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[PMID]:29288363
[Au] Autor:Hamurcu Z; Delibasi N; Geçene S; Sener EF; Dönmez-Altuntas H; Özkul Y; Canatan H; Ozpolat B
[Ad] Endereço:Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
[Ti] Título:Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin ß1/ Src signaling in triple negative breast cancer cells.
[So] Source:J Cancer Res Clin Oncol;144(3):415-430, 2018 Mar.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Autophagy is a catabolic process for degrading dysfunctional proteins and organelles, and closely associated with cancer cell survival under therapeutic, metabolic stress, hypoxia, starvation and lack of growth factors, contributing to resistance to therapies. However, the role of autophagy in breast cancer cells is not well understood. In the present study, we investigated the role of autophagy in highly aggressive and metastatic triple negative breast cancer (TNBC) and non-metastatic breast cancer cells and demonstrated that the knockdown of autophagy-related genes (LC3 and Beclin-1) inhibited autophagy and significantly suppressed cell proliferation, colony formation, migration/invasion and induced apoptosis in MDA-MB-231 and BT-549 TNBC cells. Knockdown of LC3 and Beclin-1 led to inhibition of multiple proto-oncogenic signaling pathways, including cyclin D1, uPAR/integrin-ß1/Src, and PARP1. In conclusion, our study suggests that LC3 and Beclin-1 are required for cell proliferation, survival, migration and invasion, and may contribute to tumor growth and progression of highly aggressive and metastatic TNBC cells and therapeutic targeting of autophagy genes may be a potential therapeutic strategy for TNBC in breast cancer.
[Mh] Termos MeSH primário: Beclina-1/antagonistas & inibidores
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Proteínas Associadas aos Microtúbulos/antagonistas & inibidores
Terapia de Alvo Molecular/métodos
RNA Interferente Pequeno/farmacologia
Neoplasias de Mama Triplo Negativas/patologia
[Mh] Termos MeSH secundário: Autofagia/genética
Beclina-1/genética
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Ciclina D1/antagonistas & inibidores
Ciclina D1/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Integrina beta1/metabolismo
Células MCF-7
Proteínas Associadas aos Microtúbulos/genética
Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
Neoplasias de Mama Triplo Negativas/genética
Quinases da Família src/antagonistas & inibidores
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (CCND1 protein, human); 0 (Integrin beta1); 0 (Microtubule-Associated Proteins); 0 (RNA, Small Interfering); 0 (Receptors, Urokinase Plasminogen Activator); 0 (light chain 3, human); 136601-57-5 (Cyclin D1); EC 2.7.10.2 (src-Family Kinases)
[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:171231
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2557-5


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[PMID]:28747345
[Au] Autor:Dang J; Bian X; Ma X; Li J; Long F; Shan S; Yuan Q; Xin Q; Li Y; Gao F; Gong Y; Liu Q
[Ad] Endereço:Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China.
[Ti] Título:ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway.
[So] Source:J Immunol;199(5):1647-1659, 2017 09 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The genetic association of orosomucoid-like 3 (ORMDL3) with an array of immunoinflammatory disorders has been recently unraveled in multiple ethnic groups, and functional exploration has received attention of the particular relevance of this gene in endoplasmic reticulum stress, lipid metabolism, and inflammatory response. In this study, we demonstrated the upregulation of ORMDL3 in both patients with systemic lupus erythematosus and lupus mice compared with controls. By establishing ORMDL3 knockout mice ( ), we showed that silencing Ormdl3 in vivo significantly decreased the proportions of mature B lymphocytes and transitional 2B cells in spleen and B1a cells from abdominal cavity perfusion fluid, the secretion of IgG and IgM, and the expression of Baff. Additionally, knockdown of Ormdl3 augmented the apoptosis of total splenic cells and splenic CD19 B cells but did not affect B cell proliferation and cell cycle. Subsequently, we in vitro and in vivo demonstrated that ORMDL3 potentially mediates the autophagy via the ATF 6-Beclin1 autophagy pathway, and it facilitates the survival of splenic B cells via promoting autophagy and suppressing apoptosis. Taken together, we uncovered a role of ORMDL3 in fine-tuning B cell development and survival, besides highlighting a potential mechanism by which ORMDL3 regulates autophagy via ATF6 pathway.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Estresse do Retículo Endoplasmático/imunologia
Lúpus Eritematoso Sistêmico/imunologia
Proteínas de Membrana/metabolismo
[Mh] Termos MeSH secundário: Fator 6 Ativador da Transcrição/metabolismo
Adulto
Animais
Apoptose
Autofagia
Beclina-1/metabolismo
Sobrevivência Celular
Células Cultivadas
Modelos Animais de Doenças
Feminino
Seres Humanos
Metabolismo dos Lipídeos
Masculino
Proteínas de Membrana/genética
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Transdução de Sinais
Baço/patologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ATF6 protein, human); 0 (Activating Transcription Factor 6); 0 (Beclin-1); 0 (Membrane Proteins); 0 (ORMDL3 protein, human); 0 (ORMDL3 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180128
[Lr] Data última revisão:
180128
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1602124


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[PMID]:29197865
[Au] Autor:Liu Y; Zhang Y; Zou J; Yan L; Yu X; Lu P; Wu X; Li Q; Gu R; Zhu D
[Ad] Endereço:Department of Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, China.
