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2.
Am J Med Genet A ; 194(7): e63603, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38511620

RESUMO

There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Osteocondrodisplasias , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Pré-Escolar , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/etiologia , Transtornos do Crescimento/patologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética
3.
Methods Cell Biol ; 164: 95-112, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34225921

RESUMO

In the perspective to evaluate the toxicity of drug candidates or the exploration of intracellular signaling pathways of cell stress response and pathophysiological conditions, we propose to evaluate cell death, autophagy, mitochondrial network and energetic metabolism by a series of optimized joint protocols for neonatal primary rat cardiomyocytes or H9c2 cardiac cell line in 96 well microtiter plates. We used Digitoxigenin and Digoxin, two cardiac glycosides, and Rapamycin as control drugs, for inhibition of oxidative stress-induced cell death and autophagy induction, respectively.


Assuntos
Autofagia , Mitocôndrias , Animais , Apoptose , Morte Celular , Mitocôndrias/metabolismo , Miócitos Cardíacos , Estresse Oxidativo , Ratos
4.
Free Radic Biol Med ; 154: 119-131, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32437928

RESUMO

Berries are rich sources of (poly)phenols which have been associated with the prevention of cardiovascular diseases in animal models and in human clinical trials. Recently, a berry enriched diet was reported to decrease blood pressure and attenuate kidney disease progression on Dahl salt-sensitive rats. However, the relationship between kidney function, metabolism and (poly)phenols was not evaluated. We hypothesize that berries promote metabolic alterations concomitantly with an attenuation of the progression of renal disease. For that, kidney and urinary metabolomic changes induced by the berry enriched diet in hypertensive rats (Dahl salt-sensitive) were analyzed using liquid chromatography (UPLC-MS/MS) and 1H NMR techniques. Moreover, physiological and metabolic parameters, and kidney histopathological data were also collected. The severity of the kidney lesions promoted in Dahl rats by a high salt diet was significantly reduced by berries, namely a decrease in sclerotic glomeruli. In addition, was observed a high urinary excretion of metabolites that are indicators of alterations in glycolysis/gluconeogenesis, citrate cycle, and pyruvate metabolism in the salt induced-hypertensive rats, a metabolic profile counteracted by berries consumption. We also provide novel insights that relates (poly)phenols consumption with alterations in cysteine redox pools. Cysteine contribute to the redox signaling that is normally disrupted during kidney disease onset and progression. Our findings provide a vision about the metabolic responses of hypertensive rats to a (poly)phenol enriched diet, which may contribute to the understanding of the beneficial effects of (poly)phenols in salt-induced hypertension.


Assuntos
Frutas , Hipertensão , Animais , Pressão Sanguínea , Cromatografia Líquida , Hipertensão/metabolismo , Rim/metabolismo , Metaboloma , Ratos , Ratos Endogâmicos Dahl , Espectrometria de Massas em Tandem
5.
Ir Med J ; 113(4): 61, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32268054

RESUMO

Presentation To describe a case of cystic echinococcosis (CE) in a previously healthy child and review epidemiology of CE in Ireland. Diagnosis A previously healthy 6 year old girl was found to have a cystic lesion in the right lobe of her liver. Serology for Echinococcus granulosus was positive, and radiological features were suggestive of CE. Treatment The patient was pre-treated with anti-helminthic medications before undergoing a liver segmentectomy to remove the cyst, and received further treatment with albendazole after surgery. Histological findings were consistent with CE due to E. granulosus, likely acquired during travel to continental Europe. Conclusion CE should be considered in the differential of children with asymptomatic cysts in the liver and/or lung, and a travel history elucidated in such cases.


Assuntos
Equinococose Hepática/diagnóstico , Equinococose Hepática/terapia , Viagem , Albendazol/administração & dosagem , Animais , Anti-Helmínticos/administração & dosagem , Anticorpos Anti-Helmínticos/sangue , Infecções Assintomáticas , Biomarcadores/sangue , Criança , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Equinococose Hepática/diagnóstico por imagem , Equinococose Hepática/parasitologia , Echinococcus granulosus/imunologia , Feminino , Hepatectomia/métodos , Humanos , Irlanda , Resultado do Tratamento
6.
Rev Sci Instrum ; 89(7): 073502, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30068096

RESUMO

The characterisation of x-rays from laser-plasma interactions is of utmost importance as they can be useful for both monitoring electron dynamics and also applications in an industrial capacity. A novel versatile scintillator x-ray spectrometer diagnostic that is capable of single shot measurements of x-rays produced from laser-plasma interactions is presented here. Examples of the design and extraction of the temperature of the spectrum of x-rays produced in an intense laser-solid interaction (479 ± 39 keV) and the critical energy from a betatron source (30 ± 10 keV) are discussed. Finally, a simple optimisation process involving adjusting the scintillator thickness for a particular range of input spectra is demonstrated.

