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)

Eurocollins has almost been abandoned because of the glucose disadvantage. UW is certainly the most used preservation solution for livers, kidneys, and pancreases with excellent clinical and experimental preservation data. UW can certainly be considered the current golden standard solution. However, the disadvantage of high viscosity, high price, uneasy handling of many 1-L bags, and the fact that the radical scavenger glutathion cannot be detected in the bags by chemical analysis (presumably due to diffusion) encourage competitors to produce new compounds with better cost to effect ratios. HTK has a firm place in cardiac preservation; by demonstration of equal safety and efficacy in preserving livers and kidneys, at least in the middle and lower range of cold ischemia time, HTK will be sued more frequently, particularly with the consideration of lower price and more easy handling aspects. The suggested high volume perfusion is not really necessary, calculation based on a total volume of 10 L for a multiorgan donor show significant cost reductions. Celsior is current only used for cardiac preservation. Beyond all aspects of conservation and preservation potencies of all these fluids, it must not be forgotten that cold ischemia itself is a risk factor for organ function. Therefore, cold ischemia time should be kept as short as possible. People are willing to accept 24 hours or more cold ischemia time in kidney transplantation because organ failure can be treated by dialysis. In other organs, where immediate organ function is essential, like in clinical heart transplantation, cold ischemia is hardly ever extended beyond 6 hours. Why are hearts and kidneys so different? Very likely, there is no difference, and the outstanding results in living unrelated kidney transplants is mostly due to short cold ischemia time.
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PMID:Preservation solutions for transplantation. 1045 72

Neutral endopeptidase (NEP, 24.11) is an ectoenzyme involved in the degradation of peptide hormones such as endothelin (ET), atrial natriuretic factor and enkephalins. The current study was designed to assess the involvement of NEP in ischemia-induced acute renal failure (ARF). In unilaterally nephrectomized Sprague-Dawley rats, the left renal artery was occluded for 30 min under pentobarbital anesthesia (40 mg/kg, i.p.) at 37 degree C. In addition to plasma creatinine levels, NEP activity was determined in renal cortical membranes at 0, 2, 5, and 24 h following reperfusion. Plasma creatinine levels significantly increased at 2, 5 and 24 h. There was a significant decrease in NEP activity as early as 2 h following reperfusion that was maintained up to 24 h (57.9 +/- 4%) with a concomitant loss of enzyme protein shown by Western analysis. Northern analysis of kidney cortical RNA, probed with an NEP cDNA, showed a 45% decrease in NEP mRNA level by the end of the ischemic period and decreased further during reperfusion. Thus, decrease in NEP mRNA levels preceded the changes in protein level, enzyme activity and plasma creatinine levels. These data, along with the reported increase in the tissue level of ET in kidney cortex, and the beneficial effect of ET antibody as well as ET receptor antagonist in ARF, suggest that down regulation of NEP, one of the mechanisms leading to increased tissue level of ET, may be a contributing factor to ARF.
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PMID:Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure: possible mechanism for ischemia-induced acute renal failure in rats? 1048 24

The quality of organ preservation is of major importance in minimizing the incidence of primary graft nonfunction and organ rejection. For this study a new semiquantitative score was developed that grades morphologic tissue alterations in the liver according to their frequency and severity. It was applied to assess commonly used perfusion solutions for their efficacy in preventing early and late tissue damage after rat liver transplantation. For transplantation the livers were stored in Euro-Collins (EC, group I; n = 11), histidine-tryptophan-alpha-ketoglutarate (HTK, group II; n = 11), or University of Wisconsin solution (UW, group III; n = 11). Rat liver transplantation was performed with graft arterialization by the method of Engemann. Biopsies were taken for morphological examination and semiquantitative scoring during the donor operation, after 4 h of cold storage, 1 h after reperfusion, and 4 weeks postoperatively. An immunohistological bromodeoxyuridine (BrdU) assay was also performed on the day of dissection to assess the rate of hepatic proliferation. Semiquantitative morphological analysis gave widely differing results in all experimental groups after 4 h of ischemia. There was less intracellular and interstitial edema, fatty degeneration, intralobular necrosis, and hepatocellular proliferation in the HTK group than in the other groups. Neither after cold ischemia nor 1 h after reperfusion did Kupffer-cell activation occur; this is known to play a major role in the development ofischemia and reperfusion injury. Furthermore, late changes such as bile-duct proliferation and vascular and sinusoidal alterations appeared less frequently in this group. The hepato-protective powers of HTK solution might therefore be due to decreased Kupffer-cell activation.
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PMID:Organ preservation with EC, HTK, and UW, solution in orthotopic rat liver transplantation. Part II. Morphological study. 1050 Oct 78

