Search results for "p38 mitogen-activated protein kinases"
showing 10 items of 145 documents
Effects of cerivastatin on adrenergic pathways, hypertrophic growth and TGFbeta expression in adult ventricular cardiomyocytes.
2010
Abstract The effects of statin treatment in the setting of heart failure have already been shown. Nevertheless, there is little knowledge about its influence on adrenergic pathways in cardiomyocytes. Therefore, this study investigated the impact of cerivastatin on adrenoceptor-mediated signalling pathways in isolated adult ventricular cardiomyocytes. It focused on two endpoints: hypertrophic growth and TGFbeta expression. Cultured cardiomyocytes were used to study rac activation (analysed by its translocation into the membrane fraction), ROS formation (H 2 DCF fluorescence) and hypertrophic growth ( 14 C-phenylalanine incorporation). Alpha- and beta-adrenoceptor stimulation showed significa…
Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms
2015
Background: There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms. Methods: Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GA…
Rac1 GTPase, a multifunctional player in the regulation of genotoxic stress response
2013
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the Ras-homologous (Rho) family of small GTPases, which transduce signals from the outside to the inside of a cell. Rac1 becomes activated upon ligand binding of a variety of receptors, including receptor tyrosine kinases and heterotrimeric G-protein-coupled receptors. After GTP loading by guanine exchange factors (GEFs), GTP-bound Rac1 engages numerous effector proteins, thereby eventually regulating cell motility and adhesion, cell cycle progression through G1, mitosis and meiosis, as well as cell death and metastasis.1 Besides, Rac1 adjusts cellular responses to genotoxic agents, such as UV light and alkylating agents, by r…
Pharmacologic therapies in endometriosis: a systematic review
2012
To assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of endometriosis, we performed a systematic review of publications from March 2002 to January 2012 via PubMed search. Additional relevant articles were identified from citations within these publications. A high number of medications were tested in preclinical models of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease, such as inflammatory response, angiogenesis and cell survival, proliferation, migration, adhesion, and invasion. Tumor necrosis factor α-blockers, nuclear factor κB inhibitors, antiangioge…
Fas signaling-mediated T
2018
Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-β activation. In addition, PKC-β also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, rel…
From Five- to Six-Membered Rings: 3,4-Diarylquinolinone as Lead for Novel p38MAP Kinase Inhibitors
2007
In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38alphaMAPK IC50 of 1.8 muM. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38alpha- and JNK3-assay, whereas 5 was selective for p38alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compound…
Signaling pathways of the TREM-1- and TLR4-mediated neutrophil oxidative burst.
2008
The triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in the innate inflammatory response to microbial infections. Activation and expression of TREM-1 by polymorphonuclear neutrophils (PMN) occurs in concert with Toll-like receptors (TLR) such as TLR4 for bacterial lipopolysaccharide. However, it is currently unclear how this is mediated on a molecular level. Using pharmacological inhibitors and Western blot analysis we demonstrate that phosphatidyl inositide 3-kinase, phospholipase C and the mitogen-activated kinase p38MAPK are essential for the TREM-1- and TLR4-induced oxidative burst of human PMN. The activation of protein kinase B and extracellular signal-related kin…
Molecular mechanism of α2β1 integrin interaction with human echovirus 1
2009
Conformational activation increases the affinity of integrins to their ligands. On ligand binding, further changes in integrin conformation elicit cellular signalling. Unlike any of the natural ligands of alpha2beta1 integrin, human echovirus 1 (EV1) seemed to bind more avidly a 'closed' than an activated 'open' form of the alpha2I domain. Furthermore, a mutation E336A in the alpha2 subunit, which inactivated alpha2beta1 as a collagen receptor, enhanced alpha2beta1 binding to EV1. Thus, EV1 seems to recognize an inactive integrin, and not even the virus binding could trigger the conformational activation of alpha2beta1. This was supported by the fact that the integrin clustering by EV1 did …
Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activat…
2012
Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kin…
Structure-Activity Relationships and X-ray Structures Describing the Selectivity of Aminopyrazole Inhibitors for c-Jun N-terminal Kinase 3 (JNK3) ove…
2009
c-Jun N-terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structure-based drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC(50) = 7 nm)…