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1.
Mol Med Rep ; 20(6): 5265-5271, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702812

RESUMO

Vitamin D deficiency may lead to an increased risk of tuberculosis. In the present study, the effects of Mycobacterium tuberculosis (Mtb) infection on dendritic cells (DCs) derived from vitamin D­deficient mice or normal control mice were investigated. A vitamin D­deficient mouse model was established, and bone marrow­derived DCs (BMDCs) were isolated and treated with GM­CSF and interleukin (IL)­4 for 6 days, followed by an additional 24 h of treatment with Bacillus Calmette­Guérin (BCG). The expression levels of surface molecules of DCs, including integrin alpha­X and T­lymphocyte activation antigen CD86, were significantly increased by BCG in the vitamin D­deficient mice model group compared with the control group, while those of T­lymphocyte activation antigen CD80, major histocompatibility complex class I and major histocompatibility complex class II were significantly decreased. These changes were BCG concentration­dependent. In addition, the levels of IL­4, IL­6 and IL­10 in the BMDCs from the vitamin D­deficient mice were significantly decreased compared with the control mice, while the levels of tumor necrosis factor­α, IL­5, IL­2, IL­12 and interferon­Î³ were significantly increased. Furthermore, the expression levels of vitamin D receptor (VDR) and CYP27B1 protein in the BMDCs from the vitamin D­deficient mice were decreased compared with the control. BCG significantly increased the expression levels of VDR and CYP27B1 in the BMDCs. The DCs treated with BCG significantly induced the viability of CD4+ T lymphocytes. Therefore, BCG increases DCs and may enhance immunofunction, which may assist in preventing the risk of tuberculosis in patients with a vitamin D deficiency.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Vacina BCG/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Deficiência de Vitamina D/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Células da Medula Óssea/patologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II/metabolismo , Interleucina-10 , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/metabolismo , Tuberculose/imunologia , Vitamina D/metabolismo
2.
J Steroid Biochem Mol Biol ; 195: 105484, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31574299

RESUMO

Vitamin D deficiency has been associated with increased risk for aggressive prostate cancer (PCa). Prostate epithelium has a unique metabolism compared to other tissues. Normal prostate exhibits low levels of mitochondrial respiration and there is a metabolic switch to increased oxidative phosphorylation in PCa. 25-hydroxyvitamin D (25(OH)D) is the major circulating form of vitamin D and is used clinically to determine vitamin D status. Activation of 25(OH)D to the transcriptionally active form, 1,25(OH)2D occurs via a reduction-oxidation (redox) reaction within the mitochondria that is catalyzed by the P450 enzyme, CYP27B1. We sought to determine if hydroxylation of 25(OH)D by CYP27B1 contributes to non-genomic activity of vitamin D by altering the redox-dependent state of the mitochondria in benign prostate epithelial cells. Exposure to 25(OH)D produced a transient pro-oxidant effect and change in mitochondrial membrane potential that was dependent on CYP27B1. Extended exposure ultimately suppressed mitochondrial respiration, consistent with a protective effect of 25(OH)D in supporting benign prostate metabolism. To model physiologically relevant changes in vitamin D, cells were cultured in constant 25(OH)D then changed to high or deficient concentrations. This model also incurred a biphasic effect with a pro-oxidant shift after short exposure followed by decreased respiration after 16 h. Several genes involved in redox cycling and Mitochondrial Health were regulated by 25(OH)D in these cells. These results indicate a secondary non-genomic mechanism for vitamin D to contribute to prostate cell health by supporting normal mitochondrial respiration.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Mitocôndrias/efeitos dos fármacos , Próstata/citologia , Próstata/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Genômica , Humanos , Hidroxilação/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , RNA Interferente Pequeno/genética , Receptores de Calcitriol/genética
3.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652924

