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[PMID]:29374920
[Au] Autor:Huang YS
[Ad] Endereço:Institute of Burn Research, the First Affiliated Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University (the Third Military Medical University), Chongqing 400038, China.
[Ti] Título:[Autophagy and hypoxic ischemic myocardial damage after severe burn].
[So] Source:Zhonghua Shao Shang Za Zhi;34(1):3-7, 2018 Jan 20.
[Is] ISSN:1009-2587
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:It is an important clinical subject to illuminate the mechanisms of myocardial damage in the early stage post severe burn in prevention against and treatment of burn shock, which may offer a targeted " dynamic support" in the treatment of severe burn patients. In recent years, the role of autophagy in hypoxic myocardial injury has attracted much attention. Autophagy is a physiological phenomenon on intracellular digestion process of long-life proteins and the aging and damaged organelles through lysosomal system, and it is essential for maintaining the homeostasis of cells. Severe hypoxia/ischemia causes lysosome dysfunction, insufficient fusion between autophagosome and lysosome, accumulation of autophagosomes, and damaged autophagy flux, thus leading to cell dysfunction and cell death. To study the roles of autophagy and explore the potential signals in autophagy modulation will provide a new therapeutic target for alleviating cardiac dysfunction following severe burn.
[Mh] Termos MeSH primário: Autofagia
Queimaduras/complicações
Queimaduras/patologia
Miocárdio/patologia
[Mh] Termos MeSH secundário: Animais
Queimaduras/terapia
Seres Humanos
Hipóxia/etiologia
Lisossomos
Traumatismo por Reperfusão Miocárdica
Choque/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180129
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.1009-2587.2018.01.002


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[PMID]:29348617
[Au] Autor:Miranda AM; Lasiecka ZM; Xu Y; Neufeld J; Shahriar S; Simoes S; Chan RB; Oliveira TG; Small SA; Di Paolo G
[Ad] Endereço:Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
[Ti] Título:Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures.
[So] Source:Nat Commun;9(1):291, 2018 01 18.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.
[Mh] Termos MeSH primário: Precursor de Proteína beta-Amiloide/metabolismo
Exossomos/metabolismo
Lipídeos/análise
Lisossomos/metabolismo
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/química
Animais
Autofagia/genética
Biomarcadores/metabolismo
Linhagem Celular Tumoral
Classe III de Fosfatidilinositol 3-Quinases/genética
Classe III de Fosfatidilinositol 3-Quinases/metabolismo
Células HEK293
Seres Humanos
Lisofosfolipídeos/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Knockout
Monoglicerídeos/metabolismo
Doenças Neurodegenerativas/diagnóstico
Doenças Neurodegenerativas/metabolismo
Fragmentos de Peptídeos/metabolismo
Fosfatos de Fosfatidilinositol/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Biomarkers); 0 (Lipids); 0 (Lysophospholipids); 0 (Monoglycerides); 0 (Peptide Fragments); 0 (Phosphatidylinositol Phosphates); 0 (bis(monoacylglyceryl)phosphate); 0 (phosphatidylinositol 3-phosphate); EC 2.7.1.137 (Class III Phosphatidylinositol 3-Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02533-w


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[PMID]:28454554
[Au] Autor:Mittal S; Sharma PK; Tiwari R; Rayavarapu RG; Shankar J; Chauhan LKS; Pandey AK
[Ad] Endereço:Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India.
[Ti] Título:Impaired lysosomal activity mediated autophagic flux disruption by graphite carbon nanofibers induce apoptosis in human lung epithelial cells through oxidative stress and energetic impairment.
[So] Source:Part Fibre Toxicol;14(1):15, 2017 Apr 28.
[Is] ISSN:1743-8977
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Graphite carbon nanofibers (GCNF) have emerged as a potential alternative of carbon nanotubes (CNT) for various biomedical applications due to their superior physico-chemical properties. Therefore in-depth understanding of the GCNF induced toxic effects and underlying mechanisms in biological systems is of great interest. Currently, autophagy activation by nanomaterials is recognized as an emerging toxicity mechanism. However, the association of GCNF induced toxicity with this form of cell death is largely unknown. In this study, we have assessed the possible mechanism; especially the role of autophagy, underlying the GCNF induced toxicity. METHODS: Human lung adenocarcinoma (A549) cells were exposed to a range of GCNF concentrations and various cellular parameters were analyzed (up to 48 h). Transmission electron microscopy, immunofluorescent staining, western blot and quantitative real time PCR were performed to detect apoptosis, autophagy induction, lysosomal destabilization and cytoskeleton disruption in GCNF exposed cells. DCFDA assay was used to evaluate the reactive oxygen species (ROS) production. Experiments with N-acetyl-L-cysteine (NAC), 3-methyladenine (3-MA) and LC3 siRNA was carried out to confirm the involvement of oxidative stress and autophagy in GCNF induced cell death. Comet assay and micronucleus (MN) assay was performed to assess the genotoxicity potential. RESULTS: In the present study, GCNF was found to induce nanotoxicity in human lung cells through autophagosomes accumulation followed by apoptosis via intracellular ROS generation. Mechanistically, impaired lysosomal function and cytoskeleton disruption mediated autophagic flux blockade was found to be the major cause of accumulation rather than autophagy induction which further activates apoptosis. The whole process was in line with the increased ROS level and their pharmacological inhibition leads to mitigation of GCNF induced cell death. Moreover the inhibition of autophagy attenuates apoptosis indicating the role of autophagy as cell death process. GCNF was also found to induce genomic instability. CONCLUSION: Our present study demonstrates that GCNF perturbs various interrelated signaling pathway and unveils the potential nanotoxicity mechanism of GCNF through targeting ROS-autophagy-apoptosis axis. The current study is significant to evaluate the safety and risk assessment of fibrous carbon nanomaterials prior to their potential use and suggests caution on their utilization for biomedical research.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Grafite/toxicidade
Lisossomos/efeitos dos fármacos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Nanofibras/toxicidade
Estresse Oxidativo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células A549
Sobrevivência Celular/efeitos dos fármacos
Células Epiteliais/efeitos dos fármacos
Seres Humanos
Pulmão/efeitos dos fármacos
Tamanho da Partícula
Espécies Reativas de Oxigênio/metabolismo
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 7782-42-5 (Graphite)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1186/s12989-017-0194-4


