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1.
Nutrients ; 16(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38999892

RESUMO

Vitamin D (vitD) deficiency (25-hydroxy-vitamin D < 50 nmol/L) is common in pregnancy and associated with an increased risk of adverse pregnancy outcomes. High-dose vitD supplementation is suggested to improve pregnancy health, but there is limited knowledge about the effects on placental vitD transport and metabolism and the vitD status of newborns. Comparing the current standard maternal supplementation, 10 µg/day to a 90 µg vitD supplement, we investigated placental gene expression, maternal vitD transport and neonatal vitD status. Biological material was obtained from pregnant women randomized to 10 µg or 90 µg vitD supplements from week 11-16 onwards. Possible associations between maternal exposure, neonatal vitD status and placental expression of the vitD receptor (VDR), the transporters (Cubilin, CUBN and Megalin, LRP2) and the vitD-activating and -degrading enzymes (CYP24A1, CYP27B1) were investigated. Maternal vitD-binding protein (VDBP) was determined before and after supplementation. Overall, 51% of neonates in the 10 µg vitD group were vitD-deficient in contrast to 11% in the 90 µg group. High-dose vitD supplementation did not significantly affect VDBP or placental gene expression. However, the descriptive analyses indicate that maternal obesity may lead to the differential expression of CUBN, CYP24A1 and CYP27B1 and a changed VDBP response. High-dose vitD improves neonatal vitD status without affecting placental vitD regulation.


Assuntos
Suplementos Nutricionais , Placenta , Deficiência de Vitamina D , Vitamina D , Humanos , Feminino , Gravidez , Placenta/metabolismo , Placenta/efeitos dos fármacos , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/sangue , Recém-Nascido , Adulto , Deficiência de Vitamina D/tratamento farmacológico , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Fenômenos Fisiológicos da Nutrição Materna , Receptores de Superfície Celular
2.
Front Endocrinol (Lausanne) ; 15: 1401975, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846489

RESUMO

Background: Vitamin D binding protein (DBP) might increase substantially after ovarian stimulation and hence could be associated with IVF/ICSI outcomes because it determines the fraction of free bioavailable 25(OH) vitamin D. In this study, we aim to determine whether DBP is associated with E2 level after ovarian stimulation and IVF/ICSI outcomes. Design: Post-hoc analysis of a prospective observational cohort. Setting: Single-center study. Participants: 2569 women receiving embryo transfer. Intervention: None. Main outcome measures: The main outcomes were oocyte and embryo quality as well as pregnancy outcomes. Results: DBP concentration correlates with E2 on hCG day (=day of inducing ovulation with hCG; correlation coefficient r = 0.118, P<0.001) and E2 x-fold change to baseline level (r = 0.108, P<0.001). DBP is also positively correlated with total 25(OH)D (r = 0.689, R2 = 0.475, P<0.001) and inversely with free 25(OH)D (r=-0.424, R2=0.179, P<0.001), meaning that E2-stimulated DBP synthesis results in a decrease of free 25(OH)D during ovarian stimulation. However, such alteration does not affect IVF/ICSI outcomes when considering confounding factors, such as the number and quality of oocytes nor embryo quality as well as pregnancy outcomes. Conclusion: DBP concentration correlates with the degree of E2 increase after ovarian stimulation. DBP is also positively correlated with total 25(OH)D and inversely with free 25(OH)D, suggesting that the proportion of free 25(OH)D decreases during ovarian stimulation caused by E2-stimulated DBP synthesis. However, such alteration does not affect clinical IVF/ICSI outcomes.