7.
Psychol Med ; 48(3): 451-462, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28712364

RESUMO

BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal α coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross-national mental health strategies.


Assuntos
Inventário de Personalidade , Psicometria/estatística & dados numéricos , Transtorno da Personalidade Esquizotípica/diagnóstico , Transtorno da Personalidade Esquizotípica/psicologia , Adolescente , Adulto , Análise Fatorial , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Inquéritos e Questionários , Adulto Jovem
8.
Int J Cardiol ; 244: 30-36, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28663047

RESUMO

BACKGROUND: MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients. METHODS: Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Δ) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint. RESULTS: Expression of miR-1, miR-21 and miR-29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with ΔIV and showed a trend for correlation with ΔLVEF. Only miR-29b levels at day 9 correlated with ΔLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome. CONCLUSION: Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future.


Assuntos
MicroRNAs/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Remodelação Ventricular/fisiologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Prognóstico , Fosfato de Sitagliptina/administração & dosagem
9.
Int Rev Cell Mol Biol ; 331: 245-287, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28325213

RESUMO

Mitochondria are deeply involved in cell fate decisions via their multiple roles in metabolism, cell growth, and cell death. In healthy cells, these functions are highly regulated to provide sufficient energy for cell function, maintain cell homeostasis, and avoid undesirable cell death. This is achieved by an orchestrated cooperation of cellular and molecular mechanisms such as mitochondrial mass control (mitophagy vs biogenesis), oxidative phosphorylation, redox and calcium homeostasis, and the balance between pro- and antiapoptotic proteins. In the 1990s, mitochondria have been demonstrated to directly control some forms of regulated cell death as well indirectly through energetic metabolism modulation. However, a large body of literature revealed that distinct cell death modalities can coexist in vivo as well as that mitochondria can be dispensable for certain forms of cell death. Likewise, unexpected interconnections between cell death pathways can lead to an amplification of lethality, as well as a defeat of cell death resistance mechanisms. This revealed a complexity of the control of cell fate and a crucial need to reevaluate the role of mitochondria. Here, we will review the various cell death pathways such as apoptosis and mitochondrial permeability transition-driven necrosis and discuss how mitochondrial proteins and mitophagy regulate them. Finally, the role of mitochondrial proteins in the triggering of cell death and mitophagy in pathological models, such as cardiac and brain pathologies, will be highlighted. This may help to define efficient cytoprotective therapeutic strategies based on the targeting of mitochondria.


Assuntos
Apoptose , Mitocôndrias/metabolismo , Animais , Doença , Humanos , Mitofagia , Modelos Biológicos , Necrose
10.
Cell Death Dis ; 7: e2198, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27100892

RESUMO

Although cardiac cytosolic cyclic 3',5'-adenosine monophosphate (cAMP) regulates multiple processes, such as beating, contractility, metabolism and apoptosis, little is known yet on the role of this second messenger within cardiac mitochondria. Using cellular and subcellular approaches, we demonstrate here the local expression of several actors of cAMP signaling within cardiac mitochondria, namely a truncated form of soluble AC (sACt) and the exchange protein directly activated by cAMP 1 (Epac1), and show a protective role for sACt against cell death, apoptosis as well as necrosis in primary cardiomyocytes. Upon stimulation with bicarbonate (HCO3(-)) and Ca(2+), sACt produces cAMP, which in turn stimulates oxygen consumption, increases the mitochondrial membrane potential (ΔΨm) and ATP production. cAMP is rate limiting for matrix Ca(2+) entry via Epac1 and the mitochondrial calcium uniporter and, as a consequence, prevents mitochondrial permeability transition (MPT). The mitochondrial cAMP effects involve neither protein kinase A, Epac2 nor the mitochondrial Na(+)/Ca(2+) exchanger. In addition, in mitochondria isolated from failing rat hearts, stimulation of the mitochondrial cAMP pathway by HCO3(-) rescued the sensitization of mitochondria to Ca(2+)-induced MPT. Thus, our study identifies a link between mitochondrial cAMP, mitochondrial metabolism and cell death in the heart, which is independent of cytosolic cAMP signaling. Our results might have implications for therapeutic prevention of cell death in cardiac pathologies.


