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)

Over a century has passed since the anticoagulant properties of hirudin were identified. Our understanding of this unique and promising 65 amino acid polypeptide has grown steadily, allowing clinical experience to be gained. In acute myocardial infarction, hirudin has been associated with a higher incidence of early and sustained TIMI grade 3 flow, a higher rate of infarct-related artery patency at 18-36 hours with a decreased rate of reocclusion, and a lower incidence of in-hospital death and reinfarction as compared with heparin. hirudin has also been associated with a stable level of articoagulation and an acceptable hemorrhagic complication rate when given in carefully chosen doses. In acute coronary syndromes, the initial results indicate that hirudin can improve the resolution of coronary thrombus and reduce the incidence of recurrent ischemic events. Similarly impressive reductions in thrombotic complications and ischemia have been observed in the early balloon angioplasty experience. Promising results have also been seen with hirudin in preventing deep venous thrombosis following orthopedic surgery. The favorable effects of hirudin as compared with heparin in phase II clinical trials have prompted further investigation in two large phase III trials, TIMI 9 and GUSTO 2. It is hoped that these initial results can be confirmed and that hirudin can be proved to be a safe and effective treatment for thrombotic syndromes of the venous and arterial circulatory systems.
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PMID:Hirudin: Its Biology and Clinical Use. 1060 6

The present symposium during Brain 99 was convened to explore the current aspects of the neural (extrinsic and intrinsic) and chemical control of the microvasculature in the brain with specific relevance to stimuli and rapid flow responses. N. Suzuki demonstrated the presence of neurokinin-1 receptors along the axons of vasoactive intestinal polypeptide-containing cerebrovascular parasympathetic nerves. Since the receptors were activated by substance P, calcitonin gene-related peptide and neurokinin released from coexisting sensory nerve fibers, the parasympathetic (vasodilating) fibers could effect rapid local flow increases. N. Suzuki, however, considered this as part of an elaborate defensive network protecting the brain from invasions by noxious substances. E. Hamel discussed the responses of the microvessels to neurotransmitters and suggested that nitric oxide (NO) released from intrinsic neurons may serve as a relay in the flow activation responses by intracerebral cholinergic fibers originating in the basal forebrain nuclei. D. Busija summarized a vasodilating system of activated N-methyl-D-asparate receptors located on neurons involving Ca influx-NO production, and activated ATP-sensitive potassium channels located in the vascular system. According to Busija, such interactions were disrupted during hypoxia and ischemia due to cyclooxygenase-derived superoxide anion. M. Lauritzen observed a 10 times larger increase in blood flow on stimulation of the climbing nerve as compared with that following the parallel nerve stimulation. The former transmitters are considered by him to be NO and K, and the latter NO and adenosine. Each speaker singled out NO as a common mediator for the microvasculature in the rapid local flow increases.
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PMID:Regulation of cerebral microcirculation--update. 1075 Mar 78

Basic fibroblast growth factor (bFGF) is a polypeptide with potent survival-promoting and protective effects on brain cells. In previous studies, we showed that intravenous administration of bFGF reduced infarct volume in models of focal cerebral ischemia in rats, mice, and cats. In these previous studies, infarct volume was measured within 1-7days of the onset of ischemia. The current study was undertaken to determine whether the reduction in infarct volume by bFGF was persistent beyond the first week after stroke. Mature male Sprague-Dawley rats received an intravenous infusion of bFGF (50 microg/kg per h) or vehicle during 0.5-3.5h after permanent proximal middle cerebral artery occlusion. We found a 27% reduction in infarct volume in bFGF- compared to vehicle-treated animals at three months after infarction (P<0.05). The data show that intravenous bFGF treatment produces a persistent reduction in infarct volume, at least up to three months following focal stroke.
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PMID:Intravenous basic fibroblast growth factor produces a persistent reduction in infarct volume following permanent focal ischemia in rats. 1117 28

The present study investigated the effects of the herbal medicine Dai-kenchu-to (DKCT) and its 4 individual ingredients on intestinal blood flow (IBF) in rats by laser Doppler flowmetry. Intraduodenal administration of DKCT (30, 100 and 300 mg/kg) increased IBF in a dose-dependent manner, whereas the mean arterial blood pressure was not affected. One of the ingredients in DKCT is dried ginger rhizome (150 mg/kg), whose main component is [6]-shogaol (2 mg/kg), both of which showed similar effects to those shown by DKCT, while the other ingredients in DKCT only slightly increased IBF or had no effect. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP (8-37), completely abolished the hyperemia induced by DKCT, dried ginger rhizome and [6]-shogaol. However, the vasoactive intestinal polypeptide (VIP) receptor antagonist, [4-Cl-DPhe6, Leul7]-VIP, and atropine were less inhibitory than CGRP (8-37), and the substance P (SP) receptor antagonist, spantide, had no effect. The present study demonstrated that DKCT and one of its active components, [6]-shogaol, produced an increase in IBF which was mainly mediated by CGRP and suggests that DKCT may be useful in the treatment of intestinal ischemia-related diseases.
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PMID:The herbal medicine Dai-kenchu-to and one of its active components [6]-shogaol increase intestinal blood flow in rats. 1214 98

