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Extracellular Regulated Kinase (extracellular + regulated_kinase)
Selected AbstractsProstaglandin F2, stimulates MEK-ERK signalling but decreases the expression of alkaline phosphatase in dental pulp cellsINTERNATIONAL ENDODONTIC JOURNAL, Issue 6 2010M. C. Chang Chang MC, Chen YJ, Lee MY, Lin LD, Wang TM, Chan CP, Tsai YL, Wang CY, Lin BR, Jeng JH. Prostaglandin F2, stimulates MEK-ERK signalling but decreases the expression of alkaline phosphatase in dental pulp cells. International Endodontic Journal, 43, 461,468, 2010. Abstract Aim, To study prostaglandin F2, (PGF2,) receptor expression and downstream signalling in cultured human dental pulp cells and the effect of PGF2, on the alkaline phosphatase (ALP) activity of dental pulp cells. Methodology, Human dental pulp cells were cultured and exposed to PGF2,. The expression of PGF2, (FP) receptors was analysed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. The activation of extracellular regulated kinase (ERK) and cAMP responsive element binding protein/activating transcription factor-1 (CREB/ATF-1) signalling was determined by Western blotting. The expression of ALP in pulp cells after exposure to PGF2, was evaluated by ALP staining and PCR. Results, Dental pulp cells expressed FP receptor mRNA and protein. Exposure to PGF2, revealed little cytotoxicity to pulp cells. PGF2, induced both ERK and CREB/ATF-1 phosphorylation in pulp cells. Exposure to PGF2, (>1 ,mol L,1) further decreased the ALP activity and mRNA expression. However, U0126 (an inhibitor of MEK1) showed little preventive effect on the decline of ALP activity in dental pulp cells by PGF2,. Conclusion, PGF2, may potentially activate FP receptors leading to ERK/CREB-ATF-1 activation during its production in inflamed dental pulp. PGF2, attenuated the ALP activity of pulp cells possibly via pathways not solely by MEK/ERK activation. PGF2, is a contributing factor of pulpal inflammation by regulating the activities of pulp cells. [source] ERK 1/2 signaling pathway is involved in nicotine-mediated neuroprotection in spinal cord neuronsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Michal Toborek Abstract Evidence indicates that agonists of neuronal nicotinic receptors (nAChRs), including nicotine, can induce neuroprotective and anti-apoptotic effects in the CNS. To study these mechanisms, the present study focused on nicotine-mediated modulation of the extracellular regulated kinase 1 and 2 (ERK1/2) pathway in cultured spinal cord neurons. Exposure to nicotine (0.1,10 µM) for as short as 1 min markedly upregulated levels of phosphorylated ERK1/2 (pERK1/2) and increased total ERK1/2 activity. Inhibition studies with mecamylamine and ,-bungarotoxin revealed that these effects were mediated by the ,7 nicotinic receptor. In addition, pre-exposure to U0126, a specific inhibitor of the ERK1/2 signaling, prevented nicotine-mediated anti-apoptotic effects. To indicate if treatment with nicotine also can activate ERK1/2 in vivo, a moderate spinal cord injury (SCI) was induced in rats using a weight-drop device and nicotine was injected 2 h post-trauma. Consistent with in vitro data, nicotine increased levels of pERK1/2 in this animal model of spinal cord trauma. Results of the present study indicate that the ERK1/2 pathway is involved in anti-apoptotic effects of nicotine in spinal cord neurons and may be involved in therapeutic effects of nicotine in spinal cord trauma. J. Cell. Biochem. 100: 279,292, 2007. © 2006 Wiley-Liss, Inc. [source] Nicotine inhibits human gingival fibroblast migration via modulation of Rac signalling pathwaysJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 12 2005Yiyu Fang Abstract Aim: Cigarette smoking is a risk factor in the development of periodontal diseases. In addition, a delayed healing process has been shown in smokers compared with non-smokers after periodontal treatment. Cell migration is a key process of wound healing and it is highly regulated by a variety of signalling pathways. The small G protein, Rac, is necessary for cell migration. Our aim was to determine if nicotine disrupted Rac and its downstream signalling proteins, p21-activated kinase 1/2 (PAK1/2), and p44/42 mitogen-activated protein kinase (MAPK) (extracellular regulated kinase 1/2). Material and Methods: Primary human fibroblasts from healthy gingival tissues were cultured and grown to confluence. Cells were serum starved for 24 h, and then treated with nicotine (0 or 0.5 ,M) prior to in vitro wounding. Cell migration was analysed in live cell assays following in vitro wounds. Rac activity, phosphorylation levels of PAK1/2, and p44/42 MAPK were assessed in cultures treated with or without nicotine after multiple wounds. Results: Nicotine decreased cell migration rates by 50% compared with controls. In addition, nicotine altered the activation patterns of Rac and PAK 1/2 and up-regulated p44/42 MAPK. Conclusion: