestinal functions, such as calcium absorption and epithelial barrier maintenance. However, the crosstalk between vitamin D signaling and zinc signaling in intestinal cells remains poorly understood. MATERIALS AND METHODS: Colon cancer SW480 and HCT116 cells were treated with zinc chloride (ZnCl2) with/without 1,25(OH)2D3 Expression of zinc-inducible genes [metallothionein 1A (MT1A) and MT2A] and VDR target genes [cytochrome P450 family 24 subfamily A member 1 (CYP24A1), transient receptor potential cation channel subfamily V member 6 (TRPV6) and cadherin 1 (CDH1)] was examined. RESULTS: Treatment of cells with ZnCl2 effectively induced MT1A and MT2A mRNA expression, and interestingly suppressed mRNA expression of CDH1, which was induced by 1,25(OH)2D3 in both cell lines. ZnCl2 also reduced the CDH1 protein level in HCT116 cells. CONCLUSION: Zinc signaling suppresses VDR-induced expression of CDH1.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Calcitriol/farmacologia , Cloretos/farmacologia , Neoplasias do Colo/metabolismo , Receptores de Calcitriol/agonistas , Compostos de Zinco/farmacologia , Antígenos CD/genética , Caderinas/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Metalotioneína/genética , Metalotioneína/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de Sinais
2.
J Health Popul Nutr ; 40(1): 46, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727991

RESUMO

BACKGROUND: Both human genes and environmental exposures, due to complex interplay, play important role in the cancer etiology. Vitamin D is associated with a reduced risk of incidence and mortality of several human cancers. This study will aim to investigate the possible effects of individual polymorphisms in vitamin D receptor (VDR) as well as effects of VDR haplotypes on response to vitamin D supplementation in breast cancer survivors. METHODS: This is an interventional study in which the effects of vitamin D supplementation on plasma vitamin D levels, inflammatory and antioxidant biomarkers and factors associated with cell proliferation, differentiation, damage, and apoptosis will be investigated stratified by variations in VDR genotype. The present study will be conducted on breast cancer survivors referred to the Shohadaye Tajrish hospital and its associated clinics. One hundred ninety-eight breast cancer survivors will receive 4000 IU of vitamin D3 daily for 12 weeks. VDR Fok1, ApaI, TaqI, BsmI, and Cdx-2 genotype will be determined at the end of the study and responses to vitamin D supplements (inflammatory, antioxidant, cell proliferation, differentiation, damage, and apoptosis biomarkers) will be compared between the three subgroups of each VDR polymorphism as well as different VDR haplotype categories. DISCUSSION: Genetic variation is a fundamental factor influencing individuals' divergent responses to diet, nutritional status, metabolic response, and diet-related health disorders. Furthermore, studies of gene and environment interactions will provide a precise and accurate assessments of individuals' dietary requirements by considering both the genetic and environmental aspects simultaneously. The results of the current study, to some extent, will highlight the discrepancies existing in the findings of different studies regarding vitamin D, VDR, and cancer by considering both the genetic and environmental aspects simultaneously. If responses to vitamin D supplementation could be modified by VDR SNPs, determining the distribution of VDR polymorphisms in both breast cancer survivors and healthy populations will provide a new insight into the vitamin D requirements of individuals to prevent cancer and its related mortality based on their genotypes. Trial registration This trial has been registered on Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Vitamina D , Biomarcadores , Neoplasias da Mama/genética , Suplementos Nutricionais , Feminino , Genótipo , Humanos , Inflamação , Irã (Geográfico) , Estresse Oxidativo/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/administração & dosagem
3.
J Biol Chem ; 297(4): 101233, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34562448

