维生素D在神经系统疾病中的作用

维生素D是一种"被遗忘的神经甾体",它不仅能调节钙磷代谢维持骨骼健康,而且在神经系统发育和功能中也发挥着重要作用。近年来大量流行病学研究报道,维生素D缺乏和多种神经精神疾病的发生发展相关。本文对维生素D在神经系统疾病中的作用和其可能的机制作一综述。     

Vitamin D analogs: novel therapeutic agents for cardiovascular disease?

Vitamin D3 plays a key role in regulating calcium and mineral homeostasis in support of normal development and maintenance of bone. The classic effects of vitamin D3 include promoting absorption of dietary calcium in the gut and, through its actions as a steroid endocrine hormone, regulating the synthesis and secretion of parathyroid hormone. The effects of the vitamin D3 system are mediated through the highly regulated generation of the potent, active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D3 exerts its effects through the vitamin D3 receptor (VDR), a ligand-activated nuclear receptor expressed in a wide array of tissue and cell types. Studies performed in mice rendered deficient for VDR suggest that calcitriol and VDR may inhibit the renin-angiotensin system and reduce blood pressure in the long-term. Clinical studies suggest that administration of vitamin D3 analogs produces differential benefit with regards to mortality in dialysis patients; other studies suggest that vitamin D3 analogs may provide cardiovascular benefit in both dialysis and nondialysis patients. This paper reviews clinical and preclinical studies, which suggest that vitamin D3 analogs may provide therapeutic utility in the treatment of cardiovascular disease independent of those mechanisms typically associated with the vitamin D3 endocrine system.     

Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells

The active form of vitamin D (1α,25‐dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25‐dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose‐dependently, in concentrations between 1 nM and 10 μM. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound‐healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle‐treated cells. However, they had no effect on caspase‐3 and ‐7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.     

The biochemical basis of renal osteodystrophy and post-menopausal osteoporosis: a view from the vitamin D system

Summary

The vitamin D endocrine system is now known to play an essential role in the regulation of plasma calcium and phosphorus concentrations and in overall organismal calcium economy. These two basic functions of the vitamin D endocrine system have provided important new insight into several disease states. The two disease states discussed here are the genesis of renal osteodystrophy and of post-menopausal osteoporosis. It seems likely that defects or alternations in the vitamin D system play important roles in the development of these disease states. Successful treatment undoubtedly will involve the vitamin D system and most likely the active form of vitamin D, 1,25-(OH)₂D₃.     

1,25-Dihydroxyvitamin D3 regulates genes responsible for detoxification in intestine

1α,25-Dihydroxyvitamin D₃ (1,25-(OH)₂D₃), the biologically active form of vitamin D₃, not only plays a major role in mammalian calcium and phosphorous homeostasis but also exerts pleiotropic effects on cell proliferation, differentiation and the immune system. Further, vitamin D is believed to play a significant role in the prevention of colon, prostate, and breast cancer and in reducing the risk of autoimmune diseases. To gain insight into the mechanism whereby vitamin D can have such diverse actions, we have employed microarray technology. We studied the effect of a single dose of 1,25-(OH)₂D₃ on gene expression in the intestine of vitamin D-deficient rats. Within 6 h, 1,25-(OH)₂D₃ stimulates the expression of several phase I and phase II biotransformation genes. There is also an increased expression of antioxidant genes. These results support the idea that vitamin D is a significant factor in detoxification and protection against environmental toxins.     

活性维生素D3的免疫调节作用

活性维生素 D3[1,25(OH)2VitD3]对钙磷代谢有重要的调节作用.近年来,大量体外实验和临床研究发现,活性维生素D3有重要的抗炎和免疫调节作用.此文就活性维生素D3对免疫系统和免疫相关疾病的调节作用作一系统性总结.     

活性维生素D3的免疫调节作用

活性维生素 D3[1,25(OH)2VitD3]对钙磷代谢有重要的调节作用.近年来,大量体外实验和临床研究发现,活性维生素D3有重要的抗炎和免疫调节作用.此文就活性维生素D3对免疫系统和免疫相关疾病的调节作用作一系统性总结.     

