Intestinal Ca~(2+) absorption revisited: A molecular and clinical approach

Ca~(2+) has an important role in the maintenance of the skeleton and is involved in the main physiological processes. Its homeostasis is controlled by the intestine,kidney, bone and parathyroid glands. The intestinal Ca~(2+) absorption occurs mainly via the paracellular and the transcellular pathways. The proteins involved in both ways are regulated by calcitriol and other hormones as well as dietary factors. Fibroblast growth factor 23(FGF-23) is a strong antagonist of vitamin D action. Part of the intestinal Ca~(2+) movement seems to be vitamin D independent.Intestinal Ca~(2+) absorption changes according to different physiological conditions.It is promoted under high Ca~(2+) demands such as growth, pregnancy, lactation,dietary Ca~(2+) deficiency and high physical activity. In contrast, the intestinal Ca~(2+)transport decreases with aging. Oxidative stress inhibits the intestinal Ca~(2+)absorption whereas the antioxidants counteract the effects of prooxidants leading to the normalization of this physiological process. Several pathologies such as celiac disease, inflammatory bowel diseases, Turner syndrome and others occur with inhibition of intestinal Ca~(2+) absorption, some hypercalciurias show Ca~(2+)hyperabsorption, most of these alterations are related to the vitamin D endocrine system. Further research work should be accomplished in order not only to know more molecular details but also to detect possible therapeutic targets to ameliorate or avoid the consequences of altered intestinal Ca~(2+) absorption.     

大剂量1,25(OH)_2D_3口服冲击治疗血透患者甲状旁腺素和血小板胞内游离钙异常

目的：了解大剂量１，２５（ＯＨ）２Ｄ３口服冲击对血透患者血清甲状旁腺素［ＰＴＨ（１～８４）］和血小板胞内游离钙浓度（Ｐｔ［Ｃａ２＋］ｉ）的影响和相互关系。方法：用Ｆｕｒａ２荧光测定法和免疫放射法对１２例血透患者测定Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４）。结果：静息Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４），治疗前是升高的，治疗后则降低；且两者密切相关，其Ｐ值治疗前＜０００１，治疗后＜００２５。多因素逐步回归显示：ＰＴＨ（１～８４）在Ｐｔ［Ｃａ２＋］ｉ的影响中起显著作用。结论：大剂量１，２５（ＯＨ）２Ｄ３冲击治疗能降低Ｐｔ［Ｃａ２＋］ｉ和ＰＴＨ（１～８４），其降低Ｐｔ［Ｃａ２＋］ｉ的作用可能是通过抑制ＰＴＨ合成与分泌     

老年男性2型糖尿病患者骨质疏松与各种钙调激素的关系研究

目的　测定老年男性 2型糖尿病 (2 - DM)患者骨密度及各种钙调激素 ,探讨老年男性 2 - DM患者骨质疏松的发病机理。方法　测定70例老年男性 2 - DM患者及 60例年龄、体重指数相匹配的健康对照者的骨密度 ,血清骨钙素 (BGP)、抗酒石酸酸性磷酸酶 (TRAP)、甲状旁腺素(PTH)、降钙素 (CT)、1 ,2 5(OH) 2 D3、2 5(OH) D3、尿羟脯氨酸 (HOP)等 ,两组进行比较。结果　老年男性 2 - DM患者较健康对照组骨密度显著降低。BGP、CT、1 ,2 5(OH) 2 D3、2 5(OH) D3浓度低于对照组 (P<0 .0 5) ;TRAP、PTH、HOP显著高于对照组 (P<0 .0 5)。结论　老年男性 2 - DM患者PTH、CT、1 ,2 5(OH) 2 D3等钙调激素分泌及代谢失常 ,影响骨代谢 ,导致糖尿病性骨质疏松。     

维生素D受体作用的分子基础

维生素D受体 (VDR)是由 6个功能区组成 ,每个功能区分工不同但又相互协调。配体结合区介导与 1 ,2 5(OH) 2 D3结合并与视黄酸X受体形成异二聚体 ,DNA结合区则通过两个锌指结构选择性地识别靶基因上DR3型维生素D反应元件 (VDRE)并由此改变局部DNA的构象 ,在其他协同转录激活 /抑制因子和AF 1、AF 2两个亚区的共同参与下激活转录过程 ,进行基因表达。在这一过程中 ,磷酸化对VDR转录活性的意义目前仍不清楚。VDR的异常与多种疾病有关。     

Glutathione depleting drugs,antioxidants and intestinal calcium absorption

Glutathione(GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca2+ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K3, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca2+ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca2+ transport or the paracellular Ca2+ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca2+ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca2+ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca2+ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca2+ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.     

