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)

Melatonin is a product of the amino acid tryptophan in the pineal gland. Once synthesized, the specific mechanisms governing the release of melatonin from the pineal gland and its functions are largely unknown. Besides its regulatory role in circadian rhythms in mammals, because of its widespread subcellular distribution, melatonin contributes to the reduction of oxidative damage in both the lipid and the aqueous environments of the cell. This postulate is widely supported by the experimental observations showing that melatonin protects lipids in membranes, proteins in the cytosol, and DNA in the nucleus and mitochondria from free radical damage. Melatonin thus reduces the severity of disease conditions where free radicals are implicated. The direct free radical scavenging effects of melatonin are receptor independent. It has recently been shown that it has an ability to scavenge free radicals, including hydroxyl radicals, hydrogen peroxide, peroxyl radicals, singlet oxygen and nitric oxide (NO) and peroxynitrite anion. An excessive amount of NO, a free radical which is generated by the inducible form of NO synthase, is known to cause cytotoxic changes in cells. Hence, NO synthase is considered a pro-oxidative enzyme, and any factor that reduces its activity would be considered an antioxidant. Recent studies have shown that melatonin inhibits the activity of NO synthase, beside its NO and peroxynitrite scavenging activity. Thus, inhibition of NO production may be another means whereby melatonin reduces oxidative damage under conditions, such as ischemia-reperfusion, sepsis, etc, where NO seems to be important in terms of the resulting damage.
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PMID:Melatonin and nitric oxide. 1668 46

The technique of right hepatic trisegmentectomy has been standardized for large tumors that involve the right lobe and extend into the medial segment of the left lobe. However, these tumors are deemed unresectable if they encroach across the falciform ligament into the left lateral segment. We report the technique of extended right trisegmentectomy in a patient with a large intrahepatic cholangiocarcinoma that involved the right lobe of the liver and extended into the medial and lateral segments of the left lobe. The resection was performed by using total hepatic vascular isolation and in situ hypothermic perfusion with modified histidine-tryptophan-ketoglutarate (HTK) solution into the left lateral segment. The biliary enteric anastomosis was constructed using a double hepaticojejunostomy to Segments II and III bile ducts. The procedure allowed safe parenchymal dissection with preservation of the blood supply to Segments II and III. Furthermore, in situ hypothermic perfusion protected the remnant liver from the deleterious effects of warm ischemia during parenchymal dissection and facilitated postoperative recovery. To the best of our knowledge, this is the first report of extended right trisegmentectomy for the treatment of intrahepatic cholangiocarcinoma in the Western literature.
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PMID:Extended right trisegmentectomy using in situ hypothermic perfusion with modified HTK solution for a large intrahepatic cholangiocarcinoma. 1722 25

Isolated perfusion of rat livers (IPRL) represents an attractive set-up to be used as a an evaluative tool in the easy and reproducible assessment of liver injury, allowing for screening of new approaches to organ preservation without the expenditure of actual transplantation experiments. Depending on the pathology under investigation, controversy exists concerning the inclusion of albumin in the IPRL. The present study evaluates the use of bovine serum albumin (BSA), simultaneously comparing its effect on healthy and ischemically challenged livers in the same model. Rat livers were excised, flushed via portal vein with Histidine-Tryptophan-Ketoglutarate (HTK) solution and preserved for up to 18 h in HTK at 4 degrees C. Perfusion was performed with Krebs-Henseleit buffer with or without addition of 3% BSA. Control preparations were perfused without prior ischemic storage. In the described model, stability of the preparations was documented for up to 120 min of isolated perfusion and addition of 3% BSA had no adverse effects on the viability of nonischemic livers. While liver perfusion without albumin was inappropriate to reveal alterations in parenchymal or vascular integrity after 18 h of cold preservation, albumin in the perfusate significantly and gradually unmasked differences between nonischemic liver preparations and livers stored ischemically for 8 or 18 h. It could be shown that BSA did have a significant modulatory effect on hepatic induction of apoptosis after ischemia in reducing cleavage of caspase 3. The implementation of albumin is advocated since experimental results are pivotally influenced by the presence or absence of this physiologically constitutive compound in the perfusate.
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PMID:Assessment of hepatic integrity after ischemic preservation by isolated perfusion in vitro: the role of albumin. 1732 95

