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)

Fibroblast growth factor 1 (FGF1) is an angiogenic factor known to play a role in the growth of arteries. The purpose of this study was to evaluate the usefulness of direct intramuscular injection of an optimized expression plasmid encoding FGF1 to augment collateral formation and tissue perfusion in a rabbit ischemic hindlimb model. Truncated FGF1 fused to the human fibroblast interferon (FIN) signal peptide was expressed from a newly designed plasmid backbone with an improved safety profile for gene therapy applications. In vitro, optimization of plasmid design yielded in a dramatic increase in expression efficiency for FGF1, independent of the presence of a signal peptide, as analyzed by Western Blotting. In vivo, successful transgene expression could be demonstrated by FGF1 immunostaining after gene application. FGF1 plasmid containing FIN signal peptide (100, 500, and 1,000 mug), when injected into ischemic muscle areas of rabbits 10 days after ligation of the external iliac artery, exhibited a pronounced therapeutic effect on collateral formation to the ischemic hindlimb in a dose-depending manner, as assessed by physiological (blood pressure ratio, maximal intra-arterial Doppler flow) and anatomical (angiographic score, histologic evaluation of capillary density) measurements 30 days after therapy, compared to saline or lacZ control plasmid. FGF1 plasmid without a signal peptide sequence resulted in a comparable therapeutic effect on collateral formation at comparable doses (500 and 1,000 mug). Our results indicate that intramuscular FGF1 gene application could be useful to stimulate collateral formation in a situation of chronic peripheral ischemia. The presence of a signal peptide does not seem to be obligatory to achieve bioactivity of intramuscular transfected FGF1. An optimized vector design improved both biosafety of gene transfer and expression efficiency of the transgene, rendering this vector highly suitable for human gene therapy. Therefore, this new generation vector encoding FGF1 might be useful as an alternative treatment for patients with chronic ischemic disorders not amenable to conventional therapy.
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PMID:Intramuscular gene transfer of fibroblast growth factor-1 using improved pCOR plasmid design stimulates collateral formation in a rabbit ischemic hindlimb model. 1638 46

Animal models have assisted in understanding the mechanisms of brain injury underlying cerebral palsy. Nevertheless, no such models replicate every aspect of the human disease. This review summarizes the classic and more recent studies of the neuropathology of human perinatal brain injury most commonly associated with cerebral palsy, for use by researchers and clinicians alike who need to analyze published animal models with respect to their fidelity to the human disorder. The neuropathology underlying cerebral palsy includes white-matter injury, known as periventricular leukomalacia, as well as germinal matrix hemorrhage with intraventricular extension, and injury to the cortex, basal ganglia, and thalamus. Each has distinctive features while sharing some risk factors, such as prematurity and/or hypoxia-ischemia in the perinatal period. Periventricular leukomalacia consists of diffuse injury of deep cerebral white matter, with or without focal necrosis. Recent work directly in human postmortem tissue has focused on the role of free radical injury, cytokine toxicity (especially in light of the epidemiologic association of periventricular leukomalacia with maternofetal infection), and excitotoxicity in the development of periventricular leukomalacia. Premyelinating oligodendrocytes, which predominate in periventricular regions during the window of vulnerability to periventricular leukomalacia (24-34 postconceptional weeks), are the targets of free radical injury, as determined by immunocytochemical markers of lipid peroxidation and protein nitration. This maturational susceptibility can be attributed in part to a relative deficiency of superoxide dismutases in developing white matter. Microglia, which respond to cytokines and to bacterial products such as lipopolysaccharide via Toll-like receptors, are increased in periventricular leukomalacia white matter and can contribute to cellular damage. Indeed, several cytokines, including tumor necrosis factor-a and interleukins 2 and 6, as well as interferon-g, have been demonstrated in periventricular leukomalacia. Preliminary work suggests a role for glutamate receptors and glutamate transporters in periventricular leukomalacia based on expression in human developing oligodendrocytes. Germinal matrix hemorrhage, with or without intraventricular hemorrhage, occurs in premature infants and can coexist with periventricular leukomalacia. Studies in human germinal matrix tissue have focused on maturation-based vascular factors, such as morphometry and expression of molecules related to the structure of the blood-brain barrier. Gray-matter injury, seen more commonly in term infants, includes cortical infarcts and status marmoratus. Subtle cortical injury overlying periventricular leukomalacia is the subject of current interest as a possible substrate for the cognitive difficulties seen in patients with cerebral palsy. In summary, it is hoped that work in human tissue, in conjunction with experimental animal models, will lead to eventual therapeutic or preventive strategies for the perinatal brain injury underlying cerebral palsy.
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PMID:Neuropathologic substrate of cerebral palsy. 1641 40

