RESUMO
Dr [...].
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Gastrectomia , Neoplasias Gástricas , Redução de Peso , Humanos , Neoplasias Gástricas/cirurgia , Gastrectomia/efeitos adversos , Gastrectomia/métodos , Olfato/fisiologia , Período Pós-OperatórioRESUMO
Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-ß-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1ß. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.
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Citocinas , MAP Quinase Quinase Quinases , Atrofia Muscular , Animais , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/antagonistas & inibidores , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/tratamento farmacológico , Camundongos , Citocinas/metabolismo , Debilidade Muscular/metabolismo , Debilidade Muscular/tratamento farmacológico , Miostatina/metabolismo , Miostatina/antagonistas & inibidores , Proteínas Musculares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , NF-kappa B/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Inflamação/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Fosforilação/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Zearalenona/farmacologia , Zearalenona/análogos & derivadosRESUMO
Patients undergoing gastrectomy for gastric cancer may experience alterations in olfaction, yet the association between olfactory changes and postoperative weight loss remains uncertain. This study aimed to elucidate the relationship between olfactory changes and postoperative weight loss in patients with gastric cancer. Patients who underwent radical gastrectomy for gastric cancer between February 2022 and August 2022 were included in the study. Those experiencing a higher Visual Analog Scale (VAS) score postoperatively compared to preoperatively were deemed to have undergone olfactory changes. Postoperative weight loss was determined using the 75th percentile as a cutoff value, designating patients surpassing this threshold as experiencing significant weight loss. Multivariate logistic regression analysis was employed to identify risk factors for postoperative weight loss, with statistical significance set at p < 0.05. Out of 58 patients, 10 (17.2%) exhibited olfactory changes. The rate of postoperative weight loss at one month was markedly higher in the group with olfactory changes compared to those without (9.6% versus 6.2%, respectively; p = 0.002). In addition, the group experiencing olfactory changes demonstrated significantly lower energy intake compared to the group without such changes (1050 kcal versus 1250 kcal, respectively; p = 0.029). Logistic regression analysis revealed olfactory changes as an independent risk factor for significant weight loss at one month postoperatively (odds ratio: 7.64, 95% confidence interval: 1.09-71.85, p = 0.048). In conclusion, olfactory changes emerged as an independent risk factor for postoperative weight loss at one month in patients with gastric cancer following gastrectomy.
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Transtornos do Olfato , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/complicações , Complicações Pós-Operatórias/etiologia , Gastrectomia/efeitos adversos , Redução de Peso , Estudos RetrospectivosRESUMO
BACKGROUND: This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). METHODS: Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20-25 kcal/day. Protein mass was calculated as SBW kg × 1.0-1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. RESULTS: The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien-Dindo [CD] III). A retrospective comparison between with and without WLP using propensity score-matching analysis revealed that WLP group showed better NLR value, however, there were no significant differences in both short and long-term outcomes after Hx based on participation in the WLP. CONCLUSIONS: WLP with multidisciplinary intervention improved immune-nutrition status and liver function of obese patients. WLP had not affected both short and long-term outcomes after Hx.
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Carcinoma Hepatocelular , Laparoscopia , Neoplasias Hepáticas , Programas de Redução de Peso , Humanos , Carcinoma Hepatocelular/patologia , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/patologia , Índice de Massa Corporal , Estudos Retrospectivos , Pontuação de Propensão , Resultado do TratamentoRESUMO
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
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Tecido Adiposo Marrom , Temperatura Baixa , Metabolismo Energético , Neoplasias , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Glicemia/metabolismo , Terapia Combinada , Glicólise , Humanos , Camundongos , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Neoplasias/terapia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/terapia , Termogênese/genética , Proteína Desacopladora 1/metabolismoRESUMO
Taste recognition mediated by taste receptors is critical for the survival of animals in nature and is an important determinant of nutritional status and quality of life in humans. However, many factors including aging, diabetes, zinc deficiency, infection with influenza or cold viruses, and chemotherapy can trigger dysgeusia, for which a standard treatment has not been established. We here established an engineered strain of medaka (Oryzias latipes) that expresses green fluorescent protein (GFP) from the endogenous taste 1 receptor 3 (T1R3) gene locus with the use of the CRISPR-Cas9 system. This T1R3-GFP knock-in (KI) strain allows direct visualization of expression from this locus by monitoring of GFP fluorescence. The pattern of GFP expression in the T1R3-GFP KI fish thus mimicked that of endogenous T1R3 gene expression. Furthermore, exposure of T1R3-GFP KI medaka to water containing monosodium glutamate or the anticancer agent 5-fluorouracil resulted in an increase or decrease, respectively, in GFP fluorescence intensity, effects that also recapitulated those on T1R3 mRNA abundance. Finally, screening for agents that affect GFP fluorescence intensity in T1R3-GFP KI medaka identified tryptophan as an amino acid that increases T1R3 gene expression. The establishment of this screening system for taste receptor expression in medaka provides a new tool for the development of potential therapeutic agents for dysgeusia.
