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1.
Genes (Basel) ; 14(1)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36672957

RESUMO

Vitamin D requires activation to show its pharmacological effect. While most studies investigate the association between vitamin D and disease, only a few focus on the impact of vitamin D metabolism gene polymorphisms (vitDMGPs). This bibliometric study aims to provide an overview of current publications on vitDMGPs (CYP27B1, CYP24A1, CYP2R1, CYP27A1, CYP2R1, DHCR7/NADSYN1), compare them across countries, affiliations, and journals, and inspect keywords, co-citations, and citation bursts to identify trends in this research field. CiteSpace© (version 6.1.R3, Chaomei Chen), Bibliometrix© (R version 4.1.3 library, K-Synth Srl, University of Naples Federico II, Naples, Italy), VOSviewer© (version 1.6.1, Nees Jan van Eck and Ludo Waltman, Leiden University, Leiden, Netherlands) and Microsoft® Excel 365 (Microsoft, Redmond, Washington, USA) classified and summarized Web of Science articles from 1998 to November 2022. We analyzed 2496 articles and built a timeline of co-citations and a bibliometric keywords co-occurrence map. The annual growth rate of vitDMGPs publications was 18.68%, and their relative research interest and published papers were increasing. The United States of America leads vitDMGPs research. The University of California System attained the highest quality of vitDMGPs research, followed by the American National Institutes of Health and Harvard University. The three productive journals on vitDMGPs papers are J. Steroid. Biochem. Mol. Biol., PLOS ONE, and J. Clin. Endocrinol. Metab. We highlighted that the vitDMGPs domain is relatively new, and many novel research opportunities are available, especially those related to studying single nucleotide polymorphisms or markers in a specific gene in the vitamin D metabolism cycle and their association with disease. Genome-wide association studies, genetic variants of vitDMGPs, and vitamin D and its role in cancer risk were the most popular studies. CYP24A1 and CYB27A1 were the most-studied genes in vitDMGPs. Insulin was the longest-trending studied hormone associated with vitDMGPs. Trending topics in this field relate to bile acid metabolism, transcriptome and gene expression, biomarkers, single nucleotide polymorphism, and fibroblast growth factor 23. We also expect an increase in original research papers investigating the association between vitDMGPs and coronavirus disease 2019, hypercalcemia, Smith-Lemli-Opitz syndrome, 27-hydroxycholesterol, and mendelian randomization. These findings will provide the foundations for innovations in the diagnosis and treatment of a vast spectrum of conditions.


Assuntos
COVID-19 , Estudo de Associação Genômica Ampla , Humanos , Vitamina D3 24-Hidroxilase , Polimorfismo de Nucleotídeo Único/genética , Vitamina D/genética , Vitaminas , Bibliometria
2.
Ann Biol Clin (Paris) ; 80(5): 460-463, 2022 09 01.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-36453734

RESUMO

Background: 25-Hydroxyvitamin D 24-hydroxylase (CYP24A1) deficiency is a rare cause of autosomal recessive infantile hypercalcemia due to vitamine D hypersensitivity. Case presentation: We report the case of a 2-year-old boy who presented with severe hypercalcemia-hypercalciuria and a bilateral nephrocalcinosis. Laboratory investigations detected a collapsed parathormone and a highly elevated 1α,25-dihydroxycholecalciferol along with an increased phosphate excretion (hypophosphatemia and hyperphosphaturia). An adapted management with two courses of palmidronic acid and an eviction of vitamin D and calcium allowed to stabilize him. A homozygous p.Leu409Ser pathogenic variant on CYP24A1 gene resulting in a collapsed 25-Hydroxyvitamin D24-hydroxylase activity was found. A normal development is possible with a meticulous clinical, biological and nutritional management and monitoring. Conclusions: Vitamin D hypersensitivity is challenging during childhood, especially due to the need to avoid vitamin D while requiring a close nutritional monitoring to maintain a normal growth. Biomarkers such as vitamin D metabolite ratio and 24,25(OH)2D3 along with ionized calcium and nutritional management can contribute to properly follow patients with vitamin D hypersensitivity.


