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Exercise is a potential treatment to improve sleep quality in middle-aged and elderly individuals. Understanding exercise-induced changes in functional plasticity of brain circuits that underlie improvements in sleep among middle-aged and older adults can inform treatment of sleep problems. The aim of the study is to identify the effects of a 12-week exercise program on sleep quality and brain functional connectivity in middle-aged and older adults with insomnia. The trial was registered with Chinese Clinical Trial Register (ChiCTR2000033652). We recruited 84 healthy sleepers and 85 individuals with insomnia. Participants with insomnia were assigned to receive either a 12-week exercise intervention or were placed in a 12-week waitlist control condition. Thirty-seven middle-aged and older adults in the exercise group and 30 in the waitlist group completed both baseline and week 12 assessments. We found that middle-aged and older adults with insomnia showed significantly worse sleep quality than healthy sleepers. At the brain circuit level, insomnia patients showed decreased connectivity in the widespread motor network. After exercise intervention, self-reported sleep was increased in the exercise group (P < 0.001) compared to that in the waitlist group. We also found increased functional connectivity of the motor network with the cerebellum in the exercise group (P < 0.001). Moreover, we observed significant correlations between improvement in subjective sleep indices and connectivity changes within the motor network. We highlight exercise-induced improvement in sleep quality and functional plasticity of the aging brain.
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Trastornos del Inicio y del Mantenimiento del Sueño , Anciano , Humanos , Persona de Mediana Edad , Encéfalo/diagnóstico por imagen , Ejercicio Físico , Terapia por Ejercicio , Sueño , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Resultado del TratamientoRESUMEN
Dielectrophoresis technology is applied to microfluidic chips to achieve microscopic control of cells. Currently, microfluidic chips based on dielectrophoresis have certain limitations in terms of cell sorting species, in order to explore a microfluidic chip with excellent performance and high versatility. In this paper, we designed a microfluidic chip that can be used for continuous cell sorting, with the structural design of a curved channel and curved double side electrodes. CM factors were calculated for eight human healthy blood cells and cancerous cells using the software MyDEP, the simulation of various blood cells sorting and the simulation of the joule heat effect of the microfluidic chip were completed using the software COMSOL Multiphysics. The effect of voltage and inlet flow velocity on the simulation results was discussed using the control variables method. We found feasible parameters from simulation results under different voltages and inlet flow velocities, and the feasibility of the design was verified from multiple perspectives by measuring cell movement trajectories, cell recovery rate and separation purity. This paper provides a universal method for cell, particle and even protein sorting.
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Periodically tunable nano-gratings have an irreplaceable role in spectral scanning and optical communication, but the performance of gratings manufactured from different materials varies considerably, and the development of superior materials has energized the preparation of high-precision devices. This paper presents a nanoscale preparation process based on Norland Optical Adhesive 73 (NOA73), which enables the rapid preparation of periodically tunable nano-gratings with up to 100% light transmission. The powerful fluidity and shear rate of NOA73 make it uniquely suited to the preparation of precision devices, allowing the production of up to dense grating structures and offering the possibility of making nanoscale gratings. This paper uses multi-angle hierarchical lithography, die stretching, and replication to achieve further improvements in accuracy and successfully prepare gratings with a period of 500 nm. The successful preparation of NOA73 nano-gratings demonstrates the practicality of NOA73 as a material for precision device fabrication.
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INTRODUCTION: Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D. METHODS: Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines. RESULTS: Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism. CONCLUSION: These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.
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In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.