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Oryzias , Animais , Sistemas CRISPR-Cas/genética , Disgeusia/genética , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Oryzias/genética , Qualidade de Vida , PaladarRESUMO
(Background) We investigated the effect of dietary supplementation with monosodium glutamate (MSG) on chemotherapy-induced downregulation of the T1R3 taste receptor subunit expression in the tongue of patients with advanced head and neck cancer. (Methods) Patients undergoing two rounds of chemoradiotherapy were randomly allocated to a control or intervention group (dietary supplementation with MSG at 2.7 g/day during the second round of chemotherapy). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative polymerase chain reaction analysis. Dysgeusia was assessed with a visual analog scale and daily energy intake was evaluated. (Results) T1R3 expression levels in the tongue, taste sensitivity, and daily energy intake were significantly reduced after the first round of chemotherapy compared with before treatment. Furthermore, these parameters significantly decreased after the second round of chemotherapy, but the extent of decrease was significantly attenuated in the MSG group compared with the control group. (Conclusions) MSG supplementation suppresses chemotherapy-induced dysgeusia, possibly due to the inhibition of the T1R3-containing taste receptor downregulation in the tongue, thereby increasing energy intake in patients with advanced head and neck cancer.
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Disgeusia/terapia , Neoplasias de Cabeça e Pescoço/terapia , Receptores Acoplados a Proteínas G/metabolismo , Glutamato de Sódio/administração & dosagem , Língua/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Quimiorradioterapia/efeitos adversos , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Disgeusia/etiologia , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas G/genética , Paladar/efeitos dos fármacos , Papilas Gustativas/metabolismoRESUMO
Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4 receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through down-regulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4 via the PDK1-FoxO1 pathway and thereby maintains systemic insulin sensitivity.
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Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Adipócitos/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Proteína Forkhead Box O1 , Resistência à Insulina , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Animais , Células Cultivadas , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Leucotrieno B4/metabolismo , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genéticaRESUMO
Background and aimsâ :â Severe aortic stenosis (AS) has been normally treated with surgical aortic valve replacement (AVR) whereas recently, transcatheter aortic valve implantation (TAVI) has been introduced as a minimally invasive operation for patients with high surgical risk and frailty. In this study, we have evaluated postoperative physical function and nutrition intake in the patients following AVR and TAVI. Methodsâ :â This prospective observational study involved 9 patients with surgical aortic valve replacement (AVR) and 7 patients with transcatheter aortic valve implantation (TAVI). Body composition was measured one day prior surgery, postoperative day (POD) 1, POD 3, POD 5 and POD 7. Hand grip strength, calf circumference and gait speed were measured one day before surgery and on the day of discharge. Resultsâ :â Skeletal muscle was significantly decreased in AVR patients at postoperative day 3 and 7, while there was no change in TAVI patients. Patients with TAVI showed higher dietary intake after surgery compared to patients with AVR, and they maintained hand grip strength and calf circumference at discharge. Conclusionsâ :â In elderly patients with AS, TAVI can improve post-operative recovery maintaining nutritional status and physical function even. J. Med. Invest. 67 : 139-144, February, 2020.
