Signaling pathways leading to the induction of ornithine decarboxylase: Opposite effects of p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK inhibitors

2001 ◽  
Vol 61 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Flavio Flamigni ◽  
Annalisa Facchini ◽  
Emanuele Giordano ◽  
Benedetta Tantini ◽  
Claudio Stefanelli
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Ornithine Decarboxylase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

scholarly journals The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death

2019 ◽  
Vol 12 ◽  
pp. 117863611986459 ◽  
Author(s):  
Jessica Gräb ◽  
Jan Rybniker
Keyword(s):  
Protein Kinase ◽  
Host Cell ◽  
P38 Mapk ◽  
Bacterial Infections ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Host Cell Apoptosis ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

The p38 mitogen-activated protein kinase (MAPK) is involved in a multitude of essential cellular processes. The kinase is activated in response to environmental stresses, including bacterial infections and inflammation, to regulate the immune response of the host. However, recent studies have demonstrated that pathogens can manipulate p38 MAPK signaling for their own benefit to either prevent or induce host cell apoptosis. In addition, there is evidence demonstrating that p38 MAPK is a potent trigger of pathogen-induced necrosis driven by mitochondrial membrane disruption. Given the large number of p38 MAPK inhibitors that have been tested in clinical trials, these findings provide an opportunity to repurpose these drugs for improved control of infectious diseases.

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

2007 ◽  
Vol 292 (4) ◽  
pp. H1978-H1985 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Mitogen Activated Protein Kinase ◽  
Transient Ischemia ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Ampk Activity ◽  
Mapk Inhibitors

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

scholarly journals Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection

2007 ◽  
Vol 51 (12) ◽  
pp. 4324-4328 ◽  
Author(s):  
Shuang Wei ◽  
Benjamin J. Daniel ◽  
Michael J. Brumlik ◽  
Matthew E. Burow ◽  
Weiping Zou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
P38 Mapk ◽  
Human Fibroblasts ◽  
Mitogen Activated Protein Kinase ◽  
Encephalitozoon Cuniculi ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

ABSTRACT We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

scholarly journals Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Andrzej P. Herman ◽  
Agata Krawczyńska ◽  
Joanna Bochenek ◽  
Hanna Antushevich ◽  
Anna Herman ◽  
...  
Keyword(s):  
Gene Expression ◽  
P38 Mapk ◽  
Proinflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Competitive Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors ◽  
P38 Mapk Inhibitor

The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF)αin the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFαsynthesis. Intravenous injection of SB203580 successfully inhibited (P<0.01) synthesis of IL-1βand reduced (P<0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P<0.01) gene expression of TNFαbut its effect was not observed at the level of TNFαprotein synthesis. SB203580 also reduced (P<0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

scholarly journals Parallel and Independent Regulation of Interleukin-3 mRNA Turnover by Phosphatidylinositol 3-Kinase and p38 Mitogen-Activated Protein Kinase

2001 ◽  
Vol 21 (17) ◽  
pp. 5778-5789 ◽  
Author(s):  
Xiu-Fen Ming ◽  
Georg Stoecklin ◽  
Min Lu ◽  
Renate Looser ◽  
Christoph Moroni
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Binding Proteins ◽  
Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Turnover ◽  
Phosphatidylinositol 3 Kinase ◽  
Interleukin 3 ◽  
Mitogen Activated Protein

ABSTRACT AU-rich elements (ARE) present in the 3′ untranslated regions of many cytokines and immediate-early genes are responsible for targeting the transcripts for rapid decay. We present evidence from cotransfection experiments in NIH 3T3 cells that two signaling pathways, one involving phosphatidylinositol 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kinase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabilization mediated by either of the two pathways was antagonized by tristetraprolin (TTP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via activating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are under the positive control of independent phosphokinase signaling pathways.

Neurotoxicity of Lidocaine Involves Specific Activation of the p38 Mitogen-activated Protein Kinase, but Not Extracellular Signal–regulated or c-jun N-Terminal Kinases, and Is Mediated by Arachidonic Acid Metabolites

2006 ◽  
Vol 105 (5) ◽  
pp. 1024-1033 ◽  
Author(s):  
Ingrid Haller ◽  
Barbara Hausott ◽  
Bettina Tomaselli ◽  
Christian Keller ◽  
Lars Klimaschewski ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
P38 Mapk ◽  
Ganglion Cells ◽  
Time Dependent ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

Background Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways. Methods The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity. Results All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures. Conclusions Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.

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