Assuntos
Gonadotropina Coriônica , Fertilização in vitro , Indução da Ovulação , Ovulação , Resultado da Gravidez , Proteína de Ligação a Vitamina D , Humanos , Feminino , Gravidez , Proteína de Ligação a Vitamina D/sangue , Adulto , Indução da Ovulação/métodos , Gonadotropina Coriônica/administração & dosagem , Ovulação/efeitos dos fármacos , Estudos Prospectivos , Fertilização in vitro/métodos , Estrogênios/administração & dosagem , Transferência Embrionária , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas
3.
Int J Mol Sci ; 25(11)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38892458

RESUMO

Vitamin D-binding protein (DBP), also known as Gc-globulin, is a protein that affects several physiological processes, including the transport and regulation of vitamin D metabolites. Genetic polymorphisms in the DBP gene have a significant impact on vitamin D levels and may have implications for disease risk. DBP polymorphisms are linked to differential immune responses, which could influence the onset of juvenile diseases. This narrative review examines the various roles of DBP, with a focus on bone health, immunological regulation, and lipid metabolism in children. Chronic disorders affected by DBP polymorphisms include bone abnormalities, autoimmune diseases, cardiovascular issues, childhood asthma, allergies, cystic fibrosis, acute liver failure, celiac disease, inflammatory bowel disease, and chronic kidney disease. Future research should focus on identifying the processes that underpin the many roles that DBP plays and developing customized therapeutics to improve health outcomes in the juvenile population.


Assuntos
Proteína de Ligação a Vitamina D , Humanos , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo , Criança , Saúde da Criança , Vitamina D/metabolismo , Metabolismo dos Lipídeos , Polimorfismo Genético
4.
Eur J Endocrinol ; 190(6): K53-K56, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38788201

RESUMO

A 29-year-old female, born to consanguineous parents, was found with unmeasurable levels of vitamin D (<10 nmol/L) after routine biochemical screening during her first pregnancy. She did not respond to either oral or intramuscular vitamin D supplementation and was an otherwise healthy young woman, with no signs of rickets, osteomalacia, osteoporosis, or secondary hyperparathyroidism. Western blot analysis revealed total lack of vitamin D binding protein, and next generation sequencing confirmed a novel, pathogenic homozygote loss-of-function mutation in exon 13 of the group-specific component gene, that encodes the poly A tail for vitamin D binding protein. She was therefore diagnosed with hereditary DBP deficiency, and vitamin D supplementation was diminished to life-long regular vitamin D supplementation (25 µg per day). This case is extremely interesting, as it expands our knowledge of vitamin D physiology and supports the free hormone hypothesis, given that the patient was asymptomatic despite no measurable levels of vitamin D.


Assuntos
Homozigoto , Deficiência de Vitamina D , Proteína de Ligação a Vitamina D , Vitamina D , Humanos , Feminino , Adulto , Vitamina D/sangue , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética , Mutação com Perda de Função
5.
Nutrients ; 16(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38732523

RESUMO

The presence of vitamin D3 deficiency associated with the presence of metabolic syndrome (MS) has important public health effects. This study aims to investigate the relationship between vitamin D3 deficiency, MS and vitamin D3 receptor (VDR), GC Vitamin D binding protein (GC), and cytochrome P450 family 2 subfamily R member 1 (CYP2R1) gene polymorphisms, and genes whose encoded proteins are responsible for vitamin D3 metabolism and transport. A total of 58 participants were included in this study (age 39 ± 12 years) and were selected over a 12-month period. They were divided into four groups, depending on the presence of polymorphisms in VDR, GC, and CYP2R1 genes and their weight status. At baseline, in months 3, 6, and 12, biochemical parameters including 25(OH)D3, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and homeostatic model assessment (HOMA index), the insulin resistance indicator were measured. Our results show that all subjects in the polymorphism group supplemented with vitamin D3 reached an optimal level of vitamin D3 associated with high concentrations of 25(OH)D3. Weight loss was most significant in patients in the POW group (overweight patients).