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Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Extractos Vegetales/administración & dosificación , ARN Mensajero/genética , Estrés Psicológico/metabolismo , Animales , Cinnamomum zeylanicum/química , Corticosterona/genética , Corticosterona/metabolismo , Dieta Occidental/efectos adversos , Suplementos Dietéticos , Fructosa/administración & dosificación , Insulina/fisiología , Resistencia a la Insulina , Masculino , ARN Mensajero/metabolismo , Ratas Wistar , Transducción de Señal , TranscriptomaRESUMEN
IL-25 or IL-17E is a member of IL-17 cytokine family and has immune-modulating activities. The role of IL-25 in maintaining lipid metabolic homeostasis remains unknown. We investigated the effects of exogenous IL-25 or deficiency of IL-25 on hepatic lipid accumulation. IL-25 expression was examined in paraffin-embedded tissue sections of liver from patients or in the livers from mice. Mouse model of steatosis was induced by feeding a high-fat diet (HFD). Extent of steatosis as well as expression of cytokines, key enzymes for lipid metabolic pathways, markers for Kupffer cells/macrophages, and lipid droplet (LD) proteins, were analyzed. Our results show that hepatic steatosis in mice was accompanied by increased LD proteins, but decreased IL-25 in the liver. Decreased hepatic IL-25 was also observed in patients with fatty liver. Administration of IL-25 to HFD-fed wild-type mice led to a significant improvement in hepatic steatosis. This effect was associated with increased expression of IL-13, development of alternatively activated Kupffer cells/macrophages, and decreased expression of LD proteins in the liver. In contrast, administration of IL-25 to HFD-fed mice deficient in STAT6 or IL-13 had no effects. In addition, stimulation of primary hepatocytes with IL-13, but not IL-25, resulted in downregulation of LD proteins. Finally, mice deficient in IL-25 had exacerbated hepatic lipid accumulation when fed the HFD. These data demonstrate that dysregulated IL-25 expression contributes to lipid accumulation, whereas exogenous IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 and IL-13 are potential therapeutic agents for hepatic steatosis and associated pathologies.
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Grasas de la Dieta/efectos adversos , Hígado Graso/inmunología , Interleucina-13/inmunología , Interleucinas/inmunología , Gotas Lipídicas/inmunología , Factor de Transcripción STAT6/inmunología , Animales , Células Cultivadas , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Hígado Graso/inducido químicamente , Hígado Graso/genética , Hígado Graso/patología , Hígado Graso/prevención & control , Hepatocitos/inmunología , Hepatocitos/patología , Interleucina-13/genética , Interleucinas/genética , Interleucinas/farmacología , Gotas Lipídicas/patología , Ratones , Ratones Noqueados , Factor de Transcripción STAT6/genéticaRESUMEN
Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood-brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-α or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca(2+)]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca(2+)]i.
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Isquemia Encefálica/tratamiento farmacológico , Células Endoteliales/efectos de los fármacos , Extractos Vegetales/farmacología , Proantocianidinas/farmacología , Estilbenos/farmacología , Animales , Antioxidantes/farmacología , Calcio/metabolismo , Línea Celular , Quimiocina CCL2/metabolismo , Ciclosporina/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Células Endoteliales/patología , Glucosa/deficiencia , Hipoxia , Interleucina-6/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Estrés Oxidativo/efectos de los fármacos , Polifenoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Resveratrol , Té/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIMS: It is well established that the brain is particularly susceptible to oxidative damage due to its high consumption of oxygen. The objective of this study was to investigate the protective effects of a water soluble polyphenol-rich extract of cinnamon and the possible mechanisms, under conditions of oxidative stress-induced by hydrogen peroxide, in rat C6 glioma cells. MAIN METHODS: After 24h of H2O2 incubation, the secretion and intracellular expression of S100ß were determined by immunoprecitation/immunoblotting and immunofluorescence imaging. KEY FINDINGS: Cinnamon polyphenols (CP) counteracted the oxidative effects of H2O2 on S100ß secretion and expression. CP also enhanced the impaired protein levels of sirtuins 1, 2, and 3, which are deacetylases important in cell survival. H2O2 also induced the overexpression of the proinflammatory factors, TNF-α, phospho-NF-κB p65, as well as of Bcl-xl, Bax and Caspase-3, which are all the members of the Bcl-2 family. CP not only suppressed the expression of these proteins but also attenuated the phosphorylation induced by H2O2. CP also upregulated the decreased Bcl-2 protein levels in H2O2 treated C6 cells. The effects of CP on H2O2-induced downregulation of S100ß secretion were blocked by SIRT1 siRNA demonstrating that SIRT1 plays a regulatory role in CP-mediated prevention by H2O2. SIGNIFICANCE: These data demonstrate that Cinnamon polyphenols may exert neuroprotective effects in glial cells by the regulation of Bcl-2 family members and enhancing SIRT1 expression during oxidative stress.
