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[PMID]:29410090
[Au] Autor:Brewer RA; Collins HE; Berry RD; Brahma MK; Tirado BA; Peliciari-Garcia RA; Stanley HL; Wende AR; Taegtmeyer H; Rajasekaran NS; Darley-Usmar V; Zhang J; Frank SJ; Chatham JC; Young ME
[Ad] Endereço:Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
[Ti] Título:Temporal partitioning of adaptive responses of the murine heart to fasting.
[So] Source:Life Sci;197:30-39, 2018 Mar 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recent studies suggest that the time of day at which food is consumed dramatically influences clinically-relevant cardiometabolic parameters (e.g., adiposity, insulin sensitivity, and cardiac function). Meal feeding benefits may be the result of daily periods of feeding and/or fasting, highlighting the need for improved understanding of the temporal adaptation of cardiometabolic tissues (e.g., heart) to fasting. Such studies may provide mechanistic insight regarding how time-of-day-dependent feeding/fasting cycles influence cardiac function. We hypothesized that fasting during the sleep period elicits beneficial adaptation of the heart at transcriptional, translational, and metabolic levels. To test this hypothesis, temporal adaptation was investigated in wild-type mice fasted for 24-h, or for either the 12-h light/sleep phase or the 12-h dark/awake phase. Fasting maximally induced fatty acid responsive genes (e.g., Pdk4) during the dark/active phase; transcriptional changes were mirrored at translational (e.g., PDK4) and metabolic flux (e.g., glucose/oleate oxidation) levels. Similarly, maximal repression of myocardial p-mTOR and protein synthesis rates occurred during the dark phase; both parameters remained elevated in the heart of fasted mice during the light phase. In contrast, markers of autophagy (e.g., LC3II) exhibited peak responses to fasting during the light phase. Collectively, these data show that responsiveness of the heart to fasting is temporally partitioned. Autophagy peaks during the light/sleep phase, while repression of glucose utilization and protein synthesis is maximized during the dark/active phase. We speculate that sleep phase fasting may benefit cardiac function through augmentation of protein/cellular constituent turnover.
[Mh] Termos MeSH primário: Adaptação Fisiológica
Autofagia
Jejum/metabolismo
Miocárdio/metabolismo
Fases do Sono
[Mh] Termos MeSH secundário: Animais
Masculino
Camundongos
Proteínas Associadas aos Microtúbulos/metabolismo
Biossíntese de Proteínas/fisiologia
Proteínas Serina-Treonina Quinases/biossíntese
Serina-Treonina Quinases TOR/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAP1LC3 protein, mouse); 0 (Microtubule-Associated Proteins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE


  2 / 15054 MEDLINE  
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[PMID]:29185092
[Au] Autor:Ma M; Dai J; Xu T; Yu S; Yu H; Tang H; Yan J; Wu X; Yu J; Chi Z; Si L; Cui C; Sheng X; Kong Y; Guo J
[Ad] Endereço:Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
[Ti] Título:Analysis of TSC1 mutation spectrum in mucosal melanoma.
[So] Source:J Cancer Res Clin Oncol;144(2):257-267, 2018 Feb.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma. METHODS: We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1. RESULTS: The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007). CONCLUSIONS: Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.
[Mh] Termos MeSH primário: Melanoma/genética
Mutação
Proteínas Supressoras de Tumor/genética
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Análise Mutacional de DNA
Feminino
Seres Humanos
Masculino
Melanoma/metabolismo
Melanoma/patologia
Meia-Idade
Membrana Mucosa/patologia
Estadiamento de Neoplasias
Fosfoproteínas/metabolismo
Prognóstico
Proteína S6 Ribossômica/metabolismo
Serina-Treonina Quinases TOR/metabolismo
Proteínas Supressoras de Tumor/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (EIF4EBP1 protein, human); 0 (Phosphoproteins); 0 (Ribosomal Protein S6); 0 (Tumor Suppressor Proteins); 0 (tuberous sclerosis complex 1 protein); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2550-z


