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)

We tested the hypothesis that intravenous infusion of human marrow stromal cells (hMSC) with a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate), enhances angiogenesis, neurogenesis and neurological functional recovery after stroke in rats compared to individual therapy. Experimental groups consist of rats subjected to 2 h of middle cerebral artery occlusion (MCAo) and at 24 h after MCAo intravenous injection of (n=10/group): Group 1: phosphate buffered saline (PBS 1 ml) for control. Group 2: NONOate alone (0.4 mg/kg). Group 3: hMSCs (1 x 10(6)) alone. Group 4: hMSCs (1 x 10(6)) with NONOate (0.4 mg/kg). Functional tests and immunohistochemical staining were performed. Marginal functional recovery after treatment of stroke was found with 1 x 10(6) hMSCs alone (p=0.06) and no benefit was detected with NONOate alone (0.4 mg/kg, p=0.64). However, NONOate+hMSCs in combination significantly induced functional recovery (p<0.05). Treatment using hMSC in combination with NONOate significantly increased vessel perimeter and endothelial cell proliferation compared with hMSC or NONOate alone treatment (p<0.05). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Combination treatment promoted increased, BrdU positive cell number in the subventricular zone (SVZ), migrating neuronal doublecortin immunoreactive cells and VEGF and bFGF expression in the ischemic boundary area compared to individual treatment. The functional therapeutic enhancement of combination treatment may be attributed to increased plasticity induced by the combination of a nitric oxide donor and hMSC therapy. These data suggest that pharmacological and cellular therapy may provide an additive therapeutic benefit after stroke.
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PMID:Combination therapy of stroke in rats with a nitric oxide donor and human bone marrow stromal cells enhances angiogenesis and neurogenesis. 1504 60

Inflammatory-activated glia are seen in numerous central nervous system (CNS) pathologies and can kill nearby neurons through the release of cytotoxic mediators. Glia, when activated, can express the inducible isoform of nitric oxide synthase (iNOS) producing high levels of nitric oxide (NO), which can kill neurons in certain conditions. We show, however, that inflammatory activation of glia in a mature culture of cerebellar granule neurons and glia causes little or no neuronal death under normal (21%) oxygen conditions. Similarly, hypoxia (2% oxygen) or low levels of an NO donor (100 microM DETA/NO) caused little or no neuronal death in nonactivated cultures. If inflammatory activation of glia or addition of NO donor was combined with hypoxia, however, extensive neuronal death occurred. Death in both cases was prevented by the N-methyl-D-aspartate (NMDA) receptor blocker MK-801, implying that death was mediated by the glutamate receptor. Low levels of NO were found to increase the apparent K(M) of cellular oxygen consumption for oxygen, probably due to NO-induced inhibition of mitochondrial respiration, in competition with oxygen, at cytochrome oxidase. Necrotic death, induced by hypoxia plus DETA/NO, was increased further by deoxyglucose, an inhibitor of glycolysis, suggesting that necrosis was mediated by energy depletion. Hypoxia was found to be a potent stimulator of microglia proliferation, but this proliferation was not significant in inflammatory-activated cultures. These results suggest that low levels of NO can induce neuronal death under hypoxic conditions, mediated by glutamate after NO inhibition of respiration in competition with oxygen. Brain inflammation can thus sensitize to hypoxia-induced death, which may be important in pathologies such as stroke, neurodegeneration, and brain aging.
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PMID:Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. 1555 52

Reactive nitrogen and oxygen species (O2*-, H2O2, NO* and ONOO-) have been strongly implicated in the pathophysiology of neurodegenerative and mitochondrial diseases. In the present study, we examined the effects of nitrosative and/or nitrative stress generated by DETA-NO {(Z)-1-[2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate}, SIN-1 (3-morpholinosydnonimine hydrochloride) and SNP (sodium nitroprusside) on U87MG glioblastoma cybrids carrying wt (wild-type) and mutant [A3243G (Ala3243-->Gly)] mtDNA (mitochondrial genome) from a patient suffering from MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The mutant cybrids had reduced activity of cytochrome c oxidase, significantly lower ATP level and decreased mitochondrial membrane potential. However, endogenous levels of reactive oxygen species were very similar in all cybrids regardless of whether they carried the mtDNA defects or not. Furthermore, the cybrids were insensitive to the nitrosative and/or nitrative stress produced by either DETA-NO or SIN-1 alone. Cytotoxicity, however, was observed in response to SNP treatment and a combination of SIN-1 and glucose-deprivation. The mutant cybrids were significantly more sensitive to these insults compared with the wt controls. Ultrastructural examination of dying cells revealed several characteristic features of autophagic cell death. We concluded that nitrosative and/or nitrative stress alone were insufficient to trigger cytotoxicity in these cells, but cell death was observed with a combination of metabolic and nitrative stress. The vulnerability of the cybrids to these types of injury correlated with the cellular energy status, which were compromised by the MELAS mutation.
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PMID:Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation. 1596 53