Contexte: Le déficit en 25-hydroxyvitamine D 24-hydroxylase (CYP24A1) est une cause rare d'hypercalcémie infantile autosomique récessive due à une hypersensibilité à la vitamine D. Présentation du cas: Nous rapportons le cas d'un garçon de 2 ans qui a présenté une hypercalcémie-hypercalciurie sévère et une néphrocalcinose bilatérale. Les examens de laboratoire ont détecté une parathormone effondrée et un 1α,25-dihydroxycholécalciférol très élevé ainsi qu'une excrétion accrue de phosphate (hypophosphatémie et hyperphosphaturie). Une prise en charge adaptée avec deux cures d'acide palmidronique et une éviction de la vitamine D et du calcium a permis de le stabiliser. Un variant pathogène homozygote p.Leu409Ser sur le gène CYP24A1 entraînant un effondrement de l'activité de la 25-hydroxyvitamine D24-hydroxylase a été retrouvé. Un développement normal est possible avec une prise en charge et un suivi clinique, biologique et nutritionnel méticuleux. Conclusions: L'hypersensibilité à la vitamine D est un défi pendant l'enfance, notamment en raison de la nécessité d'éviter la vitamine D tout en exigeant un suivi nutritionnel étroit pour maintenir une croissance normale. Les biomarqueurs tels que le rapport des métabolites de la vitamine D et la 24,25(OH)2D3, ainsi que le calcium ionisé et la gestion nutritionnelle peuvent contribuer à un suivi adéquat des patients souffrant d'hypersensibilité à la vitamine D.


Assuntos
Hipercalcemia , Masculino , Lactente , Humanos , Pré-Escolar , Hipercalcemia/complicações , Hipercalcemia/diagnóstico , Vitamina D3 24-Hidroxilase/genética , Cálcio , Vitamina D , Hipercalciúria
3.
BMC Cancer ; 22(1): 1317, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36527000

RESUMO

BACKGROUND: Acquired chemo-drug resistance constantly led to the failure of chemotherapy for malignant cancers, consequently causing cancer relapse. Hence, identifying the biomarker of drug resistance is vital to improve the treatment efficacy in cancer. The clinical prognostic value of CYP24A1 remains inconclusive, hence we aim to evaluate the association between CYP24A1 and the drug resistance in cancer patients through a meta-analysis approach. METHOD: Relevant studies detecting the expression or SNP of CYP24A1 in cancer patients up till May 2022 were systematically searched in four common scientific databases including PubMed, EMBASE, Cochrane library and ISI Web of Science. The pooled hazard ratios (HRs) indicating the ratio of hazard rate of survival time between CYP24A1high population vs CYP24A1low population were calculated. The pooled HRs and odds ratios (ORs) with 95% confidence intervals (CIs) were used to explore the association between CYP24A1's expression or SNP with survival, metastasis, recurrence, and drug resistance in cancer patients. RESULT: Fifteen studies were included in the meta-analysis after an initial screening according to the inclusion and exclusion criteria. There was a total of 3784 patients pooled from all the included studies. Results indicated that higher expression or SNP of CYP24A1 was significantly correlated with shorter survival time with pooled HRs (95% CI) of 1.21 (1.12, 1.31), metastasis with pooled ORs (95% CI) of 1.81 (1.11, 2.96), recurrence with pooled ORs (95% CI) of 2.14 (1.45, 3.18) and drug resistance with pooled HRs (95% CI) of 1.42 (1.17, 1.68). In the subgroup analysis, cancer type, treatment, ethnicity, and detection approach for CYP24A1 did not affect the significance of the association between CYP24A1 expression and poor prognosis. CONCLUSION: Findings from our meta-analysis demonstrated that CYP24A1's expression or SNP was correlated with cancer progression and drug resistance. Therefore, CYP24A1 could be a potential molecular marker for cancer resistance.


Assuntos
Biomarcadores Tumorais , Neoplasias , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Resistência a Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Vitamina D3 24-Hidroxilase
4.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555202

RESUMO

Vitamin D takes part in the functioning of many processes that ensure the homeostasis of the body. In orthopedics, it is indicated as an inseparable element ensuring proper bone growth and functioning, and its deficiencies are indicated in various diseases, mainly in the proper structure and function of the skeleton. In this review, we focus on the most important components of the vitamin D metabolic pathway, in correlation with selected orthopedic conditions. Records were obtained from the PubMed database in a timeline of 2010-2022. The keywords were as follows: vitamin D/cholesterol/vitamin D binding protein/ VDBP/Cytochrome/CYP24A1/CYP 27B1/Vitamin D receptor/VDR/ + diseases (ACL reconstruction, rotator cuff, arthroplasty knee/hip/shoulder). The recent original studies were analyzed, discussed, and the most important data were shown. The vast majority of articles concern the metabolite of vitamin D (25(OH)D), which is measured as a standard in diagnostic laboratories. Even though there is a lot of valuable information in the literature, we believe that the other elements of the vitamin D pathway also deserve attention and suggest their research in correlation with orthopedic disorders to supplement the missing knowledge on this topic.


