Search results for "PROTEIN KINASE"
showing 10 items of 1188 documents
Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth.
1993
We have investigated in Ehrlich-ascites-tumour-bearing mice the effect of buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, on the rate of GSH depletion of tumour versus normal tissues and its relation to tumour cell proliferation. In normal tissues, GSH and GSSG remain unchanged or close to normal values during tumour growth, even at the last stage of growth when the animal is close to death. After administration of a single dose of BSO (4 mmol/kg), the rates of GSH depletion and recovery in the tumour and in several normal tissues are very different. BSO depletes GSH in cancer cells to a level of 0.3-0.4 mumol/g. The fall in GSH levels is faster when tumour cells do n…
Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide.
2007
The aim of this article is to review the role of mitochondria in the pathogenesis of Alzheimer's disease. Additionally, the effect of gender on the incidence of Alzheimer's disease and the pathophysiological mechanisms involved will be discussed. Mitochondria, in the presence of Alzheimer's amyloid-beta peptide, increase the formation of reactive oxygen species which act both as damaging agents and also as signaling molecules. These radicals, in fact, unleash a mechanism involving the liberation of cytochrome c that leads to neuronal apoptosis. Notably, young females appear protected against the mitochondrial toxicity of amyloid-beta, likely due to the upregulation of antioxidant enzymes wh…
Activation of L-arginine transport by protein kinase C in rabbit, rat and mouse alveolar macrophages
1998
1 The role of protein kinase C in controlling L-arginine transport in alveolar macrophages was investigated. 2 L-[3H]Arginine uptake in rabbit alveolar macrophages declined by 80 % after 20 h in culture. 4β-Phorbol 12-myristate 13-acetate (PMA), but not 4α-phorbol 12-myristate 13-acetate (α-PMA), present during 20 h culture, enhanced L-[3H]arginine uptake more than 10-fold. Staurosporine and chelerythrine opposed this effect. 3 L-[3H]Arginine uptake was saturable and blockable by L-lysine. After PMA treatment Vmax was increased more than 5-fold and Km was reduced from 0.65 to 0.32 mM. 4 Time course experiments showed that PMA increased L-[3H]arginine uptake almost maximally within 2 h. This…
Vitamin E activates CRABP-II gene expression in cultured human fibroblasts, role of protein kinase C
2004
The treatment of human fibroblasts with different tocopherols in the presence of retinol caused an increase in cytoplasmic retinoic acid binding protein II (CRABP-II) mRNA and protein. The possibility of an involvement of protein kinase C (PKC) in the response to tocopherols was supported by the results obtained with the PKC-specific inhibitors, calphostin C and bisindolylmaleimide I. The effect of alpha-tocopherol was prevented by okadaic acid, suggesting that a protein phosphatase is responsible for PKC dephosphorylation produced by the presence of tocopherols. The results shown support the hypothesis that phosphorylation/dephosphorylation of RXRalpha via PKC may be involved in the regula…
TGF-β Signaling Pathways in Different Compartments of the Lower Airways of Patients With Stable COPD
2017
Background: The expression and localization of transforming growth factor-β (TGF-β) pathway proteins in different compartments of the lower airways of patients with stable COPD is unclear. We aimed to determine TGF-β pathway protein expression in patients with stable COPD. Methods: The expression and localization of TGF-β pathway components was measured in the bronchial mucosa and peripheral lungs of patients with stable COPD (n = 44), control smokers with normal lung function (n = 24), and control nonsmoking subjects (n = 11) using immunohistochemical analysis. Results: TGF-β1, TGF-β3, and connective tissue growth factor expression were significantly decreased in the bronchiolar epithelium…
Midostaurin upregulates eNOS gene expression and preserves eNOS function in the microcirculation of the mouse
2005
Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is a powerful vasodilator and possesses vasoprotective effects. Therefore, augmentation of eNOS expression and -activity by pharmacological means could provide protection against cardiovascular disease. However, this concept has been questioned recently, because in several disease models, eNOS upregulation was associated with a dysfunctional enzyme (referred to as eNOS uncoupling). In contrast, the present study demonstrates that an eNOS gene expression-enhancing compound with additional protein kinase C (PKC) inhibitory properties can upregulate eNOS while preserving its enzymatic function. Apolipoprotein E-knockout mice were tr…
cAMP-dependent phosphorylation of CYP2B1 as a functional switch for cyclophosphamide activation and its hormonal controlin vitro andin vivo
2001
An important feature of cytochrome P450 (CYP) 2B1 is its high ability to convert the prodrug cyclophosphamide (CPA) to therapeutically cytotoxic metabolites, resulting in interstrand DNA-cross-linking and cell death. We have examined whether and how the phosphorylation of CYP2B1 influences CPA metabolic activation in vitro and in vivo. We found first that only part of the total CYP2B1 pool undergoes phosphorylation. This part is fully inactivated. Second, phosphorylation of CYP2B1 in intact hepatocytes reduced by up to 75% toxification of CPA to mutagenic metabolites (totally dependent on the same preferentially CYP2B-catalyzed 4-hydroxylation of CPA as is the generation of highly cytotoxic…
Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model
2008
Trastuzumab (Herceptin) has improved therapy of breast cancer. Only patients overexpressing ERBB2 are treated with trastuzumab, whereas its use in tumours without ERBB2 expression is useless. This led to the concept that the subgroup of trastuzumab-sensitive tumours is ‘ERBB2-dependent', meaning that ERBB2 signalling is indispensable for growth of these tumours. We used a mouse model that allows anhydrotetracycline (ATc)-controlled downregulation of ERBB2 in tumour tissue. ERBB2 mRNA and protein expression were downregulated below detection limit leading to a macroscopically complete tumour remission within 14 days. Tumour remission was accompanied by a strong decrease in proliferation, a m…
Cardiovascular Toxicity in Cancer Patients Treated with Tyrosine Kinase Inhibitors: A Real-World Single-Center Experience
2019
<b><i>Background:</i></b> Target therapy can cause various cardiovascular complications. The aim of this study was to evaluate the burden of cardiovascular complications related to treatment with anti-BCR-ABL tyrosine kinase inhibitors (TKIs) and to determine if there are differences between the latest- and first-generation TKIs. <b><i>Methods:</i></b> A retrospective observational study was carried out on 55 patients (39 men, 16 women; mean age ± SD: 58 ± 11 years) treated with TKIs targeting Bcr-Abl for a median period of 3.5 years. Patients were divided in two groups according to the type of treatment. Group A included patients treated with…
CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity
2003
Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protecti…