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1.
Nat Commun ; 15(1): 5506, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38951527

RESUMO

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.


Assuntos
Fígado Gorduroso , Resistência à Insulina , Interferon gama , Interleucina-12 , Fígado , Macrófagos , Camundongos Knockout , Obesidade , Transdução de Sinais , Animais , Interferon gama/metabolismo , Interleucina-12/metabolismo , Masculino , Obesidade/metabolismo , Camundongos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Macrófagos/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Receptores de Interferon/metabolismo , Receptores de Interferon/genética , Receptor de Interferon gama , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/genética
2.
J Chromatogr Sci ; 61(5): 428-439, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35022688

RESUMO

According to the upcoming ICH Q14 guideline, the development of an analytical method by the implementation of the AQbD approach based on analytical quality risk management and design of experiments will become a regulatory requirement for the registration of new drug substances and products. In literature, the HPTLC method has not been reported yet for simultaneous estimation of metronidazole and norfloxacin. Hence, the robust HPTLC method has been developed and validated for simultaneous estimation of metronidazole and norfloxacin using QRM and the DoE-based enhanced AQbD approach. The principal component analysis was applied for chemometric-based risk assessment of method risk parameters. The high-risk method parameters were optimized by a DoE-based full-factorial design. The MODR and control strategy was estimated for quality risk management throughout the lifecycle of the HPTLC method. The HPTLC method was developed using silica gel 60 F254 as stationary phase and acetonitrile-methanol-formic acid-ammonia (9.5 + 0.5 + 0.5 + 0.3, v/v) as mobile phase. The developed method was validated as per ICH Q2 (R1) guideline. The developed method was applied for the assay of combined pharmaceutical dosage forms of metronidazole and norfloxacin and results were found in compliance with their respective labeled claim.


Assuntos
Metronidazol , Norfloxacino , Quimiometria , Gestão de Riscos , Cromatografia Líquida de Alta Pressão/métodos
3.
BMJ Case Rep ; 12(11)2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31712231

RESUMO

Pazopanib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) that inhibits the vascular endothelial growth factor receptor A pathway and has the potential to cause ischaemic bowel changes, including perforation. Here we report a case of a 51-year-old man with large, metastatic, retroperitoneal leiomyosarcoma that developed a tumour-bowel fistula after 4 weeks of pazopanib therapy. He presented to the emergency department with sepsis and 1-week history of worsening fever, chills, nausea and diarrhoea. Abdominal CT findings of mesenteric and portal vein gas, commonly found in mesenteric ischaemia and VEGFR modulator-induced bowel toxicity, provided evidence for the causal relation. Unfortunately, the case was not amenable to surgery and patient succumbed to the illness.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Fístula Intestinal/induzido quimicamente , Perfuração Intestinal/induzido quimicamente , Leiomiossarcoma/tratamento farmacológico , Pirimidinas/efeitos adversos , Neoplasias Retroperitoneais/tratamento farmacológico , Sulfonamidas/efeitos adversos , Diagnóstico Diferencial , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
4.
Neuroimage ; 151: 117-127, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26921712

RESUMO

BACKGROUND: Meditation is increasingly showing beneficial effects for psychiatric disorders. However, learning to meditate is not straightforward as there are no easily discernible outward signs of performance and thus no direct feedback is possible. As meditation has been found to correlate with posterior cingulate cortex (PCC) activity, we tested whether source-space EEG neurofeedback from the PCC followed the subjective experience of effortless awareness (a major component of meditation), and whether participants could volitionally control the signal. METHODS: Sixteen novice meditators and sixteen experienced meditators participated in the study. Novice meditators were briefly trained to perform a basic meditation practice to induce the subjective experience of effortless awareness in a progressively more challenging neurofeedback test-battery. Experienced meditators performed a self-selected meditation practice to induce this state in the same test-battery. Neurofeedback was provided based on gamma-band (40-57Hz) PCC activity extracted using a beamformer algorithm. Associations between PCC activity and the subjective experience of effortless awareness were assessed by verbal probes. RESULTS: Both groups reported that decreased PCC activity corresponded with effortless awareness (P<0.0025 for each group), with high median confidence ratings (novices: 8 on a 0-10 Likert scale; experienced: 9). Both groups showed high moment-to-moment median correspondence ratings between PCC activity and subjective experience of effortless awareness (novices: 8, experienced: 9). Both groups were able to volitionally control the PCC signal in the direction associated with effortless awareness by practicing effortless awareness meditation (novices: median % of time=77.97, P=0.001; experienced: 89.83, P<0.0005). CONCLUSIONS: These findings support the feasibility of using EEG neurofeedback to link an objective measure of brain activity with the subjective experience of effortless awareness, and suggest potential utility of this paradigm as a tool for meditation training.