[Ti] Título:Andrographolide Induces Autophagic Cell Death and Inhibits Invasion and Metastasis of Human Osteosarcoma Cells in An Autophagy-Dependent Manner.
[So] Source:Cell Physiol Biochem;44(4):1396-1410, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue. Although treatment effectiveness has improved, the OS survival rate has fluctuated in recent years. Andrographolide (AG) has been reported to have antitumor activity against a variety of tumors. Our aim was to investigate the effects and potential mechanisms of AG in human osteosarcoma. METHODS: Cell viability and morphological changes were assessed by MTT and live/dead assays. Apoptosis was detected using Annexin V-FITC/PI double staining, DAPI, and caspase-3 assays. Autophagy was detected with mRFP-GFP-LC3 adenovirus transfection and western blot. Cell migration and invasion were detected by wound healing assay and Transwell® experiments. RESULTS: AG dose-dependently reduced the viability of osteosarcoma cells. No increase in apoptosis was detected in AG-treated human OS MG-63 and U-2OS cells, and the pan-caspase inhibitor z-VAD did not attenuate AG-induced cell death. However, AG induced autophagy by suppressing PI3K/Akt/mTOR and enhancing JNK signaling pathways. 3-MA and Beclin-1 siRNA could reverse the cytotoxic effects of AG. In addition, AG inhibited the invasion and metastasis of OS, and this effect could be reversed with Beclin-1 siRNA. CONCLUSION: AG inhibits viability and induces autophagic death in OS cells. AG-induced autophagy inhibits the invasion and metastasis of OS.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Diterpenos/toxicidade
[Mh] Termos MeSH secundário: Antracenos/farmacologia
Beclina-1/antagonistas & inibidores
Beclina-1/genética
Beclina-1/metabolismo
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/patologia
Caspase 3/metabolismo
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Diterpenos/química
Seres Humanos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Oligopeptídeos/farmacologia
Osteossarcoma/metabolismo
Osteossarcoma/patologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthracenes); 0 (Beclin-1); 0 (Diterpenes); 0 (Oligopeptides); 0 (RNA, Small Interfering); 0 (benzyloxycarbonyl-valyl-alanyl-aspartic acid); 1TW30Y2766 (pyrazolanthrone); 410105JHGR (andrographolide); 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 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE
[do] DOI:10.1159/000485536


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[PMID]:28463668
[Au] Autor:Feizi N; Mehrbod P; Romani B; Soleimanjahi H; Bamdad T; Feizi A; Jazaeri EO; Targhi HS; Saleh M; Jamali A; Fotouhi F; Nargesabad RN; Abdoli A
[Ad] Endereço:1​Influenza and Other Respiratory Viruses Department, Pasteur Institute of Iran, Tehran, Iran.
[Ti] Título:Autophagy induction regulates influenza virus replication in a time-dependent manner.
[So] Source:J Med Microbiol;66(4):536-541, 2017 Apr.