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[PMID]:28449707
[Au] Autor:Llorens F; Thüne K; Sikorska B; Schmitz M; Tahir W; Fernández-Borges N; Cramm M; Gotzmann N; Carmona M; Streichenberger N; Michel U; Zafar S; Schuetz AL; Rajput A; Andréoletti O; Bonn S; Fischer A; Liberski PP; Torres JM; Ferrer I; Zerr I
[Ad] Endereço:Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE), Robert Koch Strasse 40, 37075, Göttingen, Germany. franc.llorens@gmail.com.
[Ti] Título:Altered Ca homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.
[So] Source:Acta Neuropathol Commun;5(1):35, 2017 04 27.
[Is] ISSN:2051-5960
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP ). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca ) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca responsive genes in sCJD brain tissue, accompanied by two Ca -dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Cálcio/metabolismo
Calpaína/metabolismo
Catepsinas/metabolismo
Síndrome de Creutzfeldt-Jakob/metabolismo
Homeostase/fisiologia
[Mh] Termos MeSH secundário: Animais
Encéfalo/patologia
Cátions Bivalentes/metabolismo
Células Cultivadas
Síndrome de Creutzfeldt-Jakob/patologia
Modelos Animais de Doenças
Seres Humanos
Lisossomos/metabolismo
Lisossomos/patologia
Mesocricetus
Camundongos Transgênicos
Neurônios/metabolismo
Neurônios/patologia
Proteínas PrPSc/metabolismo
Ratos Wistar
Proteínas Recombinantes/metabolismo
Ovinos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cations, Divalent); 0 (PrPSc Proteins); 0 (Recombinant Proteins); EC 3.4.- (Cathepsins); EC 3.4.22.- (Calpain); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1186/s40478-017-0431-y