The present study was performed to evaluate the cardioprotective effects of KR-33028, a novel Na+/H+ exchanger subtype 1 (NHE-1) inhibitor, in rat and dog models of coronary artery occlusion and reperfusion. In anesthetized rats subjected to a 45-min coronary occlusion and a 90-min reperfusion, KR-33028 at 5 min before occlusion (i.v. bolus) dose-dependently reduced myocardial infarct size from 58.0% to 46.6%, 40.3%, 39.7%, 33.1%, and 27.8% for 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg respectively (P < 0.05). In anesthetized beagle dogs that underwent a 1.0-h occlusion followed by a 3.0-h reperfusion, KR-33028 (3 mg/kg, i.v. bolus) markedly decreased infarct size from 45.6% in vehicle-treated group to 16.4% (P < 0.05), and reduced the reperfusion-induced release in creatine kinase myocardial band isoenzyme (MB), lactate dehydrogenase, troponin-I, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase. In separate experiments to assess the effects of timing of treatment, KR-33028 (1 mg/kg, i.v. bolus) given 10 min before or at reperfusion in rat models also significantly reduced the myocardial infarct size (46.3% and 44.1% respectively) compared with vehicle-treated group. In all studies, KR-33028 caused no significant changes in any hemodynamic profiles. In an isolated rat heart model of hypothermic cardioplegia, KR-33028 (30 mum), which was added to the heart preservation solution (histidin-tryptophan-ketoglutarate) during hypothermic cardioplegic arrest, significantly improved the recovery of left ventricular developed pressure, heart rate and dP/dt(max) after reperfusion. Taken together, these results indicate that KR-33028 significantly reduced the myocardial infarction induced by ischemia and reperfusion in rats and dogs, without affecting hemodynamic profiles.
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PMID:Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on ischemia and reperfusion-induced myocardial infarction in rats and dogs. 1752 Dec 94

Exposure of renal tubular epithelial cells (TEC) to IFN-gamma/TNF-alpha leads to Fas/FasL-mediated self-injury, which contributes to allograft rejection. Indoleamine 2,3-dioxygenase (IDO) converts tryptophan to N-formyl-kynurenine and contributes to immune privilege in tissues by increasing Fas-mediated T cell apoptosis. However, renal expression of IDO and its role in promoting Fas-mediated TEC death have not been examined. IDO expression was analyzed by RT-PCR and Western blot. Apoptosis was measured by fluorescence-activated cell sorting analysis and terminal deoxytransferase-mediated dUTP nick end labeling. We demonstrated that functional IDO is expressed in TEC and is increased by IFN-gamma/TNF-alpha exposure. Increased IDO activity promoted TEC apoptosis, whereas inhibition of IDO by its specific inhibitor 1-methyl-d-tryptophan attenuated IFN-gamma/TNF-alpha-mediated TEC apoptosis and augmented TEC survival. Transgenic expression of IDO resulted in increased TEC apoptosis in the absence of proinflammatory cytokine exposure, supporting a central role for IDO in TEC injury. Inhibition of IDO-mediated TEC death by a caspase-8-specific inhibitor (Z-IETD-FMK), as well as the absence of an IDO effect in Fas-deficient and FasL-deficient TEC, supports a Fas/FasL-dependent, caspase-8-mediated mechanism for IDO-enhanced TEC death. These data suggest that renal IDO expression may be deleterious during renal inflammation, because it enhances TEC self-injury through Fas/FasL interactions. Thus attenuation of IDO may represent a novel strategy to promote kidney function following ischemia and renal allograft rejection.
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PMID:Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells. 1760 91

Organ preservation solutions have been designed to protect grafts against the injury inflicted by cold ischemia. However, toxicity of University of Wisconsin (UW) solution during rewarming has been reported. Therefore, we here assessed the toxicity of UW, histidine-tryptophan-ketoglutarate (HTK), Euro-Collins, histidine-lactobionate (HL), sodium-lactobionate-sucrose and Celsior solutions in cultured hepatocytes under hypothermic (4 degrees C), intermediate (21 degrees C) and physiological (37 degrees C) conditions. Marked toxicity of UW, HTK, HL and Euro-Collins solutions was observed at both 37 and 21 degrees C. With the exception of UW solution, these solutions also increased cell injury during cold incubation (LDH release after 18 h at 4 degrees C: HTK 76+/-2%, Euro-Collins 78+/-17%, HL 81+/-15%; control: Krebs-Henseleit buffer 20+/-6%). Testing of individual components using modified Krebs-Henseleit buffers suggested that histidine and phosphate are responsible for (part of) this toxicity. These potential toxicities should be taken into account in the development of future preservation solutions.
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PMID:Inherent toxicity of organ preservation solutions to cultured hepatocytes. 1802 50

