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)

Human diploid fibroblasts (HDF) do not divide indefinitely and eventually lead to an arrest of cell division by a process termed cellular or replicative senescence. Irreversible growth arrest of senescent cells is strongly related to the attenuated response to growth factors. Recently, we reported that up-regulation of caveolin in the senescent cells is responsible for the attenuated response to growth factors. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation, whereas young cells did. In those senescent cells, we found an increased level of caveolin proteins and strong interactions between caveolin-1 and EGFR. When we overexpressed caveolin-1 in young HDF, the activation of Erk-1/2 on EGF stimulation was significantly suppressed. These results suggest that the hyporesponsiveness of senescent fibroblasts to EGF stimulation might be due to the overexpression of caveolin. In addition, the clathrin-dependent endocytosis system plays the more active and dominant role over the caveolae system. Therefore, we monitored the efficiency of clathrin-dependent receptor-mediated endocytosis in the senescent cells in order to elucidate the exact mode of the attenuated response to growth factors in the senescent cells. Using a transferrin-uptake assay and Western blot analysis of endocytosis-related proteins, we found a significant decrease of amphiphysin-1 in human diploid fibroblasts of multipassages. By adjusting the level of amphiphysin, we could modulate the efficiency of receptor-mediated endocytosis either in young or old cells toward growth factors: that is, a dominant negative mutant of amphiphysin-1 blocked the endocytosis in the young cells, while microinjection of the gene resumed its activity in the old cells. Taken together, we conclude that the loss of endocytotic activity of senescent cells is directly related to the down-regulation of amphiphysin-1 and/or up-regulation of caveolins. This opens a new field of functional recovery of the senescent cells simply through adjusting the receptor-mediated endocytosis capacity.
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PMID:Down-regulation of receptor-mediated endocytosis is responsible for senescence-associated hyporesponsiveness. 1197 84

The aim of the present study was to evaluate the potential benefit of machine preservation with the Belzer MPS or HTK solution, compared to standard cold storage, after procurement of marginal livers from non-heart beating donors in an experimental pilot study. Livers from male Wistar rats (250-300 g bw) were harvested after 60 min of cardiac arrest, flushed via the portal vein and cold stored submerged in HTK for 24 h at 4 degrees C while other organs were subjected to oxygenated machine perfusion with HTK or Belzer's MPS at 5 ml/min at 4 degrees C. Cold perfusion of livers with the non-colloidal HTK was not compromised by the lack of oncotic agents and there was no rise in vascular resistance during the 24 h of machine preservation with HTK or the colloidal Belzer MPS. Viability of the livers was assessed after the cold preservation period by warm reperfusion in vitro. Oxygenated machine perfusion was found to significantly increase viability of the livers vs simple cold storage with respect to portal vascular resistance upon reperfusion, enzyme release as well as functional recovery of oxygen utilization or bile production. Moreover, tissue antigen expression of ICAM-1 or histocompatibility antigen class II could be markedly reduced by oxygenated perfusion preservation as compared to cold storage. It is concluded that predamaged organs should preferably be preserved by oxygenated machine perfusion thus minimizing functional alterations and immunogenicity of the graft. In this setup HTK appeared equally effective as Belzer's MPS for machine preservation.
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PMID:Oxygenated machine perfusion mitigates surface antigen expression and improves preservation of predamaged donor livers. 1262 28

Hyporesponsiveness to growth factors is one of the fundamental characteristics of senescent cells. We previously reported that the up-regulation of caveolin attenuates the growth factor response and the subsequent downstream signal cascades in senescent human diploid fibroblasts. Therefore, in the present experiment, we investigated the modulation of caveolin status in senescent cells to determine the effect of caveolin on mitogenic signaling efficiency and cell cycling. We reduced the level of caveolin-1 in senescent human diploid fibroblasts using its antisense oligonucleotides and small interfering RNA, and this resulted in the restoration of normal growth factor responses such as the increased phosphorylation of Erk, the nuclear translocation of p-Erk, and the subsequent activation of p-Elk upon epidermal growth factor stimulation. Moreover, DNA synthesis and the re-entry of senescent cells into cell cycle were resumed upon epidermal growth factor stimulation concomitantly with decreases in p53 and p21. Taken together, we conclude that the loss of mitogenic signaling in senescent cells is strongly related to their elevated levels of caveolin-1 and that the functional recovery of senescent cells at least in the terms of growth factor responsiveness and cell cycle entry might be achieved simply by lowering the caveolin level.
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PMID:Senescent phenotype can be reversed by reduction of caveolin status. 1273 Feb 43

