scholarly journals Inhibition of LPS-Induced Activation of Coagulation by p38 MAPK Inhibitor

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Lutz Koch ◽  
Stefan Hofer ◽  
Markus A. Weigand ◽  
David Frommhold ◽  
Johannes Poeschl ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Sandwich Elisa ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Inhibitory Effects ◽  
Coagulation Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

During Gram-negative sepsis, lipopolysaccharide (LPS) activates toll-like receptor (TLR) 4 and induces complex responses of immune system and coagulation. However, the underlying LPS signalling mechanism on coagulation activation remains complex. To determine the role of the intracellular signalling factors p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK) in the procoagulant response to LPS, coagulation process of human whole blood exposed to specific inhibitors was measured by thrombelastography. Samples were stimulated with LPS (100 μg/mL) after preincubation with BAY117082 (specific NF-κB inhibitor), SP600125 (specific JNK inhibitor), SB203580 (specific p38 MAPK inhibitor), or vehicle. SB203580 strongly inhibited LPS-induced coagulation activation, whereas BAY117082 and SP600125 showed no significant effect. Activation of p38 MAPK, NF-κB, and JNK and respective inhibitory effects were confirmed by Multi-Target Sandwich ELISA. In conclusion, activation of p38 MAPK is crucial for early LPS-induced activation of coagulation.

Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro  and In Vivo 

2006 ◽  
Vol 104 (6) ◽  
pp. 1266-1273 ◽  
Author(s):  
Philipp Lirk ◽  
Ingrid Haller ◽  
Robert R. Myers ◽  
Lars Klimaschewski ◽  
Yi-Chuan Kau ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
P38 Mapk ◽  
Local Anesthetic ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic. Methods Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition. Results Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580. Conclusions The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.

BIRB796 Inhibits p38 MAPK/Hsp27 Pathway and Enhances Cytotoxicity Triggered by Bortezomib, Hsp90 Inhibitor, and Dexamethasone in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3440-3440
Author(s):  
Hiroshi Yasui ◽  
Teru Hideshima ◽  
Hiroshi Ikeda ◽  
Janice Jin ◽  
Enrique M. Ocio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
P38 Mapk ◽  
Inhibitory Effect ◽  
Hsp90 Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Hsp27 Phosphorylation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract We have previously shown that heat shock protein (Hsp) 27 or its upstream molecule p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM). In this study, we evaluate the anti-tumor activity of combination treatment with novel p38 MAPK inhibitor BIRB796 and other therapeutics agents in MM. Although BIRB796 alone triggers a marginal growth inhibitory effect in MM cells, it blocked baseline and bortezomib-triggered upregulated phosphorylation of p38 MAPK and Hsp27, associated with enhanced cytotoxicity in combination with bortezomib. BIRB796 augmented bortezomib- triggered cleavage of caspase-8, caspase-9, and poly(ADP)-ribose polymerase (PARP). We next examined the combination of BIRB796 with Hsp90 inhibitor 17-AAG. Surprisingly, 17-AAG up-regulates protein expression and phosphorylation of Hsp27; conversely, BIRB796 inhibits this phosphorylation and enhances 17-AAG-induced cytotoxicity. Importantly, BIRB796 enhances cytotoxicity induced by 17-AAG plus bortezomib. BIRB796 also augments cytotoxicity of Dex in MM cells, associated with inhibition of Hsp27 phosphorylation. In bone marrow stromal cells (BMSCs), BIRB796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) triggered by either tumor necrosis factor-α or tumor growth factor-β 1. BIRB796 also inhibits IL-6 secretion in BMSCs triggered by adherence to MM cells, thereby inhibiting MM cell proliferation. These studies therefore suggest that BIRB796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor alone, and in combination with bortezomib, Hep90 inhibitor, or Dex, to improve patient outcome in MM.

scholarly journals The Proto-oncoprotein Brx Activates Estrogen Receptor β by a p38 Mitogen-activated Protein Kinase Pathway

2001 ◽  
Vol 276 (50) ◽  
pp. 46792-46797 ◽  
Author(s):  
Paul H. Driggers ◽  
James H. Segars ◽  
Domenica M. Rubino
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Active Form ◽  
Mitogen Activated Protein Kinase ◽  
The Novel ◽  
Mapk Activity ◽  
Dependent Activity ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERα via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERβ. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERβ activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERβ function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the β2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERβ. Our findings suggest that p38 MAPKs may be important regulators of ERβ activity.

scholarly journals A selective p38 MAPK inhibitor alleviates neuropathology and cognitive impairment by modulating microglia function in 5XFAD mouse

2020 ◽  
Author(s):  
Min Sung Gee ◽  
Seung Hwan Son ◽  
Seung Ho Jeon ◽  
Jimin Do ◽  
Namkwon Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
Mapk Inhibitor

