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[PMID]:28726391
[Au] Autor:Dagbay KB; Hill ME; Barrett E; Hardy JA
[Ad] Endereço:Department of Chemistry, University of Massachusetts Amherst , Amherst, Massachusetts 01003, United States.
[Ti] Título:Tumor-Associated Mutations in Caspase-6 Negatively Impact Catalytic Efficiency.
[So] Source:Biochemistry;56(34):4568-4577, 2017 Aug 29.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Unregulated, particularly suppressed programmed cell death is one of the distinguishing features of many cancer cells. The cysteine protease caspase-6, one of the executioners of apoptotic cell death, plays a crucial role in regulation of apoptosis. Several somatic mutations in the CASP6 gene in tumor tissues have been reported. This work explores the effect of CASP6 tumor-associated mutations on the catalytic efficiency and structure of caspase-6. In general, these mutations showed decreased overall rates of catalytic turnover. Mutations within 8 Å of the substrate-binding pocket of caspase-6 were found to be the most catalytically deactivating. Notably, the R259H substitution decreased activity by 457-fold. This substitution disrupts the cation-π stacking interaction between Arg-259 and Trp-227, which is indispensable for proper assembly of the substrate-binding loops in caspase-6. Sequence conservation analysis at the homologous position across the caspase family suggests a role for this cation-π stacking in the catalytic function of caspases generally. These data suggest that caspase-6 deactivating mutations may contribute to multifactorial carcinogenic transformations.
[Mh] Termos MeSH primário: Caspase 6/química
Mutação de Sentido Incorreto
Proteínas de Neoplasias/química
Neoplasias/enzimologia
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Caspase 6/genética
Caspase 6/metabolismo
Domínio Catalítico
Seres Humanos
Proteínas de Neoplasias/metabolismo
Neoplasias/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); EC 3.4.22.- (CASP6 protein, human); EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00357


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[PMID]:28686630
[Au] Autor:Bartel A; Göhler A; Hopf V; Breitbach K
[Ad] Endereço:Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, Greifswald, Germany.
[Ti] Título:Caspase-6 mediates resistance against Burkholderia pseudomallei infection and influences the expression of detrimental cytokines.
[So] Source:PLoS One;12(7):e0180203, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caspase-6 is a member of the executioner caspases and known to play a role in innate and adaptive immune processes. However, its role in infectious diseases has rarely been addressed yet. We here examined the impact of caspase-6 in an in vivo infection model using the Gram-negative rod Burkholderia pseudomallei, causing the infectious disease melioidosis that is endemic in tropical and subtropical areas around the world. Caspase-6-/- and C57BL/6 wild type mice were challenged with B. pseudomallei for comparing mortality, bacterial burden and inflammatory cytokine expression. Bone-marrow derived macrophages were used to analyse the bactericidal activity in absence of caspase-6. Caspase-6 deficiency was associated with higher mortality and bacterial burden in vivo after B. pseudomallei infection. The bactericidal activity of caspase-6-/- macrophages was impaired compared to wild type cells. Caspase-6-/- mice showed higher expression of the IL-1ß gene, known to be detrimental in murine melioidosis. Expression of the IL-10 gene was also increased in caspase-6-/- mice as early as 6 hours after infection. Treatment with exogenous IL-10 rendered mice more susceptible against B. pseudomallei challenge. Thus, caspase-6 seems to play a crucial role for determining resistance against the causative agent of melioidosis. To our knowledge this is the first report showing that caspase-6 is crucial for mediating resistance in an in vivo infection model. Caspase-6 influences the expression of detrimental cytokines and therefore seems to be important for achieving a well-balanced immune response that contributes for an efficient elimination of the pathogen.
