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)

Recent reports argue that the performance of University of Wisconsin (UW) solution is limited by the presence of hydroxyethyl starch (HES) as an additive, since HES could be responsible for human red blood cell aggregation. We investigated the effect on rat liver preservation of replacing HES in UW solution by polyethylene glycols (PEG20 and PEG35) at two concentrations. An isolated perfused rat liver model was used. Six groups of preserved livers (n = 7 for each group) were compared to controls (nonpreserved livers, n = 7). The following preservation solutions were assayed: UW without oncotic supply, UW-HES (0.25 mmol/L), UW-PEG20 (0.03 and 0.25 mmol/L), and UW-PEG35 (0.03 and 0.25 mmol/L). After 24-hour cold storage, the livers were perfused for 120 minutes at 37 degrees C with oxygenated Krebs-Henseleit solution. During perfusion, transaminase release, portal and bile flows, and bromosulfophthalein (BSP) clearance were assessed. Results showed that the omission of oncotic supply in UW statistically increased ALT and AST release in perfusate and decreased bile and portal flows. PEG addition in UW solution, especially PEG35 at 0.25 mmol/L, effectively protected the rat liver graft from the onset of hypothermic ischemia/reperfusion damage. In conclusion, data reported here reveal that oncotic supply is essential for liver preservation and that HES can be effectively replaced by PEG in UW solution.
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PMID:Efficacy of polyethylene glycols in University of Wisconsin preservation solutions: a study of isolated perfused rat liver. 1638 93

Pulmonary oxidant stress plays an important pathogenetic role in disease conditions including acute lung injury/adult respiratory distress syndrome (ALI/ARDS), hyperoxia, ischemia-reperfusion, sepsis, radiation injury, lung transplantation, COPD, and inflammation. Reactive oxygen species (ROS), released from activated macrophages and leukocytes or formed in the pulmonary epithelial and endothelial cells, damage the lungs and initiate cascades of pro-inflammatory reactions propagating pulmonary and systemic stress. Diverse molecules including small organic compounds (e.g. gluthatione, tocopherol (vitamin E), flavonoids) serve as natural antioxidants that reduce oxidized cellular components, decompose ROS and detoxify toxic oxidation products. Antioxidant enzymes can either facilitate these antioxidant reactions (e.g. peroxidases using glutathione as a reducing agent) or directly decompose ROS (e.g. superoxide dismutases [SOD] and catalase). Many antioxidant agents are being tested for treatment of pulmonary oxidant stress. The administration of small antioxidants via the oral, intratracheal and vascular routes for the treatment of short- and long-term oxidant stress showed rather modest protective effects in animal and human studies. Intratracheal and intravascular administration of antioxidant enzymes are being currently tested for the treatment of acute oxidant stress. For example, intratracheal administration of recombinant human SOD is protective in premature infants exposed to hyperoxia. However, animal and human studies show that more effective delivery of drugs to cells experiencing oxidant stress is needed to improve protection. Diverse delivery systems for antioxidants including liposomes, chemical modifications (e.g. attachment of masking pegylated [PEG]-groups) and coupling to affinity carriers (e.g. antibodies against cellular adhesion molecules) are being employed and currently tested, mostly in animal and, to a limited extent, in humans, for the treatment of oxidant stress. Further studies are needed, however, in order to develop and establish effective applications of pulmonary antioxidant interventions useful in clinical practice. Although beyond the scope of this review, antioxidant gene therapies may eventually provide a strategy for the management of subacute and chronic pulmonary oxidant stress.
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PMID:Antioxidant strategies in respiratory medicine. 1640 15

