Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study / Associação de polimorfismos do gene do receptor de vitamina D com diabetes mellitus tipo 2 na população Taif: um estudo de caso-controle

Abstract Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Resumo Várias razões podem estar subjacentes ao aumento dramático da diabetes mellitus tipo 2. Um desses motivos é a base genética e variações. Os polimorfismos do receptor da vitamina D estão associados a diferentes doenças, como artrite reumatoide e diabetes. O objetivo deste estudo é investigar a possível associação de duas mutações identificadas ApaI (rs7975232) e TaqI (rs731236). Oitenta e nove indivíduos saudáveis ​​e 56 pacientes com diabetes tipo 2 (T2D) foram investigados usando a técnica RFLP para genotipagem e haplotipagem também. A distribuição dos genótipos Apal não foi estatisticamente significativa entre o controle (P = 0,65), bem como para os pacientes diabéticos (P = 0,58). Para as frequências do alelo Taql, o alelo T foi de 0,61, onde o alelo G foi de 0,39. A distribuição de frequência dos genótipos Taql não foi estatisticamente significativa entre o controle (P = 0,26), bem como os pacientes diabéticos (P = 0,17). O risco relativo do alelo T do gene Apa1 é 1,28 e a razão de chances do mesmo alelo é 1,53, enquanto ambas as estimativas foram < 1,0 do alelo G. Da mesma forma, com o gene Taq1, os valores de risco relativo e razão de chances para o alelo T são 1,09 e 1,27, respectivamente, e ambas as estimativas do alelo C foram de 0,86 para o risco relativo e 0,79 para o odds ratio. O desequilíbrio de ligação par a par entre os dois SNPs Taq1 / apa1 foi estatisticamente significativo no grupo de controle (D = 0,218, D' = 0,925 e valor P < 0,001) e dados semelhantes em grupos diabéticos (D = 0,2, D' = 0,875 e valor P < 0,001). Esses dados sugerem que o alelo T de ambos os genes Apa1 e Taq1 está associado ao aumento do risco de diabetes tipo 2. Achamos que precisamos de um número maior de voluntários para chegar a uma conclusão mais precisa.

Allosteric modulation on specific gene mutated Vitamin D receptor by essential PUFAs and its distinct molecular effects on type 2 diabetes mellitus

A serious health threat affecting the T2DM group is evident more cases T2DM are diagnosed. In this research, we choose to research into all of this possible mechanism of 3T3-L1 Cell lines and Molecular Docking studies Schrodinger software identified Vitamin D, Omega-3, and 6 PUFAs (EPA DHA & AA) Compounds of hydrophilic and hydrophobic pocket throughout molecular modeling besides T2DM. A group of three analog VDRs is being developed for discovery treatment with T2DM. Its use as it was agreed to run a molecular cell culture and docking study. Recognize the binding method involving the compound in T2DM through ADME prediction. The molecular dynamics simulation was enhanced by confirmation of the strength of the possible composite binding. Based on the computational results, the Omega-3 and 6 PUFAs compound encourages energy interaction. The composite contains an in vitro anti-diabetic activity; the compounds have clearly shown that they are active on T2DM. Our studies provide vital information on the findings of the bimolecular T2DM inhibitors.

Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5) / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.

The correlation between the expression levels of vitamin D receptor in bile duct epithelial cells and the prognosis of biliary atresia / 国际儿科学杂志

Objective:To investigate the expression of vitamin D receptor(VDR)in biliary epithelial cells of children with biliary atresia(BA)and explore the correlation between VDR epression levels and clinical pathological prognosis.Methods:A total of 48 BA patients who underwent Kasai surgery in the Pediatric Surgery Department of the Second Affiliated Hospital of Xi′an Jiaotong University from January 2017 to December 2020 with confirmed pathological results were selected as the study subjects.Immunohistochemistry was used to determine the expression of VDR in biliary epithelial cells, and Masson staining was used to determine the degree of liver tissue fibrosis.Based on the VDR expression levels, the 48 BA patients were divided into the significantly low VDR expression group(30 cases)and the normal/high expression group(18 cases).Laboratory testing results within 1 week before Kasai surgery and liver shear wave elastography(SWE)data were collected for all patients.Follow-up was conducted for a period of 0 to 60 months after Kasai surgery or liver transplantation, meanwhile, the occurrence of refractory cholangitis and auto-liver survival time were collected.Results:There was a negative correlation between the degree of liver fibrosis and SWE value in children with BA( r=-0.805, P<0.01).In comparison between the two groups, the significantly low VDR expression group had higher SWE values[(20.57±1.28)kPa vs.(18.02±1.41)kPa, P<0.05], higher liver injury biochemical indicators[ALT(215.8±24.7)U/L vs.(182.6±21.2)U/L, P=0.021; AST(165.4±22.3)U/L vs.(139.6±21.4)U/L, P=0.014], a higher frequency of post-Kasai surgery refractory cholangitis(60.00% vs.22.22%, P=0.037), and a shorter median autologous liver survival time(27.00 months vs.36.00 months, P=0.032)than those in the normal/high expression group. Conclusion:The significant decrease in VDR expression in biliary epithelial cells may serve as an indicator of poor prognosis in BA.