Assuntos
Apoptose , Cálcio/metabolismo , AMP Cíclico/farmacologia , Mitocôndrias Cardíacas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/química , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bicarbonatos/farmacologia , Camptotecina/toxicidade , Células Cultivadas , Dactinomicina/toxicidade , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Peróxido de Hidrogênio/toxicidade , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Permeabilidade , Ratos , Ratos Wistar , Troponina I/metabolismo
11.
Clin Neurophysiol ; 127(1): 369-378, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25868929

RESUMO

OBJECTIVE: Many breast cancer survivors (BCS) report cognitive problems following chemotherapy, yet controversy remains concerning which cognitive domains are affected. This study investigated a domain crucial to daily function: the ability to maintain attention over time. METHODS: We examined whether BCS who self-reported cognitive problems up to 3 years following cancer treatment (n=19) performed differently from healthy controls (HC, n=12) in a task that required sustained attention. Participants performed a target detection task while periodically being asked to report their attentional state. Electroencephalogram was recorded during this task and at rest. RESULTS: BCS were less likely to maintain sustained attention during the task compared to HC. Further, the P3 event-related potential component elicited by visual targets during the task was smaller in BCS relative to HC. BCS also displayed greater neural activity at rest. CONCLUSIONS: BCS demonstrated an abnormal pattern of sustained attention and resource allocation compared to HC, suggesting that attentional deficits can be objectively observed in breast cancer survivors who self-report concentration problems. SIGNIFICANCE: These data underscore the value of EEG combined with a less traditional measure of sustained attention, or attentional states, as objective laboratory tools that are sensitive to subjective complaints of chemotherapy-related attentional impairments.


Assuntos
Antineoplásicos/efeitos adversos , Atenção/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Eletroencefalografia/efeitos dos fármacos , Adulto , Idoso , Atenção/fisiologia , Transtornos Cognitivos/diagnóstico , Eletroencefalografia/tendências , Potenciais Evocados P300/efeitos dos fármacos , Potenciais Evocados P300/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Autorrelato , Fatores de Tempo
13.
Cell Death Dis ; 6: e1926, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26492363

RESUMO

Platinum-based drugs remain as the cornerstone of cancer chemotherapy; however, development of multidrug resistance presents a therapeutic challenge. This study aims at understanding the molecular mechanisms underlying resistance to cisplatin and unraveling surrogate signaling networks that could revert sensitivity to apoptosis stimuli. We made use of three different sets of cell lines, A549 and H2030 non-small-cell lung cancer (NSCLC) and A2780 ovarian cancer cells and their cisplatin-resistant variants. Here we report that cisplatin-resistant cell lines displayed a multidrug-resistant phenotype. Changes in mitochondrial metabolism and defective mitochondrial signaling were unraveled in the resistant cells. More interestingly, a marked increase in sensitivity of the resistant cells to death receptor-induced apoptosis, in particular TRAIL (TNF-related apoptosis-inducing ligand)-mediated execution, was observed. Although this was not associated with an increase in gene transcription, a significant increase in the localization of TRAIL death receptor, DR4, to the lipid raft subdomains of plasma membrane was detected in the resistant variants. Furthermore, exposure of cisplatin-resistant cells to TRAIL resulted in upregulation of inducible nitric oxide synthase (iNOS) and increase in nitric oxide (NO) production that triggered the generation of peroxynitrite (ONOO(-)). Scavenging ONOO(-) rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO(-) in TRAIL-induced execution of cisplatin-resistant cells. Notably, preincubation of cells with TRAIL restored sensitivity of resistant cells to cisplatin. These data provide compelling evidence for employing strategies to trigger death receptor signaling as a second-line treatment for cisplatin-resistant cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Ácido Peroxinitroso/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Microdomínios da Membrana/metabolismo , Transporte Proteico , Espécies Reativas de Nitrogênio/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
14.
Int J Cardiol ; 199: 163-9, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26197403