Acute traumatic spinal cord injury (SCI) results in a devastating loss of neurological function below the level of injury and adversely affects multiple systems within the body. The pathobiology of SCI involves a primary mechanical insult to the spinal cord and activation of a delayed secondary cascade of events, which ultimately causes progressive degeneration of the spinal cord. Whereas cell death from the mechanical injury is predominated by necrosis, secondary injury events trigger a continuum of necrotic and apoptotic cell death mechanisms. These secondary events include vascular abnormalities, ischemia-reperfusion, glutamate excitotoxicity and disturbances in ionic homeostasis, oxidative cell injury, and a robust inflammatory response. No gold standard therapy for SCI has been established, although clinical trials with methylprednisolone (NASCIS II and III) and GM-1 ganglioside (Maryland and Sygen) have demonstrated modest, albeit potentially important therapeutic benefits. In light of the overwhelming impact of SCI on the individual, other therapeutic interventions are urgently needed. A number of promising pharmacological therapies are currently under investigation for neuroprotective abilities in animal models of SCI. These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO). Moreover, clinical trials investigating the putative neuroprotective and neuroregenerative properties ascribed to the Rho pathway antagonist, Cethrin (BioAxone Therapeutic, Inc.), and implantation of activated autologous macrophages (ProCord; Proneuron Biotechnologies) in patients with thoracic and cervical SCI are now underway. We anticipate that these studies will harken an era of renewed interest in translational clinical trials. Ultimately, due to the multi-factorial pathophysiology of traumatic SCI, effective therapies will require combined approaches.
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PMID:Pharmacological approaches to repair the injured spinal cord. 1662 19

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) may result from several clinic situations and carries high morbidity and mortality risk, particularly in intensive care unit patients. The clinical spectrum changes from splanchnic hypoperfusion and intestinal ischemia to multiple organ failure. Previous studies demonstrated that serum D-lactate levels may be an early indicator in intestinal ischemia. This study aimed to investigate the relationship between intestinal ischemia and serum D-lactate levels during experimental IAH. Thirty-two male Wistar Albino rats weighing 250+/-50 g were divided into four groups. Three different intra-abdominal pressure (IAP) levels supplied by placement of an intraperitoneal Peritofix catheter and iso-osmotic polyethylene glycol infusion. Each of the IAP levels (15, 20, and 25 mm Hg groups) was checked with the monitor system and fixed for an hour. Control-group animals were not subjected to increased IAP. One hour later, 5-ml blood samples were taken for measurement of serum D-lactate levels and 2-cm intestinal tissue samples were taken 5 cm proximal to the ileocecal valve for histopathologic examination. Elevated serum D-lactate levels were recorded in animals with higher IAP levels. There was a positive correlation between serum D-lactate levels and IAP levels. Histological examinations of the intestinal tissue samples showed no significant pathologic changes in concordance with intestinal ischemia. Serum D-lactate levels may be an early indicator for increased IAP pressure before intestinal ischemic changes occur.
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PMID:The relationship between intestinal hypoperfusion and serum d-lactate levels during experimental intra-abdominal hypertension. 1708 Feb 44

A simple and rapid MEKC method was developed for the simultaneous determination of myo-inositol, scyllo-inositol, and glucose. Prior to electrophoretic separation, the nonfluorescent inositols and glucose were derivatized by N-methylisatoic anhydride at 25 degrees C for 10 min so that they could be detected by a fluorescence detector during separation. The good separation with high efficiency by MEKC was achieved in 13 min with a glycine buffer containing SDS and PEG 4000. Several parameters affecting the separation were studied, including the pH of BGE, the concentrations of glycine, SDS, and PEG 4000, and the applied voltage. Using glycerol as an internal standard, the linear ranges of the method for myo-inositol, scyllo-inositol, and glucose were 0.03-10, 0.01-5, and 0.05-20 mM; the concentration LODs of myo-inositol, scyllo-inositol, and glucose were 0.020, 0.0078, and 0.026 mM, respectively. The method was applied to analyze extracellular myo-inositol and glucose in the microdialysates from rat brain cortex of ischemia animal model and intracellular myo-inositol and scyllo-inositol in the rat brain extract.
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PMID:Simultaneous determination of myo-inositol and scyllo-inositol by MEKC as a rapid monitoring tool for inositol levels. 1735 85

