Association of Fokl polymorphism of the VDR gene with systemic lupus erythematosus in an adolescent population of the Colombian Caribbean

Introduction: Vitamin D and vitamin D receptor (VDR) polymorphisms are associated with autoimmune diseases including systemic lupus erythematosus (SLE). The aim of this study is to assess the genetic association between VDR polymorphisms: TaqI, ApaI, Bsml and FokI and SLE with serum levels of Vitamin D in the Colombian Caribbean population. Method: Case and control study. One hundred and thirty-three patients with SLE and 100 healthy individuals were included. VDR polymorphism were genotyped by RT-PCR and Taqman® probes. Allelic, genotypic and haplotype associations were estimated. Serum vitamin D concentrations were quantified by Elisa. Values of 30 to 100ng/ml were established as a normal reference range. P values <.05 were considered statistically significant. Results: A high prevalence of SLE was observed in women (94%) and was associated with a higher risk of SLE [OR: 10.8; 95% CI: 4.7-24.6] (p<.05). Moreover, higher risk of SLE was observed in individuals with FokI VDR [rs2228570] [OR: 1.58; 95% CI: 1.05-2.36] in allelic models. The ACCA Haplotype of TaqI/ApaI/Bsml/FokI polymorphisms was associated with higher risk of SLE [OR = 2.28, 95% CI = 1.12-4.66, psim <.01]. Vitamin D deficiency was evidenced in 11.3% of the patients. Conclusion: In this study, the VDR rs2228570 polymorphism and ACCA haplotype were associated with higher SLE risk in an adolescent population.

Introducción: La vitamina D y los polimorfismos en el receptor de vitamina D (VDR) se asocian con enfermedades autoinmunes, incluido el lupus eritematoso sistémico (LES). El objetivo de este estudio es analizar la asociación genética entre los polimorfismos de VDR (Taql, Apal, Bsml y Fokl) y la susceptibilidad al LES, así como su relación con los niveles séricos de vitamina D en población del Caribe colombiano. Metodología: Estudio de casos y controles. Se incluyeron 133 pacientes adultos con diagnóstico de LES y 100 individuos sanos. Los polimorfismos VDR fueron genotipados por RT-PCR y sondas Taqman®. Se estimaron asociaciones alélicas, genotípicas y haplotípicas. Las concentraciones séricas de vitamina D fueron cuantificadas por Elisa. Se establecieron valores de 30 a 100ng/ml como rango normal de referencia. Valores p<0,05 fueron considerados estadísticamente significativos. Resultados: Se observó una alta prevalencia de LES en pacientes femeninas (94%) y se asoció a mayor riesgo de LES (OR: 10,8; IC95%: 4,7-24,6; p < 0,05). Se evidenció mayor riesgo de LES en individuos con polimorfismo Fokl del gen VDR [rs2228570] (OR: 1,58; IC95%: 1,05-2,36) en modelos alélicos. El haplotipo ACCA de los polimorfismos Taql, Apal, Bsml y Fokl se asoció a mayor riesgo de LES (OR: 2,28, IC95%: 1,12-4,66; psim<0,01). Se evidenció deficiencia de vitamina D en el 11,3% de los pacientes. Conclusión: En este estudio, el polimorfismo VDR rs2228570 y el haplotipo ACCA se asociaron a mayor riesgo de LES en población adolescente.

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.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Signaling pathway of vitamin D, vitamin D receptor and autophagy in infection: a systematic review