小剂量1，25（OH）_2D_3口服冲击治疗尿毒症患者继发性甲状旁腺功能亢进

目的：对２０例尿毒症继发性甲状旁腺功能亢进患者使用小剂量１，２５（ＯＨ）２Ｄ３口服冲击治疗，以比较其与常规治疗的疗效。方法：４０例尿毒症透析患者，随机分为常规治疗组（ｎ＝２０），口服罗钙全０．２５μｇ／ｄ；冲击治疗组（ｎ＝２０），口服罗钙全２μｇ／次，每周２次，８周后改为０．２５μｇ／ｄ维持１个月。结果：冲击治疗组血ＰＴＨ、ＡＫＰ、Ｐ３＋较常规治疗组下降明显，血钙上升，症状改善，无高血钙发生。结论：应用小剂量１，２５（ＯＨ）２Ｄ３，无发生高血钙的危险，是一种经济合理安全有效的治疗方法     

乙肝后肝硬化患者血清1,25(OH)2D3检测及其临床意义

采用竞争性放射受体法测定３２例乙肝后肝硬化患者血清１Ｍ２５（ＯＨ）２Ｄ３水平,并与３２例性乙型肝炎、３１例健康者对照。发现：肝硬化组血清１,２５（ＯＨ）２Ｄ３水平较肝炎组和对照组明显下降（Ｐ〈０．０１,Ｐ〈０．００１）,且与血清骨钙素、尺桡密度呈正相关（Ｐ〈０．０１,Ｐ〈０．０５）。提示：测定乙肝后肝硬化患者血清１,２５（ＯＨ）２Ｄ３水平有利于肝性骨病的早期发现。     

维生素D_3代谢物和氢化可的松对人胎成骨细胞生长、碱性磷酸酶活性及骨钙蛋白合成的影响

我们使用人胎成骨细胞(OB)作为体外模型,观察了1,25-双羟维生素D_3[1,25(OH)_2D_3]、24,25-双羟维生素D_3[24.25(OH)_2D_3]和氢化可的松对OB生长和代谢的影响。结果证实:1,25(OH)_2D_3在浓度为10~(-8)mol/L时,刺激OB的碱性磷酸酶(AKP)活性、增加骨钙蛋白(BGP)的合成,但抑制OB的生长。24,25(OH)_2D_3在10~(-8)mol/L时无上述作用。氢化可的松在10~(-6)mol/L浓度可抑制1,25(OH)_2D_3刺激BGP合成的功能。     

肝硬化患者血清1,25(OH)_2D_3变化对骨代谢的影响

分别采用竞争性放射受体法及放免法测定32例肝硬化患者血清1,25(OH)2D3、PTH水平,并与32例慢性乙型活动性肝炎、31例健康者对照。发现:肝硬化组血清1 ,25(OH)2D3较肝炎组和对照组明显下降(P<0.01,P<0.001),并与血钙、尺桡骨密度呈正相关(P<0.01,P<0.05);肝硬化组血清 PTH较肝炎组和对照组明显升高(P<0.05,P<0.05),但与血钙、尺桡骨密度无相关性。提示:肝硬化患者血清 1,25(OH)2D3降低与肝性骨病的发生关系密切,检测其水平,有利于该病的早期发现。     

腹膜透析患者1,25二羟基D3冲击治疗的疗效观察

为了探讨口服１，２５（ＯＨ）２Ｄ３冲击治疗对腹膜透析患者钙磷代谢及甲状旁腺功能的影响，我们给予３２例ＣＡＰＤ患者口服１．２５（ＯＨ）２Ｄ３大剂量冲击治疗（２－４μｇ／次，每周２次）．另２９例为常规治疗组（０．２５－０．５ｕｇ／ｄ）作为对照组。结果显示，两组患者血钙均明显升主，血磷及血ＡＫＰ均明显降低；ＰＴＨ和ＣＴ在常规治疗组有轻度降低，但无统计学差异；而口服冲击治疗组，ＰＴＨ和ＣＴ则明显降低，且临床症状明显改善，用药过程中未发现明显副作用。上述结果表明，１，２５（ＯＨ）２Ｄ３口服冲击治疗是纠正钙磷代谢紊乱和甲状旁腺功能亢进的较佳疗法，值得推荐。     