Decreased cell migration in periodontal wounds exposed to nicotine may be mediated through the Rac and PAK1/2 signalling pathways. [source] Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3-kinase (PI3) kinase-dependent manner in Neuro2a cellsJOURNAL OF NEUROCHEMISTRY, Issue 1 2003L. P. Van Der Heide Abstract Insulin signalling is well studied in peripheral tissue, but not in neuronal tissue. To gain more insight into neuronal insulin signalling we examined protein kinase B (PKB) and extracellular regulated kinase 1 and 2 (ERK1/2) regulation in serum-deprived Neuro2a cells. Insulin phosphorylated PKB in a dose-dependent manner but reduced phosphorylation of ERK1/2. Both processes were phosphatidylinositol 3-kinase (PI3K) dependent. Interestingly, blockade of PI3K in combination with insulin induced phosphorylation of ERK1/2. The phosphorylation of ERK1/2 could be blocked with a specific inhibitor of mitogen-activated protein/ERK kinase (MEK), suggesting that it was mediated through the highly conserved Ras,Raf,MEK,ERK1/2 pathway. Prolonged exposure to high concentrations of insulin resulted in a desensitized PI3K,PKB route. The insulin-induced inhibition of ERK1/2 phosphorylation was also diminished when the PI3K,PKB route was desensitized. Blockade of PI3K in combination with insulin, however, still resulted in an unaltered MEK-dependent phosphorylation of ERK1/2. We conclude that PI3K is an important integrator of insulin signalling in Neuro2a cells as it regulates activation of PKB and inhibition of ERK1/2, and is sensitive to the duration of the insulin stimulus. [source] The Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide Exerts Anti-Apoptotic and Differentiating Effects during Neurogenesis: Focus on Cerebellar Granule Neurones and Embryonic Stem CellsJOURNAL OF NEUROENDOCRINOLOGY, Issue 5 2007A. Falluel-Morel Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated from ovine hypothalamus on the basis of its hypophysiotrophic activity. It has subsequently been shown that PACAP and its receptors are widely distributed in the central nervous system of adult mammals, indicating that PACAP may act as a neurotransmitter and/or neuromodulator. It has also been found that PACAP and its receptors are expressed in germinative neuroepithelia, suggesting that PACAP could be involved in neurogenesis. There is now compelling evidence that PACAP exerts neurotrophic activities in the developing cerebellum and in embryonic stem (ES) cells. In particular, the presence of PACAP receptors has been demonstrated in the granule layer of the immature cerebellar cortex, and PACAP has been shown to promote survival, inhibit migration and activate neurite outgrowth of granule cell precursors. In cerebellar neuroblasts, PACAP is a potent inhibitor of the mitochondrial apoptotic pathway through activation of the MAPkinase extracellular regulated kinase. ES cells and embryoid bodies (EB) also express PACAP receptors and PACAP facilitates neuronal orientation and induces the appearance of an electrophysiological activity. Taken together, the anti-apoptotic and pro-differentiating effects of PACAP characterised in cerebellar neuroblasts as well as ES and EB cells indicate that PACAP acts not only as a neurohormone and a neurotransmitter, but also as a growth factor. [source] Urinary proteins from patients with nephrotic syndrome alters the signalling proteins regulating epithelial,mesenchymal transitionNEPHROLOGY, Issue 1 2010QIONG WEN ABSTRACT: Aim: Proteinuria plays an important role in the progression of tubulointerstitial fibrosis, but the mechanism for the differential renal damage induced by proteinuria is unknown. This study examined the effects of urinary proteins from patients with idiopathic minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) on several epithelial,mesenchymal transition (EMT)-related marker proteins in cultured proximal tubular HK-2 cells. Methods: Urinary proteins from MCD and FSGS patients were extracted by ultrafiltration and incubated with HK-2 cells; the expression of the cytokeratin-18, ,-smooth muscle actin (,-SMA) and vimentin were assessed. p38 and extracellular regulated kinase (ERK) activation were measured by western blotting, and SB203580 (a p38 inhibitor) and PD98059 (an ERK1/2 inhibitor) were used to inhibit their activation. Results: It was observed that urinary proteins from FSGS patients more significantly induced the expression of ,-SMA and vimentin and reduced cytokeratin-18 expression than those from MCD patients in HK-2 cells. Both ERK1/2 and p38 were activated by urinary proteins from MCD or FSGS patients. Pretreatment of the cells with SB203580 or PD98059 abolished the effect of urinary proteins from FSGS patients on the expression of ,-SMA, vimentin and cytokeratin-18, while only SB203580 elicited this effect when cells were treated with urinary proteins from MCD patients. Conclusion: The urinary proteins from MCD and FSGS patients induced