Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
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PMID:[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases]. 857 69

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D, exerts an immunosuppressive effect and can completely prevent experimental autoimmune encephalomyelitis (EAE). 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptors. To investigate the possible role of vitamin D receptor gene (VDRG) polymorphism in susceptibility to or disease-modulation of MS, we evaluated 77 Japanese patients with 'conventional' MS and 95 controls. A VDRG allelic polymorphism was assessed by Bsm1 endonuclease restriction after specific PCR amplification. Genotypic polymorphism was clearly defined as BB (absence of restriction site on both alleles), bb (presence of restriction site on both alleles), or Bb (heterozygous). We found overexpression of the b allele (92.9 vs. 84.2%: P=0.0138) and homozygote bb (85.7 vs. 71.6%; P=0.0263) in MS patients compared with controls. The results indicate for the first time an association of MS with VDRG polymorphism, which may be involved in pathogenesis of MS, or in the linkage disequilibrium of VDRG to another pathogenic gene loci. The role of VDR gene polymorphism should be further studied in other populations, and the distribution of other polymorphism, such as Apa I, Taq I, should be also analyzed to confirm another susceptibility gene for MS and to obtain more adequate strategies for treatment of MS.
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PMID:Association of vitamin D receptor gene polymorphism with multiple sclerosis in Japanese. 1046 99

Inheriting genetic risk factors for multiple sclerosis (MS) is not sufficient to cause this demyelinating disease of the central nervous system; exposure to environmental risk factors is also required. MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS. Since the vitamin D endocrine system is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of vitamin D are lowest, we have proposed that the hormone, 1, 25-dihydroxycholecalciferol (1,25-(OH)2D3), may protect genetically-susceptible individuals from developing MS. Evidence consistent with this hypothesis comes not only from geographic studies, but also genetic and biological studies. Over-representation of the vitamin D receptor gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish oil is an excellent vitamin D source, and diets rich in fish may lower MS prevalence or severity. Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates. However, the clearest evidence that vitamin D may be a natural inhibitor of MS comes from experiments with experimental autoimmune encephalomyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression. The hormone stimulated the synthesis of two anti-encephalitogenic cytokines, interleukin 4 and transforming growth factor beta-1, and influenced inflammatory cell trafficking or apoptosis. If vitamin D is a natural inhibitor of MS, providing supplemental vitamin D to individuals who are at risk for MS would be advisable.
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PMID:Vitamin D: a natural inhibitor of multiple sclerosis. 1111 87

In addition to its role in calcium and phosphorous homeostasis, 1 alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] appears to be a modulator of the immune system. Administration of 1,25-(OH)(2)D(3) prevents disease in several autoimmune animal models, including experimental autoimmune encephalomyelitis (EAE). The vitamin D receptor is believed to mediate this activity. Among cells of the immune system, CD8(+) T cells have the highest levels of the vitamin D receptor. Because CD8(+) T cells have been implicated as both suppressors and effectors of the inflammation associated with multiple sclerosis and EAE, we examined the question of whether the 1,25-(OH)(2)D(3) suppression of EAE occurs through a CD8(+) T cell-dependent mechanism. To test this hypothesis, mice that are homozygous knockouts for the alpha chain of the CD8 receptor and have been characterized as lacking functional CD8(+) T cells (CD8(+) -/-) were provided 1,25-(OH)(2)D(3) in their diet before EAE induction. Although CD8(+) -/- mice fed the same diet lacking 1,25-(OH)(2)D(3) have a high incidence of EAE, EAE did not occur in CD8(+) -/- mice fed the diet containing 1,25-(OH)(2)D(3). We conclude that CD8(+) T cells neither are needed nor do they play a role in the prevention of EAE by 1,25-(OH)(2)D(3).
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PMID:CD8(+) T cells are not necessary for 1 alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. 1192 84

The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3), suppresses autoimmune disease in several animal models including experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The molecular mechanism of this immunosuppression is at present unknown. While 1alpha,25-dihydroxyvitamin D(3) is believed to function through a single vitamin D receptor, there are reports of other vitamin D receptors as well as a "nongenomic" mode of action. We have prepared the EAE model possessing the vitamin D receptor null mutation and determined if 1alpha,25-dihydroxyvitamin D(3) can suppress this disease in the absence of a functional vitamin D receptor. Vitamin D receptor null mice develop EAE although the incidence rate is one-half that of wild-type controls. The administration of 1alpha,25-dihydroxyvitamin D(3) had no significant effect on the incidence of EAE in the vitamin D receptor null mice, while it completely blocked EAE in the wild-type mice. We conclude that 1alpha,25-dihydroxyvitamin D(3) functions to suppress EAE through the well-known VDR and not through an undiscovered receptor or through a "nongenomic" mechanism.
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PMID:The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. 1246 72

