scholarly journals Flavonoid Naringenin: A Potential Immunomodulator forChlamydia trachomatisInflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Abebayehu N. Yilma ◽  
Shree R. Singh ◽  
Lisa Morici ◽  
Vida A. Dennis
Keyword(s):  
Inflammatory Mediators ◽  
Mapk Pathway ◽  
Costimulatory Molecule ◽  
Asymptomatic Infection ◽  
Mitogen Activated Protein Kinase ◽  
Gene Transcript ◽  
Dependent Manner ◽  
Sexually Transmitted ◽  
Gm Csf ◽  
Mitogen Activated Protein

Chlamydia trachomatis, the agent of bacterial sexually transmitted infections, can manifest itself as either acute cervicitis, pelvic inflammatory disease, or a chronic asymptomatic infection. Inflammation induced byC. trachomatiscontributes greatly to the pathogenesis of disease. Here we evaluated the anti-inflammatory capacity of naringenin, a polyphenolic compound, to modulate inflammatory mediators produced by mouse J774 macrophages infected with liveC. trachomatis. Infected macrophages produced a broad spectrum of inflammatory cytokines (GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10) and chemokines (CCL4, CCL5, CXCL1, CXCL5, and CXCL10) which were downregulated by naringenin in a dose-dependent manner. Enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4 in addition to the CD86 costimulatory molecule on infected macrophages were modulated by naringenin. Pathway-specific inhibition studies disclosed that p38 mitogen-activated-protein kinase (MAPK) is involved in the production of inflammatory mediators by infected macrophages. Notably, naringenin inhibited the ability ofC. trachomatisto phosphorylate p38 in macrophages, suggesting a potential mechanism of its attenuation of concomitantly produced inflammatory mediators. Our data demonstrates that naringenin is an immunomodulator of inflammation triggered byC. trachomatis, which possibly may be mediated upstream by modulation of TLR2, TLR4, and CD86 receptors on infected macrophages and downstream via the p38 MAPK pathway.

scholarly journals Phosphorylation of High-Mobility Group Protein A2 by Nek2 Kinase during the First Meiotic Division in Mouse Spermatocytes

2004 ◽  
Vol 15 (3) ◽  
pp. 1224-1232 ◽  
Author(s):  
Silvia Di Agostino ◽  
Monica Fedele ◽  
Paolo Chieffi ◽  
Alfredo Fusco ◽  
Pellegrino Rossi ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Chromatin Condensation ◽  
High Mobility ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Correct Process ◽  
High Mobility Group Protein ◽  
Mitogen Activated Protein ◽  
Pachytene Spermatocytes

The mitogen-activated protein kinase (MAPK) pathway is required for maintaining the chromatin condensed during the two meiotic divisions and to avoid a second round of DNA duplication. However, molecular targets of the MAPK pathway on chromatin have not yet been identified. Here, we show that the architectural chromatin protein HMGA2 is highly expressed in male meiotic cells. Furthermore, Nek2, a serine-threonine kinase activated by the MAPK pathway in mouse pachytene spermatocytes, directly interacts with HMGA2 in vitro and in mouse spermatocytes. The interaction does not depend on the activity of Nek2 and seems constitutive. On progression from pachytene to metaphase, Nek2 is activated and HMGA2 is phosphorylated in an MAPK-dependent manner. We also show that Nek2 phosphorylates in vitro HMGA2 and that this phosphorylation decreases the affinity of HMGA2 for DNA and might favor its release from the chromatin. Indeed, we find that most HMGA2 associates with chromatin in mouse pachytene spermatocytes, whereas it is excluded from the chromatin upon the G2/M progression. Because hmga2-/- mice are sterile and show a dramatic impairment of spermatogenesis, it is possible that the functional interaction between HMGA2 and Nek2 plays a crucial role in the correct process of chromatin condensation in meiosis.

scholarly journals Paclitaxel Inhibits Synoviocyte Migration and Inflammatory Mediator Production in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaochen Chen ◽  
Haofeng Lin ◽  
Jinyang Chen ◽  
Lisheng Wu ◽  
Junqing Zhu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Mediator ◽  
Mapk Pathway ◽  
Bone Destruction ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Inflammatory Mediator Production ◽  
Tnf Α ◽  
Mitogen Activated Protein

Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.