Ischemic injury to the kidney, a major cause of acute renal failure, leads to the detachment and loss of numerous tubular epithelial cells. Integrin-laminin interactions may promote regeneration of the damaged epithelium by influencing kidney epithelial cell adhesion and differentiation. Laminins are major structural components of basement membranes. Of the various laminin isoforms, laminin-5 is of particular interest because of its proposed role in the healing of skin wounds. In this study, we investigate the expression of laminin-5 in rat kidney after unilateral ischemia. Using a polyclonal antibody generated against laminin-5, we find that immunostaining is confined to the basement membranes of collecting ducts in the papilla and the major and minor calyces in normal kidney. With injury and regeneration, however, immunostaining becomes much more intense and widespread in basement membranes along the nephron. Immunoblotting of ischemic kidney extracts reveals significantly increased expression of a polypeptide of approximately 220 kDa, possibly corresponding to a precursor of one of the three laminin-5 chains. Immunoblotting and immunostaining also demonstrate significantly increased expression and altered localization of the alpha(3)-integrin subunit, a receptor for laminin-5. These results indicate that there is induction of a laminin isoform, possibly laminin-5, and alpha(3)beta(1)-integrin in the ischemic kidney and may implicate this receptor-ligand combination in the pathogenesis of acute renal failure and/or repair of the injured kidney epithelium.
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PMID:Induction of a laminin isoform and alpha(3)beta(1)-integrin in renal ischemic injury and repair in vivo. 1237 73

Basic fibroblast growth factor (bFGF) is a polypeptide with potent trophic and protective effects on the brain. bFGF has been reported to exert neuroprotection against a wide variety of insults, including ischemic neuronal injury. To date, animal models of focal ischemia have not been translated to efficacy in stroke clinically with respect to testing of neuroprotective agents. Because functional outcome is the measurement of efficacy for putative neuroprotective agents in the clinic, we sought to evaluate the functional consequences of bFGF administration in rats subjected to focal ischemia. In this study, we assessed the effects of bFGF on functional outcome as well as infarct size in rats subjected to severe cerebral ischemia by permanent occlusion of the middle cerebral artery (MCAO). Male Sprague-Dawley rats were subjected to permanent MCAO by the intraluminal filament technique. Two hours following occlusion, rats were infused intravenously with either bFGF, at a dose of 150 microg/kg, or vehicle alone. Functional sensorimotor impairment, which was assessed by the accelerating rotarod test, was recorded at baseline and compared to performance assessed at 24 h after MCAO. Permanent occlusion of the MCA caused marked impairment in rotarod performance in both groups. Treatment of rats with bFGF showed a significant 46% improvement in rotarod fall latency when compared with that from the animals treated with vehicle alone. The volume of cortical infarction was significantly reduced by 32% as a function of bFGF treatment. These results suggest that the delayed intravenous administration of bFGF improves sensorimotor function as well as reduces infarct size following permanent focal ischemia in rat.
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PMID:Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat. 1242 98

Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2-mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In the early expression, FGF-2 directly stimulated HGF mRNA without the requirement of new protein synthesis, whereas sustained induction of HGF in the later phase was partly mediated by platelet-derived growth factor-AA. Furthermore, in vivo overexpression of FGF-2 significantly improved the blood perfusion, and the effect was abolished by systemic blockade of HGF in ischemic limbs. This is the first demonstration of a regulational mechanism of HGF expression via FGF-2 that was independent of the presence of hypoxia. The harmonized therapeutic effects of FGF-2, accompanied with the activity of endogenous HGF, may provide a beneficial effect for the treatment of limb ischemia.
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PMID:Fibroblast growth factor-2 gene transfer can stimulate hepatocyte growth factor expression irrespective of hypoxia-mediated downregulation in ischemic limbs. 1243 37

IGF-I and IGF-II are single-chain polypeptide growth factors that regulate pleiotropic cellular responses. We have characterized the effect of recombinant IGF proteins, as well as third-generation adenoviral vectors encoding either IGF-I or IGF-II genes, on cardiomyocyte apoptosis and on angiogenesis. We found that endothelial cells cultured in the presence of the extracellular protein laminin exhibit a robust response to IGF-I and -II proteins via enhanced cell migration and angiogenic outgrowth. Furthermore, IGF vectors greatly enhanced neovascularization in an in vivo Matrigel model. Transduction of cardiomyocytes with the IGF adenoviral vectors resulted in a dose- and time-dependent increase in the expression of IGF-I or IGF-II protein. This correlated with abrogation of apoptosis induced by ischemia-reoxygenation, ceramide, or heat shock with optimal inhibition of approximately 80%. We conclude that gene transfer of IGF-I and IGF-II is a plausible strategy for the local delivery of IGFs to treat ischemic heart disease and heart failure by stimulating angiogenesis and protecting cardiomyocytes from cell death.
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PMID:Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization. 1250 77

Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARF. Seven genes that are upregulated >10-fold were identified, one of which (Cyr61) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that co-localized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARF. The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within 1 h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatin-induced nephrotoxicity, again preceding the appearance of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury.
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PMID:Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. 1451 31

Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has been investigated as a potential neuroprotective drug for the treatment of stroke and other forms of neural damage. Preclinical studies over the last decade have demonstrated that IGF-I and some of its fragments can protect against neuronal and glial cell degeneration in animal models of stroke such as hypoxia-ischemia. Although the results to date are encouraging, the size of the IGF-I molecule has proved problematic and has led researchers to investigate routes of administration that bypass the blood-brain barrier, such as intranasal application, or to focus on fragments of IGF-I, such as the N-terminal peptide Gly-Pro-Glut (GPE). While the results of these studies have also been positive, systematic dose-response comparisons with recognized neuroprotectants have not yet been published, the time window for therapeutic effects is not yet clear and long-term functional studies have not been conducted.
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PMID:Neuroprotection against hypoxia-ischemia by insulin-like growth factor-I (IGF-I). 1466 28


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