Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O14944 (EPR)
 13,097 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen is the essential molecule for all aerobic organisms, and plays predominant role in ATP generation, namely, oxidative phosphorylation. During this process, reactive oxygen species (ROS) including superoxide anion (O(2)(-)) and hydrogen peroxide (H(2)O(2)) are produced as by-products, while it seems indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, during times of environmental stress ROS levels may increase dramatically, resulting in significant damage to cell structure and functions. This cumulated situation of ROS is known as oxidative stress, which may, however, be utilized for eradicating cancer cells. It is well known that oxidative stress, namely over-production of ROS, involves in the initiation and progression of many diseases and disorders, including cardiovascular diseases, inflammation, ischemia-reperfusion (I/R) injury, viral pathogenesis, drug-induced tissue injury, hypertension, formation of drug resistant mutant, etc. Thus, it is reasonable to counter balance of ROS and to treat such ROS-related diseases by inhibiting ROS production. Such therapeutic strategies are described in this article, that includes polymeric superoxide dismutase (SOD) (e.g., pyran copolymer-SOD), xanthine oxidase (XO) inhibitor as we developed water soluble form of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP), heme oxygenase-1 (HO-1) inducers (e.g., hemin and its polymeric form), and other antioxidants or radical scavengers (e.g., canolol). On the contrary, because of its highly cytotoxic nature, ROS can also be used to kill cancer cells if one can modulate its generation selectively in cancer. To achieve this goal, a unique therapeutic strategy was developed named as "oxidation therapy", by delivering cytotoxic ROS directly to the solid tumor, or alternatively inhibiting the antioxidative enzyme system, such as HO-1 in tumor. This anticancer strategy was examined by use of O(2)(-) or H(2)O(2)-generating enzymes (i.e., XO and d-amino acid oxidase [DAO] respectively), and by discovering the inhibitor of HO-1 (i.e., zinc protoporphyrin [ZnPP] and its polymeric derivatives). Further for the objective of tumor targeting and thus reducing side effects, polymer conjugates or micellar drugs were prepared by use of poly(ethylene glycol) (PEG) or styrene maleic acid copolymer (SMA), which utilize EPR (enhanced permeability and retention) effect for tumor-selective delivery. These macromolecular drugs further showed superior pharmacokinetics including much longer in vivo half-life, particularly tumor targeted accumulation, and thus remarkable antitumor effects. The present review concerns primarily our own works, in the direction of "Controlling oxidative stress: Therapeutic and delivery strategy" of this volume.
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PMID:Therapeutic strategies by modulating oxygen stress in cancer and inflammation. 1924 31

Liposome-based nanoSized Particles with Incorporated Nitroxides, or nanoSPINs, were designed for EPR applications as pH probes in biological systems. Phospholipid membrane of the liposomes with incorporated gramicidin A showed selective permeability to a small analyte, H(+), while protecting entrapped sensing nitroxide from biological reductants. An application of the pH-sensitive nanoSPIN in an ischemia model in rat heart homogenate allows for monitoring ischemia-induced acidosis while protecting encapsulated nitroxide against bioreduction.
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PMID:Design of liposome-based pH sensitive nanoSPIN probes: nano-sized particles with incorporated nitroxides. 1938 83

EPR signals of the tissues were registered in experiment on 20 mongrel dogs. Experimental infarction of the small intestine caused death in all 8 dogs (group 1). Tissues of the small intestine and the liver were obtained before and 1, 3, 6 and 9 hours after intestinal ischemia. Twelve dogs of group 2 were exposed to 2-hour ischemia of the small intestine. Intestinal and liver tissues were studied on reperfusion hour 1, 3 and 6. Of 12 animals 7 survived and 5 died. It was found that ischemia and reperfusion in the small intestine result in suppression of cell antioxidant defense, in generation of excessive amount of active oxygen forms, acceleration of lipid peroxidation in hepatic and intestinal tissues. Severe changes in oxidant-antioxidant processes in the liver took part in the dead animals of group 2. It is suggested that free radical production in the liver in ischemia-reperfusion may serve a prognostic sign of survival.
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PMID:[Oxidant-antioxidant processes in tissues in ischemic and reperfusion damage to the small intestine]. 1953 83