[Is] ISSN:1473-5644
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Autophagy plays a key role in host defence responses against microbial infections by promoting degradation of pathogens and participating in acquired immunity. The interaction between autophagy and viruses is complex, and this pathway is hijacked by several viruses. Influenza virus (IV) interferes with autophagy through its replication and increases the accumulation of autophagosomes by blocking lysosome fusion. Thus, autophagy could be an effective area for antiviral research. METHODOLOGY: In this study, we evaluated the effect of autophagy on IV replication. Two cell lines were transfected with Beclin-1 expression plasmid before (prophylactic approach) and after (therapeutic approach) IV inoculation.Results/Key findings. Beclin-1 overexpression in the cells infected by virus induced autophagy to 26 %. The log10haemagglutinin titre and TCID50 (tissue culture infective dose giving 50 % infection) of replicating virus were measured at 24 and 48 h post-infection. In the prophylactic approach, the virus titre was enhanced significantly at 24 h post-infection (P≤0.01), but it was not significantly different from the control at 48 h post-infection. In contrast, the therapeutic approach of autophagy induction inhibited the virus replication at 24 and 48 h post-infection. Additionally, we showed that inhibition of autophagy using 3-methyladenine reduced viral replication. CONCLUSION: This study revealed that the virus (H1N1) titre was controlled in a time-dependent manner following autophagy induction in host cells. Manipulation of autophagy during the IV life cycle can be targeted both for antiviral aims and for increasing viral yield for virus production.
[Mh] Termos MeSH primário: Autofagia/imunologia
Beclina-1/metabolismo
Vírus da Influenza A/crescimento & desenvolvimento
Infecções por Orthomyxoviridae/imunologia
Replicação Viral/imunologia
[Mh] Termos MeSH secundário: Adenina/análogos & derivados
Adenina/farmacologia
Animais
Autofagia/efeitos dos fármacos
Beclina-1/genética
Cães
Hemaglutininas/imunologia
Vírus da Influenza A/genética
Células Madin Darby de Rim Canino
Infecções por Orthomyxoviridae/virologia
Transfecção/métodos
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (Hemagglutinins); 5142-23-4 (3-methyladenine); JAC85A2161 (Adenine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1099/jmm.0.000455


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[PMID]:29107113
[Au] Autor:Guo J; Yang Z; Yang X; Li T; Liu M; Tang H
[Ad] Endereço:Tianjin Life Science Research Center, Department of Pathogen, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Clinical Laboratory of Guangdong Women and Children Hospital, Guangzhou, China.
[Ti] Título:miR-346 functions as a pro-survival factor under ER stress by activating mitophagy.
[So] Source:Cancer Lett;413:69-81, 2018 Jan 28.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which attempts to restore normal function of the ER. Both autophagy and miRNAs have been reported to participate in the process of ER stress, but the relationship between these two factors is still obscure. In this study, we demonstrated that miR-346, which was induced under ER stress, modulated autophagic flux in HeLa cells. By regulating the process of autophagy, miR-346 reduced the ROS level in the cells, thus protecting them from death following ER stress. Furthermore, we demonstrated that GSK3B was the target of miR-346 and participated in ER stress-related autophagy. miR-346 activated autophagy by interrupting the association between BCL2 and BECN1 in a GSK3B-dependent manner. Our findings shed new light on the role of miRNAs during ER stress and suggest a new mechanism for the induction of autophagy under ER stress.
[Mh] Termos MeSH primário: Autofagia
Estresse do Retículo Endoplasmático
Retículo Endoplasmático/metabolismo
MicroRNAs/metabolismo
Mitocôndrias/metabolismo
Degradação Mitocondrial
Neoplasias do Colo do Útero/metabolismo
[Mh] Termos MeSH secundário: Autofagia/efeitos dos fármacos
Beclina-1/metabolismo
Brefeldina A/farmacologia
Morte Celular
Relação Dose-Resposta a Droga
Retículo Endoplasmático/efeitos dos fármacos
Retículo Endoplasmático/patologia
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Feminino
Glicogênio Sintase Quinase 3 beta/metabolismo
Células HeLa
Seres Humanos
MicroRNAs/genética
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/patologia
Degradação Mitocondrial/efeitos dos fármacos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais
Fatores de Tempo
Ubiquitinação
Neoplasias do Colo do Útero/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL2 protein, human); 0 (BECN1 protein, human); 0 (Beclin-1); 0 (MIRN346 microRNA, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Reactive Oxygen Species); 20350-15-6 (Brefeldin A); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171107
[St] Status:MEDLINE


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[PMID]:28930963
[Au] Autor:Zhang DY; Qiu W; Jin P; Wang P; Sun Y
[Ad] Endereço:From the Department of Burn Surgery (D.Y.Z., W.Q., P.W., Y.S.), Huaihai Hospital affiliated to Xuzhou Medical University; Department of Burn Surgery (D.Y.Z., W.Q., P.W., Y.S.), No. 97 Hospital of PLA; and Department of Plastic Surgery (P.J.), the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
[Ti] Título:Role of autophagy and its molecular mechanisms in mice intestinal tract after severe burn.