Application progress in the role of vitamin D3 in transplantation immunity / 器官移植

Vitamin D3 is a kind of vitamin that plays important roles in maintaining the normal physiological function of the human body, and its metabolites and analogues exhibit strong anti-inflammatory activity. Vitamin D3 could be activated and converted into 1α, 25-dihydroxyvitamin D3, a kind of steroid hormone, in the human body, which participates in the regulation of cellular metabolism by activating vitamin D receptor (a kind of transcription factor), thus exerting immunomodulatory effects. This is essential for maintaining the physiological health of the body. Currently, there is a growing number of studies that suggest important roles for 1α, 25-dihydroxyvitamin D3 in organ transplantation immunomodulation and tolerance. Therefore, we reviewed the overview and physiological effects of 1α, 25-dihydroxyvitamin D3, the immunomodulatory effects of vitamin D3 and the application of vitamin D3 in clinical organ transplantation, and summarized the value of applying vitamin D3 in inducing immune tolerance in transplantation, with the aim of providing a reference for promoting the application of vitamin D3 in transplantation immunity.

Clinical efficacy of moxibustion for ulcerative colitis and its influence on vitamin D receptor / 针灸推拿医学（英文版）

Objective: To observe the clinical efficacy of herbal cake-partitioned moxibustion for ulcerative colitis (UC) and elucidate its mechanism by targeting the vitamin D receptor (VDR) signaling pathway. Methods: A total of 63 patients with UC were randomly divided into an observation group (30 cases, treated with herbal cake-partitioned moxibustion) and a control group (33 cases, treated with sham herbal cake-partitioned moxibustion). Moxibustion treatment was performed at Qihai (CV6) and bilateral Tianshu (ST25) and Shangjuxu (ST37), 3 times per week for 12 weeks. The total effective rate, visual analog scale (VAS) score for abdominal bloating and pain, and hospital anxiety and depression scale (HADS) score were compared between the two groups. Enzyme-linked immunosorbent assay was used to detect the concentrations of serum C-reactive protein (CRP), 25-hydroxyvitamin D [25(OH)D], and interleukin-12 (IL-12)/interleukin-23 (IL-23) p40. Immunohistochemistry was used to observe the expression levels of VDR and regenerating gene Ⅳ (Reg Ⅳ) proteins in colonic mucosa. The expression levels of VDR, cytochrome p45027B1 (CYP27B1), and Reg Ⅳ mRNAs were detected by real-time fluorescence quantitive polymerase chain reaction. Results: After treatment, the total effective rate in the observation group was 86.7％, which was significantly higher than 51.5％ in the control group (P<0.05). After treatment, the VAS scores for abdominal bloating and pain in the observation group were significantly decreased (P<0.01), as well as the HADS-depression subscale (HADS-D) and HADS-anxiety subscale (HADS) scores (P<0.05), while only the VAS score for abdominal pain in the control group was reduced (P<0.05), and the improvements of the scores in the observation group were more significant than those in the control group (P<0.05). After treatment, the serum CRP concentrations in both groups and the IL-12/IL-23 p40 concentration in the observation group were significantly decreased (P<0.05), and the concentrations in the observation group were lower than those in the control group (P<0.05). The expression levels of VDR protein and mRNA in the colon in both groups were all increased (P<0.01), and the expression levels of Reg Ⅳ protein and mRNA and CYP27B1 mRNA were all decreased in the two groups (P<0.05 or P<0.01); the improvements in the observation group were more notable than those in the control group (P<0.05 or P<0.01). Conclusion: Herbal cake-partitioned moxibustion can effectively alleviate abdominal pain and diarrhea in patients with UC, improve depression and anxiety disorders, and regulate the expression of related proteins in the VDR signaling pathway. The mechanism may be related to inhibiting intestinal inflammation by reducing the release of the proinflammatory cytokine IL-12/IL-23 p40.

Metodología para la evaluación automatizada de la expresión del receptor de vitamina D mediante técnica inmunocitoquímica / Methodology of automated Vitamin D receptor immunocytochemical expression análisis

