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)

The clinical features of 426 pituitary adenomas were retrospectively analyzed, focusing on the factors that affect the development of pituitary apoplexy. Immunohistochemical analysis was used to define the different hormone types of the tumors and the expression of various immunologic targets, including the pituitary tumor transforming gene, basic fibroblast growth factor-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and proliferating cell nuclear antigen. Of the 426 patients, 83 presented with pituitary apoplexy (19.48%). Among them, 43 patients (43/83, 51.82%) developed apoplexy in the absence of any obvious precipitating factor. Clinical manifestations included headaches (80/83, 96.38%), vision loss (69/83, 83.13%), pituitary function change (51/83, 61.45%), visual field defects (41/83, 49.39%), and nausea and vomiting (34/83, 40.96%). Male patients and patients with functional adenoma had a higher probability of developing apoplexy. Complicated immunological expression patterns were found in adenomas associated with pituitary apoplexy, with adenomas of different hormone types identified.
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PMID:Clinical features and immunohistochemical changes of pituitary apoplexy. 1904 83

Brain arteriovenous malformations cause intracranial hemorrhage. Molecular characterization of lesional tissue implicates angiogenic (vascular endothelial growth factor, ANG-2, matrix metalloproteinase-9) and inflammatory (cytokines and chemokines) pathways, but the pathogenesis remain obscure and medical therapy is lacking. Macrophage and neutrophil invasion has also been observed in the absence of prior intracranial hemorrhage. Common polymorphisms in interleukin-1beta and activin receptor-like kinase-1 are associated with arteriovenous malformation susceptibility, and polymorphisms in interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and APOE are associated with arteriovenous malformation rupture. These observations suggest that even without a complete understanding of the determinants of arteriovenous malformation development, the recent discoveries of downstream derangements in vascular function and integrity may offer potential targets for therapy development. Furthermore, biomarkers can be established for assessing intracranial hemorrhage risk. Finally, these data will aid in development of model systems for mechanistic testing by development of surrogate phenotypes (microvascular dysplasia) and/or models recapitulating the clinical syndrome of recurrent spontaneous intracranial hemorrhage.
Stroke 2009 Mar
PMID:Brain arteriovenous malformation biology relevant to hemorrhage and implication for therapeutic development. 1906 91

Intracranial aneurysm (IA) rupture is one of the leading causes of stroke in the United States and remains a major health concern today. Most aneurysms are asymptomatic with a minor percentage of rupture annually. Regardless, IA rupture has a devastatingly high mortality rate and does not have specific drugs that stabilize or prevent aneurysm rupture, though other preventive therapeutic options such as clipping and coiling of incidental aneurysms are available to clinicians. The lack of specific drugs to limit aneurysm growth and rupture is, in part, attributed to the limited knowledge on the biology of IA growth and rupture. Though inflammatory macrophages and lymphocytes infiltrate the aneurysm wall, a link between their presence and aneurysm growth with subsequent rupture is not completely understood. Given our published results that demonstrate that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), is highly expressed in human ruptured aneurysms, we hypothesize that pro-inflammatory cell types are the prime source of TNF-alpha that initiate damage to endothelium, smooth muscle cells (SMC) and internal elastic lamina (IEL). To gain insights into TNF-alpha expression in the aneurysm wall, we have examined the potential regulators of TNF-alpha and report that higher TNF-alpha expression correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium (Ca2+), and Toll like receptors (TLR) that mediate innate immunity. Moreover, the reduction of tissue inhibitor of metalloproteinase-1 (TIMP-1) expression provides insights on why higher matrix metalloproteinase (MMP) activity is noted in ruptured IA. Because TNF-alpha is known to amplify several signaling pathways leading to inflammation, apoptosis and tissue degradation, we will review the potential role of TNF-alpha in IA formation, growth and rupture. Neutralizing TNF-alpha action in the aneurysm wall may have a beneficial effect in preventing aneurysm growth by reducing inflammation and arterial remodeling.
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PMID:TNF-alpha-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture. 1906 97

Ischemic brain infarction is high among th causes of death in Japan, and the medical and social burden by severe sequela is also extremely serious. In this symposium, we show that treatment with anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by 2-hour occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Whereas HMGB1 is usually localized in nucleus, after stimulation it is secreted into extracellular space by an unknown non-classical pathway, and exhibits an inflammatory cytokine-like activity. Treatment with mAb reduced infarct size, and the accompanying neurological deficits in locomotor function were significantly improved. In addition, some biochemical markers such as permeability of the blood-brain barrier, the expression of tumor necrosis factor-alfa, inducible nitric oxide synthase and matrix metalloproteinase-9 were altered by mAb injection. These findings indicate the usefulness of HMGB1 as a novel therapeutic to target ischemic stroke.
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PMID:[Therapeutic effect of anti-nucleokine monoclonal antibody on ischemic brain infarction]. 1912 33

Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated. We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr). Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00-4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1-3: 1.83, 95%CI 1.06-3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1-3; p=0.04). Neither biomarker was associated with SCI. Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging.
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PMID:Association of matrix metalloproteinases with MRI indices of brain ischemia and aging. 1912 58

Early blood-brain barrier (BBB) disruption resulting from excessive neurovascular proteolysis by matrix metalloproteinases (MMPs) is closely associated with hemorrhagic transformation events in ischemic stroke. We have shown that normobaric hyperoxia (NBO) treatment reduces MMP-9 increase in the ischemic brain. The aim of this study was to determine whether NBO could attenuate MMP-9-mediated early BBB disruption following ischemic stroke. Rats were exposed to NBO (95% O(2)) or normoxia (30% O(2)) during 90-min middle cerebral artery occlusion, followed by 3-hour reperfusion. NBO-treated rats showed a significant reduction in Evan's blue extravasation in the ischemic hemisphere compared with normoxic rats. Topographically, Evan's blue leakage was mainly seen in the subcortical regions including the striatum, which was accompanied by increased gelatinolytic activity and reduced immunostaining for tight-junction protein, occludin. Increased gelatinolytic activities and occludin protein loss were also observed in isolated ischemic microvessels. Gel gelatin zymography identified that MMP-9 was the main enzymatic source in the cerebral microvessels. Incubation of brain slices or isolated microvessels with purified MMP-9 revealed specific degradation of occludin. Inhibition of MMP-9 by NBO or MMP-inhibitor, BB1101, significantly reduced occludin protein loss in ischemic microvessels. These results suggest that NBO attenuates early BBB disruption, and inhibition of MMP-9-mediated occludin degradation is an important mechanism for this protection.
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PMID:Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. 1918 98

We previously reported that the blood-brain barrier (BBB) function was deteriorated in vessels located in the hippocampus, but not the cerebral cortex, in 3-month-old stroke-prone spontaneously hypertensive rats (SHRSP). Recently published data suggest that matrix metalloproteinase (MMP)-2 and MMP-9 play a critical role in the BBB disruption in stroke or cerebral ischemia. In this study, we examined gene and protein expressions of MMPs in the BBB-damaged hippocampal vessels of 3-month-old SHRSP, in the cerebral cortical vessels without BBB damage of SHRSP, and in the hippocampal and cerebral cortical ones without BBB damage of 3-month-old Wistar Kyoto (WKY) rats. The expressions of MMPs were examined by real-time quantitative reverse transcriptase-PCR (RT-PCR), western blotting and immunohistochemical techniques. The gene and protein expressions of MMP-13 were significantly increased in the hippocampal samples of SHRSP compared with samples without BBB damage, such as cerebral cortical samples of SHRSP or hippocampal samples of WKY. Immunostaining of MMP-13 was seen in the cytoplasm of ED-1-positive perivascular cells in both rats and was colocalized with those of type IV collagen or osteopontin. The type IV collagen was also localized in the basement membrane. These findings indicate that the expression of MMP-13 is increased in BBB-damaged hippocampal vessels in hypertensive SHRSP compared with vessels without BBB impairment in normotensive WKY rats and may be involved in vascular remodeling.
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PMID:The expression of matrix metalloproteinase-13 is increased in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model. 1930 Apr 51

Twenty-nine patients with acute atherothrombotic ischemic stroke and 36 patients with acute Q-wave myocardial infarction have been studied. Each group has been stratified into 2 subgroups: patients of subgroups A received an ACE inhibitor perindopril in the complex therapy from the 1st day of disease. Patients of subgroups B were not assigned to this drug. Along with routine tests, the level of tumor necrosis factor-alpha and matrix metalloproteinase-9 (MMP-9) measured with ELISA using test-systems (BCM Diagnostics, USA) and reagents (R&D, England) have been determined. The administration of perindopril did not cause side-effects, including arterial hypotonia after the first dosage, in patients in the acute period of atherothrombotic ischemic stroke and myocardial infarction. Perindopril may decrease the activity of MMP-9 in these patients and produces an anticytokine effect. Some similar mechanisms of ischemic lesions of the heart and the brain and a commonness of biochemical "response" to the same medical intervention (the administration of an ACE inhibitor perindopril) in patients of both groups were found. The results support the pathogenetic validity of perindopril therapy in the secondary prevention of ischemic stroke and myocardial infarction.
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PMID:[An effect of perindopril on the level of tumor necrosis factor-alpha and matrix metalloproteinase-9 in peripheral blood in the acute period of atherothrombotic ischemic stroke and myocardial infarction]. 1942 65

