Selective cyclooxygenase-2 inhibitors stimulate glucose transport in L6 myotubes in a protein kinase Cδ-dependent manner

2007 ◽  
Vol 73 (3) ◽  
pp. 368-377 ◽  
Author(s):  
Evgenia Alpert ◽  
Arie Gruzman ◽  
Tamar Tennenbaum ◽  
Shlomo Sasson
Keyword(s):  
Protein Kinase ◽  
Glucose Transport ◽  
Cyclooxygenase 2 ◽  
Dependent Manner ◽  
L6 Myotubes ◽  
Cyclooxygenase 2 Inhibitors ◽  
Protein Kinase Cδ

Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle

2004 ◽  
Vol 287 (1) ◽  
pp. E166-E173 ◽  
Author(s):  
Taro Toyoda ◽  
Tatsuya Hayashi ◽  
Licht Miyamoto ◽  
Shin Yonemitsu ◽  
Masako Nakano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Activation Process ◽  
Dependent Manner ◽  
Upstream Kinase ◽  
Metabolic Stresses ◽  
Amp Activated Protein Kinase

Recent studies have suggested that 5′AMP-activated protein kinase (AMPK) is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation, which leads to insulin-independent glucose transport in skeletal muscle. In the present study, we hypothesized that acute oxidative stress increases the rate of glucose transport via an AMPK-mediated mechanism. When rat epitrochlearis muscles were isolated and incubated in vitro in Krebs buffer containing the oxidative agent H2O2, AMPKα1 activity increased in a time- and dose-dependent manner, whereas AMPKα2 activity remained unchanged. The activation of AMPKα1 was associated with phosphorylation of AMPK Thr172, suggesting that an upstream kinase is involved in the activation process. H2O2-induced AMPKα1 activation was blocked in the presence of the antioxidant N-acetyl-l-cysteine (NAC), and H2O2 significantly increased the ratio of oxidized glutathione to glutathione (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. H2O2 did not cause an increase in the conventional parameters of AMPK activation, such as AMP and AMP/ATP. H2O2 increased 3- O-methyl-d-glucose transport, and this increase was partially, but significantly, blocked in the presence of NAC. Results were similar when the muscles were incubated in a superoxide-generating system using hypoxanthine and xanthine oxidase. Taken together, our data suggest that acute oxidative stress activates AMPKα1 in skeletal muscle via an AMP-independent mechanism and leads to an increase in the rate of glucose transport, at least in part, via an AMPKα1-mediated mechanism.

Chemosensitivity of newly established human malignant pleural mesothelioma cells: Significant growth inhibition by amrubicin, a novel 9-aminoanthracycline, or cyclooxygenase 2 inhibitor

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19060-e19060
Author(s):  
T. Hida ◽  
S. Ogawa ◽  
J. Park ◽  
J. Park ◽  
J. Shimizu ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Malignant Mesothelioma ◽  
Cyclooxygenase 2 ◽  
Pleural Mesothelioma ◽  
Dependent Manner ◽  
Promising Therapeutic Approach ◽  
Cyclooxygenase 2 Inhibitors

e19060 Background: Malignant pleural mesothelioma is asbestos-related malignancy that is highly resistant to current therapeutic modalities. Survival of patients with malignant mesothelioma is very poor, especially in advanced stage, regardless of a recent advancement of chemotherapeutical modalities of combination with cisplatin and antifolate. Methods: Eleven cell lines derived from malignant mesothelioma were established in our laboratory. Chemosensitivity of these cell lines to nine chemotherapeutic drugs (cisplatin, vinorelbine, irinotecan, gemcitabine, pemetrexed, gefitinib, erlotinib, and amrubicin and its active in vivo substance, amrubicin-13-OH) and four cyclooxygenase 2 inhibitors was tested by MTT assay. Results: Anti-cancer agents, cisplatin, vinorelbine, gemcitabine, gefitinib, or erlotinib, showed little growth inhibition, and pemetrexed and irinotecan showed modest growth inhibition in malignant mesothelioma cells, whereas amrubicin-13-OH showed strong growth inhibition. Cyclooxygenase 2 inhibitors inhibit proliferation of malignant mesothelioma cells in a dose-dependent manner: modest growth inhibition at clinically achievable low concentrations and complete growth inhibition at clinically achievable high concentrations by intrapleural instillation. In addition, enhanced growth suppression was obtained by using amrubicin-13-OH in combination with cyclooxygenase 2 inhibitor. Conclusions: Our study suggests that amrubicin can inhibit proliferation of malignant mesothelioma cells. In addition, the use of a cyclooxygenase 2 inhibitor may be a promising therapeutic approach in the treatment of mesothelioma, because previous studies indicated the presence of increased cyclooxygenase 2 expression in malignant mesothelioma, which is notoriously resistant to chemotherapy. No significant financial relationships to disclose.

