Ginsenoside Rg1 Downregulates the Shear Stress Induced MCP-1 Expression by Inhibiting MAPK Signaling Pathway

2015 ◽  
Vol 43 (02) ◽  
pp. 305-317 ◽  
Author(s):  
Jian He ◽  
Yu-Lin Li
Keyword(s):  
Shear Stress ◽  
Mapk Pathway ◽  
Inhibitory Effect ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ginsenoside Rg1 ◽  
Negative Effects ◽  
Specific Chemical ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

Ginsenoside Rg1 has been reported to possess anti-inflammatory activities, but the effects of Rg1 on the shear induced MCP-1 upregulation mechanism on endothelial cells (ECs) remain to be determined. In this study, we show that Rg1 down modulates shear induced pro-inflammatory cytokine MCP-1 gene expression and monocytes adhesion without potential cell toxicity. The negative effects on monocytes adhesion is due to a decrease in MCP-1 protein release. Furthermore, the inhibitory effect of Rg1 on the phosphorylation level of ERK, p38, and JNK mitogen-activated protein kinase (MAPK) induced by shear stress (SS) is similar with that of specific chemical inhibitors for MAPK pathways activation. These results demonstrate that ginsenoside Rg1 inhibits the shear induced inflammation by suppressing the MAPK pathway. This suggests that Rg1 may serve as a novel anti-inflammatory agent for inflammation-induced cardiovascular diseases treatment.

scholarly journals Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

2017 ◽  
Vol 43 (2) ◽  
pp. 540-552 ◽  
Author(s):  
Hany H. Arab ◽  
Samir A. Salama ◽  
Tamer M. Abdelghany ◽  
Hany A. Omar ◽  
El-Shaimaa A. Arafa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mapk Pathway ◽  
Lipid Peroxide ◽  
Mitogen Activated Protein Kinase ◽  
Camel Milk ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Anti Oxidant ◽  
Cox 2 ◽  
Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

scholarly journals 15-deoxy-Δ12,14-prostaglandin J2Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-κB and MAPK Signaling in HepG2 Cells

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Seung-Won Park ◽  
Chunghee Cho ◽  
Byung-Nam Cho ◽  
Youngchul Kim ◽  
Tae Won Goo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepg2 Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Activin A ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Regulatory Effects ◽  
Activin Receptors

15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ2regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ2(2 μM and 5 μM) had no effect. Activin A and 15d-PGJ2showed different regulatory effects on ActR and Smad expression, NF-κB p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ2and activin, 15d-PGJ2inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ2inhibited activin-induced NF-κB p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ2suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-κB and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-κB and the MAPK pathway via interaction with 15d-PGJ2/activin/Smad signaling.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals The Rho1p Exchange Factor Rgf1p Signals Upstream from the Pmk1 Mitogen-activated Protein Kinase Pathway in Fission Yeast

2009 ◽  
Vol 20 (2) ◽  
pp. 721-731 ◽  
Author(s):  
Patricia Garcia ◽  
Virginia Tajadura ◽  
Yolanda Sanchez
Keyword(s):  
Mapk Pathway ◽  
Osmotic Shock ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Integrity ◽  
Actin Reorganization ◽  
Exchange Factor ◽  
Mitogen Activated Protein ◽  
Chlorine Ion ◽  
Kinase Pathway

The Schizosaccharomyces pombe exchange factor Rgf1p specifically regulates Rho1p during polarized growth. Rgf1p activates the β-glucan synthase (GS) complex containing the catalytic subunit Bgs4p and is involved in the activation of growth at the second end, a transition that requires actin reorganization. In this work, we investigated Rgf1p signaling and observed that Rgf1p acted upstream from the Pck2p-Pmk1p MAPK signaling pathway. We noted that Rgf1p and calcineurin play antagonistic roles in Cl− homeostasis; rgf1Δ cells showed the vic phenotype (viable in the presence of immunosuppressant and chlorine ion) and were unable to grow in the presence of high salt concentrations, both phenotypes being characteristic of knockouts of the MAPK components. In addition, mutations that perturb signaling through the MAPK pathway resulted in defective cell integrity (hypersensitivity to caspofungin and β-glucanase). Rgf1p acts by positively regulating a subset of stimuli toward the Pmk1p-cell integrity pathway. After osmotic shock and cell wall damage HA-tagged Pmk1p was phosphorylated in wild-type cells but not in rgf1Δ cells. Finally, we provide evidence to show that Rgf1p regulates Pmk1p activation in a process that involves the activation of Rho1p and Pck2p, and we demonstrate that Rgf1p is unique in this signaling process, because Pmk1p activation was largely independent of the other two Rho1p-specific GEFs, Rgf2p and Rgf3p.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

scholarly journals Comparative Analysis of Transmembrane Regulators of the Filamentous Growth Mitogen-Activated Protein Kinase Pathway Uncovers Functional and Regulatory Differences