Molecular modification with polyethylene glycol (PEGylation) is an effective approach to improve protein biostability and decrease protein immunogenic activity. To create a PEGylated recombinant human acid fibroblast growth factor (rhaFGF) and improve its bio-stability, we have produced a rhaFGF mutant (rhaFGF(ser98,132)) by replacing the 98th and the 132nd cysteine residues with serine residues. The rhaFGF(ser98,132) that retains the bioactivity of rhaFGF was then site-specifically conjugated with PEG-maleimide at the 31st cysteine residue. PEGylated rhaFGF(ser98,132) has less effect than the native rhaFGF(ser98,132) on stimulating 3T3 cell proliferation in vitro; however, its biostability at a prolonged incubation under various temperatures and resistance to trypsinization were significantly enhanced, and half-life time in vivo was elongated while its immunogenicity was significantly decreased. The physiological function of PEGylated rhaFGF(ser98,132) was evaluated in a rat model of retinal ischemia/reperfusion injury, showing that in vivo supplementation of PEGylated rhaFGF(ser98,132) provided a significantly better protection than the native rhaFGF(ser98,132) against ischemia/reperfusion-induced retinal morphological changes and lipid peroxidation. The protection is probably mediated by antioxidant protective mechanisms.
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PMID:Enhanced protection of modified human acidic fibroblast growth factor with polyethylene glycol against ischemia/reperfusion-induced retinal damage in rats. 1741 72

Megacolon, defined as dilation of the abdominal colon, may occur acutely or in a chronic form. Acute megacolon that occurs in association with severe inflammation of the colon is known as toxic megacolon, whereas acute megacolon without obvious colonic disease is known as Ogilvie's syndrome. The pathophysiology and management of toxic megacolon, Ogilvie's syndrome, and chronic megacolon in adults differ significantly, and it is critically important to distinguish among these entities. Toxic megacolon is a medical emergency that requires coordinated intensive medical and surgical management. In addition to vigorous resuscitation with fluids, electrolytes, and blood products, medical treatment consists of parenteral corticosteroids, broad-spectrum antibiotics, and close monitoring of the patient. Surgical intervention is required if there is no improvement, or deterioration after 12 to 24 hours of intensive medical management, or if there is evidence of colon perforation. Ogilvie's syndrome usually occurs in hospitalized patients with serious underlying medical or surgical illnesses. Management is directed at preventing ischemia and perforation of the distended colon. Supportive therapy includes nasogastric suction, correction of fluid and electrolyte imbalances, stopping potentially aggravating medications, and decompressing the colon with a rectal tube and positional changes. Intravenous neostigmine is the only pharmacologic agent of proven efficacy; colonoscopic decompression is an alternative in patients who do not respond to neostigmine or who have conditions that contraindicate its use. Daily oral administration of polyethylene glycol electrolyte solutions appears to decrease the relapse rate after initial decompression is achieved. Chronic megacolon in adults represents advanced colon failure that does not respond to pharmacologic stimulation. Goals of therapy are to cleanse the colon, prevent impaction, and minimize stool volume and gas buildup. For patients with disabling symptoms, surgical exclusion of the colon, decompression and antegrade enemas via cecostomy, or subtotal or segmental resection may be palliative.
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PMID:Acute and chronic megacolon. 1754 62

Transient focal ischemia caused by middle cerebral artery occlusion (MCAo) produces apoptotic cell death in the penumbra area. Bcl-2 is a protooncogene that plays a major antiapoptotic role, at the cellular level, by counteracting the activation of apoptosis effectors, that is, caspases. It has been suggested that nitroglycerin (NTG), a nitric oxide donor, reduces ischemia/reperfusion-induced brain damage via the inhibition of caspase activity and NMDA receptor. In this chapter, we evaluated the protective effects of NTG against cerebral damage caused by transient (2h) MCAo (tMCAo) focusing our interest on the potential effects on Bcl-2 expression. Male Wistar rats were administered intraperitoneally (i.p.) with NTG (10mg/kg) or vehicle (PEG, 1ml/kg) 20min before the induction of MCAo by intraluminal silicon-coated filament (0.37-mm diameter). Cerebral infarct volume was measured 22h after reperfusion, while cortical Bcl-2 expression was evaluated at the end of 2-h MCAo (without reperfusion) and at 5h of reperfusion. The results show significant reduction of the infarct volume in rats preinjected with NTG, as compared to the vehicle group. After 2h of occlusion, no significant difference was seen in Bcl-2 expression in the ipsilateral and contralateral cortex of either experimental groups (NTG and vehicle). However, 5h after reperfusion, a significant increase of Bcl-2 expression was detected in the damaged cortex of control rats, probably reflecting a compensatory response aiming at counteracting the cell death process; this increase was absent in the NTG-treated rats. These data, while confirming the neuroprotective effect of NTG in an in vivo ischemia/reperfusion model, seem to suggest that the drug may act by downsizing the complex chain of events underlying apoptosis activation and consequent activation of antiapoptotic responses.
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PMID:Neuroprotective effect of nitroglycerin in a rodent model of ischemic stroke: evaluation of Bcl-2 expression. 1767 76

