ABSTRACT
BACKGROUND AND OBJECTIVES: Since statins and angiotensin receptor blockers are a frequently prescribed combination in patients with atherosclerotic cardiovascular diseases, we tested the interactive effects of simvastatin and losartan on atherosclerosis in apolipoprotein E (apoE)-/- mice. MATERIALS AND METHODS: Apolipoprotein E-/- mice were fed a high-fat, high-cholesterol (HFHC) diet for 12 weeks, with and without simvastatin (40 mg/kg) and/or losartan (20 mg/kg). The mice were divided into 5 groups and were fed as follows: regular chow (control diet, n=5), HFHC diet (n=6), HFHC diet with losartan (n=6), HFHC diet with simvastatin (n=6), and HFHC diet with both losartan and simvastatin (n=6). RESULTS: Losartan treatment in apoE-/- mice significantly decreased atherosclerotic lesion areas in whole aortic strips stained with Oil Red O. The plaque area measured at the aortic sinus level was reduced significantly by 17% (HFHC; 346830.9+/-52915.8 microm2 vs. HFHC plus losartan; 255965.3+/-74057.7 microm2, p<0.05) in the losartan-treated group. Simvastatin and simvastatin plus losartan treatments reduced macrophage infiltration into lesions by 33% (HFHC; 183575.6+/-43211.2 microm2 vs. HFHC plus simvastatin; 120556.0+/-39282.8 microm2, p<0.05) and 44% (HFHC; 183575.6+/-43211.2 microm2 vs. HFHC plus simvastatin and losartan; 103229.0+/-8473.3 microm2, p<0.001, respectively). In mice fed the HFHC diet alone, the smooth muscle cell layer in the aortic media was almost undetectable. In mice co-treated with losartan and simvastatin, the smooth muscle layer was more than 60% preserved (p<0.05). Given alone, losartan showed a slightly stronger effect than simvastatin; however, treatment with losartan plus simvastatin induced a greater inhibitory effect on atherosclerosis than either drug given alone. Serum lipid profiles did not differ significantly among the groups. CONCLUSION: Losartan displayed anti-atherosclerotic effects in apoE-/- mice that were equivalent to or greater than the effects of simvastatin. Combined treatment with these drugs had greater effect than either drug alone.
Subject(s)
Animals , Humans , Mice , Angiotensin Receptor Antagonists , Apolipoproteins , Atherosclerosis , Azo Compounds , Cardiovascular Diseases , Diet , Losartan , Macrophages , Mice, Knockout , Models, Animal , Muscle, Smooth , Myocytes, Smooth Muscle , Simvastatin , Sinus of ValsalvaABSTRACT
Herpesvirus saimiri (HVS), a member of the gamma-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. However, a detailed mechanism of STP-A11-induced oncogenesis has not been revealed yet. We first report that STP-A11 oncoprotein interacts with TNF-alpha receptor-associated factor (TRAF) 6 in vivo and in vitro. Mutagenesis analysis of the TRAF6-binding motif 10PQENDE15 in STP-A11 reveals that Glu (E)12 residue is critical for binding to TRAF6 and NF-kappaB activation. Interestingly, co-expression of E12A mutant, lack of TRAF6 binding, with cellular Src (Src) results in decreased transcriptional activity of Stat3 and AP-1, a novel target of STP-A11 compared to that of wild type. Furthermore, the presence of STP-A11 enhances the association of TRAF6 with Src and induces the translocation of both TRAF6 and Src to a nonionic detergent-insoluble fraction. Taken together, these studies suggest that STP-A11 oncoprotein up-regulates both NF-kappaB and AP-1 transcription activity through TRAF6, which would ultimately contribute cellular transformation.