Assuntos
Ortopedia , Vitamina D , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Redes e Vias Metabólicas , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/metabolismo , Vitaminas
5.
Nutrients ; 14(23)2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36501215

RESUMO

The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)2D) by downregulating transcription of 1α-hydroxylase (CYP27B1), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (CYP24A1). Conversely, the peptide hormone PTH stimulates 1,25(OH)2D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology.


Assuntos
Hormônio Paratireóideo , Hormônios Peptídicos , Humanos , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônio Paratireóideo/metabolismo , Hormônios Peptídicos/metabolismo , Sistema Renina-Angiotensina , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitaminas
6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(6): 1021-1027, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36443046

RESUMO

Objective: To investigate the regulatory effect and mechanism of vitamin D on the local renin-angiotensin system at maternal-fetal interface in the pathological process of preeclampsia (PE). Methods: The mRNA and protein expression of renin in decidua of normal pregnancy and PE placentas was determined by RT-PCR and Western blot. Normal decidual tissues were treated with active and inactive vitamin D for 48 h in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Normal decidual stromal cells and glandular epithelial cells were isolated and purified, and identified by immunocytochemical staining. RT-PCR was used to examine the mRNA of vdr, cyp27 b1, cyp24 a1, and renin in the two types of cells and in decidual tissue, and the mRNA products were subjected to gel electrophoresis. These two cell types were treated with active and inactive vitamin D in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Decidual gland epithelial cells were treated with protein kinase A (PKA) activator forskolin or inhibitor H89 to explore the interaction between PKA pathway and vitamin D in the regulation of renin expression. Results: The expression of renin in PE decidua was significantly higher than that of normal control at transcriptional and translational levels ( P<0.05). Vitamin D treatment could significantly down-regulate the expression of renin in normal decidua tissues ( P<0.05), while it significantly up-regulated CYP24A1 expression ( P<0.001). Decidual stromal cells and gland epithelial cells were successfully isolated from decidual tissue. Compared with that in decidual stromal cells, the mRNA level of vitamin D-related molecules in gland epithelial cells was more similar to that in decidual tissue. Active or inactive vitamin D treatment significantly inhibited the expression of renin in glandular epithelial cells ( P<0.05), but the expression of renin in decidual stromal cells was not affected. However, the treatment of active or inactive vitamin D in these two kinds of cells significantly increased the expression of CYP24A1 ( P<0.001). Active vitamin D could significantly inhibit the upregulation of renin by PKA agonist forskolin, and could inhibit the expression of renin through synergy with PKA inhibitor H89. Conclusion: The expression of renin in placental decidua is up-regulated in patients with PE, and the activation of local renin-angiotensin system at the maternal-fetal interface may be involved in the pathogenesis of PE. Vitamin D can specifically down-regulate renin expression in human decidual gland epithelial cells by competing with the PKA pathway. Vitamin D supplementation may have potential value for clinical intervention of PE.


Assuntos
Pré-Eclâmpsia , Vitamina D , Gravidez , Humanos , Feminino , Vitamina D/farmacologia , Renina , Vitamina D3 24-Hidroxilase/genética , Colforsina , Placenta , RNA Mensageiro
7.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36362448

RESUMO

Vitamin D, formerly known for its role in calcium-phosphorus homeostasis, was shown to exert a broad influence on immunity and on differentiation and proliferation processes in the last few years. In the field of endocrinology, there is proof of the potential role of vitamin D and vitamin D-related genes in the pathogenesis of thyroid cancer-the most prevalent endocrine malignancy. Therefore, the study aimed to systematically review the publications on the association between vitamin D-related gene variants (polymorphisms, mutations, etc.) and thyroid cancer. PubMed, EMBASE, Scopus, and Web of Science electronic databases were searched for relevant studies. A total of ten studies were found that met the inclusion criteria. Six vitamin D-related genes were analyzed (VDR-vitamin D receptor, CYP2R1-cytochrome P450 family 2 subfamily R member 1, CYP24A1-cytochrome P450 family 24 subfamily A member 1, CYP27B1-cytochrome P450 family 27 subfamily B member 1, DHCR7-7-dehydrocholesterol reductase and CUBN-cubilin). Moreover, a meta-analysis was conducted to summarize the data from the studies on VDR polymorphisms (rs2228570/FokI, rs1544410/BsmI, rs7975232/ApaI and rs731236/TaqI). Some associations between thyroid cancer risk (VDR, CYP24A1, DHCR7) or the clinical course of the disease (VDR) and vitamin D-related gene polymorphisms were described in the literature. However, these results seem inconclusive and need validation. A meta-analysis of the five studies of common VDR polymorphisms did not confirm their association with increased susceptibility to differentiated thyroid cancer. Further efforts are necessary to improve our understanding of thyroid cancer pathogenesis and implement targeted therapies for refractory cases.