Chunghyuldan (CHD), a combinatorial drug that has antihyperlipidemic and anti-inflammatory activities, has been shown to improve arterial stiffness and inhibit stroke recurrence in clinical study. To understand the molecular basis of CHD's clinical effects, we explored its effect on cell proliferation and expression of nitric oxide synthase (NOS) and vascular cell adhesion molecule (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Cell number counting and [3H]thymidine incorporation assay demonstrated that nontoxic doses of CHD have an inhibitory effect on DNA synthesis and suppress cell cycle progression of HUVECs. CHD treatment led to a marked induction of NO production through up-regulation of NOS mRNA expression in a dose- and time-dependent manner, whereas it suppressed VCAM-1 expression. CHD inhibition of VCAM-1 expression was totally blocked by pretreatment with the NO synthesis inhibitor L-NMMA, whereas pretreatment with the NO donor DETA-NO further decreased VCAM-1 level in CHD-treated HUVECs, indicating that VCAM-1 regulation by CHD is mediated through increased NO synthesis by CHD. In addition, TNF-alpha-mediated VCAM-1 activation was substantially impeded by CHD treatment. Collectively, our data suggest that anti-inflammatory or anti-hyperlipidemic effects of CHD might be associated with its ability to activate NO production and suppress VCAM-1 expression in human endothelial cells.
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PMID:Chunghyuldan activates NOS mRNA expression and suppresses VCAM-1 mRNA expression in human endothelial cells. 1646 9

Adverse neurologic outcomes after cardiac surgery can have devastating consequences, among them increased mortality risk and, among survivors, loss of independence and a diminished quality of life. They also represent a burden on the health-care system, requiring prolonged hospitalizations and additional aftercare and, therefore, greater costs. Adverse outcomes are classified by their severity. Frank stroke is the most serious. This complication is associated with patient age; however, the presence of significant ascending aortic disease represents the greatest hazard. Multivariable analysis also indicates that prior neurologic events, diabetes, chronic obstructive pulmonary disease, preoperative status, and diffuse vascular disease are predictive. The second type of adverse cerebral outcome includes neurocognitive abnormalities such as memory loss and diminished emotional health. The strongest predictors of these abnormalities are hypertension and a history of alcohol use, as well as age. These predictive factors have been incorporated into the Multicenter Study of Perioperative Ischemia stroke-risk index, which clinicians can use to better assess the risk of adverse neurologic events. Clinical research examining the relationship between the predictive variables for neurologic adverse events and cerebral blood flow has suggested some surgical strategies for minimizing risk, such as limiting manipulation of the ascending aorta. The benefits of strategies such as using low or high mean arterial pressures and manipulating pump flow remain unclear. Off-pump coronary bypass surgery has been proposed as a means of reducing neurologic risk, but its effectiveness is unproved in this area. One pharmacologic strategy, the administration of aprotinin, has been shown to reduce the incidence of stroke in high-risk patients.
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PMID:Predicting and preventing adverse neurologic outcomes with cardiac surgery. 1649 92

Off-pump beating heart coronary revascularization is a valuable surgical technique for high-risk patients, particularly those with severe atherosclerotic changes of the aorta, COPD, recent stroke, or for those in whom blood administration is contraindicated. Advances in clampless surgical techniques should further the benefit of OPCAB versus conventional CABG mostly in terms of stroke risk reduction. For now, routine use of OPCAB for all surgical revascularization procedures remains in question.
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PMID:Beating heart surgery. 1651 2

