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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction.
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PMID:Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms. 1757 97

Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thalidomide's specific effects on gamma-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on gamma-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34+ cells. We found that thalidomide induced gamma-globin mRNA expression in a dose-dependent manner, but had no effect on beta-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thalidomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced gamma-globin gene expression. These data indicate that thalidomide induces increased expression of the gamma-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation.
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PMID:Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. 1762 Apr 52

Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting of 165 amino acids produced mainly in the kidney and in the liver and regulating erythrocyitosis. It primarily acts on erythroid precursor cell at colony-forming units-erythroid stage inhibiting the apoptosis. EPO binds on a specific membrane receptor thereby activating at least three specific intracellular signaling pathways, such as phosphatidylinositol 3-kinase/ protein kinase B, Ras-mitogen-activated protein kinase and some members of the signal transducers and activators of transcription family. In addition to kidney and liver, EPO mRNA has been detected in other tissues; accordingly EPO receptor has been identified in several type of cells and recent reports have suggested new roles for EPO in non-haematopoietic tissues with a robust evidence for neuroprotective and cardioprotective activity. In different animal models, in vitro, in isolated perfused heart and in vivo, recombinant human erythropoietin protects heart from ischemia reperfusion injury and reduces myocardial damage. EPO tissue protective activity can be separated from erythropoietic activity. Molecules owing the first property but not the second one have been described. In patients with acute myocardial infarction serum EPO level correlates inversely with infarct size. Acute coronary syndrome, extracorporeal circulation and percutaneous coronary intervention are potential fields of application for tissue protective EPO activity to reduce myocardial damage, increase cardiac function ad improve outcome.
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PMID:Structure, production and function of erythropoietin: implications for therapeutical use in cardiovascular disease. 1789 76

The combination of cisplatin and pemetrexed represents the newly established standard of care for patients with unresectable malignant mesothelioma (MM). However, this chemotherapy regimen appears to be associated with an increased prevalence of higher grade anemia as compared to treatment with cisplatin alone. Human recombinant erythropoietin (rHuEpo) is currently used for the treatment of anemia in cancer patients. Still, following the finding that the erythropoietin receptor (EpoR) is expressed by several tumor cells types and after the trials reporting that the recombinant cytokine can adversely affect tumor progression and patient survival, the clinical safety of rHuEpo administration to neoplastic patients has recently been questioned. The observation that the expression of EpoR, variably associated with the expression of the cognate ligand, is a common feature of MM cells prompted us to investigate whether treatment with rHuEpo could elicit proliferative and cytoprotective signals in EpoR-positive MM cell lines. Biochemical responsiveness of MM cells to rHuEpo was demonstrated by the time-course activation of both ERK1/2 and AKT following treatment with the recombinant cytokine. A moderately increased mitogenic activity was observed in two out of five MM cell lines treated with pharmacologically relevant concentrations of rHuEpo. On the other hand, the recombinant cytokine, administered either before or after cisplatin and pemetrexed, failed to interfere with the cytotoxic effects exerted by the chemotherapeutic drugs on the five MM cell lines. According to the presented findings, rHuEpo appears to have an overall limited impact on cell growth and no effect on MM sensitivity to chemotherapy.
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PMID:Recombinant erythropoietin differently affects proliferation of mesothelioma cells but not sensitivity to cisplatin and pemetrexed. 1792 27

The last five years have witnessed a remarkable resurgence of interest in myocardial reperfusion injury. Reperfusion is absolutely essential to salvage ischaemic myocardium but experimental and clinical studies show that reperfusion-associated injury may mask the full benefits of prompt reperfusion in acute myocardial infarction. In the current issue of the British Journal of Pharmacology, Mudalagiri et al demonstrate a protective effect against simulated reperfusion injury using exogenously applied erythropoietin in human isolated myocardium. Crucially, the benefits of erythropoietin were observed when it was administered specifically during re-oxygenation. The demonstration that the protective effects of the cytokine were dependent on PI3-kinase/Akt and ERK1/2 activation provides compelling evidence that reperfusion injury salvage kinases (RISKs) are key survival mechanisms in human myocardium, as they are in experimental animal species. Although erythropoietin may be only one of several potential pharmacological approaches in human patients, this study establishes the important proof-of-principle that activation of RISKs is protective in human myocardium and could be a promising therapeutic target in acute myocardial infarction.
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PMID:Reperfusion and calculated RISKs: pharmacological postconditioning of human myocardium. 1795 11

Cisplatin, a widely used chemotherapeutic is approved for the management of various solid tumors. Administration of cisplatin is associated with induction of significant toxicities that include neurotoxicity and nephrotoxicity, the latter leading to severe and debilitating anemia. Since erythropoietin, a hematopoietic growth factor that corrects chemotherapy-induced anemia, reduces transfusion requirements and seems to improve the patient's quality of life, has been shown to exert cytoprotective effects we decided to investigate its direct influence on cisplatin-induced neurotoxicity against primary cortical neurons isolated from rats. We observed that pre-treatment of neurons with erythropoietin significantly protects these cells from cisplatin-induced cytotoxicity. These effects correlated with amelioration of cisplatin-mediated activation of ERK1/2 kinases and decreased cleavage of caspase 3. Similarly to erythropoietin, a selective ERK1/2 inhibitor significantly reduced cisplatin-induced cytotoxicity against neuronal cells. Importantly, using the same experimental setting we did not observe any protection from cisplatin cytotoxicity against four established tumor cell lines. Altogether our studies confirm that erythropoietin might be an effective cytoprotective agent that reduces cisplatin-induced neurotoxicity.
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PMID:Erythropoietin reduces cisplatin-induced neurotoxicity without impairment of cytotoxic effects against tumor cells. 1798 82