Assuntos
Colecalciferol , Colestanotriol 26-Mono-Oxigenase , Síndrome Metabólica , Receptores de Calcitriol , Deficiência de Vitamina D , Proteína de Ligação a Vitamina D , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Colecalciferol/sangue , Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Resistência à Insulina/genética , Síndrome Metabólica/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética
6.
Medicine (Baltimore) ; 103(20): e38219, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758851

RESUMO

Studies have suggested that Vitamin D deficiency is associated with the occurrence of both type 1 and type 2 diabetes, and that vitamin D-binding proteins (VDBP) are necessary for metabolic stress in pancreatic α-cells. However, the causal relationship between serum 25-hydroxyvitamin D [25(OH)D] levels, VDBP, and the risk of diabetes mellitus (DM) remains unclear. Mendelian randomization (MR) was used to investigate the causal relationship between 25(OH)D, VDBP, and DM. Relevant recent data were downloaded from the NHGRI-EBI Catalog of published genome-wide association studies (GWAS) and filtered for single nucleotide polymorphisms (SNPs). We used multiple MR methods, including inverse variance weighting (IVW), and performed sensitivity analyses to detect whether pleiotropy or heterogeneity biased the results. There was a causal relationship between genetically predicted VDBP levels and serum 25(OH)D levels, and serum 25(OH)D levels increased with increasing VDBP levels (IVW: ß = 0.111, OR = 1.117, 95% CI:1.076-1.162, P = 1.41 × 10-8). There was no causal relationship between the genetically predicted VDBP levels, serum 25(OH)D levels, and DM (VDBP: IVW ß:0.001, OR:1.001, 95% CI:0.998-1.003, P > .05; 25(OH)D: IVW ß: -0.009, OR:0.991, 95% CI:0.982-1.001, P = .068). Sensitivity analysis indicated that horizontal pleiotropy was unlikely to bias causality in this study. MR analysis results demonstrated a positive causal relationship between VDBP levels and serum 25(OH)D levels in the European population. The 25(OH)D and VDBP levels were not causally related to an increased risk of diabetes.


Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Proteína de Ligação a Vitamina D , Vitamina D , Humanos , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/sangue , Vitamina D/sangue , Vitamina D/análogos & derivados , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/epidemiologia
7.
Twin Res Hum Genet ; 27(2): 69-79, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38644690

RESUMO

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS25OHD and PGSDBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.


Assuntos
Proteína de Ligação a Vitamina D , Vitamina D , Humanos , Proteína de Ligação a Vitamina D/genética , Vitamina D/sangue , Vitamina D/genética , Vitamina D/análogos & derivados , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , População Branca/genética , Fenótipo , Idoso , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Herança Multifatorial/genética
8.
Biomedica ; 44(1): 45-53, 2024 03 31.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38648345

RESUMO

INTRODUCTION: Vitamin D is required for bone and mineral metabolism and participates in the regulation of the immune response. It is also linked to several chronic diseases and conditions, usually in populations of European descent. Brazil presents a high prevalence of vitamin D deficiency and insufficiency despite the widespread availability of sunlight in the country. Thus, it is important to investigate the role of vitamin D as a risk factor for disease and to establish causal relationships between vitamin D levels and health-related outcomes in the Brazilian population. OBJECTIVE: To examine genetic variants identified as determinants of serum vitamin D in genome-wide association studies of European populations and check whether the same associations are present in Brazil. If so, these single nucleotide polymorphisms (SNPs) could be developed locally as proxies to use in genetically informed causal inference methods, such as Mendelian randomization. MATERIALS AND METHODS: We extracted SNPs associated with vitamin D from the genomewide association studies catalog. We did a literature search to select papers ascertaining these variants and vitamin D concentrations in Brazil. RESULTS: GC was the gene with the strongest association with vitamin D levels, in agreement with existing findings in European populations. However, VDR was the most investigated gene, regardless of its non-existing association with vitamin D in the genomewide association studies. CONCLUSIONS: More research is needed to validate sound proxies for vitamin D levels in Brazil, for example, prioritizing GC rather than VDR.


