Browsing by Subject "Rapamycin"

Now showing 1 - 4 of 4
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    A comparison of the effects of rapamycin and cyclosporine on kidney and heart morphology in a rabbit heterotopic heart transplant model
    (Murcia : F. Hernández, 1995) Thliveris, J.A.; Solez, K.; Yatscoff, R.W.
    Rapamycin (RAPA) or cyclosporine (CsA) was administered intravenously, daily for 60 days, to rabbits with heterotopic heart transplants. Groups of 5 rabbits were randomly assigned to receive RAPA at 0.05,O. 1,0.5 or 1 .O mg/kglday or CsA at either 5 .O, 10.0 or 15 mg/kg/day. Dmg vehicle and saline controls were also included. Animals were examined daily and the cervical allografts assessed by palpation for viabilitylrejection. In those animals in which the heart stopped beating, the heart was removed and processed for light microscopic evaluation. The duration of the study was for 60 days at which time the animals were sacrificed and the transplanted heart and native kidneys removed and processed for light microscopic assessment of rejection and drug toxicity respectively. Biochemical and functional parameters in these animals were previously reported (Transplantation 5: 340-345, 1993). Animals that rejected their grafts were maintained on the dmg until the endpoint of the study to assess toxicity in the native kidneys. The rejected hearts from these animals were also harvested for microscopic evaluation. The results of the study revealed that heart rejection in drug treated animals was significantly lower than in corresponding controls but not different among the various drug treated groups. In the kidney, there were no differences in glomerular tuft area or tuft volume density amongst drug-treated or control animals. In contrast, tubule atrophy and interstitial fibrosis were markedl 3 greater in CsA-treated vs RAPA-treated animals (X 5.00, pe0.02). These data suggest that whereas drug efficacy with respect to heart allograft viability is similar between CsA and RAPA, renal toxicity is significantly less in those animals receiving RAPA.
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    Mammalian target of rapamycin: Master regulator of cell growth in the nervous system
    (Murcia : F. Hernández, 2007) Sandsmark, D.K.; Pelletier, C.; Weber, J.D.; Gutmann, D.H.
    The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for biologically-based therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.
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    Rapamycin mitigates organ damage by autophagy-mediated NLRP3 inflammasome inactivation in sepsis
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Li, Xiaofeng; Zeng, Qingqiu; Yao, Rui; Zhang, Lingyan; Kong, Ying; Shen, Bin
    Autophagy activation can alleviate sepsis-induced organ injuries. Rapamycin (Rap) has emerged as an autophagy regulator in multiple forms of organ injuries. This study aimed to assess whether Rap protects rats from cecal ligation and puncture (CLP)-induced sepsis through autophagy-mediated inactivation of the NLRP3 inflammasome. Rats were allocated to the sham, CLP, Rap (10 mg/kg), or 3-Methyladenine (3-MA) (15 mg/kg) groups. A rat CLP model was established. The survival of rats and lung wet-to-dry weight ratio in each group was assessed. Blood biochemical indexes and oxidative stress-related factors were analyzed with an automatic biochemical analyzer. The bacterial counts of blood and organs were monitored. The degrees of myeloperoxidase of the ileum, inflammation-related indexes, and pathological changes in the tissues were detected by ELISA and hematoxylin-eosin staining. The levels of NLRP3 inflammasome and autophagy-related factors were analyzed by Western blot. Rap increased the survival and SOD activity, and repressed ALT, AST, BUN, SCr, MDA, and inflammation-related marker levels in CLP rats, it also restrained the bacterial counts of blood, lung, liver, and kidney in CLP rats; the effects of 3-MA on CLP rats on the above-mentioned indicators were opposite to those of Rap. Additionally, Rap alleviated the pathological injury of the lung, liver, and kidney, which was the opposite to the effect of 3-MA on CLP rats. Furthermore, Rap mitigated the ASC, Pro-caspase 1, and NLRP3 levels and increased the Beclin-1 levels and the LC3II/LC3I ratio in the organ tissues. Collectively, autophagy activation can mitigate organ damage by suppressing the NLRP3 inflammasome in sepsis rats.
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    The novel involvement of podocyte autophagic activity in the pathogenesis of lupus nephritis
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Jin, Juan; Ye, Meiyu; Zhao, Li; Zou, Wenli; Shen, Wei; Zhang, Hongjuan; Gong, Jianguang; He, Qiang
    Background. Lupus nephritis (LN) is one of the most common and severe complications in Systemic lupus erythematosus patients, and the mechanism underlining the pathogenesis of LN is still unknown. Autophagy plays vital roles in maintaining cell homeostasis and is involved in the pathogenesis of many diseases. In this study, we investigated the role of autophagy in the progression of LN. Methods. Autophagic activities in podocytes of both LN patients (Class IV and V) and mice were evaluated. Podocytes were observed by electron microscopy, and autophagic activity was evaluated by immunofluorescence staining and western blot analysis. Apoptotic activity was evaluated by immunohistochemistry, TUNEL assays and flow cytometric analysis. Results. Significantly greater podocyte injury and discrepant autophagic levels were observed in LN patients. Differentiated mouse podocytes in the LN group showed reduced nephrin expression and increased apoptosis, as well as significantly higher levels of apoptosis-related proteins (cleaved caspase-3 and Bax). In the mice LN group, the increased number of autophagosomes was accompanied by increased LC3- II/LC3-I ratios and decreased p62, suggesting increased autophagic and apoptotic activity in podocytes. Blockade of autophagic activity by 3-MA or siRNAmediated silencing of Atg5 resulted in decreases in LC3- II/LC3-I ratios, podocyte apoptosis and damage in the mice LN group. Futhermore, Rapamycin treatment increased LC3-II/LC3-I ratios, and enhanced LNinduced apoptosis in podocyte from modal animal. Conclusions. This study demonstrates that autophagic activity of podocytes is a crucial factor in renal injury by directly affecting the function of podocyte; thus, inhibiting this activity during the early stages of LN is implicated as a potential therapeutic strategy for delaying the progression of LN. Also, clinical application in LN needs to consider patients’ pathological type and drugs’ comprehensive effectiveness.