Vitamin D has an immunomodulatory effect that increases antimicrobial responses in macrophages by inducing antibacterial proteins, stimulating autophagy, and increasing autophagosome activity through various signaling pathway. This review emphasizes the several signalling pathway of vitamin D and vitamin D receptor(VDR)to induce autophagy in infection and its role in infectious disease. This study was performed based on PRISMA guidelines. Literature search conducted from Cochrane, PubMed, Science Direct and ProQuest using the terms "vitamin D" and 揤DR� and "autophagy in infection". The inclusion criteria were original article, publication in English, published in 2012-2022, investigating vit D, VDRpathway and autophagy mechanism in infection. Twelves studies met our criteria. Despite numerous autophagy signalling in vitamin D and VDR, there are 2main mechanisms vit D induces autophagy; increase expression LL-37/cathelicidin, CAMP, DEFB4 and upregulated autophagy genes (LC3B, ATG5, BECN1, MMPI, ATG16L1, PR39). While, vit D induced autophagy via expression CYP27B1 and VDR in co-infection HIV and tuberculosis. In sepsis, artesunate relates with VDR to enhance autophagy via NF-?B. Similarly, vitamin D could enhance cell resistance to Aspergillus fumigatusafter modulating NF-?B. Vitamin D3 through PDIA3-STAT3-MCOLN3-Ca2+ axis and CAMP/LL-37 (cathelicidin antimicrobial peptide) are mediator for autophagy induction in H.pylori. Upregulated autophagy gene activity through vit D/VDR appears as new target therapy for infection in future.

Polymorphism of Vitamin D Receptor Gene -Taq1 (RS 731236) Associated With Plasma Vitamin D Group Levels Among Breast Cancer Patients in H. Adam Malik Hospital, Medan

Aim Breast cancer was one of the most cancer occurred in women worldwide. Taq 1 polymorphism, a silent SNP,was thought to be genetic risk factor for breast cancer. This study was aimed to understand the relationshipbetween vitamin D receptor gene–Taq 1 (RS 731236) polymorphism and plasma vitamin D level among breastcancer patients in RSU H. Adam Malik Medan. Material and Methods Blood sample was collected from 53 newbreast cancer cases that had not received any chemotherapy. DNA isolation and gene amplification was doneusing PCR then followed with RFLP using Taq 1 restriction enzyme. The level of 25(OH)D was measured usingELISA. Result and Discussion Study results showed TT genotype was 92.5%, TC genotype was 7.5%, CC genotypewas 0 % using Hardy-Winberg Equilibrium (HWE) p=0.77, mean value of vitamin D level in study subject was28.16 ng/ml (CI 95%: 25.71-30.60). Fisher exact test analysis concluded that polymorphism of vitamin D receptorgene-Taq1 associated with plasma vitamin D group levels among breast cancer patients in H. Adam MalikHospital, Medan (p= 0.033) but there was no difference in mean plasma vitamin D levels between genotypegroups of Taq1 (p=0.141). Conclusion Vitamin D receptor gene-Taq1 polymorphism was associated with plasmavitamin D group level and but no significant differences in mean plasma vitamin D levels between genotypegroups of Taq1.

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition the regulation of target ADME gene expression

Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression imperfect complementary Watson-Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down and mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1'-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.

Role of vitamin D receptor in the regulation of gene expression

Vitamin D (VD) is a multifunctional nutrient which can be either synthesized or absorbed from the diet. It plays a pivotal role in systemic calcium and phosphate homeostasis, as well as in various physiological and pathological processes. VD is converted to the active form, 1,25-dihydroxyvitamin D (1,25-D3), by cytochrome P450 2R1 (CYP2R1)/CYP27A1 and CYP27B1 sequentially, and deactivated by multiple enzymes including CYP3A4. On the other hand, 1,25-D3 is capable of activating the transcription of genes in humans, mice and rats. The vitamin D receptor (VDR)-mediated transactivation of human and resembles that known for pregnane X receptor (PXR). Activated VDR forms a heterodimer with retinoid X receptor (RXR), recruits co-activators, translocates to the cell nucleus, binds to the specific vitamin D responsive elements (VDRE), and activates the gene transcription. In mice, intestinal mRNA levels, but not those of hepatic CYP3As, were induced by administration of VDR and PXR agonists. In rats, intestinal and mRNAs were induced by 1,25-D3 or lithocholic acid (LCA), whereas hepatic , but not and , was modulated to 1,25-D3 treatment. In general, the VDR-mediated regulation of CYP3A presents species and organ specificity.

