Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cysteine is known to cause neuronal cell death and has been reported to be elevated in brain ischemia, but it has not been studied in clinical stroke. In this study, we correlated plasma levels of cyst(e)ine with long-term clinical outcome at 3 months in acute stroke. Patients were classified into 3 groups at 3 months as follows: good outcome (Rankin 0-1, n = 11), poor outcome (Rankin 2-5, n = 20), and dead (n = 5). Their plasma cyst(e)ine levels within 24 hours of stroke onset were 61 +/- 12, 67 +/- 9, and 82 +/- 14 micromol/L (standard deviation), respectively. The correlation between early plasma cyst(e)ine levels and long-term clinical outcome assessed at 3 months is significant with p < 0.001. None of the other 4 amino acids studied showed any significant correlation. Cyst(e)ine was also significantly elevated in patients who had early stroke deterioration (p < 0.02). Dose-dependent administration of cysteine increased the infarct volume by approximately 30% in a rat stroke model. This effect of cysteine was abolished by aminooxyacetic acid, an inhibitor of the enzyme cystathionine beta-synthase that converts cysteine to hydrogen sulfide (H2S), indicating that this novel neuromodulator may be acting as a mediator of ischemic brain damage. Raised plasma cyst(e)ine in patients with stroke may reflect increased production of H2S in the brain and thus predispose to poor outcome in clinical stroke. Inhibition of H2S formation may therefore be a novel approach in acute stroke therapy.
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PMID:High plasma cyst(e)ine level may indicate poor clinical outcome in patients with acute stroke: possible involvement of hydrogen sulfide. 1646 2

Inflammation is an important feature of the pathophysiological response to ischaemic stroke. The ischaemic brain-invading leukocytes, neutrophils in particular, contribute to the exacerbation of tissue injury in stroke. Chemokines are a growing family of proteins performing chemotactic activity on selective leukocyte subpopulations. Chemokines are broadly divided into two major subfamilies on the basis of the arrangement of the two N-terminal cysteine residues, CXC and CC, depending on whether the first two cysteine residues have an amino acid between them (CXC) or are adjacent (CC). CXC chemokines possessing, close to the N terminus, the amino acid sequence glutamic acid-leucine-arginine (ELR motif) specifically act on neutrophils. CXCL5 is one of the ELR-expressing CXC chemokines and is a potent neutrophil attractant and activator. The objective of the study was to detect CXCL5 levels in the cerebrospinal fluid (CSF) and sera of stroke patients and to investigate the relation between these levels and the volume of brain computed tomography (CT) hypodense areas representing early ischaemic lesions. A total of 23 ischaemic stroke patients were studied. CSF and blood sampling and brain CT were performed within the first 24 hours of stroke. The control group consisted of 15 patients with tension headache. CXCL5 levels were determined by the ELISA method. CSF CXCL5 levels in stroke patients were significantly higher in comparison with the control group (38.2 +/- 18.4 pg/ml vs. 18.7 +/- 8.2 pg/ml; p < 0.001). No significant differences in serum CXCL5 levels were found between the stroke patients and the control group. CSF CXCL5 levels correlated positively with the volume of early brain CT hypodense areas (p < 0.0001). The results suggest that CXCL5 may play a role in the inflammatory reaction during the early phase of ischaemic stroke.
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PMID:The level of chemokine CXCL5 in the cerebrospinal fluid is increased during the first 24 hours of ischaemic stroke and correlates with the size of early brain damage. 1678 27

Cysteine proteases are connected to various viral and parasitic infections, as well as to other severe diseases like arthritis, stroke and cancer. Due to its alpha,beta-unsaturated carbonyl moiety etacrynic acid, a well known diuretic, can inhibit cysteine proteases in a Michael-type reaction by reaction with the nucleophilic cysteine residue of the active site. For first structure-activity-relationship studies modifications at various positions of the etacrynic acid structure have been investigated concerning inhibition potency against the CAC1 protease papain: length of the side chain, substitution pattern of the aromatic ring as well as influence and necessity of acidic groups, esters or amides. Additionally, the effect of the aromatic ring was evaluated by replacement with a cyclohexyl moiety.
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PMID:New non-peptidic inhibitors of papain derived from etacrynic acid. 1678 93

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders, or dementia, are also frequently found in these patients. Missense mutations in the Notch3 gene that create or destroy cysteine residues, have been found in most cases with a family history of the disease, although a few sporadic cases harbouring Notch3 mutations have also been described. Here, we describe a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128-->gly. Both parents were alive and healthy, and negative for the mutation. This case illustrates the interest of analysing the Notch3 gene in cases with clinical features of CADASIL, even in the absence of a family history of the disease.
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PMID:A new de novo Notch3 mutation causing CADASIL. 1679 87