We report here that curative treatment of the multiple sclerosis paradigm, chronic relapsing experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, by 1,25-dihydroxyvitamin D(3 )(1,25-D3) leads to a rapid clinical improvement accompanied by an inhibition of CD4, MHC class II and type II nitric oxide synthase (NOS II) expression in the posterior areas of the central nervous system (CNS). In contrast, the hormone has no effect on transforming growth factor-beta1 transcripts. Computer analysis of the NOS II promoter, expressed by microglia and astrocytes, reveals consensus sequence for vitamin D receptor binding, emphasizing the idea that 1,25-D3 may regulate some aspects of EAE by acting directly on CNS constituent cells. We also demonstrate that vitamin D deprivation leads to minimal effects on the kinetic profile of EAE accompanied by a moderate exacerbation of the clinical symptoms. Interestingly, curative treatment of vitamin D-deprived rats with a non-toxic-1,25-D3 analogue (MC1288) strongly inhibited EAE symptoms, thus promulgating the potential interest of such compounds in the management of multiple sclerosis.
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PMID:Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system. 1267 43

Multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. Here, we first review the metabolism and immune functions of vitamin D. Then, we describe the current thinking on the etiology of vitamin D in MS and the accumulating evidence pointing to a link between vitamin D and MS. Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the vitamin D receptor. This review also discusses the therapeutic potential of vitamin D for treating MS.
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PMID:Therapeutic potential of vitamin D for multiple sclerosis. 1828 5

Although the role of 1alpha,25-dihydroxyvitamin D3 in calcium homeostasis of bone tissue is clear, evidence of the involvement of vitamin D3 in the central nervous system functions is increasing. In fact, vitamin D3 regulates vitamin D receptor and nerve growth factor expression, modulates brain development, and reverses experimental autoimmune encephalomyelitis. Only few studies, however, address vitamin D3 effect on embryonic hippocampal cell differentiation. In this investigation, the HN9.10e cell line was used as experimental model; these cells, that are a somatic fusion product of hippocampal cells from embryonic day-18 C57BL/6 mice and N18TG2 neuroblastoma cells, show morphological and cytoskeletal features similar to their neuronal precursors. By this model, we have studied the time course of vitamin D3 localization in the nucleus and its effect on proteins involved in proliferation and/or differentiation. We found that the translocation of vitamin D3 from cytoplasm to the nucleus is transient, as the maximal nuclear concentration is reached after 10 h of incubation with (3)H-vitamin D3 and decreases to control values by 12 h. The appearance of differentiation markers such as Bcl2, NGF, STAT3, and the decrease of proliferation markers such as cyclin-1 and PCNA are late events. Moreover, physiological concentrations of vitamin D3 delay cell proliferation and induce cell differentiation of embryonic cells characterized by modification of soma lengthening and formation of axons and dendrites.
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PMID:Effect of 1alpha,25-dihydroxyvitamin D3 in embryonic hippocampal cells. 1960 26

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease with a rapidly increasing female gender bias. MS prevalence decreases with increasing sunlight exposure, supporting our hypothesis that the sunlight-dependent hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D(3) inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17beta-estradiol (E(2)) is essential for vitamin D(3)-mediated protection, ovariectomized female mice were given E(2) or placebo and evaluated for vitamin D(3)-mediated EAE resistance. Diestrus-level E(2) implants alone provided no benefit, but they restored vitamin D(3)-mediated EAE resistance in the ovariectomized females. Synergy between E(2) and vitamin D(3) occurred through vitamin D(3)-mediated enhancement of E(2) synthesis, as well as E(2)-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E(2) implants did not enable vitamin D(3) to inhibit EAE. The finding that vitamin D(3)-mediated protection in EAE is female-specific and E(2)-dependent suggests that declining vitamin D(3) supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E(2) synthesis and vitamin D(3)-mediated protection with increasing age might be contributing to MS disease progression in older women.
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PMID:Estrogen controls vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D3 metabolism and receptor expression. 1971 Apr 57

Accumulating data indicate that vitamin D, a sun-induced hormone, plays a key role in multiple sclerosis (MS) etiology. Notably, it has been shown that there is a remarkable season of birth effect in MS. We surmised that gestational vitamin D deficiency is a risk factor for MS. To test this hypothesis, a vitamin D deficiency was induced in C57BL/6 female mice 6 weeks prior to conception and prolonged until offspring birth. Contrary to our prediction, we show here that adult offspring exposed to developmental vitamin D deficiency (DVD) developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE), when compared to control offspring. Using reverse transcription and quantitative real-time PCR, we measured the expression level of 22 candidate transcripts in the spleen, the cerebrum and the spinal cord, at Day0 and Day30 post-immunization. We report here that, at Day30 post-immunization, TNF, osteopontin, H2-Eb were over-expressed and IFN was under-expressed in the spinal cord of control mice and not in DVD mice. Another discrepancy between nervous and immune systems was observed: expression of IL4 was dysregulated exclusively in the spleen. Reduced symptom severity in DVD mice can partially be explained by a nervous system-restricted over-expression of vitamin D receptor (VDR), two heat shock proteins (HSP90, HSPa8) and FK506 binding protein 1a (FKBP1a), at Day0. Our clinical test and molecular findings converge to indicate that maternal hypovitaminosis D imprints the foetus and alters the susceptibility of the offspring to EAE. We propose a new hypothesis to explain our unexpected observations.
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PMID:Severity of experimental autoimmune encephalomyelitis is unexpectedly reduced in mice born to vitamin D-deficient mothers. 2021 84


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