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)

Sulphated glycoprotein-2, thought to be involved in programmed cell death in peripheral organs, has been detected at increased levels in brain degenerative states. In this paper we have investigated the regional and cellular expression of this protein during development of brain lesion. With this aim sulphated glycoprotein-2 mRNA levels were studied in models of ischemic (transient forebrain ischemia) or mechanical (partial mesodiencephalic hemitransection) brain injuries using in situ hybridization histochemistry. Marked increases in sulphated glycoprotein-2 mRNA were observed in lesioned brains in both models. In addition, we report a shift in the regional distribution of positive cells in both lesion models 1-7 days post-lesion. After transient forebrain ischemia, sulphated glycoprotein-2 mRNA increases were always localized in selectively vulnerable regions (caudate-putamen, hippocampal formation), showing a temporal change in the pattern of intraregional distribution from less to more lesioned parts. In the case of mechanical lesion at 1 day, increased labelling had a widespread distribution on the lesioned side and was also observed on the intact side near the midline. In contrast, at 7 days increased labelling was restricted to regions directly lesioned (either areas whose input and/or output connections were severed by the transection or areas which were directly affected by the mechanical lesion). Analysis at the cellular level revealed that at both time intervals and in both lesion models most cell bodies overlain by dense clusters of specific grains were non-neuronal cells. The distribution patterns and their change over time suggest that at least some of these cells are inflammatory and phagocytic cells. The majority of degenerating neuronal cells after ischemia did not show increased levels of sulphated glycoprotein-2 mRNA. However, seven days after hemitransection and at all time intervals after transient ischemia, some cells clearly identifiable as neurons exhibited increased sulphated glycoprotein-2 mRNA levels.
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PMID:Increases in sulphated glycoprotein-2 mRNA levels in the rat brain after transient forebrain ischemia or partial mesodiencephalic hemitransection. 847 84

The purpose of this study was to define the differences in heat shock protein (hsp)70, albumin, alpha(-1)-acid glycoprotein (AGP), and CCAAT enhancer binding proteins (C/EBP) alpha and beta mRNA between hepatic ischemia and reperfusion, and to begin to explore C/EBP protein production. These genes have been found important in the hepatic response to lipopolysaccharide and inflammation. In two experiments, Sprague-Dawley rats underwent temporary occlusion of the median and left hepatic lobe vasculature. The first experiment included a single sham-operated group and ligation of the right hepatic lobes during reperfusion. It compared 30 and 60 min ischemia to 2 h reperfusion. The second experiment included a sham-operated group for every time point, and the right hepatic lobes were not ligated during reperfusion; a 30-min ischemia group was compared to 2-, 5-, and 24-h reperfusion groups. Total RNA from the ischemic lobes was analyzed by Northern hybridization for hsp70, albumin, AGP, and C/EBPalpha and beta. C/EBPalpha and beta proteins were compared by Western blotting. Differences in experimental design played an important role in interpretation of results. hsp70 mRNA began to increase during ischemia. Albumin mRNA remained constant during ischemia and reperfusion. The ischemic hepatocyte nucleus is not quiescent and retains the ability to upregulate certain genes, e.g., hsp70. Changes in mRNA in response to hepatic ischemia/reperfusion occur rapidly. Hepatic ischemia/reperfusion does not recapitulate the classic acute phase response; albumin is not down regulated during reperfusion.
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PMID:Early gene response to hepatic ischemia reperfusion. 866 Nov 80

Many nuclear medicine procedures, originally developed more than 20 years ago, are now performed with new radiopharmaceuticals or instruments; it is therefore apposite to reappraise what we are doing and why we are doing it. The clinical utility of nuclear medicine is discussed with reference, by way of example, to gated blood pools scans and myocardial perfusion imaging; the importance of the referred population for the outcome of studies is stressed. Attention is drawn to the likelihood that the detection of ischemia would be enhanced by the administration of nitroglycerin prior to rest thallium injection. Emphasis is also placed on the increasing acceptance of dual-tracer studies. The significance of expression of p-glycoprotein by some tumors for sestamibi imaging is discussed, and advances in respect of fluorodeoxyglucose imaging are reviewed. The final section covers issues relating to the development of new procedures, such as the value of nuclear medicine in the detection and characterization of tissue oxygen levels and the possible future role of nuclear medicine in the management of sleeping and eating disorders.
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PMID:Nuclear medicine at the crossroads. 866 6

