Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was shown that 30-50% ethanol or 40-70% dimetilsulfoxide could efficiently induce in vitro transformation of specific monoclonal antibodies (mAbs) into non-specific polyreactive immunoglobulins (PRIG). Intravenous injection 0.4 ml of FeSO4-EDTA mixture (60 and 30 mkM respectively) could induce increase of PRIG reactivity in the blood-stream. Intramuscle injection of either 0.1 ml of 40% ethanol, or 0.1 ml of FeSO4-EDTA mixture into muscle of hind limb of C57B1 mice leads to the substantial binding of circulated immunoglobulins to the blood vessels of the muscle. The similar effect could also be induced by ischemia/reperfusion of mice hind limb. In the case of intravenous injection of specific to ovalbumin biotinilated mAbs, the subsequent intramuscle injection of 0.1 ml of 40% ethanol induces apparent transformation of these mAbs into PRIG and their binding to the blood vessels. Intramuscle injection of 0.1 ml of FeSO4-EDTA mixture induces less than ethanol though noticeable effect. The obtained data have shown that cord-blood circulating specific antibodies could be transformed into PRIG at some conditions in vivo. If so, this process might play an important role in the organism defence against infections but could, probably, facilitate the development of atherosclerosis, cardiac infarct, cerebral stroke or tumors.
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PMID:[Transformation of specific antibodies to polyreactive immunoglobulins and their binding to blood vessel walls]. 1291 52

Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia (early CaEDTA) or at 48-60 hr (late CaEDTA), but not 3-6 hr, after ischemia, afforded robust protection of CA1 neurons in approximately 50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation (and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity (but not procaspase-3 cleavage), p75NTR induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75NTR induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.
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PMID:Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death. 1552 75

Cardiac myocyte loss, regardless of insult, can trigger compensatory myocardial remodeling leading to heart failure. Identifying mediators of cardiac myocyte survival may advance clinical efforts toward myocardial preservation. Angiopoietin-1 limits ischemia-induced cardiac injury. This benefit is ascribed to angiogenesis because the receptor, tie2, is largely endothelial-specific. We propose that direct, non-tie2 interactions of angiopoietin-1 on cardiac myocytes contribute to this cardioprotection. We found that mouse C2C12 skeletal myocytes lack tie2, yet dose-dependently adhered to angiopoietin-1 and angiopoietin-2 similarly to laminin, fibronectin, vitronectin, and more than to collagen-I, -III, and -IV. Adhesion was divalent cation-mediated (Mn2+, Ca2+, not Mg2+), blocked with EDTA/EGTA, RGD-based peptides, and select integrin subunit antibodies. Similar findings were obtained with human skeletal myocytes (HSMs) and freshly isolated rat neonatal cardiac myocytes (NCMs). Furthermore, angiopoietin-1 conferred significant survival advantage exceeding that of most cell matrices, which was not fully explained by differences in cell adhesion. Angiopoietin-1 promoted survival of serum-starved C2C12, HSM, and NCM (MTT, trypan blue) and prevented taxol-induced apoptosis (caspase-3). Immobilized and soluble angiopoietin-1 phosphorylated Akt(S473) and MAPK(p42/44), (not FAK(Y397)) in C2C12 more than in endothelial cells and more than did angiopoietin-2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM Akt(S473) and MAPK(p42/44) survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vascular effects alone. Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. 1569 86

A hemorrhagic metalloproteinase has been isolated from Bothrops alternatus venom from specimens that inhabit the north-east region of Argentina. The present study aimed at evaluating the proteolytic, hemorrhagic, edematogenic and myotoxic activities of the purified metalloproteinase, in order to consider its participation on the phatophysiology of the intoxication by Bothrops alternatus venom. The hemorrhagic metalloproteinase was isolated by a combination of DEAE-Cellulose chromatography and gel filtration on Sephadex G-75. The enzyme showed a molecular mass around 55k Da, it exhibited a hemorrhagic activity with a minimal hemorrhagic dose of 1.9 microg, almost two fold minor than the whole venom (3.6 microg). The enzyme showed a weak proteolytic activity on casein (18.72 U/mg enzyme), similar to the one exhibited by the whole venom (20 U/mg venom). Besides, the ability to degrade casein could be detected by SDS-PAGE; beta-casein was the fraction that showed the higher degradation, followed by alphas(1)-casein and kappa-casein degradation. The hemorrhagic metalloproteinase rapidly hydrolysed the A alpha-chain of fibrinogen, followed by B beta-chain degradation and leaving the gamma-chain unaffected. Proteolytic activities were inhibited by EDTA whereas they were not inhibited by benzamidine and PMSF. The metalloproteinase showed several polypeptides chains after autocatalytic processing, including a chain of 28k Da, it could be the processed disintegrin-like and cysteine-rich domains. The isolated enzyme exhibited myotoxic activity with high CK levels at 6h, due to local ischemia resulting of its hemorrhagic activity, and a significant edema-inducing effect (MED=1.3 microg), corroborated both results by the histological observations of samples of gastrocnemius muscle. These findings showed that this hemorrhagic metalloproteinase, possesses high edematogenic and myotoxic activities and, in despite of exhibiting a weak proteolytic activity, it is able to degrade fibrinogen. So, this enzyme would contribute markedly to the phatophysiology of the bothropic envenomation.
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PMID:Proteolytic, edematogenic and myotoxic activities of a hemorrhagic metalloproteinase isolated from Bothrops alternatus venom. 1613 35