LPA is a novel lipid regulator of mesangial cell hexokinase activity and HKII isoform expression

2002 ◽  
Vol 283 (2) ◽  
pp. F271-F279 ◽  
Author(s):  
Platina E. Coy ◽  
Navin Taneja ◽  
Iris Lee ◽  
Claudie Hecquet ◽  
Jane M. Bryson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Glomerular Injury ◽  
Mitogen Activated Protein ◽  
Extracellular Lipid ◽  
Cell Mitogen

The prototypical extracellular phospholipid mediator, lysophosphatidic acid (LPA), exhibits growth factor-like properties and represents an important survival factor in serum. This potent mesangial cell mitogen is increased in conditions associated with glomerular injury. It is also a known activator of the classic mitogen-activated protein kinase (MAPK) pathway, which plays an important role in the regulation of mesangial cell hexokinase (HK) activity. To better understand the mechanisms coupling metabolism to injury, we examined the ability of LPA to regulate HK activity and expression in cultured murine mesangial cells. LPA increased total HK activity in a concentration- and time-dependent manner, with maximal increases of >50% observed within 12 h of exposure to LPA concentrations ≥25 μM (apparent ED50 2 μM). These effects were associated with increased extracellular signal-regulated kinase (ERK) activity and were prevented by the pharmacological inhibition of either MAPK/ERK kinase or protein kinase C (PKC). Increased HK activity was also associated with increased glucose (Glc) utilization and lactate accumulation, as well as selectively increased HKII isoform abundance. The ability of exogenous LPA to increase HK activity was both Ca2+independent and pertussis toxin insensitive and was mimicked by LPA-generating phospholipase A2. We conclude that LPA constitutes a novel lipid regulator of mesangial cell HK activity and Glc metabolism. This regulation requires sequential activation of both Ca2+-independent PKC and the classic MAPK pathway and culminates in increased HKII abundance. These previously unrecognized metabolic consequences of LPA stimulation have both physiological and pathophysiological implications. They also suggest a novel mechanism whereby metabolism may be coupled to cellular injury via extracellular lipid mediators.

scholarly journals Autophagic Cell Death byPoncirus trifoliataRafin., a Traditional Oriental Medicine, in Human Oral Cancer HSC-4 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Hye-Yeon Han ◽  
Bong-Soo Park ◽  
Guem San Lee ◽  
Seung-Hwa Jeong ◽  
Hyungwoo Kim ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Annexin V ◽  
Poncirus Trifoliata ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Anticancer Properties ◽  
Mitogen Activated Protein ◽  
Oral Cancer Cells

Poncirus trifoliataRafin. has long been used as anti-inflammatory and antiallergic agent to treat gastrointestinal disorders and pulmonary diseases such as indigestion, constipation, chest fullness, chest pain, bronchitis, and sputum in Korea.P. trifoliataextract has recently been reported to possess anticancer properties; however, its mechanisms of action remain unclear. In this study, its antiproliferative effects and possible mechanisms were investigated in HSC-4 cells. The methanol extract ofP. trifoliata(MEPT) significantly decreased the proliferation of HSC-4 cells (inhibitory concentration (IC)50= 142.7 μg/mL) in a dose-dependent manner. While there were no significant changes observed upon cell cycle analysis and ANNEXIN V and 7-AAD double staining in the MEPT-treated groups, the intensity of acidic vesicular organelle (AVO) staining and microtubule-associated protein 1 light chain (LC) 3-II protein expression increased in response to MEPT treatment. Furthermore, 3-methyladenine (3-MA, autophagy inhibitor) effectively blocked the MEPT-induced cytotoxicity of HSC-4 cells and triggered the activation of p38 and extracellular signal-regulated kinases (ERK) proteins. Taken together, our results indicate that MEPT is a potent autophagy agonist in oral cancer cells with antitumor therapeutic potential that acts through the mitogen-activated protein kinase (MAPK) pathway.

scholarly journals Involvement of the protein tyrosine phosphatase SHP-1 in Ras-mediated activation of the mitogen-activated protein kinase pathway.

1996 ◽  
Vol 16 (11) ◽  
pp. 5955-5963 ◽  
Author(s):  
S Krautwald ◽  
D Büscher ◽  
V Kummer ◽  
S Buder ◽  
M Baccarini
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Mapk Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Mitogen Activated Protein ◽  
Stimulating Factor

Ubiquitously expressed SH2-containing tyrosine phosphatases interact physically with tyrosine kinase receptors or their substrates and relay positive mitogenic signals via the activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. Conversely, the structurally related phosphatase SHP-1 is predominantly expressed in hemopoietic cells and becomes tyrosine phosphorylated upon colony-stimulating factor 1 treatment of macrophages without associating with the colony-stimulating factor 1 receptor tyrosine kinase. Mice lacking functional SHP-1 (me/me and me(v)/me(v)) develop systemic autoimmune disease with accumulation of macrophages, suggesting that SHP-1 may be a negative regulator of hemopoietic cell growth. By using macrophages expressing dominant negative Ras and the me(v)/me(v) mouse mutant, we show that SHP-1 is activated in the course of mitogenic signal transduction in a Ras-dependent manner and that its activity is necessary for the Ras-dependent activation of the MAPK pathway but not of the Raf-1 kinase. Consistent with a role for SHP-1 as an intermediate between Ras and the MEK-MAPK pathway, Ras-independent activation of the latter kinases by bacterial lipopolysaccharide occurred normally in me(v)/me(v) cells. Our results sharply accentuate the diversity of signal transduction in mammalian cells, in which the same signaling intermediates can be rearranged to form different pathways.

HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner

2001 ◽  
Vol 281 (1) ◽  
pp. F62-F70 ◽  
Author(s):  
Zhen-Xiang Liu ◽  
Christian H. Nickel ◽  
Lloyd G. Cantley
Keyword(s):  
Cell Adhesion ◽  
Mapk Pathway ◽  
Collecting Duct ◽  
Mapk Signaling ◽  
Atp Depletion ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Renal Tubular

Hepatocyte growth factor (HGF) has been shown to enhance recovery from renal tubular ischemia. We investigated the possibility that HGF improves recovery by preventing ischemia-induced loss of cell adhesion. Murine inner medullary collecting duct-3 (mIMCD-3) cells subjected to 90% ATP depletion demonstrated a 55% decrease in adhesion, an effect that was completely reversed by the addition of HGF. Assays examining release of adherent cells revealed similar results with 30 min of ATP depletion causing loss of adhesion of 25% of mIMCD-3 cells and HGF completely reversing this effect. In contrast, HGF was unable to reverse the loss of adhesion of cells exposed to 99% ATP depletion. Examination of the mitogen-activated protein kinase (MAPK) signaling pathway revealed that HGF could induce extracellular signal-regulated kinase (ERK) phosphorylation in control and 90% ATP-depleted cells but not in 99% ATP-depleted cells. Inhibition of ERK activation with U0126 completely blocked the HGF-dependent reversal of ATP-depleted cell adhesion. Thus ATP-depleted cells demonstrate a marked decrease in cell adhesion that is reversible by the addition of HGF. This effect of HGF requires activation of the MAPK pathway.

scholarly journals Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor α-β Heterodimeric Complex

1999 ◽  
Vol 19 (3) ◽  
pp. 1919-1927 ◽  
Author(s):  
Gilles B. Tremblay ◽  
André Tremblay ◽  
Fernand Labrie ◽  
Vincent Giguère
Keyword(s):  
Mapk Pathway ◽  
Activation Function ◽  
Estrogen Receptor Α ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Transcriptional Responses ◽  
Estrogen Response ◽  
Modified Dna ◽  
Mitogen Activated Protein ◽  
The Individual

ABSTRACT Estrogenic responses are now known to be mediated by two forms of estrogen receptors (ER), ERα and ERβ, that can function as homodimers or heterodimers. As homodimers the two have been recently shown to exhibit distinct transcriptional responses to estradiol (E2), antiestrogens, and coactivators, suggesting that the ER complexes are not functionally equivalent. However, because the three possible configurations of ER complexes all recognize the same estrogen response element, it has not been possible to evaluate the transcriptional properties of the ER heterodimer complex by transfection assays. Using ER subunits with modified DNA recognition specificity, we were able to measure the transcriptional properties of ERα-ERβ heterodimers in transfected cells without interference from the two ER homodimer complexes. We first demonstrated that the individual activation function 1 (AF-1) domains act in a dominant manner within the ERα-ERβ heterodimer: the mixed agonist-antagonist 4-hydroxytamoxifen acts as an agonist in a promoter- and cell context-dependent manner via the ERα AF-1, while activation of the complex by the mitogen-activated protein kinase (MAPK) pathway requires only the ERα- or ERβ-responsive MAPK site. Using ligand-binding and AF-2-defective mutants, we further demonstrated that while the ERα-ERβ heterodimer can be activated when only one E2-binding competent partner is present per dimer, two functional AF-2 domains are required for transcriptional activity. Taken together, the results of this study of a retinoid X receptor-independent heterodimer complex, the first such study, provide evidence of different stoichiometric requirements for AF-1 and -2 activity and demonstrate that AF-1 receptor-specific properties are maintained within the ERα-ERβ heterodimer.

scholarly journals KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

2019 ◽  
Vol 116 (44) ◽  
pp. 22122-22131 ◽  
Author(s):  
Dana Rabara ◽  
Timothy H. Tran ◽  
Srisathiyanarayanan Dharmaiah ◽  
Robert M. Stephens ◽  
Frank McCormick ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Structural Basis ◽  
Colorectal Cancers ◽  
Dependent Manner ◽  
Gtp Hydrolysis ◽  
Promote Tumor Growth ◽  
Mitogen Activated Protein

KRAS mutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. KRAS mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render KRAS-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that KRAS G13-mutated cancer cells are frequently comutated with NF1 GAP but NF1 is rarely mutated in cancers with KRAS codon 12 or 61 mutations. Neurofibromin protein (encoded by the NF1 gene) hydrolyzes GTP directly in complex with KRAS G13D, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset of KRAS G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.

scholarly journals Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

2006 ◽  
Vol 36 (2) ◽  
pp. 377-388 ◽  
Author(s):  
Young Sun Kang ◽  
Yun Gyu Park ◽  
Bo Kyung Kim ◽  
Sang Youb Han ◽  
Yi Hwa Jee ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vegf Mrna ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor

Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.

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