Introducción: la citología permite examinar células de un tejido de manera mínimamente invasiva, sin embargo, la capacidad de realizar técnicas complementarias como la inmunocitoquímica (ICQ) no está exenta de dificultades. Es el objetivo de nuestro trabajo presentar una metodología que permita la utilización de ICQ automatizada asociada a un análisis automatizado mediante técnica de patología digital. Métodos: se incluyeron 5 sujetos sanos y se obtuvieron muestras de superficie ocular utilizando un citocepillo. La muestra fue procesada de manera automatizada mediante citología en fase líquida. Posteriormente se realizó ICQ automatizada para detectar la positividad nuclear del receptor de vitamina D. Para la evaluación, se utilizaron dos métodos: cuantificación directa bajo microscopio de luz y análisis automatizado usando analizador de imágenes en las diapositivas digitales obtenidas con un Scanner. El porcentaje de positividad encontrado con ambos métodos fueron comparados utilizando la prueba de Kappa. Resultados: todas las muestras presentaron una celularidad adecuada. En todos los casos fue posible realizar ICQ automatizada, más aún, todas las muestras presentaron una calidad óptima. Al comparar ambos métodos (manual versus automatizado) se observó un nivel de acuerdo sustancial (Kappa=0,69). Conclusiones: la metodología presentada en este manuscrito permite la evaluación automatizada de marcadores inmunohistoquímicos de la superficie ocular de manera mínimamente invasiva, siendo similar al conteo manual, pero más objetivo y reproducible. Esta técnica podría ser útil para el estudio proteómico en patologías como la enfermedad por ojo seco.

Introduction: Cytology tests use small amounts of tissue samples for diagnosis as a minimally invasive technique; however, the ability to perform complementary methods such as immunocytochemistry (ICC) is not without difficulties. The aim of our work is to present a method that allows the use of automated ICC associated with an automated image analysis using digital pathology. Methods: Five healthy subjects were included, and ocular surface samples were obtained using a cytobrush. The sample was processed as liquid-based cytology. Automated ICC was subsequently performed to detect vitamin D receptor nuclear positivity. Two methods were used for evaluation: manual counting under a light microscope and automated analysis using an image analyzer on digitized slides. The percentage of positivity found in both methods was compared using the Kappa test. Results: All samples presented adequate cellularity. In all cases, it was possible to perform automated ICC; moreover, all samples presented optimal quality. When comparing both methods (manual versus automated), a substantial level of agreement was seen (Kappa=0.69). Conclusions. The method presented in this manuscript allows the minimally invasive automated evaluation of ocular surface ICC markers, being like manual counting but more objective and reproducible. This technique could be useful for proteomic study in pathologies such as dry eye disease.

Regulatory role of the transcriptional coactivator Mediator 1 in skin hair regeneration and its mechanisms / 中华皮肤科杂志

Objective:To investigate the effect of the transcriptional coactivator Mediator 1 (Med1) on mouse hair regeneration, and to explore potential mechanisms.Methods:Med1 flox/flox C57BL/6J mice were mated with K14-Cre mice, and the mice with epidermis-specific knockout of Med1 gene, namely K14-Cre-expressing Med1 flox/flox mice (knockout group) , were obtained by using the Cre-Loxp system, while Med1 flox/flox mice without K14-Cre expression served as control group. Mice in the two groups (3 mice in each group) were raised together for 8 weeks followed by dorsal hair removal. Hair regeneration was observed for 12 consecutive days after hair removal. After 12 days, all mice in the two groups were sacrificed, their depilated and non-depilated dorsal skin tissues were resected, and total RNA was extracted from the tissues. Real-time quantitative PCR was performed to determine the mRNA expression of hair keratin genes, vitamin D receptor/β-catenin pathway-related genes, and genes associated with maintenance of hair follicle stem cell proliferation and quiescence. Paraffin-embedded sections of depilated and non-depilated mouse skin tissues were prepared, and immunofluorescence staining was conducted to determine the number of stem cells in the hair follicle bulge. Two-independent-sample t test was used for comparisons between two groups. Results:From days 0 to 12 after depilation, hair regeneration was delayed in the depilated skin area in the knockout group compared with the control group. Real-time quantitative PCR showed significantly decreased mRNA relative expression levels of hair keratin genes Ha1 and Krt2-16, vitamin D receptor/β-catenin pathway-related genes S100a3, Dlx3 and Tubb3, and genes associated with maintenance of hair follicle stem cell proliferation and quiescence including Lhx2, Sox9 and Nfatc1 in the depilated skin tissues in the knockout group (22.09 ± 12.32, 2.07 ± 0.20, 0.02 ± 0.01, 12.36 ± 2.12, 1.75 ± 0.46, 0.39 ± 0.02, 4.42 ± 0.76, 0.44 ± 0.07, respectively) compared with the control group (70.53 ± 9.46, 7.76 ± 0.49, 0.05 ± 0.01, 26.16 ± 2.96, 2.60 ± 0.14, 0.71 ± 0.09, 11.93 ± 0.42, 0.75 ± 0.04, respectively; t = 5.40, 18.64, 3.89, 6.57, 3.04, 6.10, 15.03, 6.18, respectively, all P < 0.05) . Immunofluorescence staining showed that the number of CD34 +K15 + hair follicle stem cells in the hair follicle bulge in both depilated and non-depilated skin tissues was significantly lower in the knockout group than in the control group. Conclusion:Med1 gene knockout may down-regulate the expression of downstream genes of the vitamin D receptor/β-catenin pathway and genes associated with maintenance of hair follicle stem cell proliferation and quiescence (Sox9, Nfatc1 and Lhx2) , and reduce the number of hair follicle stem cells, leading to hair follicle differentiation disorder and hair regeneration delay.

