Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to assess whether the protective effect of ischemic preconditioning can be adapted for myocardium undergoing 6 h of no-flow ischemia. Twelve isolated rat hearts were either perfused with oxygen-bicarbonated Krebs-Henseleit buffer in the Langendorff mode for 35 min (n=6), or perfused in the same way for 20 min, following 5 min of global normothermic ischemia and 100 min of buffer-perfusion (n=6). The 12 hearts were then preserved for 6 h in HTK solution at 4 degrees C, followed by 30 min of reperfusion. Recovery of cardiac function, metabolic activity and intracellular free calcium concentration were compared between the two groups. After 6 h ischemia, the hearts that underwent preconditioning showed better recovery of left ventricular developed pressure (P<0.01), a lower end-diastolic pressure level (P<0.05), less creatine kinase leakage and a lower calcium concentration. There was no statistical difference in the recovery rate of coronary flow and leakage rate of LDH between the two groups. In conclusion, this experiment demonstrates that ischemic preconditioning improved myocardial functional recovery after 6 h of hypothermic ischemic preservation in the isolated rat heart. Preconditioning might be a potential mechanism for preserving the heart against long-term ischemia/reperfusion injury.
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PMID:Cardioprotective efficacy of ischemic preconditioning on long-term myocardial ischemia. 946 84

We evaluated three cardioplegic solutions, Bretschneider's cardioplegic solution (HTK), St. Thomas' Hospital solution (STH) and the solution of the National Institutes of Health (NIH), a solution with added nitroglycerin and lidocaine, for their ability to minimize ischemia-reperfusion injury in a working rat heart model. After cardioplegic arrest at 4 degrees C and subsequent 45 min of ischemic storage at 25 degrees C the function recovery of hearts was examined during 1 h of normothermic crystalloid reperfusion using Krebs-Henseleit buffer as perfusion medium. We noted a significantly better preservation of the maximum (+dp/dt(max)) and minimum (-dp/dt(max)) velocity of pressure development and a significantly higher coronary flow with the use of HTK (2,657 mm Hg/s, 2,122 mm Hg/s, 17 ml/min) compared to STH (1,600 mm Hg/s, p < 0.05; 1,591 mm Hg/s, p<0.05; 11 ml/ min, p<0.05), and an intermediate level of preservation of hemodynamic parameters with NIH (2,149 mm Hg/s, 1,766 mm Hg/s, 12 ml/min). Concerning the cardiac output, however, no major difference was found between the HTK (41 ml/min), the STH (34 ml/min) and the NIH group (36 ml/min). The decay of the myocardial energy charge was significantly lower in both the HTK and the NIH group as compared with conservation in STH solution. Lactate was lowest in the HTK group, CK and LDH releases in the effusate remained lowest after HTK and NIH preservation. The data of this study suggest that HTK and NIH most perfectly reduce the impairment of myocardial function and provide better myocardial protection during ischemic arrest at 25 degrees C and superior recovery compared to STH solution.
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PMID:Comparison of the solutions of Bretschneider, St. Thomas' Hospital and the National Institutes of Health for cardioplegic protection during moderate hypothermic arrest. 970 50

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (beta2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, -13 (86%), +/-1 (57%), +18 (43%), and -X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P =.01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months, P <.0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months, P =.0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the beta2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.
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PMID:Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics. 1061 Jan 15

In vivo gene delivery mediated by cationic lipids is often compromised by aggregation due to complexation with proteins in the blood. To improve the stability of cationic lipid-DNA complexes, the present study aimed to develop a novel approach in which a poly(cationic lipid) (PCL) is utilized to form stable cationic polyplexes for gene transfection. Hydrogenation of the acrylamide analogue of betaAE-DMRI, the polymerizable precursor of PCL, provided a monomeric lipid derivative (MHL) which was used for direct comparison of corresponding lipoplex stability, toxicity, and transfection activity. Various formulations of cationic liposomes, such as MHL, MHL-cholesterol (Chol), PCL, PCL-Chol, DOTAP-Chol, and commercially available lipofectamine were generated and examined in this study. The new poly(cationic lipid) did not display any significant toxicity to rat hepatocytes or Hep G2 cells as indicated by an LDH leakage assay. Furthermore, PCL was significantly less toxic than MHL, DOTAP-Chol or lipofectamine. Suspensions of PCL were resistant to aggregation even after 24 h of exposure to solutions containing 50 and 100% fetal bovine serum (FBS). In contrast, suspensions of lipofectamine extensively aggregated after 24 h of exposure to 50% FBS. To examine the influence of lipid polymerization on gene transfer activity, liposome-mediated transfections of a luciferase vector (pGL3) were performed in Hep G2 and Alexander cell lines. The luciferase activity of the PCL formulations in Hep G2 cells were similar to those of the MHL, DOTAP-Chol and lipofectamine formulations, demonstrating that lipid polymerization does not compromise transfection activity. In comparison to the monomeric precursor MHL and to the industry transfection standards DOTAP and lipofectamine, the novel poly(cationic lipid) exhibited the lowest cytotoxicity, was the most resistant to serum-induced aggregation and had comparable transfection activity when coformulated with cholesterol. This novel polymerization approach for the development of stable and active polyplexes may prove a valuable alternative for in vivo gene delivery.
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PMID:Cationic lipid polymerization as a novel approach for constructing new DNA delivery agents. 1131 86