[So] Source:J Trauma Acute Care Surg;83(4):716-724, 2017 Oct.
[Is] ISSN:2163-0763
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Severe burn can lead to hypoxia/ischemia of intestinal mucosa. Autophagy is the process of intracellular degradation, which is essential for cell survival under stresses, such as hypoxia/ischemia and nutrient deprivation. The present study was designed to investigate whether there were changes in intestinal autophagy after severe burn in mice and further to explore the effect and molecular mechanisms of autophagy on intestinal injury. METHODS: This study includes three experiments. Kunming species mice were subjected to 30% total body surface area third-degree burn. First, we determined protein of LC3 (light chain 3), beclin-1, and cleaved-caspase3 by Western blotting and immunohistochemical (paraffin) staining to investigate whether there were changes in intestinal autophagy after severe burn in mice. Then, changes of the status of enteric damage postburn were measured by observing intestinal mucosa morphology under a magnifier, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, Western blotting under the condition that the intestinal autophagy was respectively activated by rapamycin and inhibited by 3-methyladenine. Finally, protein of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, LC3-II and beclin-1 were assayed, and mice were treated with compound C before burn. RESULTS: The protein of LC3 and beclin-1 were observed at 1 hour postburn and increased to peak-point at 24 hours, reaching the normal level at 96 hours. The cleaved caspase-3 expression increased at 1 hour postburn, but the peak point occurred at 12 hours and had dropped to normal level at 72 hours. In addition, rapamycin enhanced intestinal autophagy and alleviated burn-induced gut damage, while 3-methyladenine showed the against behavior. The AMPK/mTOR pathway which was inhibited decreased the expression of phosphorylated AMPK, LC3-II, and beclin-1, increasing the expression of phosphorylated mTOR. CONCLUSION: Intestinal autophagy is activated and response to intestinal apoptosis after serious burn, which alleviated burn-induced intestinal injury. The AMPK/mTOR pathway may involve in the activation of burn-induced autophagy. LEVEL OF EVIDENCE: Therapeutic/care management, levels of evidence are not applicable to some studies, such as in vitro work, animal models, cadaver studies.
[Mh] Termos MeSH primário: Autofagia/fisiologia
Queimaduras/patologia
Intestinos/patologia
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Animais
Beclina-1/metabolismo
Queimaduras/metabolismo
Modelos Animais de Doenças
Feminino
Intestinos/metabolismo
Masculino
Camundongos
Transdução de Sinais
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1097/TA.0000000000001624


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[PMID]:28893091
[Au] Autor:Chang CJ; Lin JF; Hsiao CY; Chang HH; Li HJ; Chang HH; Lee GA; Hung CF
[Ad] Endereço:* Division of Pediatric Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
[Ti] Título:Lutein Induces Autophagy via Beclin-1 Upregulation in IEC-6 Rat Intestinal Epithelial Cells.
[So] Source:Am J Chin Med;45(6):1273-1291, 2017.
[Is] ISSN:0192-415X
[Cp] País de publicação:Singapore
[La] Idioma:eng
[Ab] Resumo:Lutein is a carotenoid with anti-oxidant properties. Autophagy, an evolutionarily conserved catabolic cellular pathway for coping with stress conditions, is responsive to reactive oxygen species (ROS) and degrades damaged organelles. We previously demonstrated that lutein can induce anti-oxidant enzymes to relieve methotrexate-induced ROS stress. We therefore hypothesized that lutein, which activates ROS-scavenging enzymes, can also induce autophagy for cell survival. In this study, we demonstrated that lutein treatment attenuated the reduction in cell viability caused by H O . Lutein dose-dependently induced the processing of microtubule-associated protein light chain 3 (LC3)-II, an autophagy marker protein, and accumulation of LC3-positive puncta in rat intestinal IEC-6 cells. Furthermore, (a) direct observation of autophagosome formation through transmission electron microscopy, (b) upregulation of autophagy-related genes including ATG4A, ATG5, ATG7, ATG12, and beclin-1 (BENC1), and (c) increased BECN1/Bcl-2 ratio confirmed the induction of autophagy by lutein. The results revealed that bafilomycin-A1-induced inhibition of autophagy reduced cell viability and increased apoptosis in lutein-treated cells, indicating a protective role of lutein-induced autophagy. Lutein treatment also activated adenosine monophosphate-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK), and p-38, but had no effects on the induction of extracellular signal-related kinase or inhibition of mTOR; however, the inhibition of activated AMPK, JNK, or p-38 did not attenuate lutein-induced autophagy. Finally, increased BECN1 expression levels were detected in lutein-treated cells, and BECN1 knockdown abolished autophagy induction. These results suggest that lutein-induced autophagy was mediated by the upregulation of BECN1 in IEC-6 cells. We are the first to demonstrate that lutein induces autophagy. Elevated autophagy in lutein-treated IEC-6 cells may have a protective role against various stresses, and this warrants further investigation.