RESUMO

Clinical and epidemiological studies support a role for vitamin D in suppressing hepatitis B virus (HBV). This antiviral role of vitamin D is widely attributed to vitamin D receptor (VDR)/retinoid X receptor-mediated regulation of host immunomodulatory genes through vitamin D response elements (VDREs) in their promoters. Here, we investigated the ability of calcitriol (1α,25-dihydroxyvitamin D3, metabolically activated vitamin D) to directly regulate HBV activity through this signaling pathway. We observed that calcitriol selectively inhibited only the HBV core promoter without affecting the HBV-PreS1, HBV-PreS2/S, or HBx promoters. We then identified a VDRE cluster in the HBV core promoter that is highly conserved across most HBV genotypes. Disruption of this VDRE cluster abrogated calcitriol-mediated suppression of the HBV core promoter. Furthermore, we showed that VDR interacts directly with the VDRE cluster in the HBV core promoter independent of retinoid X receptor. This demonstrates that calcitriol inhibits HBV core promoter activity through a noncanonical calcitriol-activated VDR pathway. Finally, we observed that calcitriol suppressed expression of the canonical HBV core promoter transcripts, pregenomic RNA, and precore RNA in multiple HBV cell culture models. In addition, calcitriol inhibited the secretion of hepatitis B "e" antigen and hepatitis B surface antigen (HBV-encoded proteins linked to poor disease prognosis), without affecting virion secretion. Our findings identify VDR as a novel regulator of HBV core promoter activity and also explain at least in part the correlation of vitamin D levels to HBV activity observed in clinical studies. Furthermore, this study has implications on the potential use of vitamin D along with anti-HBV therapies, and lays the groundwork for studies on vitamin D-mediated regulation of viruses through VDREs in virus promoters.


Assuntos
Calcitriol/farmacologia , Antígenos E da Hepatite B/biossíntese , Vírus da Hepatite B/metabolismo , Regiões Promotoras Genéticas , Receptores de Calcitriol/metabolismo , Receptores X de Retinoides/metabolismo , Células Hep G2 , Hepatite B/tratamento farmacológico , Hepatite B/genética , Hepatite B/metabolismo , Antígenos E da Hepatite B/genética , Vírus da Hepatite B/genética , Humanos , Receptores de Calcitriol/genética , Receptores X de Retinoides/genética
4.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502192

RESUMO

The release of exosomes can lead to cell-cell communication. Nutrients such as vitamin D3 and sphingolipids have important roles in many cellular functions, including proliferation, differentiation, senescence, and cancer. However, the specific composition of sphingolipids in exosomes and their changes induced by vitamin D3 treatment have not been elucidated. Here, we initially observed neutral sphingomyelinase and vitamin D receptors in exosomes released from HN9.10 embryonic hippocampal cells. Using ultrafast liquid chromatography tandem mass spectrometry, we showed that exosomes are rich in sphingomyelin species compared to whole cells. To interrogate the possible functions of vitamin D3, we established the optimal conditions of cell treatment and we analyzed exosome composition. Vitamin D3 was identified as responsible for the vitamin D receptor loss, for the increase in neutral sphingomyelinase content and sphingomyelin changes. As a consequence, the generation of ceramide upon vitamin D3 treatment was evident. Incubation of the cells with neutral sphingomyelinase, or the same concentration of ceramide produced in exosomes was necessary and sufficient to stimulate embryonic hippocampal cell differentiation, as vitamin D3. This is the first time that exosome ceramide is interrogated for mediate the effect of vitamin D3 in inducing cell differentiation.


Assuntos
Diferenciação Celular , Ceramidas/metabolismo , Colecalciferol/farmacologia , Exossomos/metabolismo , Hipocampo/metabolismo , Vitaminas/farmacologia , Células Cultivadas , Exossomos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/embriologia , Humanos , Receptores de Calcitriol/metabolismo , Esfingomielina Fosfodiesterase/metabolismo
5.
Int J Mol Sci ; 22(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34502510