2015 ◽  
Vol 14 (9) ◽  
pp. 868-883 ◽  
Author(s):  
Hema Adhikari ◽  
Lauren M. Caccamise ◽  
Tanaya Pande ◽  
Paul J. Cullen
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Filamentous Growth ◽  
Mapk Signaling ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Rate Limiting Step ◽  
Mitogen Activated Protein ◽  
Multiple Signaling ◽  
Growth Pathway

ABSTRACTFilamentous growth is a microbial differentiation response that involves the concerted action of multiple signaling pathways. In budding yeast, one pathway that regulates filamentous growth is a Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway. Several transmembrane (TM) proteins regulate the filamentous growth pathway, including the signaling mucin Msb2p, the tetraspan osmosensor Sho1p, and an adaptor Opy2p. The TM proteins were compared to identify common and unique features. Msb2p, Sho1p, and Opy2p associated by coimmunoprecipitation analysis but showed predominantly different localization patterns. The different localization patterns of the proteins resulted in part from different rates of turnover from the plasma membrane (PM). In particular, Msb2p (and Opy2p) were turned over rapidly compared to Sho1p. Msb2p signaled from the PM, and its turnover was a rate-limiting step in MAPK signaling. Genetic analysis identified unique phenotypes of cells overexpressing the TM proteins. Therefore, each TM regulator of the filamentous growth pathway has its own regulatory pattern and specific function in regulating filamentous growth. This specialization may be important for fine-tuning and potentially diversifying the filamentation response.

scholarly journals Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

2017 ◽  
Author(s):  
Helma Zecena ◽  
Daniel Tveit ◽  
Zi Wang ◽  
Ahmed Farhat ◽  
Parvita Panchal ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Mapk Pathway ◽  
Treatment Resistance ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Model ◽  
Braf Mutations ◽  
Mitogen Activated Protein ◽  
Inhibitor Resistance ◽  
Mapk Inhibitor

AbstractKinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

Nanosized Modification Strategies for Improving the Antitumor Efficacy of MEK Inhibitors

2020 ◽  
Vol 21 (3) ◽  
pp. 228-251
Author(s):  
Yanan Li ◽  
Qingrong Dong ◽  
Ting Mei ◽  
Meichen Zheng ◽  
Ramasamy Raj Kumar ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Clinical Status ◽  
Drug Efficacy ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mek Inhibitors ◽  
Mitogen Activated Protein ◽  
Frontline Treatment ◽  
Personalized Cancer ◽  
Cancer Theranostics

The RAS-RAF-MEK-ERK signaling pathway (MAPK signaling) is hyperactivated in more than 30% of human cancers. The abnormal activation of this pathway is mainly due to the gain-offunction mutations in RAS or RAF genes. Furthermore, the crucial roles of mitogen-activated protein kinase kinase (MEK) in tumorigenesis, cell proliferation and apoptosis inhibition, make MEK inhibitors (MEKi) attractive candidates for the targeted therapy of MAPK pathway-related cancer. Several highly selective and potent non-ATP-competitive allosteric MEKi have been developed and have led to substantial improvements in clinical outcomes. However, the drug efficacies and response rates are limited due to complex pathway cross-talk and pessimistic drug solubility. Nanosized modifications have made great contributions to improving drug efficacies over the past decades. In this review, the important biological status of MEK kinase in the MAPK pathway is illuminated primarily to highlight the irreplaceable position and clinical status of MEKi. In addition, nanomodification strategies to enhance drug efficacy are briefly summarized, followed by the application advances of nanotechnology in the field of MEKi-related cancer theranostics. Finally, the obstacles impeding the development of nanosized MEKi are considered, and promising prospects are suggested. This informative report lays the groundwork for the clinical development of MEKi and outlines a rational frontline-treatment approach for personalized cancer treatment.

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