Association of single nucleotide polymorphisms in the vitamin D receptor gene with the clinical outcome of influenza in children / 中国小儿急救医学

Objective:To investigate the association of single nucleotide polymorphisms(SNPs)in the vitamin D receptor(VDR)gene with influenza susceptibility and severity of disease in children.Methods:Peripheral venous blood was collected from 172 children with influenza A (study group) and 88 healthy children (healthy control group) admitted to Xi ′an Children′s Hospital and Xi ′an Central Hospital from February 2019 to February 2021.Serum 25-hydroxyvitamin D(25-OH-D) level was detected by using 25-OH-D kit.The study group was divided into three groups according to clinical syndrome: mild group, severe group, and critical group.Four candidate loci in the VDR gene(ApaI, TaqI, FokI, and BSMI)were selected, and polymorphisms in the VDR gene of each group were determined by polymerase chain reaction restriction fragment length polymorphism and analyzed in relation to children with influenza.Results:Compared with the healthy control group[(109.65±4.35) nmol/L], the serum 25-OH-D levels in the study groups were lower[(73.55±2.46)nmol/L in the mild group, (45.59±4.62) nmol/L in the severe group, and (33.65±3.87) nmol/L in the critical group]( P<0.05); Genotypes AA, Aa and allele A of the ApaI locus(51.74%, 22.67%, and 63.08%, respectively)and genotypes FF, Ff and allele F of the FokI locus(41.86%, 34.88%, and 59.30%, respectively)accounted for a significantly higher proportion of cases in the study group than those in healthy control group(11.36%, 14.77%, 18.75%, 10.23%, 13.64%, and 17.05%, respectively)( P<0.05). The proportion of allele A at the ApaI locus and genotypes AA and Aa in severe group(63.70%, 43.84%, and 28.76%) were significantly higher than those in mild group(47.37%, 35.09%, and 24.56%)( P<0.05); The proportion of allele A and genotype AA and at the ApaI locus in critical group(92.86%, 88.10%, and 49.52%) were significantly higher than those in severe group( P<0.05). Serum 25-OH-D<50 nmol/L( OR=5.087, 95% CI 3.114-5.648), ApaI site genotypes AA ( OR=4.011, 95% CI 1.217-18.624)and Aa( OR=3.839, 95% CI 2.483-1.456), FokI site genotypes FF( OR=4.112, 95% CI 3.215-20.775)and Ff( OR=4.591, 95% CI 0.032-10.936)were risk factors for the onset of influenza in children. Conclusion:Serum 25-OH-D deficiency is associated with childhood influenza, and VDR gene genotype AA and Aa of ApaI locus, and FokI site genotype FF, Ff may increase the risk of childhood influenza susceptibility, and allele A of ApaI locus and genotypes AA and Aa are associated with the severity of influenza.

Expression and clinical significance of vitamin D receptor in children with hand, foot and mouth disease / 中国小儿急救医学

Objective:To detect the expression level of vitamin D receptor(VDR) in children with hand, foot, and mouth disease(HFMD), and explore its potential value in the diagnosis and treatment of children with HFMD.Methods:A total of 82 children with HFMD hospitalized in the Second Affiliated Hospital of Xi′an Jiaotong University and Xi′an Children′s Hospital from May 2017 to May 2019 were selected as the case group.At the same time, 42 healthy children who underwent physical examination in the Child Health Department during the same period were randomly selected as the control group.Peripheral blood of two groups of children was extracted to detect and compare the expression levels of VDR mRNA in mononuclear cells, and the correlation between the expression level of VDR and HFMD and the correlation with various clinical characteristics were analyzed.Results:The relative expression of VDR in children with EV71 HFMD was 2.03%±0.38%, which was lower than that in children of control group(3.11%±1.29%), and the difference was statistically significant( t=-3.586, P=0.001). However, the relative expression of VDR in children with CA16 HFMD was 3.69%±1.79%, which was higher than that in children of control group, and the difference was not statistically significant( t=1.043, P=0.305). Among children with EV71 HFMD, the relative expression level of VDR was significantly different between the mild group and the severe group(2.18%±0.44% vs. 1.84%±0.17%, t=2.199, P= 0.041). There was no statistical difference regarding the relative expression level of VDR between mild and severe CA16 HFMD(4.16%±1.73% vs. 2.93%±1.73%, t=1.587, P=0.129). Conclusion:Compared with healthy children, the expression level of VDR is significantly lower in children with EV71 HFMD, and may be related to the severity of EV71 HFMD.

