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1.
J Prev Med Hyg ; 65(1): E43-E49, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38706769

RESUMO

Background: Overweight has been associated with several social and phycological problems and is perceived as one of the major health care challenges to focus on in the future. The purpose of the study is to investigate the correlations among nutritional status, assessed by the Body Mass Index, the perception of one's own health status and Life Satisfaction, detected in Italian adolescents living in Tuscany Region, and to investigate the influence of gender on them. Methods: A statistically representative sample of 2760 Tuscan adolescents aged 11, 13 and 15 was involved in the 2018 Health Behaviours at School-aged Children survey. The participants were divided into three nutritional status class: underweight, normal weight and overweight (overweight + obese). Results: The results show that there is a statistically significant difference in all categories between boys and girls aged 13 and 15 years; in girls aged 11 and 13 years, the Life Satisfaction of the overweight group is statistically lower than that of normal and underweight groups; Self-Rated Health is statistically lower in all age groups for overweight individuals compared to normal weight children, except for 11-year-old females. Conclusions: Viewing the psychosocial problems related to overweight, more attention and care must be placed on adolescents to ensure their healthier development.


Assuntos
Nível de Saúde , Estado Nutricional , Sobrepeso , Satisfação Pessoal , Humanos , Itália , Feminino , Masculino , Adolescente , Estudos Transversais , Criança , Sobrepeso/epidemiologia , Índice de Massa Corporal , Comportamentos Relacionados com a Saúde , Magreza/psicologia , Magreza/epidemiologia
2.
Aesthetic Plast Surg ; 48(4): 764-773, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37516709

RESUMO

BACKGROUND: This study examined the relationship between false self-presentation on Instagram and consideration of cosmetic surgery through the mediating role of body image control in photos (BICP), photo manipulation, and body shame. We predicted that false self-presentation on Instagram was indirectly associated with cosmetic surgery intentions through the aforementioned constructs. METHODS: A total of 504 young Italian adults (28.2% males, 18-30 years) completed an online survey. They completed a questionnaire containing the Self-presentation on Instagram Questionnaire, the Body Image Control in Photos Questionnaire-revised, the Photo Manipulation Scale, the Objectified Body Consciousness Scale, and the Acceptance of Cosmetic Surgery Scale. The pattern of associations between the constructs was analyzed via path analysis. RESULTS: The results show that false self-presentation on Instagram was associated with photo manipulation, both directly and indirectly, through BICP. Furthermore, photo manipulation was linked to body shame, but neither of them was associated with cosmetic surgery intentions. Finally, false self-presentation on Instagram was associated with the consideration of cosmetic surgery only through the mediation of BICP. CONCLUSION: Findings indicate that self-presentation styles might affect Instagram photo behaviors and individuals' cosmetic surgery intentions, suggesting that surgeons should fully examine patients' motivations before providing them with services. Furthermore, intervention programs encouraging users to present a more authentic version of themselves online might reduce the risk of self-objectification and reduce the consideration of procedures aimed at modifying one's body for purely aesthetic reasons. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Assuntos
Cirurgiões , Cirurgia Plástica , Adulto , Masculino , Humanos , Feminino , Cirurgia Plástica/métodos , Imagem Corporal , Inquéritos e Questionários
3.
Copenhagen; World Health Organization. Regional Office for Europe; 2024.
em Inglês | WHO IRIS | ID: who-376573

RESUMO

The Health Behaviour in School-aged Children (HBSC) study is a large school-based survey carried out every four years in collaboration with the WHO Regional Office for Europe. HBSC data are used at national/regional and international levels to gain new insights into adolescent health and well-being, understand the social determinants of health and inform policy and practice to improve young people’s lives. The 2021/2022 HBSC survey data are accompanied by a series of volumes that summarize the key findings around specific health topics. This report, Volume 3 in the series, focuses on adolescent substance use, using the unique HBSC evidence on adolescents aged 11, 13 and 15 years across 44 countries and regions in Europe, central Asia and Canada. It describes the status of adolescent substance use (cigarette smoking, electronic cigarette use, alcohol consumption, drunkenness and cannabis use), the role of gender, age and social inequality, and how adolescent substance use has changed over time. Findings from the 2021/2022 HBSC survey provide an important evidence benchmark for current research, intervention and policy-planning.