RESUMO

Background: Given the role that vitamin D (VD) plays in the regulation of the inflammatory activity of adipocytes, we aimed to assess whether obesity changes the expression of VD-related genes in adipose tissue and, if so, to investigate whether this phenomenon depends on microRNA interference and how it may influence the local inflammatory milieu. Methods: The expression of genes encoding VD 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1) and receptor (VDR), selected interleukins and microRNAs was evaluated by real-time PCR in visceral (VAT) and in subcutaneous (SAT) adipose tissues of 55 obese (BMI > 40 kg/m2) and 31 normal-weight (BMI 20-24.9 kg/m2) individuals. Results: VDR mRNA levels were higher, while CYP27B1 levels were lower in adipose tissues of obese patients than in those of normal-weight controls (VAT: P = 0.04, SAT: P < 0.0001 and VAT: P = 0.004, SAT: P = 0.016, respectively). The expression of VDR in VAT of obese subjects correlated negatively with levels of miR-125a-5p (P = 0.0006, rs = -0.525), miR-125b-5p (P = 0.001, rs = -0.495), and miR-214-3p (P = 0.009, rs = -0.379). Additionally, VDR mRNA concentrations in visceral adipose tissues of obese subjects correlated positively with mRNA levels of interleukins: 1ß, 6 and 8. Conclusions: We observed obesity-associated up-regulation of VDR and down-regulation of CYP27B mRNA levels in adipose tissue. VDR expression correlates with the expression of pro-inflammatory cytokines and may be regulated by miRNAs.


Assuntos
Tecido Adiposo/metabolismo , Citocinas/metabolismo , MicroRNAs/metabolismo , Obesidade/patologia , Receptores de Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Adulto , Citocinas/genética , Regulação para Baixo , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Receptores de Calcitriol/genética , Regulação para Cima , Adulto Jovem
4.
J Steroid Biochem Mol Biol ; 188: 134-140, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30654104

RESUMO

The development of some cancers is associated with vitamin D deficiency. We suggest that reduced conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and the resulting modification of tissue specific immune responses may be key. Non-muscle-invasive bladder cancer is highly immunoresponsive and stimulation of an inflammatory response by intravesical bacillus Calmette-Guerin (BCG) treatment prevents recurrence. To assess the relationship between serum 25(OH)D and bladder cancer risk we conducted a systematic review. To test our hypothesis, the synthesis of 1,25(OH)2D by human bladder epithelial cell lines (T24/83 and RT4) was examined. Studies were identified from Medline, Web of Science, Embase and Cochrane library (limited to English language, humans and 1990-2018). After removal of duplicates, title and abstract review 6 full papers were appraised. Low vitamin D levels were associated with bladder cancer risk in 5/6 of the studies. Both cell lines express the vitamin D receptor, 25-hydroxyvitamin D 1α-hydroxylase (1α-OHase) and 24-hydroxylase (24-OHase) mRNA, which was induced by 1,25(OH)2D. 24-OHase mRNA was also increased by 25(OH)D indicating 1α-OHase activity. Both cell types expressed TLR1,2,4 and the TLR partners MyD88 and CD14mRNA. Cathelicidin mRNA was undetectable in both cell lines but was induced by 1,25(OH)2D and 25(OH)D in RT4 cells. The systematic review demonstrated that bladder cancer risk correlates with serum 25(OH)D levels. In addition, we have shown that transitional epithelial cells express functional vitamin D signaling and can synthesize sufficient 1,25(OH)2D to stimulate a local immune response. We suggest that in order to maintain optimal immune surveillance within the bladder adequate levels of serum 25(OH)D are required for direct synthesis of 1,25(OH)2D by bladder epithelial cells.