Assuntos
Predisposição Genética para Doença , Neoplasias da Glândula Tireoide , Humanos , Polimorfismo de Nucleotídeo Único , Vitamina D/genética , Vitamina D3 24-Hidroxilase/genética , Fatores de Risco , Receptores de Calcitriol/genética , Neoplasias da Glândula Tireoide/genética , Genótipo
8.
Curr Med Sci ; 42(5): 1022-1032, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36255661

RESUMO

OBJECTIVE: While the upregulation of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene expression has been reported in colon cancer, its role in tumorigenesis remains largely unknown. In this study, we aimed to investigate the involvement of CYP24A1 in Wnt pathway regulation via the nuclear factor kappa B (NF-κB) pathway. METHODS: The human colon cancer cell lines HCT-116 and Caco-2 were subjected to stimulation with interleukin-6 (IL-6) as well as tumor necrosis factor alpha (TNF-α), with subsequent treatment using the NF-κB pathway-specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). Furthermore, CYP24A1 expression was subjected to knockdown via the use of small interfering RNA (siRNA). Subsequently, NF-κB pathway activation was determined by an electrophoretic mobility shift assay, and the transcriptional activity of ß-catenin was determined by a dual-luciferase reporter assay. A mouse ulcerative colitis (UC)-associated carcinogenesis model was established, wherein TNF-α and the NF-κB pathway were blocked by anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides, respectively. Then the tumor size and protein level of CYP24A1 were determined. RESULTS: IL-6 and TNF-α upregulated CYP24A1 expression and activated the NF-κB pathway in colon cancer cells. PDTC significantly inhibited this increase in CYP24A1 expression. Additionally, knockdown of CYP24A1 expression by siRNA could partially antagonize Wnt pathway activation. Upregulated CYP24A1 expression was observed in the colonic epithelial cells of UC-associated carcinoma mouse models. Anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides decreased the tumor size and suppressed CYP24A1 expression. CONCLUSION: Taken together, this study suggests that inflammatory factors may increase CYP24A1 expression via NF-κB pathway activation, which in turn stimulates Wnt signaling.


Assuntos
Compostos de Amônio , Neoplasias do Colo , Camundongos , Animais , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/genética , Vitamina D3 24-Hidroxilase/metabolismo , RNA Interferente Pequeno , Células CACO-2 , Inibidores do Fator de Necrose Tumoral , Proteínas I-kappa B/metabolismo , Neoplasias do Colo/genética , Luciferases/metabolismo , Anticorpos Monoclonais , Oligonucleotídeos Antissenso
9.
J Biol Chem ; 298(11): 102559, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36183832

