Search results for " KINASE"
showing 10 items of 2352 documents
Targeting a Targeted Drug: An Approach Toward Hypoxia-Activatable Tyrosine Kinase Inhibitor Prodrugs
2016
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of …
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
2019
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dr…
BCR-ABL as a target for novel therapeutic interventions.
2002
The BCR-ABL oncogene is the result of a reciprocal translocation between the long arms of chromosome 9 and 22 t(9; 22). There is good experimental evidence demonstrating that BCR-ABL is the single causative abnormality in chronic myeloid leukaemia (CML), making it a unique model for the development of molecular targets. In addition to CML, BCR-ABL transcripts can be found in a minority of acute lymphoblastic leukaemias and very rarely in acute myeloid leukaemia (AML). Elucidating the molecular mechanisms and downstream pathways of BCR-ABL has led to the design of several novel therapeutic approaches. In this review, molecular targeting of BCR-ABL will be discussed based on the inhibition of…
Laboratory testing in the emergency department: an Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) and Academy of Em…
2018
Abstract Background: The mainstay of patient-oriented laboratory testing in emergency settings entails selecting a number and the type of tests according to valid criteria of appropriateness. Since the pattern of urgent tests requesting is variable across different institutions, we designed a joined survey between the Academy of Emergency Medicine and Care (AcEMC) and the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) for reaching tentative consensus about the most informative diagnostic tests in emergency settings. Methods: A survey, containing the most commonly ordered urgent laboratory tests and the relative clinical indications, was disseminated to eigh…
Adrenergic modulation of astroglial phospholipase D activity and cell proliferation.
1999
As phospholipase D (PLD) activation has been associated with mitogenic signalling in several cell types, we tested an association between adrenergic activation of PLD and cellular proliferation in primary cultures of rat cortical astrocytes. In 2-week old cultures, PLD activation by noradrenaline (EC50: 0.49 microM) was inhibited by prazosin, a specific antagonist at alpha1-adrenergic receptors (IC50: 0.23 microM). Adrenergic PLD activation was not affected by genistein, an inhibitor of tyrosine kinases, or by Ro 31-8220, an inhibitor of protein kinase C (PKC), but was dose-dependently depressed in the presence of brefeldin A (1-100 microg/ml), an inhibitor of ARF activation. In experiments…
Age-dependent changes of nuclear envelope protein phosphokinase and protein phosphatase activities. Significance for altered nucleo-cytoplasmic mRNA …
1984
Nuclear envelopes are associated with a protein phosphokinase and a phosphoprotein phosphatase, whose activities are modulated by poly(A) in an opposite manner. The activities of these enzymes were determined in nuclear ghosts from liver and oviduct of quails of different age and of different hormone status. Under optimal conditions, kinase activity was found to increase in immature animals 8-fold in response to diethylstilbestrol; co-administration of progesterone had no marked effect on enzyme activity. After the initial burst, the activity of the enzyme increased only slightly during ageing. Two proteins present in nuclear ghosts of Mr 64 000 and of Mr 106 000 are phosphorylated during t…
The effects of rapid weight loss on skeletal muscle in judo athletes
2020
Abstract Objective To observe the effect of rapid weight loss (RWL) methods over 3 days on muscle damage in judokas. Methods Eighteen judokas participated in this crossover study, meaning that judo athletes were subjected to exercise-only phase (4 days) and RWL phase (3 days). Subjects were tested for myoglobin, creatine kinase, aldolase, hemoglobin, and hematocrit values on seven consecutive days. These biomarkers served as indicators of acute muscle damage. Results During the exercise-only phase, no significant changes were observed. Myoglobin (Mb) (p < 0.001), creatine kinase (CK) (p < 0.001) and aldolase (ALD) (p < 0.001) significantly increased only during the RWL phase, as we…
Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes.
2009
Inflammation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). The main inflammatory players in AD are the glial cells which initiate the inflammatory response. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of A beta deposition. It is desirable to find methods of tipping the balance towards anti-inflammatory state. Estrogenic compounds have shown anti-inflammatory and also antioxidant activity. Astrocytes were pretreated with 17-beta estradiol or with genistein, and 48 h later treated with 5 microM amyloid beta (A beta) for 24 h. We found that A beta induces inflammatory mediators, such as cyclooxygenase 2 (…
Effects of time of day on resistance exercise-induced anabolic signaling in skeletal muscle
2013
This study examined the effect of morning versus afternoon exercise on acute responses in phosphorylation of proteins regulating muscle size and metabolism. Twenty-two untrained men, divided into the morning (n = 11) or afternoon (n = 11) group, performed maximal isometric leg extensions before and after resistance loading at 07:30–08:30 h and 16:00–17:00 h, respectively. Muscle pre- and postloading biopsies were analyzed for phosphorylated Akt, p70S6K, rpS6, p38 mitogen-activated protein kinase (MAPK), Erk1/2, and eukaryotic elongation factor (eEF) 2. Muscle force declined after exercise in both groups (p < 0.001). p70S6K Thr389 (p < 0.05) and Thr421/Ser424 and rpS6 (all p < 0.001) increas…
Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal
2006
Endothelial NO synthase (eNOS) is the predominant enzyme responsible for vascular NO synthesis. A functional eNOS transfers electrons from NADPH to its heme center, where L-arginine is oxidized to L-citrulline and NO. Common conditions predisposing to atherosclerosis, such as hypertension, hypercholesterolemia, diabetes mellitus and smoking, are associated with enhanced production of reactive oxygen species (ROS) and reduced amounts of bioactive NO in the vessel wall. NADPH oxidases represent major sources of ROS in cardiovascular pathophysiology. NADPH oxidase-derived superoxide avidly interacts with eNOS-derived NO to form peroxynitrite (ONOO(-)), which oxidizes the essential NOS cofactor…