Assuntos
Neoplasias da Bexiga Urinária/sangue , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Linhagem Celular Tumoral , Humanos , Receptores de Calcitriol/metabolismo , Fatores de Risco , Transdução de Sinais , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/metabolismo , Vitamina D/sangue , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/metabolismo
6.
Turk J Gastroenterol ; 30(2): 132-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30429108

RESUMO

BACKGROUND/AIMS: To investigate how the serum 25-hydroxyvitamin D (25(OH)D) level change in patients with inflammatory bowel disease (IBD) and investigate the intestinal mucosa vitamin D receptor (VDR) and vitamin D1-α hydroxylase (CYP27B1) expressions. MATERIALS AND METHODS: A total of 105 patients with IBD were enrolled in the present study, including 49 cases with ulcerative colitis (UC) and 56 cases with Crohn's disease (CD), compared with 45 healthy controls (CON) during the same period by testing the permeability of the intestinal mucosa. The expressions of VDR and CYP27B1 in the intestinal mucosa were detected, so as the serum endotoxin, tumor necrosis factor (TNF)-α, and 25(OH)D levels. RESULTS: The lactulose and mannitol absorption ratio (LMR) and serum endotoxin and TNF-α levels were significantly higher in the IBD group than in the CON group (p<0.05). The levels of LMR, endotoxin, and TNF-α were higher in the UC group than in the CD group, but 25(OH)D was lower (p<0.05). VDR in the IBD and UC groups was down-regulated when compared with the CON group (p<0.05), but there was no significance between them (p>0.05). CYP27B1 in the IBD and CD groups was significantly up-regulated compared with the CON group (p<0.05), with no significant difference between them (p>0.05). CONCLUSION: Patients with IBD exhibit vitamin D metabolism imbalance, lower serum 25(OH)D, and lower VDR expression, but higher CYP27B1 expression in the colonic mucosa. However, VDR and CYP27B1 cannot be used to distinguish UC and CD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue
7.
Am J Physiol Endocrinol Metab ; 316(1): E63-E72, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30398904

RESUMO

Human studies show that obesity is associated with vitamin D insufficiency, which contributes to obesity-related disorders. Our aim was to elucidate the regulation of vitamin D during pregnancy and obesity in a nonhuman primate species. We studied lean and obese nonpregnant and pregnant baboons. Plasma 25-hydroxy vitamin D (25-OH-D) and 1α,25-(OH)2-D metabolites were analyzed using ELISA. Vitamin D-related gene expression was studied in maternal kidney, liver, subcutaneous fat, and placental tissue using real-time PCR and immunoblotting. Pregnancy was associated with an increase in plasma bioactive vitamin D levels compared with nonpregnant baboons in both lean and obese groups. Pregnant baboons had lower renal 24-hydroxylase CYP24A1 protein and chromatin-bound vitamin D receptor (VDR) than nonpregnant baboons. In contrast, pregnancy upregulated the expression of CYP24A1 and VDR in subcutaneous adipose tissue. Obesity decreased vitamin D status in pregnant baboons (162 ± 17 vs. 235 ± 28 nM for 25-OH-D, 671 ± 12 vs. 710 ± 10 pM for 1α,25-(OH)2-D; obese vs. lean pregnant baboons, P < 0.05). Lower vitamin D status correlated with decreased maternal renal expression of the vitamin D transporter cubulin and the 1α-hydroxylase CYP27B1. Maternal obesity also induced placental downregulation of the transporter megalin (LRP2), CYP27B1, the 25-hydroxylase CYP2J2, and VDR. We conclude that baboons represent a novel species to evaluate vitamin D regulation. Both pregnancy and obesity altered vitamin D status. Obesity-induced downregulation of vitamin D transport and bioactivation genes are novel mechanisms of obesity-induced vitamin D regulation.


