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Fourth-generation 'pod' e-cigarette devices have been driven by technological advances in electronic atomization of the e-liquid. Use of microporous ceramic as a wicking material improves heating efficiency, but how it affects the chemical emissions of these devices is unclear. We assessed the emissions of a pod e-cigarette with innovative ceramic wick-based technology and two flavoured e-liquids containing nicotine lactate and nicotine benzoate (57 and 18 mg mL-1 nicotine, respectively). Among the studied harmful and potentially harmful constituents (HPHCs) listed by the US FDA and/or WHO TobReg, only 5 (acetone, acetaldehyde, formaldehyde, naphthalene and nornicotine) were quantified at levels of 0.14 to 100 ng puff-1. In the combustible cigarette (Kentucky reference 1R6F), levels were from 0.131 to 168 µg puff-1. Nicotine levels ranged 0.10-0.32 mg puff-1 across the 3 study products. From the 19 proposed HPHCs specifically of concern in e-cigarettes, only 3 (glycerol, isoamyl acetate and propylene glycol) were quantified. The low/undetectable levels of HPHCs reflect not only the optimal operating conditions of the e-cigarette, including an efficient supply of e-liquid by the ceramic wick without overheating, but also the potential of the e-cigarettes to be used as an alternative to combustible cigarettes.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Acetaldeído , Acetona , Aerossóis , Benzoatos , Cerâmica , Formaldeído , Gases , Glicerol , Lactatos , Naftalenos , Nicotina , Propilenoglicol , TecnologiaRESUMO
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the evidence of steatosis in the setting of a metabolic risk condition such as type 2 diabetes mellitus (T2DM). Indeed, T2DM and liver steatosis share common pathophysiological mechanisms, and one can lead to the other. MAFLD can progress from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis as well as hepatocellular carcinoma (HCC). Because of the lack / disparity of guidelines for MAFLD screening, which is asymptomatic in its early stages, it is not rare that diabetic patients are belatedly diagnosed with NASH cirrhosis or HCC. We therefore recommend systematic non-invasive tests (NITs) that calculate an estimate of the risk based on readily available anthropometric and biological parameters. These include the fatty liver index (FLI) for steatosis detection and at least one of the following for fibrosis: non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 index (FIB-4) or Hepamet fibrosis score (HFS). Indeed, NFS and FIB-4 are the best predictors of liver-related events, while FIB-4 and HFS correlate with overall mortality. Systematic literature review found only few retrospective or cross-sectional studies using NITs for systematic steatosis and fibrosis screening in T2DM patients, with a crucial need for prospective studies. This screening strategy will allow targeted patients to be referred for further liver investigation (e.g. ultrasound, elastometry) and care. Current treatment modalities of MAFLD in T2DM patients range from lifestyle and dietary interventions to specific glucose-lowering drugs that recently showed some benefits regarding MAFLD, such as pioglitazone, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors. Other treatments are currently under investigation.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Inibidores do Transportador 2 de Sódio-Glicose , Carcinoma Hepatocelular/tratamento farmacológico , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/uso terapêutico , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Neoplasias Hepáticas/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Estudos Prospectivos , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
The knowledge of physicians regarding nutrition is often far below the expectations of patients, and does not comply with official recommendations. However, poor-quality nutrition and diet represent the first cause of mortality worldwide. As a result of an insufficient training and awareness, many physicians cannot meet patients' expectations. Moreover, nutrition is sometimes felt as a field of low scientific level, thereby opening the area to pseudo-scientific drifts. We advocate an improvement in the training in nutrition during the medical cursus, namely by the transversal integration of nutritional insights into medical courses, and the recognition of post-university training validated by the academic authorities. A clarification of the roles and the recognition of the competency are urgently required to promote the professionalism of nutritional counselling.