Introducción. La vitamina D es necesaria para el metabolismo óseo y mineral, y participa en la regulación de la respuesta inmunitaria. También está relacionada con enfermedades crónicas en poblaciones europeas. En Brasil, existe una prevalencia elevada de deficiencia e insuficiencia de vitamina D, a pesar de la amplia disponibilidad de luz solar. Por lo tanto, es importante investigar el papel de la vitamina D como factor de riesgo de diversas enfermedades y establecer relaciones causales entre los niveles de vitamina D y los problemas de salud en la población brasileña. Objetivo. Examinar variantes genéticas relacionadas con la vitamina D sérica en estudios de asociación genómica de poblaciones europeas y comprobar si estas mismas están presentes en Brasil. De ser así, estos SNPs podrían utilizarse como proxies en métodos de inferencia causal, tales como la aleatorización mendeliana. Materiales y métodos. A partir del catálogo de estudios de asociación de genoma completo se extrajeron SNPs relacionados con los niveles de vitamina D. Luego se hizo una búsqueda bibliográfica para identificar los artículos que evaluaran estos SNPs y la concentración de vitamina D en Brasil. Resultados. GC fue el gen más fuertemente asociado con los niveles de vitamina D, en concordancia con los resultados existentes en poblaciones europeas. Sin embargo, el gen VDR fue el más investigado, aunque no esté vinculado con la vitamina D en los estudios de asociación de genoma completo. Conclusiones. Se necesita más investigación para validar proxies genéticos de los niveles de vitamina D en Brasil y se recomienda priorizar el gen GC en lugar de VDR.


Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D , Vitamina D , Humanos , Brasil/epidemiologia , Vitamina D/sangue , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/epidemiologia , Receptores de Calcitriol/genética , Proteína de Ligação a Vitamina D/genética
9.
Science ; 384(6694): 428-437, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38662827

RESUMO

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.


Assuntos
Bacteroides fragilis , Microbioma Gastrointestinal , Inibidores de Checkpoint Imunológico , Neoplasias , Vitamina D , Animais , Feminino , Humanos , Masculino , Camundongos , Bacteroides fragilis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/microbiologia , Neoplasias/terapia , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Dieta , Linhagem Celular Tumoral , Calcifediol/administração & dosagem , Calcifediol/metabolismo , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo
10.
J Immunol Res ; 2024: 7484490, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455363

RESUMO

Macrophages are the immune cells of high-immunological plasticity, which can exert both pro- and anti-inflammatory activity, as well as repolarize their phenotype to the opposite or neutral one. In this regard, M2 macrophages of the tumor-associated stroma (TAS) are a promising therapeutic target in treating malignant neoplasms. Using FACS assay, we have estimated the CD11b+/Ly-6G+/Ly-6C+ fraction of macrophages from the peritoneum and TAS in intact healthy mice and those with developed Lewis carcinoma, both untreated and treated according to Karanahan technology in combination with group-specific macrophage activator (GcMAF-RF). As well, the pattern of pro- and anti-inflammatory cytokines mRNA expression in different groups of experimental and tumor-bearing animals was assessed. It was found that: (i) exposure of intact mice to GcMAF-RF results in the increased number of CD11b+/Ly-6C+ peritoneal macrophages and, at the same time, the expression pattern of cytokines in peritoneal macrophages switches from that characteristic of the mixed M1/M2 phenotype to that characteristic of the neutral M0 one; (ii) combination of Karanahan technology and GcMAF-RF treatment results in M0/M1 repolarization of TAS macrophages; (iii) in tumor-bearing mice, the response of peritoneal macrophages to such a treatment is associated with the induction of anti-inflammatory reaction, which is opposite to that in TAS macrophages.


Assuntos
Fatores Ativadores de Macrófagos , Macrófagos , Neoplasias , Proteína de Ligação a Vitamina D , Camundongos , Animais , Macrófagos Peritoneais/metabolismo , Citocinas/metabolismo , Neoplasias/patologia , Anti-Inflamatórios/metabolismo
11.
J Biol Chem ; 300(4): 107164, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38484798

RESUMO

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system.