Assuntos
Obesidade/metabolismo , Complicações na Gravidez/metabolismo , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Rim/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Papio , Placenta/metabolismo , Gravidez , Receptores de Calcitriol/metabolismo , Receptores de Superfície Celular/metabolismo , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo
8.
J Gastrointest Cancer ; 50(4): 867-878, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30187205

RESUMO

PURPOSE: The vitamin D receptor (VDR) endocrine system has emerged as an endogenous pleiotropic biological cell regulator with anti-neoplastic effects on breast, colorectal, and prostatic adenocarcinomas. We studied the association of gene expression, polymorphisms of VDR, CYP27B1, and CYP24A1 genes and serum vitamin D levels as surrogate markers of disease progression in patients with acid reflux, Barrett's esophagus (BE), or esophageal adenocarcinoma (EAC). METHODS: We analyzed blood and tissue samples from patients with biopsy-confirmed BE or EAC for vitamin D levels, gene expressions, and polymorphisms in VDR (FokI [F/f], BsmI [B/b], ApaI [A/a], and TaqI [T/t]), CYP27B1 (HinfI [H/h]), and CYP24A1 (Hpy1881 [Y/y]). Percentages of homozygous dominant/recessive or heterozygous traits were assessed for each polymorphism in all patient subgroups. RESULTS: Genomic Bb and FF polymorphisms were highly prevalent in EAC patients, whereas BE patients had a high prevalence of wild-type Hpy1881 (YY polymorphism). Some polymorphisms (Yy for CYP24A1, bb for VDR) were noted only in EAC patients. Yy and bb forms were both uniquely present in some EAC patients without associated Barrett's lesions, but not in patients with concomitant BE. AA and bb polymorphisms were associated with decreased response to neoadjuvant therapy. A high level of VDR and CYP24A1 mRNA expression was observed in EAC tissue of non-responders. Serum vitamin D deficiency was common in EAC patients. CONCLUSIONS: Specific polymorphisms in vitamin D metabolism-related genes are associated with the likelihood of reflux-BE-EAC progression. Identifying such polymorphisms may aid in development of better surveillance and diagnostic and therapeutic protocols.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Refluxo Gastroesofágico/genética , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/sangue , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Adenocarcinoma/sangue , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Esôfago de Barrett/sangue , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Biópsia , Estudos de Casos e Controles , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Mucosa Esofágica/patologia , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Esofagectomia , Feminino , Refluxo Gastroesofágico/sangue , Refluxo Gastroesofágico/metabolismo , Refluxo Gastroesofágico/patologia , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/sangue , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Resultado do Tratamento , Vitamina D/sangue , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/sangue , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
9.
Free Radic Biol Med ; 131: 376-381, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578920

RESUMO

Chronic kidney disease (CKD) is a worldwide public health problem with an estimated prevalence of 8.2%. This study reports glutathione deficiency, excess oxidative stress, and altered vitamin D metabolism in the kidney of mice fed a high-fat diet (HFD). The levels of GCLC and GCLM gene expression were significantly downregulated and the protein carbonylation level, a hallmark of oxidative damage, was significantly increased in the kidney of HFD-fed mice. While the levels of VD-regulatory genes 1-alpha-hydroxylase (CYP27B1), VDR, and RXRα were significantly downregulated in the kidney of mice fed a HFD, those of 24-hydroxylase (CYP24A1) were significantly elevated. In vitro, GSH deficiency per se causes excess oxidative damage (protein carbonylation), and significantly decreases the levels of VD-regulatory genes (CYP27B1, VDR, and RXRα), but increases levels of CYP24A1 in human renal proximal tubule epithelial cells (RPTEC), similar to findings in the kidney of HFD-fed diabetic mice. L-cysteine supplementation restores GSH and prevents oxidative damage in RPTEC. These studies suggest a potential role of GSH precursor in reducing excess oxidative stress and renal injury that commonly accompanies obesity/diabetes.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Diabetes Mellitus Experimental/enzimologia , Glutationa/deficiência , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/enzimologia , Vitamina D3 24-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Cisteína/farmacologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Cultura Primária de Células , Carbonilação Proteica , Receptores de Calcitriol/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais , Vitamina D3 24-Hidroxilase/metabolismo
10.
Medicine (Baltimore) ; 97(40): e12090, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290590