RESUMO

OBJECTIVE: Glipitins are widely used for the treatment of type 2 diabetic patients. In addition to their improvement of glycemic control, animal studies have suggested an independent anti-atherosclerotic effect of gliptins. Nevertheless, recent clinical trials regarding long-term effects of gliptin therapy on vascular events have been disappointing. This discrepancy led us to better dissect the functional role of SDF-1/CXCR4 signaling as a potential mechanism underlying gliptin action. The study should give improved understanding of the potential of gliptin therapy in the prevention and treatment of atherosclerosis. METHODS AND RESULTS: In an ApoE-/- mouse model on high cholesterol diet, long-term treatment with the DPP-4 inhibitor Sitagliptin significantly reduced atherosclerosic plaque load in the aorta. Flow cytometry analyses showed an enrichment of M2 macrophages in the aortic wall under gliptin therapy. Importantly, the number of recruited CD206+ macrophages was inversely correlated with total plaque area while no correlation was found for the overall macrophage population or M1 macrophages. Blockade of CXCR4/SDF-1 signaling by AMD3100 inhibited aortic M2 accumulation and the therapeutic effect of Sitagliptin. Correspondingly, Sitagliptin shifted the polarization profile of macrophages towards a M2-like phenotype. CONCLUSION: Sitagliptin-mediated inhibition of early atherosclerosis is based on M2-polarization during monocyte differentiation via the SDF-1/CXCR4 signaling. In contrast to earlier assumptions gliptin treatment might be especially effective in prevention of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Macrófagos/metabolismo , Monócitos/metabolismo , Priming de Repetição/fisiologia , Animais , Aorta/efeitos dos fármacos , Apolipoproteínas E/genética , Aterosclerose/prevenção & controle , Quimiocina CXCL12/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Hipercolesterolemia/tratamento farmacológico , Incretinas/sangue , Incretinas/uso terapêutico , Resistência à Insulina/fisiologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Placa Aterosclerótica/tratamento farmacológico , Receptores CXCR4/genética , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/uso terapêutico
15.
Biochim Biophys Acta ; 1852(5): 749-58, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25619687

RESUMO

Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-carnitine (PC), alters mitochondrial function leading to Ca(2+) dependent-arrhythmia. In isolated cardiac mitochondria from C57Bl/6 mice, application of 10µM PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondrial permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 µM) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca(2+) leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca(2+) leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca(2+) wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca(2+) handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions.


Assuntos
Cálcio/metabolismo , Translocases Mitocondriais de ADP e ATP/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Palmitoilcarnitina/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Ácido Bongcréquico/farmacologia , Células Cultivadas , Sequestradores de Radicais Livres/farmacologia , Immunoblotting , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/fisiologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Retículo Sarcoplasmático/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo
16.
Cell Death Differ ; 22(1): 58-73, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25236395

RESUMO

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.


Assuntos
Apoptose , Transdução de Sinais , Animais , Humanos , Terminologia como Assunto
17.
J Xray Sci Technol ; 23(6): 791-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26756414

RESUMO

X-ray backscatter imaging can be used for a wide range of imaging applications, in particular for industrial inspection and portal security. Currently, the application of this imaging technique to the detection of landmines is limited due to the surrounding sand or soil strongly attenuating the 10s to 100s of keV X-rays required for backscatter imaging. Here, we introduce a new approach involving a 140 MeV short-pulse (< 100 fs) electron beam generated by laser wakefield acceleration to probe the sample, which produces Bremsstrahlung X-rays within the sample enabling greater depths to be imaged. A variety of detector and scintillator configurations are examined, with the best time response seen from an absorptive coated BaF2 scintillator with a bandpass filter to remove the slow scintillation emission components. An X-ray backscatter image of an array of different density and atomic number items is demonstrated. The use of a compact laser wakefield accelerator to generate the electron source, combined with the rapid development of more compact, efficient and higher repetition rate high power laser systems will make this system feasible for applications in the field. Content includes material subject to Dstl (c) Crown copyright (2014). Licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: psi@ nationalarchives.gsi.gov.uk.


Assuntos
Bombas (Dispositivos Explosivos)/classificação , Lasers , Intensificação de Imagem Radiográfica/instrumentação , Espalhamento de Radiação , Tomografia Computadorizada por Raios X/instrumentação , Guerra , Desenho de Equipamento , Análise de Falha de Equipamento , Imagens de Fantasmas , Raios X
18.
Cell Death Dis ; 5: e1257, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-24874729

RESUMO

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Biologia de Sistemas , Animais , Humanos , Biologia de Sistemas/métodos , Biologia de Sistemas/tendências
19.
Cell Death Differ ; 21(5): 685-95, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24464223

RESUMO

Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/patologia
20.
Oncogene ; 33(27): 3604-11, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23995786

RESUMO

The RAS protooncogene has a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor-suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is overexpressed in numerous human cancers. Here we provide new evidence that the pleiotropic regulator of G protein signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts from wild-type and RGS6(-/-) mice, we found that oncogenic Ras induced upregulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by downregulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GTPase-activating protein activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments.


Assuntos
Apoptose , Transformação Celular Neoplásica , DNA (Citosina-5-)-Metiltransferases/metabolismo , Histona Acetiltransferases/metabolismo , Proteólise , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas RGS/metabolismo , Transativadores/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1 , Humanos , Lisina Acetiltransferase 5 , Camundongos , Transdução de Sinais
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