Hyperhomocysteinemia (HHcy) is associated with atherosclerosis, stroke, and dementia. Hcy causes extracellular matrix remodeling by the activation of matrix metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine proteases that are implicated in mitochondrial damage via oxidative burst. Mitochondrial abnormalities have been identified in HHcy. The mechanism of Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial pathway is largely unknown. We report a novel role of calpains in mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart microvascular endothelial cells. Our observations suggested that calpain regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the enhanced calpain activity was not mirrored by the decreased levels of its endogenous inhibitor calpastatin. We presented evidence that Hcy induces the translocation of active calpain from cytosol to mitochondria, leading to MMP-9 activation, in part, by causing intramitochondrial oxidative burst. Furthermore, studies with pharmacological inhibitors of calpain (calpeptin and calpain-1 inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal cascade. Taken together, these findings determine the novel role of mitochondrial translocation of calpain-1 in MMP-9 activation during HHcy, in part, by increasing mitochondrial oxidative stress.
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PMID:Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC. 1687 62

S-Allyl-L-cysteine (SAC), an active organosulfur compound derived from garlic, was found to reduce mortality with lesser incidence of stroke and also to lower the overall stroke-related behavioral score in stroke-prone spontaneously hypertensive (SHRSP) rats by dietary administration. Consequently, the anti-stroke effect of dietary SAC was demonstrated in SHRSP rats.
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PMID:Dietary S-allyl-L-cysteine reduces mortality with decreased incidence of stroke and behavioral changes in stroke-prone spontaneously hypertensive rats. 1692 10

Currently available therapies for brain ischemia, with a few exceptions, provide only symptomatic relief in patients. Recent investigations in experimental models provided an understanding of the cellular and molecular mechanisms that lead to neurodegeneration in ischemic injury, and also indicate targets for prevention and amelioration of the devastating consequences of stroke. An enormous increase in intracellular free Ca(2+) levels following stroke activates Ca(2+)-dependent enzymes, contributing to neuronal death and dysfunction. Additionally, ischemic injury generates highly reactive free radicals and triggers release of cytotoxic cytokines for activation of cysteine proteases. A number of studies already indicated a prominent role for the cysteine proteases of the calpain and caspase families in the pathogenesis of brain ischemia. Proteolytic activities of these proteases degrade various cytoskeletal proteins and membrane proteins, destabilizing the structural integrity and forcing the neurons to delayed death in ischemic penumbra. Some current studies have unequivocally confirmed the neuronal apoptosis in ischemia and showed that administration of calpain and caspase inhibitors alone or in combination can provide functional neuroprotection in various animal models of cerebral ischemia. This article will discuss the molecular structures and activities of calpain and caspase inhibitors and their therapeutic efficacy in experimental brain ischemia. However, further investigations are necessary for improvements in the structural design of calpain and caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trials in the future.
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PMID:Currently evaluated calpain and caspase inhibitors for neuroprotection in experimental brain ischemia. 1716 15

Under ambient air conditions, NO inhibits NMDAR activity by reacting with the NR2A subunit C399 along with two additional cysteine pairs if their disulfide bonds are reduced to free thiol groups [NR1(C744,C798); NR2(C87,C320)]. Here we demonstrate that relative hypoxia enhances S-nitrosylation of NMDARs by a unique mechanism involving an "NO-reactive oxygen sensor motif" whose determinants include C744 and C798 of the NR1 subunit. Redox reactions involving these two thiol groups sensitize other NMDAR sites to S-nitrosylation and consequent receptor inhibition, while their own nitrosylation has little effect on NMDAR activity. The crystal structure of the ligand-binding domain of NR1 reveals a flexible disulfide bond (C744-C798), which may account for its susceptibility to reduction and subsequent reaction with NO that is observed with biochemical techniques. These thiols may be nitrosylated preferentially during increasing hypoxia or stroke conditions, thus preventing excessive activity associated with cytotoxicity while avoiding blockade of physiologically active NMDARs.
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PMID:Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. 1719 30

Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy (CADASIL) is the most prominent known cause of inherited stroke and vascular dementia in human adult. The disease gene, NOTCH3, encodes a transmembrane receptor primarily expressed in arterial smooth muscle cells (SMC). Pathogenic mutations lead to an odd number of cysteine residues within the NOTCH3 extracellular domain (NOTCH3(ECD)), and are associated with progressive accumulation of NOTCH3(ECD) at the SMC plasma membrane. The murine homolog, Notch3, is dispensable for viability but required post-natally for the elaboration and maintenance of arteries. How CADASIL-associated mutations impact NOTCH3 function remains a fundamental, yet unresolved issue. Particularly, whether NOTCH3(ECD) accumulation may titrate the ligand and inhibit the normal pathway is unknown. Herein, using genetic analyses in the mouse, we assessed the functional significance of an archetypal CADASIL-associated mutation (R90C), in vivo, in brain arteries. We show that transgenic mouse lines expressing either the wild-type human NOTCH3 or the mutant R90C human NOTCH3, at comparable and physiological levels, can rescue the arterial defects of Notch3-/- mice to similar degrees. In vivo assessment of NOTCH3/RBP-Jk activity provides evidence that the mutant NOTCH3 protein exhibits normal level of activity in brain arteries. Remarkably, the mutant NOTCH3 protein remains functional and does not exhibit dominant negative interfering activity, even when NOTCH3(ECD) accumulates. Collectively, these data suggest a model that invokes novel pathogenic roles for the mutant NOTCH3 protein rather than compromised NOTCH3 function as the primary determinant of the CADASIL arteriopathy.
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PMID:The archetypal R90C CADASIL-NOTCH3 mutation retains NOTCH3 function in vivo. 1733 78

Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
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PMID:Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. 1737 2


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