Normal physiological functions in two animal species with highly different vitamin d status compared to that of humans / Funciones fisiológicas normales en dos especies animales con estatus de vitamina d muy diferentes del actual en seres humanos

Mole rats live in permanent darkness, in networks of underground tunnels (which extend up to 1 km in the subsoil), excavated with their incisors, in warm and semi-arid areas of South Africa. Mole rats have an unusually impoverished vitamin D3 status with undetectable and low plasma concentrations of 25- hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3, respectively. They express 25-hydroxylase in the liver and 1-hydroxylase and 24-hydroxylase in their kidneys. The presence of specific receptors (VDR) was confirmed in the intestine, kidney, Harderʼs glands and skin. In spite of their poor vitamin D3 status, the apparent fractional intestinal absorption of calcium, magnesium and phosphate was high, always greater than 90%. Oral supplementation with cholecalciferol to mole rats did not improve the efficiency of gastrointestinal absorption of these minerals. Mole ratsdo not display the typical lesion of rickets: hypertrophic and radiolucent growth cartilages. Histological studies reported normal parameters of trabecular and cortical bone quality. Marmosets (monkeys of the New World) are not hypercalcaemic, eventhough they exhibit much higher levels of 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3 and parathyroid hormonethan that of rhesus monkeys and humans. Fed a high vitamin D3 intake (110 IU/day/100 g of body weight), a fraction of the experimental group was found to display osteomalacic changes in their bones: distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption. These findings suggest that some marmosets appears to suffer vitamin D-dependent rickets, type II. The maximum binding capacity of the VDR or the dissociation constant of VDR1α,25(OH)2D3 complex of mole rats and New World monkeys are distinctly different of VDR isolated from human cells. Health status of those species appears to be adaptations to the mutations of their VDR. Though rare, as mutations may occur at any time in any patient, the overall message of this review to clinicians may be: recent clinical studies strongly suggests that the normality of physiological functions might be a better indicator of the health status than the serum levels of vitamin D metabolites. (AU)

Las ratas topo viven en la oscuridad permanente, en redes de túneles subterráneos excavadas con sus incisivos (que se extienden hasta 1 km en el subsuelo), en áreas cálidas y semiáridas de Sudáfrica. Las ratas topo tienen un estatus de vitamina D3 inusualmente empobrecido con concentraciones plasmáticas indetectables de 25-hidroxivitamina D3 y bajas de 1α, 25-dihidroxivitamina D3. Poseen 25-hidroxilasa en el hígado y 1-hidroxilasa y 24-hidroxilasa en sus riñones. La presencia de receptores específicos (VDR) ha sido confirmada en el intestino, el riñón, las glándulas de Harder y la piel. A pesar de su pobre estatus de vitamina D3,la absorción fraccional intestinal aparente de calcio, magnesio y fosfato fue alta, siempre superior al 90%. La suplementación oral con colecalciferol a las ratas topo no mejoró la eficacia de la absorción gastrointestinal de estos minerales. No muestran la lesión típica del raquitismo: cartílagos de crecimiento hipertróficos y radiolúcidos. Varios estudios histológicos confirman los hallazgos radiológicos y se informan parámetros normales de la calidad ósea trabecular y cortical. Los titíes (monos del Nuevo Mundo) exhiben calcemias normales con niveles más elevados de 25-hidroxivitamina D3, 1α,25-dihidroxivitamina D3 y hormona paratiroidea que los monos rhesus y los seres humanos. Un tercio de un grupo de titíes alimentados con una alta ingesta de vitamina D3 (110 I/día/100 g de peso corporal) exhibió cambios osteomalácicos en sus huesos: aumento en la superficie osteoide, volumen osteoide y activa reabsorción osteoclástica. Estos hallazgos sugieren que una fracción de la población de titíes padece raquitismo dependiente de vitamina D, tipo II. Debido a mutaciones ocurridas hace millones de años, las máximas capacidades de ligamiento del VDR o los valores de la constante de disociación del complejo VDR-1α,25(OH)2D3 de las ratas topo o monos del Nuevo Mundo son muy diferentes de los verificables en receptores aislados de células humanas actuales. El mensaje de esta revisión a los médicos clínicos podría ser: varios estudios clínicos recientes indican que la normalidad de las funciones fisiológicas de un paciente es un mejor indicador de su salud que los niveles séricos de los metabolitos de la vitamina D. (AU)