成纤维细胞生长因子23与慢性肾脏病钙磷代谢相关性研究

目的研究血清钙(Ca)、磷(P)、甲状旁腺激素(iPTH)、1,25(OH)2D3以及肾功能与成纤维细胞生长因子23(FGF23)的关系。方法将2009年9月至2010年2月中国医科大学附属第一医院住院的慢性肾脏病(CKD)患者58例分为3组,另设对照组20例。采用免疫酶联吸附(ELISA)法测定FGF23及1,25(OH)2D3浓度。全自动生化分析仪测定血清Ca、P、肌酐(Scr)、尿素氮(BUN)浓度,化学免疫发光法测定全段iPTH。结果 FGF23在CKD血清中的质量浓度均高于健康对照组,且随肾小球滤过率(GFR)的降低逐渐升高,在CKD 4,5期FGF23升高明显,与CKD 3期比较差异有统计学意义(P<0.05),1,25(OH)2D3显著下降,与对照组差异有统计学意义(P<0.01)。随着GFR的降低,血清Scr、P、iPTH逐渐升高。Pearson相关分析显示,CKD 3～5期logFGF23与logiPTH、Scr、P呈正相关(r=0.516,P<0.01;r=0.397,P<0.01;r=0.344,P<0.01),与GFR,1,25(OH)2D3呈负相关(r=-0.491,P<0.01;r=-0.413,P<0.01)。结论血清FGF23、iPTH、P随着GFR降低逐渐升高,1,25(OH)2D3逐渐降低,尤以CKD 4～5期明显。当GFR<30时FGF23质量浓度与GFR、血清iPTH、P、1,25(OH)2D3等因素有关。     

Effect of Sunlight Exposure on Circulating 1,25-Dihydroxyvitamin D in Hemodialyzed Patients and of Exogenous Parathyroid Hormone in Anephric Patients

ABSTRACT. Sunshine exposure increased the serum concentration of 25-hydroxyvitamin D (25-OHD) in 9 hemodialyzed patients. Mean 1,25-dihydroxyvitamin D (1,25-(OH)₂D) was unchanged, but in two patients with low initial 25-OHD values this increase was accompanied by a rise in circulating l,25-(OH)₂D, although not to normal levels. One hemodialyzed patient developed liver insufficiency with a resultant reduction of serum 25-OHD concentration accompanied by a decrease in serum 1,25-(OH)₂D concentration. The results indicate that the circulating levels of 1,25-(OH)₂D in patients with end-stage renal failure are to some extent regulated by the serum 25-OHD concentrations. Injection of parathyroid hormone (PTH) induced minor increases in serum concentrations of 1,25-(OH)₂D in patients with end-stage renal failure and even in anephric patients, suggesting the existence of an extrarenal PTH-sensitive 1-α-hydroxylase. However, the enzyme was stimulated by supra-physiological concentrations of PTH, and therefore not necessarily of importance in the normal regulation of calcium metabolism.     

人血清1,25-双羟维生素D浓度的放射受体法测定

本文报告了一种简便、精确地测定血中1, 25-双羟维生素D的方法。1ml血清与碱性K_2HPO_4缓冲液温育1小时后与硅藻土粉末混合,继之用二氯甲烷/丙酮(9:1)提取、分离,经高效液相色谱仪纯化,流动相为正己烷/异丙醇(9:1),经放射受体法测定1, 25(OH)_2D含量。1, 25(OH)_2D_3受体蛋白提取、制备自正常仔鸡小肠粘膜细胞。34例正常北京成人血清1.25(OH)_2D浓度平均为113.8±422pmol/L(47.4±17.6pg/ml)。     

Non-classical effects of vitamin D: Non-bone effects of vitamin D

Our understanding of vitamin D has improved considerably in recent years. The role of vitamin D in preventing osteoporotic fractures is now well-established. However, an important controversy has emerged in the last decade concerning the effects of the active form of vitamin D (1,25-dihydroxy-vitamin D) on tissues other than bone (non-classical effects). The demonstration that the vitamin D receptor (VDR) is ubiquitously, expressed combined with increasing observational data supporting a relationship between the level of 25-hydroxy-vitamin D in the serum and chronic metabolic disorders, cardiovascular disease and neoplasms, have led to its redefinition as a steroid hormone and the proposal of its use in preventing and/or treating those diseases. This article is an update on the different non-bone or non-classical effects of “vitamin-hormone D”, and its potential preventive or therapeutic role in certain diseases, however, this review is not exhaustive. The different modalities of substitution or supplementation proposed in France by the Groupe de Recherche et d’Information sur les Ostéoporoses (GRIO) are also summarised.     