Expression level of vitamin D receptor in intrahepatic bile duct epithelial cells and its clinical significance in children with biliary atresia / 中华实用儿科临床杂志

Objective:To explore the possible role and clinical significance of vitamin D receptor (VDR) in intrahepatic bile duct epithelial cells (IBDECs) in biliary atresia (BA).Methods:A retrospective analysis was performed on expression level of VDR in IBDECs of 38 BA children who underwent Kasai surgery in the Second Affiliated Hospital of Xi′an Jiaotong University and the Children′s Hospital of Xi′an Jiaotong University from January 2015 to December 2019.Expression level of VDR in IBDECs of 38 children with BA was detected by immunohistochemical staining, and that in children with choledochal cysts was detected as negative control.Masson staining was performed to examine the degree of liver fibrosis.The correlation between the expression level of VDR in IBDECs of children with BA, and the degree of liver fibrosis during operation, the incidence of refractory cholangitis after Kasai portoenterostomy and the survival time of autologous liver was analyzed.Human intrahepatic bile duct epithelial cells (HiBECs) were induced with dsRNA virus infection by polyinosinic acid-polycytidylic acid [Poly(I∶C)] in vitro, followed by detection of cell activity, apoptosis and VDR level.The differences between 2 independent groups were analyzed using Student t test.The relationship between the expression of VDR and clinicopathologic characteristics was conducted with χ2 test or Fisher′ s test.The Kaplan- Meier survival curve was used to analyze the differences in the survival time of autologous liver after Kasai in BA children with different VDR expression levels. Results:A total of 38 children with BA were included in this study.Among them, 23 cases showed no significant decrease of VDR protein level in IBDECs, and 15 cases showed a significant decrease in IBDECs.Compared with BA children without a significant decrease in VDR level in IBDECs, much severer liver fibrosis ( P<0.001) and significantly higher incidence of refractory cholangitis after Kasai procedure ( P=0.017) were detected in those with a significant decrease in VDR level.Compared with the control group, BA children with significantly lower VDR expression levels in HiBECs had a shorter autologous liver survival time ( P=0.030). Poly (I∶C) increased the apoptotic rate of HiBECs ( P<0.000 1) and decreased cell activity of HiBECs ( P<0.05), which significantly stimulated the secretion of inflammatory factors (interferon, tumor necrosis factor-α, interleukin-6) in the culture medium of HiBECs ( P<0.001). Poly (I∶C) significantly decreased the expression level of VDR protein in HiBECs ( P<0.001). Conclusions:Poly (I∶C) causes HiBECs damage and decreases VDR expression level in HiBECs of BA children, and the significantly decreased VDR expression level in IBDECs may be a marker of poor prognosis of BA.

Association study on vitamin D receptor gene polymorphisms and Tourette syndrome / 中华行为医学与脑科学杂志

Objective:To investigate the association between gene polymorphisms in vitamin D receptor(VDR) and Tourette syndrome (TS).Methods:The genetic contributions of VDR FokI (rs2228570), BsmI (rs1544410), and Cdx2 (rs11568820) polymorphisms were genotyped by TaqMan allelic discrimination real-time (RT)-PCR, which evaluated by a case-control analysis in 417 TS patients and 442 healthy controls, and followed by a family-based study in 417 TS trios.Chi-square test and relative risk analysis were conducted by IBM SPSS 23.0 software.Results:FokI (rs2228570) had three genotypes(CC=109, CT=235, TT=73); BsmI (rs1544410) had three genotypes(AA=2, AG=45, GG=370); Cdx2 (rs11568820) had three genotypes(AA=71, AG=200, GG=146). No significant difference in genotype ( χ2=5.516, P=0.063; χ2=3.466, P=0.177; χ2=0.561, P=0.755, respectively) or allele frequencies( χ2=0.840, P=0.359; χ2=3.376, P=0.066; χ2=0.051, P=0.822, respectively)of FokI, BsmI and Cdx2 were identified between TS patients and control groups.No significant over-transmission was identified for these three polymorphisms among 417 TS trios in the family-based study (TDT for FokI: χ2=0.009, P=0.962; for BsmI: χ2=1.220, P=0.320; and for Cdx2: χ2=0.260, P=0.646). Haplotype relative risk (HRR) analysis and haplotype-based haplotype relative risk (HHRR) analysis showed no significant difference in allele frequencies distribution of FokI, BsmI and Cdx2 (all P>0.05). Conclusion:VDR receptor gene polymorphism has no effect on TS susceptibility in the Chinese Han population. However, a potential role of VDR should be explored in more polymorphisms, different populations and larger samples.