RESUMO

RATIONALE: Malakoplakia is a rare disease characterized by the presence of nongranulomatous macrophage infiltration. In most cases, it affects the urinary tract. Malakoplakia can cause acute kidney injury when it is localized in the kidneys. PATIENT CONCERNS: Here, we report the case of a 65-year-old female patient with renal malakoplakia responsible for hypercalcemia. During her initial assessment, she was also diagnosed 25-OH vitamin D insufficiency, for which she was prescribed oral cholecalciferol. Three months later, she developed severe hypercalcemia with normal 25-OH vitamin D and parathyroid hormone levels and high 1,25-dihydroxyvitamin D levels. DIAGNOSES: After a superimposed granulomatous disease was excluded, malakoplakia cells were suspected to be responsible for the abnormal 25-hydroxyvitamin D3 1-alpha-hydroxylase activity, which was confirmed by immunohistochemistry. INTERVENTIONS: Cholecalciferol was stopped, the patient was rehydrated with intravenous physiological saline, and prednisone was initiated to decrease the enzyme activity. OUTCOMES: Six months later, she displayed normal serum calcium, 25-OH vitamin D and 1,25-dihydroxyvitamin D levels. LESSONS: This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation. Therefore, such supplementation should not be given in malakoplakia patients without an actual deficiency and requires careful monitoring of serum calcium.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Hipercalcemia/genética , Nefropatias/complicações , Malacoplasia/complicações , Deficiência de Vitamina D/terapia , Idoso , Cálcio/sangue , Colecalciferol/efeitos adversos , Suplementos Nutricionais , Expressão Ectópica do Gene , Feminino , Humanos , Nefropatias/sangue , Nefropatias/genética , Malacoplasia/sangue , Malacoplasia/genética , Hormônio Paratireóideo/sangue , Deficiência de Vitamina D/complicações , Vitaminas/efeitos adversos
11.
PLoS One ; 13(10): e0199856, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30281599

RESUMO

Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/-mice) are congenitally deficient in 1α,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1-/-mice, they respond normally to 1α,25D3. Accordingly, in Cyp27b1-/-mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1α,25D3. We used Cyp27b1-/-mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1α,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1-/-mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1α,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly. In the future, this study may enable the development of next-generation active vitamin D derivatives with higher affinity for bone than ELD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Hidroxicolecalciferóis/farmacologia , Osteogênese/efeitos dos fármacos , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Peso Corporal , Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Fêmur/diagnóstico por imagem , Humanos , Masculino , Camundongos , Camundongos Knockout , Osteoporose Pós-Menopausa/tratamento farmacológico , Receptores de Calcitriol , Tíbia/diagnóstico por imagem , Transfecção , Vitamina D/metabolismo , Vitamina D/farmacologia
12.
Eur J Obstet Gynecol Reprod Biol ; 229: 117-122, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30172168

RESUMO

OBJECTIVES: To evaluate tissue concentration of 1, 25 dihydroxyvitamin D3, and gene expression level of CYP27B1 that codes for 1-α hydroxylase (vitamin D activating enzyme), and CYP24A1 that codes for 24-hydroxylase (vitamin D catabolizing enzyme) in human uterine leiomyoma (ULM), its adjacent myometrium (Myo-F), and normal myometrium (Myo-N). STUDY DESIGN: Levels of 1, 25 dihydroxyvitamin D3 were measured using HPLC and Diode detectors whereas CYP27B1, and CYP24A1 expressions were assessed using Real-Time PCR in ULM, Myo-F, and Myo-N. Non-parametric statistics were used. RESULTS: ULMs contained significantly less 1, 25 dihydroxy vitamin D3 compared to Myo-F (3.0, IQR: 1.0-9.0 versus 6.0, IQR: 3.0-13.0 µg/ kg, P value is 0.03). No significant difference was detected between ULM and Myo-N, or Myo-F and Myo-N. Intratumoral level of the active form of vitamin D did not differ according to the type of ULM (submucous or interstitial/subserous), or to the ULM volume. CYP27B1 was expressed in ULM (2.17, IQR: 0.65-4.9), Myo-F (4.94, IQR: 1.04-22.59), and Myo-N (0.99, IQR: 0.49-1.71) to a comparable level. CYP24A1 expression was significantly higher in ULM compared to Myo-N (2.00, IQR: 0.69-10.77 versus 0.22, IQR: 00- 0.96, respectively, P value is 0.04). CONCLUSIONS: Human ULMs contain significantly lower 1, 25 dihydroxyvitamin D3 than its adjacent myometrium. ULM, Myo-F, and Myo-N express CYP27B1 and CYP24A1. ULMs express significantly higher level of CYP24A1 than normal myometrium indicating that over expression of 24-hydroxylase is a mechanism by which ULMs sustain a relative state of hypovitaminosis D.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Calcitriol/metabolismo , Leiomioma/metabolismo , Neoplasias Uterinas/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Miométrio/metabolismo
13.
Int J Mol Sci ; 19(9)2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30200275