Assuntos
Osso e Ossos , Homeostase , Polipeptídeo N-Acetilgalactosaminiltransferase , Vitamina D , Animais , Masculino , Camundongos , Osso e Ossos/anatomia & histologia , Osso e Ossos/química , Osso e Ossos/metabolismo , Cálcio/metabolismo , Glicosilação , Homeostase/genética , Hormônio Paratireóideo/metabolismo , Vitamina D/metabolismo , Vitamina D/análogos & derivados , Proteína de Ligação a Vitamina D/metabolismo
12.
J Neuroinflammation ; 21(1): 52, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368354

RESUMO

Establishing biomarkers to predict multiple sclerosis diagnosis and prognosis has been challenging using a single biomarker approach. We hypothesised that a combination of biomarkers would increase the accuracy of prediction models to differentiate multiple sclerosis from other neurological disorders and enhance prognostication for people with multiple sclerosis. We measured 24 fluid biomarkers in the blood and cerebrospinal fluid of 77 people with multiple sclerosis and 80 people with other neurological disorders, using ELISA or Single Molecule Array assays. Primary outcomes were multiple sclerosis versus any other diagnosis, time to first relapse, and time to disability milestone (Expanded Disability Status Scale 6), adjusted for age and sex. Multivariate prediction models were calculated using the area under the curve value for diagnostic prediction, and concordance statistics (the percentage of each pair of events that are correctly ordered in time for each of the Cox regression models) for prognostic predictions. Predictions using combinations of biomarkers were considerably better than single biomarker predictions. The combination of cerebrospinal fluid [chitinase-3-like-1 + TNF-receptor-1 + CD27] and serum [osteopontin + MCP-1] had an area under the curve of 0.97 for diagnosis of multiple sclerosis, compared to the best discriminative single marker in blood (osteopontin: area under the curve 0.84) and in cerebrospinal fluid (chitinase-3-like-1 area under the curve 0.84). Prediction for time to next relapse was optimal with a combination of cerebrospinal fluid[vitamin D binding protein + Factor I + C1inhibitor] + serum[Factor B + Interleukin-4 + C1inhibitor] (concordance 0.80), and time to Expanded Disability Status Scale 6 with cerebrospinal fluid [C9 + Neurofilament-light] + serum[chitinase-3-like-1 + CCL27 + vitamin D binding protein + C1inhibitor] (concordance 0.98). A combination of fluid biomarkers has a higher accuracy to differentiate multiple sclerosis from other neurological disorders and significantly improved the prediction of the development of sustained disability in multiple sclerosis. Serum models rivalled those of cerebrospinal fluid, holding promise for a non-invasive approach. The utility of our biomarker models can only be established by robust validation in different and varied cohorts.


Assuntos
Quitinases , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/líquido cefalorraquidiano , Osteopontina , Proteína de Ligação a Vitamina D , Biomarcadores/líquido cefalorraquidiano , Recidiva
13.
Acta Clin Belg ; 79(2): 130-142, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38166537

RESUMO

Chronic kidney disease (CKD) is a growing health concern with a complex etiological landscape. Among the numerous factors implicated, vitamin D binding protein (VDBP) has emerged as a focal point of scientific studies because of its critical role in vitamin D metabolism and immune modulation. The relationship between VDBP and CKD reveals a complex web of molecular and biochemical details that have great potential for improving diagnostic understanding and treatment strategies for CKD. This review summarizes the multifaceted roles of VDBP, including its molecular dynamics, interactions with vitamin D, and subsequent implications for kidney function. The main focus of the discussion is how VDBP affects bone mineral homeostasis, highlighted by the dysregulation of calcium and phosphorus metabolism, which is a part of the pathophysiology of CKD. The discussion also touches on the immunomodulatory scope of VDBP and how it may reduce the chronic inflammatory environment that accompanies CKD. The diagnostic potential of VDBP as a biomarker for CKD has been rigorously examined, highlighting its capacity to improve early detection and prognostic assessment. Modification of VDBP activity has the potential to slow the course of CKD and improve patient outcomes. Furthermore, a detailed examination of the genetic polymorphisms of VDBP and their implications for CKD susceptibility and treatment responsiveness provides a perspective for personalized medical methods. Prospects for the future depend on the expansion of studies that try to understand the molecular mechanisms underlying the VDBP-CKD interaction, in addition to clinical trials that evaluate the effectiveness of VDBP-focused treatment approaches.


