Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is considered to be an important pathogenic event in ischemia-reperfusion injury, leading to apoptosis or necrosis. We show acute cytotoxicity upon exposure to hydrogen peroxide (H(2)O(2)) in BEAS-2B cells and A549 cells. Single-cell gel electrophoresis showed formation of large comet tails from DNA upon oxidant exposure suggestive of DNA damage. The ATP content of the cells decreased upon exposure to H(2)O(2). Preincubation with 3-aminobenzamide (3-ABA), an inhibitor of poly (ADP-ribosyl) polymerase (PARP), prevented the cytotoxicity. The decrease in the ATP content of the cells was also prevented by 3-ABA. Increase in PARP activity was further confirmed by measuring incorporation of [(32)P]-NAD into nuclear proteins in presence of the cell extracts. Markers of apoptosis were not seen in cells treated with H(2)O(2) with or without 3-ABA pretreatment. These studies suggest that DNA damage is one of the primary reasons for oxidant-induced cell death and that PARP plays an important role in cell death due to its consumption of ATP. Further elaboration of this and other pathways that consume ATP may help prevent oxidant-mediated acute lung injury.
 ...
PMID:Oxidant-induced cell death in respiratory epithelial cells is due to DNA damage and loss of ATP. 1249 35

Myocardial and endothelial damage is still a widely debated problem during the ischemia-reperfusion sequence in heart surgery. We evaluated myocardial purine metabolites, antioxidant defense mechanisms, oxidative status and endothelial dysfunction markers in 14 patients undergoing coronary artery by-pass graft (CABG). Heart biopsies were taken before aortic cross-clamping (t1), before clamp removal (t2) and 30 min after reperfusion (t3); perchloric extracts of the tissue were analyzed for glutathione, NAD, nucleotide nucleoside and base content by capillary electrophoresis (CE). In plasma samples from the coronary sinus we evaluated: nitrate and nitrite concentrations by CE, plasma glutathione peroxidase (plGPx) by ELISA, endothelin-1 (ET-1) by RIA and reactive oxygen metabolites (ROM) by colorimetric assay. During the ischemic period (t2) we observed a reduction in cellular NAD and GSH levels, as well as nitrate, nitrite and plGPx. ATP and GTP levels decreased and their catabolic products AMP, GMP, IMP, adenosine, inosine and hypoxanthine accumulated. The energy charge, ATP/ADP ratio, and nucleotide/(nucleoside + base) ratios decreased. At t3, levels of plasma ET-1 increased and monophosphate nucleotides tended to return to basal values. The energy charge did not increase but the nucleotide/(nucleoside + nucleobase) ratio recovered to some extent. Levels of nitrates plus nitrites continued to decrease. No significant variation in ROM levels was observed. Our data indicate that oxidative stress and endothelial damage are major events during CABG, overwhelming the scavenging capacity of the myocyte and preventing restoration of the normal energy balance for 30 min after reperfusion. The AMP deaminase pathway leading to IMP production is active during ischemia and adenosine is not the main compound derived from ATP break-down in the human heart. The possible role of extracorporeal circulation is also discussed.
 ...
PMID:Cardiac surgery: myocardial energy balance, antioxidant status and endothelial function after ischemia-reperfusion. 1250 69

Excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme catalyzing the transfer of ADP-ribose units from NAD to acceptor proteins, induces cellular energy failure by NAD and ATP depletion and has been proposed to play a causative role in a number of pathological conditions, including ischemia/reperfusion injury. In this study, we used an in vitro enzyme activity assay to characterize a series of newly synthesized isoquinolinone derivatives as potential PARP-1 inhibitors. Several compounds displayed powerful inhibitory activity: thieno[2,3-c]isoquinolin-5-one (TIQ-A) displayed a submicromolar IC50 of 0.45 +/- 0.1 microM, whereas the 5-hydroxy and 5-methoxy TIQ-A derivatives had IC50 values of 0.39 +/- 0.19 and 0.21 +/- 0.12 microM, respectively. We then examined the neuroprotective effects of the newly characterized compounds in cultured mouse cortical cells exposed to 60 min of oxygen and glucose deprivation (OGD). When PARP-1 inhibitors were present in the incubation medium during OGD and the subsequent 24-h recovery period, they significantly attenuated neuronal injury. TIQ-A provided neuroprotection even when added to the culture 30 min after OGD and was able to reduce the early activation of PARP induced by OGD as detected by flow cytometry. When the IC50 values observed in the PARP-1 activity assay for selected compounds were compared with their IC50 values for the neuroprotective activity, a significant correlation (r = 0.93, P < 0.01) was observed. Our results suggest that TIQ-A and its derivatives are a new class of neuroprotectants that may be helpful in studies aimed at understanding the involvement of PARP-1 in physiology and pathology.
 ...
PMID:Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia. 1260 24