RESUMO

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D-21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)2D3 and 25(OH)D3, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)2D3 and became VDR-/-CYP27B1-/-). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog-21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)2D3, 25(OH)D3 and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR-/-. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Melanoma/metabolismo , Receptores de Calcitriol/genética , Vitamina D/farmacologia
14.
Exp Dermatol ; 27(11): 1201-1209, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30066343

RESUMO

Renal 25-hydroxyvitamin D-1α-hydroxylase (1αOHase, CYP27B1) and 24-hydroxylase (24OHase, CYP24A1) are tightly regulated. However, little is known about the regulation of 1α(OH)ase and 24(OH)ase in extrarenal tissue such as the epidermis. This study was to determine the roles of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF 23) in the regulation of 1α(OH)ase and 24(OH)ase in epidermal keratinocytes as well as epidermal keratinocyte proliferation and differentiation. The results showed that PTH increased the protein level of 1α(OH)ase in human epidermal keratinocyte cell line HaCaT, but had no effect on the level of 24(OH)ase. The effect of PTH on 1α(OH)ase was blocked by the PKC inhibitor. Treatment with FGF23 decreased mRNA and protein levels of 1α(OH)ase and increased mRNA and protein levels of 24(OH)ase in HaCaT cells. The effect of FGF23 on 1α(OH)ase and 24(OH)ase was blocked by the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) inhibitor. In addition, treatment with PTH enhanced levels of differentiation markers including keratin 1, involucrin, loricrin, and filaggrin but reduced levels of BrdU incorporation in HaCaT cells. These effects were inhibited by the PKC inhibitor. FGF23 enhanced proliferation of HaCaT cells, but reduced levels of early differentiation markers including keratin 1 and involucrin and enhanced levels of the later differentiation markers including loricrin and filaggrin. These results suggest that PTH stimulates 1α(OH)ase expression and differentiation of HaCaT cells and inhibits proliferation via PKC. The data also suggest that FGF23 inhibits 1α(OH)ase expression and stimulates 24(OH)ase expression via MAPK/ERK. In addition, FGF23 enhances proliferation and late differentiation and inhibits early differentiation of HaCaT keratinocytes.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Epiderme/enzimologia , Fatores de Crescimento de Fibroblastos/farmacologia , Queratinócitos/enzimologia , Hormônio Paratireóideo/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vitamina D3 24-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Epiderme/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Glucuronidase/metabolismo , Humanos , Indóis/farmacologia , Queratinócitos/metabolismo , Maleimidas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Transdução de Sinais , Vitamina D3 24-Hidroxilase/genética
15.
J Steroid Biochem Mol Biol ; 183: 221-227, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30004013