Oxidative stress as well as expression and activity of matrix metalloproteinase 9 (MMP-9) are rapidly enhanced after cerebral ischemia. The magnitude of these effects is related to stroke outcome. In human stroke, the extent of oxidative stress correlates well with increased MMP-9 expression. The aim of this study was to evaluate whether treatment with the antioxidant molecule uric acid (UA) decreased the levels of MMP-9 in stroke patients treated with rtPA. The patients were part of a pilot, double-blind, randomized, vehicle-controlled study of patients with acute stroke treated with rtPA (< 3 h) and randomized to receive an intravenous infusion of UA (n = 16) or vehicle (n = 8). Total matrix metalloproteinase (tMMP)-9 and active (aMMP-9) levels were measured in serum at baseline (< 3 h), at the end of study treatment infusion (< 5.5 h), and at 48 hours. Total MMP-9 and aMMP-9 increased very early after stroke onset in patients allocated vehicle after rtPA therapy. Lower increments of aMMP-9 were associated with better outcome at 3 months. UA treatment was associated with reduced levels of aMMP-9 at T1 (p < 0.02) in multivariate models adjusted for age, NIHSS score, and baseline aMMP-9 levels. The decline of aMMP-9 attained after UA administration supports further clinical assessment of UA therapy in patients with acute stroke.
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PMID:Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study. 1944 35

The purpose of this study was to determine if decreased heart function after hypoxia followed by reoxygenation (H-R) is associated with increased degradation of cardiac myosin light chain 1 (MLC1) by matrix metalloproteinase-2 (MMP-2), and to investigate the effects of the increased level of peroxynitrite in the hearts of H-R animals on MLC1 degradation by MMP-2. Total of 12 newborn piglets were acutely instrumented to monitor cardiac function as assessed by stroke volume. Anesthetized piglets were block randomized to the normoxic group (n = 6), which received ventilation with room air for 6 h, or to the H-R group (n = 6), which received ventilation with 10-15% oxygen for 2 h, followed by reoxygenation with 100% oxygen for 1 h and then with 21% oxygen for 3 h. Hearts were removed and snap frozen for subsequent biochemical analyses. At the end of the 2-h hypoxia period, cardiac output, mean arterial pressure and stroke volume were significantly decreased in the H-R group. After 1 h of 100% oxygen, these parameters had increased slightly, but remained significantly lower than the normoxic controls throughout the reoxygenation period. Compared to normoxic animals, cardiac MLC1 levels were decreased and MMP-2 activity was increased in H-R animals. MMP-2 was co-localized with MLC1, and the amount of MLC1 associated with MMP-2 was higher in the hearts of H-R animals. In normoxic animals, cardiac MLC1 level was negatively, and cardiac MMP-2 activity was positively, strongly correlated with stroke volume index. This relationship was not seen in the H-R group. However, in both the normoxic group and the H-R group, the activity of cardiac MMP-2 was negatively correlated with the level of cardiac MLC1. There was a more than twofold increase in the level of nitrates, a marker for peroxynitrite formation, in the hearts of H-R animals. Mass spectrometric analyses detected peroxynitrite-induced nitration and S-nitrosylation of MLC1 protein in the hearts of H-R animals. These peroxynitrite-induced modifications of MLC1 were localized directly adjacent to the site at which MMP-2 cleaves MLC1. Peroxynitrite, formed during cardiac reoxygenation following a period of hypoxia, modifies the structure of cardiac MLC1 by nitrating and nitrosylating amino acids adjacent to the site where MMP-2 cleaves MLC1. This facilitates the degradation of MLC1 by MMP-2 and may contribute to cardiac dysfunction induced by H-R and other forms of oxidative stress. The high correlation between MMP-2 activity and MLC1 level in control animals suggests that MMP-2 may play an important role in regulating MLC1 turnover under normal physiological conditions. Determining the optimal parameters for controlled reoxygenation after hypoxia, together with pharmacological treatment with MMP-2 inhibitors and/or inhibitors of nitration/nitrosylation of MLC1, could reduce heart injury during the resuscitation of asphyxiated newborns and improve their long-term prognosis by reducing MLC1 degradation. Since the degradation of MLC1 by MMP-2 appears to be a common feature of oxidative stress, these pharmacological interventions may be useful in reducing tissue damage in other oxidative stress-related disorders as well.
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PMID:Cardiac dysfunction in an animal model of neonatal asphyxia is associated with increased degradation of MLC1 by MMP-2. 1945 90


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