RESUMO

Vitamin D showed a protective effect on intervertebral disc degeneration (IDD) although conflicting evidence is reported. An explanation could be due to the presence of the FokI functional variant in the vitamin D receptor (VDR), observed as associated with spine pathologies. The present study was aimed at investigating-through high-throughput gene and protein analysis-the response of human disc cells to vitamin D, depending on the VDR FokI variants. The presence of FokI VDR polymorphism was determined in disc cells from patients with discopathy. 1,25(OH)2D3 was administered to the cells with or without interleukin 1 beta (IL-1ß). Microarray, protein arrays, and multiplex protein analysis were performed. In both FokI genotypes (FF and Ff), vitamin D upregulated metabolic genes of collagen. In FF cells, the hormone promoted the matrix proteins synthesis and a downregulation of enzymes involved in matrix catabolism, whereas Ff cells behaved oppositely. In FF cells, inflammation seems to hamper the synthetic activity mediated by vitamin D. Angiogenic markers were upregulated in FF cells, along with hypertrophic markers, some of them upregulated also in Ff cells after vitamin D treatment. Higher inflammatory protein modulation after vitamin D treatment was observed in inflammatory condition. These findings would help to clarify the clinical potential of vitamin D supplementation in patients affected by IDD.


Assuntos
Disco Intervertebral/efeitos dos fármacos , Receptores de Calcitriol/genética , Vitamina D/farmacologia , Adulto , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Proteômica/métodos , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitaminas/farmacologia
6.
Nutrients ; 13(9)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34578802

RESUMO

It is urgent to seek new potential targets for the prevention or relief of gastrointestinal syndrome in clinical radiation therapy for cancers. Vitamin D, mediated through the vitamin D receptor (VDR), has been identified as a protective nutrient against ionizing radiation (IR)-induced damage. This study investigated whether VDR could inhibit IR-induced intestinal injury and explored underlying mechanism. We first found that vitamin D induced VDR expression and inhibited IR-induced DNA damage and apoptosis in vitro. VDR was highly expressed in intestinal crypts and was critical for crypt stem/progenitor cell proliferation under physiological conditions. Next, VDR-deficient mice exposed to IR significantly increased DNA damage and crypt stem/progenitor cell apoptosis, leading to impaired intestinal regeneration as well as shorter survival time. Furthermore, VDR deficiency activated the Pmaip1-mediated apoptotic pathway of intestinal crypt stem/progenitor cells in IR-treated mice, whereas inhibition of Pmaip1 expression by siRNA transfection protected against IR-induced cell apoptosis. Therefore, VDR protects against IR-induced intestinal injury through inhibition of crypt stem/progenitor cell apoptosis via the Pmaip1-mediated pathway. Our results reveal the importance of VDR level in clinical radiation therapy, and targeting VDR may be a useful strategy for treatment of gastrointestinal syndrome.


Assuntos
Apoptose/efeitos dos fármacos , Intestinos/efeitos da radiação , Lesões Experimentais por Radiação/prevenção & controle , Receptores de Calcitriol/metabolismo , Células-Tronco/metabolismo , Vitamina D/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Lesões Experimentais por Radiação/patologia , Protetores contra Radiação/farmacologia , Ratos
7.
Cell Biochem Funct ; 39(7): 874-885, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231237

RESUMO

The development of chronic kidney disease (CKD) drugs remains a challenge due to the variations in the genes. The vitamin D receptor (VDR) and Cytochrome 24A1 (CYP24A1) genetic variants might affect the drug potency, efficacy and pathway. Here we have to analyse and determine the deleterious single-nucleotide polymorphisms (nsSNPs) of VDR and CYP24A1 genes and their different population's drug responses in different populations to understand the key role in CKD. Among that the large scale of nsSNP, we used certain computational tools that predicted six missense variants are observed to be significantly damaging effect and SNP variability with large differences in various populations. Molecular docking studies were carried out by clinical and our screened compounds to VDR and CYP24A1. Docking results revealed all the compounds have a good binding affinity (Score). The screened compounds (TCM_2868 and UNPD_141613) show good binding affinity when compared to known compounds. The QM/MM study revealed that the compounds have electron transfer ability and act as a donor/acceptor to mutated proteins. The structural and conformational changes of protein complexes were analysed by molecular dynamics study. Hence, this study helps to identify suitable drugs through drug discovery in CKD treatment. The abovementioned compounds have more binding affinity, efficacy, and potency of both wild and mutant of VDR and CYP24A1.


