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Severe Alterations (severe + alteration)
Selected AbstractsSevere alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx miceGLIA, Issue 3 2003Beatrice Nico Abstract In this study, we investigated the involvement of the blood-brain barrier (BBB) in the brain of the dystrophin-deficient mdx mouse, an experimental model of Duchenne muscular dystrophy (DMD). To this purpose, we used two tight junction markers, the Zonula occludens (ZO-1) and claudin-1 proteins, and a glial marker, the aquaporin-4 (AQP4) protein, whose expression is correlated with BBB differentiation and integrity. Results showed that most of the brain microvessels in mdx mice were lined by altered endothelial cells that showed open tight junctions and were surrounded by swollen glial processes. Moreover, 18% of the perivascular glial endfeet contained electron-dense cellular debris and were enveloped by degenerating microvessels. Western blot showed a 60% reduction in the ZO-1 protein content in mdx mice and a similar reduction in AQP4 content compared with the control brain. ZO-1 immunocytochemistry and claudin-1 immunofluorescence in mdx mice revealed a diffuse staining of microvessels as compared with the control ones, which displayed a banded staining pattern. ZO-1 immunogold electron microscopy showed unlabeled tight junctions and the presence of gold particles scattered in the endothelial cytoplasm in the mdx mice, whereas ZO-1 gold particles were exclusively located at the endothelial tight junctions in the controls. Dual immunofluorescence staining of ,-actin and ZO-1 revealed colocalization of these proteins. As in ZO-1 staining, the pattern of immunolabeling with anti,,-actin antibody was diffuse in the mdx vessels and pointed or banded in the controls. ,-actin immunogold electron microscopy showed gold particles in the cytoplasms of endothelial cells and pericytes in the mdx mice, whereas ,-actin gold particles were revealed on the endothelial tight junctions and the cytoskeletal microfilaments of pericytes in the controls. Perivascular glial processes of the mdx mice appeared faintly stained by anti-AQP4 antibody, while in the controls a strong AQP4 labeling of glial processes was detected at light and electron microscope level. The vascular permeability of the mdx brain microvessels was investigated by means of the horseradish peroxidase (HRP). After HRP injection, extensive perivascular areas of marker escape were observed in mdx mice, whereas HRP was exclusively intravascularly localized in the controls. Inflammatory cells, CD4-, CD8-, CD20-, and CD68-positive cells, were not revealed in the perivascular stroma of the mdx brain. These findings indicate that dystrophin deficiency in the mdx brain leads to severe injury of the endothelial and glial cells with disturbance in ,-actin cytoskeleton, ZO-1, claudin-1, and AQP4 assembly, as well as BBB breakdown. The BBB alterations suggest that changes in vascular permeability are involved in the pathogenesis of the neurological dysfunction associated with DMD. GLIA 42:235,251, 2003. © 2003 Wiley-Liss, Inc. [source] A metabolic approach to the treatment of dilated cardiomyopathy in BIO T0,2 cardiomyopathic Syrian hamstersBIOFACTORS, Issue 1-4 2005Rino Mancinelli Abstract Mechanisms underlying dilated cardiomyopathy (DCM) are poorly understood and effective therapy is still unavailable. The aim of this study was to examine the heart ultrastructure and dynamic of BIO T0,2 cardiomyopathic hamsters, an animal model of DCM, and to study in these animals, the effects of a co-formulation (HS12607) of propionyl-L-carnitine, coenzyme Q10 and omega-3 fatty acids on cardiac mechanical parameters. Sarcomere length, Frank-Starling mechanism and force-frequency relations were studied on isolated ventricular papillary muscle from age-matched BIO F1B normal Syrian hamsters, BIO T0,2 control and BIO T0,2 HS12607-treated cardiomyopathic Syrian hamsters. At the optimum length to maximum active force, electron microscopy of left ventricular papillary muscle revealed that seven out of ten muscles studied showed shorter sarcomeres (1.20 ± 0.29,m), and the remaining three showed longer sarcomeres (2.80 ± 0.13,m), compared to those of normal hamsters (2.05± 0.06,m, n=10). Severe alterations of the Frank-Starling mechanism, force-frequency relations and derivative parameters of contractile waves were also observed in vitro in the BIO T0,2 control hamsters. Long-term (8 weeks) treatment with HS12607 prevented alterations in sarcomere length in the BIO T0,2 cardiomyopathic hamsters; the Frank-Starling mechanism and force-frequency relations were also significantly (P<0.05) improved in these hamsters. Therefore results of the present study strongly suggest the need for clinical studies on metabolic therapeutic intervention in the effort to stop the progression of dilated cardiomyopathy. [source] Oral administration of diphenyl diselenide potentiates hepatotoxicity induced by carbon tetrachloride in ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2009Cristina W. Nogueira Abstract Carbon tetrachloride (CCl4) is a model for studying free radical-induced liver injury and screening hepato-protective drugs. Numerous studies have reported the involvement of oxidative stress in CCl4 -induced liver damage and the hepato-protective effects mediated by different antioxidants. The present study examined the effects of diphenyl diselenide, (PhSe)2, on