Asociación del déficit de vitamina D con patologías de la piel humana / Association of vitamin D deficiency with human skin pathologies

La vitamina D es una de las vitaminas fundamentales en el día a día del ser humano. No solo juega un rol importante en la homeostasis del calcio y salud ósea, sino también en distintos sistemas del organismo. El déficit de esta vitamina se ha asociado a enfermedades como: cánceres, hipertensión y síndrome metabólico. La epidermis es la principal fuente de vitamina D del organismo, seguida de una dieta rica en vegetales, pescados y leche fortificada. Esta capa de la piel no sólo es productora, sino además presenta diversas patologías producto del déficit de este nutriente. La vitamina D regula la función de la barrera cutánea, a través de la modulación de la expresión de filagrina e involucrina. La filagrina es una proteína estructural de la piel, que produce agregación y compactación de los filamentos intermedios de queratina. Esta proteína estaría implicada en el desarrollo de la dermatitis atópica. La vitamina D promueve la diferenciación celular e inhibe la proliferación y reduce el crecimiento de tumores, tal como ocurre en el melanoma maligno, a través de la expresión de su receptor (VDR). Dado los actuales descubrimientos respecto del déficit de este nutriente, la recomendación actual es consumir productos lácteos de forma habitual, asociado a la exposición de 5 minutos diarios idealmente en horarios de menor irradiación UV, manteniendo el uso de bloqueador solar y ropa adecuada durante el día. En conclusión, la vitamina D no sólo presenta utilidad en la mantención del equilibrio óseo, sino que interactúa a través de su receptor en diversos tejidos del organismo, permitiendo la homeostasis de la piel.

Vitamin D is one of the essential vitamins in the evolutionary development on earth. The best known of this function is the regulation of calcium homeostasis. Deficiency of this vitamin has been associated with some cancers, hypertension and metabolic syndrome. The epidermis is the main source of vitamin D in the body, followed by a diet increased vegetables, fish and fortified milk. The epidermis is not productive but also presents several pathologies resulting from the deficiency of this nutrient. The VD regulates the function of the cutaneous barrier through the modulation of filagrine and involucrin expression. Filagrine is a structural protein in the skin that produces aggregation and compaction of intermediate keratin filaments. This protein would be involved in the development of atopic dermatitis. Vitamin D promotes cell differentiation and inhibits proliferation and reduces the growth of tumors, as in malignant melanoma, through receptor expression (VDR). Given the current findings regarding the deficiency of this nutrient, the current recommendation is to consume dairy products in a habitual way, associated to the exposure of only 5 minutes daily ideally at times of lower UV irradiation, maintaining the use of sunscreen and proper clothing during the day. In conclusion, vitamin D, not only has utility in maintaining the bone balance, but interacts through its receptor in various tissues of the body, allowing the homeostasis of the skin, vascular tissue among others.

Associations of VDR polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients / 药学学报

The paper was aimed to investigate the association of VDR polymorphisms with tacrolimus (FK506) concentration in Chinese renal transplant recipients. A total of 114 renal transplant recipients receiving tacrolimus were genotyped for VDR rs1540339 and rs2853559 by Agena Bioscience MassARRAY® system and CYP3A5*3 by PCR-RFLP method. Trough concentrations of tacrolimus on day 7 after renal transplantation were collected from clinical data. Statistical analysis was performed with Spearman's correlation, Mann-Whitney U test and Kruskal-Wallis H test. The dose-adjusted concentration of tacrolimus in VDR rs2853559 GA and GG carriers were considerably higher than that of AA carriers. After stratification by CYP3A5*3 genotypes, VDR rs2853559 GA and GG carriers had a higher dose-adjusted tacrolimus concentration than that in AA carriers in CYP3A5 nonexpresser. CYP3A5*3 and VDR rs2853559 explained 45.6% variability of tacrolimus C0/D. In CYP3A5 non-expressers, VDR rs2853559 explained 14.4% variability of tacrolimus C0/D. The results illustrated that VDR rs2853559 polymorphisms was associated with tacrolimus concentrations, and the determination of this SNP may be useful for individualized medicine of tacrolimus.

