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)

Evidence of epidemiological associations of vitamins and disease states have been found for nine vitamins. In observational studies, people with a high intake of antioxidant vitamins by regular diet or as food supplements generally have a lower risk of major chronic disease, such as myocardial infarction or stroke, than people who are low consumers of antioxidant vitamins. Prospectively, folate appears to reduce the incidence of neural tube defects. Vitamin D is associated with a decreased occurrence of fractures when taken with calcium. Zinc, betacarotene, and vitamin E appear to slow the progression of macular degeneration, but do not reduce the incidence. Vitamin E and lycopene may decrease the risk of prostate cancer. In other randomized controlled trials, the apparent beneficial results of a high intake of antioxidant vitamins seen in observational studies have not been confirmed. There is increasing concern from these trials that pharmacological supplementation of vitamins may be associated with a higher mortality risk.
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PMID:Vitamins in aging, health, and longevity. 1804 60

Matrix metalloproteinases (MMPs) comprise a family of zinc endopeptidases that play major roles in the physiology and pathology of the mammalian central nervous system (CNS). These proteinases are evolutionarily conserved as modulators of extracellular matrix during CNS development. After acute tissue injury such as that which occurs after stroke, MMPs become dysregulated and subsequently mediate acute neurovascular disruption and parenchymal destruction. Data from gene knockout models and pharmacologic experiments suggest that MMPs may be attractive therapeutic targets for stroke. However, emerging data now also suggest that some aspects of MMP activity during the delayed neuroinflammatory response may contribute to remodelling and stroke recovery. Ultimately, a more nuanced approach to modifying the MMP response after stroke may be needed in order to optimize inhibition during acute stages of injury without interfering with beneficial endogenous mechanisms of neurovascular remodelling.
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PMID:Multiphasic roles for matrix metalloproteinases after stroke. 1822 83

Stroke triggers a local and systemic inflammatory response leading to the production of cytokines that can influence blood vessel reactivity. In this study, we aimed to assess whether cerebral ischemia/reperfusion could affect vasoconstriction and vasodilatation on mesenteric resistance arteries (MRA) from Wistar Kyoto rats. The right middle cerebral artery was occluded (90 min) and reperfused (24 h). Sham-operated animals were used as controls. Plasma levels of interleukin (IL)-6 and IL-1beta were measured at 24 h. Vasoconstrictor and vasodilator responses were recorded in a wire myograph. Protein expression was determined by Western blot and immunofluorescence, and superoxide anion (O(2)(.)) production was evaluated by ethidium fluorescence. In MRA, ischemia/reperfusion increased plasma levels of IL-6, O2. production, protein expression of cyclooxygenase-2, and protein tyrosine nitrosylation, but it impaired acetylcholine (ACh) vasodilatation without modifying the vasodilatations to sodium nitroprusside or the contractions to phenylephrine and KCl. Superoxide dismutase (SOD) and indomethacin reversed the impairment of ACh relaxation induced by ischemia/reperfusion. However, N(omega)-nitro-l-arginine methyl ester affected similarly ACh-induced vasodilatations in MRA of ischemic and sham-operated rats. Protein expression of endothelial and inducible nitric-oxide synthase, copper/zinc SOD, manganese SOD, and extracellular SOD was similar in both groups of rats. Our results show MRA endothelial dysfunction 24 h after brain ischemia/reperfusion. Excessive production of O2. in MRA mediates endothelial dysfunction, and the increase in plasma cytokine levels after brain ischemia/reperfusion might be involved in this effect.
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PMID:Endothelial dysfunction in rat mesenteric resistance artery after transient middle cerebral artery occlusion. 1825 83