Assuntos
Disparidades nos Níveis de Saúde , Fatores Socioeconômicos , Equidade de Gênero , Saúde do Adolescente , Bullying , Cyberbullying , Violência
4.
Children (Basel) ; 10(11)2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38002907

RESUMO

Adolescence is a critical period for engaging in health risk behaviors. Migrant adolescents may face unique challenges due to acculturation stress. This study aims to monitor substance use and problem gambling among migrant adolescents living in Italy. Data from the 2017/18 Health Behavior in School-Aged Children survey in Italy were analyzed. The 18,794 participants included 15-year-olds, categorized as native or migrants, with ethnic backgrounds from Western, Eastern European, or non-Western/non-European countries. Girls had higher smoking rates, while boys exhibited higher prevalence of alcohol-related risk behaviors, cannabis use, and gambling. Boys from Eastern European countries displayed a greater risk of drunkenness (OR: 1.58, 95% CI: 1.06-2.37), particularly in the first generation, while those from Western countries showed a higher risk of multiple substance use (OR: 1.44, 95% CI: 1.05-1.96). Girls from Eastern European and non-Western/non-European countries had a lower risk of alcohol consumption (OR: 0.50, 95% CI: 0.29-0.85; OR: 0.55, 95% CI: 0.33-0.91, respectively). Finally, boys, especially those from Eastern European and non-Western/non-European countries, had a significantly higher risk of problem gambling (OR: 1.83, 95% CI: 1.04-3.22; OR: 2.10, 95% CI: 1.29-3.42, respectively). This disparity was more pronounced in the first generation, possibly due to acculturation challenges and socio-economic factors. Risk behaviors in adolescents are influenced by complex interplays of gender, cultural factors, and migration generation. Preventive strategies should consider these factors to effectively address substance use and gambling in this heterogeneous population.

5.
Contact Dermatitis ; 89(5): 352-358, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37394777

RESUMO

BACKGROUND: Adverse drug reactions to iodinated contrast media (ICM) have risen due to their increasing use in x-ray-based imaging modalities. Delayed hypersensitivity reactions are mainly caused by nonionic monomeric compounds and represent an issue impacting the diagnostic-therapeutic pathways of cancer, cardiology and surgery patients. OBJECTIVES: To prospectively evaluate the usefulness of skin tests in delayed hypersensitivity reactions to ICM and to evaluate the tolerability of iobitridol, a monomeric nonionic low osmolality compound, as a possible safe alternative. METHODS: Patients with delayed hypersensitivity reactions to ICM referred to us from 2020 to 2022 were prospectively enrolled in the study. All patients underwent patch test and, if negative, intradermal test with the culprit ICM and iobitridol as alternative. RESULTS: A total of 37 patients (females 24, 64.9%) were enrolled in the study. Iodixanol and iomeprol were the most frequently involved ICM (48.5% and 35.2%, respectively); 62.2% of patients presented maculopapular eruption, while 37.8% reported delayed urticaria-like rash. Skin tests resulted positive to the culprit ICM in 19 patients (51.4%), 16 to patch test and 3 to intradermal test. Skin tests with iobitridol, tested as alternative, resulted positive in 3/19 patients (15.8%). All 16 patients with negative results to iobitridol were administered this ICM and tolerated it. CONCLUSIONS: In at least half of patients, delayed-type hypersensitivity was demonstrated by skin tests, particularly by patch test. This diagnostic approach resulted simple, cost-effective and safe, not only to confirm the culprit ICM but also to identify iobitridol as feasible alternative.


