Pharmacokinetics (PK) and pharmacodynamics (PD) of SCIO-469, a p38 gamma MAP kinase inhibitor

The postreceptor events regulating the signal of insulin downstream in rat intestinal cells have not yet been analyzed. Our objectives were to identify the nature of receptor substrates and phosphorylated proteins involved in the signaling of insulin and to investigate the mechanism(s) by which insulin enhances intestinal hydrolases. In response to insulin, the following proteins were rapidly phosphorylated on tyrosine residues: 1) insulin receptor substrates-1 (IRS-1), -2, and -4; 2) phospholipase C-isoenzyme-γ; 3) the Ras-GTPase-activating protein (GAP) associated with Rho GAP and p62Src; 4) the insulin receptor β-subunit; 5) the p85 subunits of phosphatidylinositol 3-kinase (PI 3-kinase); 6) the Src homology 2 α-collagen protein; 7) protein kinase B; 8) mitogen-activated protein (MAP) kinase-1 and -2; and 9) growth receptor-bound protein-2. Compared with controls, insulin enhanced the intestinal activity of MAP kinase-2 and protein kinase B by two- and fivefold, respectively, but did not enhance p70/S6 ribosomal kinase. Administration of an antireceptor antibody or MAP-kinase inhibitor PD-98059 but not a PI 3-kinase inhibitor (wortmannin) to sucklings inhibited the effects of insulin on mucosal mass and enzyme expression. We conclude that normal rat enterocytes express all of the receptor substrates and mediators involved in different insulin signaling pathways and that receptor binding initiates a signal enhancing brush-border membrane hydrolase, which appears to be regulated by the cascade of MAP kinases but not by PI 3-kinase.

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p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00171.2004 ◽

2005 ◽

Vol 98 (1) ◽

pp. 77-82 ◽

Cited By ~ 6

Author(s):

Hong Kan ◽

Dale Birkle ◽

Abnash C. Jain ◽

Conard Failinger ◽

Sherry Xie ◽

...

Keyword(s):

Map Kinase ◽

Cardiac Myocyte ◽

Kinase Inhibitor ◽

Ventricular Myocytes ◽

Myocardial Dysfunction ◽

P38 Map Kinase ◽

Border Detection ◽

Rat Ventricular Myocytes ◽

Adult Rat ◽

Fractional Shortening

Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovascular disease remain to be elucidated. An established animal model of stress in humans is the prenatally stressed (PS) rat. We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (control) were further subjected to restraint stress (R) at 6 and 7 wk of age. Echocardiography revealed a significant decrease in fractional shortening in PS + R vs. controls + R (45.8 ± 3.9 vs. 61.9 ± 2.4%, PS + R vs. controls + R; P < 0.01; n = 12). Isolated adult rat ventricular myocytes from PS + R also revealed diminished fractional shortening (6.7 ± 0.8 vs. 12.7 ± 1.1%, PS + R vs. controls + R; P < 0.01; n = 24) and blunted inotropic responses to isoproterenol ( P < 0.01; n = 24) determined by automated border detection. The p38 mitogen-activated protein (MAP) kinase inhibitor SB-203580 blocked p38 MAP kinase phosphorylation, reversed the depression in fractional shortening, and partially ameliorated the blunted adrenergic signaling seen in adult rat ventricular myocytes from PS + R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.

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Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca2+-mediated p38 MAP kinase activation

10.1101/603456 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicola M. Blythe ◽

Vasili Stylianidis ◽

Melanie J. Ludlow ◽

Hamish T. J. Gilbert ◽

Elizabeth L. Evans ◽

...

Keyword(s):

Map Kinase ◽

Structural Integrity ◽

Kinase Inhibitor ◽

Cardiac Fibroblasts ◽

Collagen Gel ◽

Mechanical Stretch ◽

Cardiac Fibroblast ◽

Ruthenium Red ◽

P38 Map Kinase ◽

Dependent Manner

AbstractPiezo1 is a mechanosensitive cation channel with widespread physiological importance; however its role in the heart is poorly understood. Cardiac fibroblasts are responsible for preserving the structural integrity of the myocardium and play a key role in regulating its repair and remodeling following stress or injury. We investigated expression and function of Piezo1 in cultured human and mouse cardiac fibroblasts. RT-PCR studies confirmed expression ofPiezo1mRNA in cardiac fibroblasts at similar levels to endothelial cells. Fura-2 intracellular Ca2+measurements validated Piezo1 as a functional ion channel that was activated by the Piezo1 agonist, Yoda1. Yoda1-induced Ca2+entry was inhibited by Piezo1 blockers (gadolinium, ruthenium red) and the Ca2+response was reduced proportionally by Piezo1 siRNA knockdown or in cells fromPiezo1+/−mice. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation opposed cardiac fibroblast differentiation; data confirmed by functional collagen gel contraction assays. Piezo1 activation using Yoda1 or mechanical stretch also increased the expression of interleukin-6 (IL-6), a mechanosensitive pro-hypertrophic and pro-fibrotic cytokine, in a Piezo1-dependent manner. Multiplex kinase activity profiling combined with kinase inhibitor studies and phospho-specific western blotting, established that Piezo1 activation stimulated IL-6 secretion via a pathway involving p38 MAP kinase, downstream of Ca2+entry. In summary, this study reveals that cardiac fibroblasts express functional Piezo1 channels coupled to reduced myofibroblast activation and increased secretion of paracrine signaling molecules that can modulate cardiac remodeling.

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Effects of 1α,25-dihydroxy-vitamin D3 pretreatment and MAP kinase inhibitor PD 98059 on response of osteoblasts to prostate-derived osteoblastic factors

Oncology Reports ◽

10.3892/or.10.5.1529 ◽

2003 ◽

Author(s):

Ernst Ulsperger ◽

Gerhard Hamilton ◽

Ulrike Olszewski ◽

Gerhard Baumgartner ◽

Alfred Engel ◽

...

Keyword(s):

Map Kinase ◽

Vitamin D3 ◽

Kinase Inhibitor

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Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.3.g429 ◽

2000 ◽

Vol 278 (3) ◽

pp. G429-G437 ◽

Cited By ~ 21

Author(s):

Amy K. Cook ◽

Michael Carty ◽

Cherie A. Singer ◽

Ilia A. Yamboliev ◽

William T. Gerthoffer

Keyword(s):

Smooth Muscle ◽

Map Kinase ◽

Muscarinic Receptors ◽

Map Kinases ◽

Kinase Inhibitor ◽

Receptor Activation ◽

Inhibitory Effect ◽

Subsequent Treatment ◽

P38 Map Kinase

Coupling of M2 and M3 muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M3 receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser789), a putative downstream target of MAP kinases. Alkylation of M3 receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 μM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M2 receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M2receptor activation in smooth muscle.

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