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Cinnamomum zeylanicum/química , Estrés Oxidativo/efectos de los fármacos , Polifenoles/farmacología , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Sirtuina 1/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/efectos de los fármacos , Glioma/metabolismo , Peróxido de Hidrógeno/toxicidad , Inmunoprecipitación , Polifenoles/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismoRESUMEN
OBJECTIVE: Increasing evidence suggests that cinnamon has many health benefits when used in herbal medicine and as a dietary ingredient. The aim of this study was to investigate the effects of an aqueous extract of cinnamon, high in type A polyphenols, on molecular targets in rat C6 glioma cells that underlie their protective effects. METHODS: C6 rat glioma cells were seeded in 35-mm culture dishes or six-well plates, then were incubated with cinnamon polyphenols at doses of 10 and 20 µg/mL for 24 h. The targeting protein expression, secretion, and phosphorylation were evaluated by immunoprecitation/immunoblotting and immunofluorescence imaging. RESULTS: Cinnamon polyphenols significantly enhanced secretion of S100ß, a Ca(2+)-binding protein, and increased intracellular S100ß expression after 24 h of incubation, in rat C6 glioma cells. Cinnamon polyphenols also enhanced protein levels of sirtuin 1, 2, and 3, deacetylases important in cell survival, and the tumor suppressor protein, p53, and inhibited the inflammatory factors, tumor necrosis factor alpha, and phospho-p65, a subunit of nuclear factor-κß. Cinnamon polyphenols also up-regulated levels of phospho-p38, extracellular signal-regulated protein and mitogen-activated protein and kinase-activated protein kinases that may be important for prosurvival functions. CONCLUSION: Our results indicate that the effects of cinnamon polyphenols on upregulating prosurvival proteins, activating mitogen-activated protein kinase pathways, and decreasing proinflammatory cytokines may contribute to their neuroprotective effects.
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Cinnamomum zeylanicum/química , Polifenoles/farmacología , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Sirtuina 1/metabolismo , Sirtuina 2/metabolismo , Animales , Línea Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , Glioma/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación , Ratas , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Sirtuina 1/genética , Sirtuina 2/genética , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain.
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Enfermedad de Alzheimer/metabolismo , Conducta Animal/efectos de los fármacos , Corteza Cerebral/metabolismo , Cinnamomum zeylanicum/química , Grasas de la Dieta/efectos adversos , Fructosa/efectos adversos , Hipocampo/metabolismo , Insulina/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Edulcorantes/efectos adversos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Grasas de la Dieta/farmacología , Fructosa/farmacología , Hipocampo/patología , Hipocampo/fisiopatología , Masculino , Extractos Vegetales/química , Ratas , Ratas Wistar , Edulcorantes/farmacologíaRESUMEN
Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with Nippostrongylus brasiliensis decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.