Assuntos
Dermatite Alérgica de Contato , Hipersensibilidade a Drogas , Exantema , Hipersensibilidade Tardia , Compostos de Iodo , Feminino , Humanos , Meios de Contraste/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Dermatite Alérgica de Contato/complicações , Testes Cutâneos , Compostos de Iodo/efeitos adversos , Exantema/induzido quimicamente , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/diagnóstico
6.
Inflamm Bowel Dis ; 18(3): 439-48, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21793125

RESUMO

BACKGROUND: Ulcerative colitis (UC) is associated with colorectal cancer. Chronic inflammation may also play a role in the pathogenesis of sporadic colorectal cancer (SCC), particularly in younger patients (<55 years). We evaluated whether single nucleotide polymorphisms of the OCTN1 and OCTN2 genes are associated with UC, SCC, and with UC cases with cancer progression (UCCP). METHODS: We evaluated the OCTN1 and OCTN2 polymorphisms in 200 patients with UC, 59 patients with UCCP, 200 patients with SCC, and 200 controls (HC). IL-8 expression was also assessed by real-time polymerase chain reaction (PCR). Additionally, we transfected human colon carcinoma Caco2 cells, homozygous for OCTN1/1672T variant, with the OCTN1/1672C allele and NF-κB activity was evaluated by luciferase based reporter assay and IL-8 mRNA expression by real-time PCR. RESULTS: OCTN2 polymorphisms did not present a significant association with any group of patients compared to normal controls. Conversely, homozygosity for the OCTN1/1672T variant was significantly associated with UC (P = 0.047 vs. HC), with UCCP (UCCP vs. HC, P < 0.001), and with SCC developing in early age (<55 years) (P = 0.021 vs. HC). Importantly, IL-8 mRNA expression was higher in UC and UCCP patients homozygous for the OCTN1 1672T variant compared to the other genotypes. Moreover, in Caco2 cells transfection of the OCTN1/1672C variant reduced the activity of the proinflammatory factor NF-κB. CONCLUSION: Our data demonstrate that OCTN1 could have a role in modulating the severity of chronic inflammation associated with SCC in early age and in UC patients, and that its polymorphisms may help to predict malignant progression of IBD.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Células CACO-2 , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Distribuição de Qui-Quadrado , Colite Ulcerativa/metabolismo , Neoplasias Colorretais/metabolismo , Progressão da Doença , Feminino , Humanos , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Membro 5 da Família 22 de Carreadores de Soluto , Estatísticas não Paramétricas , Simportadores
7.
Proc Natl Acad Sci U S A ; 109(2): 621-6, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22190495

RESUMO

Calorie restriction delays brain senescence and prevents neurodegeneration, but critical regulators of these beneficial responses other than the NAD(+)-dependent histone deacetylase Sirtuin-1 (Sirt-1) are unknown. We report that effects of calorie restriction on neuronal plasticity, memory and social behavior are abolished in mice lacking cAMP responsive-element binding (CREB)-1 in the forebrain. Moreover, CREB deficiency drastically reduces the expression of Sirt-1 and the induction of genes relevant to neuronal metabolism and survival in the cortex and hippocampus of dietary-restricted animals. Biochemical studies reveal a complex interplay between CREB and Sirt-1: CREB directly regulates the transcription of the sirtuin in neuronal cells by binding to Sirt-1 chromatin; Sirt-1, in turn, is recruited by CREB to DNA and promotes CREB-dependent expression of target gene peroxisome proliferator-activated receptor-γ coactivator-1α and neuronal NO Synthase. Accordingly, expression of these CREB targets is markedly reduced in the brain of Sirt KO mice that are, like CREB-deficient mice, poorly responsive to calorie restriction. Thus, the above circuitry, modulated by nutrient availability, links energy metabolism with neurotrophin signaling, participates in brain adaptation to nutrient restriction, and is potentially relevant to accelerated brain aging by overnutrition and diabetes.


Assuntos
Restrição Calórica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica/fisiologia , Neurônios/metabolismo , Prosencéfalo/metabolismo , Sirtuína 1/metabolismo , Análise de Variância , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/deficiência , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Plasticidade Neuronal/fisiologia , Desempenho Psicomotor , Sirtuína 1/genética , Comportamento Social
8.
Antioxid Redox Signal ; 15(6): 1715-27, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20712406

