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)

Leukocytes have been investigated during the past decade for their roles in secondary tissue damage after ischemia/reperfusion injury. Peptide PRARIY, a synthetic fibronectin peptide, has shown an anti-adhesion effect in in vitro studies. Previous studies have demonstrated that anti-adhesion agents lead to reductions in apoptosis. The purpose of the present study was to determine whether the peptide PRARIY displays anti-inflammatory, anti-apoptotic, and neuroprotective effects following transient focal brain ischemia in rats. Twenty-six male Sprague-Dawley rats (300-350 g) were randomly divided into three groups: phosphate-buffered saline (PBS) controls, PRARI controls, and PRARIY treatments. The right middle cerebral artery was transiently occluded using a 4-0 nylon suture. One hour later, the occluder was withdrawn, and reperfusion was maintained for 48 h. Immediately after reperfusion, the peptides (20 mg/kg, dissolved in PBS) and the same volume of PBS were continuously infused through the right external carotid artery using an osmotic minipump for 24 h. Neurological deficits were examined at 3, 24, and 48 h after ischemia. Forty-eight hours after reperfusion, the rats were sacrificed for determining infarction size, leukocyte infiltration, and apoptosis in the ischemia area. Unexpectedly, PRARIY did not influence leukocyte infiltration. However, PRARIY-treated rats showed significantly functional outcome, reduction of infarction size, decrease of TUNEL positive cells, and increase of Bcl-2 (anti-apoptotic protein) positive cells in the ischemic areas when compared to the controls. These data indicate that the peptide PRARIY exerts its neuroprotective effects via supporting neural cell survival rather than anti-leukocyte recruitment following brain ischemia/reperfusion injury.
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PMID:Synthetic fibronectin peptide exerts neuroprotective effects on transient focal brain ischemia in rats. 1605 15

Ischemia is a leading cause of acute renal failure (ARF), a disease associated with high morbidity and mortality. Disruption of intercellular adhesion in the proximal tubules is linked to ARF, although the molecular mechanism(s) remains unclear. Our previous studies showed that ischemia is associated with cadherin cleavage and loss in NRK cells, putatively due to a matrix metalloproteinase (MMP) (7). In the current studies, a MMP required for E-cadherin cleavage and N-cadherin loss was identified. Chemical inhibitors against a number of soluble MMPs (1, 2, 3, 8, 9) failed to completely attenuate ischemia-induced cadherin loss. Under ischemic conditions, there was an increase in active membrane-type (MT)1-MMP but a decrease in MMP-2 protein expression. Plating cells on fibronectin protected against ischemia-induced loss of cadherins and, interestingly, no increase in active MT1-MMP levels was seen in ischemic cells on fibronectin-coated dishes. In addition, L cells stably expressing E- (LE) or N-cadherin (LN), but lacking MT1-MMP expression, were resistant to ischemia-induced cadherin loss. The role of MT1-MMP in ischemia-induced cadherin loss was confirmed by either blocking MT1-MMP activity with a neutralizing antibody or expression with shRNA constructs which protected full-length E- and N-cadherin during ischemia. Using shRNA constructs to suppress MT1-MMP expression, ischemia-induced disruption of cadherin function was ablated, and cell-cell contacts were preserved. These results demonstrate that ischemia induces increased expression of active MT1-MMP and subsequent disruption of cadherin/catenin complexes, implying that MT1-MMP plays a role in ischemia-induced ARF.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14). 1607 81

Endothelial progenitor cells (EPCs) home to sites of tissue injury and differentiate into mature endothelial cells. Their transfer feasibility has been proven in models of hindlimb ischemia and myocardial infarction. We investigated, the effect of delivery of spleen-derived EPC in a rat model of inflammatory-mediated myocardial damage. Male Lewis rats (N=25) were immunized against myosin. Healthy donor Lewis rats were sacrificed, their spleens harvested, separated on Ficoll gradient centrifugation, and grown on fibronectin coated plates with endothelial cell medium for 5 days. Ten days after myosin immunization, spleen cell derived EPC were collected, and labeled 2 x 10(7) cells per rat were injected into the femoral vein of diseased rats. Cell transplantation was repeated twice, 2 and 4 weeks after initial cell transfer. Rats with inflammatory-mediated cardiomyopathy exhibited a significant mobilization of EPC from the bone marrow to the periphery and their ability to adhere to fibronectin, mature endothelial cells and cultured cardiomyocytes was significantly reduced when compared to healthy rats. Transfer of EPC resulted in a functional improvement in cardiac performance evident by higher fractional shortening by echocardiography (a 15% increase). Histological studies exhibited reduced scar tissue and thickened ventricular walls in rats receiving EPC as compared with untreated animals. EPC transfer is effective in attenuating myocardial damage in a model of non-ischemic dilated cardiomyopathy.
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PMID:Transfer of endothelial progenitor cells improves myocardial performance in rats with dilated cardiomyopathy induced following experimental myocarditis. 1612 96