Calcidiol [25(OH)D3]: from diagnostic marker to therapeutical agent

Abstract

Objective:

Osteoporosis is a skeletal disorder characterized by diminished bone strength, which results in an increased risk of fracture. Currently, osteoporosis is a public health priority due to the large number of individuals affected and the detrimental effect on quality of life. Primary osteoporosis, the most common form, usually results from age-related reduction in bone mineral strength. Over time, the individual’s capacity to build bone is impaired, as the synthesis of vitamin D, the hormone responsible for calcium absorption, tends to decline. As serum calcium levels decrease, metabolic control serves to increase the removal of calcium from the skeleton to make up for the deficit. The synthesis of the ‘hormone’ vitamin D and its control therefore become central to intervention in involutional osteoporosis syndromes. In humans, plain vitamin D (cholecalciferol), also called parental or native vitamin D, is photosynthesized in the skin and then hydroxylated in the liver into the vitamin D analog calcidiol [25(OH)D3], which is hydroxylated again in the kidney into the vitamin D analog calcitriol [1,25(OH)2D3]. The advantage of administering vitamin D analogs is that the pro-drug calcidiol avoids the effect of declines in hepatic function, while calcitriol avoids the effect of declines in hepatic and kidney function. A strategy to enhance [25(OH)D3] levels to the optimal threshold of vitamin D is supplementation with the calcidiol metabolite itself. The goal of this paper is to review published studies on the efficacy of the calcidiol metabolite in increasing 25(OH)D3 serum levels and improving skeletal health parameters in humans.     

维生素D在心血管疾病中的作用研究进展

维生素D是机体内的一种脂溶性类固醇激素,在调节钙磷代谢方面起重要作用。维生素D还参与免疫调控、物质代谢、细胞增殖与分化等多个生理过程。近年来国内外研究显示维生素D缺乏与心血管疾病相关,但维生素D对心血管疾病的具体调节机制尚不明确,且随机对照试验研究显示维生素D对心血管疾病的影响结果不尽一致。本文对维生素D在心血管疾病中的作用进行综述,旨在为心血管病的防治提供参考。     

Hepatic drug metabolism after phenobarbital and diphenylhydantoin administration in the rat--influence of vitamin D3 status.

Measurements of aniline hydroxylation, aminopyrine N-demethylation and cytochrome P-450 content after a 3-week treatment with phenobarbital (PB), diphenylhydantoin (DPH) or a combination of the two drugs were undertaken during normal vitamin D status (D +) and vitamin D deficiency (D ?) with or without vitamin D₃(D₃) supplementation. Serum calcium concentrations were reduced after D deprivation but responded by a significant increase toward normal values to a single pharmacological dose of D₃. Serum phosphorus concentrations were also slightly raised by the supplementation. Even in the presence of higher cytochrome P-450 content in D ? rats, aniline hydroxylase and aminopyrine N-demethylase activities were lower in D ? than in D + animals. These two enzymatic parameters, as well as cytochrome P-450 content, were increased by anticonvulsant (ACV) drug treatment regardless of the D nutritional status. The in vivo hexobarbital sleeping time was shortened by ACV drugs but the sleeping time tended to be longer in D ? than in D + rats. Supplementation with 1000 I.U. of D₃, lowered aniline hydroxylase activity both in D + and D? animals; the supplementation had no effect on aminopyrine N-demethylase activity in D + animals but had an inhibitory effect after PB and a stimulatory effect after DPH treatment in D? animals. Cholecalciferol supplementation lowered cytochrome P-450 content toward normal values in D? rats while it had no effect in D + animals. These observations suggest that (1) PB and DPH pretreatment do not alter the normal response of serum calcium and phosphorus to a single pharmacological dose of D₃; (2) in a state of vitamin D deficiency accompanied by hypocalcemia, the inducing capacity of PB and DPH on the liver mixed function oxidase system is not lost; (3) under certain circumstances, vitamin D₃, can influence the catalytic activity of the mono-oxygenase complex; (4) cytochrome P-450 is influenced by vitamin D deficiency and/or changes in extracellular calcium but the forms induced by PB and DPH may not necessarily be the ones specifically involved in vitamin D metabolism.     