Intermittent hypoxia (IH) during sleep, a characteristic feature of sleep-disordered breathing (SDB) is associated with time-dependent apoptosis and spatial learning deficits in the adult rat. The mechanisms underlying such neurocognitive deficits remain unclear. Activation of the cAMP-response element binding protein (CREB) transcription factor mediates critical components of neuronal survival and memory consolidation in mammals. CREB phosphorylation and DNA binding, as well as the presence of apoptosis in the CA1 region of the hippocampus were examined in Sprague-Dawley male rats exposed to IH. Spatial reference task learning was assessed with the Morris water maze. IH induced significant decreases in Ser-133 phosphorylated CREB (pCREB) without changes in total CREB, starting as early as 1 h IH, peaking at 6 h-3 days, and returning toward normoxic levels by 14-30 days. Double-labeling immunohistochemistry for pCREB and Neu-N (a neuronal marker) confirmed these findings. The expression of cleaved caspase 3 (cC3) in the CA1, a marker of apoptosis, peaked at 3 days and returned to normoxic values at 14 days. Initial IH-induced impairments in spatial learning were followed by partial functional recovery starting at 14 days of IH exposure. We postulate that IH elicits time-dependent changes in CREB phosphorylation and nuclear binding that may account for decreased neuronal survival and spatial learning deficits in the adult rat. We suggest that CREB changes play an important role in the neurocognitive morbidity of SDB patients.
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PMID:Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates. 1462 1

This study aims to investigate applicability of poly(epsilon-caprolactone) (PCL) biodegradable films for repair of gaps in Achilles tendons in a rat model, also comparing surgical repair versus no repair approaches. PCL was synthesized with tailor-made properties, then, PCL films were prepared by solvent casting. Seventy-five outbred Sprague-Dawley rats were randomly allocated into five groups: (i) sham operated (skin incision only); (ii) no repair (complete division of the Achilles tendon and plantaris tendon without repair); (iii) Achilles repair (with a modified Kessler type suture); and (iv) plasty of Achilles tendon defects with the biodegradable PCL films, and (v) animals subjected to 1 cm mid-substance defect with no repair. Functional performance was determined from the measurements of hindpaw prints utilizing the Achilles functional index. The animals were killed 8 weeks after surgery and histological and biomechanical evaluations were made. All groups subjected to Achilles tendon division had a significant functional impairment that gradually improved so that by day 28 there were no functional impairments in any group whereas animals with a defect remained impaired. The magnitude of the biomechanical and morphological changes at postoperative 8 weeks were similar for no repair group (conservative), Achilles repair group and tendonplasty group (biodegradable PCL film group). The initial rate of functional recovery was significantly different for primary suture, Achilles repair group and PCL film group (p>0.01). But, at the 28th day, functional recovery was quite similar to the other groups. In summary, our results suggest that the PCL film can be an alternative biomaterial for tendon replacement.
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PMID:A novel biodegradable PCL film for tendon reconstruction: Achilles tendon defect model in rats. 1465 60

Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
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PMID:Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. 1567 29