  3 / 15054 MEDLINE  
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[PMID]:28464864
[Au] Autor:Shimazu K; Tada Y; Morinaga T; Shingyoji M; Sekine I; Shimada H; Hiroshima K; Namiki T; Tatsumi K; Tagawa M
[Ad] Endereço:Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
[Ti] Título:Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways.
[So] Source:BMC Cancer;17(1):309, 2017 May 02.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma. METHODS: We examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53. RESULTS: Metformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells. CONCLUSION: These data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Imidazóis/farmacologia
Neoplasias Pulmonares/metabolismo
Mesotelioma/metabolismo
Metformina/farmacologia
Piperazinas/farmacologia
Serina-Treonina Quinases TOR/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Imidazoles); 0 (Piperazines); 0 (Tumor Suppressor Protein p53); 53IA0V845C (nutlin 3); 9100L32L2N (Metformin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-017-3300-y


  4 / 15054 MEDLINE  
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[PMID]:27771126
[Au] Autor:Davis ID; Xie W; Pezaro C; Donskov F; Wells JC; Agarwal N; Srinivas S; Yuasa T; Beuselinck B; Wood LA; Ernst DS; Kanesvaran R; Knox JJ; Pantuck A; Saleem S; Alva A; Rini BI; Lee JL; Choueiri TK; Heng DYC
[Ad] Endereço:Monash University and Eastern Health, Box Hill. Victoria, Australia. Electronic address: ian.davis@monash.edu.
[Ti] Título:Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category.
[So] Source:Eur Urol;71(6):970-978, 2017 Jun.
[Is] ISSN:1873-7560
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response. OBJECTIVE: To assess outcomes of 2L according to type of therapy and change in IMDC prognostic category. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of the IMDC database for mRCC patients who received first-line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined before each line of therapy (favorable, F; intermediate, I; poor, P). Data were analyzed for 1516 patients, of whom 89% had clear cell histology. INTERVENTION: All included patients received targeted therapy for mRCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), time to treatment failure, and response to 2L were analyzed using Cox or logistic regression. RESULTS AND LIMITATIONS: At start of 2L, 60% of patients remained in the same prognostic category; 9.0% improved (3% I → F; 6% P → I); 31% deteriorated (15% F → I or P; 16% I → P). Patients with the same or better IMDC prognostic category had a longer time to treatment failure if they remained on VEGFi compared to those who switched to mTORi (adjusted hazard ratio [AHR] ranging from 0.33 to 0.78, adjusted p<0.05). Patients who deteriorated from F to I appeared more likely to benefit from switching to mTORi (median OS 16.5 mo, 95% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03). CONCLUSIONS: Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy. PATIENT SUMMARY: The pattern of treatment failure might help to predict what the next treatment should be for patients with metastatic renal cell carcinoma.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/uso terapêutico
Carcinoma de Células Renais/tratamento farmacológico
Neoplasias Renais/tratamento farmacológico
Terapia de Alvo Molecular
Inibidores de Proteínas Quinases/uso terapêutico
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/efeitos adversos
Carcinoma de Células Renais/enzimologia
Carcinoma de Células Renais/secundário
Bases de Dados Factuais
Progressão da Doença
Intervalo Livre de Doença
Substituição de Medicamentos
Feminino
Seres Humanos
Estimativa de Kaplan-Meier
Neoplasias Renais/enzimologia
Neoplasias Renais/patologia
Modelos Logísticos
Masculino
Meia-Idade
Análise Multivariada
Razão de Chances
Modelos de Riscos Proporcionais
Inibidores de Proteínas Quinases/efeitos adversos
Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
Estudos Retrospectivos
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
Resultado do Tratamento
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Protein Kinase Inhibitors); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  5 / 15054 MEDLINE  
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[PMID]:29331753
[Au] Autor:Tang B; Wan D; Wang YJ; Yi QY; Guo BH; Liu YJ
[Ad] Endereço:School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
[Ti] Título:An iridium (III) complex as potent anticancer agent induces apoptosis and autophagy in B16 cells through inhibition of the AKT/mTOR pathway.
[So] Source:Eur J Med Chem;145:302-314, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A new ligand THPDP (THPDP = 11-(6,7,8,9-tetrahydrophenazin-2-yl)dipyrido[3,2-a:2',3'-c]phenazine) and its iridium(III) complex [Ir(ppy) (THPDP)]PF (Ir-1) was synthesized and characterized by elemental analysis, IR, ESI-MS, H NMR and C NMR. The cytotoxicity in vitro of the complex against cancer cells B16, A549, Eca-109, SGC-7901, BEL-7402 and normal NIH 3T3 cell lines was evaluated using MTT method. The IC values of the complex toward B16, A549 and Eca-109 cells are 1.0 ±â€¯0.02, 1.4 ±â€¯0.03 and 1.6 ±â€¯0.06 µM, respectively. The apoptosis was investigated with AO/EB and DAPI staining methods. The complex shows strong ability to inhibit the cell growth in B16, A549 and Eca-109 cells. Ir-1 can induce apoptosis, increase the intracellular ROS level, and cause a decrease in the mitochondrial membrane potential. The intracellular Ca level and the release of cytochrome c were studied under a fluorescent microscope. The cell invasion and autophagy were also performed, and the cell cycle arrest was assayed by flow cytometry. The expression of Bcl-2 family proteins, PI3K, AKT, mTOR, P-mTOR was investigated by western blot. The results show that the complex induces apoptosis through ROS-mediated mitochondria dysfunction and inhibition of AKT/mTOR pathways. These findings are helpful for design and synthesis of iridium(III) complexes as potent anticancer drugs.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Complexos de Coordenação/farmacologia
Irídio/farmacologia
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Complexos de Coordenação/síntese química
Complexos de Coordenação/química
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Irídio/química
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Camundongos
Estrutura Molecular
Células NIH 3T3
Proteínas Proto-Oncogênicas c-akt/metabolismo
Relação Estrutura-Atividade
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Coordination Complexes); 44448S9773 (Iridium); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180115
[St] Status:MEDLINE


