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Mitogen-activated Protein Kinase Activation (mitogen-activated + protein_kinase_activation)
Selected AbstractsAttenuation of proliferation in oligodendrocyte precursor cells by activated microgliaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 8 2010Deanna L. Taylor Abstract Activated microglia can influence the survival of neural cells through the release of cytotoxic factors. Here, we investigated the interaction between Toll-like receptor 4 (TLR4)-activated microglia and oligodendrocytes or their precursor cells (OPC). Primary rat or N9 microglial cells were activated by exposure to TLR4-specifc lipopolysaccharide (LPS), resulting in mitogen-activated protein kinase activation, increased CD68 and inducible nitric oxide synthase expression, and release of the proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6). Microglial conditioned medium (MGCM) from LPS-activated microglia attenuated primary OPC proliferation without inducing cell death. The microglial-induced inhibition of OPC proliferation was reversed by stimulating group III metabotropic glutamate receptors in microglia with the agonist L-AP4. In contrast to OPC, LPS-activated MGCM enhanced the survival of mature oligodendrocytes. Further investigation suggested that TNF and IL-6 released from TLR4-activated microglia might contribute to the effect of MGCM on OPC proliferation, insofar as TNF depletion of LPS-activated MGCM reduced the inhibition of OPC proliferation, and direct addition of TNF or IL-6 attenuated or increased proliferation, respectively. OPC themselves were also found to express proteins involved in TLR4 signalling, including TLR4, MyD88, and MAL. Although LPS stimulation of OPC did not induce proinflammatory cytokine release or affect their survival, it did trigger JNK phosphorylation, suggesting that TLR4 signalling in these cells is active. These findings suggest that OPC survival may be influenced not only by factors released from endotoxin-activated microglia but also through a direct response to endotoxins. This may have consequences for myelination under conditions in which microglial activation and cerebral infection are both implicated. © 2010 Wiley-Liss, Inc. [source] Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling,MOLECULAR CARCINOGENESIS, Issue 1 2010Jane L. Watson Abstract New cytotoxic agents are urgently needed for the treatment of advanced ovarian cancer because of the poor long-term response of this disease to conventional chemotherapy. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity; however, the mechanism of curcumin-induced cytotoxicity in ovarian cancer cells remains a mystery. In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the extrinsic and intrinsic pathways of apoptosis. Bax expression was unchanged but Bcl-2, survivin, phosphorylated Akt (on serine 473), and total Akt were downregulated in curcumin-treated HEY cells. Curcumin also activated p38 mitogen-activated protein kinase (MAPK) without altering extracellular signal-regulated kinase 1/2 activity. We conclude that p53-independent curcumin-induced apoptosis in ovarian carcinoma cells involves p38 MAPK activation, ablation of prosurvival Akt signaling, and reduced expression of the antiapoptotic proteins Bcl-2 and survivin. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of ovarian cancer. © 2009 Wiley-Liss, Inc. [source] Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertensionBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009C Agard Background and purpose:, Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH. Experimental approach:, Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells. Key results:, In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg·kg,1·day,1). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth. Conclusions and implications:, Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier. [source] Apoptosis signal-regulating kinase 1-mediated sustained p38 mitogen-activated protein kinase activation regulates mycoplasmal lipoprotein- and staphylococcal peptidoglycan-triggered Toll-like receptor 2 signalling pathwaysCELLULAR MICROBIOLOGY, Issue 9 2005Takeshi Into Summary Toll-like receptor (TLR) 2 functions as a sensor for detecting various microbial components conserved in bacteria or fungi in innate immunity. TLR2 induces several signalling pathways linking to activation of the transcriptional factors NF-,B and AP-1 as well as induction of cell death. In human embryonic kidney 293 cells expressed human TLR2, mycoplasmal lipoproteins (MLP) or staphylococcal peptidoglycans (PGN) induced sustained phosphorylation of p38 mitogen-activated protein kinase (MAPK), accompanied by generation of reactive oxygen species. This observation encouraged us to examine roles of apoptosis signal-regulating kinase 1 (ASK1) in TLR2 signalling, because ASK1 is an upstream activator of p38 MAPK during exposure to oxidative stress and other stressful stimuli. A kinase-inactive mutant of ASK1 greatly impaired the sustained phosphorylation of p38 MAPK induced by MLP or PGN. This mutant also attenuated MLP- or PGN-induced transcriptional activities of NF-,B and AP-1 via inhibition of p38 MAPK activation. MLP- or PGN-induced cell death reactions, including DNA fragmentation and caspase-3/7 activation, were also downregulated by the ASK1 mutant via p38 MAPK inhibition. Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue. Thus, MLP and PGN have capabilities to induce ASK1-dependent signalling pathways which regulate p38 MAPK activation through TLR2, leading to activation of NF-,B and AP-1 as well as induction of cell death. [source] | |||||||||||||