[Mh] Termos MeSH primário: Burkholderia pseudomallei/genética
Caspase 6/genética
Interleucina-10/administração & dosagem
Interleucina-1beta/biossíntese
Melioidose/genética
[Mh] Termos MeSH secundário: Animais
Burkholderia pseudomallei/patogenicidade
Resistência Microbiana a Medicamentos/genética
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Interleucina-10/biossíntese
Interleucina-1beta/genética
Macrófagos/metabolismo
Macrófagos/patologia
Melioidose/microbiologia
Melioidose/patologia
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL1B protein, mouse); 0 (Interleukin-1beta); 130068-27-8 (Interleukin-10); EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180203


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[PMID]:28594934
[Au] Autor:Florio R; De Lellis L; di Giacomo V; Di Marcantonio MC; Cristiano L; Basile M; Verginelli F; Verzilli D; Ammazzalorso A; Prasad SC; Cataldi A; Sanna M; Cimini A; Mariani-Costantini R; Mincione G; Cama A
[Ad] Endereço:Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.
[Ti] Título:Effects of PPARα inhibition in head and neck paraganglioma cells.
[So] Source:PLoS One;12(6):e0178995, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL treatment need to be identified. However, the lack of cellular models for this rare tumor hampers this task. PPARα receptor activation was reported in several tumors and this receptor appears to be a promising therapeutic target in different malignancies. Considering that the role of PPARα in HNPGLs was never studied before, we analyzed the potential of modulating PPARα in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARα in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARα was also confirmed in HNPGL-derived cells. The specific PPARα agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARα antagonist GW6471 reduced HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis. GW6471 treatment was associated with a marked decrease of CDK4, cyclin D3 and cyclin B1 protein expression, along with an increased expression of p21 in HNPGL cells. Moreover, GW6471 drastically impaired clonogenic activity of HNPGL cells, with a less marked effect on cell migration. Notably, the effects of GW6471 on HNPGL cells were associated with the inhibition of the PI3K/GSK3ß/ß-catenin signaling pathway. In conclusion, the PPARα antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3ß/ß-catenin pathway. Therefore, PPARα could represent a novel therapeutic target for HNPGL.
[Mh] Termos MeSH primário: Neoplasias de Cabeça e Pescoço/metabolismo
PPAR alfa/antagonistas & inibidores
PPAR alfa/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Western Blotting
Caspase 3/metabolismo
Caspase 6/metabolismo
Caspase 7/efeitos dos fármacos
Caspase 7/metabolismo
Caspases/metabolismo
Caspases Iniciadoras/metabolismo
Ciclo Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Imunofluorescência
Seres Humanos
Imuno-Histoquímica
Oxazóis/farmacologia
PPAR alfa/agonistas
Pirimidinas/farmacologia
Células Tumorais Cultivadas
Tirosina/análogos & derivados
Tirosina/farmacologia
Cicatrização/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GW 6471); 0 (Oxazoles); 0 (PPAR alpha); 0 (Pyrimidines); 42HK56048U (Tyrosine); 86C4MRT55A (pirinixic acid); EC 3.4.22.- (CASP4 protein, human); EC 3.4.22.- (CASP5 protein, human); EC 3.4.22.- (Caspase 3); EC 3.4.22.- (Caspase 6); EC 3.4.22.- (Caspase 7); EC 3.4.22.- (Caspases); EC 3.4.22.- (Caspases, Initiator)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170609
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178995


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[PMID]:28373431
[Au] Autor:Suita H; Shinomiya T; Nagahara Y
[Ad] Endereço:Division of Life Science and Engineering, School of Science and Engineering, Tokyo Denki University, Hatoyama, Japan.
[Ti] Título:Caspase-6 Induces 7A6 Antigen Localization to Mitochondria During FAS-induced Apoptosis of Jurkat Cells.