Vitamin D analogues activate vitamin D receptor/glutathione peroxidase 4 pathway to improve ventilator-induced lung injury in mice / 中华危重病急救医学

Objective:To investigate the role of vitamin D analogue paricalcitol in activating vitamin D receptor/glutathione peroxidase 4 (VDR/GPX4) pathway in ventilator-induced lung injury (VILI).Methods:Twenty-four male C57BL/6J mice were randomly divided into control group, high tidal volume (HVT) induced VILI model group (HVT group), paricalcitol control group (P group), and paricalcitol pretreatment group (P+HVT group), with 6 mice in each group. The mice were endotracheal intubated and ventilated at 40 mL/kg tidal volume to prepare VILI model, while those in the control group were intubated without ventilation. The mice in the P+HVT group were intraperitoneally injected with paricalcitol 0.2 μg/kg once a day 1 week before modeling, while those in the P group were intraperitoneally injected paricalcitol 0.2 μg/kg once a day for 1 week before the experiment. After ventilation for 4 hours, the mice were sacrificed for lung tissue collection. Lung injury was evaluated by wet/dry (W/D) ratio, hematoxylin-eosin (HE) staining and Masson staining. The expressions of VDR and GPX4 were determined by Western blotting and immunohistochemistry. Malondialdehyde (MDA) and glutathione (GSH) contents were determined by micro method.Results:After HVT for 4 hours, compared with the control group, lung injury score and W/D ratio were significantly higher (lung injury score: 0.430±0.035 vs. 0.097±0.025, lung W/D ratio: 4.860±0.337 vs. 3.653±0.332, both P < 0.05), collagen fiber deposition was significantly increased, the content of MDA in lung tissue was significantly increased (nmol/g: 212.420±8.757 vs. 97.073±5.308, P < 0.05), GSH content and the protein expressions and immunoreactive score (IRS) of VDR and GPX4 were significantly decreased [GSH (μg/g): 44.229±1.690 vs. 70.840±0.781; VDR protein (VDR/GAPDH): 0.518±0.029 vs. 0.762±0.081, GPX4 protein (GPX4/GAPDH): 0.452±0.032 vs. 0.649±0.034; IRS score: VDR was 4.168±0.408 vs. 10.167±0.408, GPX4 was 4.333±1.033 vs. 10.333±0.516; all P < 0.05], which meant that the mice in HVT group showed obvious lung injury. After VDR was activated by paricalcitol, compared with the HVT group, lung injury score and W/D ratio were significantly decreased (lung injury score: 0.220±0.036 vs. 0.430±0.035, lung W/D ratio: 4.015±0.074 vs. 4.860±0.337, both P < 0.05), collagen fiber deposition was reduced, MDA content in lung tissue was decreased (nmol/g: 123.840±8.082 vs. 212.420±8.757, P < 0.05), GSH content and the protein expressions and IRS score of VDR and GPX4 were significantly up-regulated [GSH (μg/g): 63.094±0.992 vs. 44.229±1.690; VDR protein (VDR/GAPDH): 0.713±0.056 vs. 0.518±0.029, GPX4 protein (GPX4/GAPDH): 0.605±0.008 vs. 0.452±0.032; IRS score: VDR was 9.000±0.632 vs. 4.168±0.408, GPX4 was 8.833±0.408 vs. 4.333±1.033; all P < 0.05], which meant that lung injury in P+HVT group was significantly improved. Conclusion:Vitamin D analogue paricalcitol ameliorates pulmonary oxidation-reduction imbalance by activating the VDR/GPX4 pathway, thereby alleviating VILI.

Diabetic retinopathy and serum vitamin D level / 中华实验眼科杂志

Diabetic retinopathy (DR) is one of the most severe chronic complications of diabetes, which is the leading cause of blindness in working age population.The pathogenesis of DR is very complex and has not been elucidated completely.The development and severity of DR were shown to be linked to blood vitamin D concentrations.The goal of this review was to explain the link between diabetic retinopathy and vitamin D levels, as well as to explore the function of vitamin D in the development of DR and the mechanisms involved in inflammation, vascular disease, neurological disease, and insulin resistance.

Vitamin D/vitamin D receptor, autophagy, and infection / 中南大学学报(医学版)

Vitamin D plays an important role in mineral and bone homeostasis, immune responses, cardiovascular function and keratinocyte proliferation and differentiation. Vitamin D performs most of its functions by binding to vitamin D receptors (VDR), which interact with other intracellular signaling pathways to regulate bone metabolism, inflammation, immunity, cell cycle progression and apoptosis. Autophagy is a basic stress response in yeast, plants and mammals, and plays a critical role in maintaining optimal functional states at the level of cells and organs. Vitamin D/VDR plays an anti-infection role via inducing and regulating autophagy.