Regulation of renal calbindin-D28K

Calbindin-D28k is an intracellular protein with high affinity for calcium. In the kidney, this protein is exclusively localized in the distal tubule and in the proximal part of the collecting ducts. Functionally, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium and possibly magnesium in the distal nephron though the exact regulatory mechanisms are not yet known. Thus, several theories regarding the functional role of calbindin-D28k have been proposed: The carrier theory describes calbindin-D28k as a transport protein which binds calcium and then transports it from the luminal to the basolateralcell membrane. The buffer theory assumes that calbindin-D28k functions by binding calcium ions to prevent intracellular calcium concentrations from reaching toxic levels. The activator theory describes that calbindin-D28k increases the activity of calcium channels or the enzymatic activity of the Ca++-Mg++-ATPase in the luminal membrane and thereby increases the tubular reabsorption of calcium. The renal calbindin-D28k is dependent upon vitamin D. Pharmacological doses of the active vitamin D metabolite 1,25-(OH)2D increases the concentrations of renal calbindin-D28k, whereas the concentration of calbindin-D28k is low in conditions with reduced levels of circulating 1,25-(OH)2D. Likewise, plasma calcium concentrations, uremia and hypertension affect calbindin-D28k expression. However, several studies have rendered probable the effect of additional factors in the regulation of renal calbindin-D28k. The aim of the present dissertation therefore was to examine the regulation of renal calbindin-D28k in a series of physiological and pathophysiological conditions established in vivo in the rat. A possible correlation between hypertension and calbindin-D28k was examined in three models of experimental hypertension: the genetically defined spontaneous hypertensive rat, the salt-sensitive Dahl rat and the renovascular hypertensive rat. These three models clearly demonstrated three separate patterns in the calcium metabolism, but the studies were unable to support a role for calbindin-D28k in the development of hypertension. In all three models the development of hypertension caused an increased plasma 1,25-(OH)2D. This increase was accompanied by either unaltered or reduced levels of renal calbindin-D28k possibly secondary to a cellular resistance against 1,25-(OH)2D. Magnesium binds to calbindin-D28k with a relatively high affinity. The regulation of urinary magnesium excretion takes place in the distal tubule where calbindin-D28k is found in high concentrations. Therefore, a possible relation between magnesium and calbindin-D28k was examined. The studies demonstrated not previously known connections between magnesium intake, urinary magnesium excretion and renal calbindin-D28k which suggests that this protein is involved in the regulation of magnesium homeostasis by the kidney. Calcitonin increases the reabsorption of calcium in the distal tubule. Therefore, the effect ofcalcitonin on renal calbindin-D28k was examined both by eliminating the endogeneous calcitonin production by a selective thyroidectomy followed by an autotransplantation of the parathyroid glands and further by infusion of calcitonin. These studies demonstrated unchanged concentrations of renal calbindin-D28k. It was concluded that the increased calcium reabsorption induced by calcitonin in the distal tubule is not mediated by calbindin-D28k. Urinary calcium excretion is in part regulated by the action of PTH on calcium reabsorption in the distal nephron. Previous reports of increased expression of renal calbindin-D28k in uremic rats led us to suggest that secondary hyperparathyroidism associated with uremia induced the synthesis of renal calbindin-D28k. Therefore, the effect of PTH was examined in a study comprising selective parathyroidectomy and infusions of PTH, PTHrP, 1,25-(OH)2D and calcium. (ABSTRACT TRUNCATED)     

Experimental vasoprotection by a novel erythrocyte-derived depressing factor in rats with arterial calcinosis

Erythrocyte-derived depressing factor (EDDF) shows significant protective effects on blood vessels from hypertensive rats, by regulating vascular reactivity, calcium homeostasis, DNA synthesis, and cell cycle progression in vascular smooth muscles (VSMCs). Arteries from hypertensive and aging people have high levels of accumulated calcium. However, in the life span of experimental animals commonly used, arterial calcium content does not reach cytotoxic levels observed in human. An overdose of vitamin D(3) results in a rapid arterial calcium overload. Using rats with arterial calcinosis and age- and gender-matched Wistar controls, we investigated whether EDDF has beneficial effect on blood vessels from animals with arterial calcinosis. Blood vessel functions were impaired in rats with arterial calcinosis, as indicated by decreased Ca(2+)-ATPase activity, increased vasoconstrictor responses to alpha1 adrenoceptor agonist phenylephrine and increased ERK1/2 phosphorylation. Arterial calcium overload also impaired the morphological integrity of VSMCs. EDDF restored the abovementioned abnormalities caused by arterial calcinosis, and inhibited cell cycle progression of VSMCs induced by angiotensin II. In conclusion, EDDF may protect blood vessels from animals with arterial calcinosis, which is mediated by regulating calcium homeostasis, vascular reactivity and cell cycle progression as well as by improving morphological integrity of VSMCs.     