[So] Source:Anticancer Res;37(4):1697-1704, 2017 04.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mitochondria are central to apoptosis. However, apoptosis progression involving mitochondria is not fully understood. A factor involved in mitochondria-mediated apoptosis is 7A6 antigen. 7A6 localizes to mitochondria from the cytosol during apoptosis, which seems to involve 'effector' caspases. In this study, we investigated the precise role of effector caspases in 7A6 localization to mitochondria during apoptosis. MATERIALS AND METHODS: Human T-cell lymphoma Jurkat cells were treated with an antibody against FAS. 7A6 localization was analyzed by confocal laser scanning microscopy and flow cytometry. Caspases activation was determined by western blot analysis. RESULTS: 7A6 localization to mitochondria during anti-FAS-induced apoptosis was significantly reduced by the caspase-6 inhibitor, N-acetyl-Val-Glu-Ile-Asp-aldehyde, but not by the caspase-3 inhibitor, N-acetyl-Asp-Asn-Leu-Asp-aldehyde, nor caspase-7/3 inhibitor, N-acetyl-Asp-Gln-Thr-Asp-aldehyde. Moreover, caspase-6 down-regulation suppressed 7A6 localization to mitochondria. CONCLUSION: Caspase-6 regulates 7A6 localization to mitochondria during anti-FAS-induced apoptosis of Jurkat cells.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Caspase 6/farmacologia
Proteínas de Membrana/metabolismo
Mitocôndrias/patologia
Receptor fas/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Inibidores de Caspase/farmacologia
Citometria de Fluxo
Seres Humanos
Células Jurkat
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caspase Inhibitors); 0 (FAS protein, human); 0 (Membrane Proteins); 0 (antigen 7A6); 0 (fas Receptor); EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE


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[PMID]:28370734
[Au] Autor:Jafari SM; Joshaghani HR; Panjehpour M; Aghaei M; Zargar Balajam N
[Ad] Endereço:Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
[Ti] Título:Apoptosis and cell cycle regulatory effects of adenosine by modulation of GLI-1 and ERK1/2 pathways in CD44 and CD24 breast cancer stem cells.
[So] Source:Cell Prolif;50(4), 2017 Aug.
[Is] ISSN:1365-2184
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Breast cancer stem cells (CSCs) are a small population of tumour cells with the ability of self-renewal and resistance to chemotherapy. Targeting CSCs is a promising strategy for treatment of cancer. A recent study demonstrated that adenosine receptor agonists inhibit glioblastoma CSCs proliferation. At present, the effect of adenosine on breast CSCs has not been reported. Therefore, this study was designed to evaluate the effect of adenosine and its signalling pathways in breast CSCs. MATERIALS AND METHODS: Anti-proliferative effect of adenosine on breast CSCs was evaluated by mammosphere formation and MTS assay. The effect of adenosine on cell cycle progression was examined using flow cytometry. Detection of apoptosis was conducted by Annexin V-FITC. The expression levels of cell cycle and apoptosis regulatory proteins as well as ERK1/2, and GLI-1 were measured by Western blot. RESULTS: Adenosine reduced CSCs population and mammosphere formation in breast CSCs. Adenosine induced G1 cell cycle arrest in breast CSCs in conjunction with a marked down-regulation of cyclin D1 and CDK4. Adenosine also induced apoptosis by regulation of Bax/Bcl-2 ratio, mitochondrial membrane potential depletion and activation of caspase-6. Moreover, adenosine inhibited ERK1/2 phosphorylation and GLI-1 protein expression. CONCLUSIONS: These findings indicated that adenosine induces cell cycle arrest and apoptosis through inhibition of GLI-1 and ERK1/2 pathways in breast CSCs.
[Mh] Termos MeSH primário: Adenosina/toxicidade
Apoptose/efeitos dos fármacos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos
Células-Tronco Neoplásicas/metabolismo
Proteína GLI1 em Dedos de Zinco/metabolismo
[Mh] Termos MeSH secundário: Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Antígeno CD24/metabolismo
Caspase 6/metabolismo
Linhagem Celular Tumoral
Ciclina D1/metabolismo
Quinase 4 Dependente de Ciclina/metabolismo
Regulação para Baixo/efeitos dos fármacos
Feminino
Seres Humanos
Receptores de Hialuronatos/metabolismo
Sistema de Sinalização das MAP Quinases
Células MCF-7
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Células-Tronco Neoplásicas/citologia
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCND1 protein, human); 0 (CD24 Antigen); 0 (CD44 protein, human); 0 (GLI1 protein, human); 0 (Hyaluronan Receptors); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Zinc Finger Protein GLI1); 0 (bcl-2-Associated X Protein); 136601-57-5 (Cyclin D1); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 4); EC 3.4.22.- (Caspase 6); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1111/cpr.12345


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[PMID]:28322794
[Au] Autor:Ruangjaroon T; Chokchaichamnankit D; Srisomsap C; Svasti J; Paricharttanakul NM
[Ad] Endereço:Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok, Thailand.
