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)

We investigated the effects of nafamostat mesilate, a synthetic protease inhibitor clinically used for patients with pancreatitis or disseminated intravascular coagulopathy, on NO synthesis and apoptosis in lipopolysaccharide (LPS)-treated human trophoblasts. Nafamostat mesilate or aminoguanidine, an inhibitor of NO synthase, suppressed NO synthesis and apoptosis in trophoblasts induced by LPS. Both agents also suppressed matrix metalloproteinase-2 activity induced by LPS. LPS also stimulated secretion of IL-6 and IL-8 in cultured trophoblasts, which was suppressed by nafamostat mesilate. Protease inhibitors including nafamostat mesilate may be therapeutic agents for chorioamnionitis and various diseases including septic shock, ischemia-reperfusion injury in brain and heart, graft rejection, and acute phase inflammatory diseases, in which overproduction of NO or peroxynitrite is involved in tissue injury.
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PMID:Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts. 1095 57

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil. Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids. One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis. N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death. Though this is an attractive explanation, there could be other actions as well. N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease. These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function. Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias. Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18. Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus. TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids. Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter. Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids. This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis.
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PMID:Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? 1113 72

We examined the expression of IL-6 in the substantia nigra pars reticulata (SNr) at various time points after transient (3 h) middle cerebral artery occlusion (MCAO) in rats. The animals were killed at 1, 3, 7 or 14 days following operation. Coronal brain sections were processed for immunohistochemistry with antibodies against GFAP, OX-42 and IL-6 and for Nissl staining. Microglial activation was detected 3 and 7 days after ischemia. Reactive astrocytes have been found 7 and 14 days after ischemia. IL-6 expression was detected 3 and 7 days after ischemia. IL-6-positive cells beared the typical morphology of neurons. Distribution of IL-6-positive cells within the SNr was not homogenous. The lateral area of the SNr bears the highest number of IL-6-positive neurons while the central core bears the lowest. Quantification of intact neurons in the SNr 14 days after reperfusion shows that the highest amount of cell loss was found in the central core of the SNr and less neuronal cell loss was observed in the lateral area of the SNr. Thus, the SNr area with the highest IL-6 expression 3 and 7 days after ischemia bears the highest number of intact neurons 14 days after ischemia. This finding could be a clue for the neuroprotective role of IL-6 in the remote region SNr after focal cerebral ischemia.
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PMID:Focal ischemia induces transient expression of IL-6 in the substantia nigra pars reticulata. 1116

Inflammatory mediators are multifunctional cytokines that play important roles both in normal central nervous system (CNS) development and in the response of the brain to diverse forms of injury. Interleukin (IL)-1beta, tumor necrosis factor-alpha and IL-6 are among the best-characterized early-response cytokines. Recent data suggest that they may be synthesized and secreted by several CNS cell types, including microglia, astrocytes and neurons. Biological effects of these cytokines that could influence the progression of injury in the brain include stimulating the synthesis of other cytokines and neuronal injury mediators such as nitric oxide synthase, inducing leukocyte infiltration and the expression of adhesion molecules, influencing glial gene expression and damaging oligodendrocytes. In the immature brain, proinflammatory cytokines might lead to white matter damage during prenatal intrauterine infection and contribute to progressive neuronal damage in acute brain injury evoked by cerebral hypoxia-ischemia. Interrupting the proinflammatory cascade might limit the extent of irreversible injury.
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PMID:Inflammatory mediators and neonatal brain damage. 1127 56