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Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca , Estado Nutricional , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/fisiopatologia , Composição Corporal , Feminino , Força da Mão , Humanos , Masculino , Período Pós-Operatório , Estudos Prospectivos , Velocidade de CaminhadaRESUMO
Inorganic phosphate (Pi) homeostasis is regulated by intestinal absorption via type II sodium-dependent co-transporter (Npt2b) and by renal reabsorption via Npt2a and Npt2c. Although we previously reported that vitamin A-deficient (VAD) rats had increased urine Pi excretion through the decreased renal expression of Npt2a and Npt2c, the effect of vitamin A on the intestinal Npt2b expression remains unclear. In this study, we investigated the effects of treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, on the Pi absorption and the Npt2b expression in the intestine of VAD rats, as well as and the underlying molecular mechanisms. In VAD rats, the intestinal Pi uptake activity and the expression of Npt2b were increased, but were reduced by the administration of ATRA. The transcriptional activity of reporter plasmid containing the promoter region of the rat Npt2b gene was reduced by ATRA in NIH3T3 cells overexpressing retinoic acid receptor (RAR) and retinoid X receptor (RXR). On the other hand, CCAAT/enhancer-binding proteins (C/EBP) induced transcriptional activity of the Npt2b gene. Knockdown of the C/EBP gene and a mutation analysis of the C/EBP responsible element in the Npt2b gene promoter indicated that C/EBP plays a pivotal role in the regulation of Npt2b gene transcriptional activity by ATRA. EMSA revealed that the RAR/RXR complex inhibits binding of C/EBP to Npt2b gene promoter. Together, these results suggest that ATRA may reduce the intestinal Pi uptake by preventing C/EBP activation of the intestinal Npt2b gene.
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Regulação da Expressão Gênica/efeitos dos fármacos , Intestino Delgado/metabolismo , Rim/metabolismo , Regiões Promotoras Genéticas , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/genética , Transcrição Gênica/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Antineoplásicos/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Hipofosfatemia Familiar/metabolismo , Hipofosfatemia Familiar/patologia , Hipofosfatemia Familiar/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Camundongos , Células NIH 3T3 , Ratos , Ratos Wistar , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismoRESUMO
Researchers frequently use 3T3-L1 adipocytes as a fat cell line, but the capacity of this line for insulin-mediated glucose transport is lower than that of primary isolated fat cells. In this study, we found that 5-azacytidine (5-aza-C), DNA methyltransferase 1 inhibitor, enhanced insulin-stimulated 2-deoxyglucose (2-DG) transport in 3T3-L1 cells after adipogenic differentiation. We next examined the expression of the genes related to glucose transport and insulin signal transduction. The insulin independent glucose transporter, glucose transporter 1 (GLUT1), showed lower expression in 5-aza-C pre-treated 3T3-L1 adipocytes, than in un-treated control adipocytes, while the expression of insulin dependent transporter GLUT4 remained unchanged. In addition, insulin receptor substrate-1 (IRS-1) was highly expressed in 5-aza-C pre-treated adipocytes. Based on DNA microarray and functional annotation analysis, we noticed that 5-aza-C pretreatment activated the tumor suppressor p53 pathway. We confirmed that in 5-aza-C adipocytes, p53 expression was markedly higher, and the methylation level of CpGs in its promoter region was lower than in un-treated control adipocytes. Moreover, pharmacological inhibition of p53 restored GLUT1 and IRS-1 expression to the same level as in un-treated 3T3-L1 adipocytes, and significantly decreased insulin-mediated 2-DG uptake. These results suggest that glucose transport capacity in adipocytes is influenced by DNA methylation status, and demethylation induced by 5-aza-C increased it possibly through the p53 signaling pathway.
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Backgroundâ :â Mediterranean diets have been linked to a reduced risk of cancer, vascular illnesses, Parkinson's and Alzheimer's disease. Olive oil is the primary fat source in the Mediterranean dietâ ;â however, only a few studies have investigated the effect of olive oil on aging. In the present study, we aimed to determine whether consumption of olive oil significantly influences aging and memory in senescence-accelerated mouse-prone 8 (SAMP8). Methodsâ :â SAMP8 and senescence-accelerated mouse resistant 1 (SAMR1) mice were fed either 7% soy oil or 1% olive oil and 6% soy oil during a six-month study period. Reduction in memory in passive avoidance learning was examined after two months from the initiation of the experiment. Resultsâ :â The weight of organs including the liver, kidney, spleen, and fat tissue changed significantly and memory performance was reduced in SAMP8 than in SAMR1 mice. There were no significant differences in SAMP8 and SAMR1 mice; however, blood triglyceride level decreased significantly in SAMP8 mice fed on olive oil. Conclusionsâ :â These results suggest that consuming olive oil may not have a protective role in aging and memory recall, but beneficial effects may be related to improvement in lipid metabolism. J. Med. Invest. 66 : 241-247, August, 2019.
