Navegando por Palavras-chave "Ubiquitin proteasome system"
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- ItemSomente MetadadadosAerobic exercise training improves oxidative stress and ubiquitin proteasome system activity in heart of spontaneously hypertensive rats(Springer, 2015-04-01) Andrade, Luiz Henrique Soares de [UNIFESP]; Moraes, Wilson Max Almeida Monteiro de [UNIFESP]; Matsuo Junior, Eduardo Hiroshi [UNIFESP]; Moura, Elizabeth de Orleans Carvalho de [UNIFESP]; Antunes, Hanna Karen Moreira [UNIFESP]; Montemor, Jairo [UNIFESP]; Antonio, Ednei Luiz [UNIFESP]; Bocalini, Danilo Sales [UNIFESP]; Serra, Andrey Jorge [UNIFESP]; Tucci, Paulo José Ferreira [UNIFESP]; Brum, Patricia Chakur; Medeiros, Alessandra [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Univ Sao Judas Tadeu; Univ Nove Julho; Universidade de São Paulo (USP)The activity of the ubiquitin proteasome system (UPS) and the level of oxidative stress contribute to the transition from compensated cardiac hypertrophy to heart failure in hypertension. Moreover, aerobic exercise training (AET) is an important therapy for the treatment of hypertension, but its effects on the UPS are not completely known. the aim of this study was to evaluate the effect of AET on UPS's activity and oxidative stress level in heart of spontaneously hypertensive rats (SHR). A total of 53 Wi-star and SHR rats were randomly divided into sedentary and trained groups. the AET protocol was 59/week in treadmill for 13 weeks. Exercise tolerance test, non-invasive blood pressure measurement, echocardiographic analyses, and left ventricle hemodynamics were performed during experimental period. the expression of ubiquitinated proteins, 4-hydroxynonenal (4-HNE), Akt, phospho-Akt(ser473), GSK3 beta, and phospho-GSK3 beta(ser9) were analyzed by western blotting. the evaluation of lipid hydroperoxide concentration was performed using the xylenol orange method, and the proteasomal chymotrypsin-like activity was measured by fluorimetric assay. Sedentary hypertensive group presented cardiac hypertrophy, unaltered expression of total Akt, phospho-Akt, total GSK3 beta and phospho-GSK3 beta, UPS hyperactivity, increased lipid hydroperoxidation as well as elevated expression of 4-HNE but normal cardiac function. in contrast, AET significantly increased exercise tolerance, decreased resting systolic blood pressure and heart rate in hypertensive animals. in addition, the AET increased phospho-Akt expression, decreased phospho-GSK3 beta, and did not alter the expression of total Akt, total GSK3 beta, and ubiquitinated proteins, however, significantly attenuated 4-HNE levels, lipid hydroperoxidation, and UPS's activity toward normotensive group levels. Our results provide evidence for the main effect of AET on attenuating cardiac ubiquitin proteasome hyperactivity and oxidative stress in SHR rats.
- ItemSomente MetadadadosEfeito do treinamento físico aeróbico na hipertrofia cardíaca de ratos espontaneamente hipertensos: papel do sistema ubiquitina proteassoma(Universidade Federal de São Paulo (UNIFESP), 2013-08-28) Andrade, Luiz Henrique Soares de [UNIFESP]; Medeiros, Alessandra [UNIFESP]; http://lattes.cnpq.br/0071198026371230; Universidade Federal de São Paulo (UNIFESP)Hypertension is a clinical condition that contributes to the development of cardiac hypertrophy. The activity level of the ubiquitin proteasome system (UPS) is involved in the initiation and progression of cardiac hypertrophy. Moreover, physical training can decrease blood pressure, reduce or reverse the pathological cardiac hypertrophy and this response may, at least in part, occur through changes in the activity of the SUP in the heart. The purpose of this study was to investigate the effect of aerobic exercise training in cardiac hypertrophy and activity of UPS in spontaneously hypertensive rats (SHR). For this, we used Wistar and SHR rats (8 weeks old) randomly divided into sedentary and trained, and the exercise training protocol was 5x/week in treadmill, low intensity, 60 min, for 13 weeks. Before, during and after the experimental period exercise tolerance test was performed. The recording indirect systolic blood pressure (SBP), heart rate (HR) and body weight were evaluated once a week. The proteasome activity in the catalytic site of chymotrypsin was measured by fluorimetric assay. The tr aining significantly increased exercise tolerance in hypertensive animals, decreased SBP and HR at rest after the period, and elevated diastolic function. In addition, it restored the proteasome activity on the control groups levels. Data from this study demonstrated the important non-pharmacological therapeutic effect of exercise on ubiquitin proteasome system in hypertension.
