scholarly journals Pleckstrin Levels Are Increased in Patients with Chronic Periodontitis and Regulated via the MAP Kinase-p38α Signaling Pathway in Gingival Fibroblasts

2022 ◽  
Vol 12 ◽  
Author(s):  
M. Abdul Alim ◽  
Duncan Njenda ◽  
Anna Lundmark ◽  
Marta Kaminska ◽  
Leif Jansson ◽  
...  
Keyword(s):  
Map Kinase ◽  
Inflammatory Disease ◽  
Chronic Periodontitis ◽  
Alveolar Bone ◽  
Kinase Inhibitor ◽  
Chronic Inflammatory Disease ◽  
P38 Map Kinase ◽  
Gingival Tissue ◽  
Signal Pathways ◽  
Gingival Fibroblasts

Chronic periodontitis (CP) is a bacteria-driven inflammatory disease characterized by the breakdown of gingival tissue, the periodontal ligament, and alveolar bone, leading ultimately to tooth loss. We previously reported the pleckstrin gene (PLEK) to be highly upregulated in gingival tissue of patients with CP and the only gene concurrently upregulated in other inflammatory diseases including rheumatoid arthritis and cardiovascular diseases. Using saliva from 169 individuals diagnosed with CP and healthy controls, we investigated whether pleckstrin could serve as a novel biomarker of periodontitis. Additionally, we explored signal pathways involved in the regulation of PLEK using human gingival fibroblasts (HGFs). Pleckstrin levels were significantly higher (p < 0.001) in the saliva samples of patients with CP compared to controls and closely associated with CP severity. Immunohistochemical analysis revealed the expression of pleckstrin in inflammatory cells and gingival fibroblasts of CP patients. To explore the signal pathways involved in pleckstrin regulation, we stimulated HGFs with either interleukin-1β (IL-1β) or lipopolysaccharides (LPS) alone, or in combination with inhibitors targeting c-Jun N-terminal kinase, tyrosine kinase, protein kinase C, or p38 MAP kinase. Results showed that IL-1β and LPS significantly increased PLEK mRNA and pleckstrin protein levels. VX-745, the p38 MAP kinase inhibitor significantly decreased IL-1β- and LPS-induced pleckstrin levels at both the mRNA and the protein level. Together, these findings show that pleckstrin could serve as a salivary biomarker for the chronic inflammatory disease periodontitis and a regulator of inflammation via the p38 MAP kinase pathway.

p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

2005 ◽  
Vol 98 (1) ◽  
pp. 77-82 ◽  
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.

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

2019 ◽  
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.

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

2000 ◽  
Vol 278 (3) ◽  
pp. G429-G437 ◽  
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.

scholarly journals PD55-05 THERAPEUTIC EFFECTS OF P38 MAP KINASE INHIBITOR ON BLADDER DYSFUNCTION IN MICE WITH SPINAL CORD INJURY (SCI)

2018 ◽  
Vol 199 (4S) ◽  
Author(s):  
Nobutaka Shimizu ◽  
Takahisa Suzuki ◽  
Ei-ichiro Takaoka ◽  
Joombeom Kwon ◽  
Naoki Wada ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Map Kinase ◽  
Bladder Dysfunction ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Therapeutic Effects ◽  
Cord Injury

scholarly journals Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells

2009 ◽  
Vol 297 (5) ◽  
pp. G878-G885 ◽  
Author(s):  
Seema Saksena ◽  
Saritha Theegala ◽  
Nikhil Bansal ◽  
Ravinder K. Gill ◽  
Sangeeta Tyagi ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitor ◽  
Apical Membrane ◽  
P38 Map Kinase ◽  
Monocarboxylate Transporter ◽  
Maximal Velocity ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Human Intestine ◽  
Monocarboxylate Transporter 1

Somatostatin (SST), an important neuropeptide of the gastrointestinal tract has been shown to stimulate sodium chloride absorption and inhibit chloride secretion in the intestine. However, the effects of SST on luminal butyrate absorption in the human intestine have not been investigated. Earlier studies from our group and others have shown that monocarboxylate transporter (MCT1) plays an important role in the transport of butyrate in the human intestine. The present studies were undertaken to examine the effects of SST on butyrate uptake utilizing postconfluent human intestinal epithelial Caco2 cells. Apical SST treatment of Caco-2 cells for 30–60 min significantly increased butyrate uptake in a dose-dependent manner with maximal increase at 50 nM (∼60%, P < 0.05). SST receptor 2 agonist, seglitide, mimicked the effects of SST on butyrate uptake. SST-mediated stimulation of butyrate uptake involved the p38 MAP kinase-dependent pathway. Kinetic studies demonstrated that SST increased the maximal velocity ( Vmax) of the transporter by approximately twofold without any change in apparent Michaelis-Menten constant ( Km). The higher butyrate uptake in response to SST was associated with an increase in the apical membrane levels of MCT1 protein parallel to a decrease in the intracellular MCT1 pool. MCT1 has been shown to interact specifically with CD147 glycoprotein/chaperone to facilitate proper expression and function of MCT1 at the cell surface. SST significantly enhanced the membrane levels of CD147 as well as its association with MCT1. This association was completely abolished by the specific p38 MAP kinase inhibitor, SB203580. Our findings demonstrate that increased MCT1 association with CD147 at the apical membrane in response to SST is p38 MAP kinase dependent and underlies the stimulatory effects of SST on butyrate uptake.

scholarly journals p38 MAP Kinase Inhibitor Suppresses Transforming Growth Factor-β2–Induced Type 1 Collagen Production in Trabecular Meshwork Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120774 ◽  
Author(s):  
Miyuki Inoue-Mochita ◽  
Toshihiro Inoue ◽  
Tomokazu Fujimoto ◽  
Takanori Kameda ◽  
Nanako Awai-Kasaoka ◽  
...  
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Collagen Production ◽  
Trabecular Meshwork Cells ◽  
Transforming Growth Factor Β2
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