Assuntos
Teoria Quântica , Receptores de Calcitriol/química , Receptores de Calcitriol/metabolismo , Vitamina D3 24-Hidroxilase/química , Vitamina D3 24-Hidroxilase/metabolismo , Humanos , Modelos Moleculares , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética
8.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208589

RESUMO

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor ß (TGFß), insulin-like growth factor (IGF) and Wnt-ß-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Neoplasias/etiologia , Deficiência de Vitamina D/complicações , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Redes e Vias Metabólicas , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Prognóstico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/metabolismo
9.
Andrologia ; 53(9): e14172, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34197002

RESUMO

Vitamin D deficiency has been linked with different health problems including male infertility. Its function is mediated by the vitamin D receptor, which acts as a transcription factor. Epigenetic mechanisms such as DNA methylation may affect the vitamin D receptor gene and result in gene silencing. The present study aimed to assess serum vitamin D level and seminal methylation of vitamin D receptor gene in idiopathic male infertility. Blood and semen samples were collected from 60 men with idiopathic infertility and 40 healthy fertile men. Vitamin D levels were detected using enzyme-linked fluorescent assay technique and methylation status was assessed by methylation-specific PCR. Results revealed that serum levels of 25OHD were significantly lower in patients compared to controls. Positive correlation was found between serum level of 25OHD and sperm concentration in patients group and progressive motility in total studied group. Methylation of vitamin D receptor gene was significantly higher in patients compared to control group. Negative correlation was found between methylation of vitamin D receptor gene and both sperm concentration and progressive motility in total studied group. Results of the present study suggest that vitamin D deficiency and vitamin D receptor gene methylation may be involved in aetiopathogenesis of idiopathic male infertility.


Assuntos
Infertilidade Masculina , Receptores de Calcitriol/genética , Vitamina D/sangue , Metilação de DNA , Egito/epidemiologia , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Receptores de Calcitriol/metabolismo , Sêmen , Motilidade Espermática , Espermatozoides/metabolismo
10.
Mol Med Rep ; 24(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34165161

RESUMO

Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vertigo­associated disease. Vitamin D (VD) helps maintain normal otolith function and may be associated with BPPV. VD exerts its biological functions primarily via the VD receptor (VDR). The present study demonstrated that serum VD levels were significantly decreased in patients with BPPV compared with in controls. VDR, otolith­associated protein otoconin­90 (OC90) and NADPH oxidase 3 (NOX3) expression levels were also significantly decreased in patients with BPPV compared with in controls. Furthermore, a positive correlation was observed between VD levels and VDR expression. Receiver operating characteristic curve analysis identified VDR expression levels as a potential diagnostic marker for BPPV. OC90 and NOX3 expression levels were notably lower in the inner ear tissue of VDR knockout mice compared with in those of wild­type mice. In mice overexpressing VDR, OC90 and NOX3 were also overexpressed. Following intravenous injection of VD in VDR knockout mice, expression levels of OC90 and NOX3 were not significantly different from those in VDR knockout mice injected with saline. This indicated that VDR may be underexpressed in patients with BPPV and was associated with the expression levels of otolith­associated proteins. Moreover, VDR mediated VD activation, leading to otolith protein formation. The present study provided a novel theoretical basis for BPPV onset that may facilitate the development of more effective diagnostic and treatment options.