scholarly journals Protein Kinase Cδ Mediates Insulin-Induced Glucose Transport in Primary Cultures of Rat Skeletal Muscle

1999 ◽  
Vol 13 (12) ◽  
pp. 2002-2012 ◽  
Author(s):  
Liora Braiman ◽  
Addy Alt ◽  
Toshio Kuroki ◽  
Motoi Ohba ◽  
Asia Bak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Primary Cultures ◽  
Rat Skeletal Muscle ◽  
Protein Kinase Cδ

scholarly journals Substance P enhances microglial density in the substantia nigra through neurokinin-1 receptor/NADPH oxidase-mediated chemotaxis in mice

2015 ◽  
Vol 129 (8) ◽  
pp. 757-767 ◽  
Author(s):  
Qingshan Wang ◽  
Esteban Oyarzabal ◽  
Belinda Wilson ◽  
Li Qian ◽  
Jau-Shyong Hong
Keyword(s):  
Protein Kinase ◽  
Substance P ◽  
Substantia Nigra ◽  
Nadph Oxidase ◽  
Dependent Manner ◽  
Neurokinin 1 Receptor ◽  
Microglial Proliferation ◽  
Neurokinin 1 ◽  
Deficient Mice ◽  
Protein Kinase Cδ

Reduced number of nigral microglia was observed in postnatal developing substance P (SP) and neurokinin 1 receptor (NK1R)-deficient mice. SP failed to interfere with microglial proliferation but induced migration through a NK1R /protein kinase Cδ (PKCδ)/NADPH oxidase (NOX2) pathway-dependent manner.

β-Hydroxybutyrate inhibits insulin-mediated glucose transport in mouse oxidative muscle

2010 ◽  
Vol 299 (3) ◽  
pp. E364-E373 ◽  
Author(s):  
Takashi Yamada ◽  
Shi-Jin Zhang ◽  
Håkan Westerblad ◽  
Abram Katz
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Action ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Blood ketone body levels increase during starvation and untreated diabetes. Here we tested the hypothesis that ketone bodies directly inhibit insulin action in skeletal muscle. We investigated the effect of d,l-β-hydroxybutyrate (BOH; the major ketone body in vivo) on insulin-mediated glucose uptake (2-deoxyglucose) in isolated mouse soleus (oxidative) and extensor digitorum longus (EDL; glycolytic) muscle. BOH inhibited insulin-mediated glucose uptake in soleus (but not in EDL) muscle in a time- and concentration-dependent manner. Following 19.5 h of exposure to 5 mM BOH, insulin-mediated (20 mU/ml) glucose uptake was inhibited by ∼90% (substantial inhibition was also observed in 3- O-methylglucose transport). The inhibitory effect of BOH was reproduced with d- but not l-BOH. BOH did not significantly affect hypoxia- or AICAR-mediated (activates AMP-dependent protein kinase) glucose uptake. The BOH effect did not require the presence/utilization of glucose since it was also seen when glucose in the medium was substituted with pyruvate. To determine whether the BOH effect was mediated by oxidative stress, an exogenous antioxidant (1 mM tempol) was used; however, tempol did not reverse the BOH effect on insulin action. BOH did not alter the levels of total tissue GLUT4 protein or insulin-mediated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 but blocked insulin-mediated phosphorylation of protein kinase B by ∼50%. These data demonstrate that BOH inhibits insulin-mediated glucose transport in oxidative muscle by inhibiting insulin signaling. Thus ketone bodies may be potent diabetogenic agents in vivo.

scholarly journals Protein kinase Cδ regulates vaccinia-related kinase 1 in DNA damage–induced apoptosis

2011 ◽  
Vol 22 (8) ◽  
pp. 1398-1408 ◽  
Author(s):  
Choon-Ho Park ◽  
Bo-Hwa Choi ◽  
Min-Woo Jeong ◽  
Sangjune Kim ◽  
Wanil Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Protein Kinase ◽  
Cell Viability ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Regulatory Region ◽  
Dependent Manner ◽  
Protein Kinase Cδ

Vaccinia-related kinase 1 (VRK1) is a novel serine/threonine kinase that plays an important role in cell proliferation. However, little is known about the upstream regulators of VRK1 activity. Here we provide evidence for a role of protein kinase Cδ (PKCδ) in the regulation of murine VRK1. We show that PKCδ interacts with VRK1, phosphorylates the Ser-355 residue in the putative regulatory region, and negatively regulates its kinase activity in vitro. Intriguingly, PKCδ-induced cell death was facilitated by phosphorylation of VRK1 when cells were exposed to a DNA-damaging agent. In addition, p53 played a critical role in the regulation of DNA damage–induced cell death accompanied by PKCδ-mediated modulation of VRK1. In p53-deficient cells, PKCδ-mediated phosphorylation of VRK1 had no effect on cell viability. However, cells overexpressing p53 exhibited significant reduction of cell viability when cotransfected with both VRK1 and PKCδ. Taken together, these results indicate that PKCδ regulates phosphorylation and down-regulation of VRK1, thereby contributing to cell cycle arrest and apoptotic cell death in a p53-dependent manner.