Vit D promotes proliferation and differentiation of mesenchymal stem cells through regulates extracts of plastrum testudinis / 局解手术学杂志

Objective To explore the effect and the mechanism of vitamin D(Vit D) promotes proliferation and differentiation of mesenchymal stem cells (MSCs) through regulates extracts of plastrum testudinis (PTE).Methods Established the PGL3-Id1 promoter and transfered rat MSCs.PTE combined with 10-6,10-7,10-8mol/L Vit D respectively were acted on the transfected MSCs for 36 hours.The level of Id1 promoter were detected by luciferase activity measurement.1,3,30,100 pg/mL PTE combined with Vit D of 10-7 mol/L were acted on MSCs for 36 hours,3 days and 7 days,and the VDR expression were detected by RT-PCR test.Results PTE promoted the expression of Id1 in MSCs,the expression of Id1 was inhibited when PTE combined with Vit D (P ＜ 0.01),and it was significantly different among different dosis of Vit D(P ＜0.01).The expression of VDR was inhibited in different degree when PTE combined with Vit D for 36 hours,3 days and 7 days.PTE combed with large dose of Vit D for 36 hours had significant effect of inhibition,and the difference was statistically significant (P ＜ 0.05).The inhibiting effect was more obvious when PTE combined with large dose of Vit D for 3 days and 7 days.When different doses of PTE combined with Vit D for a same duration,the difference of VDR expression was statistically significant (P ＜ 0.05).Meanwhile,when same doses of PTE combined with Vit D for different durations,the difference of VDR expression at 7 days and 36 hours was statistically significant (P ＜ 0.05).Conclusion The proliferation of MSCs which promoted by PTE was inhibited by Vit D,and the nuclear receptor VDR may be one of the targets of drug action for PTE regulating proliferation and differentiation of MSCs.

Expression of VDR and GLi1 in prostate cancer cell line PC-3 and its correlation / 实用医学杂志

Objective To investigate the effect of lentivirus carrying shRNA-VDR vector on GLi1 in pros-tate cancer PC-3 cells. Methods The cells were cultured according to the culture conditions of PC-3 cells. Expression of VDR and GLi1 in PC-3 cells was detected by fluorescence quantitative PCR and immunocytochemistry SP method.The efficiency of PC-3 cell virus infection was evaluated.The effect of VDR gene interference and GLi1 transcription level on PC-3 cells was detected by RT-PCR.Results Cell culture,cell status was recorded and PC-3 cells were in good condition and the passages was 4 days. Fluorescence quantitative and immunocytochemi-cal SP showed that VDR and GLi1 were expressed in PC-3 cells.The virus infection efficiency showed that the in-fection efficiency was about 95% when adding LV3-NC lentivirus to PC-3 cells at 1:10 ratio. RT-PCR showed that VDR-shRNA lentivirus successfully disturbed VDR expression and decreased by 85%(P < 0.05)compared with the control group after 72 days of VDR-shRNA lentivirus transfection. Transcription level of GLi1 gene in the experimental group increased by 9% compared with the control group(P < 0.05). The transcription level of GLi1 gene in the experimental group increased by 248% compared with the control group(P < 0.05). Conclusion The cultured PC-3 cells were in good condition. VDR and GLi1 genes were expressed in PC-3 cells. Lentivirus showed highest efficiency in infecting PC-3 at 1:10 ratio. When VDR was disturbed,the expression of GLi1 in-creased.In prostate cancer cells,vitamin D can inhibit the Hh signaling pathway and cause GLi1 expression down expression.