Assuntos
Vertigem Posicional Paroxística Benigna/genética , Regulação para Baixo , Membrana dos Otólitos , Proteômica , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Vertigem Posicional Paroxística Benigna/sangue , Vertigem Posicional Paroxística Benigna/complicações , Proteínas de Ligação ao Cálcio , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Vitamina D/sangue
11.
J Chem Inf Model ; 61(7): 3625-3637, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34189910

RESUMO

The vitamin D receptor ligand-binding domain (VDR-LBD) undergoes conformational changes upon ligand binding. In this nuclear receptor family, agonistic or antagonistic activities are controlled by the conformation of the helix (H)12. However, all crystal structures of VDR-LBD reported to date correspond to the active H12 conformation, regardless of agonist/antagonist binding. To understand the mechanism of VDR-LBD regulation structurally, conformational samplings of agonist- and antagonist-bound rat VDR-LBD were performed using the generalized replica exchange with solute tempering (gREST) method. The gREST simulations demonstrated different structural responses of rat VDR-LBD to agonist or antagonist binding, whereas in conventional molecular dynamics simulations, the conformation was the same as that of the crystal structures, regardless of agonist/antagonist binding. In the gREST simulations, a spontaneous conformational change of H12 was observed only for the antagonist complex. The different responses to agonist/antagonist binding were attributed to hydrophobic core formation at the ligand-binding pocket and cooperative rearrangements of H11. The gREST method can be applied to the examination of structure-activity relationships for multiple VDR-LBD ligands.


Assuntos
Simulação de Dinâmica Molecular , Receptores de Calcitriol , Animais , Sítios de Ligação , Ligantes , Conformação Molecular , Ligação Proteica , Ratos , Receptores de Calcitriol/metabolismo
12.
Nutrients ; 13(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069442

RESUMO

We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast cancer patients (n = 581) in four different datasets were divided into those expressing higher (above median) and lower levels of VDR in pretreatment ER+ tumors. Across all datasets, TAM-treated patients with higher pretreatment tumor VDR expression exhibited significantly longer recurrence-free survival. Ingenuity pathway analysis identified autophagy and unfolded protein response (UPR) as top differentially expressed pathways between high and low VDR-expressing ER+ cancers. Activation of VDR with vitamin D (VitD), either calcitriol or its synthetic analog EB1089, sensitized MCF-7-derived, antiestrogen-resistant LCC9 human breast cancer cells to TAM, and attenuated increased UPR and pro-survival autophagy. Silencing of VDR blocked these effects through the IRE1α-JNK pathway. Further, silencing of VDR impaired sensitivity to TAM in antiestrogen-responsive LCC1 cells, and prevented the effects of calcitriol and EB1089 on UPR and autophagy. In a preclinical mouse model, dietary VitD supplementation induced VDR activation and reduced carcinogen-induced ER+ mammary tumor incidence. In addition, IRE1α-JNK signaling was downregulated and survival autophagy was inhibited in mammary tumors of VitD-supplemented mice. Thus, activation of VDR is predictive of reduced risk of breast cancer recurrence in ER+ patients, possibly by inhibiting antiestrogen-promoted pro-survival autophagy.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Tamoxifeno/farmacologia , Animais , Mama/metabolismo , Calcitriol/análogos & derivados , Linhagem Celular Tumoral , Endorribonucleases , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Proteínas Serina-Treonina Quinases , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados
13.
Anticancer Res ; 41(6): 2945-2952, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083285

RESUMO

AIM: To evaluate the effects of the combination of calcitriol and chemotherapy and to identify the molecular mechanisms underlying the effect of calcitriol on ovarian cancer cells. MATERIALS AND METHODS: SKOV-3 cells were treated with calcitriol and cisplatin, and their effects alone and in combination in a dose-dependent manner were compared. Cell viability, cell proliferation, and apoptosis were assessed using the following assays: PrestoBlue, intracellular adenosine triphosphate, caspase-3/7 activity, annexin V, and immunoblotting, respectively. RESULTS: Calcitriol alone caused dose-dependent inhibition of cell survival and proliferation, and induced apoptotic cell death of SKOV-3 cells. We confirmed that the expression of vitamin D receptor was increased in a dose-dependent manner by calcitriol. Combination treatment using calcitriol at a physiological concentration of 10-100 nM plus cisplatin significantly suppressed cell survival and induced apoptosis. Furthermore, when calcitriol was administered alone, the activity of vascular endothelial growth factor decreased in a dose-dependent manner, and when combined with cisplatin, activity was more suppressed. CONCLUSION: In SKOV-3 ovarian cancer cells, calcitriol plus cisplatin exerted greater antiproliferative, apoptotic, and anti-angiogenic effects than cisplatin alone. Adding calcitriol to platinum-based chemotherapy might be beneficial to patients with ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Calcitriol/farmacologia , Cisplatino/farmacologia , Neoplasias Ovarianas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Receptores de Calcitriol/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
14.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063169

