From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health

New knowledge of the biological and clinical importance of the steroid hormone 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and its receptor, the vitamin D receptor (VDR), has resulted in significant contributions to good bone health. However, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clinical knowledge is not being translated into better human health. Over the past several decades, the biological sphere of influence of vitamin D(3), as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis (intestine, bone, kidney, and parathyroid). Now, research has shown that the pluripotent steroid hormone 1alpha,25(OH)(2)D(3) initiates the physiologic responses of >/=36 cell types that possess the VDR. In addition to the kidney's endocrine production of circulating 1alpha,25(OH)(2)D(3,) researchers have found a paracrine production of this steroid hormone in >/=10 extrarenal organs. This article identifies the fundamentals of the vitamin D endocrine system, including its potential for contributions to good health in 5 physiologic arenas in which investigators have clearly documented new biological actions of 1alpha,25(OH)(2)D(3) through the VDR. As a consequence, the nutritional guidelines for vitamin D(3) intake (defined by serum hydroxyvitamin D(3) concentrations) should be reevaluated, taking into account the contributions to good health that all 36 VDR target organs can provide.     

维生素D与脑发育相关研究进展

近年来有关维生素D研究进展迅速,其中维生素D与大脑的发育之间的关系日益受到关注。维生素D是一种具有类固醇激素作用的物质,可参与调节细胞増殖、分化及凋亡,大量研究表明,维生素D除了具有促进钙磷吸收、骨骼发育及发挥免疫调节的作用,还可作为一类神经激素影响神经系统的发育和功能,本文将从大脑中的维生素D及维生素D受体、维生素D对脑发育可能的调控作用及维生素D与儿童神经精神障碍疾病的相关性等几方面进行阐述。     

A Novel Role for a Major Component of the Vitamin D Axis: Vitamin D Binding Protein-Derived Macrophage Activating Factor Induces Human Breast Cancer Cell Apoptosis through Stimulation of Macrophages

The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This al1ows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.     

维生素D缺乏与女性生殖关系的研究进展

维生素D在体内不止作为维生素，也可以作为激素发挥作用。它是一种可以调节钙磷代谢的固醇类衍生物，在心血管疾病、免疫调节、抗炎、癌症、生殖等各方面都能发挥一定的生物学作用。该生物学作用通常通过可溶性蛋白维生素D受体（VDR）来实现。VDR是一种位于靶细胞核内的转录因子，分布在人类各种系统组织中，包括女性生殖系统。近年有关维生素D与女性生殖系统的关系引起人们关注。维生素D一定程度上影响卵巢生理功能及女性生育力，同时与一些女性生殖系统疾病有关，如多囊卵巢综合征、子痫前期、子宫内膜异位症、妊娠期糖尿病等。现就维生素D缺乏与女性生殖系统关系的相关研究进行综述。     

Vitamin D and Pancreatitis: A Narrative Review of Current Evidence

Emerging research indicates that vitamin D metabolic disorder plays a major role in both acute pancreatitis (AP) and chronic pancreatitis (CP). This has been demonstrated by studies showing that vitamin D deficiency is associated with pancreatitis and its anti-inflammatory and anti-fibrotic effects by binding with the vitamin D receptor (VDR). However, the role of vitamin D assessment and its management in pancreatitis remains poorly understood. In this narrative review, we discuss the recent advances in our understanding of the molecular mechanisms involved in vitamin D/VDR signaling in pancreatic cells; the evidence from observational studies and clinical trials that demonstrate the connection among vitamin D, pancreatitis and pancreatitis-related complications; and the route of administration of vitamin D supplementation in clinical practice. Although further research is still required to establish the protective role of vitamin D and its application in disease, evaluation of vitamin D levels and its supplementation should be important strategies for pancreatitis management according to currently available evidence.     