Roles of the Taql and Bsml vitamin D receptor gene polymorphisms in hospital mortality of burn patients

OBJECTIVE: The aim of this study was to evaluate the roles of the Taql and Bsml vitamin D receptor gene polymorphisms in hospital mortality of burn patients. METHODS: In total, 105 consecutive burn injury patients over 18 years in age who were admitted to the Burn Unit of Bauru State Hospital from January to December 2013 were prospectively evaluated. Upon admission, patient demographic information was recorded and a blood sample was taken for biochemical analysis to identify the presence of the Taql(rs731236) and Bsml(rs1544410) polymorphisms. All of the patients were followed over their hospital stay and mortality was recorded. RESULTS: Eighteen of the patients did not sign the informed consent form, and there were technical problems with genotype analysis for 7 of the patients. Thus, 80 patients (mean age, 42.5±16.1 years) were included in the final analysis. In total, 60% of the patients were male, and 16.3% died during the hospital stay. The genotype frequencies for the Taql polymorphism were 51.25% TT, 41.25% TC and 7.50% CC; for the Bsml polymorphism, they were 51.25% GG, 42.50% GA and 6.25% AA. In logistic regression analysis, after adjustments for age, gender and total body surface burn area, there were no associations between the Taql (OR: 1.575; CI95%: 0.148-16.745; p=0.706) or Bsml (OR: 1.309; CI95%: 0.128-13.430; p=0.821) polymorphisms and mortality for the burn patients. CONCLUSIONS: Our results suggest that the Taql and Bsml vitamin D receptor gene polymorphisms are not associated with hospital mortality of burn patients.

Lack of association between FokI polymorphism in vitamin D receptor gene (VDR) & type 2 diabetes mellitus in the Tunisian population.

Background & objectives: The impact of several environmental and genetic factors on diabetes is well documented. Though the association between the vitamin D receptor (VDR) gene polymorphisms and type 2 diabetes mellitus (T2DM) has been analyzed in different ethnic groups, the results have been inconsistent. The aim of this study was to evaluate the possible association between VDR FokI polymorphism and genetic susceptibility to T2DM in Tunisian population. Methods: A total of 439 unrelated patients with T2DM and 302 healthy controls were included in the study. Genomic DNA was extracted from blood and genotyped for the single nucleotide polymorphism (SNP) of FokI (T/C: (rs2228570) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Results: The genotype distribution and the relative allelic frequencies for the FokI polymorphism were not significantly different between T2DM and controls: in T2DM patients the frequencies of the CC, CT, and TT genotypes were 52.6, 41.0, and 6.1 per cent, respectively, and in controls the genotype frequencies were 55.6, 38.7, and 5.6 per cent, respectively. In our study, the TT genotype of the FokI polymorphism was not associated with T2DM (OR =1.19, 95% CI 0.63 - 2.25, P=0.577). Interpretation & conclusions: Our study showed no significant association of the FokI polymorphism in the vitamin D receptor gene with type 2 diabetes mellitus in Tunisian population.

Association of VDR FokI and ApaI Genetic Polymorphisms with Parkinson’s Disease Risk in South Western Iranian Population.

Background: Parkinson’s disease comes second comparing to Alzheimer’s disease being responsible for nerve destructing diseases; it is a complex and multifactorial disease. Gene associated studies help to identify the genetic factors that introduce the Single Nucleotide Polymorphisms in different genes as genetic risk factors for non-Mendelian Parkinson’s disease in diverse populations. We intended to study the association of VDR (Vitamin D Receptor) gene polymorphisms with Parkinson’s disease in south western Iranian population. Results: In the present study 150 patients with Parkinson’s disease and 160 Healthy controls from an Iranian population were genotyped for two polymorphic sites. The prevalence of VDR polymorphisms in two restriction fragment length polymorphism sites including FokI and ApaI were analyzed in patients and controls. Our data demonstrated no significant association between VDR FokI polymorphism and PD, whereas the ApaI polymorphism showed a significant association with PD in Iranian patient. Also no association between the age at onset, the male-female ratio and the VDR polymorphism in the PD group was detected. Conclusions: In conclusion these results determined that VDR ApaI (TG and GG) genotype might affect development of PD in our study population. There was no association between FokI polymorphism and the risk of PD. Our results were analogous only with American/Hungarian Caucasian race.