- ItemAcesso aberto (Open Access)Papel da família da heat shock protein 70 (HSP70) como alvo terapêutico em mieloma múltiplo através de análises in vitro e in vivo(Universidade Federal de São Paulo (UNIFESP), 2017-03-07) Eugênio, Angela Isabel Pereira [UNIFESP]; Colleoni, Gisele Wally Braga [UNIFESP]; http://lattes.cnpq.br/2918635854077904; http://lattes.cnpq.br/1240012495336970; Universidade Federal de São Paulo (UNIFESP)Introduction: HSP70 has integrative role in protein degradation due to the interaction with many pathways, such as ubiquitin proteasome, unfolded protein response and autophagy. Objectives: To explore the role of HSP70 as a therapeutic target for multiple myeloma (MM) through in vitro and in vivo analyses. Methods: Bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 inhibitor (VER155008) and proteasome inhibitor (bortezomib) for evaluation of apoptosis by flow cytometry. HSP70 members, unfolded protein response and autophagy genes were evaluated by qPCR in the same cell lines. Immunodeficient mice were used for subcutaneous xenograft model in two different approaches: RPMI8226-LUC-PURO cells into the right flank to induce a plasmocytoma. When the tumors became palpable mice were randomised to receive bortezomib, VER155008 or bortezomib plus VER155008 or no intervention. Histologic and protein expression analysis were performed. In a second model, each mouse was inoculated at the same moment, with RPMI8226-LUC-PURO cells into the left and U266-LUC-PURO into the righ flank. Mice were randomised into four groups of treatment and received intravenously proteassome and HSP70 inhitors immediately after xenotransplantation of the cell lines. Bioluminescence (BLI) was measured once a day for seven days. Results: RPMI8226- LUC-PURO and U266-LUC-PURO cell lines express HSP70 family genes, XBP-1 and BECLINA-1. Both cell lines treated with bortezomib, VER155008 (50μM and 80μM), isolated or combined, responded with increased expression of HSPA1A/HSPA1B. RPMI8226-LUC-PURO also showed increased expression of HSPA5 and XBP-1 genes after treatment with VER155008 (50μM). RPMI8226-LUC-PURO almost 60% of late apoptosis after treatment with bortezomib (100nM) alone. Treatment with VER155008, isolated or combined with bortezomib, did not add benefit to bortezomib treatment in 128 this cell line. However, U266-LUC-PURO cell line showed over 60% of cell death after treatment with VER155008 (80μM) alone and also with VER155008 (80μM) plus bortezomib, 48 hours after treatmet. In vivo data showed tumor growth reduction by bioluminescence in the group with RPMI8226-LUC-PURO plasmocytoma after treatment with bortezomib, VER155008 or combination of drugs compared to the control group. Nevertheless, the expression of HSP70 proteins, XBP-1s and BECLINA-1 had no statistically significant changes, except for reduction of XBP-1s protein relative expression in to tumors treated with VER155008. For the group of mice that had no prior induction of tumor, treatment with bortezomib, isolated or combined with VER155008 showed inhibition of tumor growth (or incipient growth) assessed by bioluminescence after one week for both cell lines when compared with the control group. Conclusion: Our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro and in vivo (late apoptosis induction and inhibition of tumor growth). Since HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress, it can represent a key role to establish a new approach for the treatment of MM (after achievement of the best response or as maintanence therapy) mostly in patients with deletion of 17p (like U266 cell line).