Alfimeprase, a fibrolase derivative with thrombolytic activity produced by recombinant DNA technology, was discovered by Amgen and was in development with Nuvelo for the treatment of stroke and catheter occlusion. However, development has been discontinued. Fibrolase is a zinc-containing metalloendopeptidase that was first isolated from the venom of the Southern copperhead snake, Agkistrodon contortrix contortrix. Alfimeprase directly degrades fibrin to break down clots. Alfimeprase is infused directly into the thrombus (side-hole catheter pushed through the entire clot) via multiple manual pulsed infusions. Alfimeprase degrades fibrin directly and entrapped blood cells are freed. Excess alfimeprase is rapidly inactivated by alpha-2 macroglobulin through an irreversible, covalent interaction. Phase III development of alfimeprase for peripheral arterial occlusion was discontinued based on poor results from the NAPA-2 and SONOMA-2 trials; however, Nuvelo resumed development of alfimeprase in 2007 for stroke and catheter occlusion.Alfimeprase's thrombolytic activity appears to be localized to the site of delivery because it is rapidly inactivated by alpha-2 macroglobulin, a naturally occurring protein in the blood, as it moves away from the site of delivery and into general blood circulation. In January 2002, Amgen and Hyseq Pharmaceuticals (now Nuvelo) entered into a collaboration to develop and commercialize alfimeprase. Nuvelo is to develop the product through clinical trials and Amgen was to be responsible for its manufacture. Both companies were to participate in commercial activities; Amgen was to have the option to lead these. Full financial terms were not disclosed. Further to this agreement, in November 2004 Amgen granted Nuvelo worldwide rights to develop and commercialize alfimeprase in exchange for milestone and royalty payments. In August 2007, Nuvelo decided to focus on core development programmes that it believed would produce the nearest-term proof-of-concept data. As a result of this realignment of organizational expenses, Nuvelo decided to continue to pursue the development of alfimeprase. In February 2003, Hyseq Pharmaceuticals merged with Variagenics Inc. to form Nuvelo Inc. In January 2006, Nuvelo and Bayer HealthCare entered a collaboration to develop and commercialize alfimeprase. Bayer was to commercialize the drug in all territories outside the US, whilst Nuvelo retains full US rights. Nuvelo was to receive other territory royalties and milestone payments to a total of $US385 million. A $US50 million upfront payment will be made to Nuvelo, while Bayer was to be responsible for 40% of the commercialization cost for global development. This partnership was to also develop stroke and deep vein thrombosis therapies. Data from the SONOMA-3 trial fell short of the company's expectations and so Nuvelo has decided to discontinue further development of alfimeprase. Nuvelo previously had decided to resume development of alfimeprase for the treatment of multiple coagulation-related disorders, including acute ischaemic stroke, catheter occlusion (CO) and acute peripheral arterial occlusion.Previously, results from the NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) trial and SONOMA-2 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase) phase III trial of alfimeprase in patients with acute peripheral arterial occlusion and catheter occlusion did not meet their primary endpoints. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment with alfimeprase, whilst the SONOMA-2 trial's endpoint was the restoration of function at 15 minutes after dosing. In addition, these trials did not meet their secondary endpoints. As a result, Nuvelo and Bayer suspended enrolment in the NAPA-3 and SONOMA-3 phase III trials until additional analysis was complete; the SONOMA-3 trial was re-initiated. Nuvelo concluded that the delivery method for alfimeprase in the treatment of peripheral arterial occlusive disorders was suboptimal. The company closed the suspended NAPA-3 trial and planned to initiate preclinical studies focused on identifying optimized delivery methods in acute PAO in the second half of 2007. Data from the NAPA-2 trial suggested that efficacy could potentially be enhanced by maintaining alfimeprase longer at the site of the thrombus. Nuvelo's multinational phase III programme for peripheral arterial occlusion consisted of the NAPA-2 and NAPA-3 trials. Both trials were randomized, double-blind studies comparing 0.3 mg/kg of alfimeprase with placebo in a total of 600 patients in 100 centres. The primary endpoint of the NAPA-2 trial was the avoidance of surgery within 30 days of treatment; secondary endpoints included safety and pharmacoeconomics such as length of hospital and intensive care unit stay. Results from both trials have been presented. The phase II trial (NAPA-1) was completed in June 2004. This open-label, dose-escalation trial assessed the safety and efficacy of alfimeprase in 115 patients with acute peripheral arterial occlusion and was conducted in centres across the US, Europe and South Africa. Full data from the trial have been presented, which indicated that the 0.3 mg/kg dose appeared to be the optimal dose for investigation in phase III trials. In March 2003, Nuvelo announced the positive results of a phase I trial initiated in the US in July 2002; an IND was transferred from Amgen to Nuvelo in January 2002. In the SONOMA-2 trial, alfimeprase restored catheter function in patients with occluded catheters within 15 minutes with a p-value of 0.022. However, it did not meet the company's target product profile for commercial success with a p-value < 0.00125. Data from a phase II trial were presented at the 46th Annual Meeting of the American Society of Hematology held in December 2004. The study was closed in July 2004 with 55 patients enrolled. Initially the phase II study was to compare three doses of alfimeprase with the approved dose of alteplase in over 90 patients in the US. Nuvelo initiated the phase II CARNEROS-1 (Catheter Directed Alfimeprase for Restoration of Neurologic Function and Rapid Opening of Arteries in Stroke) study of alfimeprase in the treatment of acute ischaemic stroke in June 2007. CARNEROS-1 was a multicentre, open-label, dose-escalation study beginning with doses of 1, 5 and 10 mg of alfimeprase in 100 patients within 3-9 hours of stroke onset. The primary endpoints were recanalization (unblocking) of the occlusive lesion within 120 minutes of treatment, and symptomatic intracerebral haemorrhage. The first patient was dosed in December 2007; enrolment was taking place in the US and Canada. In the US, three patents have been issued relating to alfimeprase; US Patent Nos 6 261 820 (alfimeprase protein sequence), 6 440 414 (formulation of alfimeprase with a zinc stabilizer) and 6 455 269 (methods for localized administration of alfimeprase).
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PMID:Alfimeprase. 1845 71