RESUMO

Control of intracellular redox balance has emerged as a primary function of the p53 network, with crucial implications for tumor suppression, aging, and cell metabolism. Mitochondria are central to redox homeostasis, produce energy, and trigger apoptosis and senescence: not surprisingly, many "old" and "new" functions of p53 appear to be based in mitochondria. Genetic and biomolecular evidence indicates that generation of reactive oxygen species (ROS) in mitochondria can be a deliberate and finely regulated cell response on which signaling by environmental stressors, oncogenes, and nutrients converge. p53 orchestrates mitochondrial redox signaling by the coordinated control of at least two key effectors: the superoxide scavenger MnSOD, and the ROS generator p66shc. This review presents recent evidence and emerging questions regarding the p53-MnSOD-p66shc connection, and discusses how dissection of a circuitry comprising a tumor suppressor, an antioxidant, and a molecule regulating cell survival and mammalian lifespan can provide a framework to address important aspects related to the intricate connection between metabolism, aging, and cancer.


Assuntos
Envelhecimento , Mitocôndrias/fisiologia , Neoplasias/metabolismo , Proteínas Adaptadoras da Sinalização Shc/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Humanos , Camundongos , Mitocôndrias/metabolismo , Neoplasias/genética , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Estresse Fisiológico , Superóxido Dismutase/metabolismo , Superóxido Dismutase/fisiologia
9.
Aging (Albany NY) ; 2(8): 487-503, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20739737

RESUMO

Deregulated nutrient signaling plays pivotal roles in body ageing and in diabetic complications; biochemical cascades linking energy dysmetabolism to cell damage and loss are still incompletely clarified, and novel molecular paradigms and pharmacological targets critically needed. We provide evidence that in the retrovirus-packaging cell line HEK293-T Phoenix, massive cell death in serum-free medium is remarkably prevented or attenuated by either glucose or aminoacid withdrawal, and by the glycolysis inhibitor 2-deoxy-glucose. A similar protection was also elicited by interference with mitochondrial function, clearly suggesting involvement of energy metabolism in increased cell survival. Oxidative stress did not account for nutrient toxicity on serum-starved cells. Instead, nutrient restriction was associated with reduced activity of the mTOR/S6 Kinase cascade. Moreover, pharmacological and genetic manipulation of the mTOR pathway modulated in an opposite fashion signaling to S6K/S6 and cell viability in nutrient-repleted medium. Additionally, stimulation of the AMP-activated Protein Kinase concomitantly inhibited mTOR signaling and cell death, while neither event was affected by overexpression of the NAD+ dependent deacetylase Sirt-1, another cellular sensor of nutrient scarcity. Finally, blockade of the mTOR cascade reduced hyperglycemic damage also in a more pathophysiologically relevant model, i.e. in human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemia. Taken together these findings point to a key role of the mTOR/S6K cascade in cell damage by excess nutrients and scarcity of growth-factors, a condition shared by diabetes and other ageing-related pathologies.


Assuntos
Sobrevivência Celular/fisiologia , Privação de Alimentos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/fisiologia , Antimetabólitos/administração & dosagem , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro , Desoxiglucose/administração & dosagem , Células HEK293 , Humanos , Mitocôndrias/fisiologia , Estresse Oxidativo/fisiologia , Proteína S6 Ribossômica/fisiologia , Proteínas Quinases S6 Ribossômicas/fisiologia , Transdução de Sinais/fisiologia , Sirtuína 1/fisiologia , Serina-Treonina Quinases TOR/toxicidade
10.
Proc Natl Acad Sci U S A ; 107(30): 13420-5, 2010 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-20624962

RESUMO

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.


Assuntos
Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/fisiopatologia , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Citometria de Fluxo , Intolerância à Glucose/genética , Intolerância à Glucose/fisiopatologia , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatologia , Hipoglicemiantes/farmacologia , Immunoblotting , Insulina/farmacologia , Leptina/genética , Longevidade/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Interferência de RNA , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
12.
Cancer Metastasis Rev ; 29(2): 351-78, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20386957

RESUMO

According to a "canonical" view, reactive oxygen species (ROS) positively contribute, in different ways, to carcinogenesis and to malignant progression of tumor cells: they drive genomic damage and genetic instability, transduce, as signaling intermediates, mitogenic and survival inputs by growth factor receptors and adhesion molecules, promote cell motility and shape the tumor microenvironment by inducing inflammation/repair and angiogenesis. Chemopreventive and tumor-inhibitory effects of endogenous, diet-derived or supplemented antioxidants largely support this notion. However, emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance. This "heresy" has recently received important impulse from studies on the role of antioxidant capacity in cancer stem cells self-renewal and resistance to therapy; additionally, the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox-sensitive transcription factors, and results in an increase of cell resistance to oxidants. On the other hand, cytoskeleton rearrangement underlying cell motile and tumor-aggressive behavior use ROS as intermediates and are therefore facilitated by oxidative stress. Along this line of speculation, we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.