Les connaissances des médecins en matière d'alimentation et de nutrition sont souvent en-deçà des attentes des patients et en décalage par rapport aux recommandations officielles. Pourtant, la mauvaise alimentation constitue la première cause de mortalité à l'échelle planétaire. Les attentes des patients sont importantes en matière de nutrition et le médecin y est mal préparé en raison d'une formation insuffisante. De plus, la nutrition est parfois perçue comme une matière peu scientifique, et la reconnaissance des compétences en nutrition est insuffisante, ouvrant le champ à des dérives pseudo-scientifiques. Nous plaidons pour une meilleure formation en nutrition dans le cursus des études médicales, notamment en intégrant les aspects nutritionnels de manière transversale au cours de la formation des futurs médecins, et pour la reconnaissance des cursus de formation post-universitaires validés par les autorités académiques. Une clarification des rôles et une reconnaissance des compétences sont urgentes afin de professionnaliser les conseils nutritionnels.
Assuntos
Desnutrição , Ciências da Nutrição , Atenção à Saúde , HumanosRESUMO
BACKGROUND: An important part of neurosurgical training is the improvement of surgical skills. Acquiring microsurgical skills follows a learning curve, influenced by specific exercises, feedback, and training. Aim of training should be rapid learning success. The study shows the way in which video-based training can influence the learning curve. METHODS: Over a period of 18 months (2011-2012) 12 residents were evaluated in spinal surgery (12 cases per resident) by a skilled evaluator based on different criteria. The evaluation criteria (exposition of important anatomy, intraoperative bleeding, efficacy of using bipolar cauterization) were weighted and added to a single quality-score. The participating residents were divided into two groups. Only one group (n = 5) received video-based training. RESULTS: Residents showed an individually different but explicit increase in microsurgical skills. The quality-score during the first surgery compared with the end point of the study demonstrated a faster improvement of surgical skills in the group with video-based training than in the group without special training. Considering all residents together, the video-training group displayed a steeper gradient of microsurgical success. Comparison of the single resident's microsurgical skills showed individual disparities. Various biases that influence the learning success are under examination. CONCLUSION: Video-based training can improve microsurgical skills, leading to an improved learning curve. An earlier entry of the learning curve plateau in the video-training group promotes a higher acquisition of surgical skills. Because of the positive effect, we plan to apply the video-based training model to other neurosurgical subspecialties, especially neurovascular and skull base surgery.
RESUMO
A 24-year-old woman with a short bowel syndrome following post-ischemic small bowel resection, developed several episodes of lethargy, echolalia and ataxia. D-lactic acidosis was identified as the cause of neurological disturbances. This infrequent disorder can be precipitated by intake of a large amount of sugars, in patients with short bowel syndrome. It should be suspected in the presence of metabolic acidosis with increased anion gap and a normal level of L-lactic acid. The diagnosis relies on the specific dosage of D-lactic stereoisomer. Proper management involves rehydration, diet adaptation and oral administration of poorly absorbed antibiotics in order to modify the colonic flora responsible for D-lactic production.
Assuntos
Acidose Láctica/etiologia , Encefalopatias/etiologia , Síndrome do Intestino Curto/complicações , Carboidratos da Dieta/administração & dosagem , Feminino , Humanos , Adulto JovemRESUMO
Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
Assuntos
Glucocorticoides/efeitos adversos , Glucocorticoides/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Animais , Glucocorticoides/toxicidade , Humanos , Atrofia Muscular/patologia , Biossíntese de Proteínas , Transdução de SinaisRESUMO
Based on a data set on Campylobacter and Salmonella prevalence in the broiler supply chain, collected during the period 2002 through 2005 in the Netherlands, farm- and slaughterhouse-specific characteristics were tested for their effect on Campylobacter and Salmonella prevalence at different stages of the broiler supply chain. Three different sampling points were considered: departure from the farm, arrival at the slaughterhouse, and the end of the slaughterline. Strong associations were found between Salmonella and Campylobacter prevalence at a particular sampling point and their prevalence at the preceding point of the chain. Statistical analyses showed that the country of origin of the broiler farm had a significant effect on the prevalence of Salmonella and Campylobacter at slaughterhouse arrival. The feeding company delivering to the farm also showed a significant effect on the occurrence of both pathogens at departure from the broiler farm. The prevalence of Campylobacter decreased with an increasing number of birds per flock, whereas the prevalence of Salmonella increased with an increasing number of birds per flock. The number of flocks processed within a specific slaughterhouse was not associated with an increased or decreased prevalence of Campylobacter and Salmonella. The results provide more insight into factors related to the occurrence of both pathogens and in understanding their epidemiology. The results can be supportive in decision making on measures to reduce the contamination of broiler products with Salmonella and Campylobacter.
