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Cholesterol-fed Rabbits (cholesterol-fed + rabbits)
Selected AbstractsBroad DNA repair responses in neural injury are associated with activation of the IL-6 pathway in cholesterol-fed rabbitsJOURNAL OF NEUROCHEMISTRY, Issue 4 2009Min Wu Abstract The importance of DNA repair in the pathogenic mechanism of Alzheimer's Disease (AD) is still poorly understood. Here, we report that a broad range of responses by DNA repair proteins plays a critical role in the regulation of inflammatory response in rabbits fed with cholesterol-rich diet, a model system for AD. We found accumulation of oxodG DNA adduct in the brain of rabbits fed with cholesterol-enriched diets compared to control diets, which subsequently induced a broad range of DNA repair protein activities. Also, the hippocampus was identified as the primary site of oxidative DNA damage and elevated OGG1 activity. In addition, a physical interaction between XPB and OGG1 may account for a potential mechanism involving these DNA repair responses. DNA repair proteins also impact activation of various signaling cascades, including Src in response to cholesterol oxidation. Furthermore, OGG1 deficient mice showed no IL-6 activation as seen in wt mice but a drastic increase of TNF-,, a pro-inflammatory cytokine. Thus, OGG1 may be associated with cytokine production induced by high cholesterol levels, impacting neurodegeneration. Together, our studies suggest that critical DNA repair proteins are associated with development of AD, and may serve as potential targets for the treatment of AD. [source] Inhibitory effects of Keishi-bukuryo-gan on free radical induced lysis of rat red blood cellsPHYTOTHERAPY RESEARCH, Issue 4 2002Nobuyasu Sekiya Abstract Keishi-bukuryo-gan (KBG) prevents the progression of atherosclerosis in cholesterol-fed rabbits by its antioxidative effect. The present study was to test our hypothesis that ingestion of KBG would protect red blood cell (RBC) membranes from free radical induced oxidation if polyphenolic antioxidants in KBG could be absorbed and circulated in the blood. When incubated with a RBC suspension, KBG and four of five herb medicines constituting KBG provided strong protection for RBC membranes against haemolysis induced by 2,2-azo-bis (2-amidinopropane) dihydrochloride (AAPH), an azo free radical initiator. The inhibitory effect was dose dependent at concentrations of 100,1000 ,g/mL. Furthermore, the ingestion of 200,mg of KBG was associated with a significant decrease in susceptibility of RBC to haemolysis in rats. Copyright © 2002 John Wiley & Sons, Ltd. [source] A strategy for quantitative bioanalysis of non-polar neutral compounds by liquid chromatography/electrospray ionization tandem mass spectrometry: determination of TS-962, a novel acyl-CoA:cholesterol acyltransferase inhibitor, in rabbit aorta and liver tissuesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 8 2001Jun-ichi Yamaguchi A strategy for the sensitive and reliable quantitative determination of non-polar neutral compounds in biological matrices by liquid chromatography/electrospray ionization tandem mass spectrometry is described in the context of assay development for TS-962, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, in rabbit aorta and liver tissues. The electrospray ionization (ESI) mass spectrum of this compound with a mobile phase of water/acetonitrile did not give abundant [M,+,H]+ ions, but did give alkali metal cation adducts such as [M,+,Na]+, [M,+,CH3CN,+,Na]+ and [M,+,K]+ ions. The cationized species are acknowledged as unsuitable precursor ions for selected reaction monitoring (SRM) for various reasons, such as difficulty in obtaining characteristic product ions in low-energy collision-induced dissociation, and irreproducibility of the adduct-ion intensities. To overcome this problem, a solution of 3.4,mM trifluoroacetic acid in 2-propanol was added to the mobile phase as a postcolumn additive, resulting in a decrease of the undesirable adduct formation and significant enhancement of [M,+,H]+ ion intensity. An attempt was then made to prevent the matrix effect by employing a column-switching system, which allowed direct injection of a large volume of 2-propanolic tissue homogenate (950,µL) followed by sufficient clean-up, separation, and ESI-SRM on-line. This enabled development of a sensitive and reliable assay method for TS-962 in rabbit aorta and liver tissues in the concentration range of 5,500,ng/g wet tissue using a 25-mg aliquot of tissue sample. Application of this method to the determination of aortic TS-962 levels at 24,h after repeated oral administration of this compound (3,mg/kg) once a day for 12 weeks to 1% cholesterol-fed rabbits is also presented. Results showed that TS-962 is well distributed to both the thoracic and abdominal aorta tissues, at levels higher than the 50% inhibitory concentration value of this compound for microsomal ACAT activity from rabbit aorta. Copyright © 2001 John Wiley & Sons, Ltd. [source] Nitric oxide selectively depletes macrophages in atherosclerotic plaques via induction of endoplasmic reticulum stressBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007W Martinet Background and purpose: Macrophages in atherosclerotic plaques have a tremendous impact on atherogenesis and plaque destabilization. We previously demonstrated that treatment of plaques in cholesterol-fed rabbits with the nitric oxide (NO) donor molsidomine preferentially eliminates macrophages, thereby favouring features of plaque stability. In this study, we investigated the underlying mechanism. Experimental approach: Macrophages and smooth muscle cells (SMCs) were treated in vitro with the NO donors, spermine NONOate or S -nitroso- N -acetylpenicillamine (SNAP) as well as with the well-known endoplasmic reticulum (ER) stress inducers thapsigargin, tunicamycin, dithiothreitol or brefeldin A. Cell viability was analysed by Neutral Red viability assays. Cleavage of caspase-3, DNA fragmentation and ultrastructural changes were examined to characterize the type of macrophage death. Induction of ER stress was evaluated by measuring C/EBP homologous protein (CHOP) expression, phosphorylation of eukaryotic initiation factor 2, (eIF2a), splicing of X-box binding protein 1 (XBP1) and inhibition of protein synthesis. Key results: Macrophages and SMCs treated with spermine NONOate or SNAP showed several signs of ER stress, including upregulation of CHOP expression, hyperphosphorylation of eIF2,, inhibition of de novo protein synthesis and splicing of XBP1 mRNA. These effects were similar in macrophages and SMCs, yet only macrophages underwent apoptosis. Plaques from molsidomine-treated atherosclerotic rabbits showed a 2.7-fold increase in CHOP expression as compared to placebo. Beside NO, selective induction of macrophage death could be initiated with thapsigargin and tunicamycin. Conclusions and implications: Induction of ER stress explains selective depletion of macrophages in atherosclerotic plaques by a NO donor, probably via inhibition of protein synthesis. British Journal of Pharmacology (2007) 152, 493,500; doi:10.1038/sj.bjp.0707426; published online 13 August 2007 [source] | ||||||||||