[Ti] Título:Involvement of vimentin in neurite outgrowth damage induced by fipronil in SH-SY5Y cells.
[So] Source:Biochem Biophys Res Commun;486(3):652-658, 2017 May 06.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fipronil, a phenylpyrazole insecticide, is more selective in its potency towards insects than humans and is thus commonly used. In this study, we demonstrated that exposure to fipronil may pose a human health risk. We observed in vitro the shortening of neurite outgrowths of SH-SY5Y neuroblastoma cells upon treatment with fipronil, even at a non-cytotoxic concentration. Fipronil induced apoptosis involving caspase-6, which is an apoptotic effector highly implicated in neurodegenerative diseases. Moreover, at a concentration that did not induce apoptosis, mitochondrial dysfunction and autophagic vacuole formation were detected. Interestingly using proteomics, we identified vimentin to be dramatically expressed by SH-SY5Y cells as a response to fipronil treatment. Not only did the expression of total vimentin increase, different isoforms were observed, indicating alterations in post-translational modifications. Vimentin was localized at the neurite outgrowth, possibly to repair the damage in cellular structure. However at high concentrations of fipronil, vimentin was found in less defined fibrils, in bridge-like formation, and dense surrounding vacuoles. In all, our results indicate that vimentin plays an important role in fipronil-induced neurotoxicity in SH-SY5Y cells.
[Mh] Termos MeSH primário: Inseticidas/toxicidade
Crescimento Neuronal/efeitos dos fármacos
Neurônios/efeitos dos fármacos
Pirazóis/toxicidade
Vimentina/genética
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Caspase 6/genética
Caspase 6/metabolismo
Linhagem Celular Tumoral
Regulação da Expressão Gênica
Seres Humanos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Mitocôndrias/ultraestrutura
Neurônios/metabolismo
Neurônios/ultraestrutura
Isoformas de Proteínas/agonistas
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Vacúolos/efeitos dos fármacos
Vacúolos/metabolismo
Vacúolos/ultraestrutura
Vimentina/agonistas
Vimentina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Insecticides); 0 (Protein Isoforms); 0 (Pyrazoles); 0 (Vimentin); EC 3.4.22.- (CASP6 protein, human); EC 3.4.22.- (Caspase 6); QGH063955F (fipronil)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE


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[PMID]:28270702
[Au] Autor:Berta T; Lee JE; Park CK
[Ad] Endereço:Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA.
[Ti] Título:Unconventional Role of Caspase-6 in Spinal Microglia Activation and Chronic Pain.
[So] Source:Mediators Inflamm;2017:9383184, 2017.
[Is] ISSN:1466-1861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chronic pain affects ~20% of the worldwide population. The clinical management of chronic pain is mostly palliative and results in limited success. Current treatments mostly target the symptoms or neuronal signaling of chronic pain. It has been increasingly recognized that glial cells, such as microglia, and inflammatory signaling play a major role in the pathogenesis of chronic pain. Caspases (CASPs) are a family of protease enzymes involved in apoptosis and inflammation. They are pivotal components in a variety of neurological diseases. However, little is known about the role of CASPs in microglial modulation as to chronic pain. In particular, our recent studies have shown that CASP6 regulates chronic pain via microglial inflammatory signaling. Inhibition of microglia and CASP signaling might provide a new strategy for the prevention and treatment of chronic pain.
[Mh] Termos MeSH primário: Caspase 6/metabolismo
Dor Crônica/metabolismo
Inflamação/metabolismo
Microglia/metabolismo
Microglia/fisiologia
Medula Espinal/citologia
[Mh] Termos MeSH secundário: Animais
Dor Crônica/imunologia
Seres Humanos
Inflamação/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1155/2017/9383184


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[PMID]:28241839
[Au] Autor:Pakavathkumar P; Noël A; Lecrux C; Tubeleviciute-Aydin A; Hamel E; Ahlfors JE; LeBlanc AC
[Ad] Endereço:Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3999 Ch. Cote Ste-Catherine, Montreal, QC, H3T 1E2, Canada.