Assuntos
Matadouros/normas , Criação de Animais Domésticos/métodos , Criação de Animais Domésticos/normas , Campylobacter/isolamento & purificação , Carne/microbiologia , Salmonella/isolamento & purificação , Animais , Galinhas/microbiologia , Microbiologia de AlimentosRESUMO
Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.
Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Animais , Autofagia/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Glucocorticoides/antagonistas & inibidores , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/antagonistas & inibidores , Proteínas Musculares/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Atrofia Muscular/sangue , Atrofia Muscular/imunologia , Atrofia Muscular/prevenção & controle , NF-kappa B/antagonistas & inibidores , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Regulação para Cima/efeitos dos fármacosRESUMO
A meta-analysis was conducted to determine the effect of microbial phytase in pig diets on digestibility and bioavailability of Cu and Zn. Studies (n = 22) into effects of microbial phytase on digestibility and plasma levels of Cu and Zn were included in a dataset and regression analysis was performed to quantify the effect of Aspergillus niger derived 3-phytase in studies (n = 14) with a maximum dietary Zn content of 100 mg/kg and a maximum Cu addition of 20 mg/kg. Phytase inclusion increased digestibility of Zn (P = 0.003) and plasma Zn content (P < 0.001) without affecting digestibility and plasma level of Cu. Based on a comparison with dose-response studies with Zn, we estimated 500 phytase units (FTU) of microbial phytase is equivalent to 27 mg of Zn from ZnSO(4).
Assuntos
6-Fitase/farmacologia , Cobre/farmacocinética , Suínos/fisiologia , Zinco/farmacocinética , 6-Fitase/metabolismo , Animais , Disponibilidade Biológica , Cobre/sangue , Suínos/crescimento & desenvolvimento , Zinco/sangueRESUMO
Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.
Assuntos
Folistatina/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Receptor IGF Tipo 1/metabolismo , Animais , Sequência de Bases , Primers do DNA/genética , Folistatina/genética , Humanos , Hipertrofia , Fator de Crescimento Insulin-Like II/deficiência , Fator de Crescimento Insulin-Like II/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , TransfecçãoRESUMO
Urotensin II (UII) a potent vasoactive peptide is upregulated in the failing heart and promotes cardiomyocytes hypertrophy, in particular through mitogen-activated protein kinases. However, the regulation by UII of GSK-3beta, a recognized pivotal signaling element of cardiac hypertrophy has not yet been documented. We therefore investigated in adult cardiomyocytes, if UII phosphorylates GSK-3beta and Akt, one of its upstream regulators and stabilizes beta-catenin, a GSK-3beta dependent nuclear transcriptional co-activator. Primary cultures of adult rat cardiomyocytes were stimulated for 48h with UII. Cell size and protein/DNA contents were determined. Phosphorylated and total forms of Akt, GSK-3beta and the total amount of beta-catenin were quantified by western blot. The responses of cardiomyocytes to UII were also evaluated after pretreatment with the chemical phosphatidyl-inositol-3-kinase inhibitor, LY294002, and urantide, a competitive UII receptor antagonist. UII increased cell size and the protein/DNA ratio, consistent with a hypertrophic response. UII also increased phosphorylation of Akt and its downstream target GSK-3beta. beta-Catenin protein levels were increased. All of these effects of UII were prevented by LY294002, and urantide. The UII-induced adult cardiomyocytes hypertrophy involves the Akt/GSK-3beta signaling pathways and is accompanied by the stabilization of the beta-catenin. All these effects are abolished by competitive inhibition of the UII receptor, consistent with new therapeutic perspectives for heart failure treatment.