In 1974, Wu and Hoak described a method for determining circulating platelet aggregates. This method was modified by Grotemeyer in 1983. The platelet reactivity index (PR) is based on the ratio of platelet aggregates in blood samples obtained in different buffer solutions. Platelet aggregates are resolved when blood is sampled in EDTA-buffer, but remain fixed when EDTA-formalin-buffer is used. Generally, the PR is preferred, because in vitro manipulations of platelets are not necessary, and the results are calculated. PR values above 1.05 are suspicious for elevated platelet aggregation. PR values above 1.2 indicate pathological changes in platelet aggregation. The PR is inexpensive (4.0 euro dollars) and rapid to perform. PR values were used successfully to identify nonresponders to secondary prophylaxis with acetylsalicylic acid (ASA), that is, patients suffering from stroke (33%) and patients after cardiac ischemia (18%). Furthermore, elevated PR values correlated significantly with the incidence of arterial thromboembolic complications. The PR correlated well in our prospective study with values received from the retention test Homburg (RT-H) and the platelet function analyzer (PFA-100). The data indicate that the values of the PR seem to be highly predictive for the evaluation of the ASA therapy. However, the PR is not feasible for the determination of the ASA overdosage.
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PMID:Use of the platelet reactivity index by Grotemeyer, platelet function analyzer, and retention test Homburg to monitor therapy with antiplatelet drugs. 1614 25

The zinc ion (Zn2+) is abundant in neurons. However, excessive Zn2+ can induce neuronal cell death. This study examined the role of Zn2+ in transient retinal ischemia in adult male rats. The rats were sacrificed 4-24 h after retinal ischemia by high intra-ocular pressure, and the retinas were prepared for microscopic examination of retinal cell degeneration, and fluorescence microscopy using zinquin ethyl ester as the zinc ion-specific probe. Moreover, COX-2 expression was observed by Western blotting. In control retinas, there was a low Zn2+ concentration in the inner plexiform layer (IPL), a high Zn2+ concentration in the outer plexiform layer (OPL), and no detectable Zn2+ in either the ganglion cell layer (GCL) or the inner nuclear layer (INL). In contrast, in the retinas exposed to ischemia without the administration of the zinc ion chelators (Ca2+-EDTA and TPEN), Zn2+ deposits were found in the IPL and INL beginning 4 h after ischemia and degeneration of neurons was found in the GCL and INL. Less Zn2+ accumulation in the IPL and INL and less neuronal degeneration in the GCL and INL were found in the retinas treated with Ca2+-EDTA or TPEN before ischemia. Furthermore, the COX-2 protein levels increased 4-8 h after retinal ischemia, and chelation of zinc ion inhibited this effect. These results suggest that the accumulation of Zn2+ following an ischemic insult can cause retinal degeneration and induce abnormal COX-2 expression.
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PMID:Inhibition of cyclooxygenase-2 expression by zinc-chelator in retinal ischemia. 1658 53

