维生素D及其受体在帕金森病中的作用

帕金森病(Parkinson's disease,PD)是一种常见的中枢神经系统退行性疾病,引起帕金森病的发病机制至今尚未明确。帕金森病患者及老年人普遍存在维生素D缺乏,这可能是帕金森病的重要发病机制之一。由于维生素D具有免疫调节,抗氧化,调节神经营养因子,降低神经毒性的功能,能同时针对几种导致神经退行性病变因素发挥作用,特别是老年人纠正维生素D缺乏可能会阻止神经元的损失和PD相关的认知功能下降。因此补充维生素D可能成为治疗PD的方法。近年来研究发现,维生素D受体基因多态性与帕金森病的发病有相关性。该文就维生素D及其受体在帕金森病中可能发生的保护作用及其机制作一综述。     

VD缺乏相关疾病及其合理补充的临床意义

众所周知,人体内维生素D水平与少年佝偻病和老年骨质疏松直接相关。最近大量流行病学证据还表明,维生素D(VD)缺乏是多种自身免疫性疾病,癌症,心血管疾病,抑郁症,老年痴呆症,感染性疾病,肌肉骨骼功能下降等的危险因素之一。另外,胰岛素抵抗,高血压和高胆固醇血症也与维生素D缺乏有关。因此,合理补充维生素D可以降低多种疾病风险,并对心血管疾病的风险有益。本文系根据已有的研究结论,阐述维生素D水平与多种临床疾病之间的关联,并对人体血清VD浓度合理监测及合理补充的临床意义做一综述。     

VD缺乏相关疾病及其合理补充的临床意义

：众所周知,人体内维生素D水平与少年佝偻病和老年骨质疏松直接相关。最近大量流行病学证据还表明,维生素D（VD）缺乏是多种自身免疫性疾病,癌症,心血管疾病,抑郁症,老年痴呆症,感染性疾病,肌肉骨骼功能下降等的危险因素之一。另外,胰岛素抵抗,高血压和高胆固醇血症也与维生素D缺乏有关。因此,合理补充维生素D可以降低多种疾病风险,并对心血管疾病的风险有益。本文系根据已有的研究结论,阐述维生素D水平与多种临床疾病之间的关联,并对人体血清VD浓度合理监测及合理补充的临床意义做一综述。     

糖尿病患者维生素D的膳食摄入状况调查

目的：了解我国糖尿病患者群体维生素D的膳食摄入状况,为维生素D缺乏的防治提供依据。方法：收集2014年8月—2014年11月的糖尿病住院患者和门诊患者,收集患者年龄、性别、身高、体重、伴有基础疾病等基本资料,按年龄分成人组（26~64周岁）和老年人组（＞65周岁）。采用24h膳食回顾法调查就诊前一天的膳食情况,参考美国农业部发布的食物成分表,计算出膳食总能量和维生素D的摄入量。同时采用简化食物频率法调查过去1个月内患者高维生素D食物的进食频率,同时调查含维生素D膳食补充剂或功能性食品的摄入。结果：糖尿病患者机体维生素D的缺乏普遍存在,且更加严重,成人组和老年人组血清维生素D水平分别为409±114、362±155nmol/L。由于营养治疗限制了富维生素D食物的应用,糖尿病患者维生素D的总摄入（2717±913、3326±1113U）明显低于同龄正常人每日推荐量（400、600U）,这对糖尿病维生素D缺乏的防治提出了挑战。结论：糖尿病患者维生素D摄入明显不足,体内维生素D普遍缺乏,为防治维生素D缺乏,除户外活动动外可能需要膳食补充剂或强化食品额外补充。     

孕妇维生素D缺乏与妊娠期糖尿病的相关性分析

目的:调查孕妇妊娠早期维生素D水平及其影响因素,探讨维生素D缺乏与妊娠期糖尿病的相关性。方法:选取2012年7月至2013年4月在上海交通大学医学院附属新华医院产科正规产检并分娩的非孕前糖尿病孕妇,在其建卡初检时采用电化学发光免疫技术测定血清25(OH)D3水平;妊娠24-28周行糖筛查及糖耐量试验,诊断是否为妊娠期糖尿病GDM。收集并整理孕妇年龄,孕前体重指数BMI、维生素D测定孕周与测定季节、孕期维生素D补充情况等信息。结果:1000例孕妇中,GDM发病率为11.5%,维生素D缺乏比例占67.4%;其中,约有54%孕妇常规补充复合维生素,约含维生素400 IU/天,10%孕妇常规补充维生素D。GDM孕妇25(OH)D3水平显著低于正常对照组(P=0.007)。维生素D缺乏孕妇发生GDM的风险是维生素D水平较高组的1.944倍,且在秋冬季更易发生GDM。可以考虑在孕14-16周进行维生素D水平的早期测定。结论:孕妇维生素D缺乏十分普遍。妊娠早期孕妇低维生素D水平可能增加孕妇胰岛素抵抗及孕期发生GDM的发生风险。     