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibition in AD has not been ascertained yet. Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5XFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the elevation of alternatively activated M2 markers. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies. Conclusion: Taken together, our results reveal that inhibition of p38 MAPK in the brain alleviates AD pathology and represents a potential strategy for AD therapy. It also suggests that NJK14047 is a promising candidate for AD treatment. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia

scholarly journals LPS- and LTA-Induced Expression of IL-6 and TNF-αin Neonatal and Adult Blood: Role of MAPKs and NF-κB

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Lutz Koch ◽  
David Frommhold ◽  
Kirsten Buschmann ◽  
Navina Kuss ◽  
Johannes Poeschl ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Lipoteichoic Acid ◽  
Necrosis Factor Alpha ◽  
Mitogen Activated Protein ◽  
Factor Alpha ◽  
P38 Mapk Inhibitor ◽  
Lps Activation ◽  
Necrosis Factor ◽  
Mapk Inhibitor

As nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) seem to be critical mediators in the inflammatory response, we studied the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) on (a) the activation of NF-κB and MAPKs and (b) the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) with or without the specific inhibitors of these intracellular signal transduction pathways in neonatal cord and adult blood. TNF-αand IL-6 concentrations showed a sharp increase in the supernatants of cord and adult whole blood after stimulation. TNF-αconcentrations were significantly higher, whereas IL-6 concentrations were tendentially lower in adult blood after stimulation. Stimulation with LPS or LTA resulted in a significantly decreased activation of p38 MAPK in neonatal compared with adult blood. Although LTA failed to induce additional ERK1/2 phosphorylation, LPS stimulation mediated the moderately increased levels of activated ERK1/2 in neonatal monocytes. The addition of the p38 MAPK inhibitor SB202190 significantly decreased IL-6 and TNF-αproduction upon LPS or LTA stimulation. Furthermore, the inhibition of ERK1/2 was able to reduce LPS-stimulated TNF-αproduction in neonatal blood. We conclude that p38 MAPK as well as ERK1/2 phosphorylation is crucially involved in LPS activation and could explain the differences in early cytokine response between neonatal and adult blood.

Effect of selective inhibition of the p38 MAP kinase pathway on platelet aggregation

2004 ◽  
Vol 92 (12) ◽  
pp. 1387-1393 ◽  
Author(s):  
Athan Kuliopulos ◽  
Ramon Mohanlal ◽  
Lidija Covic
Keyword(s):  
Platelet Aggregation ◽  
P38 Mapk ◽  
Coronary Intervention ◽  
Selective Inhibition ◽  
P38 Map Kinase ◽  
Significant Inhibition ◽  
Mitogen Activated Protein Kinase ◽  
Thromboxane Production ◽  
Mapk Inhibitor

SummarySystemic inflammation has been shown to be a contributing factor to the instability of atherosclerotic plaques in patients with acute coronary syndromes (ACS). VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI).The role of p38 MAPK in platelet aggregation of normal individuals was examined using the selective second generation p38 MAPK inhibitor VX-702. Treatment of platelets with thrombin (activates PAR1 and PAR4 thrombin receptors), SFLLRN (PAR1), AYPGKF (PAR4), collagen (α2β1 and GPVI/FCγIIR receptors) and U46619 (TXA2) resulted in strong activation of p38 MAPK. Activation of the GPIb von Willebrand factor receptor with ristocetin did not stimulate p38 MAPK. Pre-treatment of platelets with 1 μM VX-702 completely inhibited activation of p38 MAPK by thrombin, SFLLRN, AYPGKF, U46619, and collagen. There was no effect of VX-702 on platelet aggregation induced by any of the agonists in the presence or absence of aspirin, heparin or apyrase. It has been postulated that a potential role of p38 MAPK is to activate phospholipase A2 (cPLA2) which catalyses formation of arachidonic acid leading to production of thromboxane. Interestingly, we show contrasting effects of p38 MAPK inhibition as compared to aspirin inhibition on platelet aggregation in response to collagen. Blockade of TXA2 production by aspirin results in significant inhibition of collagen activation. However, VX-702 has no effect on collagen-mediated platelet aggregation, suggesting that blocking p38 MAPK does not effect thromboxane production in human platelets. Therefore, unlike aspirin blockade of thromboxane production in platelets, p38 MAPK inhibitors such as VX-702 do not significantly affect platelet function and would not be expected to contribute to an elevated risk of bleeding side-effects in treated patients.

scholarly journals Role of Mitogen-Activated Protein Kinases in Activation of Human Neutrophils by Antineutrophil Cytoplasmic Antibodies

