scholarly journals KMUP-1 Ameliorates Ischemia-Induced Cardiomyocyte Apoptosis through the NO–cGMP–MAPK Signaling Pathways

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1376 ◽  
Author(s):  
Meng-Luen Lee ◽  
Erna Sulistyowati ◽  
Jong-Hau Hsu ◽  
Bo-Yau Huang ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Cell Viability ◽  
Soluble Guanylate Cyclase ◽  
Mapk Signaling ◽  
No Synthase ◽  
Mitogen Activated Protein Kinase ◽  
H9c2 Cells ◽  
Extracellular Signal ◽  
Induced Apoptosis

To test whether KMUP-1 (7-[2-[4-(2-chlorophenyl) piperazinyl]ethyl]-1,3-dimethylxanthine) prevents myocardial ischemia-induced apoptosis, we examined KMUP-1-treated H9c2 cells culture. Recent attention has focused on the activation of nitric oxide (NO)-guanosine 3', 5'cyclic monophosphate (cGMP)-protein kinase G (PKG) signaling pathway triggered by mitogen-activated protein kinase (MAPK) family, including extracellular-signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 in the mechanism of cardiac protection during ischemia-induced cell-death. We propose that KMUP-1 inhibits ischemia-induced apoptosis in H9c2 cells culture through these pathways. Cell viability was assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and apoptotic evaluation was conducted using DNA ladder assay and Hoechst 33342 staining. The level of intracellular calcium was detected using - Fura2-acetoxymethyl (Fura2-AM) staining, and mitochondrial calcium with Rhod 2-acetoxymethyl (Rhod 2-AM) staining under fluorescence microscopic observation. The expression of endothelium NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase α1 (sGCα1), PKG, Bcl-2/Bax ratio, ERK1/2, p38, and JNK proteins were measured by Western blotting assay. KMUP-1 pretreatment improved cell viability and inhibited ischemia-induced apoptosis of H9c2 cells. Calcium overload both in the intracellular and mitochondrial sites was attenuated by KMUP-1 pretreatment. Moreover, KMUP-1 reduced intracellular reactive oxygen species (ROS), increased plasma NOx (nitrite and nitrate) level, and the expression of eNOS. Otherwise, the iNOS expression was downregulated. KMUP-1 pretreatment upregulated the expression of sGCα1 and PKG protein. The ratio of Bcl-2/Bax expression was increased by the elevated level of Bcl2 and decreased level of Bax. In comparison with the ischemia group, KMUP-1 pretreatment groups reduced the expression of phosphorylated extracellular signal-regulated kinases ERK1/2, p-p38, and p-JNK as well. Therefore, KMUP-1 inhibits myocardial ischemia-induced apoptosis by restoration of cellular calcium influx through the mechanism of NO-cGMP-MAPK pathways.

NaF Activates MAPKs and Induces Apoptosis in Odontoblast-like Cells

2009 ◽  
Vol 88 (5) ◽  
pp. 461-465 ◽  
Author(s):  
H. Karube ◽  
G. Nishitai ◽  
K. Inageda ◽  
H. Kurosu ◽  
M. Matsuoka
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cytotoxic Effects ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways ◽  
Erk Kinase

The cytotoxic effects of fluoride on odontoblasts are not clear. In this study, we examined whether NaF induces apoptosis in MDPC-23 odontoblast-like cells and the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in NaF-induced apoptosis. MDPC-23 cells incubated with 5 mM NaF for 24 hrs exhibited caspase-3 activation, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and an increase in cytoplasmic nucleosomes. Prior to the induction of apoptosis, all MAPKs examined were phosphorylated, but in a different manner. In contrast to the sustained phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38, NaF exposure induced a biphasic phosphorylation of extracellular signal-regulated protein kinase (ERK). NaF-induced apoptosis was markedly suppressed by treatment with the JNK inhibitor, SP600125, and mildly suppressed by the MAPK/ERK kinase inhibitor, U0126. Inhibition of p38 activity did not protect cells from apoptosis. Thus, exposure to NaF induces apoptosis in odontoblast-like cells, depending on JNK and, less significantly, ERK pathways.

Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells

Blood ◽  
2001 ◽  
Vol 98 (7) ◽  
pp. 2175-2182 ◽  
Author(s):  
Amaya Puig-Kröger ◽  
Miguel Relloso ◽  
Oskar Fernández-Capetillo ◽  
Ana Zubiaga ◽  
Augusto Silva ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Mannose Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Functional Maturation ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Mitogen Activated Protein

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor α [TNF-α] and interleukin-1β [IL-1β]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1–extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-α– and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor–mediated endocytic activity; nuclear factor-κB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-α. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.

