Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is implicated in the pathogenesis of experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis. Heme oxygenase-1 (HO-1) is a heat shock protein induced by oxidative stress. HO-1 metabolizes the pro-oxidant heme to the antioxidant biliverdin and CO. HO-1 requires electrons, donated by NADPH cytochrome P450 reductase (henceforth, reductase), for catalytic activity. EAE was induced with a peptide of proteolipid protein in SJL mice, and the expression of HO-1 and reductase in the hindbrain was analyzed. HO-1 protein levels were significantly increased in EAE animals compared with control mice. HO-1 expression was present in ameboid macrophages, reactive microglia, and astrocytes in white matter tracks. Bergmann glia and ameboid macrophages also were occasionally stained in the molecular layer of the cerebellum. Unlike HO-1, reductase protein levels decreased with disease severity. HO-1 and reductase were associated with each other in endoplasmic reticulum micelles, suggesting that the decrease in reductase does not interfere with its association with HO-1. In cells that express HO-1, the association of reductase with HO-1 should competitively inhibit the interaction of reductase with cytochrome P450 isozymes and thereby limit free radical production as the latter two enzymes act cooperatively to produce superoxide. The increase in HO-1 together with the decrease in reductase may be part of a common defense mechanism attempting to minimize tissue damage in several neurological conditions.
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PMID:Heme oxygenase-1 and NADPH cytochrome P450 reductase expression in experimental allergic encephalomyelitis: an expanded view of the stress response. 1108 Feb 9

Alteration in the isoprenoid metabolites--digoxin, ubiquinone, and dolichol--have been reported in neuronal degeneration (Parkinson's disease), oncogenesis (central nervous system glioma), functional neuropsychiatric disorders (schizophrenia and epilepsy), and immune-mediated disorders (multiple sclerosis). The coexistence of these disorders has been documented in literature and a central dysfunction related to digoxin and the isoprenoid pathway may underlie all these disorders. A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome X, rheumatoid arthritis, and epilepsy has been described. The psychological behavioral patterns of the family were: creativity and high IQ, hypersexual behavior, reduced appetite and eating behavior, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less bonding and affectionate behavior, and left handedness/right hemispheric dominance. Digoxin, an endogenous Na(+)-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and red blood cell (RBC) membrane Na(+)-K+ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting in increased levels of depolarizng tryptophan catabolites, serotonin, quinolinic acid, strychnine, and nicotine, and decreased levels of hyperpolarizing tyrosine catabolites, dopamine, noradrenaline, and morphine, contributing to membrane Na(+)-K+ ATPase inhibition in all the above disorders and the indexed family. Digoxin-induced membrane Na(+)-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced Mg2+ levels, leading on to glutamate excitotoxicity, oncogene activation, and immune activation. Digoxin-induced altered Ca2+/Mg2+ ratios, reduced ubiquinone, and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure, and mitochondrial function, leading to the diverse disorders described above, including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/LH dominant and left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated hydroxymethylglutarylcoenzyme A reductase activity, with increased serum digoxin and dolichol levels. The serum ubiquinone, serum Mg2+ and RBC Na(+)-K+ ATPase activity were reduced in left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated levels of serum tryptophan, quinolinic acid, serotonin, nicotine, and strychnine. The levels of tyrosine, dopamine, noradrenaline, and morphine were low in left-handed/RH dominant compared to right-handed/LH dominant individuals. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and coordinate the functions of various cellular organelles.
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PMID:Central role of hypothalamic digoxin in conscious perception, neuroimmunoendocrine integration, and coordination of cellular function: relation to hemispheric dominance. 1232 12

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are approved for cholesterol reduction, may also be beneficial in the treatment of inflammatory diseases. Atorvastatin (Lipitor) was tested in chronic and relapsing experimental autoimmune encephalomyelitis, a CD4(+) Th1-mediated central nervous system (CNS) demyelinating disease model of multiple sclerosis. Here we show that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin induced STAT6 phosphorylation and secretion of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-10) and transforming growth factor (TGF)-beta. Conversely, STAT4 phosphorylation was inhibited and secretion of Th1 cytokines (IL-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha) was suppressed. Atorvastatin promoted differentiation of Th0 cells into Th2 cells. In adoptive transfer, these Th2 cells protected recipient mice from EAE induction. Atorvastatin reduced CNS infiltration and major histocompatibility complex (MHC) class II expression. Treatment of microglia inhibited IFN-gamma-inducible transcription at multiple MHC class II transactivator (CIITA) promoters and suppressed class II upregulation. Atorvastatin suppressed IFN-gamma-inducible expression of CD40, CD80 and CD86 co-stimulatory molecules. l-Mevalonate, the product of HMG-CoA reductase, reversed atorvastatin's effects on antigen-presenting cells (APC) and T cells. Atorvastatin treatment of either APC or T cells suppressed antigen-specific T-cell activation. Thus, atorvastatin has pleiotropic immunomodulatory effects involving both APC and T-cell compartments. Statins may be beneficial for multiple sclerosis and other Th1-mediated autoimmune diseases.
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PMID:The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. 1242 6