Subject(s)
Humans , Transcription, Genetic , Transcription Factor AP-1/agonists , TNF Receptor-Associated Factor 6/metabolism , Solubility , STAT3 Transcription Factor/metabolism , Proto-Oncogene Proteins pp60(c-src)/metabolism , Protein Binding , Oncogene Proteins, Viral/metabolism , NF-kappa B/agonists , Ions , Herpesvirus 2, Saimiriine/metabolism , Detergents , Cell LineABSTRACT
Background: Nitric oxide(NO) has been reproted to play an important role in macrophage-mediated microbicidal capacity for a variety of intracellular pathogens. NO generation is used as an indicator of microbicidal function of macrophages. OBJECTIVE: Our purpose is to investigate the production of NO rom macrophages phagocytized with Mycobacterium leprae or M. leprae phenolic glycolipid-1(PGL-1) for the purpose of elucidating the pathogenesis of leprosy. METHODS: We used a murine macrophage cell line, RAW 264.7. Macrophages were incubated with dead M. leprae or PGL-1, respectively and then treated with interfer n-gamma(IFN-r) and/or tumor necrosis factor-alpha(TNF-a). The release of NO was determined spectrophotometrically by measuring nitrite. RESULTS: M. Leprae and PGL-1 failed to stimulnte NO secretion execept at high bacteria-to-cell rations(50:1)and at the higheat concentrat,ion(100pg/ml) of PGL-1. IFN-r or IFN-r plus TNF-a markedly stimulated macrophages phagocyt,ized with M. leprae or PGL-1 to release NO . CONCLUSION: Defective IFN-r-dependent NO production of macrophages may be an important factor in the pathogenesis of leprosy.
Subject(s)
Cell Line , Cytokines , Leprosy , Macrophages , Mycobacterium leprae , Mycobacterium , Necrosis , Nitric Oxide , PhenolABSTRACT
Cells or the monocyte-macrophage lineage are known to exhibit tumoricidal activity following stimulation by BCG, interferon -gamma (INF-gamma) or bacterial products such as lipopolysaccharide(LPS). While the mechanisms involved remain obscure, the generation of reactive nitrogen intermediateds (RNI) by activated macrophage is considered a major participant in mediating the tumoricidal effect. In this study, the authors intended to know the effects of BCG infection on the production and secretion of RNI in the experimental animals. Sprauge-Dawley rats were instillated with BCG intravesically. The production of RNI from peritoneal macrophages and urinary secretion of RNI were measured after intravesical BCG instillation of the rats. The urinary concentration(micrometer/L) of nitrite, stable oxidized form of nitric oxide(N0-), 1 week after intravesical BCG instillation was 20+/-0.5 in the group I (control). 54+/-1.0 in group II (BCG 1x). 63+/-0.5 in group III (BCG 10x) and 17+/-0.5 in group IV (BCG 10x + N(G)MMA). The urinary nitrite concentration(micrometer/L) 3 weeks after intravesical BCG instillation was 17+/-2.0 in group I, 124+/-3.0 in group II, 210+2.5 in group III and 31+/-0.5 in group IV. The production of RNI by peritoneal macrophages 3 weeks after intravesical BCG instillation increased in group III (45+/-2.0 micrometer/L) compared to group I (5+/-1.0 micrometer/L). The peritoneal macrophages treated with LPS and INF-gamma increased nitrite production (36+/-0.5 in group I , 52+/-1.5 micrometer/L in group III). The production of RNI by peritoneal macrophages was inhibited by the treatment of the rats with N(G)MMA (19+/-0.5 in group 1, 17+/-1.5 micrometer/L in group III). The results of this study showed that BCG infection of the rat via intravesical instillation makes the peritoneal macrophages produced RNI and increases the secretion of RNI in the urine. This study suggest that the effects of BCG infection for the treatment of bladder cancer might be mediated by the production or RNI in the tumor bearing host.
Subject(s)
Animals , Rats , Administration, Intravesical , Interferons , Macrophages , Macrophages, Peritoneal , Mycobacterium bovis , Negotiating , Nitrogen , Urinary Bladder NeoplasmsABSTRACT
Even though the brain has been considered to be an immunologically privileged organ, recent reports showed that certain cells of the brain may be involved in immunological process in the brain. For example, some cells of the brain can present antigen to T-lymphocytes, to express class II major histocompativility antigen, and secrete interleukin-1 and -3 molecules. In addition, they are capable to phagocytose particles and possess receptors for the Fc portion on IgG. In this study, the authors tried to isolate the microglial cells from new born mice and characterize them. The isolated cells could produce such reactive oxygen intermediates(ROIs) an superoxide and hydrogen peroxide that were measured by luminometer after amplification by lucigenin and luminol respectively and could secrete reactive nitrogen intermediates(RNIs), when the cells were incubated with r-IFN plus LPS. The cells could also ingest fluorescent particles and raise intracellular calcium after stimulation with agonists when measured by flow cytometer. Our data showed that the microglial cells of the brain may belong to a member of mononuclear phagocytic system(MPS) of the body that are responsible for the host defence against invading microorganisms.