Identification of microRNAs targeting vitamin D receptor and their effect on parathyroid hormone secretion in secondary hyperparathyroidism / 南方医科大学学报

OBJECTIVE@#To identify the miRNAs targeting vitamin D receptor (VDR) gene and their effect on parathyroid hormone (PTH) secretion in secondary hyperparathyroidism.@*METHODS@#Primary parathyroid cells with secondary hyperparathyroidism were isolated by collagenase digestion and cultured. The miRNAs targeting VDR were screened by bioinformatics methods and full transcriptome sequencing, and dual-luciferase reporter assay was used to verify the targeting relationship between VDR and the screened miRNA. The effects of overexpression or inhibition of the candidate miRNA on VDR mRNA and protein expressions and PTH secretion were evaluated using qRT-PCR and Western blotting. The expression levels of the candidate miRNAs and VDR mRNA in clinical specimens of parathyroid tissues were verified by qRT-PCR, and the expression of VDR protein was detected by immunohistochemistry.@*RESULTS@#We successfully isolated primary parathyroid cells. Dual-luciferase reporter assay verified the targeting relationship of hsa-miR-149-5p, hsa-miR-221-5p, hsa-miR-222-3p, hsa-miR-29a-5p, hsa-miR-301a-5p, hsa-miR-873-5p, hsa-miR-93-3p with VDR, and among them, the overexpression of hsa-miR-149-5p and hsa-miR-301a-5p significantly increased PTH secretion in the parathyroid cells. In patients with secondary hyperparathyroidism, hsa-miR-149-5p was highly expressed in the parathyroid tissues (P=0.046), where the expressions of VDR mRNA (P=0.0267) and protein were both decreased.@*CONCLUSION@#The two miRNAs, hsa-miR-149-5p and hsa-miR-301a-5p, may promote the secretion of PTH in patients with secondary hyperparathyroidism by down-regulating the expression of VDR gene.

Polymorphisms of the Vitamin D Receptor Gene and Sex-Differential Associations with Lipid Profiles in Chinese Han Adults / 生物医学与环境科学（英文）

OBJECTIVE@#To explore the association of single nucleotide polymorphisms (SNPs) of the vitamin D receptor gene ( VDR) with circulating lipids considering gender differences.@*METHODS@#Of the Han Chinese adults recruited from a health examination center for inclusion in the study, the circulating lipids, 25-hydroxyvitamin D (25OHD), and other parameters were measured. The VDR SNPs of Cdx2 (rs11568820), Fok1 (rs2228570), Apa1 (rs7975232), and Taq1 (rs731236) were genotyped with a qPCR test using blood DNA samples, and their associations with lipids were analyzed using logistic regression.@*RESULTS@#In the female participants ( n = 236 with dyslipidemia and 888 without dyslipidemia), multiple genotype models of Fok1 indicated a positive correlation of B (not A) alleles with LDLC level ( P < 0.05). In the male participants ( n = 299 with dyslipidemia and 564 without dyslipidemia), the recessive model of Cdx2 and the additive and recessive models of Fok1 differed ( P < 0.05) between the HDLC-classified subgroups, respectively, and Fok1 BB and Cdx2 TT presented interactions with 25OHD in the negative associations with HDLC ( P < 0.05).@*CONCLUSION@#In the Chinese Han adults included in the study, the Fok1 B-allele of VDR was associated with higher LDLC in females, and the Fok1 B-allele and the Cdx2 T-allele of VDR were associated with lower HDLC in males. The interaction of VD and Fok1 BB or Cdx2 TT in males synergistically decreased HDLC levels.

Evaluation of ApaI and FokI polymorphism of VDR gene and functional characterization in patients with fibromyalgia / Avaliação do polimorfismo ApaI e FokI do gene VDR e caracterização funcional em pacientes com fibromialgia

Abstract Introduction: Fibromyalgia (FM) is a syndrome of unknown origin characterized by several symptoms, and although its pathogenesis has not been completely elucidated, it seems to be related to inflammatory path-ways and neurochemical changes in the brain. Objective: To evaluate the association between BsmI, ApaI and FokI polymorphisms of the vitamin D receptor (VDR) gene, their polymorphisms, and clinical variables in women with and without FM. Methods: This is a case-control study composed of a group of 53 women with FM and another with 40 women without the disease. The McGill Pain Questionnaire, Fibromyalgia Impact Questionnaire, Pain Visual Analogue Scale and the sit-up test were applied. Real-time PCR was performed to analyze the ApaI and FokI polymorphism. Results: There was a statistical association between race, comorbidity and FM, where 78.4% of the individuals were white and had FM (p < 0.002) and 96.1% had some comorbidity (p < 0.001). Seventy-six point five percent (76.5%) of patients with FM underperformed in the sit-up test (p < 0.001). There was also an association between the genotypic and allele frequencies of the VDR and FM gene Apal and FokI polymorphisms (p < 0.001). In the VDR gene ApaI polymorphism, the CC genotype exhibited a higher frequency in women with FM, the C allele for the Apal polymorphism was 3.33 times more likely, and the FokI polymorphism was 10.9 times more likely to develop FM (p < 0,0001). Conclusion: Women with C allele for ApaI polymorphism are 3.33 times more likely to have FM (95%CI = 1.58-7.02; p = 0.0024), and in FokI polymorphism, the prevalence of T allele is 10.9 times greater (95% CI = 4.76-25.38; p < 0.0001). No significant associations were found in relation to BsmI polymorphism and frequency alleles (p = 0.062 and p = 0.078, respectively).