RESUMO

Recently, we successfully generated a novel detection system for vitamin D receptor (VDR) ligands in vivo and in vitro, using a split-luciferase technique called the LucN-LBD-LucC biosensor that is a chimeric fusion protein of firefly luciferase with the ligand binding domain (LBD) of VDR. In this system, the luciferase light intensity of the LucN-LBD-LucC biosensor was decreased by binding of VDR ligands. Although this system is quite useful for evaluation of VDR ligands in a short time, the sensitivity of the LucN-LBD-LucC biosensor is not high enough. In this study, LXXLL motif peptides involved in the interaction between LBD and coactivators, such as the steroid receptor coactivator-1 (SRC-1), transcriptional intermediary factor 2 (TIF2), and the vitamin D receptor interacting protein 205 (DRIP205) were each inserted between LucN and LBD of the LucN-LBD-LucC biosensor. Surprisingly, the resulting LucN-LXXLL-LBD-LucC biosensor increased the light intensity in response to natural VDR ligands. This high-sensitivity biosensor system may be a powerful tool for discovery of high-affinity ligands for the mutant VDR. In addition, we have successfully estimated the activity of the wild-type and mutant CYP27B1 using the LucN-LXXLL-LBD-LucC biosensor in living cells within 90 min.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Técnicas Biossensoriais/métodos , Luciferases/metabolismo , Mutação , Receptores de Calcitriol/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Animais , Células COS , Chlorocebus aethiops , Humanos , Ligantes , Receptores de Calcitriol/genética
16.
Am J Reprod Immunol ; 80(5): e13022, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30051540

RESUMO

Recurrent pregnancy loss (RPL) affects approximately 1%-2% of reproductive women. Auto- and cellular immune responses seem to be associated with RPL. Vitamin D (VD) has been shown to play a role in the modulation of the immune system. Effects of VD deficiency (VDD) in pregnancy have been associated with preeclampsia, gestational diabetes, fetal growth restriction, preterm labor, and sporadic spontaneous abortion (SA). We systematically reviewed articles that studied women with 2 or more SA and its association with VD. Eleven studies were included. Studies reported a high prevalence of VD insufficiency (VDI) or VDD in women with RPL and suggested that this could be associated with immunological dysregulation and consequently with RPL. Immunological benefits were reported in the peripheral blood of women with RPL after VD exposure. Thus, it is possible to speculate a beneficial role for VD supplementation in RPL. It seems that there are not differences in the vitamin D receptor (VDR) and CYP27B1 expression in endometrium of women with RPL but, in villous and decidual tissues, RPL women seem to have a decreased expression of VDR and, perhaps, a decreased expression of CYP27B1. Further randomized controlled studies are required to investigate the association between VDD or VDI and RPL.


Assuntos
Aborto Espontâneo/metabolismo , Decídua/metabolismo , Deficiência de Vitamina D/epidemiologia , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Aborto Espontâneo/epidemiologia , Autoimunidade , Feminino , Humanos , Imunidade Celular , Gravidez , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Recidiva
17.
Biomed Pharmacother ; 106: 54-60, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29957466

RESUMO

Chronic kidney disease-mineral and bone disorder (CKD-MBD) play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). Zuogui pill as a traditional Chinese herbal drug has been used for nourish kidney essence improve bone malnutrition of renal bone disease by regulating the metabolism of calcium and phosphorus and participating in osteoblast metabolism. In the present study, 5/6 nephrectomy rat model was used to reveal the mechanism of zuogui pill in treatment of CKD-MBD. Compared with sham rats, the levels of serum phosphorus, PTH, iPTH and creatinine were significantly decreased, while the serum calcium level was significantly increased, and the Cbfa1 protein level was significantly decreased and FGF23 protein level was significantly increased by Zuogui pill treatment. Compared with model rats, the BMD of rat was significantly increased by Zuogui pill treatment. Histological analysis revealed that the kidney injury of rats with CKD was significantly reduced by zuogui pill treatment. Compared with model rats, the CYP27B1 mRNA level was significantly increased, and the PTH mRNA level and NaPiIIa protein level were significantly decreased in the kidney by zuogui pill treatment. We inferred that zuogui pill exhibited potential therapeutic effects on CKD-MBD in the rats by regulating bone metabolism and nourish kidney.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Rim/efeitos dos fármacos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Cálcio/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Subunidade alfa 1 de Fator de Ligação ao Core/sangue , Creatinina/sangue , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/sangue , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética , Fósforo/sangue , Ratos Wistar , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/metabolismo
18.
Sci Rep ; 8(1): 9024, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899561