It is postulated that inadequate remodeling of the uterine spiral arteries in preeclampsia leads to focal ischemia and generation of inflammatory cytokines, such as tumor necrosis factor (TNF alpha) and interleukins (ILs), by the placenta. Our objective was to compare TNF alpha, IL-1 alpha, IL-1 beta, and IL-6 levels in placentas from patients with preeclampsia and normal term pregnancies. Because the placenta is a large heterogeneous organ, we analyzed multiple sites per placenta. On the average, there was a 3-fold variation in cytokine protein levels across the eight sites analyzed for each placenta. However, there were no significant overall differences among the normal term, preeclamptic, and preterm placentas from women without preeclampsia. There were also no significant differences in TNF alpha messenger ribonucleic acid between the normal term and preeclamptic placentas, although TNF alpha messenger ribonucleic acid levels were lower in placentas from preterm patients without diagnosis of preeclampsia than in the normal term placentas. In vitro, hypoxia stimulated the production of TNF alpha, IL-1 alpha and IL-1 beta, but not that of IL-6, by placental villous explants from both groups of patients, and this was not exaggerated in preeclampsia. Finally, although peripheral and uterine venous levels of TNF alpha were elevated in preeclamptic women compared with normal term patients, the ratio of uterine to peripheral venous TNF alpha levels was not significantly different from 1.0 for either patient group. Taken together, these results suggest that sources other than the placenta contribute to the elevated concentrations of TNF alpha and IL-6 found in the circulation of preeclamptic women.
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PMID:Expression of inflammatory cytokines in placentas from women with preeclampsia. 1139 47

The objective of the present study was to determine whether hypoxia/reoxygenation in the absence or presence of intestinal bacteria would affect the integrity of the gut mucosal epithelium (as evidenced by histologic changes) and increase the local production of cytokines (interleukin 6 [IL-6] and tumor necrosis factor [TNF]). Rat ileal mucosal membranes were harvested and their electrophysiologic properties and barrier function were measured ex vivo in the Ussing chamber system. Membranes were exposed to normoxia, normoxia + Escherichia coli, hypoxia for 40 min followed by normoxia, or hypoxia for 40 min + E. coli followed by normoxia for 3 h. IL-6 and TNF levels were measured using cytokine-dependent cellular assays. Morphological changes and the degree of DNA fragmentation were used as quantitative markers of gut mucosal injury. Mucosal integrity was maintained in the normoxia group. The addition of bacteria increased the IL-6 response and reduced mucosal integrity. During the hypoxic period, a transient decline in resistance (R) occurred and cytokine production was reduced. In the hypoxic ileal membranes not exposed to E coli, reoxygenation reversed the change in R and increased IL-6 production. The combination of hypoxia/reoxygenation plus E. coli bacterial challenge resulted in the greatest extent of gut mucosal injury and increase in TNF production. The results of this study support the hypothesis that the combination of increased intestinal bacterial levels superimposed on an ischemia/reperfusion injury increases the magnitude of gut mucosal injury and the production and subsequent release of proinflammatory cytokines.
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PMID:Hypoxia combined with Escherichia coli produces irreversible gut mucosal injury characterized by increased intestinal cytokine production and DNA degradation. 1153 Oct 20

Microglia are a major glial component of the central nervous system (CNS), play a critical role as resident immunocompetent and phagocytic cells in the CNS, and serve as scavenger cells in the event of infection, inflammation, trauma, ischemia, and neurodegeneration in the CNS. Studies of human microglia have been hampered by the difficulty of obtaining sufficient numbers of human microglia. One way to circumvent this difficulty is to establish permanent cell lines of human microglia. In the present study we report the generation of immortalized human microglial cell line, HMO6, from human embryonic telencephalon tissue using a retroviral vector encoding myc oncogene. The HMO6 cells exhibited cell type-specific antigens for microglia-macrophage lineage cells including CD11b (Mac-1), CD68, CD86 (B7-2), HLA-ABC, HLA-DR, and ricinus communis agglutinin lectin-1 (RCA), and actively phagocytosed latex beads. In addition, HMO6 cells showed ATP-induced responses similar to human primary microglia in Ca2+ influx spectroscopy. Both human primary microglia and HMO6 cells showed the similar cytokine gene expression in IL-1beta, IL-6, IL-8, IL-10, IL-12, IL-15, and TNF-alpha. Using HMO6 cells, we investigated whether activation was induced by Amyloid-beta fragments or lipopolysaccharide (LPS). Treatment of HMO6 cells with Amyloid-beta 25-35 fragment (Abeta(25-35)) or Amyloid-beta 1-42 fragment (Abeta(1-42)) led to increased expression of mRNA levels of cytokine/chemokine IL-8, IL-10, IL-12, MIP-1beta MIP-1, and MCP-1, and treatment with LPS produced same results. Expression of TNF-alpha and MIP1-alpha was not detected in unstimulated HMO6 cells, but their expression was later induced by long-term exposure to Abeta(25-35) or Abeta(1-42.) ELISA assays of spent culture media showed increased protein levels of TNF-alpha and IL-8 in HMO6 cells following treatment with Abeta(25-35) or LPS. Taken together, our results demonstrate that treatment of human primary microglia and HMO6 immortalized human microglia cell line with Abeta(25-35), Abeta(1-42) and LPS upregulate gene expression and protein production of proinflammatory cytokines and chemokines in these cells. The human microglial cell line HMO6 exhibits similar properties to those documented in human microglia and should have considerable utility as an in vitro model for the studies of human microglia in health and disease.
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PMID:Generation and characterization of immortalized human microglial cell lines: expression of cytokines and chemokines. 1174 1