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Envelhecimento , Azeite de Oliva/administração & dosagem , Animais , Aprendizagem da Esquiva , Dieta Mediterrânea , Memória , Camundongos , Modelos Animais , Tamanho do Órgão , Triglicerídeos/sangueRESUMO
Cell death is closely linked to many diseases including cancer, neurodegenerative diseases, autoimmune diseases, and metabolic disorders. Increased adipocyte death has been reported during the development of obesity. Adipocyte death may be caused by excessive stress during obesity-related adipose tissue remodeling. Adipose tissue macrophages are key players in obesity-related inflammation and systemic insulin resistance. Accumulating evidence suggests that adipocyte death is involved in immune cell function and initiates inflammation through an interaction with macrophages; however, the precise mechanisms remain largely unknown. This review focuses on the contribution of dead cells (particularly dead adipocytes in adipose tissue) to the pathophysiological conditions associated with obesity. J. Med. Invest. 64: 193-196, August, 2017.
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Adipócitos/fisiologia , Morte Celular , Inflamação/etiologia , Obesidade/patologia , Doença Crônica , Humanos , Macrófagos/fisiologia , Obesidade/complicaçõesRESUMO
AIM: Accelerated thrombin action is associated with insulin resistance. It is known that upon activation by binding to dermatan sulfate proteoglycans, heparin cofactor â ¡(HCâ ¡) inactivates thrombin in tissues. Because HCâ ¡ may be involved in glucose metabolism, we investigated the relationship between plasma HCâ ¡ activity and insulin resistance. METHODS AND RESULTS: In a clinical study, statistical analysis was performed to examine the relationships between plasma HCâ ¡ activity, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR) in elderly Japanese individuals with lifestyle-related diseases. Multiple regression analysis showed significant inverse relationships between plasma HCâ ¡ activity and HbA1c (p=0.014), FPG (p=0.007), and HOMA-IR (p= 0.041) in elderly Japanese subjects. In an animal study, HCâ ¡ï¼/ï¼ mice and HCâ ¡ï¼/- mice were fed with a normal diet or high-fat diet (HFD) until 25 weeks of age. HFD-fed HCâ ¡ï¼/- mice exhibited larger adipocyte size, higher FPG level, hyperinsulinemia, compared to HFD-fed HCâ ¡ï¼/ï¼ mice. In addition, HFD-fed HCâ ¡ï¼/- mice exhibited augmented expression of monocyte chemoattractant protein-1 and tumor necrosis factor, and impaired phosphorylation of the serine/threonine kinase Akt and AMP-activated protein kinase in adipose tissue compared to HFD-fed HCâ ¡ï¼/ï¼ mice. The expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was also enhanced in the hepatic tissues of HFD-fed HCâ ¡ï¼/- mice. CONCLUSIONS: The present studies provide evidence to support the idea that HCâ ¡ plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HCâ ¡ production may serve as novel therapeutic tools for the treatment of type 2 diabetes.
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Glicemia/metabolismo , Cofator II da Heparina/fisiologia , Homeostase , Resistência à Insulina , Insulina/sangue , Animais , Biomarcadores/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Hiperglicemia/patologia , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Hiperinsulinismo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/complicações , PrognósticoRESUMO
Nonsense-mediated mRNA decay (NMD) degrades mRNAs carrying a premature termination codon (PTC) in eukaryotes. Cellular stresses, including endoplasmic reticulum (ER) stress, inhibit NMD, and up-regulate PTC-containing mRNA (PTC-mRNA) levels in several cell lines. However, whether similar effects exist under in vivo conditions that involve systemic nutritional status is unclear. Here, we compared the effects of pharmacological induction of ER stress with those of nutritional interventions on hepatic PTC-mRNA levels in mice. In mouse livers, the ER stress inducer tunicamycin increased PTC-mRNA levels of endogenous marker genes. Tunicamycin decreased body weight and perturbed nutrient metabolism in mice. Food restriction or deprivation mimicked the effect of tunicamycin on weight loss and metabolism, but did not increase PTC-mRNA levels. Hyperphagia-induced obesity also had little effect on hepatic PTC-mRNA levels. Meanwhile, in mouse liver phosphorylation of eIF2α, a factor that regulates NMD, was increased by both tunicamycin and nutritional interventions. Hepatic expression of GRP78, a central chaperone in ER stress responses, was increased by tunicamycin but not by the nutritional interventions. In cultured liver cells (Hepa), exogenous overexpression of a phosphomimetic eIF2α failed to increase PTC-mRNA levels. However, GRP78 overexpression in Hepa cells increased PTC-mRNA and PTC-mRNA-derived protein levels. ER stress promoted localization of GRP78 to mitochondria, and exogenous expression of a GRP78 fusion protein targeted to mitochondria mimicked the effect of wild type GRP78. These results indicate that GRP78, but not nutritional status, is a potent up-regulator of hepatic PTC-mRNA levels during induction of ER stress in vivo. J. Cell. Biochem. 118: 3810-3824, 2017. © 2017 Wiley Periodicals, Inc.