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Nippostrongylus , Obesidad/parasitología , Infecciones por Strongylida/patología , Tejido Adiposo , Animales , Glucemia , Modelos Animales de Enfermedad , Metabolismo Energético , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Ácido Glucárico/metabolismo , Homeostasis , Interleucina-13/genética , Interleucina-13/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Infecciones por Strongylida/metabolismo , Aumento de PesoRESUMEN
OBJECTIVE: Increasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways, which regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport, and metabolism and is closely linked to systemic lipid metabolism. Cinnamon polyphenols have been shown to improve glucose, insulin, and lipid metabolism and improve inflammation in cell culture, animal, and human studies. However, little is known of the effects of an aqueous cinnamon extract (CE) on the regulation of genes and signaling pathways related to intestinal metabolism. The aim of the study was to investigate the effects of a CE on the primary enterocytes of chow-fed rats. METHODS: Freshly isolated intestinal enterocytes were used to investigate apolipoprotein-B48 secretion by immunoprecipitation; gene expressions by quantitative reverse transcriptase-polymerase chain reaction and the protein and phosphorylation levels were evaluated by western blot and flow cytometric analyses. RESULTS: Ex vivo, the CE significantly decreased the amount of apolipoprotein-B48 secretion into the media, inhibited the mRNA expression of genes of the inflammatory cytokines, interleukin-1ß, interleukin-6, and tumor necrosis factor-α, and induced the expression of the anti-inflammatory gene, Zfp36. CE also increased the mRNA expression of genes leading to increased insulin sensitivity, including Ir, Irs1, Irs2, Pi3k, and Akt1, and decreased Pten expression. CE also inhibited genes associated with increased cholesterol, triacylglycerols, and apolipoprotein-B48 levels, including Abcg5, Npc1l1, Cd36, Mttp, and Srebp1c, and facilitated Abca1 expression. CE also stimulated the phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular-signal-regulated kinase expressions determined by flow cytometry, with no changes in protein levels. CONCLUSIONS: These results demonstrate that the CE regulates genes associated with insulin sensitivity, inflammation, and cholesterol/lipogenesis metabolism and the activity of the mitogen-activated protein kinase signal pathway in intestinal lipoprotein metabolism.
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Cinnamomum zeylanicum/química , Enterocitos/metabolismo , Intestino Delgado/metabolismo , Lipoproteínas/metabolismo , Sistema de Señalización de MAP Quinasas , Extractos Vegetales/metabolismo , Receptor de Insulina/metabolismo , Animales , Apolipoproteína B-48/genética , Apolipoproteína B-48/metabolismo , Células Cultivadas , Enterocitos/citología , Regulación de la Expresión Génica , Mediadores de Inflamación/metabolismo , Intestino Delgado/citología , Lipoproteínas/genética , Masculino , Fosforilación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor de Insulina/genética , Análisis de la Célula IndividualRESUMEN
AIMS: Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production. METHODS AND RESULTS: At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3ß mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats. CONCLUSIONS: These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.
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Apolipoproteína B-100/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Hígado Graso/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Animales , Biomarcadores/sangre , Colesterol/sangre , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Modelos Animales de Enfermedad , Dislipidemias/sangre , Dislipidemias/genética , Hígado Graso/sangre , Hígado Graso/genética , Inflamación/sangre , Inflamación/genética , Mediadores de Inflamación/sangre , Resistencia a la Insulina/genética , Lipogénesis/genética , Masculino , Fosforilación , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas OLETF , Transducción de Señal/genética , Sirtuinas/genética , Sirtuinas/metabolismo , Triglicéridos/sangre , Regulación hacia ArribaRESUMEN
Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-α and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3ß. The protein and gene expression of adiponectin and Pparγ mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1ß, Il6 and Tnfα were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation.