Adenosine is an extracellular nucleoside that is elevated in tissues during hypoxia and ischemia reperfusion and has been implicated in asthma and other lung disorders. There, adenosine is considered an important modulator of physiological functions and inflammation, but its effects on matrix expression and turnover during tissue remodeling are unknown. We examined the effects of adenosine on lung epithelial cells with particular attention to the expression of fibronectin, a matrix glycoprotein highly expressed in injured tissues that has been implicated in wound healing. In A549 lung epithelial cells, we found that adenosine induced expression of fibronectin mRNA and protein in a dose- and time-dependent manner and found that the stimulatory effect of adenosine was inhibited by specific adenosine receptor antagonists. Adenosine stimulation was associated with increased levels of intracellular cAMP and with phosphorylation and DNA binding of the cAMP response element binding protein (CREB), known for its ability to stimulate fibronectin gene transcription. To confirm the latter, A549 cells were transfected with a DNA construct containing the human fibronectin promoter connected to a luciferase reporter gene. Adenosine stimulated transcription of the gene, and this effect was blocked by inhibitors of protein kinase activation. Finally, we tested primary lung fibroblasts and primary alveolar epithelial type II cells and found increased fibronectin expression in response to adenosine. Overall, our observations suggest that adenosine might modulate tissue remodeling by stimulating fibronectin expression in lung epithelial cells through induction of purinergic receptor-mediated signals that target CREB phosphorylation and stimulate fibronectin gene transcription.
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PMID:Adenosine induces fibronectin expression in lung epithelial cells: implications for airway remodeling. 1618 71

Endothelial progenitor cells (EPCs) from the bone marrow play an important role in vascular response to injury and ischemia. The mediators involved in the mobilization, recruitment, proliferation and differentiation of EPCs are not fully understood. In this study, the role of coagulation factor thrombin and protease-activated receptor-1 (PAR-1) on bone marrow-derived cell proliferation and differentiation was investigated. Bone marrow cells (BMCs) were isolated from C57/BL6 mice and plated on fibronectin-coated flasks. Cell characteristics, proliferation and the expression of endothelial cell markers were determined using immunohistochemistry, thymidine uptake and fluorescence activated-cell sorting (FACS), respectively. The results show that thrombin stimulated enrichment of bone marrow cells with endothelial morphology, exhibiting acetylated-low-density lipoprotein (LDL) uptake and isolectin staining. Thrombin or PAR-1-activating peptide produced a 2- to 3-fold increase in the total number of cells as well as an increase in vascular endothelial (VE)-cadherin-positive cells. Thrombin treatment of VE-cadherin-negative cells prepared after cell sorting resulted in the generation of 3- to 4-fold higher VE-cadherin-positive cells than the untreated cultures. Increase in VE-cadherin-positive cells was inhibited by hirudin and efegatran. These results provide first evidence for a novel activity of thrombin and PAR-1 on bone marrow progenitor cell proliferation and EPC differentiation, and suggest their potential role in vascular regeneration and recanalization of thrombus.
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PMID:Thrombin and PAR-1 stimulate differentiation of bone marrow-derived endothelial progenitor cells. 1646 Apr 48

Although there are many studies of the neuropathology of the ischemic degeneration of peripheral nerves, the pathogenesis is not well-understood. The roles of several biomolecules on this process were previously reported. An adhesion molecule, fibronectin, which is applied locally (as a conduit material), is very effective in nerve recovery. This study was carried out to evaluate the roles of fibronectin, lipid peroxidation, and nitric oxide (NO) in an experimental model of peripheral nerves. Ischemia and reperfusion injury of sciatic nerves was rendered by clamping the femoral artery and vein. Rats were divided into nine groups. Ischemia and reperfusion were not applied to group 1. In group 2, only ischemia was performed, but reperfusion was not accomplished. For groups 3-9, 1, 2, and 24 h and 1, 2, 3, and 4 weeks of reperfusion were applied following 3 h of ischemia. Then NO, malondialdehyde (MDA), and fibronectin levels were observed in serum samples of rats. Colorimetric and nephelometric assays were used for determination of the levels of these parameters. In this study, all biochemical parameters were found to be increased in the ischemia groups when compared with the control group 1 (P < 0.05). A significant difference was observed between study groups with respect to MDA, NO, and fibronectin levels (P < 0.05). Also, some correlations were established between biochemical parameters in the same group, depending on the varying reperfusion time (r > 0.50). Ischemia causes some important changes in biochemical parameters, and depending on the reperfusion time, nerve injury continues for a while. In our study, we observed that serum levels of MDA decreased in the periods when NO and fibronectin simultaneously increased. Such increases may contribute to neural recovery, and there may be interactions among them.
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PMID:Roles of nitric oxide, malondialdehyde, and fibronectin in an experimental peripheral nerve ischemia-reperfusion model. 1648 93