This study attempts to address an important clinical issue by identifying potential candidates of VEGF signaling through Flt-1 receptor that trigger angiogenic signal under ischemic stress. To determine the significance of VEGF-Flt-1 (VEGFR1) signaling in ischemic preconditioned (PC) myocardium, we used heterozygous Flt-1 knockout (KO) mice to dissect the pathway and identify candidate genes involved in VEGF signaling. DNA microarrays were employed to detect, characterize and distinguish altered myocardial gene expression by comparing between wild type (WT) CD-1 and heterozygous Flt-1 KO mice when exposed to ischemia (30 min) and reperfusion (2 h). Moreover, KO mice demonstrated reduced beneficial effects of PC when compared to the WT with PC. In the KO and WT mice, the % recovery of the left ventricular developed pressure and the maximum first derivative of the developed pressure after ischemia/reperfusion without PC were similar. However, when animals were subjected to PC, the left ventricular functional recovery throughout the reperfusion period was significantly lower in KO mice than in WT mice. These results indicate for the first time that in the heterozygous Flt-1 KO mice, PC is not as effective as that found in WT. This observation may be due to downregulation of several important genes such as growth-regulated oncogene 1 (Gro1), heat shock proteins (HSP), I kappa B kinase beta (IKK beta), colony-stimulating factor-1 (CSF-1) and annexin A7, suggesting the importance of VEGF-Flt-1 receptor signaling during PC.
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PMID:Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice. 1569 41

The objective of the present study was to assess the cardioprotective effect of dual NEP-ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg.kg(-1).d(-1)). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.
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PMID:The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides. 1579 Dec 90

The mechanisms by which long-chain dietary polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease are largely unknown. The present study determines the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the response of neonatal rat cardiomyocytes to simulated ischaemia (SI) and reperfusion (R). Myocytes isolated from 1-2 day old Wistar rat hearts were cultured with or without EPA or ARA and exposed to 1 h SI followed by 30 minutes reperfusion. Apoptosis was evaluated by caspase-3 activation, poly-(ADP-ribose) polymerase (PARP) cleavage and nuclear condensation. EPA (20microM) and ARA (20microM) significantly inhibited caspase-3 activation and PARP-cleavage and reduced the apoptotic index during reperfusion. Both fatty acids significantly increased ERK phosphorylation and decreased p38 phosphorylation during reperfusion. The mechanism of action of ARA on the MAPKs was further investigated with okadaic acid (to inhibit serine-threonine phosphatases) and orthovanadate (to inhibit tyrosine phosphatases). Vanadate, but not okadaic acid, significantly reduced ARA-induced inhibition of p38 phosphorylation, suggesting the involvement a tyrosine phosphatase during SI/R. Mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity phosphatase, was targeted and a significant induction of MKP-1 by ARA and EPA was observed. It was demonstrated for the first time that EPA and ARA protect neonatal cardiac myocytes from ischaemia/reperfusion-induced apoptosis through activation of ERK as well as induction of a dual-specific phosphatase, causing dephosphorylation of the pro-apoptotic kinase, p38. The cardioprotective effects of EPA and ARA could also be demonstrated on the functional recovery of isolated perfused hearts subjected to global ischemia.
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PMID:Long-chain polyunsaturated fatty acids protect the heart against ischemia/reperfusion-induced injury via a MAPK dependent pathway. 1621 66

Sex differences in myocardial recovery have been reported after acute ischemia and reperfusion injury. Estrogen and the estrogen receptor are critical determinants of cardiovascular sex differences. However, the mechanistic pathways responsible for these differences remain unknown. We hypothesized that estrogen receptor-alpha is an important modulator of 1) myocardial functional recovery after ischemia and 2) inflammatory signaling via MAPK. To study this, adult male and female wild-type (WT) and estrogen receptor-alpha knockout (ER1KO) mouse hearts were isolated, perfused via Langendorff model, and subjected to 20 min of ischemia and 60 min of reperfusion. Myocardial contractile function (left ventricular developed pressure and positive and negative first derivative of pressure) was continuously recorded. After ischemia-reperfusion, hearts were assessed for expression of inflammatory cytokines (ELISA) and activation of MAPK and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student's t-test, and P < 0.05 was statistically significant. ER1KO females exhibited significantly less functional recovery than WT females and were similar to WT males. Activated ERK was increased in female WT hearts compared with female ER1KO. Activated JNK was decreased in female WT hearts compared with female ER1KO. No significant differences were found between male WT, female WT, male ER1KO, and female ER1KO in activated p38 MAPK, proinflammatory cytokine expression, and proapoptotic signaling. Estrogen receptor-alpha plays a role in the protection observed in the female heart. Differential activation of MAPK may mediate this protection. Further studies are necessary to delineate these mechanistic pathways.
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PMID:Estrogen receptor-alpha mediates acute myocardial protection in females. 1641 70


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