The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]. Here we show that the MEK/ERK pathway is activated during focal cerebral ischemia and may play a role in inducing damage. Treatment of mice 30 min before ischemia with the MEK1-specific inhibitor PD98059 [Alessi, D. R., Cuenda, A., Cohen, P. , Dudley, D. T. & Saltiel, A. R. (1995) J. Biol. Chem. 270, 27489-27494] reduces focal infarct volume at 22 hr after ischemia by 55% after transient occlusion of the middle cerebral artery. This is accompanied by a reduction in phospho-ERK1/2 immunohistochemical staining. MEK1 inhibition also results in reduced brain damage 72 hr after ischemia, with focal infarct volume reduced by 36%. This study indicates that the MEK1/ERK pathway contributes to brain injury during focal cerebral ischemia and that PD98059, a MEK1-specific antagonist, is a potent neuroprotective agent.
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PMID:MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. 1053 14

Various polypeptide growth factors are generally considered to be involved in the regulation of the nephrogenic process both after acute renal injury and during renal development. Because platelet-derived growth factor B-chain (PDGF-B) has been reported to be expressed in immature tubulus of the developing kidney, PDGF-B could play a role in the process of tubulogenesis. We examined the expression of PDGF-B and PDGF receptors alpha and beta and their localization in kidneys after ischemia/reperfusion injury. The mRNA expressions of PDGF-B, PDGFR-alpha, and PDGFR-beta were enhanced after injury. In the immunohistochemical analysis and/or in situ hybridization, PDGF-B and PDGFR-alpha, beta were expressed after reperfusion in the S3 segment of the proximal tubuli, where they were not expressed normally. The expressions of proliferating cell nuclear antigen and vimentin were concomitantly observed with PDGF-B and PDGFRs in the tubular cells of injured S3 segment at 48 hours after injury. Next, the inhibition of the PDGF-B/PDGFRs axis with either Trapidil or Ki6896, which was found to inhibit the phosphorylation of PDGFR-beta selectively, resulted in a rise of serum creatinine, higher mortality rate, abnormal regenerating process, and suppressed proliferation of tubular epithelial cells. These findings suggest that the PDGF-B/PDGFRs axis is involved in the proliferation of injured tubular cells and plays an important role in the regeneration of tubular cells from acute ischemic injury.
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PMID:Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury. 1055 Mar 25

VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability. VEGF causes extravasation of plasma protein in skin bioassays and increases hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen tension triggers VEGF expression, and increased protein and mRNA levels for VEGF and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain edema, provoked in part by enhanced cerebrovascular permeability, is a major complication in central nervous system pathologies, including head trauma and stroke. The role of VEGF in this pathology has remained elusive because of the lack of a suitable experimental antagonist. We used a novel fusion protein, mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient cortical ischemia followed by reperfusion. Using high-resolution magnetic resonance imaging, we found a significant reduction in volume of the edematous tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12 weeks after treatment, measurements of the resultant infarct size revealed a significant sparing of cortical tissue. Regional cerebral blood flow was unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury, implicating VEGF in the pathogenesis of stroke and related disorders.
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PMID:VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. 1058 25

Diabetic retinopathy (DR) still remains the leading cause of blindness in the working population of Japan and western world, though therapies such as retinal photocoagulation and vitrectomy can be remarkably effective when administered at an appropriate stage in the disease process. Consequently, there is a need for further investigation of the pathogenesis of DR to develop better therapy. DR is characterized by gradually progressive alterations in the retinal microvasculature, leading to three fundamental morbidities: 1. vascular hyperpermeability, 2. vascular occlusion, and 3. neovascularization. Recent studies have revealed that hyperglycemia causes several metabolic disorders which cause DR directly or indirectly through the abnormal expression of cytokines including vascular endothelial growth factor (VEGF). In this study, we performed precise tests of the correlation between intraocular VEGF and the three fundamental changes in the diabetic retina mentioned above. Ultrastructural study of the human retina revealed that two major pathways are responsible for hyperpermeability of diabetic retinal vessels, i.e., intercellular or paracellular transport (opening of the tight junctions) and intracellular or transcellular transport (caveolae, intracytoplasmic vesicles, and fenestration). All these pathways were induced by intravitreal injection of VEGF. The major trigger of VEGF overexpression is tissue ischemia caused by vascular occlusion. However, the retinas from the eyes with background DR revealed increased expression of VEGF without apparent incidence of vascular occlusion. We have identified accumulation of advanced glycation end products (AGEs) in these retinas, and found that AGEs are a major stimulus for VEGF overexpression in background DR. Retinal vascular occlusion was caused by thrombus formation primarily in the capillary vessels. Thrombi mainly consisted of fibrin, platelets, and leucocytes in the early stage of their formation, and glial cells and macrophages were also involved in the later stage. The blood coagulation process plays an important role in fibrin formation in thrombi. The expression of tissue factor (TF), an initiator of extrinsic blood coagulation, was upregulated by VEGF in retinal vascular endothelial cells (REC). In addition, AGEs were also thrombogenic through the induction of TF expression and suppression of the expression of prostacyclin stimulating factor (PSF), which stimulate prostacyclin synthesis in vascular endothelial cells. These findings suggest that AGEs, VEGF, and TF could interact in a vicious circle because AGEs and VEGF could induce retinal vascular occlusion which results in further increase in VEGF expression. Intravitreal injection of VEGF could induce retinal neovascularization. VEGF stimulates vascular endothelial cell proliferation by binding to a specific receptor named kinase insert domain-containing receptor/fetal liver kinase (KDR/FIk-1, KDR). AGEs and basic fibroblast growth factor (bFGF) induced expression of KDR in REC, and a transcription factor Sp 1 was involved in this process. Since the expression of KDR as well as VEGF was already upregulated in the retinas with background DR, VEGF appeared to start to induce the proliferative changes long before the actual onset of proliferative DR. These findings indicated that VEGF and its receptor system plays a pivotal role all through the disease process of DR. We considered that amelioration of the activated VEGF and its receptor system could lead to the development of new therapy for DR. We have developed two novel methods to prevent retinal neovascularization by inhibiting VEGF and its receptor system. 1. An insulin sensitizing agent (troglitazone) inhibited proliferation, migration, and in vitro tube formation by REC as well as oxygen-induced retinal neovascularization in a mouse model. Thus, glycemic control by troglitazone could reduce the incidence of neovascularization in diabetic eyes. 2. (ABSTRACT TRUNCATED)
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PMID:[Cell biology of intraocular vascular diseases]. 1064 94