Potentiation of nitric oxide-induced apoptosis in p53−/− vascular smooth muscle cells

2002 ◽  
Vol 282 (3) ◽  
pp. C625-C634 ◽  
Author(s):  
Melina R Kibbe ◽  
Jianrong Li ◽  
Suhua Nie ◽  
Byung Min Choi ◽  
Imre Kovesdi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Pathways ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53−/− and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53−/− VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53−/− cells. NO-induced apoptosis in p53−/− VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53−/− VSMC with S-nitroso- N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH2-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.

scholarly journals Novel Molecular Basis for Synapse Formation: Small Non-coding Vault RNA Functions as a Riboregulator of MEK1 to Modulate Synaptogenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Toshiyuki Araki
Keyword(s):  
Protein Kinase ◽  
Molecular Basis ◽  
Synapse Formation ◽  
Regulatory Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Small non-coding vault RNAs (vtRNAs) have been described as a component of the vault complex, a hollow-and-barrel-shaped ribonucleoprotein complex found in most eukaryotes. It has been suggested that the function of vtRNAs might not be limited to simply maintaining the structure of the vault complex. Despite the increasing research on vtRNAs, little is known about their physiological functions. Recently, we have shown that murine vtRNA (mvtRNA) up-regulates synaptogenesis by activating the mitogen activated protein kinase (MAPK) signaling pathway. mvtRNA binds to and activates mitogen activated protein kinase 1 (MEK1), and thereby enhances MEK1-mediated extracellular signal-regulated kinase activation. Here, we introduce the regulatory mechanism of MAPK signaling in synaptogenesis by vtRNAs and discuss the possibility as a novel molecular basis for synapse formation.

scholarly journals Treponema denticola Activates Mitogen-Activated Protein Kinase Signal Pathways through Toll-Like Receptor 2

2007 ◽  
Vol 75 (12) ◽  
pp. 5763-5768 ◽  
Author(s):  
John Ruby ◽  
Kunal Rehani ◽  
Michael Martin
Keyword(s):  
Protein Kinase ◽  
Mapk Signaling ◽  
Innate Immune ◽  
Mitogen Activated Protein Kinase ◽  
Signal Pathways ◽  
Treponema Denticola ◽  
Toll Like Receptor ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Toll Like Receptor 2

ABSTRACT Treponema denticola, a spirochete indigenous to the oral cavity, is associated with host inflammatory responses to anaerobic polymicrobial infections of the root canal, periodontium, and alveolar bone. However, the cellular mechanisms responsible for the recognition of T. denticola by the innate immune system and the underlying cell signaling pathways that regulate the inflammatory response to T. denticola are currently unresolved. In this study, we demonstrate that T. denticola induces innate immune responses via the utilization of Toll-like receptor 2 (TLR2) but not TLR4. Assessment of TLR2/1 and TLR2/6 heterodimers revealed that T. denticola predominantly utilizes TLR2/6 for the induction of cellular responses. Analysis of the mitogen-activated protein kinase (MAPK) signaling pathway in T. denticola-stimulated monocytes identified a prolonged up-regulation of the MAPK extracellular signal-related kinase 1/2 (ERK1/2) and p38, while no discernible increase in phospho-c-Jun N-terminal kinase 1/2 (JNK1/2) levels was observed. With the aid of pharmacological inhibitors selectively targeting ERK1/2 via the mitogen-activated protein kinase/extracellular signal-related kinase 1/2 kinase and p38, we further demonstrate that ERK1/2 and p38 play a major role in T. denticola-mediated pro- and anti-inflammatory cytokine production.

scholarly journals Activation of Mitogen-activated Protein Kinase (Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase) Cascade by Aldosterone

2002 ◽  
Vol 13 (9) ◽  
pp. 3042-3054 ◽  
Author(s):  
Eunan Hendron ◽  
James D. Stockand
Keyword(s):  
Protein Kinase ◽  
Glucocorticoid Receptor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Gtp Binding ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Subsequent Activation

Aldosterone in some tissues increases expression of the mRNA encoding the small monomeric G protein Ki-RasA. Renal A6 epithelial cells were used to determine whether induction of Ki-ras leads to concomitant increases in the total as well as active levels of Ki-RasA and whether this then leads to subsequent activation of its effector mitogen-activated protein kinase (MAPK/extracellular signal-regulated kinase) cascade. The molecular basis and cellular consequences of this action were specifically investigated. We identified the intron 1-exon 1 region (rasI/E1) of the mouse Ki-ras gene as sufficient to reconstitute aldosterone responsiveness to a heterologous promotor. Aldosterone increased reporter gene activity containing rasI/E1 threefold. Aldosterone increased the absolute and GTP-bound levels of Ki-RasA by a similar extent, suggesting that activation resulted from mass action and not effects on GTP binding/hydrolysis rates. Aldosterone significantly increased Ki-RasA and MAPK activity as early as 15 min with activation peaking by 2 h and waning after 4 h. Inhibitors of transcription, translation, and a glucocorticoid receptor antagonist attenuated MAPK signaling. Similarly, rasI/E1-driven luciferase expression was sensitive to glucocorticoid receptor blockade. Overexpression of dominant-negative RasN17, addition of antisense Ki-rasA and inhibition of mitogen-activated protein kinase kinase also attenuated steroid-dependent increases in MAPK signaling. Thus, activation of MAPK by aldosterone is dependent, in part, on a genomic mechanism involving induction of Ki-ras transcription and subsequent activation of its downstream effectors. This genomic mechanism has a distinct time course from activation by traditional mitogens, such as serum, which affect the GTP-binding state and not absolute levels of Ras. The result of such a genomic mechanism is that peak activation of the MAPK cascade by adrenal corticosteroids is delayed but prolonged.