Assuntos
Conscientização/fisiologia , Eletroencefalografia , Giro do Cíngulo/fisiologia , Meditação/métodos , Neurorretroalimentação , Feminino , Ritmo Gama , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Plena , Volição
5.
FASEB J ; 31(2): 701-710, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27811060

RESUMO

Altered energy balance and insulin resistance are important characteristics of aging. Skeletal muscle is a major site of glucose disposal, and the role of aging-associated inflammation in skeletal muscle insulin resistance remains unclear. To investigate, we examined glucose metabolism in 18-mo-old transgenic mice with muscle-specific overexpression of IL-10 (MIL10) and in wild-type mice during hyperinsulinemic-euglycemic clamping. Despite similar fat mass and energy balance, MIL10 mice were protected from aging-associated insulin resistance with significant increases in glucose infusion rates, whole-body glucose turnover, and skeletal muscle glucose uptake (∼60%; P < 0.05), as compared to age-matched WT mice. This protective effect was associated with decreased muscle inflammation, but no changes in adipose tissue inflammation in aging MIL10 mice. These results demonstrate the importance of skeletal muscle inflammation in aging-mediated insulin resistance, and our findings further implicate a potential therapeutic role of anti-inflammatory cytokine in the treatment of aging-mediated insulin resistance.-Dagdeviren, S., Jung, D. Y., Friedline, R. H., Noh, H. L., Kim, J. H., Patel, P. R., Tsitsilianos, N., Inashima, K., Tran, D. A., Hu, X., Loubato, M. M., Craige, S. M., Kwon, J. Y., Lee, K. W., Kim, J. K. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.


Assuntos
Envelhecimento/fisiologia , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Interleucina-10/metabolismo , Músculo Esquelético/metabolismo , Animais , Creatina Quinase Forma MM , Metabolismo Energético , Interleucina-10/genética , Masculino , Camundongos , Camundongos Transgênicos
6.
J Biol Chem ; 291(46): 23915-23924, 2016 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-27662905

RESUMO

High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα-/- null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα-/- mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity.


Assuntos
Fenofibrato/farmacologia , Resistência à Insulina , Insulina/metabolismo , PPAR alfa/agonistas , Animais , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Secreção de Insulina , Camundongos , Camundongos Knockout , PPAR alfa/genética , PPAR alfa/metabolismo , Pirimidinas/farmacologia
7.
Mol Cell Biol ; 36(23): 2956-2966, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27644327

RESUMO

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (MIL10). After 16 weeks of a high-fat diet (HFD), MIL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob/ob mice. Muscle-specific overexpression of IL-10 in ob/ob mice (MCK-IL10ob/ob) did not affect spontaneous obesity, but MCK-IL10ob/ob mice showed increased glucose turnover compared to that in ob/ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R-/-) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R-/- mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Resistência à Insulina , Interleucina-10/genética , Leptina/genética , Músculo Esquelético/imunologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glucose/metabolismo , Camundongos , Obesidade , Receptores de Interleucina-10/genética , Receptores de Interleucina-10/metabolismo , Transdução de Sinais
8.
J Biol Chem ; 291(15): 8121-9, 2016 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-26846848