hepatotoxicity induced by CCl4 in rats. To this end, male Wistar rats received (PhSe)2 by oral route at the dosage of 31.2 mg/kg for one or two days. After the second day of treatment, rats received CCl4 orally in a single dose. The liver and kidney were utilized for determination of histopathology, biochemical [aspartate (ALT) and alanine (AST) aminotransferases, alkaline phosphatase (ALP), total bilirrubin (TB) and gamaglutamyl transferase (GGT)] and toxicological parameters [thiobarbituric reactive species (TBARS) levels, catalase activity, ascorbic acid, nonprotein thiols (NPSH) and aminolevulinate dehydratase (, -ALA-D) activity]. Repeated administration of (PhSe)2 caused a marked potentiation of hepatotoxicity induced by CCl4 exposure, as manifested by an increase in biochemical parameters (AST, ALT, ALP, GGT and BT) and severe alteration in histopathology. This study also demonstrated a potentiation of TBARS levels and a consequent depletion of important antioxidant defenses including catalase and ascorbic acid. Pre-treatment with a single dose of (PhSe)2 prevented the effect of strychnine, a substrate for CYPs, abolishing lethality in mice. This result indicates that (PhSe)2 prevented animal death, suggesting an activator action of (PhSe)2 in CYPs. This study clearly indicates that (PhSe)2 potentiated acute hepatic damage induced by CCl4. Copyright © 2008 John Wiley & Sons, Ltd. [source] Reduced lipolysis and increased lipogenesis in adipose tissue from pinealectomized rats adapted to trainingJOURNAL OF PINEAL RESEARCH, Issue 2 2005Cristina N. Borges-Silva Abstract:, The current study investigated the effects of chronic training and pinealectomy on the lipogenic and lipolytic activity of adipose tissue. Pinealectomized and sham-operated adult male Wistar rats were distributed in to four subgroups: pinealectomized untrained, pinealectomized trained, control untrained and control trained. At the end of the training period (8 wk) the rats were killed. Blood samples were collected for glucose, insulin and leptin determinations. Peri-epididymal adipocytes were isolated for measurement of in vitro rates of lipolysis and incorporation of substrates (d -[U- 14C]-glucose, l -[U- 14C]-lactate, [2- 14C]-acetate and [1- 14C]-palmitate) into lipids, and samples of epididymal adipose tissue were homogenized for evaluation of glucose-6-phosphate dehydrogenase maximal activity. Pinealectomy resulted in a significantly increased lipolytic capacity in response to isoproterenol and a decrease in circulating leptin levels without affecting the rates of incorporation of different substrates into lipids. However, only in the intact control group did training promote a higher basal and isoproterenol-stimulated lipolysis, increase the incorporation of palmitate (esterification), decrease the incorporation of acetate (lipogenesis) into lipids and diminish circulating leptin levels. These effects of exercise training were not seen in pinealectomized rats. However, pinealectomized trained animals showed a marked reduction in lipolysis and an increased rate of acetate incorporation. In conclusion, we demonstrated for the first time that the pineal gland plays an important role in the regulation of lipid metabolism in such a way that its absence caused a severe alteration in the balance between lipogenesis and lipolysis, which becomes evident with the adaptation to exercise training. [source] Effects of tebuconazole on morphology, structure, cell wall components and trichothecene production of Fusarium culmorum in vitroPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 6 2001Zhensheng Kang Abstract The effects of tebuconazole, a systemic fungicide, on the morphology, structure, cell wall components and toxin production of Fusarium culmorum were investigated in vitro. Treatment was by application of four filter paper strips (0.75,cm,×,5.0,cm) soaked in 20,µg,ml,,1 fungicide placed around a point inoculum in Petri dishes. Mycelial growth was strongly inhibited by fungicide treatment. Scanning electron microscopic observations showed that the fungicide caused irregular swelling and excessive branching of hyphae. The morphological changes induced by the fungicide at the ultrastructural level included considerable thickening of the hyphal cell walls, excessive septation, the formation of the incomplete septa, extensive vacuolisation, accumulation of lipid bodies and progressing necrosis or degeneration of the hyphal cytoplasm. Non-membrane inclusion bodies were often detected in the hyphal cytoplasm. Furthermore, the formation of new hyphae (daughter hyphae) inside collapsed hyphal cells was common following treatment. The daughter hyphae also displayed severe alterations such as irregular thickening of the cell walls and necrosis of the cytoplasm. Using cytochemical techniques, the labelling densities of chitin and ,-1,3-glucan in the cell walls of the fungicide-treated hyphae were more pronounced than in those of the control hyphae. Moreover, immunogold labelling with antiserum against deoxynivalenol (DON) revealed that Fusarium toxin DON was localized in the cell walls, cytoplasm, mitochondria and vacuoles of the hyphae from the control and the fungicide treatment, but the labelling density in the fungicide-treated hyphae decreased dramatically compared with the control hyphae, indicating that tebuconazole reduced Fusarium toxin production of the fungus. © 2001 Society of Chemical Industry [source] | |||||||||||||