Assuntos
Insuficiência Renal Crônica , Proteína de Ligação a Vitamina D , Vitamina D , Humanos , Proteína de Ligação a Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/genética , Insuficiência Renal Crônica/metabolismo , Vitamina D/metabolismo , Vitamina D/uso terapêutico , Biomarcadores/metabolismo
14.
J Periodontal Res ; 59(3): 421-430, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38282328

RESUMO

BACKGROUND AND OBJECTIVES: Vitamin D binding protein (DBP) is biosynthesised in the liver and is predominantly expressed in serum. Its primary role centres on facilitating the systemic transportation of vitamin D and its metabolites, notably 25-hydroxyvitamin D, to specific target tissues where vitamin D exerts its biological functions. Due to the paucity of studies, it is unclear whether there is an association between DBP and periodontal status and thus its potential use as a diagnostic biomarker. Therefore, the aim of the systematic review is to investigate the association between DBP in periodontal disease. METHODS: Two independent reviewers (YD and RG) performed a systematic literature search of English publications using several databases including MEDLINE (OVID interface, 1946 onwards), EMBASE (OVID interface, 1974 onwards), and Global Health (OVID interface, 1973 onwards). This search strategy enabled the identification of relevant publications and the development of a comprehensive library of studies. Studies were included based on previously agreed eligibility criteria. Of the eight studies included as part of this systematic review, seven were case-control studies and one was a cross-sectional study. The quality assessment was based on the Newcastle-Ottawa Scale (NOS) for case-control studies and the modified NOS for the cross-sectional study. RESULTS: The NOS quality assessment was 'favorable' for 6 included case control studies; and 'fair' for one study. The modified NOS quality assessment for the single cross-sectional study demonstrated a medium risk of bias. The results of the majority of the included studies indicated a statistically significant higher concentration of DBP levels in individuals with periodontitis in comparison to those who were periodontally healthy. This trend held true irrespective of the sampling method employed for the assessment of DBP concentration. CONCLUSION: The results summarised in this systematic review indicate a positive association between DBP and periodontitis. Nonetheless, there is a need for longitudinal, prospective trials, to confirm the use of DBP as a potential biomarker for the diagnosis of periodontitis.


Assuntos
Proteína de Ligação a Vitamina D , Humanos , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/metabolismo , Biomarcadores/sangue , Doenças Periodontais/metabolismo , Vitamina D/sangue , Vitamina D/metabolismo
15.
Hum Genet ; 143(2): 101-105, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38265561

RESUMO

Vitamin D-binding protein (VDBP) deficiency is a recently discovered apparently benign biochemical disorder that can masquerade as treatment-resistant vitamin D deficiency and is likely underrecognized. We present the case of a child with persistently low 25OH vitamin D levels despite replacement therapy. Exome sequencing revealed a novel homozygous nonsense variant in the GC gene, leading to undetectable levels of VDBP. Interestingly, exome sequencing also revealed a homozygous loss-of-function variant in ZNF142, which likely explains the additional clinical features of recurrent febrile convulsions and global developmental delay. Our findings corroborate the two previously reported patients with autosomal recessive VDBP deficiency caused by biallelic GC variants and emphasize the importance of measuring VDBP levels in cases of apparent vitamin D deficiency that is treatment-resistant. We also urge caution in concluding "atypical" presentations without careful investigation of a potential dual molecular diagnosis.


Assuntos
Deficiência de Vitamina D , Proteína de Ligação a Vitamina D , Criança , Humanos , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/uso terapêutico , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/genética
16.
Theranostics ; 14(1): 436-450, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164156

RESUMO

Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , Proteína de Ligação a Vitamina D/uso terapêutico , Neoplasias Hepáticas/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral
17.
Nutr Bull ; 49(1): 63-72, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38146611