RESUMO

Polycystic ovarian syndrome (PCOS) is the most prevalent endocrinopathy of reproductive years. Salient features in presentation of patients PCOS include menstrual dysfunction, hyperandrogenism and/or polycystic appearance of ovaries on ultrasound. While the diagnosis of PCOS depends on presence of specified criteria, misdiagnoses are common. Despite years of extensive research, the exact aetiology of PCOS remains largely unknown. In the past decade, apart from insulin resistance and hyperandrogenemia, anti-mullerian hormone (AMH), an important marker of ovarian reserve, and vascular endothelial growth factor (VEGF), a crucial factor in angiogenesis, have been examined as plausible players of causative relevance for PCOS. Vitamin D, a sex-steroid hormone that is universally known for its relevance for skeletal health, has received increasing attention due to growing evidence supporting its pivotal in reproductive physiology and in PCOS. In this review we summarize our current understanding of the mechanisms relevant to the pathophysiology of PCOS and examine the role of vitamin D signalling in this context.


Assuntos
Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Vitamina D/metabolismo , Hormônio Antimülleriano/metabolismo , Feminino , Humanos , Modelos Biológicos , Síndrome do Ovário Policístico/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Calcitriol/metabolismo
15.
Front Immunol ; 12: 678354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149713

RESUMO

Hypoxia-inducible factor (HIF) is a key oxygen sensor that controls gene expression patterns to adapt cellular metabolism to hypoxia. Pharmacological inhibition of prolyl-hydroxylases stabilizes HIFs and mimics hypoxia, leading to increased expression of more than 300 genes. Whether the genetic program initialized by HIFs affects immune responses against microbial pathogens, is not well studied. Recently we showed that hypoxia enhances antimicrobial activity against Mycobacterium tuberculosis (Mtb) in human macrophages. The objective of this study was to evaluate whether the oxygen sensor HIF is involved in hypoxia-mediated antimycobacterial activity. Treatment of Mtb-infected macrophages with the prolyl-hydroxylase inhibitor Molidustat reduced the release of TNFα and IL-10, two key cytokines involved in the immune response in tuberculosis. Molidustat also interferes with the p38 MAP kinase pathway. HIF-stabilization by Molidustat also induced the upregulation of the Vitamin D receptor and human ß defensin 2, which define an antimicrobial effector pathway in human macrophages. Consequently, these immunological effects resulted in reduced proliferation of virulent Mtb in human macrophages. Therefore, HIFs may be attractive new candidates for host-directed therapies against infectious diseases caused by intracellular bacteria, including tuberculosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Macrófagos/metabolismo , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Citocinas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Modelos Biológicos , Estabilidade Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Triazóis/farmacologia , Tuberculose/microbiologia
16.
Front Immunol ; 12: 684015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093587

RESUMO

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2D3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)2D3-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)2D3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)2D3-induced translocation of the VDR to the nucleus and 1,25(OH)2D3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.