Alpha B Crystallin (alpha BC) is a putative effector protein of ischemic preconditioning (IPC), that is phosphorylated on Ser 45 by ERK1/2 and Ser 59 by the p38 MAPK substrate, MAPKAPK-2. Translocation and phosphorylation of alpha BC was determined in cytosolic and cytoskeletal fractions by 1D SDS-PAGE and IEF, or using Ser 45 and Ser 59 phospho-specific antibodies in: (1) control rabbit cardiomyocytes; (2) cells preconditioned by 10 min in vitro ischemia; or after pre-treatment with specific inhibitors of (3) Ser/Thr protein phosphatase 1/2A (calyculin A); (4) p38 MAPK (SB203580); or (5) ERK 1/2 (PD98059); all prior to 180 min ischemia. Ischemia induced a cytosolic to cytoskeletal translocation of alpha BC, which was similar in all the groups. Highly phosphorylated isoforms (D1/2) of alpha BC were present in cytosolic but not cytoskeletal fractions at 0 min ischemia. By 60-90 min ischemia, D1/2 isoforms had translocated to the cytoskeletal fraction. Calyculin A maintained D1/2 levels throughout prolonged ischemia. SB203580 decreased alpha BC phosphorylation. Neither PD98059 nor IPC altered alpha BC phosphorylation during prolonged ischemia. It is concluded that alpha BC phosphorylation during ischemia is regulated by p38 MAPK but not by ERK 1/2. The inability to detect a correlation between IPC protection and either alpha BC translocation or phosphorylation suggests that the proteins in the highly phosphorylated isoform bands of alpha BC quantitated in this study are not protective end effectors of classical IPC.
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PMID:Differential translocation or phosphorylation of alpha B crystallin cannot be detected in ischemically preconditioned rabbit cardiomyocytes. 1086 Jul 71

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.
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PMID:Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. 1086 8

H(2)O(2)-mediated elevation in endothelial solute permeability is associated with pathological events such as ischemia-reperfusion and inflammation. To understand how H(2)O(2) mediates increased permeability, we investigated the effects of H(2)O(2) administration on vascular endothelial barrier properties and tight junction organization and function. We report that H(2)O(2) exposure caused an increase in endothelial solute permeability in a time-dependent manner through extracellularly regulated kinase 1 and 2 (ERK1/ERK2) signal pathways. H(2)O(2) exposure caused the tight junctional protein occludin to be rearranged from endothelial cell-cell junctions. Occludin rearrangement involved redistribution of occludin on the cell surface and dissociation of occludin from ZO-1. Occludin also was heavily phosphorylated on serine residues upon H(2)O(2) administration. H(2)O(2) mediates changes in ERK1/ERK2 phosphorylation, increases endothelial solute permeability, and alters occludin localization and phosphorylation were all blocked by PD-98059, a specific mitogen-activated protein (MAP) or ERK kinase 1 inhibitor. These data strongly suggest that H(2)O(2)-mediated increased endothelial solute permeability involves the loss of endothelial tight junction integrity through increased ERK1/ERK2 activation.
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PMID:H(2)O(2)-mediated permeability: role of MAPK and occludin. 1089 13


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