New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion

BACKGROUND: Adequate vitamin D and calcium nutrition play a critical role in the maintenance of musculoskeletal health and are considered the first step in osteoporosis treatment. ROUNDTABLE DISCUSSION: In February 2008 Merck Sharp & Dohme sponsored a 2-day, evidence-based expert panel on the benefits of vitamin D for the patient with osteoporosis and the role of vitamin D in combination with antiresorptive therapy for the management of osteoporosis. One of the primary objectives of the meeting was to review new data on the optimal serum 25-hydroxy vitamin D [25(OH)D] levels. The symposium was attended by 29 researchers and clinicians from Europe and the Middle East. The discussion focused on optimizing vitamin D and calcium nutrition and reducing falls and fractures in osteoporotic patients. CONCLUSIONS: Current evidence and expert opinion suggests that optimal serum 25(OH)D concentrations should be at least 50 nmol/L (20 ng/mL) in all individuals. This implies a population mean close to 75 nmol/L (30 ng/mL). In order to achieve this level, vitamin D intake of at least 20 microg daily is required. There is a wider therapeutic window for vitamin D than previously believed, and doses of 800 IU per day, regardless of sun exposure, season or additional multivitamin use, appear to present little risk of toxicity. Apart from fracture and fall prevention, optimization of vitamin D status may also have additional general health benefits. Based on newly emerging data regarding calcium supplementation, and recommendations for increased vitamin D intake, the current recommendations for calcium intake in postmenopausal women may be unnecessarily high. In addition to vitamin D and calcium, treatment of patients with osteoporosis at high risk of fractures should also include pharmacologic agents with proven vertebral and non-vertebral fracture efficacy.     

The high prevalence of inadequate serum vitamin D levels and implications for bone health

BACKGROUND: Inadequate serum vitamin D is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, which increased fracture risk. Osteomalacia has also been observed in severe cases. Indeed, vitamin D and calcium are essential components of management strategies for the prevention and treatment of osteoporosis. Despite this, many people currently do not have adequate vitamin D levels. This problem has been documented in many studies around the world, regardless of age, health status, or latitude, and is especially common among older adults, who are also likely to have osteoporosis. Factors that contribute to low vitamin D include low exposure to sunlight, decreased synthesis in skin and reduced intestinal absorption related to aging, and limited dietary sources. Supplementation is the most effective means of correcting poor vitamin D nutrition. However, few patients with osteoporosis currently take sufficient vitamin D supplements. SCOPE: This review article discusses the role of vitamin D in osteoporosis and skeletal health, and summarizes what is known about the high prevalence of inadequate serum vitamin D and recommendations for supplementation. CONCLUSION: Greater awareness of the importance of vitamin D for skeletal health and more aggressive supplementation efforts are urgently needed to address this important public health problem.     

Effects of calcitriol on the immune system: new possibilities in the treatment of glomerulonephritis

1. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, is widely appreciated to play a central role in calcium and phosphate homeostasis. However, it is becoming increasingly clear that the sterol also play an important role in the regulation of cellular growth, haematopoietic tissues and the immune system, as well as in the modulation of hormone secretion by several endocrine glands. 2. In the present review, some of the mechanisms by which 1,25(OH)2D3 regulates immune function are highlighted. Moreover, a number of studies on the effects of calcitriol in several experimental animal models of renal disease are reported, suggesting new possibilities in the therapy of glomerulonephritis.     

Multiligand endocytosis and congenital defects: roles of cubilin, megalin and amnionless

Cubilin and megalin are multiligand receptors that mediate uptake of extracellular ligands. Their function has extensively been studied in the kidney where they play a key role in vitamin B12 and vitamin D homeostasis. Amnionless is a plasma membrane protein that binds to cubilin in various epithelia; the interaction cubilin-amnionless in the gut is crucial for dietary vitamin B12 uptake. Studies in patients with gene defects in these receptors, and animal models with inactivated cubilin, megalin or amnionless suggest an important role in embryonic development and normal growth. In this review we will summarize recent data on the biological function of these receptors and focus on their implication in embryonic nutrition and central nervous system malformations.