[Ti] Título:Caspase vinyl sulfone small molecule inhibitors prevent axonal degeneration in human neurons and reverse cognitive impairment in Caspase-6-overexpressing mice.
[So] Source:Mol Neurodegener;12(1):22, 2017 02 28.
[Is] ISSN:1750-1326
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The activation of the aspartate-specific cysteinyl protease, Caspase-6, is proposed as an early pathogenic event of Alzheimer disease (AD) and Huntington's disease. Caspase-6 inhibitors could be useful against these neurodegenerative diseases but most Caspase-6 inhibitors have been exclusively studied in vitro or show acute liver toxicity in humans. Here, we assessed vinyl sulfone small molecule peptide caspase inhibitors for potential use in vivo. METHODS: The IC of NWL vinyl sulfone small molecule caspase inhibitors were determined on Caspase-1 to 10, and Caspase-6-transfected human colon carcinoma HCT116 cells. Inhibition of Caspase-6-mediated axonal degeneration was assessed in serum-deprived or amyloid precursor protein-transfected primary human CNS neurons. Cellular toxicity was measured by phase contrast microscopy, mitochondrial and lactate dehydrogenase colorimetric activity assays, or flow cytometry. Caspase inhibition was measured by fluorogenic activity assays, fluorescence microscopy, and western blot analyses. The effect of inhibitors on age-dependent cognitive deficits in Caspase-6 transgenic mice was assessed by the novel object recognition task. Liquid chromatography coupled to tandem mass spectrometry assessed the blood-brain barrier permeability of inhibitors in Caspase-6 mice. RESULTS: Vinyl sulfone NWL-117 caspase inhibitor has a higher selectivity against Caspase-6, -4, -8, -9, and -10 whereas NWL-154 has higher selectivity against Caspase-6, -8, and -10. The half-maximal inhibitory concentrations (IC ) of NWL-117 and NWL-154 is 192 nM and 100 nM against Caspase-6 in vitro, and 4.82 µM and 3.63 µM in Caspase-6-transfected HCT116 cells, respectively. NWL inhibitors are not toxic to HCT116 cells or to human primary neurons. NWL-117 and NWL-154 inhibit serum deprivation-induced Caspase-6 activity and prevent amyloid precursor protein-mediated neurite degeneration in human primary CNS neurons. NWL-117 crosses the blood brain barrier and reverses age-dependent episodic memory deficits in Caspase-6 mice. CONCLUSIONS: NWL peptidic vinyl methyl sulfone inhibitors are potent, non-toxic, blood-brain barrier permeable, and irreversible caspase inhibitors with neuroprotective effects in HCT116 cells, in primary human CNS neurons, and in Caspase-6 mice. These results highlight the therapeutic potential of vinyl sulfone inhibitors as caspase inhibitors against neurodegenerative diseases and sanction additional work to improve their selectivity against different caspases.
[Mh] Termos MeSH primário: Caspase 6/efeitos dos fármacos
Inibidores de Caspase/farmacologia
Degeneração Neural/patologia
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
Sulfonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Axônios/efeitos dos fármacos
Axônios/enzimologia
Western Blotting
Cromatografia Líquida
Transtornos Cognitivos/patologia
Modelos Animais de Doenças
Citometria de Fluxo
Seres Humanos
Concentração Inibidora 50
Camundongos
Camundongos Transgênicos
Microscopia de Fluorescência
Microscopia de Contraste de Fase
Neurônios/enzimologia
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caspase Inhibitors); 0 (Neuroprotective Agents); 0 (Sulfones); 5PFN71LP8M (divinyl sulfone); EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE
[do] DOI:10.1186/s13024-017-0166-z


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[PMID]:28174059
[Au] Autor:Wu Y; Ma Y; Liu Z; Geng Q; Chen Z; Zhang Y
[Ad] Endereço:State Key Laboratory of Membrane Biology, College of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
[Ti] Título:Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer's disease mouse model.
[So] Source:Neurosci Lett;642:102-106, 2017 Mar 06.