RESUMO

Vitamin D metabolism centers on kidney regulation of Cyp27b1 by mineralotropic hormones, including induction by parathyroid hormone (PTH), suppression by fibroblast growth factor 23 (FGF23) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and reciprocal regulations for Cyp24a1. This coordinated genomic regulation results in production of endocrine 1,25(OH)2D3, which, together with PTH and FGF23, controls mineral homeostasis. However, how these events are coordinated is unclear. Here, using in vivo chromatin immunoprecipitation sequencing in mouse kidney, we demonstrate that PTH activation rapidly induces increased recruitment of phosphorylated (p-133) CREB (pCREB) and its coactivators, CBP (CREB-binding protein) and CRTC2 (CREB-regulated transcription coactivator 2), to previously defined kidney-specific M1 and M21 enhancers near the Cyp27b1 gene. At distal enhancers of the Cyp24a1 gene, PTH suppression dismisses CBP with only minor changes in pCREB and CRTC2 occupancy, all of which correlate with decreased genomic activity and reduced transcripts. Treatment of mice with salt-inducible kinase inhibitors (YKL-05-099 and SK-124) yields rapid genomic recruitment of CRTC2 to Cyp27b1, limited interaction of CBP, and a transcriptional response for both Cyp27b1 and Cyp24a1 that mirrors the actions of PTH. Surprisingly, we find that 1,25(OH)2D3 suppression increases the occupancy of CRTC2 in the M1 enhancer, a novel observation for CRTC2 and 1,25(OH)2D3 action. Suppressive actions of 1,25(OH)2D3 and FGF23 at the Cyp27b1 gene are associated with reduced CBP recruitment at these CREB-module enhancers that disrupts full PTH induction. Our findings show that CRTC2 contributes to transcription of both Cyp27b1 and Cyp24a1, demonstrate salt-inducible kinase inhibition as a key modulator of vitamin D metabolism, and provide molecular insight into the coordinated mechanistic actions of PTH, FGF23, and 1,25(OH)2D3 in the kidney that regulate mineral homeostasis.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase , Calcitriol , Camundongos , Animais , Vitamina D3 24-Hidroxilase/genética , Calcitriol/metabolismo , Vitamina D/metabolismo , Hormônio Paratireóideo/metabolismo , Rim/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Genômica , Receptores de Calcitriol/metabolismo
10.
Clin Nutr ESPEN ; 51: 367-376, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184229

RESUMO

BACKGROUND & AIMS: Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life. METHODS: One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject. RESULTS: Overall, the prevalence of vitamin D insufficiency (<30 ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p < 0.001) and the likelihood of being an earlier responder in the first 3 years of life (p < 0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status. CONCLUSIONS: Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.


Assuntos
Fibrose Cística , Deficiência de Vitamina D , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Suplementos Nutricionais , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Estudos Prospectivos , Vitamina D , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/genética , Vitamina D3 24-Hidroxilase , Vitaminas/uso terapêutico
11.
Anticancer Res ; 42(10): 5049-5067, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36191995

RESUMO

BACKGROUND/AIM: Vitamin D receptor (VDR), activated upon binding of 1,25(OH)2D3, was described as a tumor suppressor in the skin. New biological functions of non-classical vitamin D derivatives were recently identified, that are mediated via binding to alternate receptors, including the aryl hydrocarbon receptor (AHR) and that indicate functional interaction between AHR and VDR signaling in various human tissues. We aimed to gain further insights into the cross-talk of VDR and AHR signaling in skin photo-carcinogenesis. MATERIALS AND METHODS: Using real-time quantitative PCR, we analyzed in vitro effects of the complete carcinogen UVB and of 1,25(OH)2D3 on the expression of members of the AHR and VDR pathways in human keratinocytes revealing characteristics of different stages of skin photo-carcinogenesis. RESULTS: In precancerous HaCaT keratinocytes, induction of a target gene of AHR-mediated transcription (CYP1A1) was markedly stronger after treatment with UVB, as compared to treatment with 1,25(OH)2D3. In contrast, in SCL-1 cells (that reveal the complete phenotype of malignant transformation), expression of CYP1A1 was higher after treatment with 1,25(OH)2D3 as compared to treatment with UVB. The classical VDR target CYP24A1 was up-regulated by 1,25(OH)2D3, but not by UVB, in both cell lines. However, the combined treatment with UVB strongly enhanced the 1,25(OH)2D3-mediated up-regulation of CYP24A1 exclusively in SCL-1, but not in HaCaT cells. CONCLUSION: There is a differential regulation of VDR and AHR target genes by UVB and 1,25(OH)2D3 in HaCaT and SCL-1 cells, that points to a complex and highly orchestrated network of vitamin D derivatives (and other photoproducts) and its relevance for photo-carcinogenesis.


Assuntos
Queratinócitos , Receptores de Hidrocarboneto Arílico , Receptores de Calcitriol , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Calcitriol/farmacologia , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Humanos , Queratinócitos/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitamina D3 24-Hidroxilase , Vitaminas/farmacologia
12.
J Genet ; 1012022.
Artigo em Inglês | MEDLINE | ID: mdl-36226342