Oxidative stress plays a pivotal role in ischemic-reperfusion cell injury. Oxygen-derived free radicals trigger DNA strand damage, which is responsible for the activation of poly(ADP-ribose) polymerase (PARP). Recent studies have shown that peroxynitrite is the primary mediator of DNA damage and, hence, PARP activation after ischemia. PARP activation depletes NAD and ATP pools, ultimately resulting in necrotic cell death by loss of energy stores. Our study shows that PARP is upregulated as early as 15 min after 1 h of transient focal cerebral ischemia and remains for 8 h. We also examined the role of superoxide in PARP induction using copper/zinc-superoxide dismutase transgenic mice. Immunohistochemical and Western blotting data showed that there was no increased induction in PARP expression in these mice, suggesting that one of the mechanisms by which ischemic injury is attenuated in these mice might be by the inhibition of PARP induction. Furthermore, double staining of ischemic tissue with a PARP antibody and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) indicated that most cells that are positive for TUNEL do not stain for the PARP antibody, confirming recent reports that PARP activation is involved in necrotic cell death rather than apoptosis during ischemic-reperfusion injury.
 ...
PMID:Role of superoxide in poly(ADP-ribose) polymerase upregulation after transient cerebral ischemia. 1275 3

The steatotic liver is characterized by deranged intrahepatic microvasculature that is believed to predispose it to ischemia-reperfusion injury. The aim of this study was to investigate the distorted hepatic hemodynamics and its impact on the redox status of the steatotic liver. Hepatic hemodynamic parameters, hepatic microcirculatory perfusion (HMP), and in vivo reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] autofluorescence, which reflects the mitochondrial redox status and tissue oxygen levels, were measured in obese (n = 7) and lean Zucker rats (n = 7). Portal venous and total hepatic blood flow per unit of liver weight were found to exhibit a 37.9% and 35.9% reduction, respectively, in the steatotic liver compared to the nonsteatotic liver of the lean group (P < 0.0001) as was HMP (obese, 96.1 +/- 18.1 PU; lean, 143.8 +/- 12.0 PU, P < 0.05) that showed a 33.2% decrease in the former. Hepatic arterial resistance, however, was 38.7% lower in the obese rat (83.1 +/- 9.1 mmHg. ml(-1). min) than in the lean rat (135.5 +/- 15.8 mmHg. ml(-1). min) (P < 0.05). NAD(P)H fluorescence intensity was significantly elevated in the steatotic liver (0.16 +/- 0.001 aU) compared with the lean one (0.14 +/- 0.007 aU) (P = 0.014). Our results suggest that, in response to a reduced portal venous blood flow, there is a significant decrease in hepatic arterial resistance that, nevertheless, cannot completely compensate for the drop in overall hepatic perfusion and oxygenation of the microvascular bed in the steatotic liver of the obese Zucker rat.
 ...
PMID:Increased NAD(P)H fluorescence with decreased blood flow in the steatotic liver of the obese Zucker rat. 1282 70

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
 ...
PMID:Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. 1283 3

This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl-2 gene expression (the activity of which improves cell survival), upregulated excision repair cross-complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.
 ...
PMID:Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke. 1285 93

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in facilitating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they produce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may, therefore, be a promising strategy in protecting neurons from this secondary damage, as well. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.
 ...
PMID:Poly(ADP-Ribose) polymerase-1 in acute neuronal death and inflammation: a strategy for neuroprotection. 1285 16

The first part of this report on the Australian Health and Medical Research Congress, held November 25-29, 2002, in Melbourne, Australia, considers some of the symposia and three plenary lectures: Neurosteroids: Nature's Valium, G-Protein-Coupled Receptors and the Mike Rand Memorial Lecture. In the new era in relaxin research symposium, we learned that relaxin is a general antifibrotic agent rather than just a hormone of pregnancy. The drugs discussed in the drug discovery symposium included drugs from natural products, allosteric modulators, antibodies to cytokines and AM-336, an N-type Ca(2+) channel blocker. In the matrix proteases symposium, we learned of the importance of these enzymes in bone, endometrial remodeling and cardiovascular disease. The emphasis of the cytokine antagonist symposium was the involvement of cytokines in rheumatoid arthritis and how these effects could be inhibited with cytokine antagonists. The second part of this report is on the cardiovascular components of the meeting. One of the major strengths of Australian research is the cardiovascular area. Thus, it was not surprising that there were three major symposia with a cardiovascular theme this congress. Although the clinical trials of the NHE1 inhibitors in ischemia and reperfusion have been disappointing to date, evidence was presented in the sodium-hydrogen exchanger symposium that these agents might be beneficial in hypertrophy and heart failure. The discussion in the vessel wall biology in diabetes symposium ranged from molecular aspects to clinical trials. In this, and the NAD(P)H oxidases symposium, many new potential drug targets were discussed. The plenary lecture of the High Blood Pressure Research Council concerned the pathophysiology and management of obesity hypertension, and included a discussion of the drugs for weight reduction.
 ...
PMID:Health and medical research down under in 2002. 1294 54

An excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme able to catalyze the transfer of ADP-ribose from NAD to acceptor proteins, is involved in the progression of neuronal damage after brain insult. Potent and selective PARP-1 inhibitors have neuroprotective properties in experimental models of brain ischemia. As a follow up of our previous structure-activity relationship study and in search for novel potent PARP-1 inhibitors, a series of 4H-thieno[2,3-c]-isoquinolin-5-one derivatives was designed and synthesized. Tested for their ability to inhibit PARP-1, these novel derivatives showed high inhibitory potency. The unsubstituted derivative TIQ was selected for further characterization and found to be endowed with strong neuroprotective properties in models of cerebral ischemia.
 ...
PMID:Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors. 1367 79


<< Previous 1 2 3 4 5 6 7 8 9 10