孕早期妇女血清25-羟维生素D水平的表达及与甲状腺功能的相关性研究

目的:探讨孕早期妇女血清25-羟维生素D[25(OH)D]水平及与甲状腺功能的相关性。方法:选取2015年12月至2016年12月期间来我院进行常规产前检查的孕早期(≤12周)妇女90例为观察组,根据妊娠时间将观察组分为A组(4-6周)、B组(7-9周)和C组(10-12周),另选取同期在我院进行健康体检的妇女30例为对照组。采用电化学发光免疫分析法测定所有研究对象血清中的25(OH)D、促甲状腺激素(TSH)、游离甲状腺素(FT4)、游离三碘甲状腺原氨酸(FT3)水平,并分析观察组妇女血清25(OH)D水平与TSH、FT4、FT3之间的相关性。结果:A组、B组、C组出现维生素D缺乏的比例高于对照组,维生素D充足的比例低于对照组,C组出现维生素D不足的比例高于对照组,差异均有统计学意义(P0.05)。A组、B组、C组维生素D缺乏、维生素D不足、维生素D充足的比例之间差异无统计学意义(P0.05)。A组、B组、C组出现甲状腺功能异常的比例比较差异无统计学意义(P0.05)。三种甲状腺功能减退的患病率由低到高分别为临床甲减、亚临床甲减、低T4血症,且A组、B组、C组临床甲减、亚临床甲减及低T4血症组间整体比较差异无统计学意义(P0.05)。不同血清25(OH)D水平的观察组孕妇血清中TSH、FT4、FT3水平之间的差异无统计学意义(P0.05)。直线回归分析显示,观察组血清中25(OH)D水平与TSH、FT4无明显相关性(P0.05),与FT3呈正相关关系(P0.05),多元线性回归模型分析显示血清中25(OH)D水平与TSH、FT4、FT3均无相关性(P0.05)。结论:孕早期妇女普遍存在维生素D缺乏的现象,血清25(OH)D水平及与甲状腺功能无明显相关性,但仍应注意加强维生素D的补充。     

中国北方地区血清钙、维生素D水平与乳腺癌的相关性研究

目的:探讨中国北方地区血清钙、维生素D水平与乳腺癌及相关临床因素的关系.方法:选取2007年12月至2012年7月哈尔滨医科大学附属肿瘤医院794例女性乳腺癌患者及976例乳腺良性肿瘤患者,并以128例健康妇女为对照,取空腹血清采用原子吸收分光光度法检测三组血清钙含量,采用放免法检测三组中162例血清25(OH)D含量,结合相关临床资料进行分析.结果:乳腺癌组血清钙含量为2.26± 0.12 mmol/L,乳腺良性肿瘤组血清钙含量为2.26±0.09 mmol/L,正常对照组血清钙含量为2.25±0.24 mmol/L,经方差分析,三组总体均数差别无统计学意义(P＞0.05);乳腺癌患者的血清钙水平与年龄、TNM分期、BMI、绝经情况、乳腺癌家族遗传史无关(P＞0.05).乳腺癌组血清25(OH)D含量为41.91±7.55 ng/mL,乳腺良性肿瘤血清25(OH)D含量为54.62±7.48 ng/mL,正常对照组血清25(OH)D含量为56.15±8.87 ng/mL,经方差分析,乳腺癌患者血清25(OH)D含量低于乳腺良性肿瘤组,差别有统计学意义(P＜0.05),乳腺良性肿瘤组与正常对照组差别无统计学意义(P＞0.05);乳腺癌患者的维生素D水平与年龄、TNM分期、BMI、绝经情况有关(P＜0.05),而与乳腺癌家族遗传史无关(P＞0.05).结论:中国北方地区的乳腺癌患者血清钙水平与乳腺良性肿瘤患者无明显差异.乳腺癌患者的维生素D水平低于乳腺良性肿瘤患者,并且与年龄、TNM分期、BMI、绝经情况有关.维生素D水平降低可能与乳腺癌的发生有关,高水平的维生素D可能会降低女性患乳癌的风险.     