血清25(OH)D_3水平在哮喘发作期、治疗后的变化及与肺功能的相关性分析

目的探讨哮喘患者急性期及治疗后血清25(OH)D_3水平与肺功能及病情的相关性。方法选取来我院诊治的急性发作期哮喘患者60例为研究组,分为成年亚组及未成年亚组各30例,于治疗前及治疗后7d(缓解期),治疗后3个月测定其血清25(OH)D_3水平、第1秒用力呼气容积占预计值百分比(FEV1%pred)、呼气峰流速(PEF),于治疗前及治疗3个月后进行哮喘控制评分(ACT);于上述时间点选择健康人群为对照组测量相应指标,比较健康与患病人群两亚组间各项指标差异,并分析治疗前及3个月后研究组两亚组血清25-(OH)D_3水平与其他指标间的相关性。结果治疗前发作期、开始治疗后7d及3个月,对照组与研究组各亚组之间,各指标均有显著差异;而研究组治疗7d后血清25(OH)D_3水平也远高于治疗前。治疗前两亚组血清25(OH)D_3与FEV1%pred、PEF间无明显相关性;而开始治疗3个月后,两亚组血清25(OH)D_3与FEV1%pred、PEF及ACT评分均有显著正相关(未成年r=0.81,0.79,0.82;P均0.05;成年组r=0.61,0.54,0.70;P均0.05)。结论哮喘患者发作、缓解及稳定期血清25(OH)D_3水平在病情的诊断与预后评估中能发挥重要作用,值得进一步大样本深入研究。     

Levels of 1,25(OH)2D3 for patients with pulmonary tuberculosis and correlations of 1,25(OH)2D3 with the clinical features of TB

Background

To determine the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentrations to patients with tuberculosis (TB) and whether it influenced the patient’s clinical features.

Methods

For the first part, a total of 153 healthy adults and 74 patients with pulmonary TB (PTB) were enrolled. Serum concentrations of 1,25(OH)2D3 were determined by liquid chromatography-tandem mass spectroscopy to examine the 1,25(OH)2D3 concentrations of the two groups from the peripheral blood. If there are differences between the two groups, what follow will increase the experimental group numbers to examine the relationship among the 1,25(OH)2D3 concentrations with the numbers of the lesion area, the tubercule bacilli in sputum and the CD4/CD8 ratio of T lymphocytes in the peripheral blood.

Results

In the first part, the 1,25(OH)2D3 concentrations was lower in patients with TB than in those healthy adults [365.9 (SD 235.7) vs. 464.3 (SD 335.6), P<0.05]. In the second part, we increased the sample size to 134 (male 91 cases, female 43 cases). we found that the plasma levels of 1,25(OH)2D3 are not correlated with the numbers of the lesion area and the tubercule bacilli in sputum, but the 1,25(OH)2D3 levels can interact the ratio of CD4/CD8 T lymphocytes, it shows a positive correlation with the ratio of CD4/CD8 T lymphocytes.

Conclusions

The 1,25(OH)2D3 concentrations in TB patients lower than the healthy adults, it might exist as a risk factor during the development of TB or TB might affect the levels of 1,25(OH)2D3. But the different status vitamin D concentration might not affect the numbers of the lesion area, the tubercule bacilli in sputum. It shows a positive correlation with the ratio of CD4/CD8 T lymphocytes. The study will have a significance value to clinical medicine, but further study will need to study the levels of 1,25(OH)2D3 with the TB.     