RESUMO

Premature ejaculation (PE) is a common male sexual dysfunction disorder, and is considered to have the genetic predisposition. However, the internal regulation mechanisms is still unclear. Hence, this study intended to explore the effects of genetic polymorphisms of CYP24A1 on the risk of PE. This case-control study genotyped three SNPs of CYP24A1 (rs2762934, rs1570669 and rs6068816) from 139 PE patients and 372 healthy men using Agena MassARRAY platform. Collected data was then processed in SPSS 18.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression analysis to evaluate the associations between CYP24A1 polymorphisms and the PE risk. The results suggested that allele A of rs1570669 was significantly associated with the increased PE risk (OR=1.38, 95% CI=1.04-1.84, P=0.026). Meanwhile, we also identified rs1570669 as a risk factor of PE under the additive model (OR=1.47, 95% CI=1.02-2.11, P=0.039) by comparing the genotypic distributions between cases and controls, and genotype AA of rs1570669 was detected to be significantly related with an increased risk of PE under the codominant model (OR=2.26, 95% CI=1.06-4.83, P=0.036). This study is the first to proved that the genetic variants of CYP24A1 played essential role in affecting the susceptibility to PE in Chinese Han.


Assuntos
Ejaculação Precoce , Estudos de Casos e Controles , China , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Ejaculação Precoce/genética , Vitamina D3 24-Hidroxilase/genética
13.
Int J Mol Sci ; 23(18)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36142855

RESUMO

Macrophages synthesize active vitamin D (1,25-dihydroxy-vitamin D) and express the vitamin D receptor in the nucleus; however, vitamin D metabolism in relation to macrophage polarization and function is not well understood. We studied monocyte-derived macrophages (MDMs) from human buffy coats polarized into M0, M1 (LPS + IFNγ), M2a (IL4 + IL13) and M2c (IL10) macrophage subtypes stimulated with 25-hydroxy-vitamin D (1000 and 10,000 nanomolar). We measured vitamin D metabolites (25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 24,25-dihydroxy-vitamin D and 3-epi-25-hydroxy-vitamin D) in cell media with liquid chromatography-mass spectrometry-mass spectrometry. The mRNA expression (CYP27B1, CYP24A1 and CYP24A1-SV) was measured with qPCR. We found that reparative MDMs (M2a) had significantly more 1,25-dihydroxy-vitamin D compared to the other MDMs (M0, M1 and M2c). All MDMs were able to produce 3-epi-25-hydroxy-vitamin D, but this pathway was almost completely attenuated in inflammatory M1 MDMs. All MDM subtypes degraded vitamin D through the 24-hydroxylase pathway, although M1 MDMs mainly expressed an inactive splice variant of CYP24A1, coding the degrading enzyme. In conclusion, this study shows that vitamin D metabolism is highly dependent on macrophage polarization and that the C3-epimerase pathway for vitamin D is active in macrophages.


Assuntos
Lipopolissacarídeos , Receptores de Calcitriol , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Calcifediol , Humanos , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Racemases e Epimerases/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
14.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077207

RESUMO

Poly (I:C) can work as an immunostimulant and a viral vaccine; however, its functional mechanism in aquatic animals needs to be further investigated. In this study, comparative transcriptomic analyses were performed to investigate the effects of poly (I:C) on Argyrosomus japonicus at 12 h and 48 h postinjection. A total of 194 and 294 differentially expressed genes were obtained in the liver and spleen, respectively. At 12 h, poly (I:C) injection could significantly influence the function of the metabolism-related pathways and immune-related pathways in the liver through the upregulation of the genes GST, LPIN, FOXO1, CYP24A1, ECM1, and SGK1, and the downregulation of the genes IL-1ß, CXC19, TNFAIP3, and IRF1. At 48 h, poly (I:C) could enhance the liver energy metabolism by upregulating the genes TXNRD and ECM1, while it also induced some injury in the cells with the downregulation of the genes HBA and CYP24A1. In the spleen, poly (I:C) could regulate the fish immunity and inflammatory response by upregulating the genes DDIT4, C3, EFNA, and MNK, and by downregulating the genes ABCA1, SORT1, TNF, TLR2, IL8, and MHCII at 12 h, and at 48 h, the poly (I:C) had a similar influence as that in the liver. Intersection analyses demonstrated that CYP24A1 and ECM1 were the main functional genes that contributed to the health of the liver. Ten and four genes participated in maintaining the health of the two tissues after 12 h and 48 h, respectively. In summary, our results provided a new insight into ploy (I:C) application in A. japonicus, and it also helped us to better understand the fish response mechanism to the viral vaccine injection.