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Códon de Terminação , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico/biossíntese , Fígado/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Obesidade/metabolismo , Animais , Chaperona BiP do Retículo Endoplasmático , Células HEK293 , Proteínas de Choque Térmico/genética , Humanos , Hiperfagia/induzido quimicamente , Hiperfagia/genética , Hiperfagia/metabolismo , Hiperfagia/patologia , Fígado/patologia , Masculino , Camundongos , Camundongos Obesos , Células NIH 3T3 , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Tunicamicina/efeitos adversos , Tunicamicina/farmacologiaRESUMO
There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.
Assuntos
Grelina/metabolismo , Atividade Motora/efeitos dos fármacos , Condicionamento Físico Animal , Corrida/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Grelina/administração & dosagem , Infusões Intraventriculares , Atividade Motora/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , Glutamato de Sódio/administração & dosagemRESUMO
SCOPE: Fish oil-derived long-chain monounsaturated fatty acids (LCMUFA) containing chain lengths longer than 18 were previously shown to improve cardiovascular disease risk factors in mice. However, it is not known if LCMUFA also exerts anti-atherogenic effects. The main objective of the present study was to investigate the effect of LCMUFA on the development of atherosclerosis in mouse models. METHODS AND RESULTS: LDLR-KO mice were fed Western diet supplemented with 2% (w/w) of either LCMUFA concentrate, olive oil, or not (control) for 12 wk. LCMUFA, but not olive oil, significantly suppressed the development of atherosclerotic lesions and several plasma inflammatory cytokine levels, although there were no major differences in plasma lipids between the three groups. At higher doses 5% (w/w) LCMUFA supplementation was observed to reduce pro-atherogenic plasma lipoproteins and to also reduce atherosclerosis in ApoE-KO mice fed a Western diet. RNA sequencing and subsequent qPCR analyses revealed that LCMUFA upregulated PPAR signaling pathways in liver. In cell culture studies, apoB-depleted plasma from LDLR-K mice fed LCMUFA showed greater cholesterol efflux from macrophage-like THP-1 cells and ABCA1-overexpressing BHK cells. CONCLUSION: Our research showed for the first time that LCMUFA consumption protects against diet-induced atherosclerosis, possibly by upregulating the PPAR signaling pathway.
Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos Monoinsaturados/farmacologia , Óleos de Peixe/farmacologia , Animais , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Colesterol/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Ácidos Graxos/análise , Ácidos Graxos Monoinsaturados/química , Óleos de Peixe/química , Humanos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Knockout , Receptores de LDL/genéticaRESUMO
Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , DNA/metabolismo , Obesidade/metabolismo , Paniculite/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Adulto , Idoso , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Comunicação Celular , DNA/sangue , Feminino , Deleção de Genes , Expressão Gênica , Humanos , Resistência à Insulina/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Paniculite/genética , Paniculite/patologia , Transdução de Sinais , Receptor Toll-Like 9/antagonistas & inibidores , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMO
Gender difference in obesity-associated cardiovascular complication could be derived from divergent chronic inflammation. We evaluated depot- and gender-specific regulation of the innate immune system in human adipose tissues. Pair samples were obtained from subcutaneous (SAT) and visceral adipose tissue (VAT) during elective surgery (Male: 35; Female: 27). Expressions of pro- and anti-inflammatory adipocytokines were evaluated by semi-quantitative qPCR. Adipose cell-size distribution was obtained from tissue samples fixed in osmium tetroxide and analyzed by Beckman Coulter Multisizer. Levels of adiponectin were higher in SAT and VAT of female than those of male (P < 0.001 and P = 0.011, respectively). NLRP3, IL1ß-IL18, TLR2 were comparable in SAT and VAT between genders. However, TLR4 and TLR9 were increased in female SAT and VAT and HMGB1 in female VAT. Levels of adiponectin were not correlated with mean diameter of adipocyte (φ, µm) in SAT and VAT of male, but negatively well correlated in those of female (r = -0.392 and r = -0.616). Such negative correlations were also observed between levels of TLR2, TLR4, and HMGB1 and φ in female. Levels of NLRP3 and IL1ß were positively correlated with φ in male, but not in female. In conclusion, Innate signals were differentially expressed in male and female adipose tissues, suggesting that the depot- and gender-specific signals could be related to gender difference in chronic inflammation. © 2016 BioFactors, 42(4):397-406, 2016.