[Is] ISSN:1872-7972
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Alzheimer's disease (AD) is the most common cause to dementia and predicted to influence about 35 million people by the end of 2050. In this study, we discover alterations of myelin morphology in hippocampus tissues of 2-month-old APP/PS1 mouse. Myelin sheath is thicker and internodal distance is shorter in APP/PS1 mouse. Oligodendrocytes, differentiated from oligodendrocytes progenitor cells (OPCs), are responsible for formation and maintenance of myelin sheath in central nervous system (CNS). Our current results demonstrate that the oligodendrocytes development is disordered in 2-month-old APP/PS1 mouse. Neuregulin-1 type III, which is critical for both oligodendrocytes development and CNS myelination, is found up-regulated in hippocampus tissues of APP/PS1 mouse by western blots. Furthermore, we find active-caspase-6 can cleave neuregulin-1 type III at the cytoplasmic region. Given together, this study indicates the alterations of myelin morphology and oligodendrocytes development in 2-month-old APP/PS1 mouse, and the alterations might be highly associated with neuregulin-1 type III and active-caspase-6.
[Mh] Termos MeSH primário: Doença de Alzheimer/patologia
Hipocampo/patologia
Bainha de Mielina/patologia
Oligodendroglia/patologia
[Mh] Termos MeSH secundário: Doença de Alzheimer/genética
Doença de Alzheimer/metabolismo
Precursor de Proteína beta-Amiloide/genética
Animais
Caspase 6/metabolismo
Modelos Animais de Doenças
Hipocampo/metabolismo
Camundongos
Camundongos Transgênicos
Bainha de Mielina/metabolismo
Neuregulina-1/metabolismo
Oligodendroglia/metabolismo
Presenilina-1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Protein Precursor); 0 (Neuregulin-1); 0 (Presenilin-1); EC 3.4.22.- (Caspase 6)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE


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[PMID]:28154009
[Au] Autor:Dagbay KB; Bolik-Coulon N; Savinov SN; Hardy JA
[Ad] Endereço:From the Departments of Chemistry and.
[Ti] Título:Caspase-6 Undergoes a Distinct Helix-Strand Interconversion upon Substrate Binding.
[So] Source:J Biol Chem;292(12):4885-4897, 2017 Mar 24.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caspases are cysteine aspartate proteases that are major players in key cellular processes, including apoptosis and inflammation. Specifically, caspase-6 has also been implicated in playing a unique and critical role in neurodegeneration; however, structural similarities between caspase-6 and other caspase active sites have hampered precise targeting of caspase-6. All caspases can exist in a canonical conformation, in which the substrate binds atop a ß-strand platform in the 130's region. This caspase-6 region can also adopt a helical conformation that has not been seen in any other caspases. Understanding the dynamics and interconversion between the helical and strand conformations in caspase-6 is critical to fully assess its unique function and regulation. Here, hydrogen/deuterium exchange mass spectrometry indicated that caspase-6 is inherently and dramatically more conformationally dynamic than closely related caspase-7. In contrast to caspase-7, which rests constitutively in the strand conformation before and after substrate binding, the hydrogen/deuterium exchange data in the L2' and 130's regions suggested that before substrate binding, caspase-6 exists in a dynamic equilibrium between the helix and strand conformations. Caspase-6 transitions exclusively to the canonical strand conformation only upon substrate binding. Glu-135, which showed noticeably different calculated pK values in the helix and strand conformations, appears to play a key role in the interconversion between the helix and strand conformations. Because caspase-6 has roles in several neurodegenerative diseases, exploiting the unique structural features and conformational changes identified here may provide new avenues for regulating specific caspase-6 functions for therapeutic purposes.
[Mh] Termos MeSH primário: Caspase 6/metabolismo
[Mh] Termos MeSH secundário: Caspase 6/química
Caspase 7/química
Caspase 7/metabolismo
Estabilidade Enzimática
Seres Humanos
Simulação de Dinâmica Molecular
Ligação Proteica
Conformação Proteica
Conformação Proteica em alfa-Hélice
Prótons
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protons); EC 3.4.22.- (Caspase 6); EC 3.4.22.- (Caspase 7)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.773499



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