Modulation of VDR and Cell Cycle-Related Proteins by Vitamin D in Normal Pancreatic Cells and Poorly Differentiated Metastatic Pancreatic Cancer Cells

Many in vitro studies support the general idea that vitamin D plays a protective role against cancer. Increased doses of vitamin D dietary supplements have been widely used for the potential anticancer benefits of vitamin D. However, despite substantial epidemiological research, there are no clear conclusive data to support the use of vitamin D as a cancer preventive or treatment agent. In the, herein, reported study, we checked the effects of 1,25-dihydroxyvitamin D₃ concentrations on the expression level of the vitamin D receptor (VDR) and cell cycle-related proteins CDKN1A (p21) and CDK1 in pancreatic cells and Panc-1 pancreatic cancer (PC) cells. We found that VDR, CDKN1A, and CDK1 were upregulated by an increase in 1,25-dihydroxyvitamin D₃ concentration in normal pancreatic cells but not in the advanced cancer cell line Panc-1 from poorly differentiated metastatic PC cells. A further increase in 1,25-dihydroxyvitamin D₃ concentration above the physiological range significantly downregulated the expression of VDR, indicating that VDR is modulated by VDR levels to maintain normal functioning during dramatic variations in vitamin D concentration. By increasing the level of cell cycle inhibitory and promoting proteins p21 and CDK1, vitamin D theoretically has both preventive and promoting effects on pancreatic cell division.     

母胎界面维生素D受体表达与复发性自然流产相关及可能的机制

目的 探讨母胎界面维生素D受体(VDR)表达与复发性自然流产及胎盘激素的关系.方法 2014年7月至2014年9月在西安交通大学第一附属医院妇产科门诊收集复发性流产患者和正常早孕妇女绒毛和蜕膜组织,采用荧光实时定量聚合酶链式反应(FQ-PCR)检测两组绒毛组织和蜕膜组织中VDR及绒毛膜促性腺激素受体、雌激素受体和孕激素受体mRNA的含量,比较两组表达的差异.结果 复发性流产组绒毛组织中VDR、绒毛膜促性腺激素受体、雌激素受体mRNA相对水平低于对照组(t值分别为4.86、6.16、2.39,均P<0.05);绒毛膜促性腺激素受体和雌激素受体mRNA的表达水平与VDR表达水平明显正相关(F=10.21,P=0.01;F=14.52,P=0.00).复发性流产组蜕膜组织中VDR、绒毛膜促性腺激素受体、雌激素受体mRNA相对水平也低于对照组(t值分别为5.28、2.34、2.60,均P<0.05).结论 母胎界面VDR mRNA表达水平与早期自然流产相关,绒毛组织绒毛膜促性腺激素受体和雌激素受体mRNA的表达水平与VDR表达水平有一定的相关性.但是VDR导致自然流产的机制仍需进一步研究.     

维生素D与多囊卵巢综合征关系的研究进展

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是一种常见的妇科内分泌疾病,主要特征是月经紊乱、高雄激素血症和胰岛素抵抗等,PCOS患者代谢和生殖功能障碍常同时存在。近年研究发现PCOS患者维生素D水平较正常妇女普遍偏低,维生素D对PCOS代谢和生殖功能障碍的影响可能是由胰岛素抵抗介导的。由于维生素D是通过维生素D受体（VDR）来调控基因转录的,所以维生素D对PCOS的影响可能与VDR基因多态性有关,但VDR基因多态性与PCOS的相关性存在种族差异性,在亚洲人群中这种相关性更加显著。维生素D与PCOS的相关性提示补充维生素D对于缓解PCOS的代谢异常及生育能力可能有益。     

1,25-二羟维生素D3的免疫调节作用

1,25-二羟维生素D3[1,25-dihydroxyvitamin D3,1,25-(OH)2D3]是维生素D3的活性形式,是第二甾体类激素,它除了调节机体的钙和骨代谢外,还参与免疫系统的分化与调节.1,25-(OH)2D3是通过与它的特定受体--维生素D受体相互作用来实现它的大部分基因效应的,抗原呈递细胞和T细胞是它作用的靶细胞,它的作用主要是诱导产生基因耐受性树突细胞,抑制致病性T淋巴细胞,促进调节性T淋巴细胞的增生.1,25-(OH)2D3及其类似物已经在许多实验模型中被证明能够抑制自身免疫性疾病和移植排斥反应,这是一个复杂和丰富的研究领域,可能让我们发现一种新的治疗自身免疫性疾病和移植排斥反应的重要方法.     