The effects of ischemia on the maturation of secretory proteins are not well understood. Among several events that occur during ischemia-reperfusion are a rapid and extensive decrease in ATP levels and an alteration of cellular oxidative state. Since the normal folding and assembly of secretory proteins are mediated by endoplasmic reticulum (ER) molecular chaperones, the function of which depends on ATP and maintenance of an appropriate redox environment, ischemia might be expected to perturb folding of secretory proteins. In this study, whole animal and cultured cell models for the epithelial ischemic state were used to examine this possibility. After acute kidney ischemia, marked increases in the mRNA levels of the ER chaperones glucose-regulated protein (grp)78/immunoglobulin-binding protein (BiP), grp94, and ER protein (ERp)72 were noted. Likewise, when cellular ATP was depleted to less than 10% of control with antimycin A, mRNA levels of BiP, ERp72, and grp94 were increased in kidney and thyroid epithelial cell culture models. Since the signal for the up-regulation of these stress proteins is believed to be the accumulation of misfolded/misassembled secretory proteins in the ER, their induction after ischemia in vivo and antimycin treatment of cultured cells suggests that maturation of secretory proteins in the ER lumen might indeed be perturbed. To analyze the effects of antimycin A on the maturation of secretory proteins, we studied the fate of thyroglobulin (Tg), a large oligomeric secretory glycoprotein, the folding and assembly of which seems to require a variety of ER chaperones. Treatment of cultured thyroid epithelial cells with antimycin A greatly inhibited ( > 90%) the secretion of Tg. Sucrose density gradient analysis revealed that in antimycin A-treated cells Tg associates into large macromolecular complexes which, by immunofluorescence, appeared to localize to the ER. Furthermore, coimmunoprecipitation studies after antimycin A treatment demonstrated that Tg stably associates with BiP, grp94, and ERp72. Together, our results suggest that a key cellular lesion in ischemia is the misfolding of secretory proteins as they transit the ER, and this leads not only to increased expression of ER chaperones but also to their stable association with and the subsequent retention of at least some misfolded secretory proteins.
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PMID:Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. 871 Sep 14

Prosaposin, a 517-amino-acid glycoprotein, not only acts as the precursor of saposin A, B, C, and D but also possesses neurotrophic activity to rescue hippocampal CA1 neurons from ischemic damage in vivo and to promote neurite extension of neuroblastoma cells in vitro. Recently, the trophic activity of prosaposin on human neuroblastoma cells has been shown to reside in the NH2-terminal hydrophilic sequence (LIDNNRTEEILY) of the human saposin C. Here we show that prosaposin, saposin C, and a peptide comprising the 18-amino-acid sequence (18-mer peptide; LSELIINNATEELLIKGL) located in the NH2-terminal hydrophilic sequence of the rat saposin C-domain promoted survival and neurite outgrowth of cultured rat hippocampal neurons in a dose-dependent manner. Moreover, infusion for 7 days of the 18-mer peptide into the lateral ventricle of gerbils, starting either 2 h before or immediately after 3 min of forebrain ischemia, protected ischemia-induced learning disability and hippocampal CA1 neuronal loss. Thus, we ascribe the in vitro and in vivo trophic actions of prosaposin on hippocampal neurons to the linear 18-mer sequence and raise the possibility that this peptide can be used as an agent for the treatment of forebrain ischemic damage.
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PMID:A hydrophilic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo. 878 53