The delta opioid peptide [D-Ala(2),D-Leu(5)]enkephalin (DADLE) has been shown to promote organ survival and to protect against methamphetamine-induced neurodegeneration. However, the cellular mechanisms of these actions of DADLE are not totally clear. We examined the action of DADLE in serum-deprived pheochromocytoma cells (PC12) and found that DADLE protected against cell death in those cells. However, the dose-response curves of the protective effects of DADLE are U-shaped as judged by three biochemical or morphological assays: the LDH release, the DNA laddering, and the apoptotic nuclei. It was found that femtomolar to picomolar concentrations of DADLE are antiapoptotic, whereas micormolar concentrations of DADLE are cytotoxic in PC12 cells. The protective effect of DADLE could be attenuated by a selective delta2 opioid antagonist and the cytotoxic action of DADLE was reduced by a selective mu opioid receptor antagonist. The treatment of cells with PD98059, a selective inhibitor of ERK kinase (MEK), or the transfection of cells with a dominant interfering form of MEK (MEK-KA97) blocked both the protective effect of DADLE and the ERK phosphorylation induced by DADLE. Cytotoxic concentrations of DADLE, on the other hand, caused an increase of Fas-ligand (FasL) in PC12 cells that was attenuated by a selective mu antagonist. Our results suggest, therefore, that endogenous opioid peptides may, at low concentrations, promote cell survival via the MEK-ERK pathway perhaps through delta2 opioid receptors, whereas they may kill cells at high concentrations via the activation of FasL through an as-yet unknown mechanism involving mu opioid receptors.
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PMID:Antiapoptotic and cytotoxic properties of delta opioid peptide [D-Ala(2),D-Leu(5)]enkephalin in PC12 cells. 1174 37

Celsior, a new preservation solution in thoracic organ transplantation was evaluated for efficacy in cold preservation of human hepatocytes and compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). Human hepatocyte cultures were preserved at 4 degrees C in Celsior, UW and HTK for 2, 6, 12, 24 and 48 h with 6 h of reperfusion. Levels of lactate dehydrogenase (LDH; cell necrosis), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; mitochondrial function), and adenosine 5'-triphosphate (ATP; loss of intracellular energy) were measured. Cell necrosis, mitochondrial dysfunction, and loss of ATP were significantly ( P<0.001, P<0.001, P<0.002, respectively) lower in Celsior than in HTK. The amount of cell necrosis and mitochondrial dysfunction in Celsior solution (CS) and UW was equal ( P=n.s.) up to 24 h and significantly lower in UW after 48 h ( P<0.001). Additionally, the intracellular level of ATP was significantly higher after ischemia ( P<0.001) and reperfusion from long-term ischemia (24, 48 h) ( P<0.002). We can conclude that Celsior was superior to HTK and equal to UW in the protection of human hepatocytes against cold preservation injury from ischemia and reperfusion. Furthermore, Celsior was effective in long-term preservation of human hepatocytes.
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PMID:Celsior solution compared with University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) in the protection of human hepatocytes against ischemia-reperfusion injury. 1269 41

We have previously reported that free radical-mediated injury induced by cephaloridine (CER) is enhanced by phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, in rat renal cortical slices. We have also shown that PKC activation in mitochondria is involved in CER-induced nephrotoxicity in rats. We investigated the role of a downstream PKC pathway, a MEK/ERK pathway, in free radical-induced injury in rat renal cortical slices exposed to CER. Immediately after preparing slices from rat renal cortex, the slices were incubated in the medium containing MEK inhibitors. ERK1/2 activation was determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 protein in nucleus fraction prepared from the slices exposed to CER. Prominently, CER caused not only increases in lipid peroxidation as an index of free radical generation and in LDH leakage as that of cell injury in the slices, but also marked activation of ERK1/2 in nucleus fraction. PD98059 and U0126, MEK1/2 inhibitors, significantly attenuated CER-induced increases in lipid peroxidation and LDH leakage in the slices. PD98059 also suppressed ERK1/2 activation in nucleus fraction prepared from the slices treated with CER. Inhibition of other MAP kinase pathways, p38 MAP kinase and c-Jun N-terminal kinase (JNK) had no effect on CER-induced increases in lipid peroxidation level and LDH leakage in the slices. The present results suggest that a MEK/ERK pathway down stream of a PKC pathway is probably involved in free radical-induced injury in rat renal cortical slices exposed to CER.
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PMID:Involvement of MEK/ERK pathway in cephaloridine-induced injury in rat renal cortical slices. 1274 22