Nuclear factor-kappa B (NF-kappaB) is activated by oxidative stress such as that induced by transient focal cerebral ischemia (tFCI). Whether NF-kappaB has a role in cell survival or death in stroke is a matter of debate. We proposed that the status of oxidative stress may determine its role in cell death or survival after focal ischemia. To characterize the coordinated expression of genes in NF-kappaB signaling after mild cerebral ischemia, we investigated the temporal profile of a NF-kappaB-pathway-focused DNA array after 30 mins of tFCI in wild-type (WT) mice and human copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had a significantly reduced level of superoxide. Differentially expressed genes among 96 NF-kappaB-related genes were further confirmed and compared in the WT and SOD1 Tg mice using quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Persistent upregulation of NF-kappaB seen at 7 days in the WT mice was decreased in the SOD1 Tg mice. Lymphocytotrophic cytokine genes such as interleukin-2, interleukin-12, and interferon-alpha1 were increased in the SOD1 Tg mice compared with the WT mice after tFCI. In addition, antiapoptosis factors bcl-2 and tumor necrosis factor receptor-associated factor 1 rapidly increased in the SOD1 Tg mice compared with the WT mice. This study indicates that reduced oxidative stress by SOD1 overexpression increased NF-kappaB-related rapid defenses, such as immune response and antiapoptosis factors, and prevented brain damage after tFCI-induced oxidative stress.
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PMID:Reduced oxidative stress promotes NF-kappaB-mediated neuroprotective gene expression after transient focal cerebral ischemia: lymphocytotrophic cytokines and antiapoptotic factors. 1686 54

Ischemia reperfusion injury results from tissue damage during ischemia and ongoing inflammation and injury during reperfusion. Liver reperfusion injury is reduced by lymphocyte depletion or activation of adenosine A2A receptors (A2ARs) with the selective agonist 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]- prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL146e). We show that NKT cells are stimulated to produce interferon (IFN)-gamma by 2 h after the initiation of reperfusion, and the use of antibodies to deplete NK1.1-positive cells (NK and NKT) or to block CD1d-mediated glycolipid presentation to NKT cells replicates, but is not additive to, the protection afforded by ATL146e, as assessed by serum alanine aminotransferase elevation, histological necrosis, neutrophil accumulation, and serum IFN-gamma elevation. Reduced reperfusion injury observed in RAG-1 knockout (KO) mice is restored to the wild-type (WT) level by adoptive transfer of NKT cells purified from WT or A2AR KO mice but not IFN-gamma KO mice. Additionally, animals with transferred A2AR-/- NKT cells are not protected from hepatic reperfusion injury by ATL146e. In vitro, ATL146e potently inhibits both anti-CD3 and alpha-galactosylceramide-triggered production of IFN-gamma by NKT cells. These findings suggest that hepatic reperfusion injury is initiated by the CD1d-dependent activation of NKT cells, and the activation of these cells is inhibited by A2AR activation.
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PMID:Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. 1708 33

The cell-to-cell interaction through binding of intercellular adhesion molecule (ICAM)-1 on monocytes to their ligands lymphocyte function-associated antigen (LFA)-1 on T-cells plays important roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which plasma levels are elevated in patients during acute rejection following organ transplantation, induces the expression of ICAM-1 on monocytes, production of interferon (IFN)-gamma and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Activation of the adenosine A(2A) receptor on during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In the present study, we examined the effect of adenosine at increasing concentrations ranging from 0.1 to 100 microM on the IL-18-enhanced expression of ICAM-1, production of IFN-gamma and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Adenosine inhibited the IL-18-initiated immune responses. The IC(50) values of adenosine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-gamma production and lymphocyte proliferation were 20 microM, respectively. The actions of adenosine depended on the stimulation of adenosine A(2A) receptor. An inhibitor of protein kinase A (PKA) at 100 microM inhibited the actions of adenosine, suggesting that PKA might be involved in the actions of adenosine. On the other hand, the stimulation of adenosine A(1) and A(3) receptor blocked the actions of adenosine A(2A) receptor stimulation. These results suggest that adenosine inhibits the immune responses during mixed lymphocyte reaction via adenosine A(2A) receptor.
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PMID:Effect of adenosine receptor subtypes stimulation on mixed lymphocyte reaction. 1737 32

The impairment of organ function derived from ischemia-reperfusion injury is still an important problem in solid organ transplantation. Cell alterations induced by ischemia prime the tissue for subsequent damage during the reperfusion phase. The aim of present study was to examine the association between changes in cytokine and purine metabolite concentrations in graft renal vein during reperfusion. The study included 17 recipients of cadaveric renal grafts: 10 men and seven women of overall mean age of 49 +/- 7 years and cold ischemia time 25 +/- 3 hour. The levels of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, interferon (INF)-gamma, tumor necrosis factor (TNF)-beta, and TNF-alpha in renal graft vein plasma during 5 first minutes of reperfusion were quantified by flow cytometry. Increased concentrations of IL-6, TNF-alpha, and IL-1beta were observed during reperfusion. The IFN-gamma concentrations correlated negatively with xanthine (Xan) concentrations in renal vein blood during reperfusion, whereas there was a positive correlation between IL-2 and Xan concentrations. Moreover, the concentrations of IL-6 and IL-10 correlated negatively with hypoxanthine concentrations, and the concentrations of IL-4 also correlated negatively with Xan concentrations. The results of this study indicated the enhanced release of some cytokines during kidney graft reperfusion. It occurred in association with release of purine metabolites-the markers of energy status of renal tissue. Therefore, the enhanced cytokine production during reperfusion might influence ischemia-reperfusion injury and the early graft function.
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PMID:Purine and cytokine concentrations in the renal vein of the allograft during reperfusion. 1758 Jan 30