Assuntos
Quinase 3 da Glicogênio Sintase/metabolismo , Miócitos Cardíacos/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Urotensinas/farmacologia , Animais , Tamanho Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , beta Catenina/metabolismoRESUMO
Inhibiting myostatin (mstn) causes spectacular increase in muscle mass, spurring research for therapeutic approaches against neuromuscular disorders. Yet, possible functional deterioration and compromised force production have been reported in isolated muscle of null mstn(-/-) mice. We analyzed vascular and metabolic response to repeated electro-stimulated exercise in vivo in mstn(-/-) mice compared with FVB wild-type controls (WT), using interleaved multi-parametric functional nuclear magnetic resonance (NMR) imaging and spectroscopy. At steady-state exercise, specific force of plantar flexion, phosphocreatine consumption measured by phosphorus spectroscopy and maximum perfusion measured by arterial spin-labeled (ASL) NMR imaging were identical in both groups. After exercise, phosphorus spectroscopy revealed reduced oxidative mitochondrial capacity in mstn(-/-), whereas early recovery perfusion was identical and oxygen extraction, estimated from the blood oxygen level-dependent (BOLD) contrast, was decreased when compared with WT. Hyperemia was prolonged, indicating specific regulation of the perfusional response in mstn(-/-) mice. Histology showed an increased proportion of type IIb fibers in hypertrophied muscles, but the distribution of capillary contacts per fiber between oxidative and glycolytic fibers was unaltered in mstn(-/-) compared with WT. These integrated results formed coherent evidence of a congruous, non-pathologic shift toward a more glycolytic metabolism in this model of mstn(-/-).
Assuntos
Músculo Esquelético/fisiologia , Miostatina/deficiência , Animais , Teste de Esforço , Glicólise/genética , Hiperemia/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Miostatina/genética , Fosfocreatina/metabolismoRESUMO
To improve the efficacy of the in-house validation of GMO detection methods (DNA isolation and real-time PCR, polymerase chain reaction), a study was performed to gain insight in the contribution of the different steps of the GMO detection method to the repeatability and in-house reproducibility. In the present study, 19 methods for (GM) soy, maize canola and potato were validated in-house of which 14 on the basis of an 8-day validation scheme using eight different samples and five on the basis of a more concise validation protocol. In this way, data was obtained with respect to the detection limit, accuracy and precision. Also, decision limits were calculated for declaring non-conformance (>0.9%) with 95% reliability. In order to estimate the contribution of the different steps in the GMO analysis to the total variation variance components were estimated using REML (residual maximum likelihood method). From these components, relative standard deviations for repeatability and reproducibility (RSD(r) and RSD(R)) were calculated. The results showed that not only the PCR reaction but also the factors 'DNA isolation' and 'PCR day' are important factors for the total variance and should therefore be included in the in-house validation. It is proposed to use a statistical model to estimate these factors from a large dataset of initial validations so that for similar GMO methods in the future, only the PCR step needs to be validated. The resulting data are discussed in the light of agreed European criteria for qualified GMO detection methods.
Assuntos
Produtos Agrícolas/genética , Plantas Geneticamente Modificadas/genética , Reação em Cadeia da Polimerase/métodosRESUMO
Salmonella serotype distribution can give insight in contamination routes and persistence along a production chain. Therefore, it is important to determine not only Salmonella prevalence but also to specify the serotypes involved at the different stages of the supply chain. For this purpose, data from a national monitoring program in the Netherlands were used to estimate the serotype distribution and to determine whether this distribution differs for the available sampling points in the broiler supply chain. Data covered the period from 2002 to 2005, all slaughterhouses (n = 22), and the following 6 sampling points: departure from hatchery, arrival at the farm, departure from the farm, arrival at the slaughterhouse, departure from the slaughterhouse, and end of processing. Furthermore, retail data for 2005 were used for comparison with slaughterhouse data. The following serotypes were followed throughout the chain: Salmonella Enteritidis, Salmonella Typhimurium, Salmonella Paratyphi B var. Java (Salmonella Java), Salmonella Infantis, Salmonella Virchow, and Salmonella Mbandaka. Results showed that serotype distribution varied significantly throughout the supply chain (P < 0.05). Main differences were found at the farm and at the slaughterhouse (within one stage), and least differences were found between departure from one stage and arrival at the next stage. The most prominent result was the increase of Salmonella Java at farm level. This serotype remained the most prominent pathogen throughout the broiler supply chain up to the retail phase.
