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)

Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord; Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.
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PMID:Pharmacological approaches to repair the injured spinal cord. 1662 19

A greatly expanded understanding of the biology of endogenous erythropoietin (EPO) has emerged since the early 1990s. Originally viewed as the renal hormone dedicated to erythrocyte production, it is now clear that EPO is produced locally by many other tissues in response to physical or metabolic stress. In its autocrine-paracrine roles, EPO mediates preconditioning (ischemic tolerance) and specifically limits the destructive potential of tumor necrosis factor alpha and other proinflammatory cytokines in the brain, heart, kidney, and other tissues. As local production of EPO is generally suppressed following injury, administration of exogenous EPO has been a successful therapeutic approach in preclinical and clinical studies, for example, following ischemia-reperfusion and toxin-induced renal injuries, and in human stroke. The therapeutic time window of tissue protection by EPO is typically very wide in experimental models, showing effectiveness when administered before, during, or after an insult and raising optimism for a high clinical potential. Although there is progress in understanding the signaling pathways responsible for EPO's tissue-protective actions that are similar to, but not as redundant as, those employed for erythrocyte maturation, much work remains to be carried out. Experimental observations also suggest the existence of EPO receptor (EPOR) isoforms mediating EPO's diverse biological activities and have identified a tissue-protective receptor complex consisting of the EPOR and the beta common receptor (CD131) subunit that is also employed by granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5. Successfully engineered analogues of EPO that selectively activate tissue protection without stimulating hematopoiesis confirm the concept of a tissue-protective receptor and have significant potential utility in the investigational and therapeutic arenas.
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PMID:Discovering erythropoietin's extra-hematopoietic functions: biology and clinical promise. 1673 35

Erythropoietin and its receptor, a cytokine hormone long-known for its pro-erythropoietic effect, has been found to be expressed on a variety of tissues, including the cardiovascular system. Recent experimental studies in the ischemia-reperfusion model have demonstrated that erythropoietin has a significant cardioprotective and pro-angiogenic effect. This effect is quantified by a reduction in the relative infarct and apoptosis area and improved recovery of mechanical function. Despite potentially detrimental effects, erythropoietin has been used extensively in the last decade for treatment of anemia associated with chronic renal failure, and it has been found to be a safe drug in humans. The potential role of erythropoietin in the treatment of ischemic heart disease in humans has yet to be demonstrated in preliminary clinical trials.
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PMID:[Erythropoietin as a protective agent in myocardial ischemia]. 1680 23

Hypoxia and ischemia in the brain often result in brain dysfunctions and neuronal death during both the neonatal and adult periods. Though the mechanisms contributing to brain injury secondary to hypoxia-ischemia are more clearly defined, there are still no pharmacological treatments available to reduce cell death in the ischemic brain. This review highlights the beneficial effects of hypoxia-inducible factors, such as the transcriptional factor hypoxia-inducible factor-1 and its target genes, as both cytoprotective and regenerative factors, and focuses in particular on one of the most well-known: erythropoietin. Altogether, the data presented in this review suggest that further insights into the role of hypoxia-inducible factors would help develop promising strategies to improve the outcome of hypoxia/ischemia-related brain pathologies.
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PMID:Erythropoietin, a cytoprotective and regenerative cytokine, and the hypoxic brain. 1690 42

Renal failure from ischemia contributes to morbidity and mortality. Ischemic preconditioning (IP) represents a powerful strategy for kidney protection, and recent advances in transgenic mice may help elucidate its molecular mechanisms. However, murine IP is technically challenging and experimental details significantly influence results. Thus we developed a novel model for renal IP using a hanging-weight system for isolated renal artery occlusion. In contrast to previous models, this technique eliminates the need for clamping the vascular pedicle (artery/vein). In fact, assessment of renal injury after different time periods of ischemia (10-60 min) revealed highly reproducible increases in plasma creatinine and potassium levels, while creatinine clearance, urinary flow and potassium/sodium excretion were significantly attenuated. Using different numbers of IP cycles, we found maximal protection with four cycles of 4 min of ischemia-reperfusion. In contrast, no significant renal protection was observed with IP of the vascular pedicle. To assess transcriptional responses in this model, we isolated RNA from preconditioned kidneys and found time-dependent induction of erythropoietin mRNA and plasma levels with IP. Taken together, this model provides highly reproducible renal injury and protection by IP, thus minimizing variability associated with previous techniques based on clamping of the renal pedicle. Further studies on renal ischemia/IP in mice may consider this technique.
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PMID:Use of a hanging-weight system for isolated renal artery occlusion during ischemic preconditioning in mice. 1691 63