老年2 型糖尿病患者血清中25- 羟维生素D水平 与胰岛beta细胞功能的关系

目的：探讨老年2 型糖尿病患者血清中25- 羟维生素D水平与其胰岛素beta细胞功能的相关性,为老年2 型糖尿病的预防和 治疗提供理论基础。方法：选取2013 年6 月至2014 年6 月在我院接受治疗的老年2 型糖尿病患者300 例作为研究对象,另选取 同期在我院参加体检的健康志愿者300 例作为对照组。采用酶联免疫吸附法测定和比较两组研究对象血清中25-羟维生素D 的 含量,采用稳态模型胰岛素抵抗指数(HOMA-IR)、胰岛素敏感指数(IAI)、胰岛beta细胞的功能指数(HBCI)以及空腹胰岛beta细胞的功 能指数(FBCI)评估老年2 型糖尿病患者的胰岛beta细胞功能,并分析老年2 型糖尿病患者血清中25- 羟维生素D 水平与上述参数 的相关性。结果：老年2 型糖尿病患者血清中25-羟维生素D水平为(10.2± 0.9)ng/mL,显著低于正常对照人群(P<0.05);老年2 型 糖尿病患者血清中25- 羟维生素D 水平与HOMA-IR 呈显著正相关(r=0.438,P=0.019),与IAI 呈显著负相关(r=-0.392,P=0.023), 与HBCI和FBCI无明显相关性(P>0.05)。结论：老年2 型糖尿病患者血清中的25- 羟维生素D 水平较低,与其胰岛素beta细胞功能 障碍有关,补充25-羟维生素D 可能有助于老年2 型糖尿病的治疗和预防。     

北京市中小学生维生素D水平与血脂异常的相关性研究

目的：探讨北京市中小学生血清维生素D水平与血脂异常的相关性。 方法：数据来源于2015年北京市中小学生营养与健康状况监测。采用多阶段分层整群抽样方法于北京市3个城区、4个郊区每区选取小学、初中各4所学校共3 566名中小学生进行调查。抽取静脉血检测维生素D和血生化指标等,采用二元Logistic回归模型分析血清维生素D不足和缺乏对血脂异常发生风险的影响。 结果：在3 566名中小学生中,血脂异常的有735人（20.6%）,维生素D不足的有947人（26.6%）,维生素D缺乏的有824人（23.1%）。二元Logistic回归模型在调整了年龄、性别、地区、体型、尿酸和空腹血糖变量后,发现维生素D不足和维生素D缺乏对总血脂异常发生的风险没有影响;而与维生素D适宜者相比,维生素D不足降低了TC异常发生的风险,增加了TG异常发生的风险;与维生素D适宜者相比,维生素D缺乏降低了TC异常和LDL C异常发生的风险,增加了HDL C异常发生的风险。结论：北京市中小学生血脂异常、维生素D不足和缺乏的情况均较为严重,需引起重视;在该研究样本中,维生素D不足和缺乏对总血脂异常的发生风险没有影响;维生素D不足降低了TC异常发生的风险,增加了TG异常发生的风险;维生素D缺乏降低了TC异常和LDL C异常发生的风险,增加了HDL C异常发生的风险。维生素D与血脂异常的关系仍需进一步的研究加以证实。     

松滋市7～12岁单纯性肥胖儿童血清25羟基维生素D水平与其血脂关系的研究

目的：调查湖北省松滋市117例7~12岁儿童维生素D水平与其血脂关系,评价本地区维生素D水平与儿童肥胖的关系。方法：选取2016—2017年在松滋市妇幼保健院接受体检的7~12岁儿童,测定血清25羟基维生素D浓度、BMI以及血脂指标。结果：单纯性肥胖组的血清25羟基维生素D浓度为（10.96±1.64）ng/mL,严重低于正常对照组［（23.93±5.01）ng/mL］（P＜0.05）,超重组的维生素D水平［（16.33±3.54）ng/mL］也低于正常对照组,具有统计学意义（P＜0.05）。儿童血清25羟基维生素D水平与其对应的BMI呈显著负相关（r=-0.78,P=0.000）。肥胖组的TC、TG、LDL C水平显著高于超重组和正常对照组（P＜0.05）。结论：松滋市肥胖、超重的儿童体内血清维生素D水平营养状况存在不足和严重缺乏的现象,与光照时间不足、户外活动缺乏有关,建议对维生素D缺乏的儿童进行膳食干预,加强户外活动,重视肥胖与维生素D等相关营养素的知识宣教,减少因维生素D缺乏导致其他疾病的发生。     

High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice

Blood–brain barrier (BBB) breakdown and mitochondrial dysfunction have been implicated in the pathogenesis of Alzheimer''s disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Besides vitamin C being as one of the important antioxidants, recently, it has also been reported as a modulator of BBB integrity and mitochondria morphology. Plasma levels of vitamin C are decreased in AD patients, which can affect disease progression. However, investigation using animal models on the role of vitamin C in the AD pathogenesis has been hampered because rodents produce with no dependence on external supply. Therefore, to identify the pathogenic importance of vitamin C in an AD mouse model, we cross-bred 5 familial Alzheimer''s disease mutation (5XFAD) mice (AD mouse model) with ι-gulono-γ-lactone oxidase (Gulo) knockout (KO) mice, which are unable to synthesize their own vitamin C, and produced Gulo KO mice with 5XFAD mice background (KO-Tg). These mice were maintained on either low (0.66 g/l) or high (3.3 g/l) supplementation of vitamin C. We found that the higher supplementation of vitamin C had reduced amyloid plaque burden in the cortex and hippocampus in KO-Tg mice, resulting in amelioration of BBB disruption and mitochondrial alteration. These results suggest that intake of a larger amount of vitamin C could be protective against AD-like pathologies.     