[Mh] Termos MeSH primário: Antioxidantes
Proteínas Relacionadas à Autofagia/genética
Proteínas Relacionadas à Autofagia/metabolismo
Autofagia/efeitos dos fármacos
Autofagia/genética
Beclina-1/genética
Beclina-1/metabolismo
Células Epiteliais/citologia
Células Epiteliais/fisiologia
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Regulação da Expressão Gênica no Desenvolvimento/genética
Intestinos/citologia
Luteína/farmacologia
Regulação para Cima/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Animais
Sobrevivência Celular/efeitos dos fármacos
Sobrevivência Celular/genética
Células Cultivadas
Relação Dose-Resposta a Droga
Depuradores de Radicais Livres/metabolismo
MAP Quinase Quinase 4/metabolismo
Proteínas Associadas aos Microtúbulos/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Estresse Oxidativo/genética
Ratos
Espécies Reativas de Oxigênio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Autophagy-Related Proteins); 0 (Beclin-1); 0 (Free Radical Scavengers); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); 0 (Reactive Oxygen Species); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 2.7.12.2 (MAP Kinase Kinase 4); X72A60C9MT (Lutein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1142/S0192415X17500707


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[PMID]:28886014
[Au] Autor:Bian A; Shi M; Flores B; Gillings N; Li P; Yan SX; Levine B; Xing C; Hu MC
[Ad] Endereço:Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
[Ti] Título:Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice.
[So] Source:PLoS One;12(9):e0181848, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:C-reactive protein (CRP), was recently reported to be closely associated with poor renal function in patients with acute kidney injury (AKI), but whether CRP is pathogenic or a mere biomarker in AKI remains largely unclear. Impaired autophagy is known to exacerbate renal ischemia-reperfusion injury (IRI). We examined whether the pathogenic role of CRP in AKI is associated with reduction of autophagy. We mated transgenic rabbit CRP over-expressing mice (Tg-CRP) with two autophagy reporter mouse lines, Tg-GFP-LC3 mice (LC3) and Tg-RFP-GFP-LC3 mice (RG-LC3) respectively to generate Tg-CRP-GFP-LC3 mice (PLC3) and Tg-CRP-RFP-GFP-LC3 mice (PRG-LC3). AKI was induced by IRI. Compared with LC3 mice, PLC3 mice developed more severe kidney damage after IRI. Renal tubules were isolated from LC3 mice at baseline for primary culture. OKP cells were transiently transfected with GFP-LC3 plasmid. CRP addition exacerbated lactate dehydrogenase release from both cell types. Immunoblots showed lower LC-3 II/I ratios and higher levels of p62, markers of reduced autophagy flux, in the kidneys of PLC3 mice compared to LC3 mice after IRI, and in primary cultured renal tubules and OKP cells treated with CRP and H2O2 compared to H2O2 alone. Immunohistochemistry showed much fewer LC-3 punctae, and electron microscopy showed fewer autophagosomes in kidneys of PLC3 mice compared to LC3 mice after IRI. Similarly, CRP addition reduced GFP-LC3 punctae induced by H2O2 in primary cultured proximal tubules and in GFP-LC3 plasmid transfected OKP cells. Rapamycin, an autophagy inducer, rescued impaired autophagy and reduced renal injury in vivo. In summary, it was suggested that CRP be more than mere biomarker in AKI, and render the kidney more susceptible to ischemic/oxidative injury, which is associated with down-regulating autophagy flux.