The aim of the present study was to investigate the influence of a prolonged initial intestinal ischemic insult on transmucosal permeability after a subsequent ischemic event and whether microdialysis of biomarkers released to the gut lumen is able to reflect changes in intestinal permeability. The superior mesenteric artery was cross-clamped for 60 min followed by 4 h of reperfusion in 16 pigs. Nine pigs had a second cross-clamp of 60 min and 3 h of reperfusion, whereas seven pigs were observed for a further 4 h of reperfusion. Intestinal mucosal integrity was assessed by permeability of C-polyethylene glycol (PEG-4000) over the gut mucosa, luminal microdialysis of lactate, glucose and glycerol, and tonometry. During reperfusion, the PEG-4000 amount in venous blood was two times higher after the first than after the second ischemia (area under the curve, 44,780 [13,441-82,723] vs. 22,298 (12,213-49,698] counts min mL(-1), P=0.026 [mean {range}]). There was less lactate detected in the gut lumen after the second ischemia compared with the first (area under the curve, 797 [412-1,700] vs. 1,151 [880-1,969] mmol min L(-1), P=0.02) and a lower maximum concentration (4.8 [2.7-9.4] vs. 8.5 [5.0-14.9] mM, P=0.01). The same pattern was also seen for luminal glycerol and glucose. During the second ischemia, the intestinal mucosal/arterial CO2 gap was identical to the level during the first ischemic episode. A prolonged ischemic insult of the intestine confers protection, for reduced hyperpermeability against further ischemia. Microdialysis of biomarkers mirrors permeability changes associated with this type of protection. Lactate reflects permeability across the intestinal mucosa more precisely than glycerol.
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PMID:Gut luminal lactate measured by microdialysis mirrors permeability of the intestinal mucosa after ischemia. 1769 38

The medical utility of proteins, e.g. therapeutic enzymes, is greatly restricted by their labile nature and inadequate delivery. Most therapeutic enzymes do not accumulate in their targets and are inactivated by proteases. Targeting of enzymes encapsulated into substrate-permeable polymer nano-carriers (PNC) impermeable for proteases might overcome these limitations. To test this hypothesis, we designed endothelial targeted PNC loaded with catalase, an H(2)O(2)-detoxifying enzyme, and tested if this approach protects against vascular oxidative stress, a pathological process implicated in ischemia-reperfusion and other disease conditions. Encapsulation of catalase (MW 247 kD), peroxidase (MW 42 kD) and xanthine oxidase (XO, MW 300 kD) into approximately 300 nm diameter PNC composed of co-polymers of polyethylene glycol and poly-lactic/poly-glycolic acid (PEG-PLGA) was in the range approximately 10% for all enzymes. PNC/catalase and PNC/peroxidase were protected from external proteolysis and exerted enzymatic activity on their PNC diffusible substrates, H(2)O(2) and ortho-phenylendiamine, whereas activity of encapsulated XO was negligible due to polymer impermeability to the substrate. PNC targeted to platelet-endothelial cell (EC) adhesion molecule-1 delivered active encapsulated catalase to ECs and protected the endothelium against oxidative stress in cell culture and animal studies. Vascular targeting of PNC-loaded detoxifying enzymes may find wide medical applications including management of oxidative stress and other toxicities.
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PMID:Endothelial targeting of semi-permeable polymer nanocarriers for enzyme therapies. 1795 Aug 37


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