The carbohydrate moieties of glycoprotein hormones or growth factor molecules may have a variety of effects that impact biological potency. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a 45 kD heparin-binding, endothelial cell (EC) specific mitogen with a putative N-linked glycosylation site. Recent studies have shown that VEGF/VPF may successfully augment collateral development in animal models of myocardial and hindlimb ischemia. The extent to which glycosylation of the 75 asparagine site affects the angiogenic properties of VEGF/VPF has not been studied in vivo. Specifically unaddressed to date is the concern that nonglycosylated VEGF/VPF may be less stable, and therefore characterized by a shorter half-life, reducing its utility for therapeutic angiogenesis. Accordingly, the purpose of this study was to investigate the extent to which posttranslational modification, specifically glycosylation, mofies the angiogenic properties of VEGF/VPF in vivo. Glycosylated (g+) recombinant human VEGF165 was purified from media conditioned by Chinese hamster ovary (CHO) cells. Nonglycosylated (g-) VEGF165 was expressed, purified and refolded from E. coli. The purity of both materials was assessed by silver-stained SDS/PAGE and characterized by the presence of a single amino terminal sequence as indicated by Edman degradation. Tryptic mapping by reverse-phase HPLC confirmed that the potential glycosylation site at 75 asparagine was occupied by N-linked carbohydrate for the Chinese hamster ovary-derived VEGF/VPF, but not for E. coli-derived VEGF/VPF. The mitogenic effects of Chinese hamster ovary-derived (g+) VEGF165 and E. coli-derived (g-) VEGF165 wre studied in vitro using microvascular EC. At concentrations of VEGF/VPF ranging from 10(-4) to 10(2) nM, both produced similar concentration-dependent effects on EC proliferation. For in vivo studies, (g-) (n = 8) and (g+) (n = 8) formulations of VEGF/VPF were administered to New Zealand white rabbits with unilateral hindlimb ischemia. For (g-) versus (g+) VEGF/VPF-treated groups, respectively, calf blood pressure ratio was 0.40 +/- 0.04 versus 0.37 +/- 0.04; angiographic score (of collateral vessels) was 0.37 +/- 0.04 versus 0.35 +/- 0.04; capillary density (capillaries/mm2) at necropsy was 246.9 +/- 21.5 versus 253.9 +/- 18.8; and tissue perfusion (colored microspheres) was 92.8 +/- 5.5 versus 90.30 +/- 13.47 (all p = ns). Moreover, intravascular Doppler-based analyses of resting, maximum, and endothelium-dependent flow was similar for (g-) and (g+) VEGF/VPF. These in vitro and in vivo findings establish that the potential for VEGF/VPF to stimulate therapeutic angiogenesis persists unaltered in the nonglycosylated state.
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PMID:The in vivo bioactivity of vascular endothelial growth factor/vascular permeability factor is independent of N-linked glycosylation. 878 Jan 72

The selectins are carbohydrate-binding cell adhesion molecules acting in the vascular system. They mediate the docking of leukocytes to the blood vessel wall and the rolling of these cells along the endothelial cell surface. These adhesion phenomena initiate the entry of leukocytes into sites of inflammation as well as the migration of recirculating lymphocytes into secondary lymphoid tissues. Blocking selectin function with antibodies or oligosaccharides has proven to be beneficial in various animal models of inflammation and models of ischemia/reperfusion damage. This has raised much interest in the identification of the physiological ligands of the selectins. Several glycoprotein ligands have been identified, some of which can even be selectively isolated from cellular detergent extracts using a selectin as an affinity probe. Four of these "high affinity" ligands have been cloned. The structural requirements of their interaction with the selectins is discussed.
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PMID:Ligand-specificity of the selectins. 880 82