Aldehyde oxidase (AO) is a cytosolic enzyme with an important role in drug and xenobiotic metabolism. Although AO has structural similarity to bacterial nitrite reductases, it is unknown whether AO-catalyzed nitrite reduction can be an important source of NO. The mechanism, magnitude, and quantitative importance of AO-mediated nitrite reduction in tissues have not been reported. To investigate this pathway and its quantitative importance, EPR spectroscopy, chemiluminescence NO analyzer, and immunoassays of cGMP formation were performed. The kinetics and magnitude of AO-dependent NO formation were characterized. In the presence of typical aldehyde substrates or NADH, AO reduced nitrite to NO. Kinetics of AO-catalyzed nitrite reduction followed Michaelis-Menten kinetics under anaerobic conditions. Under physiological conditions, nitrite levels are far below its measured K(m) value in the presence of either the flavin site electron donor NADH or molybdenum site aldehyde electron donors. Under aerobic conditions with the FAD site-binding substrate, NADH, AO-mediated NO production was largely maintained, although with aldehyde substrates oxygen-dependent inhibition was seen. Oxygen tension, substrate, and pH levels were important regulators of AO-catalyzed NO generation. From kinetic data, it was determined that during ischemia hepatic, pulmonary, or myocardial AO and nitrite levels were sufficient to result in NO generation comparable to or exceeding maximal production by constitutive NO synthases. Thus, AO-catalyzed nitrite reduction can be an important source of NO generation, and its NO production will be further increased by therapeutic administration of nitrite.
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PMID:Characterization of the magnitude and mechanism of aldehyde oxidase-mediated nitric oxide production from nitrite. 1980 39

The effects of the drug, a complex of dinitrosyl iron with glutathione lyophilized on dextrane, and its components: glutathione, nitrosoglutathione, dextrane, as well as nitric oxide released from dinitrosyl iron with glutathione--on the energy metabolism and functional recovery of isolated perfused rat heart subjected to global ischemia and reperfusion have been studied. The infusion of 100 nM dinitrosyl iron with glutathione after ischemia substantially enhanced the recovery of coronary flow, the cardiac contractile and pump functions during reperfusion with simultaneous preservation of myocardial high-energy phosphates, and cell membrane integrity. It was shown by the EPR method that these effects were associated with the transfer of Fe+(NO+)2 groups from dinitrosyl iron with glutathione to thiol-containing proteins of cardiomyocytes and coronary vessels. The combined infusion of 100 nM dinitrosyl iron with glutathione and 25 MM 2-(phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO), a nitric oxide scavenger, after ischemia profoundly reduced the metabolic and functional recovery of reperfused hearts. After the postischemic administration of a 100 nM aliquot of hydrolysate of dinitrosyl iron with glutathione (a completely decomposed complex), the recovery of coronary flow, the majority of cardiac function indices, as well as the myocardial metabolic state and cell membrane injury did not differ from those in control or were significantly lower. The results obtained demonstrate that that inclusion of Fe+(NO+)2 groups into myocardial tissue and a spontaneous release of nitric oxide trigger the cardioprotective mechanisms of action of dinitrosyl iron with glutathione on ischemic heart.
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PMID:[Effects of dinitrosyl iron complex with glutathione and its components on ischemic rat heart during reperfusion]. 2006 90

Acute ischemic stroke (AIS) results in focal deprivation of blood-borne factors, one of them being oxygen. The purpose of this study was two-fold: (1) to identify therapeutic conditions for supplemental oxygen in AIS and (2) to use transcriptome-wide screening toward uncovering oxygen-sensitive mechanisms. Transient MCAO in rodents was used to delineate the therapeutic potential of normobaric (NBO, 100% O(2), 1ATA) and hyperbaric oxygen (HBO, 100% O(2), 2ATA) during ischemia (iNBO, iHBO) and after reperfusion (rNBO, rHBO). Stroke lesion was quantified using 4.7 T MRI at 48 h. Supplemental oxygen during AIS significantly attenuated percent stroke hemisphere lesion volume as compared with that in room air (RA) controls, whereas identical treatment immediately after reperfusion exacerbated lesion volume (RA=22.4+/-1.8, iNBO=9.9+/-3.6, iHBO=6.6+/-4.8, rNBO=29.8+/-3.6, rHBO=35.4+/-7.6). iNBO and iHBO corrected penumbra tissue pO(2) during AIS as measured by EPR oxymetry. Unbiased query of oxygen-sensitive transcriptome in stroke-affected tissue identified 5,769 differentially expressed genes. Candidate genes were verified by real-time PCR using neurons laser-captured from the stroke-affected somatosensory cortex. Directed microarray analysis showed that supplemental oxygen limited leukocyte accumulation to the infarct site by attenuation of stroke-inducible proinflammatory chemokine response. The findings provide key information relevant to understanding oxygen-dependent molecular mechanisms in the AIS-affected brain.
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PMID:Oxygen-sensitive outcomes and gene expression in acute ischemic stroke. 2014 54

Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (-I/R; -TMZ), I/R (+I/R; -TMZ), and TMZ (+I/R; +TMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 +/- 5 versus 84 +/- 3% in control), was restored to 72 +/- 3% in the TMZ group. Myocardial pO2 in the TMZ group returned to baseline levels (approximately 20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 +/- 3 versus 47 +/- 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction.
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PMID:Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. 2016 41

EPR oximetry using implantable resonators allows measurements at much deeper sites than are possible with surface resonators (> 80 vs. 10 mm) and achieves greater sensitivity at any depth. We report here the development of an improved technique that enables us to obtain the information from multiple sites and at a variety of depths. The measurements from the various sites are resolved using a simple magnetic field gradient. In the rat brain multi-probe implanted resonators measured pO(2) at several sites simultaneously for over 6 months under normoxic, hypoxic, and hyperoxic conditions. This technique also facilitates measurements in moving parts of the animal such as the heart, because the orientation of the paramagnetic material relative to the sensing loop is not altered by the motion. The measured response is fast, enabling measurements in real time of physiological and pathological changes such as experimental cardiac ischemia in the mouse heart. The technique also is quite useful for following changes in tumor pO(2), including applications with simultaneous measurements in tumors and adjacent normal tissues.
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PMID:Implantable resonators--a technique for repeated measurement of oxygen at multiple deep sites with in vivo EPR. 2020 2

Ischemia complicates wound closure. Here, we are unique in presenting a murine ischemic wound model that is based on bipedicle flap approach. Using this model of ischemic wounds we have sought to elucidate how microRNAs may be implicated in limiting wound re-epithelialization under hypoxia, a major component of ischemia. Ischemia, evaluated by laser Doppler as well as hyperspectral imaging, limited blood flow and lowered tissue oxygen saturation. EPR oximetry demonstrated that the ischemic wound tissue had pO(2) <10 mm Hg. Ischemic wounds suffered from compromised macrophage recruitment and delayed wound epithelialization. Specifically, epithelial proliferation, as determined by Ki67 staining, was compromised. In vivo imaging showed massive hypoxia inducible factor-1alpha (HIF-1alpha) stabilization in ischemic wounds, where HIF-1alpha induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds. E2F3 was recognized as a key facilitator of cell proliferation. In keratinocytes, knock-down of E2F3 limited cell proliferation. Forced stabilization of HIF-1alpha using Ad-VP16- HIF-1alpha under normoxic conditions up-regulated miR-210 expression, down-regulated E2F3, and limited cell proliferation. Studies using cellular delivery of miR-210 antagomir and mimic demonstrated a key role of miR-210 in limiting keratinocyte proliferation. In summary, these results are unique in presenting evidence demonstrating that the hypoxia component of ischemia may limit wound re-epithelialization by stabilizing HIF-1alpha, which induces miR-210 expression, resulting in the down-regulation of the cell-cycle regulatory protein E2F3.
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PMID:Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds. 2030 62

The PrP(C) protein, which is especially present in the cellular membrane of nervous system cells, has been extensively studied for its controversial antioxidant activity. In this study, we elucidated the free radical scavenger activity of purified murine PrP(C) in solution and its participation as a cell protector in astrocytes that were subjected to treatment with an oxidant. In vitro and using an EPR spin-trapping technique, we observed that PrP(C) decreased the oxidation of the DMPO trap in a Fenton reaction system (Cu(2+)/ascorbate/H(2)O(2)), which was demonstrated by approximately 70% less DMPO/OH(). In cultured PrP(C)-knockout astrocytes from mice, the absence of PrP(C) caused an increase in intracellular ROS (reactive oxygen species) generation during the first 3h of H(2)O(2) treatment. This rapid increase in ROS disrupted the cell cycle in the PrP(C)-knockout astrocytes, which increased the population of cells in the sub-G1 phase when compared with cultured wild-type astrocytes. We conclude that PrP(C) in solution acts as a radical scavenger, and in astrocytes, it is essential for protection from oxidative stress caused by an external chemical agent, which is a likely condition in human neurodegenerative CNS disorders and pathological conditions such as ischemia.
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PMID:PrPC displays an essential protective role from oxidative stress in an astrocyte cell line derived from PrPC knockout mice. 2222 74


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