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)

This study was designed to characterize the role of arachidonate 5-lipoxygenase metabolism during experimental intestinal ischemia-reperfusion (I/R) injury. Canines were subjected to 3 hr of intestinal ischemia followed by 1 hr of normobaric reperfusion. Intestinal ischemia followed by 1 hr of normobaric reperfusion. Intestinal mucosal leukotriene B4 and leukotriene C4 synthesis tripled after ischemia and ischemia-reperfusion, relative to non-ischemic intestinal mucosa. The flux of fluid and protein from the capillary to the lumen also increased 3-fold after I/R. The selective 5-lipoxygenase synthesis inhibitor A-64077 (Ziluten, 5 mg/kg, p.o.) abolished I/R-induced leukotriene synthesis and reduced transluminal protein flux (50%) but did not influence the lumenal accumulation of fluid after I/R. In animals treated with the leukotriene synthesis inhibitor, intestinal vascular resistance significantly declined during the imposed ischemia period and after 60 min of reperfusion. Mucosal myeloperoxidase activity, a biochemical marker for tissue neutrophils, rose significantly after I/R, and these increases were prevented with the 5-lipoxygenase synthesis inhibitor. In other experiments, the lipoxygenase inhibitor nondihydroguaretic acid produced similar results to those of A64077. In an attempt to determine the source of mucosal leukotrienes during intestinal I/R, we imposed in vitro ischemia and reperfusion on normal mucosal tissue in a blood-free environment. Mucosal tissue was incubated in Krebs buffer under oxygen for 3 hr to simulate the control condition, under nitrogen for 3 hr to simulate ischemia and under nitrogen for 2 hr followed by oxygen for 1 hr to simulate I/R.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the arachidonate 5-lipoxygenase synthesis inhibitor A-64077 in intestinal ischemia-reperfusion injury. 816 54

It is well known that 5-lipoxygenase derivates of arachidonic acid play an important pathogenic role during myocardial infarction. Therefore, the gene encoding arachidonate 5-lipoxygenase (ALOX5) appears to be an attractive target for RNA interference (RNAi) application. In experiments on cultivated cardiomyocytes with anoxia-reoxygenation (AR) and in vivo using rat model of heart ischemia-reperfusion (IR) we determined influence of ALOX5 silencing on myocardial cell death. ALOX5 silencing was quantified using real-time PCR, semi-quantitative PCR, and evaluation of LTC(4) concentration in cardiac tissue. A 4.7-fold decrease of ALOX5 expression (P < 0.05) was observed in isolated cardiomyocytes together with a reduced number of necrotic cardiomyocytes (P < 0.05), increased number live (P < 0.05) and unchanged number of apoptotic cells during AR of cardiomyocytes. Downregulation of ALOX5 expression in myocardial tissue by 19% (P < 0.05) resulted in a 3.8-fold reduction of infarct size in an open chest rat model of heart IR (P < 0.05). Thus, RNAi targeting of ALOX5 protects heart cells against IR injury both in culture and in vivo.
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PMID:Cardioprotective effect of 5-lipoxygenase gene (ALOX5) silencing in ischemia-reperfusion. 2001 86

Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing, and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti-inflammatory drug, zileuton (which is an inhibitor of arachidonate 5-lipoxygenase), is known to have a positive effect on bone tissue repair and brain ischemia. We studied the effect of zileuton on osteopenic bone and its healing and on the genes considered to be crucial for the cross talks between bone and brain. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 wk, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10, or 100 mg/kg body wt) for 5 wk. In tibiae, bone volume, callus and cortical volume, and gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 or 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal, decreasing their density. The expression level of brain Sema3a, known to regulate bone mass positively, was downregulated after ovariectomy. In contrast, bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy, whereas zileuton treatment (10 or 100 mg) resulted in reverse effects. Here, we describe for the first time the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in cross talk between bones and brain, and may be a potent drug for further examination in estrogen deficiency-related dysfunction(s). NEW & NOTEWORTHY Zileuton, a 5-lipoxygenase inhibitor, increased bone volume, callus and cortical volume in osteotomized tibia, and trabecular and cortical volume in femur. Although the expression of Sema3a (positively regulating bone mass) in brain was downregulated and Sema4d (negatively regulating bone mass) was upregulated in tibia callus after ovariectomy, zileuton could counteract these effects. Rbbp4 (involved in age-related memory loss) was increased in tibia callus after ovariectomy.
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PMID:Effect of zileuton on osteoporotic bone and its healing, expression of bone, and brain genes in rats. 2886 Jan 77