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[PMID]:29343687
[Au] Autor:Frith JE; Kusuma GD; Carthew J; Li F; Cloonan N; Gomez GA; Cooper-White JJ
[Ad] Endereço:Materials Science and Engineering, Monash University, Clayton, VIC, 3800, Australia. Jessica.Frith@monash.edu.
[Ti] Título:Mechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling.
[So] Source:Nat Commun;9(1):257, 2018 01 17.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mechanotransduction is a strong driver of mesenchymal stem cell (MSC) fate. In vitro, variations in matrix mechanics invoke changes in MSC proliferation, migration and differentiation. However, when incorporating MSCs within injectable, inherently soft hydrogels, this dominance over MSC response substantially limits our ability to couple the ease of application of hydrogels with efficiently directed MSC differentiation, especially in the case of bone generation. Here, we identify differential miRNA expression in response to varying hydrogel stiffness and RhoA activity. We show that modulation of miR-100-5p and miR-143-3p can be used to bias MSC fate and provide mechanistic insight by demonstrating convergence on mTOR signalling. By modulating these mechanosensitive miRNAs, we can enhance osteogenesis in a soft 3D hydrogel. The outcomes of this study provide new understanding of the mechanisms regulating MSC mechanotransduction and differentiation, but also a novel strategy with which to drive MSC fate and significantly impact MSC-based tissue-engineering applications.
[Mh] Termos MeSH primário: Diferenciação Celular/genética
Proliferação Celular/genética
Células Mesenquimais Estromais/metabolismo
MicroRNAs/genética
[Mh] Termos MeSH secundário: Células Cultivadas
Regulação da Expressão Gênica
Seres Humanos
Hidrogéis/metabolismo
Mecanotransdução Celular
Células Mesenquimais Estromais/citologia
Microscopia Confocal
Osteogênese/genética
Transdução de Sinais/genética
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
Engenharia Tecidual/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Hydrogels); 0 (MicroRNAs); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02486-0