significant changes of EMT-related proteins through activation of distinct mitogen-activated protein kinase-related signalling pathways. Quality of proteinuria may play an important role in determining the severity and progression of tubular injury associated with different kidney diseases. [source] Adalimumab therapy rapidly inhibits p38 mitogen-activated protein kinase activity in lesional psoriatic skin preceding clinical improvementBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2010L. Soegaard-Madsen Summary Background, The pathogenesis of psoriasis and the mechanisms of action of antitumour necrosis factor (TNF)-, therapies are incompletely understood. Objectives, To investigate the early molecular effects of adalimumab in psoriatic skin. Methods, Biopsies taken from patients with psoriasis were examined before and after the onset of adalimumab therapy. TNF-, protein level and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative reverse transcription,polymerase chain reaction, respectively. The activities of p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1 and 2 (ERK1/2) as well as the downstream kinases MAPK-activated protein kinase 2 (MK2) and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) were measured by Western blot analyses. Results, We demonstrated that clinical and histological improvements were detected from day 14. The increased activity of p38 MAPK in lesional psoriatic skin was significantly inhibited by adalimumab already at day 4. The activities of ERK1/2, MSK1/2 and MK2 were reduced at the end of study (day 84) when the level of TNF-, in lesional psoriatic skin reached the nonlesional level, and the Psoriasis Area and Severity Index score was reduced. Conclusions, The rapid inhibition of p38 MAPK by adalimumab in lesional psoriatic skin preceded clinical and histological improvements, demonstrating an association between TNF-, neutralization and p38 MAPK inhibition. Thus, inhibition of p38 MAPK may be a novel mechanism by which adalimumab mediates its antipsoriatic effect. [source] Glioblastoma chemotherapy adjunct via potent serotonin receptor-7 inhibition using currently marketed high-affinity antipsychotic medicinesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2010RE Kast Glioblastoma treatment as now constituted offers increased survival measured in months over untreated patients. Because glioblastomas are active in synthesizing a bewildering variety of growth factors, a systematic approach to inhibiting these is being undertaken as treatment adjunct. The serotonin 7 receptor is commonly overexpressed in glioblastoma. Research documentation showing agonists at serotonin receptor 7 cause increased extracellular regulated kinase 1/2 activation, increased interleukin-6 synthesis, increased signal transducer and activator of transcription-3 activation, increased resistance to apoptosis and other growth enhancing changes in glioblastoma is reviewed in this paper. Because three drugs in wide use to treat thought disorders , paliperidone, pimozide and risperidone , are also potent and well-tolerated inhibitors at serotonin receptor 7, these drugs should be studied for growth factor deprivation in an adjunctive role in glioblastoma treatment. [source] Leishmania donovani infection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanismCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2008Dinesh Chandra Summary The failure of Leishmania, an intracellular pathogen, to stimulate a pro-inflammatory response following entry into macrophages has been well reported. This occurs in spite of the fact that ligands for the toll-like receptors (TLR) have been recently shown on the parasite surface and their role in disease protection well documented. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature of the effector response and the generation of IL-12 and IL-10 by the infected macrophages is important for this decision. We evaluated the effect of L. donovani infection of monocytes (cell line THP-1, and monocytes derived from human peripheral blood) on Pam3cys (TLR2 ligand) and lipopolysaccharide (TLR4 ligand) stimulated production of IL-12p40 and IL-10. L. donovani infection caused suppression of TLR2 and TLR4-stimulated IL-12p40, with an increase in IL-10 production. Parasites also modulated the TLR2-stimulated mitogen-activated protein kinase (MAPK) pathway by suppressing MAPK P38 phosphorylation and activating extracellular regulated kinase (ERK)1/2 phosphorylation. These effects could be reversed either by using a MAPK P38 activator, anisomycin, or ERK1/2 inhibitor, U0126. L. donovani caused modulation of TLR2-stimulated MAPK pathways in a contact-dependent mechanism. In addition parasite structural integrity but not viability was required for suppression of TLR2-stimulated IL-12p40 and activation of IL-10. These observations suggest that L. donovani has evolved survival strategies that subvert the pro-inflammatory response generated