Hypoxic preconditioning can play a significant neuroprotective role. However, it has not been employed clinically because of safety concerns. To find a safer preconditioning stimulus that is both practical and effective, we investigated whether ginkgolides are capable of preconditioning as hypoxia to protect C6 cells against ischemic injury. We demonstrated that both ginkgolides (37.5microg/mL) and hypoxia (1% O(2) for 16h) can significantly increase cell viabilities and expression of phosphorylated glycogen synthase kinase (p-GSK), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) in ischemic cells. The inhibitors of mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3'-kinase (PI3K) significantly but not completely reduced the enhanced expression of these proteins and cell viabilities induced by ginkgolides and hypoxic preconditioning. These indicated that ginkgolides could mimic hypoxic preconditioning by increasing expression of HIF-1alpha as well as its target protein EPO and that the ginkgolides and hypoxic preconditioning role might be partly mediated by the activation of the p42/p44-mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase 3beta pathways. The similar tendency in the changes of protein expression, cell viabilities and responses to MAPK or PI3K inhibitors of the cells treated with ginkgolides and hypoxia suggests that ginkgolides and hypoxic preconditioning might operate by similar mechanisms. The findings also imply that ginkgolides might have the potential for clinical use to prevent injury in high-risk conditions.
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PMID:Ginkgolides mimic the effects of hypoxic preconditioning to protect C6 cells against ischemic injury by up-regulation of hypoxia-inducible factor-1 alpha and erythropoietin. 1805 69

Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine- and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropoiesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling.
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PMID:Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. 1823 84

1. The aim of the present study was to determine the critical timing of Akt activation and its interaction with the mitochondrial permeability transition pore (mPTP) in the mechanism of infarct size limitation by erythropoietin (Epo). 2. In an isolated, buffer-perfused preparation, rabbit hearts were subjected to 30 min ischaemia/2 h reperfusion. Infusion of Epo (1 unit/mL) before ischaemia reduced infarct size from 36.6 +/- 2.6% of the risk area to 15.4 +/- 3.2%, whereas a 10-fold higher dose of Epo infused for 65 min commencing 5 min before reperfusion failed to afford significant cardioprotection. The protection afforded by Epo pretreatment was abolished by coinfusion of 5 micromol/L LY294002, a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Infusion of Epo induced phosphorylation of Akt, extracellular signal-regulated kinase, glycogen synthase kinase 3beta and p70s6 kinase before ischaemia and tended to enhance reperfusion-induced phosphorylation of these protein kinases. Erythropoietin increased phospho-Akt in the mitochondria and induced complex formation of Akt with adenine nucleotide translocase (ANT), a major subunit of mPTP, upon reperfusion. 3. In another series of experiments, cardiomyocytes were isolated from rat hearts and loaded with Rhod-2 to determine mitochondrial Ca(2+) levels. Increases in mitochondrial Ca(2+) levels following exposure to 1 mmol/L ouabain for 30 min were similar in untreated and Epo-pretreated cells. However, ouabain-induced hypercontracture was significantly suppressed from 45.1 +/- 1.6 to 39.2 +/- 1.9% by Epo. 4. In conclusion, activation of PI3-K-Akt signalling before ischaemia is crucial for Epo-induced myocardial protection and this protection may be achieved by complex formation of activated Akt with mPTP components upon reperfusion, leading to elevation of the threshold for opening of mPTP.
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PMID:Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion. 1834 68

The main clinical problems of low-risk patients with myelodysplastic syndromes (MDS), as defined by the International Prognostic Scoring System, are infections and the need for frequent transfusions due to ineffective myelopoiesis and peripheral blood cytopenia. Promising results in treating MDS-related anemia have been obtained using high-dose recombinant human erythropoietin (rhEPO). To evaluate the molecular basis of the response to rhEPO, we used commercially available macro-arrays to investigate gene expression profiles in the glycophorin-expressing (Gly+) bone marrow (BM) erythroid cells of five responders (ERs) and five non-responders (ENRs) to rhEPO treatment. The cells were separated by means of positive selection using an immunomagnetic procedure, after which flow cytometry showed that their purity was more than 97% in all cases. The array data were validated by means of real time RT-PCR. The results showed that the genes responsible for proliferation/differentiation and DNA repair/stability were repressed in the BM Gly+ erythroid cells of the ENRs, but almost normally expressed in the ERs. Furthermore, the expression of genes involved in signal transduction suggested that the activity of the MAPK signaling pathway is inhibited in ERs. The different gene expression profiles of ERs and ENRs may provide a basis for early gene testing as a means of predicting the response to rhEPO of MDS patients with low endogenous EPO levels.
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PMID:Bone marrow glycophorin-positive erythroid cells of myelodysplastic patients responding to high-dose rHuEPO therapy have a different gene expression pattern from those of nonresponders. 1838 21


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