  7 / 15054 MEDLINE  
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[PMID]:29402262
[Au] Autor:Liu MW; Wei R; Su MX; Li H; Fang TW; Zhang W
[Ad] Endereço:Department of Emergency, the First Hospital Affiliated To Kunming Medical University, 295 Xichang Road, Wu Hua District, Kunming, 650032, China. Lmw2004210@163.com.
[Ti] Título:Effects of Panax notoginseng saponins on severe acute pancreatitis through the regulation of mTOR/Akt and caspase-3 signaling pathway by upregulating miR-181b expression in rats.
[So] Source:BMC Complement Altern Med;18(1):51, 2018 Feb 05.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: In China, Panax notoginseng has been used to treat oxidative stress-related diseases for a long time. Panax notoginseng saponins is an extract from Panax notoginseng Ledeb. Its therapeutic potential is related to antioxidant activity, but related mechanisms are still unclear. The study aims to assess the protection effects of Panax notoginseng saponins in the taurocholate-induced rat model of acute pancreatitis (AP) and explore underlying mechanisms. METHODS: A rat model of severe acute pancreatitis (SAP) was established in rats induced with taurocholate. Panax notoginseng saponins was firstly administered in the treatment group via intravenous injection. After 2 h, taurocholate administration was performed. After 24 h, the expression levels of miR-181b, Beclin1, LC3-II, Akt and mTOR from pancreas tissues were measured by Western Blotting and RT-PCR. Then the expression levels of Caspase-3 and Blc-2 were determined by immunohistochemistry. Apoptosis was assessed by the TUNEL assay. Amylase and lipase in serum were determined by ELISA and pancreatic water contents in pancreatic tissue were measured. After eosin and hematoxylin staining, the histologic analysis was performed. RESULTS: After SAP induction by taurocholate and the treatment with Panax notoginseng saponins for 24 h, we detected the up-regulated miR-181b, the reduced Bcl-2 expression, the increased activity of mTOR/Akt, the blocked Beclin1 and LC3-II expressions, and the enhanced Caspase-3 expression. Serum lipase and amylase levels were significantly decreased in the treatment group of Panax notoginseng saponins compared to the control group. Histological analysis results verified the attenuation effects of Panax notoginseng saponins on taurocholate-induced pancreas injury, apoptosis, and autophagy. CONCLUSION: By up-regulating the miR-181b expression level, Panax notoginseng saponins significantly reduced taurocholate-induced pancreas injury and autophagy and increased apoptosis. The significant protection effects of Panax notoginseng saponins suggested its potential in treating taurocholate induced-acute pancreatitis.
[Mh] Termos MeSH primário: Caspase 3/metabolismo
MicroRNAs/metabolismo
Panax notoginseng
Pancreatite/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Saponinas/farmacologia
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Modelos Animais de Doenças
Masculino
MicroRNAs/genética
Pâncreas/efeitos dos fármacos
Pâncreas/patologia
Pancreatite/patologia
Extratos Vegetais
Ratos
Ratos Sprague-Dawley
Transdução de Sinais/efeitos dos fármacos
Ácido Taurocólico/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN181 microRNA, rat); 0 (MicroRNAs); 0 (Plant Extracts); 0 (Saponins); 5E090O0G3Z (Taurocholic Acid); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, rat); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-018-2118-8


  8 / 15054 MEDLINE  
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[PMID]:29355544
[Au] Autor:Li X; Zhou N; Wang J; Liu Z; Wang X; Zhang Q; Liu Q; Gao L; Wang R
[Ad] Endereço:Key Laboratory of Pharmacology, Chifeng University, Hongshan, Chifeng, Inner Mongolia 024000, China.
[Ti] Título:Quercetin suppresses breast cancer stem cells (CD44 /CD24 ) by inhibiting the PI3K/Akt/mTOR-signaling pathway.
[So] Source:Life Sci;196:56-62, 2018 Mar 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Cancer stem cells (CSCs) are considered the prime source of cancer recurrence, metastasis, and progression and represent important targets for developing novel anticancer agents and therapeutic strategies. The aim of this study was to investigate the effect of treating breast CSCs with the anticancer flavonoid, quercetin. MAIN METHODS: We examined changes in the cluster of differentiation CD44 /CD24 CSC population and behavior using the breast cancer cell line MCF-7. KEY FINDINGS: Our results indicated that cell viability, clone formation, mammosphere generation, and nude mice tumor metastasis were inhibited in the CD44 /CD24 population and that MCF-7 cells exhibited G1-phase arrest after quercetin treatment. Additionally, CyclinD1 and B cell lymphoma-2 expression were suppressed and Bcl-2-like protein-4 expression was enhanced after quercetin treatment. We also observed that estrogen receptor α and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling were downregulated concurrently with the inhibition of CD44 /CD24 viability and clone formation. Our findings suggested that quercetin treatment promoted weaker malignant activity associated with CSCs relative to that observed in normal cancer cells through its inhibition of the PI3K/Akt/mTOR-signaling pathway. SIGNIFICANCE: These results indicated that CSCs are potential therapeutic targets for quercetin treatment of breast cancer.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Antígeno CD24/efeitos dos fármacos
Receptores de Hialuronatos/efeitos dos fármacos
Proteína Oncogênica v-akt/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Quercetina/farmacologia
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Feminino
Fase G1/efeitos dos fármacos
Seres Humanos
Células MCF-7
Camundongos Nus
Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (CD24 Antigen); 0 (CD44 protein, human); 0 (Hyaluronan Receptors); 0 (Proto-Oncogene Proteins c-bcl-2); 9IKM0I5T1E (Quercetin); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Oncogene Protein v-akt)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