Resumo Introdução: A fibromialgia (FM) é uma síndrome de origem desconhecida caracterizada por diversos sintomas, e embora sua patogênese não tenha sido completamente elucidada, parece estar relacionada às vias inflamatórias e alterações neuroquímicas no cérebro. Objetivo: Avaliar a associação entre os polimorfismos BsmI, ApaI e FokI do gene do receptor da vitamina D (VDR), seus polimorfismos e variáveis clínicas em mulheres com e sem FM. Métodos: Trata-se de um estudo caso-controle composto por um grupo de 53 mulheres com FM e outro com 40 mulheres sem a doença. Foram aplicados o Questionário de Dor de McGill, Questionário de Impacto da Fibromialgia, Escala Visual Analógica da Dor e o teste de sentar. A PCR em tempo real foi realizada para analisar o polimorfismo ApaI e FokI. Resultados: Houve associação estatística entre raça, comorbidade e FM, onde 78,4% dos indivíduos eram brancos e apresentavam FM (p < 0,002) e 96,1% tinham alguma comorbidade (p < 0,001). Setenta e seis vírgula cinco por cento (76,5%) dos pacientes com FM tiveram desempenho inferior no teste de abdominais (p < 0,001). Também houve associação entre as frequências genotípicas e alélicas dos polimorfismos Apal e FokI do gene VDR e FM (p < 0,001). No polimorfismo ApaI do gene VDR, o genótipo CC apresentou maior frequência em mulheres com FM, o alelo C para o polimorfismo Apal foi 3,33 vezes mais provável, e o polimorfismo FokI teve 10,9 vezes mais chance de desenvolver FM (p < 0,0001). Conclusão: Mulheres com alelo C para polimorfismo ApaI têm 3,33 vezes mais chance de ter FM (IC 95% = 1,58-7,02; p = 0,0024), e no polimorfismo FokI, a prevalência do alelo T é 10,9 vezes maior (IC 95% = 4,76-25,38; p < 0,0001). Não foram encontradas associações significativas em relação ao polimorfismo BsmI e alelos de frequência (p = 0,062 e p = 0,078, respectivamente).

Study on vitamin D levels in serum and intestinal mucosa of 37 adult patients with celiac disease / 中华消化杂志

Objective:To analyze the expression of 25-hydroxyvitamin D [25(OH)D] in serum and vitamin D receptor (VDR) in descending duodenum of adult patients with celiac disease and the correlation between 25 (OH) D, VDR and the clinical characteristics and indexes of celiac disease.Methods:From September 1, 2020 to May 1, 2022, 37 patients who were diagnosed with celiac disease (celiac disease group) in the Department of Gastroenterology of People′s Hospital of Xinjiang Uygur Autonomous Region were enrolled. During the same period, according to gender, age and nationality matched at a ratio of 1 to 1, 37 patients who visited the hospital with suspected symptoms of celiac disease and finally were excluded from the diagnosis of celiac disease after screening (non-celiac disease group) were selected. General data and clinical characteristics of all the patients were collected, including diarrhea, bone mineral density (BMD), Marsh stage. Serum 25(OH)D levels were detected, and the expression of VDR(high or low expression) in the descending duodenum was evaluated by immunohistochemical staining. Independent sample t test, chi-square test and Spearman correlation analysis were used for statistical analysis. Results:The serum 25(OH)D level and the proportion of patients with high VDR expression in the celiac disease group were both lower than those of the non-celiac disease group ((12.40±8.93) μg/L vs. (16.78±7.09) μg/L; 45.9%, 17/37 vs. 75.7%, 28/37), and the proportion of patients with diarrhea was higher than that of the non-celiac disease group (45.9%, 17/37 vs. 21.6%, 8/37), and the differences were statistically significant ( t=-2.52, χ2=6.86 and 4.89, all P<0.05). The serum 25(OH)D level was positively correlated with the VDR expression level in the descending duodenum both in the celiac disease group and the non-celiac disease group ( r=0.75 and 0.64, both P<0.001), and was not correlated with the diarrhea symptoms in the 2 groups (both P>0.05). There was a positive correlation between serum 25(OH)D and BMD in the celiac disease group ( r=0.48, P=0.017), and serum 25(OH)D was also correlated with BMD in the non-celiac disease group ( r=0.93, P<0.001). The VDR expression level in the descending duodenum was negatively correlated with the Marsh stage in the celiac disease group ( r=-0.36, P=0.031), while the VDR expression level was not related to the Marsh stage in the non-celiac disease group ( P>0.05). Conclusions:Vitamin D metabolism imbalance exists in the serum and duodenal mucosa of adult patients with celiac disease, which is related to the severity of osteoporosis and histopathology. It is suggested that patients with celiac disease should receive vitamin D metabolism regulation treatment.