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Adiponectina/metabolismo , Citocinas/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Síndrome Metabólico/prevención & control , Obesidad/prevención & control , Photinia/química , Extractos Vegetales/uso terapéutico , Adiponectina/sangre , Adiponectina/genética , Tejido Adiposo Blanco/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/uso terapéutico , Citocinas/sangre , Citocinas/genética , Suplementos Dietéticos , Fructosa/efectos adversos , Frutas/química , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/patología , PPAR gamma/genética , PPAR gamma/metabolismo , Extractos Vegetales/administración & dosificación , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Transducción de Señal , Aumento de PesoRESUMEN
The objective of this study was to determine the effects of cinnamon on glycogen synthesis, related gene expression, and protein levels in the muscle and liver using an animal model of insulin resistance, the high-fat/high-fructose (HF/HFr) diet-fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with (1) HF/HFr diet to induce insulin resistance, (2) HF/HFr diet containing 20 g cinnamon per kilogram of diet, (3) control diet, and (4) control diet containing 20 g cinnamon per kilogram of diet. In the liver, cinnamon added to the HF/HFr diet led to highly significant increases of liver glycogen. There were no significant changes in animals consuming the control diet plus cinnamon. In the liver, cinnamon also counteracted the decreases of the gene expressions due to the consumption of the HF/HFr diet for the insulin receptor, insulin receptor substrates 1 and 2, glucose transporters 1 and 2, and glycogen synthase 1. In muscle, the decreased expressions of these genes by the HF/HFr diet and glucose transporter 4 were also reversed by cinnamon. In addition, the overexpression of glycogen synthase 3ß messenger RNA levels and protein observed in the muscle of HF/HFr fed rats was decreased in animals consuming cinnamon. These data demonstrate that, in insulin-resistant rats, cinnamon improves insulin sensitivity and enhances liver glycogen via regulating insulin signaling and glycogen synthesis. Changes due to cinnamon in control animals with normal insulin sensitivity were not significant.
Asunto(s)
Cinnamomum zeylanicum/fisiología , Resistencia a la Insulina , Glucógeno Hepático/metabolismo , Animales , Dieta , Modelos Animales de Enfermedad , Ingestión de Energía/efectos de los fármacos , Ingestión de Energía/fisiología , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Preparaciones de Plantas/farmacología , Ratas , Ratas WistarRESUMEN
Metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve all of these variables in in vitro, animal, and/or human studies. In addition, cinnamon has been shown to alleviate factors associated with Alzheimer's disease by blocking and reversing tau formation in vitro and in ischemic stroke by blocking cell swelling. In vitro studies also show that components of cinnamon control angiogenesis associated with the proliferation of cancer cells. Human studies involving control subjects and subjects with metabolic syndrome, type 2 diabetes mellitus, and polycystic ovary syndrome all show beneficial effects of whole cinnamon and/or aqueous extracts of cinnamon on glucose, insulin, insulin sensitivity, lipids, antioxidant status, blood pressure, lean body mass, and gastric emptying. However, not all studies have shown positive effects of cinnamon, and type and amount of cinnamon, as well as the type of subjects and drugs subjects are taking, are likely to affect the response to cinnamon. In summary, components of cinnamon may be important in the alleviation and prevention of the signs and symptoms of metabolic syndrome, type 2 diabetes, and cardiovascular and related diseases.
Asunto(s)
Cinnamomum zeylanicum , Diabetes Mellitus Tipo 2/prevención & control , Resistencia a la Insulina , Síndrome Metabólico/prevención & control , Fitoterapia/métodos , Extractos Vegetales/farmacología , Animales , HumanosRESUMEN
The aim of this study was to determine whether systemic elevation of tumor necrosis factor (TNF)-alpha induces intestinal-derived apolipoprotein B (apoB)48-containing very low-density lipoprotein (VLDL) production in hamsters after fat loading and whether TNF-alpha disturbs the related mRNA expression in inflammatory, insulin and lipoprotein signaling pathways in primary enterocytes. In vivo TNF-alpha and Triton-WR1339 infusion, Western blotting and reverse transcriptase-polymerase chain reaction were combined to explore the mechanisms underlying intestinal overproduction of apoB48-containing chylomicrons and VLDL(1) particles by TNF-alpha. TNF-alpha infusion increased intestinal production of chylomicron and VLDL(1)-apoB48 in postprandial (fat load) states. Following TNF-alpha-treatment in enterocytes, there was enhanced gene expression of Il1alpha and beta, Il6 and Tnf and decreased mRNA levels of components of the insulin signaling pathway including the insulin receptor (Ir), Ir substrate-1 and 2, PI3 k, and Akt, but increased phosphatase and tensin homolog deleted on chromosome ten (Pten) protein and mRNA expression. TNF-alpha also induced Cd36 and peroxisome proliferators-activated receptor (Ppar)gamma expression, as well as microsomal triglyceride transfer protein (Mtp) protein and mRNA, but suppressed the sterol regulatory element binding protein (Srebp)1c protein and mRNA level. Systemic elevation of TNF-alpha stimulates the postprandial overproduction of apoB48-containing chylomicrons and VLDL(1) particles by disturbing intestinal gene expression of the inflammatory, insulin and lipoprotein pathways. These findings provide mechanistic links among the inflammatory factor, TNF-alpha, intestinal inflammatory/insulin insensitivity and the overproduction of intestinal apoB48-containing lipoproteins.