This study was performed to evaluate the alterations of glomerular filtration barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by unilateral renal artery occlusion for either 20 or 60 min, followed by reperfusion during 20 or 60 min, respectively, with the contralateral kidney serving as control. Sieving coefficients (theta) were obtained by analyzing Ficoll [mol.radius (a(e)) 13-85 A] in urine and plasma after 20 and 60 min I/R. Furthermore, theta for human serum albumin (HSA) was estimated using a tissue uptake technique after 20 and 60 min of I/R, while clearance of HSA compared with that for neutralized HSA (nHSA) was assessed after 20 min of I/R only. Glomerular filtration rate (GFR) was measured by [51Cr]EDTA and inulin. I/R reduced GFR and increased theta for Ficoll molecules of a(e) >55 A and theta for albumin. theta for Ficoll vs. a(e), analysed using a two-pore model, demonstrated that, despite increases in theta, the large-pore fractional ultrafiltration coefficient (alpha(L)) was unchanged after 20 min of I/R, owing to the decline in GFR, but increased after 60 min of I/R. However, the apparent alpha(L) for albumin increased already after 20 min of I/R (P < 0.005) and the nHSA/HSA clearance ratio was slightly reduced, possibly reflecting a diminished negative charge barrier. In conclusion, after 20 min of I/R, indications of a reduced charge selectivity were noted, while after 60 min of I/R, there was mainly a reduction in size selectivity, compatible with an increased formation of large pores.
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PMID:Nature of glomerular capillary permeability changes following acute renal ischemia-reperfusion injury in rats. 1682 38

The aims of this study were to review the prevalence and outcome of all surgically treated upper and lower limb emboli presenting to one vascular unit in the last 3 years and to compare transthoracic with transesophageal echocardiography for defining the source of the embolus. All patients who underwent surgical embolectomy for acute limb ischemia from January 2001 to June 2004 were reviewed. Transthoracic and transesophageal echocardiography were carried out on a subset of consecutive unselected patients. Forty-two patients, with a mean age of 80 years, underwent surgical embolectomy from January 2001 to June 2004 (M/F 1:1.8): 27 for lower limb ischemia and 15 for upper limb ischemia. Two thirds of these patients were found to be in atrial fibrillation at presentation (n = 28), of whom less than a third were receiving anticoagulants or antiplatelet agents (n = 8). The mean hospital stay was 15 days with 36 patients (86%) being fully anticoagulated before discharge from hospital. The 30-day mortality rate was 11% (n = 3/27) with 5 patients requiring fasciotomies (12%) and 3 patients requiring an amputation of the lower limb (11%). Postoperatively, 34 patients (81%) had transthoracic echocardiography (TTE), which demonstrated a source or potential source for thrombus in 19 (56%). Fifteen patients (36%) had transesophageal echocardiography (TEE), which changed the subsequent management in 3 patients. All patients in whom TEE altered clinical management would have required this investigation if standard clinical guidelines were followed. TEE did not identify any additional patients with cardiac embolic sources that were not detected by TTE. Arterial limb emboli are still prevalent, but limb salvage and mortality rates appear to be improving. Despite clear guidelines on anticoagulation for patients in atrial fibrillation, many are not receiving appropriate treatment. Transthoracic echocardiography is a good screening tool for detecting a potential cardiac source for peripheral embolism, with transesophageal echocardiography being reserved for specific indications.
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PMID:Peripheral arterial embolism: prevalence, outcome, and the role of echocardiography in management. 1695 21

NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a highly complicated, membrane-bound enzyme. It is central to energy transduction, an important source of cellular reactive oxygen species, and its dysfunction is implicated in neurodegenerative and muscular diseases and in aging. Here, we describe the effects of Zn2+ on complex I to define whether complex I may contribute to mediating the pathological effects of zinc in states such as ischemia and to determine how Zn2+ can be used to probe the mechanism of complex I. Zn2+ inhibits complex I more strongly than Mg2+, Ca2+, Ba2+, and Mn2+ to Cu2+ or Cd2+. It does not inhibit NADH oxidation or intramolecular electron transfer, so it probably inhibits either proton transfer to bound quinone or proton translocation. Thus, zinc represents a new class of complex I inhibitor clearly distinct from the many ubiquinone site inhibitors. No evidence for increased superoxide production by zinc-inhibited complex I was detected. Zinc binding to complex I is mechanistically complicated. During catalysis, zinc binds slowly and progressively, but it binds rapidly and tightly to the resting state(s) of the enzyme. Reactivation of the inhibited enzyme upon the addition of EDTA is slow, and inhibition is only partially reversible. The IC50 value for the Zn2+ inhibition of complex I is high (10-50 microm, depending on the enzyme state); therefore, complex I is unlikely to be a major site for zinc inhibition of the electron transport chain. However, the slow response of complex I to a change in Zn2+ concentration may enhance any physiological consequences.
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PMID:The inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase) by Zn2+. 1698 Mar 8

C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.
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PMID:Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement. 1710 Nov 76


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