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[PMID]:28460485
[Au] Autor:Lv LX; Zhou ZX; Zhou Z; Zhang LJ; Yan R; Zhao Z; Yang LY; Bian XY; Jiang HY; Li YD; Sun YS; Xu QQ; Hu GL; Guan WJ; Li YQ
[Ad] Endereço:Institute of Pharmaceutical Biotechnology and College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China.
[Ti] Título:Hispidin induces autophagic and necrotic death in SGC-7901 gastric cancer cells through lysosomal membrane permeabilization by inhibiting tubulin polymerization.
[So] Source:Oncotarget;8(16):26992-27006, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hispidin and its derivatives are widely distributed in edible mushrooms. Hispidin is more cytotoxic to A549, SCL-1, Bel7402 and Capan-1 cancer cells than to MRC5 normal cells; by contrast, hispidin protects H9c2 cardiomyoblast cells from hydrogen peroxide-induced or doxorubicin-induced apoptosis. Consequently, further research on how hispidin affects normal and cancer cells may help treat cancer and reduce chemotherapy-induced side effects. This study showed that hispidin caused caspase-independent death in SGC-7901 cancer cells but not in GES-1 normal cells. Hispidin-induced increases in LC3-II occurred in SGC-7901 cells in a time independent manner. Cell death can be partially inhibited by treatment with ATG5 siRNA but not by autophagy or necroptosis inhibitors. Ultrastructural evidence indicated that hispidin-induced necrotic cell death involved autophagy. Hispidin-induced lysosomal membrane permeabilization (LMP) related to complex cell death occurred more drastically in SGC-7901 cells than in GES-1 cells. Ca2+ rather than cathepsins from LMP contributed more to cell death. Hispidin induced microtubule depolymerization, which can cause LMP, more drastically in SGC-7901 cells than in GES-1 cells. At 4.1 µM, hispidin promoted cell-free tubulin polymerization but at concentrations higher than 41 µM, hispidin inhibited polymerization. Hispidin did not bind to tubulin. Alterations in microtubule regulatory proteins, such as stathmin phosphorylation at Ser16, contributed to hispidin-induced SGC-7901 cell death. In conclusion, hispidin at concentrations higher than 41 µM may inhibit tubulin polymerization by modulating microtubule regulatory proteins, such as stathmin, causing LMP and complex SGC-7901 cell death. This mechanism suggests a promising novel treatment for human cancer.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Membranas Intracelulares/efeitos dos fármacos
Lisossomos/metabolismo
Multimerização Proteica/efeitos dos fármacos
Pironas/farmacologia
Tubulina (Proteína)/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspases/metabolismo
Morte Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Seres Humanos
Microtúbulos/química
Microtúbulos/metabolismo
Óxido Nítrico/biossíntese
Permeabilidade
Fosforilação
Estatmina/metabolismo
Tubulina (Proteína)/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrones); 0 (STMN1 protein, human); 0 (Stathmin); 0 (Tubulin); 31C4KY9ESH (Nitric Oxide); EC 3.4.22.- (Caspases); SSJ18CG55E (hispidin)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15935


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[PMID]:28749043
[Au] Autor:Cao N; Li W; Li B; Tian Y; Xu D
[Ad] Endereço:Institute of Animal Nutrition, Genetics and Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, China.
[Ti] Título:Transcriptome profiling reveals the immune response of goose T cells under selenium stimuli.
[So] Source:Anim Sci J;88(12):2001-2009, 2017 Dec.
[Is] ISSN:1740-0929
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:The goose is an economically important poultry species and a principal natural host of avian viruses. This study aimed to determine the effects of selenium on the immune response of geese. Under selenium stimulation, gene expression profiling was investigated using transcriptome sequencing. The selenoproteins were promoted by selenium stimulation, while the heat shock proteins, interleukin and interferons were mainly down-regulated. After comparison, 2228 differentially expressed genes were primarily involved in immune and environmental response, and infectious disease and genetic information processing related pathways were identified. Specifically, the enzymes of the lysosomes which acted as a safeguard in preventing pathogens were mostly up-regulated and six randomly selected differentially expressed genes were validated by quantitative polymerase chain reaction. In addition, the most proportional increased transcription factor family basic helix-loop-helix (bHLH) located in the 5' flank of selenoprotein P-like protein for selenium metabolism was identified by response to the selenium stimulation in this study. These analyses show that selenium can promote immune function by activating selenoproteins, transcript factors and lysosome pathway related genes, while weakening cytokine content genes in geese.
[Mh] Termos MeSH primário: Gansos/imunologia
Imunidade Celular/genética
Selênio/imunologia
Linfócitos T/imunologia
Transcriptoma/genética
Transcriptoma/imunologia
[Mh] Termos MeSH secundário: Animais
Fatores de Transcrição Hélice-Alça-Hélice Básicos
Células Cultivadas
Citocinas
Lisossomos/enzimologia
Selenoproteínas
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cytokines); 0 (Selenoproteins); H6241UJ22B (Selenium)
[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:170728
[St] Status:MEDLINE
[do] DOI:10.1111/asj.12861