Asunto(s)
Apolipoproteína B-48/biosíntesis , Enterocitos/metabolismo , Lipoproteínas VLDL/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Secuencia de Bases , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Quilomicrones/biosíntesis , Cricetinae , Cartilla de ADN/genética , Enterocitos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Mediadores de Inflamación/metabolismo , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Masculino , Mesocricetus , PPAR gamma/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor de Insulina/genética , Receptores Depuradores de Clase B/genética , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Epidemiological studies indicate that the consumption of green tea polyphenols (GTP) may reduce the risk of coronary artery disease. To explore the underlying mechanisms of action at the molecular level, we examined the effects of GTP on the cardiac mRNA and protein levels of genes involved in insulin and lipid metabolism and inflammation. In rats fed a high-fructose diet, supplementation with GTP (200 mg/kg BW daily dissolved in distilled water) for 6 wk, reduced systemic blood glucose, plasma insulin, retinol-binding protein 4, soluble CD36, cholesterol, triglycerides, free fatty acids and LDL-C levels, as well as the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and IL-6. GTP did not affect food intake, bodyweight and heart weight. In the myocardium, GTP also increased the insulin receptor (Ir), insulin receptor substrate 1 and 2 (Irs1 and Irs2), phosphoinositide-3-kinase (Pi3k), v-akt murine thymoma viral oncogene homolog 1 (Akt1), glucose transporter 1 and 4 (Glut1 and Glut4) and glycogen synthase 1 (Gys1) expression but inhibited phosphatase and tensin homolog deleted on chromosome ten (Pten) expression and decreased glycogen synthase kinase 3beta (Gsk3beta) mRNA expression. The sterol regulatory element-binding protein-1c (Srebp1c) mRNA, microsomal triglyceride transfer protein (Mttp) mRNA and protein, Cd36 mRNA and cluster of differentiation 36 protein levels were decreased and peroxisome proliferator-activated receptor (Ppar)gamma mRNA levels were increased. GTP also decreased the inflammatory factors: Tnf, Il1b and Il6 mRNA levels, and enhanced the anti-inflammatory protein, zinc-finger protein, protein and mRNA expression. In summary, consumption of GTP ameliorated the detrimental effects of high-fructose diet on insulin signaling, lipid metabolism and inflammation in the cardiac muscle of rats.