维生素D受体在肠道肿瘤生长中与β-catenin通路之间的关系

目的探讨维生素D受体（VDR）对肠道肿瘤生长的影响以及与β-catenin信号通路之间的关系。方法体外培养的人类结肠癌SW480细胞株经维生素D处理4h,免疫沉淀法检测VDR和t3-catenin蛋白的交互作用,24h后用Westernblot检测细胞E．cadherin蛋白的表达。体内实验比较APCmin／＋VDR-／-与APCmin／＋小鼠,免疫组化法检测两型小鼠肠道肿瘤VDR、β-catenin和Brdu蛋白的表达,Westernblot检测肿瘤和肿瘤旁组织β-catenin蛋白的表达。结果维生素D处理SW480细胞后,VDR和β-catenin蛋白相互结合,随后E-cadherin蛋白表达增高（对照组灰度值145．57±4．21,实验组109．35±3．56,t=32．63,P〈0．05）。缺失VDR的APCmin／＋VDR-／-小鼠肠道肿瘤中β-catenin蛋白表达免疫组化（灰度值140．51±2．57）及Westemblot（灰度值166．47±2．36）检测均高于APCmin／＋肿瘤（分别为145．41±3．62、182．35±3．24,t=2．65,4．36,P〈0．05）。结论维生素D抑制肠道肿瘤增殖的作用可能通过VDR影响β-catenin信号通路来完成。     

Association of Vitamin D Receptor and Vitamin D-Binding Protein Polymorphisms with Familial Breast Cancer Prognosis in a Mono-Institutional Cohort

Low 25-hydroxyvitamin D (25OHD) has been associated with an increased cancer incidence and poorer prognosis. Single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) and vitamin D binding protein (GC gene) may interfere with vitamin D activity. This study assesses the role of VDR and GC SNPs on breast cancer (BC) recurrence and survival in a cohort of patients with a family history of breast cancer, without the pathogenic variant for BRCA1 and BRCA2. A consecutive series of patients who underwent genetic testing were genotyped for VDR and GC genes. Specifically, ApaI, FokI, TaqI, BsmI and rs2282679, rs4588, rs7041 SNPs were determined. A total of 368 wild type (WT) patients with BC were analyzed for VDR and GC SNPs. The GC rs2282679 minor allele was significantly associated with luminal subtype of the primary tumor compared to Her2+/TN breast cancer (p = 0.007). Multivariate Cox models showed that BmsI and TaqI are significantly associated with BC outcome. Patients with the major alleles showed more than 30% lower hazard of relapse (BsmI p = 0.02 and TaqI p = 0.03). Our study supports the evidence for a pivotal role of 25OHD metabolism in BC. GC SNPs may influence the hormone tumor responsiveness and VDR may affect tumor prognosis.     

孕期鼠补充维生素D对子鼠胸腺维生素D受体表达

目的 研究给予母孕期大鼠补充不同剂量维生素D,检测子代鼠胸腺中VDR表达变化。方法 健康雌性Wistar大鼠18只,雄性Wistar大鼠9只,以每日晚间17时将雌鼠、雄鼠按2∶1合笼,次日8时对雌鼠阴道分泌物涂片,在40倍光学显微镜检查到精子表示受孕,记为妊娠0 d( gestational day 0,GD0) 。将孕鼠随机入对照组、维生素D低剂量、维生素D高剂量组。于GD 15 d起对照组每日给予肌肉注射生理盐水0.25 ml/(kg·次),低剂量组给予肌肉注射维生素D 20 μg/kg,高剂量组给予肌肉注射维生素D 100 μg/kg,直至子鼠娩出。子鼠哺乳21 d后分离子鼠胸腺,Real-time PCR检测VDRmRNA表达水平,Western blot检测VDR蛋白表达水平。结果 通过Real-tine PCR分析仔鼠胸腺VDR基因表达三组之间差异无统计学意义(P＞0.05)。Western blot检测VDR蛋白水平的表达显示,低剂量及高剂量组VDR蛋白的表达量均高于对照组,三组之间差异存在统计学意义(P＜0.05)。结论 给予母鼠补充维生素D,其仔鼠胸腺VDR蛋白表达量明显增加,与维生素D补充量呈正相关。     

Vitamin D and adipogenesis: new molecular insights

The focus of the current review is to highlight some new insights into the molecular mechanism by which vitamin D, a potentially nutritionally modulated factor, influences adipogenesis. Recent studies, predominantly using the mouse 3T3-L1 pre-adipocyte cell culture model, have shown that the role of vitamin D in inhibiting adipogenesis is mediated at the molecular level through a vitamin D receptor (VDR)-dependent inhibition of CCAAT enhancer binding protein-alpha (C/EBP alpha) and peroxisome proliferator-activated receptor-gamma (PPAR gamma) expression and a decrease in PPAR gamma transactivating activity in the pre-adipocyte. The latter action may reflect a vitamin D-induced decrease in endogenous PPAR gamma ligand availability and a competition between VDR and PPAR gamma for a limiting amount of retinoid X receptor (RXR), a common heterodimeric binding partner of both nuclear receptors.     

