Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia.

OBJECTIVE: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. METHODS: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. RESULTS: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic ß-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and ß-cell staining for insulin and glucagon. CONCLUSIONS: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted.

Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia / Expressão do mRNA da uncoupling protein-2 em camundongos submetidos à hipóxia intermitente

Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic β-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. .

Objetivo: Investigar o efeito da hipóxia intermitente com um modelo de apneia obstrutiva do sono (AOS) sobre a expressão de uncoupling protein-2 (UCP2), assim como sobre perfis glicêmicos e lipídicos, em camundongos C57BL. Métodos: Camundongos C57BL machos foram expostos a hipóxia intermitente ou hipóxia simulada (grupo controle) 8 h/dia durante 35 dias. A condição de hipóxia intermitente envolveu a exposição dos camundongos a uma atmosfera de 92% de N e 8% de CO2 por 30 s, com redução progressiva de fração de O2 inspirado até 8 ± 1%, seguida por exposição a ar ambiente por 30 s e repetições do ciclo (480 ciclos no período experimental de 8 h). Os pâncreas foram dissecados para isolar as ilhotas. Foi realizada PCR em tempo real utilizando o método TaqMan. Resultados: A expressão do mRNA da UCP2 nas ilhotas pancreáticas foi 20% maior no grupo controle que no grupo hipóxia (p = 0,11). A insulina sérica de jejum foi maior no grupo hipóxia do que no grupo controle (p = 0,01). O modelo de avaliação da homeostase de resistência à insulina indicou que, em comparação com os camundongos controle, aqueles expostos à hipóxia intermitente apresentaram 15% menor resistência à insulina (p = 0,09) e 21% maior função das células beta (p = 0,01). A coloração das ilhotas pancreáticas por imuno-histoquímica não mostrou diferenças significativas entre os grupos em termos da área ou da intensidade das células alfa e beta, marcadas por insulina e glucagon. Conclusões: Segundo nosso conhecimento, esta é a primeira descrição do efeito da hipóxia intermitente sobre a expressão da UCP2. Nossos achados sugerem que UCP2 regula a produção de insulina na AOS. Futuras investigações sobre o papel da UCP2 no controle glicêmico em pacientes com AOS são justificadas. .

Neurobehavioral effects of L-carnitine and its ability to modulate genotoxicity and oxidative stress biomarkers in mice.

L-Carnitine, a natural vitamin-like compound supplied to the body by biosynthesis and dietary sources, has been shown to exert beneficial effects in disorders affecting cardiovascular, urinary, and nervous systems. However, the paucity of data on its effects does not guarantee the safe use of L-carnitine as a nutritional supplement, and further pre-clinical studies are required to assess toxicological aspects. The present study evaluated the effects of L-carnitine (10, 50 or, 100 mg/kg) in mice, in the open field test. Also, lipoperoxidation was assessed measuring thiobarbituric acid reactive substances (TBARS) and genotoxic/antigenotoxic activities were evaluated using the comet assay in several tissues. L-Carnitine 50 mg/kg impaired exploration, though with no effects on habituation to a novel environment. L-Carnitine increased TBARS in the brain and liver tissues, but it did not induce genotoxicity in any tissue. In ex vivo comet assay, a decrease in DNA damage in the blood and liver tissues was observed, while the opposite occurred in the brain tissue. In conclusion, L-carnitine may increase lipid peroxidation, though without inducing genotoxic effects, protect DNA against endogenous and induced oxidative damages in blood and liver; however, L-carnitine impaired exploratory behavior and increased the vulnerability of the brain tissue to oxidative stress, suggesting that the excessive consumption of L-carnitine may promote deleterious effects on the central nervous system.

Immediate and overnight recumbence-dependent changes of neck circumference: relationship with OSA severity in obese and nonobese subjects.

BACKGROUND: Overnight increases in neck circumference - attributed to rostral fluid displacement - correlate with the severity of obstructive sleep apnea (OSA). No studies were found investigating the relationship between OSA severity and recumbence-related immediate changes in neck circumference. We evaluated the relationship of OSA severity with immediate recumbence-related and overnight changes in neck circumference in obese and nonobese subjects. METHODS: Male patients undergoing full-night in-laboratory polysomnography had their neck and ankle circumferences determined before and after sleep, both while standing and supine. Circumference changes were calculated by the difference between standing and recumbent positions (Immediate Change) and between before and after sleep (Overnight Change). RESULTS: Immediate Change in neck circumference showed a linear significant correlation with apnea-hypopnea index (AHI; r=0.37373; p=0.012) and with lowest O2 saturation (r=-0.35355; p=0.017). In a multivariate model to predict AHI, adjusting for age and obesity, Immediate Change in neck circumference is the only significant regressor (beta=0.34; p=0.03). The Overnight Change in neck circumference correlated neither with the AHI nor with the lowest SaO2. CONCLUSION: Correlation of AHI with the immediate increase in neck circumference on assuming recumbence indicates that fast components of tissue displacement, besides overnight fluid displacement, may have implications in the pathogenesis of OSA.

Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice.

AIM: Aripiprazole is an antipsychotic agent to treat schizophrenia, which acts through dopamine D(2) partial agonism, serotonin 5-HT(1A) partial agonism and 5-HT(2A) antagonism. This study was designed to evaluate the neurobehavioral effects and genotoxic/mutagenic activities of the agent, as well as its effects on lipoperoxidation. METHODS: Open field and inhibitory avoidance tasks were used. Thirty min before performing the behavioral tasks, adult male CF-1 mice were administered aripiprazole (1, 3 or 10 mg/kg, ip) once for the acute treatment, or the same doses for 5 d for the subchronic treatment. Genotoxic effects were assessed using comet assay in the blood and brain tissues. Mutagenic effects were evaluated using bone marrow micronucleus test. Lipoperoxidation was assessed with thiobarbituric acid reactive substances (TBARS). RESULTS: Acute and subchronic treatments significantly decreased the number of crossing and rearing in the open field task. Acute treatment significantly increased the step-down latency for both the short- and long-term memory in the inhibitory avoidance task. Subchronic treatments with aripiprazole (3 and 10 mg/kg) caused significant DNA strain-break damage in peripheral blood but not in the brain. Mutagenic effect was not detected in the acute and subchronic treatments. Nor TBARS levels in the liver were affected. CONCLUSION: Aripiprazole improved memory, but could impair motor activities in mice. The drug increased DNA damage in blood, but did not show mutagenic effects, suggesting that it might affect long-term genomic stability.