scholarly journals Role of Glycine Receptor α3 in the Phosphorylation of Extracellular Signal-Regulated Kinase by Prostaglandin E2

2020 ◽  
Author(s):  
Hung-Chen Wang ◽  
Kuang-I Cheng ◽  
Kuang-Yi Tseng ◽  
Aij-Lie Kwan ◽  
Lin-Li Chang
Keyword(s):  
Protein Kinase ◽  
Cell Viability ◽  
Glycine Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Prostaglandin E ◽  
Activating Transcription Factor 3 ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Protein Kinase C Inhibitor

Abstract Background: Glycine receptors (GlyRs) play a key role in the processing of inflammatory pain. We used Adeno-associated virus (AAV) for GlyRα1/3 gene transfer in F11 neuron cells, and investigated the effects and roles of pAAV-GlyRα1/3 on cell cytotoxicity and the prostaglandin E2 (PGE2)-mediated inflammatory response. Methods: pAAV-GlyRα1 and pAAV-GlyRα3 recombinant vectors were constructed, and cell viability was measured following pAAV-GlyRα1/3 transfection. The activation of mitogen-activated protein kinase (MAPK) inflammatory signaling and neuronal injury marker activating transcription factor 3 (ATF-3) were evaluated by western blotting; the level of cytokine expression was measured by ELISA.Results: We found that pAAV/pAAV-GlyRα1/3 transfection slightly, but not significantly, increased cell viability and induced extracellular signal-regulated kinase (ERK1/2) phosphorylation and ATF-3 activation. However, the transfection reagent lipofectamine significantly increased cell death and induced ERK1/2 phosphorylation and ATF-3 activation. More importantly, the PGE2-induced ERK1/2 phosphorylation in F11 cells was repressed by the expression of pAAV-GlyRα3 and administration of an EP2 inhibitor (PF-04418948), GlyRαs antagonist (strychnine), and protein kinase C inhibitor (G06983).Conclusions: PGE2-induced ERK1/2 phosphorylation can be modulated by GlyRα3. In addition, no changes in the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or IL-6 of the F11 cells were observed 6 hours after lipopolysaccharide (LPS) or complete Freund's adjuvant (CFA) treatment. These data suggest that delivering pAAV-GlyRα3 into neuron cells should be safe for downregulating PGE2-induced ERK1/2 phosphorylation and inflammation.

scholarly journals Extracellular Signal-Regulated Kinase (ERK) Activation and Mitogen-Activated Protein Kinase Phosphatase 1 Induction by Pulsatile Gonadotropin-Releasing Hormone in Pituitary Gonadotrophs

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Haruhiko Kanasaki ◽  
Indri Purwana ◽  
Aki Oride ◽  
Tselmeg Mijiddorj ◽  
Kohji Miyazaki
Keyword(s):  
Protein Kinase ◽  
Calcium Influx ◽  
Mapk Signaling ◽  
Gonadotropin Releasing Hormone ◽  
Mitogen Activated Protein Kinase ◽  
Erk Activation ◽  
Releasing Hormone ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The frequency of gonadotropin-releasing hormone (GnRH) pulse secreted from the hypothalamus differently regulates the expressions of gonadotropin subunit genes, luteinizing hormone β (LHβ) and follicle-stimulating hormone β (FSHβ), in the pituitary gonadotrophs. FSHβ is preferentially stimulated at slower GnRH pulse frequencies, whereas LHβ is preferentially stimulated at more rapid pulse frequencies. Several signaling pathways are activated, including mitogen-activated protein kinase (MAPK), protein kinase C, calcium influx, and calcium-calmodulin kinases, and these may be preferentially regulated under certain conditions. Previous studies demonstrated that MAPK pathways, especially the extracellular signal-regulated kinase (ERK), play an essential role for induction of gonadotropin subunit gene expression by GnRH, whereas, MAPK phosphatases (MKPs) inactivate MAPKs through dephosphorylation of threonine and/or tyrosine residues. MKPs are also induced by GnRH, and potential feedback regulation between MAPK signaling and MKPs within the GnRH signaling pathway is evident in gonadotrophs. In this paper, we reviewed and mainly focused on our observations of the pattern of ERK activation and the induction of MKP by different frequencies of GnRH stimulation.

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