Assuntos
Raquitismo Hipofosfatêmico Familiar/metabolismo , Receptores de Calcitriol/genética , Linfócitos T/metabolismo , Vitamina D/genética , Criança , Família , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Mutação , Receptores de Calcitriol/metabolismo , Regulação para Cima , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo
17.
Int J Med Sci ; 18(11): 2449-2456, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967623

RESUMO

Parkinson protein 7 (PARK7)/DJ-1 (DJ-1) is a redox sensitive molecular and stabilizer of nuclear factor erythroid 2-related factor 2 (Nrf-2). Nrf-2 regulates the downstream antioxidant defense system and exerts a significant function in patients with chronic obstructive pulmonary disease (COPD). Vitamin D receptor (VDR) is the nuclear receptor that regulates the downstream target genes. This study aimed to analyze the associations among pulmonary function, DJ-1, VDR and Nrf-2 in COPD patients. Serum was collected from 180 COPD patients and control subjects. Thirty-five lung tissues were obtained. DJ-1 was measured using ELISA and western blotting. Nrf-2 and VDR were detected by immunohistochemistry. Serum and pulmonary DJ-1 levels were lower in COPD patients than those in control subjects. Pulmonary VDR-positive nuclei were reduced in COPD patients. Nrf-2-positive nuclei were reduced in lung tissues of COPD patients. On the contrary, Nrf-2-related downstream target proteins were elevated in COPD patients. Further correlation analysis indicated that forced expiratory volume in 1 second (FEV1) was positively associated with pulmonary DJ-1, VDR and Nrf-2 in patients with COPD. In addition, there were positive correlations among DJ-1, VDR and Nrf-2 in lung tissues of COPD patients. In conclusion, DJ-1, VDR and Nrf-2 were decreased in COPD patients compared with control subjects. The reduction of DJ-1 and VDR associating with Nrf-2 downregulation may be involved in the process of COPD.


Assuntos
Pulmão/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Desglicase DJ-1/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Receptores de Calcitriol/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Humanos , Pulmão/fisiopatologia , Pulmão/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/cirurgia , Testes de Função Respiratória , Índice de Gravidade de Doença
18.
J Steroid Biochem Mol Biol ; 211: 105907, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33965570

RESUMO

The H9N2 avian influenza viruses infect poultry worldwide, and can potentially cause a human pandemic without adaptation. Vitamin D3 (D3) is increasingly being recognized for its extra-skeletal roles, such as the inflammatory and immune responses to infection. The aim of this study was to analyze the changes in vitamin D metabolizing enzymes and vitamin D receptor (VDR) in the lung tissues of mice infected with H9N2. The mice were intranasally inoculated with the appropriate dose of the virus, and various clinical indices were measured on days 3, 7, 14 and 21 post-infection. H9N2 infection significantly increased the expression levels of 1α-hydroxylase mRNA and protein, which is the activating enzyme of 25-hydroxyvitamin D (25(OH)D3), but had no significant effect on the 25(OH)D3 inactivating enzyme 24-hydroxylase, indicating that inactive D3 might be converted to its active form in the H9N2-infected lungs. Furthermore, a significant increase was also observed in the VDR mRNA and protein levels, suggesting enhanced responsiveness of the lung tissues to 1, 25(OH)2D3 post H9N2 infection. In addition, daily 25(OH)D3 injection from day 2-14 post-infection did not affect the clinical signs, virus replication and cytokine (IL-1ß and TNF-α) production in the lungs of the infected mice. Given that the biological effects of D3 rely on its activation, and the binding of 1, 25(OH)2D3 to VDR in specific tissues, our findings provide novel insights into the possible role of vitamin D in the development and progression of influenza.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Vírus da Influenza A Subtipo H9N2/isolamento & purificação , Pulmão/virologia , Infecções por Orthomyxoviridae/complicações , Receptores de Calcitriol/metabolismo , Infecções Respiratórias/virologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Animais , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Receptores de Calcitriol/genética , Infecções Respiratórias/metabolismo , Infecções Respiratórias/patologia
19.
FASEB J ; 35(6): e21543, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34046950