Assessment of evidence for a protective role of vitamin D in multiple sclerosis

Evidence for a role of vitamin D insufficiency in determining risk in Multiple Sclerosis (MS) is supported by studies in both pediatric- and adult-onset patients. The potential role of vitamin D in modulating MS disease activity is an area of active clinical trials research, and the possibility of primary disease prevention with vitamin D supplementation in early life is an emerging concept. With Sir Austin Bradford Hill's criteria as a framework, the present review assesses the evidence for a causal relationship between vitamin D insufficiency and the pathobiology of MS, and discusses rationale for future clinical trials with vitamin D.     

Molecular docking analysis of hyperphosphorylated tau protein with compounds derived from Bacopa monnieri and Withania somnifera

Tau protein, the major player in Alzheimer’s disease forms neurofibrillary tangles in elderly people. Bramhi (Baccopa Monniera) is often used as an ayurvedic treatment for Alzheimer''s disease. Therefore it is of interest to study the interaction of compounds derived from Baccopa with the Tau protein involved in tangle formation. We show that compounds such as bacopaside II, bacopaside XII, and nicotine showed optimal binding features with the R2 repeat domain of hyperphosphorylated tau protein for further consideration in the context of Alzheimer''s disease (AD).     

ACTIGRAPHIC SLEEP-WAKE PATTERNS AND URINARY 6-SULFATOXYMELATONIN EXCRETION IN PATIENTS WITH ALZHEIMER'S DISEASE

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimer's disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513–524, 2001)     

The effects of vitamin D receptor silencing on the expression of LVSCC-A1C and LVSCC-A1D and the release of NGF in cortical neurons

Background

Recent studies have suggested that vitamin D can act on cells in the nervous system. Associations between polymorphisms in the vitamin D receptor (VDR), age- dependent cognitive decline, and insufficient serum 25 hydroxyvitamin D₃ levels in Alzheimer''s patients and elderly people with cognitive decline have been reported. We have previously shown that amyloid β (Aβ) treatment eliminates VDR protein in cortical neurons. These results suggest a potential role for vitamin D and vitamin D-mediated mechanisms in Alzheimer''s disease (AD) and neurodegeneration. Vitamin D has been shown to down-regulate the L-type voltage-sensitive calcium channels, LVSCC-A1C and LVSCC-A1D, and up-regulate nerve growth factor (NGF). However, expression of these proteins when VDR is repressed is unknown. The aim of this study is to investigate LVSCC-A1C, LVSCC-A1D expression levels and NGF release in VDR-silenced primary cortical neurons prepared from Sprague-Dawley rat embryos.

Methodology/Principal Findings

qRT-PCR and western blots were performed to determine VDR, LVSCC-A1C and -A1D expression levels. NGF and cytotoxicity levels were determined by ELISA. Apoptosis was determined by TUNEL. Our findings illustrate that LVSCC-A1C mRNA and protein levels increased rapidly in cortical neurons when VDR is down-regulated, whereas, LVSCC-A1D mRNA and protein levels did not change and NGF release decreased in response to VDR down-regulation. Although vitamin D regulates LVSCC-A1C through VDR, it may not regulate LVSCC-A1D through VDR.

Conclusions/Significance

Our results indicate that suppression of VDR disrupts LVSCC-A1C and NGF production. In addition, when VDR is suppressed, neurons could be vulnerable to aging and neurodegeneration, and when combined with Aβ toxicity, it is possible to explain some of the events that occur during neurodegeneration.     

The impact of curcumin and its modified formulations on Alzheimer's disease

Alzheimer's disease (AD) is a major health problem worldwide, with no effective treatment approach. Curcumin is the main ingredient of turmeric traditionally used in Asian medicine. Several experimental studies have indicated the protective effect of curcumin and its novel formulations in AD. Curcumin has antioxidant, anti-inflammatory and neurotrophic activities, proposing a strong potential to prevent neurodegenerative diseases. However, there are no sufficient clinical trials to confirm curcumin use in AD patients. Low bioavailability following oral administration of curcumin limits its usage in human. The present study was designed to gather the effects of curcumin and its modified formulations in human and experimental models of AD.