Preconditioning (PC) exhibits earlier and delayed protection. But the mechanism of cellular signaling in delayed protection of PC remains unclear. We explored the roles of ERK(1/2) and p38 MAPK(alpha/beta) (p38(alpha/beta)) in delayed protection of anoxia preconditioning (APC). The anoxia/reoxygenation (A/R) injury and APC models were established in cultured neonatal rat cardiomyocytes. An ERK(1/2) inhibitor (PD98059) and a p38(alpha/beta) blocker (SB203580) were applied and their effects on A/R and APC models were observed. The cellular contents of MDA, SOD, cell viability and LDH release was measured at the end of the study. ERK(1/2) and p38 MAPK total activity was measured by in-gel myelin basic protein phosphorylation assay at different points during sustained anoxia. The results obtained are as follows: (1) PD98059 (but not SB203580), administered in preconditioning anoxia phase in APC group, abolished completely the delayed protection of APC; (2) SB203580 administered in sustained anoxia phase in A/R group could relieve cell injury induced by anoxia, but not by PD98059; (3) the highest activity of ERK(1/2) and p38 MAPK induced by anoxia appeared at 4 h after the beginning of sustained anoxia. APC inhibited the over activation of both ERK(1/2) and p38 during the following sustained anoxia. These results suggest that ERK(1/2) activation during preconditioning may be an important link of cell signal transduction in the mechanism of APC delayed protection. p38(alpha/beta) activation at the preconditioning stage dose not participate in signaling of APC delayed protection. The excessive activation of p38(alpha/beta) is possibly a key factor in mediating cell injury induced by sustained anoxia. The inhibition of p38(alpha/beta) excessive activation during subsequent sustained anoxia might play a role in delayed protection mechanism of APC.
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PMID:[Different roles of ERK(1/2) and p38 MAPK(alpha/beta) in cellular signaling during cardiomyocyte anoxia preconditioning]. 1293 27

Cold preservation results in cell death via iron-dependent formation of reactive oxygen species, leading to apoptosis during rewarming. We aimed to study cold-induced damage (i.e., injury as a consequence of hypothermia itself and not cold ischemia) in proximal tubular cells (PTC) in various preservation solutions presently applied and to clarify the role of mitochondria in this injury. Primary cultures of rat PTC were incubated at 4 degrees C for 24 h in culture medium, UW, Euro-Collins or HTK solution with and without the iron chelator desferal and rewarmed at 37 degrees C in culture medium. Cell damage, morphology, and apoptosis were studied and mitochondrial membrane potential was assessed by fluorescence microscopy. Cold incubation of PTC in culture medium followed by rewarming caused marked cell damage compared to warm incubation alone (LDH release 39+/-10% vs. 1.6+/-0.3%). Cold-induced damage was aggravated in all preservation solutions (LDH release 85+/-2% for UW; similar in Euro-Collins and HTK). After rewarming, cells showed features suggestive for apoptosis. Desferal prevented cell injury in all solutions (e.g., 8+/-2% for UW). Mitochondrial membrane potential was lost during rewarming and this loss could also be inhibited by desferal. Trifluoperazine, which is known to inhibit mitochondrial permeability transition (MPT), was able to prevent cold-induced injury (LDH 85+/-5% vs. 12+/-2%). We conclude that cold-induced injury occurs in PTC and is aggravated by UW, Euro-Collins, and HTK solution. Iron-dependent MPT is suggested to play a role in this damage. Strategies to prevent cold-induced injury should aim at reducing the availability of "free" iron.
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PMID:Hypothermia causes a marked injury to rat proximal tubular cells that is aggravated by all currently used preservation solutions. 1296 15

Diabetes activates all three groups of MAP kinases in sensory ganglia. Inhibition of this activation for the ERK and p38 groups prevents nerve damage, and agents that improve neuronal function in diabetic rats-antioxidants and aldose reductase inhibitors-also inhibit activation of ERK and p38 in dorsal root ganglia (DRG). However, these same treatments consistently increase activation of JNK. Thus, in DRG from rats with streptozotocin (STZ)-induced diabetes of 12-week duration, the p54/56 isoforms of JNK were activated by 2.75 compared to controls (P <.05). In DRG from diabetic rats treated with a gamma-linolenic acid and alpha-lipoic acid diester (GLA/LA), the activity of the p54/56 isoform was 3.75 that of controls and the p46 isoform was also increased to 1.75 that of controls (both P <.05 compared to both controls and untreated diabetics). We therefore tested the hypothesis that JNK activation is protective. Exposure of rats to diabetes increased activation of JNK in DRG, but treatment with GLA/LA increased this effect (P <.05). Specific inhibition of JNK in primary cultures of DRG neurons using a peptide inhibitor of JNK (JNKi1, 159-600-R100, 7.5 micro M, Alexis Biochemicals) increased the release of LDH and reduced MTT staining; both findings indicate an increase in neuronal damage. Taken together these findings indicate that multiple isoforms of JNK were activated in sensory neurons of diabetic rats, probably by a combination of raised glucose and oxidative stress, and that this activation of JNK serves to protect the neurons from damage.
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PMID:Activation of JNK in sensory neurons protects against sensory neuron cell death in diabetes and on exposure to glucose/oxidative stress in vitro. 1503 1


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