Asunto(s)
Flavonoides/farmacología , Resistencia a la Insulina/fisiología , Proteínas Musculares/metabolismo , Miocardio/metabolismo , Fenoles/farmacología , ARN Mensajero/genética , Té , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Antígenos CD36/sangre , Eliminación de Gen , Regulación de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Guanosina Trifosfato/farmacología , Inflamación/prevención & control , Insulina/sangre , Tamaño de los Órganos/efectos de los fármacos , Polifenoles , ARN Mensajero/metabolismo , Ratas , Proteínas Plasmáticas de Unión al Retinol/metabolismoRESUMEN
We have reported previously that a cinnamon extract (CE), high in type A polyphenols, prevents fructose feeding-induced decreases in insulin sensitivity and suggested that improvements of insulin sensitivity by CE were attributable, in part, to enhanced insulin signaling. In this study, we examined the effects of CE on postprandial apolipoprotein (apo) B-48 increase in fructose-fed rats, and the secretion of apoB48 in freshly isolated intestinal enterocytes of fructose-fed hamsters. In an olive oil loading study, a water-soluble CE (Cinnulin PF, 50 mg/kg body weight, orally) decreased serum triglyceride (TG) levels and the over production of total- and TG-rich lipoprotein-apoB48. In ex vivo (35)S labeling study, significant decreases were also observed in apoB48 secretion into the media in enterocytes isolated from fructose-fed hamsters. We also investigated the molecular mechanisms of the effects of CE on the expression of genes of the insulin signaling pathway [insulin receptor (IR), IR substrate (IRS)1, IRS2 and Akt1], and lipoprotein metabolism [microsomal TG transfer protein (MTP), sterol regulatory element-binding protein (SREBP1c) in isolated primary enterocytes of fructose-fed hamsters, using quantitative real-time polymerase chain reaction. The CE reversed the expression of the impaired IR, IRS1, IRS2 and Akt1 mRNA levels and inhibited the overexpression of MTP and SREBP1c mRNA levels of enterocytes. Taken together, our data suggest that the postprandial hypertriglycerides and the overproduction of apoB48 can be acutely inhibited by a CE by a mechanism involving improvements of insulin sensitivity of intestinal enterocytes and regulation of MTP and SREBP1c levels. We present both in vivo and ex vivo evidence that a CE improves the postprandial overproduction of intestinal apoB48-containing lipoproteins by ameliorating intestinal insulin resistance and may be beneficial in the control of lipid metabolism.
Asunto(s)
Apolipoproteína B-48/biosíntesis , Cinnamomum zeylanicum/química , Carbohidratos de la Dieta/farmacología , Fructosa/farmacología , Extractos Vegetales/farmacología , Periodo Posprandial/fisiología , Alimentación Animal , Animales , Proteínas Portadoras/biosíntesis , Colesterol/sangre , Cricetinae , Enterocitos/efectos de los fármacos , Enterocitos/metabolismo , Proteínas Sustrato del Receptor de Insulina/biosíntesis , Resistencia a la Insulina/fisiología , Masculino , Mesocricetus , Periodo Posprandial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/biosíntesis , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/biosíntesis , Triglicéridos/sangreRESUMEN
OBJECTIVE: To evaluate whether cryopreserved newborn mouse ovaries can generate sufficient numbers of parthenogenetic mouse embryonic stem (pmES) cells for autologous stem cell therapy. DESIGN: Prospective study. SETTING: Reproductive clinic of Xinhua Hospital in Shanghai. ANIMAL(S): Kunming, C57BL/6J, BALB/c, and NOD-SCID mice. INTERVENTION(S): Cryopreserved newborn mouse ovaries were thawed, grafted into immunodeficient mice, treated with pregnant mare serum gonadotropin to promote follicular maturation, and collected oocytes activated in vitro to generate parthenogenetic embryonic stem cells. MAIN OUTCOME MEASURE(S): Preimplantation development and stem cell characterization. RESULT(S): This new protocol yielded a large number of oocytes from cryopreserved ovaries over a long period. These oocytes were used to derive pmES cell lines, which expressed embryonic stem cell-specific markers and differentiated into embryoid bodies in vitro and teratomas in vivo. The pmES cell line was propagated in an undifferentiated state for more than 30 passages and maintained a diploid karyotype. CONCLUSION(S): The pmES cells lines established by our protocol exhibited the same degree of pluripotency as standard embryonic stem cell lines. This approach may be used for exploring autologous stem cell therapies.