Effect of vitamin D on ACE2 and vitamin D receptor expression in rats with LPS-induced acute lung injury / 中华急诊医学杂志

Objective To observe the effect of vitamin D on angiotensin converting enzyme 2 (ACE2) and vitamin D receptor (VDR) expression in Wister rat models of acute lung injury (ALI) induced by using lipopolysaccharide (LPS).Methods The rat models of ALI induced by LPS were established by intravenous injection of LPS via tail vein.Thirty Wistar rats were randomly (random number) divided into 6 groups:normal control group,LPS group,calcitriol (25 μg/kg) group,LPS + calcitriol 1 μg/kg group,LPS + calcitriol 5 μg/kg group and LPS + calcitriol 25 μg/kg group.The changes of general condition,lung pathology,lung wet/dry weight ratio and changes of VDR mRNA and ACE2 mRNA expressions and protein levels of VDR and ACE2 in rats were observed.Results The clinical manifestations (rapid shallow breathing;listlessness;the oral and nose hemorrhage) in LPS group were obvious,and the clinical manifestations and pathological changes of lung tissues in the LPS + calcitriol groups were significantly milder than those in LPS group.The expressions of VDR mRNA and ACE2 mRNA in LPS group was significantly lower than those in normal control group and calcitriol group (P ＜ 0.05).The expressions of VDR mRNA and ACE2 mRNA in LPS + calcitriol groups were significantly higher than those in LPS group (P ＜ 0.05),and lower than those in normal control group significantly (P ＜ 0.05).Meanwhile,among LPS + calcitriol groups,there was no significant difference in expression of VDR mRNA (P ＞ 0.05) and there was significant difference in ACE2 mRNA expression (P ＜ 0.05).Conclusions Calcitriol can increase the expressions of VDR mRNA and ACE2 mRNA and protein levels of VDR and ACE2 in rat models of LPS-induced ALI,thus suggesting the increased expressions of ACE2 mRNA and VDR mRNA playing a role in protection against the development of ALI.

Synthesis and in vitro bioIogicaI activity of 3-phenyI-3-pyrroIyIpentane deriva-tives / 中国药科大学学报

A new series of 3-phenyl-3-pyrrolylpentane derivatives are synthesized through modifying the structure of lead compound LG19055,a nonsecosteroidal vitamin D receptor(VDR)agonist.The VDR-agonistic ability of target compounds was measured indirectly by evaluating the differentiation ability of HL-60 cell.The results showed that compounds 13a,13c,13d,13h,13i,13j have excellent VDR-agonistic ability(EC50 <50 μmol /L), especially for compound 13j (EC50 =0.10 μmol /L),which was more potential than that of lead compound LG190155.Their proliferation inhibitory activities in vitro were evaluated by MTT assay in MCF-7,PC-3,Caco-2, HepG2 and L02 cell lines.Compound 13a exhibited significant inhibitory effects on HepG2 cell line(IC50 =0.11μmol /L).Moreover,the inhibitory effect of compound 13a on non-tumor liver L02 cell line was relatively weak (IC50 =15.24 μmol /L ),suggesting that compound 13a has selective inhibitory effects on liver cancer cells.Additionally,HL-60 cell differentiation-inducing activity and the inhibitory effect of cancer cells were posi-tively related.

Association between VDR gene FokI polymorphism and colorectal cancer susceptibility:a meta-analysis / 实用肿瘤学杂志