Assuntos
Perciformes , Vacinas Virais , Animais , Fígado , Perciformes/genética , Poli I-C/farmacologia , Baço , Transcriptoma , Vitamina D3 24-Hidroxilase/genética
15.
Front Immunol ; 13: 937476, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36172344

RESUMO

Aim: Vitamin D (VitD) signaling has been increasingly investigated for its role in stimulating the innate and adaptive immune systems and suppressing inflammatory responses. Therefore, we examined the associations between VitD-related genetic polymorphisms, plasma 25-hydroxyvitamin D (25(OH)D), and the efficacy and safety of immune checkpoint inhibitors (ICIs). Patients and methods: A total of 13 single-nucleotide polymorphisms (SNPs) in VitD metabolic pathway genes were genotyped in 343 cancer patients receiving ICI treatment using the MassARRAY platform. In 65 patients, the associations between plasma 25(OH)D levels and ICI treatment outcomes were investigated further. Results: We found that the CYP24A1 rs6068816TT and rs2296241AA genotypes were significantly higher in patients who responded to ICIs. Furthermore, patients with higher plasma 25(OH)D levels had a better treatment response. The distribution of allele and genotype frequencies showed that three SNPs (rs10877012, rs2762934, and rs8018720) differed significantly between patients who had immune-related adverse events (irAEs) and those who did not. There was no statistically significant relationship between plasma 25(OH)D levels and the risk of irAEs. Conclusion: In summary, our findings showed that genetic variations in the VitD metabolism pathway were associated with ICI treatment outcomes, and VitD supplementation may be useful in improving ICI treatment efficacy.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase , Inibidores de Checkpoint Imunológico , Humanos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Inibidores de Checkpoint Imunológico/efeitos adversos , Polimorfismo de Nucleotídeo Único , Vitamina D , Vitamina D3 24-Hidroxilase/genética , Vitaminas
16.
J Trace Elem Med Biol ; 74: 127085, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36179462

RESUMO

BACKGROUND: Chronic iron overload could induce nephropathy via oxidative stress and inflammation, and chelating therapy has limited efficacy in removing excess intracellular iron. Although vitamin D (VD) has shown potent antioxidant and anti-inflammatory effects, as well contribute to iron homeostasis, none of the previous studies measured its potential remedial effects against chronic iron toxicity. AIMS: To measure the alleviating effects of deferasirox (DFX) and/or vitamin D (VD) single and combined therapies against nephrotoxicity induced by chronic iron overload. METHODS: Forty male rats were divided into negative (NC) and positive (PC) controls, DFX, VD, and DFX/VD groups. The designated groups received iron for six weeks followed by DFX and/or VD for another six weeks. Then, the expression pattern of renal genes and proteins including hepcidin, ferroportin (FPN), megalin, transferrin receptor 1 (TfR1), ferritin heavy and light chains, VD receptor (VDR), VD synthesizing (Cyp27b1) and catabolizing (Cyp24a1) enzymes were measured alongside serum markers of renal function and iron biochemical parameters. Additionally, several markers of oxidative stress (MDA/H2O2/GSH/SOD1/CAT/GPx4) and inflammation (IL-1ß/IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 (Casp-3) were measured. RESULTS: The PC rats showed pathological iron and renal biochemical markers, hypovitaminosis D, increased renal tissue iron contents with increased Cyp24a1/Megalin/ferritin-chains/hepcidin, and decreased Cyp27b1/VDR/TfR1/FPN expression than the NC group. The PC renal tissues also showed abnormal histology, increased inflammatory (IL-1ß/IL-6/TNF-α), oxidative stress (MDA/H2O2), and apoptosis markers with decreased IL-10/GSH/SOD1/CAT/GPx4. Although DFX monotherapy reduced serum iron levels, it was comparable to the PC group in renal iron concentrations, VD and iron-homeostatic molecules, alongside markers of oxidative stress, inflammation, and apoptosis. On the other hand, VD monotherapy markedly modulated renal iron and VD-related molecules, reduced renal tissue iron concentrations, and preserved renal tissue relative to the PC and DFX groups. However, serum iron levels were equal in the VD and PC groups. In contrast, the best significant improvements in serum and renal iron levels, expression of renal iron-homeostatic molecules, oxidative stress, inflammation, and apoptosis were seen in the co-therapy group. CONCLUSIONS: iron-induced nephrotoxicity was associated with dysregulations in renal VD-system together with renal oxidative stress, inflammation, and apoptosis. While DFX reduced systemic iron, VD monotherapy showed better attenuation of renal iron concentrations and tissue damage. Nonetheless, the co-therapy approach exhibited the maximal remedial effects, possibly by enhanced modulation of renal iron-homeostatic molecules alongside reducing systemic iron levels. AVAILABILITY OF DATA AND MATERIALS: All data generated or analysed during this study are included in this published article [and its Supplementary information files].