Assuntos
Metástase Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos
13.
Antioxid Redox Signal ; 11(11): 2791-806, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19686053

RESUMO

We review here current evidence on the role of reactive oxygen species (ROS) and of the intracellular redox state in governing crucial steps of the metastatic process, from cell detachment from the primary tumor to final colonization of the distant site. In particular, we discuss the redox-dependent aspects of cell glycolytic metabolism (Warburg effect), of cell juggling between different motility styles (epithelial-to-mesenchymal and mesenchymal-to-amoeboid transition), of cell resistance to anoikis and of cell interaction with the stromal components of the metastatic niche. Central to this overview is the concept that metastasis can be viewed as an integrated "escape program" triggered by redox changes and instrumental at avoiding oxidative stress within the primary tumor. In this novel perspective, metabolic, motility, and prosurvival choices of the cell along the entire metastatic process can be interpreted as exploiting redox-signaling cascades to monitor oxidative/reductive environmental cues and escape oxidative damage. We also propose that this theoretic framework be applied to "normal" evasion/invasion programs such as in inflammation and development. Furthermore, we suggest that the intimate connection between metastasis, inflammation, and stem cells results, at least in part, by the sharing of a common redox-dependent strategy for infiltration, survival, dissemination, and patterning.


Assuntos
Metástase Neoplásica/fisiopatologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/fisiologia , Humanos , Modelos Biológicos , Metástase Neoplásica/patologia , Oxirredução
14.
Int J Biochem Cell Biol ; 41(5): 1002-5, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18992840

RESUMO

Once considered as a mere by-product of respiration, mitochondrial generation of reactive oxygen species (ROS) has recently emerged as a genetically controlled phenomenon, involved in complex intracellular signal transduction cascades that directly regulate cell survival and death in responses to environmental stressors. These cascades are involved in the pathogenesis of several major age-related diseases, such as cancer and neurodegeneration, and also appear to somehow regulate the "normal" ageing process. The present short review summarizes recent discoveries on mitochondrial reactive oxygen species regulation by p53, a tumor suppressor protein and p66shc, a protein implicated in the life-span determination. It also outlines the emerging network whereby these molecules cross-talk with each other and with the mitochondrial antioxidant system, namely MnSOD (SOD2), another life-span determining protein, to regulate oxidative stress in the organelle. This molecular circuit, which comprises two genetic determinants of longevity and a major tumor suppressor gene, also provides a theoretical framework connecting senescence and cancer.


Assuntos
Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Proteínas Adaptadoras da Sinalização Shc/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Superóxido Dismutase/genética , Proteína Supressora de Tumor p53/genética
15.
Sci Signal ; 1(43): pl3, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18957692

RESUMO

We present the application of a redox-sensitive mutant of the yellow fluorescent protein (rxYFP) to image, with elevated sensitivity and high temporal and spatial resolution, oxidative responses of eukaryotic cells to pathophysiological stimuli. The method presented, based on the ratiometric quantitation of the distribution of fluorescence by confocal microscopy, allows us to draw real-time "redox maps" of adherent cells and to score subtle changes in the intracellular redox state, such as those induced by overexpression of redox-active proteins. This strategy for in vivo imaging of redox signaling circumvents many of the technical limitations currently encountered in the study of complex redox-based phenomena and promises to contribute substantially to this expanding area of signal transduction.