Previous studies have demonstrated the immunomodulatory potential of Lovastatin, a hydroxy methyl glutaryl-CoA reductase inhibitor, in lessening the clinical and histological manifestations in the neuroinflammatory animal model experimental autoimmune encephalomyelitis (EAE) (Neurosci. Lett., 269 (1999) 71, and J. Neurosci. Res., 66 (2001) 155). To determine the mechanism behind the observed amelioration of EAE by Lovastatin, we examined the cytokine profile of stimulated splenocytes from control, EAE and Lovastatin treated EAE rats. Splenocytes from Lovastatin-treated EAE rats showed decreased levels of interferon-gamma, a Th1 type cytokine, while interleukin (IL)-10, a Th2 type cytokine, was markedly increased as compared to untreated EAE animals. In addition, we also observed reduced levels of IL-6 and nitric oxide production in lipopolysaccharide-stimulated splenocytes isolated from Lovastatin-treated animals. This study documents for the first time that Lovastatin induces a bias towards Th2 cytokines ex vivo, and as a result may be of therapeutic value for cell-mediated diseases such as multiple sclerosis.
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PMID:Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin. 1242 74

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is crucial for cholesterol biosynthesis, and are widely used as lipid-lowering agents. These drugs greatly reduce atherosclerosis and cardiovascular morbidity, which in the past was mainly attributed to their cholesterol-lowering properties. However, recent evidence suggests that statins are also potent immunomodulators. They exerted beneficial effects on animal models of experimental autoimmune encephalomyelitis and thus have therapeutic potential for multiple sclerosis. Their exact mechanism of action is still unclear. HMG-CoA-dependent effects and a direct effect on immune receptors are conceivable and are reviewed here.
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PMID:[Cholesterol-reducing medications-a new therapeutic option for multiple sclerosis? Statins as immunomodulators]. 1290 73

Statins, 3-hydroxy-3 methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, are approved for cholesterol reduction and are commonly used to treat atherosclerosis and coronary disease. Statins may also be potent immunomodulatory agents and be beneficial in the treatment of autoimmune diseases. Statins have already been used to reduce the rejection of human heart transplants by the immune system, and there have been reports of a protective effect of injected statins in models of brain autoimmunity similar to experimental autoimmune encephalomyelitis. In vitro studies in multiple sclerosis(MS) revealed that statins reduced the expression of activation-induced adhesion molecules on T cells, modified Th1/Th2 cytokine balance, reduced matrix metalloproteinase(MMP)-9, and downregulated chemokine receptors on both B and T cells. Thus statins are effective immunomodulators in vitro that merit evaluation as treatment for MS. In vivo studies using three different animal models of MS revealed that oral atorvastatin prevented or reversed chronic and relapsing paralysis. Atorvastatin has been shown to have pleiotropic immunomodulatory effects involving both antigen presenting cells and T cell compartment. Thus, statins may be beneficial for MS, and clinical trials of the effects of statins on MS are now in progress, hopefully in a favorable way.
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PMID:[Effects of atorvastatin in multiple sclerosis]. 1296 38

Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neurological impairment. While traditionally CNS autoantigen-specific CD4(+) T cells have been considered the culprits in the initial phase of the disease, recent observations have altered this concept. It is now recognised that other T lymphocyte subclasses can initiate CNS demyelination. In addition, other cell types and molecules may play an important role in MS pathogenesis. There is overwhelming evidence that MS is a dynamic process, in which recurrent episodes of blood-brain barrier disruption and CNS inflammation play a crucial role in early disease stages, leading eventually to the largely irreversible changes of demyelination, gliosis and axonal degeneration. These observations may have important therapeutic implications. Within the last ten years, several medications have been approved for MS treatment. These agents, all of which are given parenterally, are only partially effective and are often associated with adverse effects and potential toxicities. The number and different types of medications used for MS are likely to increase in the near future, as several novel therapies are currently tested in clinical trials. 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, 'statins', are cholesterol-lowering drugs that are given orally, are safe and have biological effects independent of their cholesterol-reducing properties. Recent reports have shown that statins have anti-inflammatory and neuroprotective properties that may be beneficial in the treatment of MS. This article will outline experimental evidence that suggests potential clinical benefits of statins for MS patients.
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PMID:Statins and their potential targets in multiple sclerosis therapy. 1449 24

3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their cholesterol-reducing properties. Recent studies indicate that statins have antiinflammatory and neuroprotective properties which may be beneficial in the treatment of multiple sclerosis as well as other central nervous system (CNS) neurodegenerative diseases. This article will outline current experimental evidence that may suggest potential clinical benefits for patients with CNS autoimmune disorders. Ultimately, clinical trials will have to determine the safety and efficacy of statins in this patient population.
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PMID:The potential therapeutic role of statins in central nervous system autoimmune disorders. 1462 90

Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of autoreactive lymphocytes, and skewing of the extracellular proteinase balance, are targets for new therapies. Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was recently shown to degrade interferon beta, one of the drugs used to treat MS. Consequently, the effect of endogenously produced interferon beta or parenterally given interferon beta may be increased by gelatinase B inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and inhibition of hydroxymethyl-glutaryl-coenzyme-A reductase to lower expression of gelatinase B, may become effective treatments of MS, alone or in combination with interferon beta. This may allow interferon beta to be used at lower doses and prevent side-effects.
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PMID:Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis. 1463 80

Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.
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PMID:Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. 1578 47


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