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)

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-gamma and TNF-alpha) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-kappaB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-gamma. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.
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PMID:Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. 1470 6

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.
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PMID:Statins as potential therapeutic agents in multiple sclerosis. 1510 50

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 L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.
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PMID:[Statins for treatment of CNS diseases. Status report from research and clinical practice]. 1544 14

Spinal cord injury (SCI) is a devastating and complex clinical condition involving proinflammatory cytokines and nitric oxide toxicity that produces a predictable pattern of progressive injury entailing neuronal loss, axonal destruction, and demyelination at the site of impact. The involvement of proinflammatory cytokines and inducible nitric oxide synthase (iNOS) in exacerbation of SCI pathology is well documented. We have reported previously the antiinflammatory properties and immunomodulatory activities of statins (3-hydroxy-3-methylglutaryl [HMG]-CoA reductase inhibitors) in the animal model of multiple sclerosis, experimental allergic encephalitis (EAE). The present study was undertaken to investigate the efficacy of atorvastatin (Lipitor; LP) treatment in attenuating SCI-induced pathology. Immunohistochemical detection and real-time PCR analysis showed increased expression of iNOS, tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) after SCI. In addition, neuronal apoptosis was detected 24 hr after injury followed by a profound increase in ED1-positive inflammatory infiltrates, glial fibrillary acidic protein (GFAP)-positive reactive astrocytes, and oligodendrocyte apoptosis by 1 week after SCI relative to control. LP treatment attenuated the SCI-induced iNOS, TNFalpha, and IL-1beta expression. LP also provided protection against SCI-induced tissue necrosis, neuronal and oligodendrocyte apoptosis, demyelination, and reactive gliosis. Furthermore, rats treated with LP scored much higher on the locomotor rating scale after SCI (19.13 +/- 0.53) than did untreated rats (9.04 +/- 1.22). This study therefore reports the beneficial effect of atorvastatin for the treatment of SCI-related pathology and disability.
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PMID:Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats. 1560 75

HMG-CoA (3-hydroxy-3-methyglutaryl coenzyme A) reductase inhibitors (statins) reduce cardiovascular morbidity and mortality. Although statins work in part via lipid modulation, several findings of statins indicate they have broader properties, including alteration of inflammatory pathways. Ex-vivo activities of statins include suppression of adhesion molecule expression, MHC class II expression, and effects on reactive oxygen and nitrogen intermediate production. Statins also modify apoptosis in smooth muscle and endothelial cells leading to altered vascular function and neovascularization. These properties offer the potential to modify the states of chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis with drugs that show minimal toxic effects in both the short and long term.
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PMID:[Immunomodulatory activities of statins]. 1567 87

Modulation of T cell response is a novel property of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors. Previously we reported the benefits of atorvastatin treatment in experimental autoimmune encephalomyelitis, the murine model of the T cell-mediated autoimmune disorder multiple sclerosis, in which a blockade of the T cell cycle by atorvastatin was attributed to an accumulation of the negative regulator p27(Kip1). We show in this report that, in line with the documented role of p27(Kip1) in T cell anergy, treatment with atorvastatin results in a deficient response to a second productive stimulus in human T cells. This effect of atorvastatin was dependent on HMG-CoA reduction and required IL-10 signaling. Importantly, atorvastatin induced an early and sustained phosphorylation of ERK1, but not ERK2, which was crucial for the induction of anergy. On the basis of the therapeutic impact of HMG-CoA reductase inhibitors, the present findings should pave the way for future therapeutic concepts related to tolerance induction in neuroinflammatory disorders such as multiple sclerosis.
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PMID:Atorvastatin induces T cell anergy via phosphorylation of ERK1. 1584 62

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by the morphological hallmarks of inflammation, demyelination and axonal loss. Until now, little attention has been paid to the contribution of mitochondrial respiratory chain enzyme activities to MS. In this study, kinetic analysis of mitochondrial respiratory chain complex I enzyme (measured as NADH-ferricyanide reductase) was performed on intact mitochondria isolated from fresh skeletal muscle in MS patients (n = 10) and control subjects (n = 11). Mitochondrial DNA common deletion and deletions were also tested in MS patients. Our findings showed that complex I activities were significantly reduced (P = 0.007) in patients compared with control. However, we could not find deletion in mtDNA of patients with MS. The presupposition of relationship between MS and mitochondrial disorders is due to predominant maternal transmission of MS in affected parent-child pairs, pathoaetiological role of respiratory chain dysfunction in multisystem disorders and important role of it in neurodegenerative disorders, a number of patients such as LHON or other mtDNA abnormality with developed neurological symptoms indistinguishable from MS and similarity of clinical symptoms in mitochondrial disorders to those of MS. This study suggested that a biochemical defect in complex I activity may be involved in pathogenesis of MS.
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PMID:Complex I deficiency in Persian multiple sclerosis patients. 1641 82

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.
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PMID:Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. 1647 65

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.
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PMID:Statins: potential new indications in inflammatory conditions. 1650 22

Nitric oxide is a diatomic gaseous molecule with unpaired electron in the molecule. Physical properties such as solubility, diffusibility and half-life decide the chemical reactivity of nitric oxide. Nitric oxide is the unstable free radical in vessels, immune system and central nervous system. The reactivity of nitric oxide under physiological and pathological conditions depends upon its concentration and site of production. Nitric oxide is thought to play a role in many pathological situations: septic shock, cardiovascular diseases, arthritis, diabetes, multiple sclerosis, asthma, and hypertension. Nitric oxide synthase is a self-sufficient flavohemoprotein capable of producing nitric oxide from L-arginine by two successive monooxygenation steps. Although the N-terminal heme domain functionally resembles cytochromes P450, no structural similarities exist between cytochrome P450 and nitric oxide synthases heme domains. The C-terminal domain of nitric oxide synthases containing flavin adenine dinucleotide and flavin mononucleotide as cofactors exhibits a high degree of sequence similarity with NADPH-cytocrome P450 reductase. The reductase domains serve as an intermediary for the transfer of electrons from NADPH for the catalytic reaction. The connecting domain between the oxygenase and the reductase domains of nitric oxide synthase isoforms binds calmodulin in the presence of calcium. The binding of calmodulin to all nitric oxide synthase isoforms is obligatory for the production of nitric oxide. At the same time, the presence of one or more phosphorylation sites in nitric oxide synthase puts them among the kinase-mediated signaling pathways. This also means that nitric oxide synthases are regulated indirectly by the events that regulate kinases. This field of research of nitric oxide synthase regulation has become one of the most actively pursued and much has been learned from basic biochemical mechanisms to physiological processes and to medical applications, but many more questions still remain to be answered.
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PMID:[Nitric oxide synthase, typical flavohemoproteins and their complicated enzymology]. 1692 79


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