Regulation of proteasome assembly and activity in health and disease

The proteasome degrades most cellular proteins in a controlled and tightly regulated manner and thereby controls many processes, including cell cycle, transcription, signalling, trafficking and protein quality control. Proteasomal degradation is vital in all cells and organisms, and dysfunction or failure of proteasomal degradation is associated with diverse human diseases, including cancer and neurodegeneration. Target selection is an important and well-established way to control protein degradation. In addition, mounting evidence indicates that cells adjust proteasome-mediated degradation to their needs by regulating proteasome abundance through the coordinated expression of proteasome subunits and assembly chaperones. Central to the regulation of proteasome assembly is TOR complex 1 (TORC1), which is the master regulator of cell growth and stress. This Review discusses how proteasome assembly and the regulation of proteasomal degradation are integrated with cellular physiology, including the interplay between the proteasome and autophagy pathways. Understanding these mechanisms has potential implications for disease therapy, as the misregulation of proteasome function contributes to human diseases such as cancer and neurodegeneration.</p

Institutional Mergers in Ireland

The importance of knowledge as a driver of social and economic growth and prosperity, and the increasingly competitive “global race for knowledge and talent” (Hazelkorn, Higher Educ Manage Policy 21(1):55–76, 2009) have combined to transform the higher education landscape, forcing national governments and higher education institutions (HEIs) to pursue new ways of addressing the challenges of a multi-polar world order. Rising demand for higher education (HE), as part of the broader shift from elite to mass to universal participation, has led to the emergence of new models of provision. At the same time, many governments face restrictions on public resources due to high levels of public and private debt; accordingly, system-level and institutional restructuring has been contemplated as a way to enhance quality, performance and efficiency

Hepatoprotective effects of methanol extract of Carissa opaca leaves on CCl4-induced damage in rat

<p>Abstract</p> <p>Background</p> <p><it>Carissa opaca </it>(Apocynaceae) leaves possess antioxidant activity and hepatoprotective effects, and so may provide a possible therapeutic alternative in hepatic disorders. The effect produced by methanolic extract of <it>Carissa opaca </it>leaves (MCL) was investigated on CCl₄-induced liver damages in rat.</p> <p>Methods</p> <p>30 rats were divided into five groups of six animals of each, having free access to food and water <it>ad libitum</it>. Group I (control) was given olive oil and DMSO, while group II, III and IV were injected intraperitoneally with CCl₄(0.5 ml/kg) as a 20% (v/v) solution in olive oil twice a week for 8 weeks. Animals of group II received only CCl₄. Rats of group III were given MCL intragastrically at a dose of 200 mg/kg bw while that of group IV received silymarin at a dose of 50 mg/kg bw twice a week for 8 weeks. However, animals of group V received MCL only at a dose of 200 mg/kg bw twice a week for 8 weeks. The activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and γ-glutamyltransferase (γ-GT) were determined in serum. Catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), glutathione reductase (GSR) and quinone reductase (QR) activity was measured in liver homogenates. Lipid peroxidation (thiobarbituric acid reactive substances; TBARS), glutathione (GSH) and hydrogen peroxide (H₂O₂) concentration was also assessed in liver homogenates. Phytochemicals in MCL were determined through qualitative and high performance liquid chromatography (HPLC) analysis.</p> <p>Results</p> <p>Hepatotoxicity induced with CCl₄was evidenced by significant increase in lipid peroxidation (TBARS) and H₂O₂level, serum activities of AST, ALT, ALP, LDH and γ-GT. Level of GSH determined in liver was significantly reduced, as were the activities of antioxidant enzymes; CAT, POD, SOD, GSH-Px, GSR, GST and QR. On cirrhotic animals treated with CCl₄, histological studies showed centrilobular necrosis and infiltration of lymphocytes. MCL (200 mg/kg bw) and silymarin (50 mg/kg bw) co-treatment prevented all the changes observed with CCl₄-treated rats. The phytochemical analysis of MCL indicated the presence of flavonoids, tannins, alkaloids, phlobatannins, terpenoids, coumarins, anthraquinones, and cardiac glycosides. Isoquercetin, hyperoside, vitexin, myricetin and kaempherol was determined in MCL.</p> <p>Conclusion</p> <p>These results indicate that MCL has a significant protective effect against CCl₄induced hepatotoxicity in rat, which may be due to its antioxidant and membrane stabilizing properties.</p

Sporothrix schenckii Lipid Inhibits Macrophage Phagocytosis: Involvement of Nitric Oxide and Tumour Necrosis Factor-alpha

The role of cell-wall compounds in the immune response to sporotrichosis is unknown. The effect of cell-wall compounds and exoantigen obtained from Sporothrix schenckii in macrophage/fungus interaction was analysed with respect to nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha). The lipid compound of the cell wall plays an important role in the pathogenesis of this mycosis and was found to inhibit the phagocytic process and to induce high liberation of NO and TNF-alpha in macrophage cultures in the present study. This is a very interesting result because it is the first report about one compound of the fungus S. schenckii that presents this activity.Univ Estadual Paulista Julio Mesquita Filho, Fac Ciências Farmaceut Araraquara, Dept Anal Clin, BR-14801902 Araraquara, SP, BrazilUniv Fed Fluminense, Inst Biomed, Dept Microbiol & Parasitol, Niteroi, RJ, BrazilUniv Estadual Paulista Julio Mesquita Filho, Fac Ciências Farmaceut Araraquara, Dept Anal Clin, BR-14801902 Araraquara, SP, Brazi