Objective To discuss the relationship between FokI gene polymorphism and colorectal canc-er.Method The references that met the inclusive criteria were assessed .The extracted data were summarized in the form of tables .Data were analyzed by heterogeneity test .Meta-analysis was conducted by using fixed effects model or random effects model .Results Fifteen experimental studies were included in this study ,including 7, 859 colorectal cancer patients and 9,933 controls.The association between VDR gene FokI and colorectal cancer was expressed as the odds ratio(OR)and 95% confidence interval(CI).FokI recessive genetic model,ff versus FF+Ff,ORrecessive=1.01(95% CI=0.87~1.17,I2 =54%,P=0.91),ORdominant =0.94(95% CI=0.83~1.06,I2 =64%,P=0.30);allele model,fversus F,OR=0.98(95% CI=0.89~1.08,I2 =71%,P=0.72).In subgroup analysis,recessive genetic model,ORCaucasian race =0.95(95% CI=0.86~1.05,I2 =0%,P=0.33);ORyellow race=1.12(95%CI=0.77~1.63,I2 =72%,P=0.54).In subgroup analysis,dom-inant gene model,ORCaucasian race =0.95(95% CI=0.86~1.04,I2 =27%,P=0.29);ORyellow race =0.89(95%CI=0.65~1.22,I2 =78%,P=0.47).In subgroup analysis,allele model,ORCaucasian race=0.97 (95%CI=0.90~1.04,I2 =31%,P=0.38);ORyellow race =1(95% CI =0.79 ~1.27,I2 =82%,P=1.00).Conclusion Our results suggested that in VDR gene FokI ,F and f alleles were not obviously directly correlated with colorectal cancer .No difference was found between Asian and Caucasian .The conclusions in other populations should be further identified by extensive experimental studies .

Quercetin Directly Interacts with Vitamin D Receptor (VDR): Structural Implication of VDR Activation by Quercetin

The vitamin D receptor (VDR) is a member of the nuclear receptor (NR) superfamily. The VDR binds to active vitamin D3 metabolites, which stimulates downstream transduction signaling involved in various physiological activities such as calcium homeostasis, bone mineralization, and cell differentiation. Quercetin is a widely distributed flavonoid in nature that is known to enhance transactivation of VDR target genes. However, the detailed molecular mechanism underlying VDR activation by quercetin is not well understood. We first demonstrated the interaction between quercetin and the VDR at the molecular level by using fluorescence quenching and saturation transfer difference (STD) NMR experiments. The dissociation constant (K(d)) of quercetin and the VDR was 21.15 ± 4.31 µM, and the mapping of quercetin subsites for VDR binding was performed using STD-NMR. The binding mode of quercetin was investigated by a docking study combined with molecular dynamics (MD) simulation. Quercetin might serve as a scaffold for the development of VDR modulators with selective biological activities.

1,25(OH)2D3 promotes M1 macrophage switching to M2 via VDR-PPARγ pathway induced by high glucose / 中华肾脏病杂志

Objective To investigate the effect of 1,25(OH)2D3 on high glucose induced macrophage activation and its underlying signal transduction mechanism.Methods RAW 264.7 cells were used to perform cell culture,the activity of intracellular iNOS was measured.VDR siRNA and PPARγ antagonist pre-treatment with macrophages were done before using 10-8 mol/L1,25(OH)2D3 to intervene high glucose pre-incubated macrophages.M1 markers including iNOS,TNF-α,IL-12,M2 markers including MR,Arg-1,IL-10 and nuclear receptors VDR and PPARγ were separately examined.Results The iNOS activity was increased in a glucose-dose and time dependent manner.Particularly,25 mmol/L glucose at 24 h gave the maximum response.After being treated with 25 mmol/L glucose for 24 h,not only inflammatory cytokines of TNF-α,IL-12 in the supernatant were increased,but quantitative real-time PCR and Western blotting analysis showed iNOS was also up-regulated (P ＜ 0.05).However,M2 markers,i.e.MR and Arg-l were significantly decreased (P ＜ 0.05).When in the presence of 1,25(OH),D3,the trends were reversed:the markers of M1,including TNF-α,IL-12 and iNOS were obviously reduced (P ＜ 0.05),while M2 markers,IL-10,Arg-1 and MR were increased (P ＜ 0.05).In addition,VDR and PPARγ were also increased (P ＜ 0.05).However,the above effects of 1,25 (OH)2D3 were abolished when further inhibited the expression of VDR and PPARγby VDR siRNA and PPARγ antagonist.Besides,accompanied by VDR,PPARγwas also decreased upon the treatment with VDR siRNA (P ＜ 0.05).Conclusion 1,25(OH)2D3 can promote high glucose induced classically activated macrophages (M1) converting to alternatively activated macrophages (M2) and this is achieved through VDR-PPARγ pathway.