Reperfusion of acutely ischemic skeletal muscle is associated with neutrophil activation, which may augment local injury or cause damage to distant organs. Polymorphonuclear neutrophil glycoprotein CD18 plays a role in this injury, since its blockade substantially reduces damage; however, its mechanisms of control during reperfusion are poorly understood. The purpose of this study was to investigate the importance of circulating plasma factors to CD18-dependent neutrophil function during reperfusion and to relate these to quantitative expression of CD18. Eight rabbits were subjected to hindlimb ischemia for 5 h, followed by 48 h of reperfusion. Plasma collected at seven intervals was incubated with unstimulated neutrophils from uninjured rabbits. CD18-specific neutrophil activation was evaluated by quantifying adherence to protein-coated polystyrene and by measuring oxidant production, detected by chemiluminescence after exposure to complement-opsonized zymosan. CD18 was quantified cytofluorometrically. Plasma collected at end ischemia and during early reperfusion affected no significant alterations of adhesion, oxidant production, or CD18. Late reperfusion plasma (between 8 and 48 h) significantly increased adherence and oxidant production (to 4.11 +/- 0.61 and 2.60 +/- 0.32 times the values of preischemic plasma, P < 0.006). Peak adherence, oxidant production, and CD18 expression were evoked synchronously by 24 h plasma. CD18 expression increased only at 24 h and did not increase proportional to increases in adherence and oxidant production. Control plasma (nonischemic, n = 5) elicited no significant differences of any inflammatory measure during sham ischemia or reperfusion. These results indicate that endogenous mediators may evoke a progressive systemic inflammatory response after ischemia by stimulating CD18-dependent neutrophil function in a delayed but prolonged manner.
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PMID:Plasma activation of neutrophil CD18 after skeletal muscle ischemia: a potential mechanism for late systemic injury. 892 55

Neutrophils are important in ischemia and reperfusion injury. Multiple factors may be responsible for the adhesion of granulocytes to endothelial cells. P-selectin is a carbohydrate-binding glycoprotein that is stored preformed in endothelial cells as Weibel-Palade bodies. This preformation implies a very early role of P-selectin in the leukocyte adhesion process. Previous studies of P-selectin have not quantified its expression. The purpose of this study is to quantitate the expression and time course of P-selectin in response to renal ischemia and reperfusion injury. P-selectin was measured in 34 C57BL-6 mice after 30 minutes of occlusive left renal ischemia followed by 20 minutes, 2, 5, 10, and 24 hours of reperfusion. This was also performed in control and sham laparotomy groups. P-selectin was quantified using a new double radiolabeled 125I/131I monoclonal antibody technique and reported as percent injected dose per gram of tissue. P-selectin expression peaked at 20 minutes, plateaued up to 5 hours, and fell at 10 hours. Additionally, genetically altered mice that do not express P-selectin showed no up regulation after 5 hours of reperfusion. Pathology results confirmed significant renal injury. Renal ischemia and reperfusion injury caused significant upregulation of P-selectin. Expression of P-selectin at the short reperfusion time of 20 minutes reinforces the premise that P-selectin is one of the earliest adhesion molecules expressed. This early peak is probably caused by the release of preformed P-selectin. The delineation of these mechanisms of injury may be important in understanding and preventing renal injury in transplantation, sepsis, and shock.
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PMID:Quantification of P-selectin expression after renal ischemia and reperfusion. 924 23

The acute ischemic coronary syndromes of unstable angina and non-Q-wave myocardial infarction are most commonly caused by intracoronary thrombosis at the site of ruptured atherosclerotic plaque. The main goals of therapy are the relief of ischemia and prevention of life-threatening thrombotic events. Current antithrombotic management includes heparin and aspirin, but recent insights into the pathophysiology of these syndromes have revealed that more effective management may be achieved by direct inhibition of the final common pathway to platelet aggregation--the platelet glycoprotein (GP) IIb-IIIa receptor. Earlier studies of the reversible peptide inhibitor of the GP IIb-IIIa receptor, eptifibatide (INTEGRILIN), in patients with unstable angina have demonstrated its potential in reducing acute ischemic events. The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, the largest clinical trial of any GP IIb-IIIa receptor inhibitor to date, is a recently completed phase III evaluation of eptifibatide as primary management for patients with acute coronary syndromes presenting without persistent ST-segment elevation.
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PMID:Design and methodology of the PURSUIT trial: evaluating eptifibatide for acute ischemic coronary syndromes. Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. 929 Dec 44


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