It is well established that the immune potential declines with age. However, there is a great paucity of information regarding role of monocytes in elderly suffering from cerebrovascular accident. This present study was undertaken to investigate if the functions of peripheral blood mononuclear cells have any correlation to the manifestation of an age-associated cerebrovascular disorders: myocardial infraction, cerebrovascular (infract & hemorrhage). An age-associated inhibition in the production of interleukin-1 (IL-1) by monocytes was observed while the production of nitric oxide (NO) remained unaltered in the response of monocytes, obtained from normal elderly donors, to Lipopolysaccharide (LPS) treatment in vitro. Cerebrovascular pathologies were found to be associated with an augmentation of IL-1 production by monocyte, while NO production was augmented in case of CVA (hemorrhage) and MI. Trace element copper was found to be lower in the serum of patients suffering from CVA, while concentration of zinc was found to be elevated in serum compared to these trace elements in normal adults. Thus these factors are likely to play a role in the pathogenesis of age-related cerebrovascular disorders.
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PMID:Effect of immunosenescence on the induction of cardiovascular disease pathogenesis: role of peripheral blood mononuclear cells. 1856 93

Zinc dyshomeostasis in brain might be involved in the pathogenesis of brain diseases such as Alzheimer's disease and stroke. Resting neurons tightly regulate and maintain low to subnanomolar levels of intracellular free Zn2+, but mechanisms of normal Zn2+ homeostasis are poorly understood. In this study, the mechanisms of transporter-mediated Zn2+extrusion across the plasma membrane of cultured cortical neurons were studied. Changes in intracellular free Zn2+ levels were tracked in individual neurons by microfluorometry using a Zn2+ selective fluorophore, FluoZin3. Unopposed Zn2+efflux was measured by first loading cultured cortical neurons with Zn2+ then reducing extracellular Zn2+ to near zero by addition of EDTA. Studies revealed that the primary means of Zn2+ efflux in cortical neurons required both extracellular Na+ and Ca2+. The actions of either Na+ or Ca2+ on Zn2+ efflux were blunted in the absence of the other cation. Reversed Na+ gradients could induce Zn2+ uptake. The Na+ dependence of Zn2+ efflux was not affected by a small pHo shift (7.6-8);whereas an effect of Ca2+ was not observed at pHo 8. In summary, a Na+, Ca2+/Zn2+ exchanger mechanism is proposed to be the primary transport mechanism that extrudes Zn2+ when neuronal intracellular free Zn2+ levels rise.
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PMID:Mechanisms of Zn2+ efflux in cultured cortical neurons. 1880 47