Assuntos
Galinhas , Salmonelose Animal/microbiologia , Salmonella/classificação , Matadouros , Animais , Países Baixos/epidemiologia , Salmonelose Animal/epidemiologia , SorotipagemRESUMO
BACKGROUND: Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoid (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy results from decreased protein synthesis and increased protein degradation. The inhibitory effect of GCs on protein synthesis is thought to result mainly from the inhibition of the p70 ribosomal S6 protein kinase. The stimulatory effect of GCs on muscle proteolysis results from the activation of two major cellular proteolytic systems: ubiquitin proteasome and lysosomal systems. The decrease in muscle production of insulin-like growth factor I (IGF-I), a muscle anabolic growth factor, could contribute to GC-induced muscle atrophy. By activating the phosphatidylinositol-3-kinase/Akt pathway, IGF-I overrides GC action to stunt muscle atrophy. Evidence also indicates that increased production of myostatin, a catabolic growth factor, could play a critical role in GC-induced muscle atrophy. CONCLUSIONS: Recent progress in understanding the role of growth factors in GC-induced muscle atrophy allows investigation into new therapies to minimize this myopathy.
Assuntos
Glucocorticoides/efeitos adversos , Proteínas Musculares/metabolismo , Atrofia Muscular/induzido quimicamente , Animais , Fatores de Transcrição Forkhead/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Glicogênio Sintase Quinase 3 beta , Humanos , Fator de Crescimento Insulin-Like I/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Atrofia Muscular/patologia , Miostatina/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR , Ubiquitina-Proteína Ligases/metabolismo , beta Catenina/fisiologiaRESUMO
Decrease of muscle IGF-I plays a critical role in muscle atrophy caused by glucocorticoids (GCs) because IGF-I gene electrotransfer prevents muscle atrophy caused by GCs. The goal of the present study was to identify the intracellular mediators responsible for the IGF-I anti-atrophic action in GC-induced muscle atrophy. We first assessed the IGF-I transduction pathway alterations caused by GC administration and their reversibility by local IGF-I overexpression performed by electrotransfer. Muscle atrophy induced by dexamethasone (dexa) administration occurred with a decrease in Akt (-53%; P<0.01) phosphorylation together with a decrease in beta-catenin protein levels (-40%; P<0.001). Prevention of atrophy by IGF-I was associated with restoration of Akt phosphorylation and beta-catenin levels. We then investigated whether muscle overexpression of these intracellular mediators could mimic the IGF-I anti-atrophic effects. Overexpression of a constitutively active form of Akt induced a marked fiber hypertrophy in dexa-treated animals (+175% of cross-sectional area; P<0.001) and prevented dexa-induced atrophy. This hypertrophy was associated with an increase in phosphorylated GSK-3beta (+17%; P<0.05) and in beta-catenin content (+35%; P<0.05). Furthermore, overexpression of a dominant-negative GSK-3beta or a stable form of beta-catenin increased fiber cross-sectional area by, respectively, 23% (P<0.001) and 29% (P<0.001) in dexa-treated rats, preventing completely the atrophic effect of GC. In conclusion, this work indicates that Akt, GSK-3beta, and beta-catenin probably contribute together to the IGF-I anti-atrophic effect in GC-induced muscle atrophy.