Vitamin d and its role in cancer and immunity: a prescription for sunlight.

Vitamin D has been recognized for more than a century as essential for the normal development and mineralization of a healthy skeleton. More extensive roles for vitamin D were suggested by the discovery of the vitamin D receptor (VDR) in tissues that are not involved in calcium and phosphate metabolism. VDR has been discovered in most tissues and cells in the body and is able to elicit a wide variety of biologic responses. These observations have been the impetus for a reevaluation of the physiologic and pharmacologic actions of vitamin D. Here, we review the role of vitamin D in regulation of the immune system and its possible role in the prevention and treatment of cancer and immune-mediated diseases.     

婴幼儿佝偻病VDR基因ApaI、BsmI位点多态性与连锁不平衡分析

目的 探讨婴幼儿佝偻病患者维生素D受体（VDR）基因ApaI、BsmI位点多态性分布特征及连锁不平衡关系及其与佝偻病的遗传易感因素.方法 应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对56例佝偻病患儿和76例健康对照儿进行VDR基因ApaI、BsmI位点多态性的检测,分析两组VDR基因型和等位基因频率及两位点间连锁不平衡的关系.结果 两组VDR基因ApaI、BsmI位点基因型频率分布比较差异均无统计学意义（P＞0.05）.VDR基因ApaI、BsmI 位点等位基因频率在两组人群中的分布差异均无统计学意义（P＞0.05）.ApaI与BsmI二位点连锁不平衡系（D＇=0.230,r2=0.01）.结论 VDR基因ApaI、BsmI位点的多态性与维生素D缺乏性佝偻病无明显关系,且两位点不存在连锁不平衡关系.     

The Increase in FGF23 Induced by Calcium Is Partially Dependent on Vitamin D Signaling

Background: Increased FGF23 levels are an early pathological feature in chronic kidney disease (CKD), causing increased cardiovascular risk. The regulation of FGF23 expression is complex and not completely understood. Thus, Ca²⁺ has been shown to induce an increase in FGF23 expression, but whether that increase is mediated by simultaneous changes in parathyroid hormone (PTH) and/or vitamin D is not fully known. Methods: Osteoblast-like cells (OLCs) from vitamin D receptor (VDR)^+/+ and VDR^−/− mice were incubated with Ca²⁺ for 18 h. Experimental hypercalcemia was induced by calcium gluconate injection in thyro-parathyroidectomized (T-PTX) VDR ^+/+ and VDR^−/− mice with constant PTH infusion. Results: Inorganic Ca²⁺ induced an increase in FGF23 gene and protein expression in osteoblast-like cells (OLCs), but the increase was blunted in cells lacking VDR. In T-PTX VDR ^+/+ and VDR^−/− mice with constant PTH levels, hypercalcemia induced an increase in FGF23 levels, but to a lower extent in animals lacking VDR. Similar results were observed in FGF23 expression in bone. Renal and bone 1α-hydroxylase expression was also modulated. Conclusions: Our study demonstrates that Ca²⁺ can increase FGF23 levels independently of vitamin D and PTH, but part of the physiological increase in FGF23 induced by Ca²⁺ is mediated by vitamin D signaling.     

Vitamin D and tuberculosis

Tuberculosis is highly prevalent worldwide, accounting for nearly two million deaths annually. Vitamin D influences the immune response to tuberculosis, and vitamin D deficiency has been associated with increased tuberculosis risk in different populations. Genetic variability may influence host susceptibility to developing active tuberculosis and treatment response. Studies examining the association between genetic polymorphisms, particularly the gene coding for the vitamin D receptor (VDR), and TB susceptibility and treatment response are inconclusive. However, sufficient evidence is available to warrant larger epidemiologic studies that should aim to identify possible interactions between VDR polymorphisms and vitamin D status.