RESUMO

Clinically, bone destruction caused by Mycobacterium tuberculosis was serious especially in patients with vitamin D (VD) deficiency. However, the role of VD in M. tuberculosis-induced bone destruction remains clear. In this context, we investigate the role of VD and vitamin D receptor (VDR) in the M. tuberculosis-induced bone destruction. First, we infected RAW264.7 and bone marrow-derived macrophages (BMMs) with Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) in vitro. Then, we activated VDR through VD administration. TRAP and FAK staining, bone resorption assays, immunofluorescence staining, qPCR, and western blot were carried out. In vivo, the M. tuberculosis-induced osteolytic model on the murine skull was established and the µCT and histological analyses were performed. We found that VDR and TRAP were upregulated in bone tuberculosis tissue and proved that M. tuberculosis infection promoted osteoclastogenesis in RAW264.7 and BMMs. VD could inhibit osteoclasts differentiation, fusion, and bone resorption dose-dependently. However, when VDR was knocked down, the inhibitory effect of VD on osteoclasts disappeared. In mechanism, activation of VDR inhibits the phosphorylation of IκB α, thereby inhibiting NFκB signaling pathway and alleviating osteoclastogenesis. Furthermore, in the skull osteolysis model, VD administration reduced osteolysis, but not in VDR-/- mice. Our study, for the first time, demonstrates that activation of VDR by VD administration inhibits M. tuberculosis-induced bone destruction. Our results reveal that VD and VDR are potential therapeutic targets for M. tuberculosis-induced bone destruction, and are of great clinical significance for the development of new therapeutic strategies.


Assuntos
Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , NF-kappa B/antagonistas & inibidores , Osteólise/prevenção & controle , Receptores de Calcitriol/metabolismo , Tuberculose/complicações , Vitamina D/administração & dosagem , Animais , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Osteólise/etiologia , Osteólise/metabolismo , Osteólise/patologia , Receptores de Calcitriol/genética , Tuberculose/microbiologia , Vitaminas/administração & dosagem
20.
Gene ; 791: 145691, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33961971

RESUMO

AIMS: The study aimed to examine genetic polymorphism of vitamin D-related genes and association between those genes and vitamin D and cytokines levels in children with type 1 diabetes (T1D). MATERIALS AND METHODS: This study was conducted among 100 T1D children and 100 controls at Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, during 2016 to 2018. Vitamin D metabolite levels were measured by liquid chromatography-tandem mass spectrometry method, serum cytokine levels of IFN- É£, IL-10, IL-13, IL-17α, IL-2, IL-4, IL-6, and TNF-α by immunoassay, and genetic variations at VDR, CYP2R1, CYP27B1, GC, DHCR7, and CYP24A1 by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: A relationship between studied single nucleotide polymorphisms and T1D was found in CYP2R1 (rs10741657) (GA, OR: 1.83, 95% CI: 1.01-3.31; p = 0.04). VDR haplotypes were also remarkably different between T1D patients and controls. Controls had higher frequency of haplotype TACT than T1D patients (p = 0.02). Vitamin D and all cytokine levels, except for IL-17α, were significantly increased in T1D compared to controls. The polymorphism of DHCR7 (rs12785878) was positively associated with 25OHD3 and 3epi25OHD3 levels and was negatively associated with 25OHD2 level. On the other hand, polymorphism of CYP27B1 (rs4646536) was negatively associated with 3epi25OHD3 level. Polymorphisms of CYP27B1 (rs4646536) and GC (rs2282679) were positively associated with TNF-α levels. VDR variation of rs1544410, rs731236, and rs7975232 also showed negative association with IL-10 levels. In contrast, the level of IL-10 was positively associated with DHCR7 (rs12785878). CONCLUSION: Relationships between T1D and CYP2R1 polymorphism and VDR haplotype were found. Vitamin D gene-related variations were associated with vitamin D and circulating cytokine levels in children with T1D.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Receptores de Calcitriol/genética , Vitamina D/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Adolescente , Criança , Colestanotriol 26-Mono-Oxigenase/metabolismo , Família 2 do Citocromo P450/metabolismo , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/metabolismo , Vitamina D/sangue , Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo , Adulto Jovem
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