High blood pressure or hypertension is a condition affecting many individuals and represents a controllable risk factor for cardiovascular diseases such as coronary heart disease and stroke. A non-pharmacological approach to manage these includes the application of food components with antihypertensive activity. Milk protein-derived peptides have been exploited as natural hypotensive agents, namely the peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), already commercialized in functional foods as a potential alternative to synthetic drugs. These bioactive peptides inhibit in vitro and in vivo the Angiotensin I-converting enzyme (ACE), a protein with an important role in blood pressure regulation. In this work, we attempted to elucidate the possible mode of interaction between the peptides and ACE, including mechanisms of binding to the cofactor Zn2+, and further contrast this with the known mode of inhibition exerted by synthetic drugs (Captopril, Enalaprilat and Lisinopril). The bioactive peptide Ala-Leu-Pro-Met-His-Ile-Arg (ALPMHIR), also known to inhibit the enzyme ACE but with a lower efficiency than VPP and IPP, was utilized in the docking studies for comparison. It was observed that the best docking poses obtained for VPP and IPP were located at the ACE catalytic site with very high resemblance to the drugs mode of interaction, including the coordination with Zn2+. As for ALPMHIR, the best docking poses were located in the narrow ACE channel outside the catalytic site, representing higher affinity energies and fewer resemblances with the interaction established by drugs.
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PMID:Studies on the molecular recognition between bioactive peptides and angiotensin-converting enzyme. 1881 84

Endothelin-converting enzyme I (ECE-1) is a mammalian type II integral membrane zinc-containing endopeptidase. ECE-1 catalyzes the final step in the biosynthesis of endothelins in a rate-limiting fashion, through post-translational conversion of the biologically inactive big endothelins. Endothelin-1 overproduction has been implicated in a heterogeneous list of diseases including systemic and pulmonary hypertension, stroke and asthma, cardiac and renal failure. Therefore, ECE-1 is a prime therapeutic target for the regulation of endothelin-1 production in vivo and there is considerable interest in selective inhibitors of this enzyme. Here, we present the crystal structure of the extracellular domain (residues 90-770) of human ECE-1 (C428S) with the generic metalloprotease inhibitor phosphoramidon determined at 2.38 A resolution. The structure is closely related to that of human NEP, providing essential information for a detailed understanding of ligand-binding, specificity determinants as well as selectivity criteria. Selective inhibitors of ECE-1s should have beneficial effects for the treatment of diseases in which an overproduction of ETs plays a pathogenic role.
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PMID:Structure of human endothelin-converting enzyme I complexed with phosphoramidon. 1899 53

The hypoxic brain damage induced by stroke is followed by an ischemia-reperfusion injury modulated by oxidative stress. Magnetoencephalographic (MEG) recording of rest and evoked cortical activities is a sensitive method to analyse functional changes following the acute ischemic damage. We aimed at investigating whether MEG signals are related to oxidative stress compounds in acute stroke. Eighteen stroke patients and 20 controls were enrolled. All subjects underwent MEG assessment to record background activity and somatosensory evoked responses (M20 and M30) of rolandic regions, neurological examination assessed by National Institute of Health Stroke Scale (NIHSS) and plasmatic measurement of copper, iron, zinc, ceruloplasmin, transferrin, total peroxides and Total Anti-Oxidant Status. Magnetic Resonance was performed to estimate the lesion site and volume. Delta power and M20 equivalent current dipole (ECD) strength in the affected hemisphere (AH) correlated with NIHSS scores (respectively, rho=.692, p=.006 and rho=-.627, p=.012) and taken together explained 67% of NIHSS variability (p=.004). Higher transferrin and lower peroxides levels correlated with better clinical status (respectively, rho=-.600, p=.014 and rho=.599, p=.011). Transferrin also correlated with AH M20 ECD strength (rho=.638 p=.014) and inversely with AH delta power (rho=-.646 p=.023) and the lesion volume, especially in cortico-subcortical stroke (p=.037). Our findings strengthen MEG reliability in honing the evaluation of neuronal damage in acute ischemic stroke also demonstrating an association between the MEG parameters most representing the clinical status and the oxidative stress compounds. Our results meet at a possible protective role of transferrin in limiting the oxidative damage in acute stroke.
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PMID:Neuronal functionality assessed by magnetoencephalography is related to oxidative stress system in acute ischemic stroke. 1901 Apr 27

The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Abeta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the 5' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.
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PMID:Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease. 1902 41


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