Assuntos
Colecalciferol , Sobrecarga de Ferro , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Caspase 3/metabolismo , Deferasirox/farmacologia , Ferritinas/metabolismo , Hepcidinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Rim , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Estresse Oxidativo , Ratos , Receptores da Transferrina/metabolismo , Superóxido Dismutase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Vitamina D3 24-Hidroxilase/metabolismo
17.
Nutrients ; 14(15)2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35956396

RESUMO

Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D3 to 24,25(OH)2D3 ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396w/w mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors.


Assuntos
Hipercalcemia , Animais , Feminino , Homeostase , Hipercalcemia/genética , Camundongos , Minerais , Mutação , Gravidez , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo , Vitaminas
18.
Adv Healthc Mater ; 11(20): e2200849, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35930707

RESUMO

Exosomes show great potential in diagnostic and therapeutic applications. Inspired by the human innate immune defense, herein, we report engineered exosomes derived from monocytic cells treated with immunomodulating compounds 1α,25-dihydroxyvitamin D3, and CYP24A1 inhibitor VID400 which are slowly released from electrospun nanofiber matrices. These engineered exosomes contain significantly more cathelicidin/LL-37 when compared with exosomes derived from either untreated cells or Cathelicidin Human Tagged ORF Clone transfected cells. In addition, such exosomes exhibit multiple biological functions evidenced by killing bacteria, facilitating human umbilical vein endothelial cell tube formation, and enhancing skin cell proliferation and migration. Taken together, the engineered exosomes developed in this study can be used as therapeutics alone or in combination with other biomaterials for effective infection management, wound healing, and tissue regeneration.


Assuntos
Exossomos , Humanos , Vitamina D3 24-Hidroxilase , Peptídeos Catiônicos Antimicrobianos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Materiais Biocompatíveis , Catelicidinas
19.
Int J Mol Sci ; 23(16)2022 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-36012386

RESUMO

BACKGROUND: Studies have demonstrated the link between vitamin-D-related genetic variations and nonskeletal outcomes. We aimed to identify all available data on the association of vitamin-D-related genetic variations with nonalcoholic fatty liver disease (NAFLD). METHODS: Potentially eligible studies were identified from Embase and Medline databases from inception to June 2022 using a search strategy that comprised terms for "Vitamin D" and "NAFLD". Eligible studies must report the association between vitamin D-related genetic variations and presence, severity or response to treatment of NAFLD. Data were extracted from each eligible study. RESULTS: A total of 3495 articles were identified. After a systematic review, twelve studies were included. A total of 26 genetic variations were identified. Presence of NAFLD was associated with variations of GC (rs222054, rs222020, rs10011000, rs7041), VDR (rs2228570, rs11168287, rs10783219, rs4752), CYP24A1 (rs3787557, rs6068816, rs2296241, rs2248359) and CYP27B1 (rs4646536). Severity of NAFLD was associated with variations of GC (rs4588), VDR (rs2228570, rs4334089), CYP2R1 (rs10741657), DHCR7 (rs1544410, rs3829251, rs12785878) and CYP24A1 (rs3787557, rs6068816, rs6097809, rs6127119, rs2248359, rs3787554, rs4809960, rs6022999). Response to calcitriol treatment was associated with variation of VDR (rs10735810). CONCLUSIONS: Multiple vitamin D-related genetic variations were associated with NAFLD, indicating the role of vitamin D in the pathogenesis of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Vitamina D , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Variação Genética , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , Vitaminas
20.
Molecules ; 27(16)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-36014588

RESUMO

In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D3 (5) and its 24-hydroxylated analogues (7,8), which are candidates for the CYP24A1 main metabolites of 5. The key fragments, 23,23-difluoro-CD-ring precursors (9-11), were synthesized starting from Inhoffen-Lythgoe diol (12), and introduction of the C23 difluoro unit to α-ketoester (19) was achieved using N,N-diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F2-25(OH)D3 (5) showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D3 (1).


Assuntos
Calcifediol , Calcitriol , Calcifediol/metabolismo , Calcitriol/farmacologia , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitamina D3 24-Hidroxilase/metabolismo
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