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Qiryat Shemona, Israel

Najajreh Y.,Al-Quds University | Khamaisie H.,Migal Galilee Technology Center | Ruimi N.,Migal Galilee Technology Center | Khatib S.,Oxidative Stress Research Laboratory | And 4 more authors.
Molecular Biology Reports | Year: 2013

Chronic myeloid leukemia (CML) is characterized by the presence of p210Bcr-Abl which exhibits an abnormal kinase activity. Selective Abl kinase inhibitors have been successfully established for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance against these kinase inhibitors mainly due to point mutations within the Abl protein kinase domain. Previously, we have identified oleic acid as the active component in the mushroom Daedalea gibbosa that inhibited the kinase activity of Bcr-Abl. Here, we report that the oleyl amine derivatives, S-1-(1- Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylaminocarbonyl-L-N- valinol,oroleylaminocarbonyl-S-2-isopropyl-N-ethanolamine,oleylamine-carbonyl-L- valinol] (cpd 6) and R-1-(1-Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylamineocarbonyl-D-N-valinol, oleylaminocarbonyl-R-2-isopropyl-N- ethanolamine, or oleylamine-carbonyl-D-valinol] (cpd 7), inhibited the activity of the native and T315I mutated Bcr-Abl. Furthermore, cpd 6 and 7 exhibited higher activity towards the oncogenic Bcr-Abl in comparison to native c-Abl in SupB15 Ph-positive ALL cell line. © 2012 Springer Science+Business Media Dordrecht.

Farbstein D.,Technion - Israel Institute of Technology | Blum S.,Technion - Israel Institute of Technology | Pollak M.,Technion - Israel Institute of Technology | Asaf R.,Technion - Israel Institute of Technology | And 20 more authors.
Atherosclerosis | Year: 2011

Objective: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. Research design and methods: Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400. IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. Results: Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. Conclusion: There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671). © 2011 Elsevier Ireland Ltd.

Tavori H.,Oxidative Stress Research Laboratory | Tavori H.,Tel-Hai Academic College | Tavori H.,Rappaport Family Institute for Research in the Medical science | Aviram M.,Rappaport Family Institute for Research in the Medical science | And 8 more authors.
Free Radical Biology and Medicine | Year: 2011

Human atherosclerotic lesions contain oxidized lipids that facilitate further oxidation of macrophages, LDLs, and oxidative stress (OS)-sensitive markers and inhibit the antiatherogenic enzyme paraoxonase 1 (PON1). Our aim was to isolate and identify the oxidizing agent in a human atherosclerotic lesion lipid extract (LLE) and to explore the mechanisms of oxidation and of PON1's effect on the oxidizing agent. Of the five main fractions separated from the LLE, only fraction 2 (F2) promoted macrophage reactive oxygen species (ROS) production via a mechanism requiring mitochondrial involvement, whereas the NADPH oxidase system was not involved. Incubation of F2 with PON1 abridged the former's peroxide value and reduced its capacity to oxidize OS markers. The active agent was a triglyceride composed of palmitic, oleic, and linoleic acids, with 0.3% of its linoleic moiety in oxidized form. Incubation of either F2 or an identical synthetic triglyceride with PON1 reduced their ability to oxidize macrophages, without affecting cellular accumulation of triglycerides. We conclude that macrophage ROS production by LLE occurs in the presence of a specific triglyceride and requires mitochondrial involvement. Lipid peroxide in the triglyceride can also facilitate lipid autoxidation. Both atherogenic pathways are suppressed by PON1, which acts as an antiatherogenic element. © 2011 Elsevier Inc. All rights reserved.

Tavori H.,Oxidative Stress Research Laboratory | Tavori H.,Galilee College | Tavori H.,Rappaport Family Institute for Research in the Medical science | Aviram M.,Rappaport Family Institute for Research in the Medical science | And 8 more authors.
Free Radical Biology and Medicine | Year: 2011

Paraoxonase 1 (PON1) is an HDL-associated lactonase with antiatherogenic properties. These include dampening the oxidation properties of human carotid lesion lipid extract (LLE), which in turn inactivates the enzyme. The aims of this study were to identify the PON1 inhibitor in LLE and explore the mechanism of inhibition. LLE inhibited both recombinant PON1 and HDL-PON1 lactonase activity in a dose- and time-dependent manner. Addition of antioxidants or electrophiles to LLE did not prevent PON1 inhibition. LLE was unable to inhibit a PON1 mutant lacking Cys284, whereas it did inhibit all other PON1 mutants tested. The inhibitor in the LLE was identified as linoleic acid hydroperoxide (LA-OOH) and inhibition was specific to this hydroperoxide. During its inhibition, PON1 acted like a peroxidase enzyme, reducing LA-OOH to LA-hydroxide via its Cys284. A similar reaction occurred with external thiols, such as DDT or cysteine, which also prevented PON1 inhibition and restored enzyme activity after inhibition. Thus, the antiatherogenic properties of HDL could be, at least in part, related to the sulfhydryl-reducing characteristics of its associated PON1, which are further protected and recycled by the sulfhydryl amino acid cysteine. © 2010 Elsevier Inc. All rights reserved.

Vaya J.,Oxidative Stress Research Laboratory | Vaya J.,Tel Hi College | Szuchman A.,Oxidative Stress Research Laboratory | Szuchman A.,Tel Hi College | And 4 more authors.
Chemistry and Physics of Lipids | Year: 2011

Oxysterols are cholesterol (CH)-oxidized products generated in organs via either enzymatic or non-enzymatic pathways. Their presence or absence in cells, tissues and organs may provide information related to, for example, CH level and environmental status, inflammatory conditions near the CH molecules, activity of specific enzymes at and around the CH site, types and concentrations of biochemicals interacting with the CH, and the existence of specific signals. Here we present a mini-review of our lab findings on oxysterols formation in vitro and in vivo, including: the effects of different reactive species and availability of endogenous compounds on the type of oxysterol generated, the effects of enhanced activity of paraoxonase 1 or hemeoxygenase on oxysterol level, the correlation between human diseases such as diabetes and oxysterol accumulation, and the correlation between oxidative stress in neurons pre-Parkinsonian conditions in an animal model and intracellular oxidative stress. © 2011 Elsevier Ireland Ltd.

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