Assuntos
Células/citologia , Proteínas Luminescentes , Transdução de Sinais , Animais , Humanos , Métodos , Microscopia Confocal , Oxirredução
16.
Lab Invest ; 88(7): 750-60, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18490896

RESUMO

Mice lacking the 66 kDa isoform of the adapter molecule shcA (p66(shcA)) display increased resistance to oxidative stress and delayed aging. In cultured cell lines, p66 promotes formation of Reactive Oxygen Species (ROS) in mitochondria, and apoptotic cell death in response to a variety of pro-oxidant noxious stimuli. As mitochondrial ROS and oxidative cell damage are clearly involved in alcohol-induced pathology, we hypothesized that p66 may also have a role in ethanol. In vivo, changes observed in p66+/+ mice after 6-week exposure to ethanol in the drinking water, including elevated serum alanine aminotransferase (ALT), liver swelling and evident liver steatosis, were significantly attenuated in p66-/- mutant mice. Biochemical analysis of liver tissues revealed induction of the p66 protein by ethanol, whereas p66-deficient livers responded to alcohol with a significant upregulation of the mitochondrial antioxidant enzyme MnSOD, nearly absent in control mice. Evidence of an inverse correlation between expression level of p66 and protection from alcohol-induced oxidative stress was also confirmed in vitro in primary hepatocytes and in HepG2-E47 cells, an ethanol-responsive hepatoma cell line. In fact, MnSOD upregulation by exposure to ethanol in vitro was much more pronounced in p66KO versus wild-type isolated liver cells, and blunted in HepG2 cells overexpressing p66shc. p66 overexpression also prevented the activation of a luciferase reporter gene controlled by the SOD2 promoter, indicating that p66 repression of MnSOD operates at a transcriptional level. Finally, p66 generated ROS in HepG2 cells and potentiated oxidative stress and mitochondrial depolarization by ethanol. Taken together, the above observations clearly indicate a role for p66 in alcohol-induced cell damage, likely via a cell-autonomous mechanism involving reduced expression of antioxidant defenses and mitochondrial dysfunction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Etanol/farmacologia , Fígado/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Alanina Transaminase/sangue , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias Hepáticas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Adaptadoras da Sinalização Shc , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Superóxido Dismutase/metabolismo
17.
J Neurosci Res ; 86(10): 2235-49, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18338802

RESUMO

Bilirubin is neurotoxic upon excess accumulation in the brain, but it also plays important physiological roles related to its antioxidant properties. Here we report that exposure of PC12 and primary rat cerebellar granule neurons to bilirubin (0.5-10 microM) drastically decreases nerve growth factor (NGF)/brain-derived neurotrophic factor signaling to Akt and extracellular signal-regulated kinases (ERKs), indicating a direct interference of the molecule with crucial prosurvival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, the latter being able to inhibit, in PC12 cells, accumulation of intracellular reactive oxygen species and phosphorylation of Akt and ERKs in response to extracellular hydrogen peroxide. Interestingly, in the absence of exogenous growth factor, bilirubin elicited the phosphorylation of ERKs and of the cAMP responsive element binding (CREB) transcription factor, a signature of NGF-dependent survival signaling. These growth factor-like signaling effects were paralleled by the induction of the neuronal nitric oxide synthase (nNOS) and generation of nitric oxide (NO). Pharmacological dissection of the signaling cascade triggered by bilirubin revealed that phosphorylation of ERKs requires NO signaling through soluble guanylyl cyclase, and, further upstream, influx of extracellular calcium is necessary for nNOS induction and NO release, likely through calcium-dependent phosphorylation of CREB. Importantly, the cascade elicited by bilirubin through NO and ERK is cytoprotective, as revealed by exacerbated bilirubin toxicity in cultures treated by either NOS or MEK inhibitors. Taken together, these observations indicate an important action of bilirubin on redox signaling by neurotrophins, with either inhibitory or agonistic effects based on growth factor availability.