Stroke is one of the leading causes of death in major industrial countries. Many factors contribute to the cellular damage resulting from ischemia/reperfusion (I/R). Experimental data indicate an important role for oxidative stress and the inflammatory cascade during I/R. We are testing the hypothesis that the mechanism of protection against I/R damage observed in transgenic mice overexpressing human antioxidant enzymes (particularly intracellular glutathione peroxidase) involves the modulation of inflammatory response as well as reduced sensitivity of neurons to cytotoxic cytokines. Transgenic animals show significant reduction of expression of chemokines, IL-6, and cell death-inducing ligands as well as corresponding receptors in a focal cerebral I/R model. Reduction of DNA binding activity of consensus and potential AP-1 binding sites in mouse Fas ligand promoter sequence was observed in nuclear extracts from transgenic mice overexpressing intracellular glutathione peroxidase compared with normal animals following I/R. This effect was accompanied by modulation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway. Cultured primary neurons from the transgenic mice demonstrated protection against hypoxia/reoxygenation injury as well as cytotoxicity after TNF-alpha and Fas ligand treatment. These results indicate that glutathione peroxidase-sensitive reactive oxygen species play an important role in regulation of cell death during cerebral I/R by modulating intrinsic neuronal sensitivity as well as brain inflammatory reactions.
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PMID:Inflammatory response and glutathione peroxidase in a model of stroke. 1182 28

Prolonged cold ischemia has been suggested as a factor that will exacerbate later graft arterial disease (GAD), a major limiting factor for long-term transplant survival. We therefore examined the effects of cold ischemia on GAD as well as adhesion molecule and cytokine expression in murine cardiac grafts. Mild GAD developed in isografts undergoing 4-hour cold ischemia. Relative to control isografts, cold ischemia induced transiently enhanced endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at 4 hours post-transplant. There was also transiently-augmented gene expression of interleukin (IL)-1beta, IL-6, and transforming growth factor-beta in these cold-ischemic isografts. By 3 days post-transplantation, however, there were no longer any differences between control and cold ischemic isografts. Cold ischemia did not significantly affect the final grade of either parenchymal rejection or GAD in long-term (4 to 12 weeks) major histocompatibility complex (MHC) I- or MHC II-mismatched allografts molecules transplanted without immunosuppression. At early time points after cold ischemia (4 to 24 hours), allografts mismatched for MHC I and/or MHC II showed enhanced expression of ICAM-1 and cytokines comparable to that seen in isografts. By day 7 post-transplant, both control and cold ischemia allografts showed comparable expression of cytokines and adhesion molecules. Although prolonged cold ischemia can initiate mild GAD in isografts by transiently enhancing antigen non-specific inflammatory responses, it does not significantly augment subsequent alloresponses.
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PMID:Cold ischemia induces isograft arteriopathy, but does not augment allograft arteriopathy in non-immunosuppressed hosts. 1189 Dec 4

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90


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