  9 / 15054 MEDLINE  
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[PMID]:29323924
[Au] Autor:Zhang T; Huang J; Yi Y; Zhang X; Loor JJ; Cao Y; Shi H; Luo J
[Ad] Endereço:Shanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University , Yangling, Shaanxi 712100, PR China.
[Ti] Título:Akt Serine/Threonine Kinase 1 Regulates de Novo Fatty Acid Synthesis through the Mammalian Target of Rapamycin/Sterol Regulatory Element Binding Protein 1 Axis in Dairy Goat Mammary Epithelial Cells.
[So] Source:J Agric Food Chem;66(5):1197-1205, 2018 Feb 07.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Akt serine/threonine kinase acts as a central mediator in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, regulating a series of biological processes. In lipid metabolism, Akt activation regulates a series of gene expressions, including genes related to intracellular fatty acid synthesis. However, the regulatory mechanisms of Akt in dairy goat mammary lipid metabolism have not been elaborated. In this study, the coding sequences of goat Akt1 gene were cloned and analyzed. Gene expression of Akt1 in different lactation stages was also investigated. For in vitro studies, a eukaryotic expression vector of Akt1 was constructed and transfected to goat mammary epithelial cells (GMECs), and specific inhibitors of Akt/mammalian target of rapamycin (mTOR) signaling were applied to GMECs. Results showed that Akt1 protein was highly conserved, and its mRNA was highly expressed in midlactation. In vitro studies indicated that Akt1 phosphorylation activated mTOR and subsequently enhanced sterol regulatory element binding protein 1 (SREBP1), thus increasing intracellular triacylglycerol content. Inhibition of Akt/mTOR signaling down-regulated the gene expression of lipogenic genes. Overall, Akt1 plays an important role in regulating de novo fatty acid synthesis in goat mammary epithelial cells, and this process probably is through the mTOR/SREBP1 axis.
[Mh] Termos MeSH primário: Ácidos Graxos/biossíntese
Cabras
Glândulas Mamárias Animais/metabolismo
Proteínas Proto-Oncogênicas c-akt/fisiologia
Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia
Serina-Treonina Quinases TOR/fisiologia
[Mh] Termos MeSH secundário: Animais
Epitélio/metabolismo
Regulação da Expressão Gênica/fisiologia
Lipogênese/genética
Proteínas Proto-Oncogênicas c-akt/genética
Transdução de Sinais/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Sterol Regulatory Element Binding Protein 1); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b05305


  10 / 15054 MEDLINE  
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[PMID]:29317619
[Au] Autor:Chen X; Wang S; Zhou Y; Han Y; Li S; Xu Q; Xu L; Zhu Z; Deng Y; Yu L; Song L; Chen AP; Song J; Takahashi E; He G; He L; Li W; Chen CD
[Ad] Endereço:Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
[Ti] Título:Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway.
[So] Source:Nat Commun;9(1):114, 2018 01 09.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 (Phf8) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID.
[Mh] Termos MeSH primário: Disfunção Cognitiva/genética
Histona Desmetilases/genética
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Animais
Disfunção Cognitiva/metabolismo
Disfunção Cognitiva/fisiopatologia
Feminino
Perfilação da Expressão Gênica
Hipocampo/metabolismo
Hipocampo/fisiopatologia
Histona Desmetilases/deficiência
Potenciação de Longa Duração/genética
Aprendizagem em Labirinto/fisiologia
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Atividade Motora/genética
Atividade Motora/fisiologia
Serina-Treonina Quinases TOR/metabolismo
Fatores de Transcrição/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Transcription Factors); EC 1.14.11.- (Histone Demethylases); EC 1.14.11.27 (PHF8 protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02531-y



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