Assuntos
Bilirrubina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Animais , Western Blotting , Encéfalo/metabolismo , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Oxirredução , Células PC12 , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
BMC Gastroenterol ; 7: 45, 2007 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-18078519

RESUMO

BACKGROUND: To compare tumor necrosis in hepatoma induced in rats by a single percutaneous injection of ethanol (PEI) or acetic acid (PAI). METHODS: BW7756 hepatomas of 1 mm3 were implanted in the liver of 40 male healthy rats. After 14 days, the 36 surviving rats were treated, in a single session, by ultrasound-guided injection of 300 microl of 95% ethanol (n = 17) or 100 microl of 50% acetic acid (n = 19). They were sacrificed 14 days after treatment and explanted tumoral livers were examined. The same PAI procedure was repeated on 13 additional rats to exclude a suspected occurrence of technical failures during the experiment, due to a surprisingly high rate of deaths within 30 minutes after PAI. RESULTS: Four rats died within four days after tumor implantation; after PEI, 1/17 (6%) died, whereas after PAI 9/19 (47%) died. The remaining 26 rats, after 14 days post-percutaneous ablation, were sacrificed. Gross and microscopic examinations showed that the hepatoma's nodules treated with PEI had 45.3 +/- 19.4% tumor necrosis compared to 49 +/- 23.3% (P = NS) for those treated with PAI. Complete tumor necrosis was not found in any animal. Peritoneal invasion was present in 4/16 (25%) and 2/10 (20%) rats treated with PEI or PAI, respectively (P = NS). Autopsy was performed in the 5 additional rats that died within 30 minutes after PAI. CONCLUSION: Our results show that there is no significant difference in the percentage of tumor necrosis between two local ablation methods in spite of the different dosages used. However, mortality in the PAI-treated group was greater than in PEI-treated group, presumably due to greater acetic acid systemic diffusion and its metabolic side effects. In human subjects, HCC occurs in the setting of cirrhosis, where the non-tumoral tissue is firmer than the tumor structure, with consequent reduction of drug diffusion. This could be the reason why some human studies have concluded similar or even better safety and efficacy with PAI compared to PEI.


Assuntos
Ácido Acético/administração & dosagem , Etanol/administração & dosagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Solventes/administração & dosagem , Administração Cutânea , Animais , Quimioterapia Assistida por Computador , Injeções , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/patologia , Masculino , Ratos , Ultrassonografia
20.
Toxicol Lett ; 158(1): 61-71, 2005 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-15993744

RESUMO

Pyrrolidine-dithiocarbamate (PDTC), a synthetic compound widely used in cell biological investigations, recently attracted considerable interest as a putative anticancer agent. However, different dithiocarbamates have previously shown to cause neurological symptoms and morphological alterations in peripheral nerves. The purpose of the present study was to determine whether a 15-day oral administration with low doses of PDTC may produce adverse effects in peripheral nerves of rats. Female Wistar rats were assigned to receive PDTC [0.1, 0.5 or 1.0mmol/(kg body weight/day)] by gavage for 15 days. Reduced conduction velocity was observed by electrophysiological analysis in tibial nerves of treated animals, accompanied by a marked decrease in Shwann cell S100-protein expression determined by immunohistochemistry. Electron microscopy evaluation revealed marked myelin degeneration in the fibers of treated animals. In particular, both morphological and electrophysiological data suggested an impairment of large, fast conducting fibers, whereas the smallest and slowest ones remained intact. However, the activity of plasma and liver alkaline-phosphatase, an enzymic marker of hepatic dithiocarbamate toxicity, was not altered by the treatment. The total contents of the redox-active metal copper increased in tibial nerves of treated rats and was accompanied by raised levels of lipid peroxidation products. This finding suggests a role for oxidative stress in the development of PDTC-induced pathological and functional alterations of tibial nerves. The observation that a 15-day treatment with low doses of PDTC causes functional and morphological derangement of peripheral nerves advices against the possible use of this compound as a chemopreventive agent against cancer.


Assuntos
Antioxidantes/toxicidade , Bainha de Mielina/efeitos dos fármacos , Pirrolidinas/toxicidade , Tiocarbamatos/toxicidade , Nervo Tibial/efeitos dos fármacos , Degeneração Walleriana/induzido quimicamente , Fosfatase Alcalina/metabolismo , Animais , Biomarcadores/metabolismo , Cobre/metabolismo , Relação Dose-Resposta a Droga , Feminino , Técnicas Imunoenzimáticas , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Bainha de Mielina/ultraestrutura , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Ratos , Ratos Wistar , Proteínas S100/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Nervo Tibial/patologia , Nervo Tibial/fisiopatologia , Degeneração Walleriana/patologia
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