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[PMID]:29366749
[Au] Autor:Gonzalez EA; Martins GR; Tavares AMV; Viegas M; Poletto E; Giugliani R; Matte U; Baldo G
[Ad] Endereço:Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Post-Graduation Program in Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil.
[Ti] Título:Cathepsin B inhibition attenuates cardiovascular pathology in mucopolysaccharidosis I mice.
[So] Source:Life Sci;196:102-109, 2018 Mar 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder with multisystemic features, including heart enlargement, heart valve dysfunction, and aortic stiffness and dilatation. Previous studies have shown that MPS I mice overexpress cathepsin B (CtsB) in multiple tissues, including those from the cardiovascular system. Here, we hypothesized that inhibition of CtsB could ameliorate cardiac function parameters, as well as aorta and valve abnormalities found in MPS I. First, we found that total elastase activity in an MPS I aorta is elevated. Following that, we demonstrated that CtsB leaks from the lysosome in MPS I human fibroblasts, possibly acting as a degradative agent of extracellular matrix components from the aorta, cardiac muscle, and heart valves. We then used a CtsB inhibitor in vivo in the MPS I mouse model. After 4 months of treatment, partial inhibition of CtsB activity in treated mice reduced aortic dilatation, as well as heart valve thickening, and led to improvements in cardiac function parameters, although none of these were completely normalized. Based on these results, we conclude that lysosomal alterations in this disease promote leakage of CtsB to outside the organelle, where this protein can have multiple pathological roles. CtsB inhibition improved cardiovascular parameters in MPS I mice and can have a potential benefit in this disease.
[Mh] Termos MeSH primário: Sistema Cardiovascular/patologia
Catepsina B/antagonistas & inibidores
Inibidores de Cisteína Proteinase/uso terapêutico
Dipeptídeos/uso terapêutico
Mucopolissacaridose I/diagnóstico por imagem
Mucopolissacaridose I/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Aorta/patologia
Aorta/fisiopatologia
Sistema Cardiovascular/diagnóstico por imagem
Catepsina B/metabolismo
Colagenases/metabolismo
Feminino
Fibroblastos/metabolismo
Testes de Função Cardíaca
Doenças das Valvas Cardíacas/diagnóstico por imagem
Doenças das Valvas Cardíacas/tratamento farmacológico
Doenças das Valvas Cardíacas/patologia
Seres Humanos
Lisossomos/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Mucopolissacaridose I/patologia
Elastase Pancreática/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cysteine Proteinase Inhibitors); 0 (Dipeptides); 134448-10-5 (N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline); EC 3.4.21.36 (Pancreatic Elastase); EC 3.4.22.1 (Cathepsin B); EC 3.4.24.- (Collagenases)
[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:180126
[St] Status:MEDLINE


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[PMID]:29248575
[Au] Autor:Natale A; Boeckmans J; Desmae T; De Boe V; De Kock J; Vanhaecke T; Rogiers V; Rodrigues RM
[Ad] Endereço:Department of In Vitro Toxicology & Dermato-Cosmetology (IVTD), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Electronic address: alessandra.natale@vub.be.
[Ti] Título:Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone.
[So] Source:Toxicol Lett;284:184-194, 2018 Mar 01.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process.
[Mh] Termos MeSH primário: Avaliação Pré-Clínica de Medicamentos/métodos
Hepatócitos/efeitos dos fármacos
Lipidoses/induzido quimicamente
Fosfolipídeos/metabolismo
Pele/citologia
Células-Tronco/citologia
[Mh] Termos MeSH secundário: Amiodarona/toxicidade
Diferenciação Celular/efeitos dos fármacos
Células Cultivadas
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
Citometria de Fluxo
Expressão Gênica/efeitos dos fármacos
Células Hep G2
Hepatócitos/ultraestrutura
Seres Humanos
Lipidoses/genética
Lisossomos/efeitos dos fármacos
Lisossomos/metabolismo
Masculino
Fosfolipídeos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phospholipids); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:29233882
[Au] Autor:Seranova E; Connolly KJ; Zatyka M; Rosenstock TR; Barrett T; Tuxworth RI; Sarkar S
[Ad] Endereço:Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
[Ti] Título:Dysregulation of autophagy as a common mechanism in lysosomal storage diseases.
[So] Source:Essays Biochem;61(6):733-749, 2017 12 12.
[Is] ISSN:1744-1358
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life-limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy.
[Mh] Termos MeSH primário: Autofagia/fisiologia
Doenças por Armazenamento dos Lisossomos/metabolismo
[Mh] Termos MeSH secundário: Animais
Autofagia/genética
Seres Humanos
Doenças por Armazenamento dos Lisossomos/genética
Lisossomos/metabolismo
Esfingolipidoses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1042/EBC20170055


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[PMID]:29233880
[Au] Autor:Karabiyik C; Lee MJ; Rubinsztein DC
[Ad] Endereço:Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, U.K.
[Ti] Título:Autophagy impairment in Parkinson's disease.
[So] Source:Essays Biochem;61(6):711-720, 2017 12 12.
[Is] ISSN:1744-1358
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Parkinson's disease (PD) is a debilitating movement disorder typically associated with the accumulation of intracytoplasmic aggregate prone protein deposits. Over recent years, increasing evidence has led to the suggestion that the mutations underlying certain forms of PD impair autophagy. Autophagy is a degradative pathway that delivers cytoplasmic content to lysosomes for degradation and represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Autophagy up-regulation is a promising therapeutic strategy that is being explored for its potential to protect cells against the toxicity of aggregate-prone proteins in neurodegenerative diseases. Here, we describe how the mutations in different subtypes of PD can affect different stages of autophagy.
[Mh] Termos MeSH primário: Autofagia/fisiologia
Doença de Parkinson/metabolismo
Doença de Parkinson/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Autofagia/genética
Seres Humanos
Lisossomos/metabolismo
Mutação
Doença de Parkinson/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1042/EBC20170023



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