This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4 degrees C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4+ T cell infiltration, interferon (IFN)-gamma-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, and IFN-gamma, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses.
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PMID:Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. 1790 30

We have documented the key role of toll-like receptor 4 (TLR4) activation and its signaling pathway mediated by interferon (IFN) regulatory factor 3, in the induction of inflammation leading to the hepatocellular damage during liver ischemia/reperfusion injury (IRI). Because type I IFN is the major downstream activation product of that pathway, we studied its role in comparison with IFN-gamma. Groups of type I (IFNAR), type II (IFNGR) IFN receptor-deficient mice, along with wild-type (WT) controls were subjected to partial liver warm ischemia (90 minutes) followed by reperfusion (1-6 hours). Interestingly, IFNAR knockout (KO) but not IFNGR KO mice were protected from IR-induced liver damage, as evidenced by decreased serum alanine aminotransferase and preservation of tissue architecture. IR-triggered intrahepatic pro-inflammatory response, assessed by tumor necrosis factor (TNF-alpha), interleukin 6 (IL-6), and chemokine (C-X-C motif) ligand 10 (CXCL-10) expression, was diminished selectively in IFNAR KO mice. Consistent with these findings, our in vitro cell culture studies have shown that: (1) although hepatocytes alone failed to respond to lipopolysaccharide (LPS), when co-cultured with macrophages they did respond to LPS via macrophage-derived IFN-beta; (2) macrophages required type I IFN to sustain CXCL10 production in response to LPS. This study documents that type I, but not type II, IFN pathway is required for IR-triggered liver inflammation/damage. Type I IFN mediates potential synergy between nonparenchyma and parenchyma cells in response to TLR4 activation.
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PMID:Type I, but not type II, interferon is critical in liver injury induced after ischemia and reperfusion. 1793 77

Three major cytokines, namely, tumor necrosis factor (TNF-alpha), interleukin (IL)-1, and IL-6 are produced by cultured brain cells after various stimuli such as ischemia. Neurones, astrocytes, microglia and oligodendrocytes can produce inflammatory mediators, and cytokine receptors are expressed constitutionally throughout the Central Nervous System (CNS), albeit at low levels. Cytokines are involved in virtually every facet of stroke and they have numerous pro-inflammatory and pro-coagulant effects on endothelium. TNF-alpha expression after stroke stimulates expression of tissue factor and adhesion molecules for leukocytes, release of interleukin-1 (IL-1), nitric oxide, factor VIII/von Willebrand factor, platelet-activating factor and endothelin, suppression of the thrombomodulin-protein C-protein S system, reduction of tissue-plasminogen activator and release of plasminogen activator inhibitor-1. Research into the actions of IL-1beta in the brain initially focused on its role in host defence responses to systemic disease. IL-1beta can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. IL-6 can be induced by a variety of molecules including IL-1, TNF-alpha, transforming growth factor-beta and prostaglandins (PGs), and many other mediators such as b-amyloid, interferon-g (IFNg) and IL-4 can potentiate these primary inducers, highlighting the complex nature of IL-6 modulation. Several studies reported that plasma levels of TNF-alpha and IL-6 are associated with prognosis after ischemic stroke and our group showed that plasma levels of cytokines such as TNF-alpha, IL-1beta are different in every diagnostic subtype of ischemic stroke, and how plasma levels of some immunoinflammatory markers and thrombotic-phybrinolitic markers are predictive of acute ischemic stroke diagnosis in the acute setting.
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PMID:Inflammatory cytokines in acute ischemic stroke. 1907 34

Since first being described in the fruit fly Drosophila melanogaster, Toll-like receptors (TLRs) have proven to be of great interest to immunologists and investigators interested in the molecular basis to inflammation. They recognize pathogen-derived factors and also products of inflamed tissue, and trigger signaling pathways that lead to activation of transcription factors such as nuclear factor-kappaB and the interferon regulatory factors. These in turn lead to induction of immune and inflammatory genes, including such important cytokines as tumor necrosis factor-alpha and type I interferon. Much evidence points to a role for TLRs in immune and inflammatory diseases and increasingly in cancer. Examples include clear roles for TLR4 in sepsis, rheumatoid arthritis, ischemia/reperfusion injury, and allergy. TLR2 has been implicated in similar pathologic conditions and also in systemic lupus erythematosus (SLE) and tumor metastasis. TLR7 has also been shown to be important in SLE. TLR5 has been shown to be radioprotective. Recent advances in our understanding of signaling pathways activated by TLRs, structural insights into TLRs bound to their ligands and antagonists, and approaches to inhibit TLRs (including antibodies, peptides, and small molecules) are providing possiblemeans by which to interfere with TLRs clinically. Here we review these recent advances and speculate about whether manipulating TLRs is likely to be successful in fighting off different diseases.
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PMID:Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. 1947 10


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