scholarly journals Antidiabetic Activity of Zingiber officinale Roscoe Rhizome Extract: an In Vitro Study

2018 ◽  
Vol 25 (4) ◽  
pp. 160
Author(s):  
Kusumarn Noipha ◽  
Putrada Ninla-Aesong
Keyword(s):  
Glucose Uptake ◽  
Glucose Transport ◽  
Zingiber Officinale ◽  
Pi3 Kinase ◽  
Antidiabetic Activity ◽  
Protein Synthesis Inhibitor ◽  
Dependent Manner ◽  
Ginger Extract ◽  
L6 Myotubes ◽  
Zingiber Officinale Roscoe

  The potential roles of Zingiber officinale Roscoe (ginger) for treating and preventing diabetes have been investigated in both humans and experimental animals. However, the mode of its action has not yet been elucidated. This study aimed to investigate the effects of ginger extract on glucose uptake activity and its activation pathway in L6 myotubes. Cells were co-cultured for 24 h with a variable concentration of either ginger extract or 2 mM metformin or 200 nM insulin or 20 μM Troglitazone (TGZ), followed by a 10-min 2-[3H]-deoxy-D-glucose (2-DG) uptake. The levels of glucose transporters 1 (GLUT1) and GLUT4 protein and mRNA expression were determined. Ginger extract at 400 μg/ml significantly enhanced glucose uptake in L6 myotubes (208.03 ± 10.65% above basal value, p<0.05) after co-culture for 24 h. The ginger-enhancement of glucose uptake was inhibited by 3.5 μM cycloheximide, a protein synthesis inhibitor, 1 μM wortmannin (Phosphatidylinositol 3-Kinase (PI3 kinase) inhibitor) and 15 nM rapamycin (mammalian target of rapamycin (mTOR) inhibitor). The enhancement of glucose transport by ginger extract at 400 μg/ml was accompanied with the increased expression of GLUT1 protein (1.60 ± 0.20, 2.03 ± 0.19, and 2.25 ± 0.35 folds of basal at 4, 8, and 24 h, respectively p<0.05) and mRNA (1.22 ± 0.96, 1.45 ± 0.93, 1.91 ± 0.75, 2.32±0.92, and 2.20 ± 0.64 folds of basal at 1, 2, 4, 8, and 24 h, respectively p<0.05) in a time-dependent manner. Z. officinale Roscoe rhizome extract increase glucose transport activity of L6 myotubes by enhancing GLUT1 expression, the results of PI3-Kinase and 5’-AMP-activated kinase (AMPK) stimulation.

scholarly journals Posttranslational Modification of the AU-Rich Element Binding Protein HuR by Protein Kinase Cδ Elicits Angiotensin II-Induced Stabilization and Nuclear Export of Cyclooxygenase 2 mRNA

2008 ◽  
Vol 28 (8) ◽  
pp. 2608-2625 ◽  
Author(s):  
Anke Doller ◽  
El-Sayed Akool ◽  
Andrea Huwiler ◽  
Roswitha Müller ◽  
Heinfried H. Radeke ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Mrna Stability ◽  
Posttranslational Modification ◽  
Nuclear Export ◽  
Mesangial Cells ◽  
Cyclooxygenase 2 ◽  
Class Iii ◽  
Cox 2 ◽  
Protein Kinase Cδ

ABSTRACT The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate that in human mesangial cells (hMC) the amplification of cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase of mRNA stability. Using COX-2 promoter constructs with different portions of the 3′ untranslated region of COX-2, we found that the increase in COX-2 mRNA stability is attributable to a distal class III type of AU-rich element (ARE). Likewise, the RNA immunoprecipitation assay showed AngII-induced binding of HuR to this ARE. Using the RNA pulldown assay, we demonstrate that the AngII-caused HuR assembly with COX-2 mRNA is found in free and cytoskeleton-bound polysomes indicative of an active RNP complex. Mechanistically, the increased HuR binding to COX-2-ARE by AngII is accompanied by increased nucleocytoplasmic HuR shuttling and depends on protein kinase Cδ (PKCδ), which physically interacts with nuclear HuR, thereby promoting its phosphorylation. Mapping of phosphorylation sites identified serines 221 and 318 as critical target sites for PKCδ-triggered HuR phosphorylation and AngII-induced HuR export to the cytoplasm. Posttranslational modification of HuR by PKCδ represents an important novel mode of HuR activation implied in renal COX-2 regulation.

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