Acute renal failure--characterized by a sudden loss of the ability of the kidneys to excrete nitrogenous waste, and to maintain electrolyte homeostasis and fluid balance--is a frequently encountered clinical problem, particularly in the intensive care unit. Unfortunately, advances in supportive interventions have done little to reduce the high mortality associated with this condition. Might erythropoietin (EPO) have utility as a therapeutic agent in acute renal failure? This hormone mediates anti-apoptotic effects in the bone marrow, facilitating maturation and differentiation of erythroid progenitors. New evidence indicates that EPO also exerts anti-apoptotic effects in the brain, heart and vasculature, which can limit the degree of organ damage. Here, we review the emerging biological role of EPO in the kidney and the pathophysiology of ischemia-reperfusion injury in an attempt to understand the therapeutic potential of EPO in acute renal failure.
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PMID:Mechanisms of disease: Cell death in acute renal failure and emerging evidence for a protective role of erythropoietin. 1693 74

Recently we found that post-infarct remodeling disrupts PI3KAkt signaling triggered by erythropoietin (EPO) but an unknown compensatory mechanism preserves EPO-induced protection against infarction in those hearts. In this study, we examined the possibility that ERK-mediated signaling is the compensatory mechanism affording protection in post-infarct remodeled hearts. Four weeks after coronary ligation in situ (post-MI group, post-MI) or a sham operation (sham group, Sham), hearts were isolated, perfused and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area size (%I/R), from which scarred infarct by coronary ligation was excluded. EPO infusion (5 U/ml) before ischemia reduced %I/R similarly in Sham and post-MI (from 62.0 +/- 5.1 to 39.4 +/- 4.8 in Sham and from 58.6 +/- 6.6 to 36.3 +/- 3.8 in post-MI). PD98059, a MEK1/2 inhibitor, abolished this EPO-induced protection in post-MI (%I/R = 60.7 +/- 4.9) but not in Sham (%I/R = 35.1 +/- 5.4). EPO induced PI3K-dependent phosphorylation of Akt in Sham but not in post-MI. EPO increased phosphorylation levels of ERK1/2 both in Sham and post-MI, but this phosphorylation was diminished by a PI3K inhibitor in Sham but not in post-MI. These results suggest that PI3K-independent activation of ERK compensates the lack of signal input from the PI3K-Akt pathway to achieve EPO-induced protection in the remodeled myocardium.
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PMID:Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. 1694 59

The hemopoietic growth factor erythropoietin (EPO) has been recognized to be a multifunctional cytokine that plays a key role in ischemic preconditioning in the brain and heart. The EPO receptor is expressed widely in the kidney, and we review the important findings from the use of EPO in experimental models of acute renal failure that show that EPO reduces tubular cell death and hence the dysfunction induced by ischemia reperfusion injury, and we explore how these observations may be translated into the clinical arena.
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PMID:Erythropoietin and acute renal failure. 1694 72

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction.
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PMID:EPO: renoprotection beyond anemia correction. 1695 90

Gene therapy with the vascular endothelial growth factor (VEGF) gene is a potential treatment for many disorders or injuries with ischemia. However, unregulated expression of VEGF may induce pathological angiogenesis, promoting tumor growth, diabetic proliferative retinopathy and rupture of atherosclerotic plaque. Therefore, the effective regulation of the gene expression is one of the requirements for the VEGF gene therapy. In this research, we evaluated the hypoxia-inducible gene expression system with the erythropoietin (Epo) enhancer and the Epo 3'-untranslated region (UTR). The luciferase plasmids were constructed with the Epo enhancer (pEpo-SV-Luc), the Epo 3'-UTR (pSV-Luc-EpoUTR) or both (pEpo-SV-Luc-EpoUTR). The polyethylenimine/plasmid complexes were transfected to 293 or A7R5 cells and the cells were incubated under normoxia or hypoxia. The results showed that the Epo enhancer or Epo 3'-UTR increased the target gene expression under hypoxia. pEpo-SV-Luc-EpoUTR showed the highest luciferase expression. The VEGF expression plasmid with the Epo enhancer and 3'-UTR was also constructed. The VEGF expression by pEpo-SV-VEGF-EpoUTR showed the highest specificity of the gene expression in the hypoxic cells. The results suggest that the VEGF plasmid with the Epo enhancer and the Epo 3'-UTR may be useful for gene therapy for ischemic diseases.
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PMID:Hypoxia-inducible gene expression system using the erythropoietin enhancer and 3'-untranslated region for the VEGF gene therapy. 1696 97


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