[Mh] Termos MeSH primário: Lesão Renal Aguda/etiologia
Autofagia/genética
Proteína C-Reativa/genética
Expressão Gênica
Traumatismo por Reperfusão/complicações
Traumatismo por Reperfusão/genética
[Mh] Termos MeSH secundário: Lesão Renal Aguda/patologia
Animais
Autofagia/efeitos dos fármacos
Beclina-1/metabolismo
Proteína C-Reativa/metabolismo
Modelos Animais de Doenças
Células Epiteliais/metabolismo
Seres Humanos
Túbulos Renais/metabolismo
Camundongos
Ligação Proteica
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Coelhos
Traumatismo por Reperfusão/patologia
Índice de Gravidade de Doença
Sirolimo/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (Proto-Oncogene Proteins c-bcl-2); 9007-41-4 (C-Reactive Protein); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181848


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[PMID]:28876241
[Au] Autor:Li Y; Zhao Y; Su M; Glover K; Chakravarthy S; Colbert CL; Levine B; Sinha SC
[Ad] Endereço:Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, USA.
[Ti] Título:Structural insights into the interaction of the conserved mammalian proteins GAPR-1 and Beclin 1, a key autophagy protein.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 9):775-792, 2017 Sep 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mammalian Golgi-associated plant pathogenesis-related protein 1 (GAPR-1) is a negative autophagy regulator that binds Beclin 1, a key component of the autophagosome nucleation complex. Beclin 1 residues 267-284 are required for binding GAPR-1. Here, sequence analyses, structural modeling, mutagenesis combined with pull-down assays, X-ray crystal structure determination and small-angle X-ray scattering were used to investigate the Beclin 1-GAPR-1 interaction. Five conserved residues line an equatorial GAPR-1 surface groove that is large enough to bind a peptide. A model of a peptide comprising Beclin 1 residues 267-284 docked onto GAPR-1, built using the CABS-dock server, indicates that this peptide binds to this GAPR-1 groove. Mutation of the five conserved residues lining this groove, H54A/E86A/G102K/H103A/N138G, abrogates Beclin 1 binding. The 1.27 Šresolution X-ray crystal structure of this pentad mutant GAPR-1 was determined. Comparison with the wild-type (WT) GAPR-1 structure shows that the equatorial groove of the pentad mutant is shallower and more positively charged, and therefore may not efficiently bind Beclin 1 residues 267-284, which include many hydrophobic residues. Both WT and pentad mutant GAPR-1 crystallize as dimers, and in each case the equatorial groove of one subunit is partially occluded by the other subunit, indicating that dimeric GAPR-1 is unlikely to bind Beclin 1. SAXS analysis of WT and pentad mutant GAPR-1 indicates that in solution the WT forms monomers, while the pentad mutant is primarily dimeric. Thus, changes in the structure of the equatorial groove combined with the improved dimerization of pentad mutant GAPR-1 are likely to abrogate binding to Beclin 1.
[Mh] Termos MeSH primário: Beclina-1/metabolismo
Proteínas de Membrana/metabolismo
Mapas de Interação de Proteínas
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Autofagia
Beclina-1/química
Sítios de Ligação
Sequência Conservada
Cristalografia por Raios X
Seres Humanos
Proteínas de Membrana/química
Proteínas de Membrana/genética
Simulação de Acoplamento Molecular
Mutação
Ligação Proteica
Conformação Proteica
Multimerização Proteica
Espalhamento a Baixo Ângulo
Alinhamento de Sequência
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BECN1 protein, human); 0 (Beclin-1); 0 (GLIPR2 protein, human); 0 (Membrane Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317011822


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[PMID]:28872463
[Au] Autor:Bartolomeo R; Cinque L; De Leonibus C; Forrester A; Salzano AC; Monfregola J; De Gennaro E; Nusco E; Azario I; Lanzara C; Serafini M; Levine B; Ballabio A; Settembre C
[Ad] Endereço:Telethon Institute of Genetics and Medicine (TIGEM), and.
[Ti] Título:mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy.
[So] Source:J Clin Invest;127(10):3717-3729, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.
[Mh] Termos MeSH primário: Autofagia
Desenvolvimento Ósseo
Doenças por Armazenamento dos Lisossomos/metabolismo
Complexos Multiproteicos/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Beclina-1/genética
Beclina-1/metabolismo
Condrócitos/metabolismo
Condrócitos/patologia
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/patologia
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos
Camundongos Knockout
Complexos Multiproteicos/genética
Fosfatidilinositóis/genética
Fosfatidilinositóis/metabolismo
Fosforilação/genética
Fosforilação/efeitos da radiação
Serina-Treonina Quinases TOR/genética
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (Becn1 protein, mouse); 0 (Multiprotein Complexes); 0 (Phosphatidylinositols); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE



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