Stroke is one of the leading causes of unnatural death and disability. No effective therapy is available. Recombinant human granulocyte colony-stimulating factor (rhG-CSF), as a mobilizing agent for bone marrow stem cells, can promote stem cell mobilization, homing to brain after cerebral ischemia. In the present study, the administration of G-CSF significantly increased number of CD34(+) cells in the marginal zone of the infarction. Rats receiving G-CSF had higher survival rate and lower infarction volume. Neurological behavior was improved, and the expression of fibronectin in the ischemic brain was increased, as compared to rats treated with vehicle. To mimic the ischemia-reperfusion injury in experimental animals, we employed hippocampal slice cultures that were first treated with oxygen and glucose deprivation (OGD) and then with oxygen-glucose resupply, finding that fibronectin significantly increased the neurite outgrowth of OGD hippocampal slices, upregulated the expression of Bcl-2 protein, and ameliorated the ultrastructure damage of OGD hippocampal slices.
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PMID:Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. 1681 50

Liver ischemia-reperfusion injury is characterized by cell necrosis and apoptosis and by profound modifications in the extracellular matrix (ECM). During the complex series of events that take place both during ischemia and when normal blood flow is restored (reperfusion), a concerted regulation of release and activation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) mainly by stellate cells, Kupffer cells and inflammatory cells leads first to endothelial cell injury and subsequent infiltration of neutrophils into the wounded area. Later, MMP activation causes degradation of extracellular matrix components of the liver, mainly collagen and fibronectin, altering tissue architecture. The fibrosis that can result after liver injury is also dependent on the imbalance between MMPs and TIMPs and to new collagen deposition. Several experimental models of liver ischemia-reperfusion injury have demonstrated protective effects of MMP inhibitors in terms of cell necrosis, apoptosis and rearrangement of the extracellular matrix. This review summarizes current knowledge of MMP biology, with particular attention to the most recent evidence of novel, non-extracellular matrix MMP substrates involved in inflammation and cell cycle regulation. An overview of MMP and TIMP expression and activation in hepatic ischemia-reperfusion injury is provided. The analysis of such provides a rational basis for MMP inhibition as a viable strategy to prevent liver injury.
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PMID:The role of matrix metalloproteinase inhibitors in ischemia-reperfusion injury in the liver. 1691 22

Ischemia/reperfusion injury is a major cause of the highly dysfunctional rate observed in marginal steatotic orthotopic liver transplantation. In this study, we document that the interactions between fibronectin, a key extracellular matrix protein, and its integrin receptor alpha4beta1, expressed on leukocytes, specifically up-regulated the expression and activation of metalloproteinase-9 (MMP-9, gelatinase B) in a well-established steatotic rat liver model of ex vivo ice-cold ischemia followed by isotransplantation. The presence of the active form of MMP-9 was accompanied by massive intragraft leukocyte infiltration, high levels of proinflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, and impaired liver function. Interestingly, MMP-9 activity in steatotic liver grafts was, to a certain extent, independent of the expression of its natural inhibitor, the tissue inhibitor of metalloproteinases-1. Moreover, the blockade of fibronectin-alpha4beta1-integrin interactions inhibited the expression/activation of MMP-9 in steatotic orthotopic liver transplantations without significantly affecting the expression of metalloproteinase-2 (MMP-2, gelatinase A). Finally, we identified T lymphocytes and monocytes/macrophages as major sources of MMP-9 in steatotic liver grafts. Hence, these findings reveal a novel aspect of the function of fibronectin-alpha4beta1 integrin interactions that holds significance for the successful use of marginal steatotic livers in transplantation.
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PMID:Fibronectin-alpha4beta1 integrin interactions regulate metalloproteinase-9 expression in steatotic liver ischemia and reperfusion injury. 1725 25

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
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PMID:Microglial activation and matrix protease generation during focal cerebral ischemia. 1726 8


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