through TLRs. [source] Probiotic lactobacilli and VSL#3 induce enterocyte ,-defensin 2CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2008M. Schlee Summary Recent evidence suggests that probiotic bacteria may stabilize gut barrier function via induction of anti-microbial peptides such as defensins. This study aimed to elucidate the induction mechanism of the human beta defensin-2 (hBD-2) gene by different probiotic lactobacillus strains. The expression of hBD-2 mRNA peaked at 6 h of incubation upon treatment of Caco-2 cells and increased with higher dosage of various probiotic bacteria. Deletion of nuclear factor (NF)-,B and activator protein-1 (AP-1) binding sites on the hBD-2 promoter resulted in a complete abrogation of promoter activation by probiotics. As revealed by the use of specific mitogen-activated protein kinase (MAPK) inhibitors the hBD-2 induction was dependent on the MAPK extracellular regulated kinase (ERK 1/2), p38 and c-Jun N-terminal kinase (JNK), although to varying degrees. Several Lactobacillus strains and VSL#3, a probiotic cocktail of four lactobacilli, three bifidum and one streptococcus species, induced the secretion of the hBD-2 peptide into the culture media as shown by enzyme-linked immunosorbent assay (ELISA). Thus, the present study suggests that lactobacilli and the VSL#3 bacterial mixture strengthen intestinal barrier functions through the up-regulation of hBD-2 via induction of proinflammatory pathways including NF-,B and AP-1 as well as MAPKs. [source] INHIBITION OF TOLL-LIKE RECEPTOR-4, NUCLEAR FACTOR-,B AND MITOGEN-ACTIVATED PROTEIN KINASE BY LIGNOCAINE MAY INVOLVE VOLTAGE-SENSITIVE SODIUM CHANNELSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2008Ping-Ying Lee SUMMARY 1We have shown previously that lignocaine inhibits the upregulation of inducible nitric oxide synthase (iNOS), a crucial factor that initiates the systemic inflammatory response during sepsis, possibly through voltage-sensitive sodium channels (VSSC). Toll-like receptor-4 (TLR-4), nuclear factor (NF)-,B and mitogen activated protein kinases (MAPKs) participate in the upstream regulation of iNOS expression induced by endotoxin. In the present study, we investigated the effects of lignocaine in the regulation of the expression of these enzymes. The role of VSSC in the effects of lignocaine was also investigated. 2Confluent murine macrophages (RAW264.7 cells) were randomized to receive lipopolysaccharide (LPS; 100 ng/mL), LPS + lignocaine (50 µmol/L), LPS + tetrodotoxin (TTX; 1 µmol/L; a VSSC inhibitor), LPS + lignocaine + veratridine (Ver; 50 µmol/L; a VSSC activator) or LPS + TTX + Ver. After reacting with LPS for 0, 15, 30, 45 and 60 min, cell cultures were harvested and enzyme expression was evaluated. 3We found that LPS significantly increased the concentrations of TLR-4, NF-,B and MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38 MAPK, in activated macrophages. Lignocaine and TTX significantly attenuated the effects of LPS on TLR-4, NF-,B, ERK and p38 MAPK expression, but not on JNK. Veratridine mitigated the effects of lignocaine and TTX. 4These data demonstrate that lignocaine has significant inhibitory effects on the activation of TLR-4, NF-,B and MAPKs in activated macrophages. Moreover, these effects involve VSSC. [source] Hydroxytyrosol induces antioxidant/detoxificant enzymes and Nrf2 translocation via extracellular regulated kinases and phosphatidylinositol-3-kinase/protein kinase B pathways in HepG2 cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 7 2010María Angeles Martín Abstract Hydroxytyrosol (HTy) is a natural polyphenol abundant in olive oil, which possesses multiple biological actions. Particularly, HTy has cytoprotective activity against oxidative-stress-induced cell damage, but the underlying mechanisms of action remain unclear. Here, we have investigated the molecular mechanism involved in the protection exerted by HTy on tert -butyl hydroperoxide-induced damage in human HepG2 liver cells. Treatment of HepG2 cells with HTy increased the expression and the activity of glutathione-related enzymes such as glutathione peroxidase, glutathione reductase and glutathione S -transferase. HTy also induced the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Moreover, two important signalling proteins involved in Nrf2 translocation, the protein kinase B and the extracellular regulated kinases, were also activated by HTy. Further studies with specific inhibitors confirmed that both molecular pathways are critical for the nuclear translocation of Nrf2, the increased enzyme expression and activity and the beneficial effect against oxidative stress induced by HTy. In conclusion, together with the inherent radical scavenging activity of HTy, our results provide an additional mechanism of action to prevent oxidative stress damage through the modulation of signalling pathways involved in antioxidant/detoxifying enzymes regulation. [source] | |||||||||||||