Age and gender effects on 1,25-dihydroxyvitamin D3-regulated gene expression

Several factors involved in regulation of bone mineral metabolism were compared in male and female Fischer 344 rats of different ages (1, 2.5, 6, and 18 months). Plasma 1,25-(OH)₂D₃ concentrations decreased with age in rats of both genders. Abundance of calbindin-D_28K and its mRNA in kidney and calbindin-D_9K and its mRNA in duodenum also decreased with age in both male and female rats. Renal 24-hydroxylase activity and 24-hydroxylase mRNA content were elevated significantly in 18-month-old males and females, compared with younger ages. These data suggest that increased renal catabolism of 1,25-(OH)₂D₃ may be responsible for low plasma 1,25-(OH)₂D₃ concentrations observed in older animals. Plasma PTH and 1,25-(OH)₂D₃ concentrations, renal 24-hydroxylase enzyme activity and 24-hydroxylase mRNA content, duodenal 24-hydroxylase mRNA abundance, and duodenal calbindin-D_9K and calbindin-D_9K mRNA content were greater in males than in females at 2.5 months of age. Lower plasma 1,25-(OH)₂D₃ concentrations in females seem to explain observed gender differences in expression of 1,25-(OH)₂D₃-stimulated genes. The combined effects of these gender differences at ages when peak bone density is being developed may contribute to the greater incidence of osteoporosis in females than in males.     

不同糖耐量人群血清25(OH)D3水平及与胰岛β细胞功能的关系

目的 比较不同糖耐量人群血清25(OH)D3水平,分析其与胰岛β细胞功能的关系.方法 共纳入131例受试者,包括新诊断2型糖尿病患者(T2DM组)50例,糖调节受损者(IGR组)45名和糖耐量正常者(NGT组)36名.收集临床资料并检测相关生化指标,采用酶联免疫吸附法测定空腹血清25(OH)D3水平.结果 NGT组、IGR组和T2DM组血清25(OH)D3水平依次下降(F=25.984,P＜0.05).血清25 (OH)D3与体重指数、腰围、臀围、腰臀比、空腹血糖、口服葡萄糖耐量试验2 h血糖(2 hPG)呈负相关(r=-0.600 ～-0.175,P均＜0.05),与空腹胰岛素(FINS)、胰岛素曲线下面积、稳态模型评估-胰岛β细胞功能指数、早相胰岛素分泌指数(△INS30/△G30)呈直线正相关(r=0.296～0.693,P均＜0.05).多元逐步回归分析显示,2hPG、△INS30/△G30是血清25(OH)D3水平的独立相关因素(β=0.204,-0.178,P均＜0.05).结论 IGR者与T2DM患者25(OH)D3水平降低.血清25(OH)D3与胰岛素分泌功能呈正相关,与肥胖、血糖水平呈负相关.     

新诊断2型糖尿病患者25羟维生素D3与血糖波动相关性的分析

目的探讨新诊断T2DM患者25羟维生素D3[25(OH)D3]水平与血糖波动的关系。方法选取2014年1月至2017年12月于我院内分泌科就诊的188例新诊断T2DM患者,根据25(OH)D3水平分为正常组(≥30 ng/ml组)58例、减少组(20~30 ng/ml组)66例和缺乏组(<20 ng/ml组)64例,比较各组临床指标及血糖波动指标的差异。结果25(OH)D3≥30 ng/ml、<20 ng/ml组2 h C-P、胰岛素抵抗指数、血糖波动最大幅度(LAGE)、血糖变异系数(CVBG)均差异有统计学意义(P<0.05)。各组2 hPG、平均血糖波动幅度(MAGE)、血糖标准差(SDBG)比较,差异有统计学意义(P<0.05)。Pearson相关分析显示,25(OH)D3水平与2 hC-P呈正相关(r=0.395,P<0.05),与MAGE、SDBG呈负相关(r=-0.631、-0.456,P<0.05)。结论T2DM患者25(OH)D3水平与血糖波动显著相关。     

原发性高血压患者血清1,25二羟维生素D水平的相关性研究

目的:探讨原发性高血压患者血清1,25二羟维生素D水平与健康人群的差异,及可能影响1,25二羟维生素D水平的因素。方法 :随机选取原发性高血压患者124例(高血压组)与血压正常的健康人58例(对照组),进行血肌酐、血清1,25-二羟维生素D、肾素、钙离子水平测定和对比分析。结果 :与对照组比较,高血压组的血肌酐水平显著升高[(81.91±30.75)μmol/L比(76.53±11.77)μmol/L]及肾素[(3.14±9.22)ng/ml.h比(0.43±0.22)ng/ml.h],差异具有统计学意义(均P<0.01),1,25-二羟维生素D水平降低[(38.72±8.02)pg/ml比(39.59±11.53)pg/ml],差异具有统计学意义(P<0.05)。两组的钙离子浓度无差异。Pearson分析显示血肌酐水平与血清1,25-二羟维生素D水平存在负相关(r=-0.15,P<0.05)。结论 :高血压患者的1,25二羟维生素D水平显著低于健康人群。