2001 ◽  
Vol 12 (1) ◽  
pp. 37-46
Author(s):  
RALPH KETTRITZ ◽  
ADRIAN SCHREIBER ◽  
FRIEDRICH C. LUFT ◽  
HERMANN HALLER
Keyword(s):  
Flow Cytometry ◽  
Cell Surface ◽  
P38 Mapk ◽  
Respiratory Burst ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Human Neutrophils ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract. Antineutrophil cytoplasmic antibodies (ANCA) may be important in the pathophysiology of necrotizing vasculitis. ANCA activate human neutrophils primed with tumor necrosis factor-α (TNF-α) in vitro. TNF-α priming results in translocation of ANCA antigens to the cell surface, where they are recognized by the antibodies. The signaling mechanisms involved in TNF-α priming and subsequent ANCA-induced activation were investigated. TNF-α-primed neutrophils were stimulated with monoclonal antibodies (MAb) to human myeloperoxidase (MPO) and proteinase 3 (PR3), and with preparations of human ANCA (three patients with PR3-ANCA and two patients with MPO-ANCA). Respiratory burst was measured with superoxide dismutase-inhibitable ferricytochrome C reduction and using dihydro-rhodamine-1,2,3. Phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) and the extracellular signal-regulated kinase (ERK) were assessed by immunoblotting. ANCA-antigen translocation was studied by flow cytometry. The tyrosine phosphorylation inhibitor genistein, but not calphostin or staurosporin, resulted in a significant dose-dependent superoxide generation inhibition (11.6 ± 1.7 nmol to 2.1 ± 0.5 for PR3-ANCA, and 16.0 ± 2.8 to 3.3 ± 1.3 for MPO-ANCA). The p38-MAPK inhibitor (SB202190) and the ERK inhibitor (PD98059) diminished PR3-ANCA-mediated superoxide production dose dependently (11.6 ± 1.7 nmol O2- to 1.9 ± 0.6 with 50 μM SB202190 and 4.0 ± 0.6 with 50 μM PD098059, respectively). For MPO-ANCA, the results were similar (16.0 ± 2.8 nmol to 0.9 ± 1.0 nmol with SB202190 and 6.4 ± 2.4 nmol with PD98059, respectively). Western blot showed phosphorylation of both p38-MAPK and ERK during TNF-α priming. The p38-MAPK inhibitor and the ERK inhibitor showed the strongest effect on respiratory burst when added before TNF-α priming, further supporting an important role for both signaling pathways in the priming process. Flow cytometry showed that p38-MAPK inhibition decreased the translocation of PR3 (by 93 ± 2%) and of MPO (by 64 ± 2%). In contrast, no such effect was seen when ERK was inhibited. Thus, p38-MAPK and ERK are important for the TNF-α-mediated priming of neutrophils enabling subsequent ANCA-induced respiratory burst. However, both pathways show differential effects, whereby p38-MAPK controls the translocation of ANCA antigens to the cell surface.

scholarly journals The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Sônia A. L. Corrêa ◽  
Katherine L. Eales
Keyword(s):  
Neurodegenerative Diseases ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Cellular Localisation ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Normal Ageing ◽  
Actin Remodelling

A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

scholarly journals P38 MAPK Pharmacological Inhibitor SB203580 Alleviates Total Parenteral Nutrition-Induced Loss of Intestinal Barrier Function but Promotes Hepatocyte Lipoapoptosis

2017 ◽  
Vol 41 (2) ◽  
pp. 623-634 ◽  
Author(s):  
Yong-Tao Xiao ◽  
Wei-Hui Yan ◽  
Yi Cao ◽  
Jun-Kai Yan ◽  
Wei Cai
Keyword(s):  
Parenteral Nutrition ◽  
Palmitic Acid ◽  
Total Parenteral Nutrition ◽  
P38 Mapk ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Mitogen Activated Protein Kinase ◽  
Intestinal Barrier Function ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Background & Aims: Our previous studies have provided evidence that p38 mitogen-activated protein kinase (MAPK) is involved in total parenteral nutrition (TPN)-associated complications, but its exact effects and mechanisms have not been fully understood. This study aimed to evaluate the roles of p38 MAPK inhibitor SB203580 in the TPN-induced loss of intestinal barrier function and liver disease. Methods: A rodent model of TPN was used to analyze the roles of SB203580 in TPN-associated complications.Intestinal barrier function was evaluated by transepithelial electrical resistance (TER) and paracellular permeability in Caco-2 cells. The palmitic acid (PA) was used to induce hepatic lipoapoptosis in vitro. The lipoapoptosis was detected using Caspase-3/7 and lipid staining. Results: In the present study, we showed that SB203580 treatment significantly suppressed TPN-mediated intestinal permeability in rats. SB203580 treatment significantly inhibited IL-1β-induced an increase in tight junction permeability of Caco-2 cells via repressing the p38/ATF-2 signaling. Unexpectedly, SB203580 treatment enhanced hepatic lipoapoptosis in the model of TPN. Palmitic acid (PA)-induced hepatic lipoapoptosis in human liver cells was significantly augmented by the SB203580 treatment. Conclusions: We demonstrate that the p38 MAPK inhibitor SB203508 ameliorates intestinal barrier function but promotes hepatic lipoapoptosis in model of TPN.

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