Assuntos
Citoproteção/genética , Glucocorticoides/efeitos adversos , Quinase 3 da Glicogênio Sintase/fisiologia , Fator de Crescimento Insulin-Like I/genética , Atrofia Muscular/induzido quimicamente , Proteínas Proto-Oncogênicas c-akt/fisiologia , beta Catenina/fisiologia , Animais , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Masculino , Atrofia Muscular/genética , Especificidade de Órgãos/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Transdução de Sinais/fisiologia , Transfecção , beta Catenina/genéticaRESUMO
Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. Muscle proteolysis, in particular through the ubiquitin- proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes ('genes involved in atrophy'), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoid-induced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.
Assuntos
Glucocorticoides/toxicidade , Atrofia Muscular/induzido quimicamente , Fator 4 Ativador da Transcrição/fisiologia , Animais , Proteína beta Intensificadora de Ligação a CCAAT/fisiologia , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Glicogênio Sintase Quinase 3 beta , Humanos , Fator de Crescimento Insulin-Like I/fisiologia , Atrofia Muscular/prevenção & controle , Miostatina/fisiologia , Proteínas Quinases/fisiologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TORRESUMO
Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg.d for 10 d or 5 mg/kg.d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: -15%; gastrocnemius: -13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 +/- 31 vs. 1918 +/- 64 microm(2), P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (-35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.
Assuntos
Dexametasona/farmacologia , Deleção de Genes , Glucocorticoides/farmacologia , Atrofia Muscular/fisiopatologia , Fator de Crescimento Transformador beta/genética , Animais , Peso Corporal , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Fibras Musculares Esqueléticas/enzimologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Miofibrilas/enzimologia , Miofibrilas/patologia , Miostatina , Tamanho do Órgão , Peptídeo Hidrolases/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismoRESUMO
BACKGROUND: Neuronal and synaptic function in Alzheimer's disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). OBJECTIVE: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. METHOD: Glucose metabolism was measured using [18F]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score > or = 17). PET data were corrected for brain atrophy. RESULTS: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. CONCLUSION: PET activity measured during audiovisual stimulation was more sensitive to functional alterations in glucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Córtex Cerebral/metabolismo , Cognição/fisiologia , Glucose/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Atrofia/diagnóstico por imagem , Encéfalo/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
Catabolic states caused by injury are characterized by a loss of skeletal muscle. The anabolic action of IGF-I on muscle and the reduction of its muscle content in response to injury suggest that restoration of muscle IGF-I content might prevent skeletal muscle loss caused by injury. We investigated whether local overexpression of IGF-I protein by gene transfer could prevent skeletal muscle atrophy induced by glucocorticoids, a crucial mediator of muscle atrophy in catabolic states. Localized overexpression of IGF-I in tibialis anterior (TA) muscle was performed by injection of IGF-I cDNA followed by electroporation 3 d before starting dexamethasone injections (0.1 mg/kg.d sc). A control plasmid was electroporated in the contralateral TA muscle. Dexamethasone induced atrophy of the TA muscle as illustrated by reduction in muscle mass (403 +/- 11 vs. 461 +/- 19 mg, P < 0.05) and fiber cross-sectional area (1759 +/- 131 vs. 2517 +/- 93 mum(2), P < 0.05). This muscle atrophy was paralleled by a decrease in the IGF-I muscle content (7.2 +/- 0.9 vs. 15.7 +/- 1.4 ng/g of muscle, P < 0.001). As the result of IGF-I gene transfer, the IGF-I muscle content increased 2-fold (15.8 +/- 1.2 vs. 7.2 +/- 0.9 ng/g of muscle, P < 0.001). In addition, the muscle mass (437 +/- 8 vs. 403 +/- 11 mg, P < 0.01) and the fiber cross-sectional area (2269 +/- 129 vs. 1759 +/- 131 mum(2), P < 0.05) were increased in the TA muscle electroporated with IGF-I DNA, compared with the contralateral muscle electroporated with a control plasmid. Our results show therefore that IGF-I gene transfer by electroporation prevents muscle atrophy in glucocorticoid-treated rats. Our observation supports the important role of decreased muscle IGF-I in the muscle atrophy caused by glucocorticoids.