Biliary complications remain a significant problem following liver transplantation in the Model for End-Stage Liver Disease (MELD) era. We hypothesized that donor, recipient, and technical variables may differentially affect anastomotic biliary complications in MELD era liver transplants. We reviewed 256 deceased donor liver transplants after the institution of MELD at our center and evaluated these variables' association with anastomotic biliary complications. The bile leak rate was 18%, and the stricture rate was 23%. Univariate analysis revealed that recipient age, MELD, donor age, and warm ischemia were risk factors for leak, whereas a Roux limb or stent was protective. A bile leak was a risk factor for anastomotic stricture, whereas use of histidine tryptophan ketoglutarate (HTK) versus University of Wisconsin (UW) solution was protective. Additionally, use of a transcystic tube/stent was also protective. Multivariate analysis showed that warm ischemia was the only independent risk factor for a leak, whereas development of a leak was the only independent risk factor for a stricture. HTK versus UW use and transcystic tube/stent use were the only independent protective factors against stricture. Use of an internal stent trended in the multivariate analysis toward being protective against leaks and strictures, but this was not quite statistically significant. This represents one of the first MELD era studies of deceased donor liver transplants evaluating factors affecting the incidence of anastomotic bile leaks and strictures. Donor, recipient, and technical factors appear to differentially affect the incidence of anastomotic biliary complications, with warm ischemia, use of HTK, and use of a stent emerging as the most important variables.
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PMID:Biliary complications following liver transplantation in the model for end-stage liver disease era: effect of donor, recipient, and technical factors. 1816 43

Histidine-tryptophan-ketoglutarate (HTK) is replacing University of Wisconsin (UW) solution as the preservation fluid for renal allografts in many centers, but recent large-scale data to support this transition are lacking. We conducted a retrospective analysis of patient and graft outcomes after renal transplantation at our center, comparing 475 consecutive living donor and 317 deceased donor transplants since the adoption of HTK with equal numbers of grafts preserved using UW solution. Data collected included donor and recipient age, race, sex, comorbidities and graft ischemia time. Graft and patient survival, as well as the incidence of delayed graft function (DGF), were studied by Kaplan-Meier and Cox regression analysis. No significant difference was seen in either patient or graft survival. Deceased donor kidneys in the HTK group had a higher incidence of DGF than the UW cohort, whereas this trend was reversed in the case of living donor organs. In multivariate analysis, HTK was associated with a significant risk reduction on the incidence of DGF. Prolonged preservation with HTK compared to UW was not associated with excess risk to the graft or patient. In summary, HTK demonstrated efficacy similar to UW in terms of patient and graft survival.
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PMID:Comparison of histidine-tryptophan-ketoglutarate and University of Wisconsin preservation in renal transplantation. 1851 Jun 34

Melatonin, the main product of the pineal gland, is also released from the gastrointestinal endocrine-neurocrine (EE) cells. The concentrations of melatonin produced in the gut exceeds that originating from central nervous system. In spite of the presence of melatonin receptors in the pancreatic tissue little is known about the role of this indole in the pancreas. Our experimental studies have shown that exogenous melatonin, as well as this produced endogenously from its precursor; L-tryptophan, strongly stimulates pancreatic amylase secretion when given intraperitoneally, or into the gut lumen. This was accompanied by significant increases of CCK plasma level. Above pancreatostimulatory effects of luminal administration of melatonin, were completely reversed by bilateral vagotomy, capsaicin deactivation of sensory nerves or pretreatment of the rats with CCK1 receptor antagonist; tarazepide as well as serotonin antagonist; ketanserin. Melatonin, as well as its precursor; L-tryptophan, effectively protects the pancreas against the damage induced by caerulein overstimulation or ischemia/reperfusion. The beneficial effects of melatonin or L-tryptophan on acute pancreatitis could be related to the ability of melatonin to scavenge the free radicals, to activate antioxidative enzymes and to modulate the cytokine production.
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PMID:Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector. 1821 1

Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of ischemic stroke. In particular, the gelatinases MMP-2 and MMP-9 contribute to disruption of the blood-brain barrier and hemorrhagic transformation following ischemic injury. In addition to extracellular matrix degradation, MMPs may directly regulate neuronal cell death through mechanisms that are not completely understood. Here we describe the spatio-temporal distribution of activated MMP-2 and MMP-9 in the brain of rats subjected to 2 h middle cerebral artery occlusion (MCAo) followed by different periods of reperfusion (15 min, 2 h, 6 h and 22 h). By in situ zymography we have observed that gelatinases become activated 15 min and 2 h after the beginning of reperfusion in the ischemic core and penumbra, respectively. In situ zymography signal broadly co-localized with NeuN-positive cells, thus suggesting that proteolysis mainly occurs in neurons. Gelatinolytic activity was mainly detected in cell nuclei, marginally appearing in the cytosol only at later stages following the insult; we did not detect variations in gelatinolysis in the extracellular matrix. Finally, we report that pharmacological inhibition of MMPs by N-[(2R)-2-(hydroxamidocarbonyl-methyl)-4-methylpenthanoyl]-L-tryptophan methylamide (GM6001) significantly reduces brain infarct volume induced by transient MCAo. Taken together our data underscore the crucial role of gelatinases during the early stages of reperfusion and further extend previous observations documenting the detrimental role of these enzymes in the pathophysiology of brain ischemia.
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PMID:Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion. 1825 36


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