Neurogenesis may contribute to functional recovery after neural injury. Nitric oxide donors such as DETA-NONOate promote functional recovery after stroke. However, the mechanisms underlying functional improvement have not been ascertained. We therefore investigated the effects of DETA-NONOate on neural progenitor/stem cell neurospheres derived from the subventricular zone from young and retired breeder rat brain. Subventricular zone cells were dissociated from normal young adult male Wistar rats (2-3 months old) and retired breeder rats (14 months old), treated with or without DETA-NONOate. Subventricular zone neurosphere formation, proliferation, telomerase activity, and Neurogenin 1 mRNA expression were significantly decreased and glial fibrillary acidic protein expression was significantly increased in subventricular zone neurospheres from retired breeder rats compared with young rats. Treatment of neurospheres with DETA-NONOate significantly decreased neurosphere formation and telomerase activity, and promoted neuronal differentiation and neurite outgrowth concomitantly with increased N-cadherin and beta-catenin mRNA expression in both young and old neurospheres. DETA-NONOate selectively increased Neurogenin 1 and decreased glial fibrillary acidic protein mRNA expression in retired breeder neurospheres. N-cadherin significantly increased Neurogenin 1 mRNA expression in young and old neurospheres. Anti-N-cadherin reversed DETA-NONOate-induced neurosphere adhesion, neuronal differentiation, neurite outgrowth, and beta-catenin mRNA expression. Our data indicate that age has a potent effect on the characteristics of subventricular zone neurospheres; neurospheres from young rats show significantly higher formation, proliferation and telomerase activity than older neurospheres. In contrast, older neurospheres exhibit significantly increased glial differentiation than young neurospheres. DETA-NONOate promotes neuronal differentiation and neurite outgrowth in both young and older neurospheres. The molecular mechanisms associated with the DETA-NONOate modulation of neurospheres from young and older animals as well age dependent effects of neurospheres appear to be controlled by N-cadherin and beta-catenin gene expression, which subsequently regulates the neuronal differentiating factor Neurogenin expression in both young and old neural progenitor cells.
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PMID:N-cadherin mediates nitric oxide-induced neurogenesis in young and retired breeder neurospheres. 1658 Jul 82

We tested whether the nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA-NONOate), increases expression of Angiopoietin (Ang1)/Tie2, which may play a role in regulating angiogenesis and vascular integrity after stroke in rats. Wistar rats were subjected to middle cerebral artery occlusion and treated with or without DETA-NONOate. Stroke rats treated with DETA-NONOate show significantly increased Ang1, Tie2 and Occludin expression in the ischemic border compared with control stroke animals (p < 0.05). Consistent with in vivo data, DETA-NONOate promotes capillary tube formation in cultured brain endothelial cells. Neutralizing Ang1 antibody attenuates DETA-NONOate-induced capillary tube formation. The data suggest that the Ang1/Tie2 axis promotes DETA-NONOate-induced angiogenesis and stabilizes of angiogenic vessels after stroke.
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PMID:Nitric oxide regulates Angiopoietin1/Tie2 expression after stroke. 1676 1

Off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) is a useful technique of coronary revascularization in terms of reduction of operative mortality and morbidity. Because the biggest advantage of OPCAB may be that it can prevent perioperative stroke, we selected patients for OPCAB based on the preoperative evaluation of neck and intracranial vessels. We could totally eliminate intraoperative stroke in patients undergoing OPCAB, although some patients with a severe neck vessel disease developed postoperative stroke/transient ischemic attack in an early postoperative period (the 4th approximately 8th postoperative day) mostly due to thrombosis from the diseased vessel. Therefore, high-risk patients with a severe neck vessel disease should be treated with a more aggressive anticoagulation protocol postoperatively. As for the quality of grafting, the number of graft, the rate of complete revascularization, and early graft patency were comparable between OPCAB and CABG with a cardiopulmonary bypass. The long-term results in terms of freedom from cardiac death and cardiac events were also comparable. We conclude that we could achieve less invasiveness in coronary revascularization by using an OPCAB technique without compromising the quality of grafting.
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PMID:[Off-pump coronary artery bypass via median sternotomy]. 1691 May 2

Off-pump coronary artery bypass surgery is a well established surgical option for patients candidate to coronary artery bypass. Current evidence suggests that there are no differences between off-pump and on-pump coronary surgery in terms of major perioperative outcomes such as perioperative mortality, myocardial infarction, stroke, and renal failure, whereas off-pump coronary surgery seems to reduce some minor complications like atrial fibrillation, transfusion requirements, and postoperative hospital stay. However, some recent papers suggest that graft patency may be lower for grafts performed with the off-pump technique. In this paper we review current knowledge about pros and cons of off-pump and on-pump coronary bypass surgery.
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PMID:[Off-pump coronary bypass surgery: pros and cons]. 1717 96


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