RESUMO

Recently, the antiproliferative action of 1,25(OH)2D3 (1,25D3), an active metabolite of vitamin D3, in the management of prostate cancer has been argued rigorously. In this study, we found that at a physiological concentration, 25(OH)D3 (25D3), the precursor of 1,25D3 and an inactive form of vitamin D because of its much weaker binding activity to the vitamin D receptor (VDR) compared with 1,25D3, had a gene expression profile similar to that of 1,25D3 in prostate cancer LNCaP cells. By immunocytochemistry, western blotting, and CYP27B1 and/or VDR knockdown by small interfering RNAs, we found that 10-7 M 25D3, which is within its uppermost physiological concentration in the bloodstream, induced VDR nuclear import and robustly activated its target genes in the virtual absence of CYP27B1 expression. Comprehensive microarray analyses verified 25D3 bioactivity, and we found that 25D3 target gene profiles largely matched those of 1,25D3, while the presence a small subset of 25D3- or 1,25D3-specific target genes was not excluded. These results indicated that 25D3 shares bioactivity with 1,25D3 without conversion to the latter. Metallothionein 2A was identified as a 1,25D3-specific repressive target gene, which might be a prerequisite for 1,25D3, but not 25D3, to exert its anti-proliferative action in LNCaP cells.


Assuntos
Calcifediol/farmacologia , Calcitriol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Próstata/genética , Transcriptoma/efeitos dos fármacos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Calcifediol/química , Calcitriol/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Hidroxilação , Masculino , Metalotioneína , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitaminas/farmacologia
19.
Domest Anim Endocrinol ; 64: 70-76, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29754009

RESUMO

In livestock, feeding a reduced nitrogen (N) diet is favored for economic and ecological reasons. Ruminants cope more easily with a reduced N diet than monogastric species. However, changes in mineral homeostasis such as a reduction in 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) concentrations, calcium (Ca), and IGF1 levels were observed in goats kept on a reduced N diet. The decrease in 1,25-(OH)2D3 occurred even during a simultaneous reduction in dietary N and Ca, whereas a solitary Ca reduction stimulated 1,25-(OH)2D3 synthesis. The aim of the present study was to examine the effects of N- and/or Ca-reduced diets on the expression of 24-hydroxylase (CYP24A1), 1-alpha-hydroxylase (CYP27B1), vitamin D receptor (VDR), retinoid X receptor alpha (RXRα), IGF1 receptor (IGF1R), Klotho, and fibroblast growth factor receptor 1c (FGFR1c) in kidneys of young goats. Four groups were kept on a control diet, an N-reduced diet, a Ca-reduced diet or an N- and a Ca-reduced diet. Renal expression of CYP24A1 was not affected, whereas CYP27B1 expression was significantly diminished in the N-reduced diet fed goats (P < 0.05) and significantly elevated with the Ca reduction (P < 0.001). The VDR expression was not modified, whereas RXRα (P < 0.05) and Klotho expression (P < 0.001) were stimulated during Ca reduction. The IGF1R (P < 0.05) and FGFR1c (P < 0.05) expression were enhanced with the N reduction. From these data, it can be concluded that the downregulation of renal CYP27B1 expression observed with dietary N reduction is probably mediated by a complex interaction between the somatotropic axis and the Klotho/FGF signaling pathway in young goats.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Ração Animal/análise , Cálcio na Dieta/farmacologia , Dieta/veterinária , Cabras/fisiologia , Nitrogênio/administração & dosagem , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Calcitriol/sangue , Cálcio na Dieta/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Glucuronidase/genética , Glucuronidase/metabolismo , Rim/enzimologia , Rim/metabolismo , Masculino , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
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