RESUMO

Hypovitaminosis D during infancy is associated with the development of chronic diseases and poor health later in life. While the effect of environmental factors on vitamin D concentration has been extensively explored, this study aimed to explore the effect of genetic factors on vitamin D concentration among Chinese infants. We conducted a multi-centre cross-sectional study in Hong Kong from July 2019 to May 2021. A candidate genetic approach was adopted to study four selected genetic variants of the vitamin D-binding protein (DBP) and vitamin D receptor (VDR) (rs4588, rs7041, rs2282679 and rs2228570) to examine their associations with measured serum 25(OH)D concentration. A total of 378 Chinese infants aged 2-12 months were recruited in this study. Peripheral blood samples were collected from the infants to measure serum 25(OH)D concentration and extract DNA. Results showed that rs7041T and rs2282679C were significantly associated with lower serum 25(OH)D concentration. Further analysis of the DBP variants revealed that the GC1F allele was significantly associated with lower 25(OH)D concentration and identified as the risk DBP isoform in infants. While our results revealed that there is no direct association between VDR-FokI genotype and serum 25(OH)D concentration, a VDR-FokI genotype-specific pattern was observed in the association between DBP isoforms and serum 25(OH)D concentration. Specifically, significant associations were observed in the DBP genotypes GC1F/F, GC1F/2 and GC1S/2 among VDR-FokI TT/TC carriers, but not in VDR-FokI CC carriers. Our findings lay down the basis for the potential of genetic screening to identify high risk of hypovitaminosis D in Chinese infants.


Assuntos
Raquitismo , Deficiência de Vitamina D , Humanos , Receptores de Calcitriol/genética , Estudos Transversais , Proteína de Ligação a Vitamina D/genética , Polimorfismo de Nucleotídeo Único/genética , Vitamina D , Genótipo , Deficiência de Vitamina D/genética , China/epidemiologia
18.
BMC Med Genomics ; 16(1): 319, 2023 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066559

RESUMO

BACKGROUND: The severity of chronic hepatitis C and susceptibility to hepatocellular carcinoma (HCC) are associated with genetic variations within vitamin D receptor (VDR) in several populations. This study aims to determine the significance of the VDRs (rs2228570, rs3782905, rs11568820) and DBP (rs7041) for the susceptibility to HCC in Egyptian patients with chronic HCV infection and their effect on the progression of liver cirrhosis to carcinogenesis. METHODS: Single nucleotide polymorphisms (SNPs) VDR (rs2228570, rs3782905), and DBP rs7041 were genotyped using restriction fragment length-PCR (RFLP-PCR) technique and VDR rs11568820 was genotyped using single strand polymorphism PCR (SSP PCR). These SNPs genotypes, haplotypes and linkage disequilibrium analyses were examined in 299 Egyptian individuals (100 HCV-cirrhotic patients, 99 HCC- HCV patients, and 100 healthy controls). RESULT: The VDR rs2228570 CC genotype, VDR rs3782905 GC and CC genotypes, and DBP rs7041 GG genotype are significantly higher in HCC. It is noteworthy that, VDR rs3782905 CC and DBP rs7041 TG genotypes are higher in HCV induced liver cirrhosis than with HCC progression in HCV infected patients. Furthermore, among patients, the relationship between these SNPs and smoking status, gender, and HCC susceptibility was reported. CONCLUSION: Among the four investigated SNPs, there are associations between VDR rs3782905 and DBP rs7041 and the HCC progression in Egyptian patients chronically infected with HCV. These SNPs are considered as risk factors in HCV induced liver cirrhosis and HCC. The combinations of these SNPs with smoking status and gender are statistically linked to a high risk of HCC. Future research with a larger sample size of subjects with HCV infection is advised, because chronic liver disease induced by HCV infection is the primary cause of HCC in Egypt. We recommend screening of these SNPs for prediction of LC and HCC development in HCV infected patients, which may improve the used therapeutic protocol. These results suggest that VDR polymorphisms may be potential determinants for HCC susceptibility in Egyptian HCV patients.


Assuntos
Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Receptores de Calcitriol , Proteína de Ligação a Vitamina D , Humanos , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Hepatite C/complicações , Hepatite C/genética , Cirrose Hepática/complicações , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/genética , Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/genética
19.
Front Endocrinol (Lausanne) ; 14: 1281112, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38144557

RESUMO

Introduction: Vitamin D binding protein (VDBP) plays a crucial role in vitamin D transport and metabolism. The rs4588-A polymorphism of the GC gene, encoding VDBP, has been associated with altered serum VDBP and 25-hydroxyvitamin D (25OHD) levels. However, the mechanisms underlying these effects remain unclear. We aimed to investigate the relationship between urinary VDBP excretion and serum VDBP and 25OHD levels in individuals with and without the rs4588-A allele. Methods: A cross-sectional study was conducted on 109 children (mean age: 11.96 years) to explore the impact of rs4588-A on vitamin D metabolism and urinary VDBP excretion. Biochemical analyses determined serum 25OHD and VDBP levels, and urinary VDBP-to-creatinine ratio (u-VDBP/Cr). Genotyping for rs4588 SNP was performed using LightSNiP assay. Statistical analyses included correlation, linear regression, and comparison between allele groups. Results: Participants carrying the rs4588-A allele exhibited lower serum 25OHD levels compared to non-carriers (median (IQR): 11.85 (3.5) vs. 12.86 (4.9), p = 0.023). However, no statistically significant differences were observed in serum VDBP levels (126.34 ± 59.3 in rs4588-A vs. 136.49 ± 51.3 in non-rs4588-A, p = 0.141) or in u-VDBP/Cr (median (IQR): 0.4 (0.35) in rs4588-A vs. 0.386 (0.43) in non-rs4588-A, p = 0.189) between the two allele groups. A significant inverse correlation between u-VDBP/Cr and serum VDBP levels was found only in rs4588-A carriers (r = -0.367, p = 0.024). No such correlation was observed in non-carriers or the entire cohort. A linear regression analysis confirmed the impact of u-VDBP/Cr on serum VDBP levels in rs4588-A carriers (B = -0.269, t = -2.185, p = 0.035). Conclusion: Individuals with the rs4588-A allele in the GC gene had lower serum 25OHD levels. An inverse correlation between urinary VDBP excretion and serum VDBP levels was observed, suggesting a partial role of the renal pathway in altered serum VDBP and 25OHD levels linked to the rs4588-A allele.


Assuntos
Polimorfismo Genético , Proteína de Ligação a Vitamina D , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/urina , Estudos Transversais , Humanos , Masculino , Feminino , Criança , Adolescente , Frequência do Gene , Genótipo
20.
Int J Mol Sci ; 24(24)2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38139225

RESUMO

Group-specific component macrophage-activating factor (GcMAF) is the vitamin D3-binding protein (DBP) deglycosylated at Thr420. The protein is believed to exhibit a wide range of therapeutic properties associated with the activation of macrophagal immunity. An original method for GcMAF production, DBP conversion to GcMAF, and the analysis of the activating potency of GcMAF was developed in this study. Data unveiling the molecular causes of macrophage activation were obtained. GcMAF was found to interact with three CLEC10A derivatives having molecular weights of 29 kDa, 63 kDa, and 65 kDa. GcMAF interacts with high-molecular-weight derivatives via Ca2+-dependent receptor engagement. Binding to the 65 kDa or 63 kDa derivative determines the pro- and anti-inflammatory direction of cytokine mRNA expression: 65 kDa-pro-inflammatory (TNF-α, IL-1ß) and 63 kDa-anti-inflammatory (TGF-ß, IL-10). No Ca2+ ions are required for the interaction with the canonical 29 kDa CLEC10A. Both forms, DBP protein and GcMAF, bind to the 29 kDa CLEC10A. This interaction is characterized by the stochastic mRNA synthesis of the analyzed cytokines. Ex vivo experiments have demonstrated that when there is an excess of GcMAF ligand, CLEC10A forms aggregate, and the mRNA synthesis of analyzed cytokines is inhibited. A schematic diagram of the presumable mechanism of interaction between the CLEC10A derivatives and GcMAF is provided. The principles and elements of standardizing the GcMAF preparation are elaborated.


Assuntos
Fatores Ativadores de Macrófagos , Macrófagos , Proteína de Ligação a Vitamina D , Anti-Inflamatórios , Fatores Ativadores de Macrófagos/metabolismo , Macrófagos/metabolismo , RNA Mensageiro , Humanos , Proteína de Ligação a Vitamina D/metabolismo
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