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed at high levels in the hepatocyte, consistent with its role in promoting insulin clearance in liver. CEACAM1 also mediates a negative acute effect of insulin on fatty acid synthase activity. Western blot analysis reveals lower hepatic CEACAM1 expression during fasting. Treating of rat hepatoma FAO cells with Wy14,643, an agonist of peroxisome proliferator-activated receptor α (PPARα), rapidly reduces Ceacam1 mRNA and CEACAM1 protein levels within 1 and 2 h, respectively. Luciferase reporter assay shows a decrease in the promoter activity of both rat and mouse genes by Pparα activation, and 5'-deletion and block substitution analyses reveal that the Pparα response element between nucleotides -557 and -543 is required for regulation of the mouse promoter activity. Chromatin immunoprecipitation analysis demonstrates binding of liganded Pparα toCeacam1promoter in liver lysates ofPparα(+/+), but notPparα(-/-)mice fed a Wy14,643-supplemented chow diet. Consequently, Wy14,643 feeding reduces hepatic Ceacam1 mRNA and CEACAM1 protein levels, thus decreasing insulin clearance to compensate for compromised insulin secretion and maintain glucose homeostasis and insulin sensitivity in wild-type mice. Together, the data show that the low hepatic CEACAM1 expression at fasting is mediated by Pparα-dependent mechanisms. Changes in CEACAM1 expression contribute to the coordination of fatty acid oxidation and insulin action in the fasting-refeeding transition.


Assuntos
Antígenos CD/genética , Moléculas de Adesão Celular/genética , Jejum , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , PPAR alfa/metabolismo , Animais , Antígenos CD/análise , Antígenos CD/metabolismo , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Deleção de Genes , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Ratos
9.
J Biol Chem ; 291(2): 980-8, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26586918

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2(-/-)). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in ß-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-ß-cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2(-/-) islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2(-/-) mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2(-/-) mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors.


Assuntos
Moléculas de Adesão Celular/deficiência , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/farmacologia , Animais , Antígenos CD/metabolismo , Canais de Cálcio Tipo L/metabolismo , Moléculas de Adesão Celular/metabolismo , Imunofluorescência , Teste de Tolerância a Glucose , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Vigília
10.
FASEB J ; 30(3): 1328-38, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26644351

RESUMO

Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common γ chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had ∼50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (∼10%) and physical activity (∼40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.


Assuntos
Resistência à Insulina/fisiologia , Interleucina-2/metabolismo , Linfócitos/metabolismo , Camundongos Endogâmicos NOD/metabolismo , Obesidade/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Metabolismo Energético/fisiologia , Glucose/metabolismo , Técnica Clamp de Glucose/métodos , Insulina/metabolismo , Linfócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Obesidade/fisiopatologia , Transdução de Sinais/fisiologia
11.
Diabetes ; 64(8): 2780-90, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25972571

RESUMO

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic ß-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance.


Assuntos
Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Dieta Hiperlipídica , Resistência à Insulina/genética , Fígado/metabolismo , Animais , Antígenos CD/genética , Moléculas de Adesão Celular/genética , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Insulina/sangue , Camundongos , Camundongos Transgênicos
12.
FASEB J ; 29(8): 3182-92, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25888600

RESUMO

Insulin resistance is a major characteristic of obesity and type 2 diabetes, but the underlying mechanism is unclear. Recent studies have shown a metabolic role of capsaicin that may be mediated via the transient receptor potential vanilloid type-1 (TRPV1) channel. In this study, TRPV1 knockout (KO) and wild-type (WT) mice (as controls) were fed a high-fat diet (HFD), and metabolic studies were performed to measure insulin and leptin action. The TRPV1 KO mice became more obese than the WT mice after HFD, partly attributed to altered energy balance and leptin resistance in the KO mice. The hyperinsulinemic-euglycemic clamp experiment showed that the TRPV1 KO mice were more insulin resistant after HFD because of the ∼40% reduction in glucose metabolism in the white and brown adipose tissue, compared with that in the WT mice. Leptin treatment failed to suppress food intake, and leptin-mediated hypothalamic signal transducer and activator of transcription (STAT)-3 activity was blunted in the TRPV1 KO mice. We also found that the TRPV1 KO mice were more obese and insulin resistant than the WT mice at 9 mo of age. Taken together, these results indicate that lacking TRPV1 exacerbates the obesity and insulin resistance associated with an HFD and aging, and our findings further suggest that TRPV1 has a major role in regulating glucose metabolism and hypothalamic leptin's effects in obesity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo , Canais de Cátion TRPV/metabolismo , Tecido Adiposo Marrom/metabolismo , Envelhecimento/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Gorduras na Dieta/metabolismo , Metabolismo Energético/fisiologia , Glucose/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Diabetes ; 63(6): 1948-65, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24520121

RESUMO

In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.


Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica , Inflamação/metabolismo , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Receptores Imunológicos/metabolismo , Animais , Técnica Clamp de Glucose , Inflamação/genética , Resistência à Insulina/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor para Produtos Finais de Glicação Avançada , Aumento de Peso/genética
14.
J Pediatr Endocrinol Metab ; 26(9-10): 971-4, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23729537

RESUMO

Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.


Assuntos
Síndrome de Denys-Drash/fisiopatologia , Detecção Precoce de Câncer , Gonadoblastoma/etiologia , Achados Incidentais , Neoplasias Testiculares/etiologia , Substituição de Aminoácidos , Síndrome de Denys-Drash/genética , Síndrome de Denys-Drash/patologia , Progressão da Doença , Éxons , Família , Feminino , Identidade de Gênero , Aconselhamento Genético , Gonadoblastoma/diagnóstico , Gonadoblastoma/cirurgia , Gônadas/patologia , Gônadas/cirurgia , Humanos , Lactente , Falência Renal Crônica/etiologia , Masculino , Mutação de Sentido Incorreto , Cirurgia de Readequação Sexual , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/cirurgia , Proteínas WT1/genética
15.
J Neurooncol ; 112(2): 141-52, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23344789

RESUMO

Differentiating post radiation necrosis from progression of glioma and pseudoprogression poses a diagnostic conundrum for many clinicians. As radiation therapy and temozolomide chemotherapy have become the mainstay of treatment for higher-grade gliomas, radiation necrosis and post treatment changes such as pseudoprogression have become a more relevant clinical problem for neurosurgeons and neurooncologists. Due to their radiological similarity to tumor progression, accurate recognition of these findings remains paramount given their vastly different treatment regimens and prognoses. However, no consensus has been reached on the optimal technique to discriminate between these two lesions. In order to clarify the types of imaging modalities for recurrent enhancing lesions, we conducted a systematic review of case reports, case series, and prospective studies to increase our current understanding of the imaging options for these common lesions and their efficacy. In particular, we were interested in distinguishing radiation necrosis from true tumor progression. A PubMed search was performed to include all relevant studies where the imaging was used to differentiate between radiation necrosis and recurrent gliomas with post-radiation enhancing lesions. After screening for certain parameters in our study, seventeen articles with 435 patients were included in our analysis including 10 retrospective and 7 prospective studies. The average time from the end of radiation therapy to the onset of a recurrent enhancing lesion was 13.2 months. The most sensitive and specific imaging modality was SPECT with a sensitivity of 87.6 % and specificity of 97.8 %. Based on our review, we conclude that certain imaging modalities may be preferred over other less sensitive/specific techniques. Overall, tests such as SPECT may be preferable in differentiating TP (tumor progression) from RN (radiation necrosis) due to its high specificity, while nonspecific imaging such as conventional MRI is not ideal.


Assuntos
Neoplasias Encefálicas/diagnóstico , Diagnóstico por Imagem , Glioma/diagnóstico , Lesões por Radiação/diagnóstico , Diagnóstico Diferencial , Progressão da Doença , Humanos , Necrose
16.
Endocrinology ; 151(11): 5157-64, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20861239

RESUMO

Rats selectively bred for low aerobic running capacity exhibit the metabolic syndrome, including hyperinsulinemia, insulin resistance, visceral obesity, and dyslipidemia. They also exhibit features of nonalcoholic steatohepatitis, including chicken-wire fibrosis, inflammation, and oxidative stress. Hyperinsulinemia in these rats is associated with impaired hepatic insulin clearance. The current studies aimed to determine whether these metabolic abnormalities could be reversed by caloric restriction (CR). CR by 30% over a period of 2-3 months improved insulin clearance in parallel to inducing the protein content and activation of the carcinoembryonic antigen-related cell adhesion molecule 1, a main player in hepatic insulin extraction. It also reduced glucose and insulin intolerance and serum and tissue (liver and muscle) triglyceride levels. Additionally, CR reversed inflammation, oxidative stress, and fibrosis in liver. The data support a significant role of CR in the normalization of insulin and lipid metabolism in liver.


Assuntos
Restrição Calórica , Fígado Gorduroso/metabolismo , Resistência à Insulina , Insulina/metabolismo , Fígado/metabolismo , Condicionamento Físico Animal , Análise de Variância , Animais , Western Blotting , Fígado Gorduroso/patologia , Fibrose , Glucose/metabolismo , Metabolismo dos Lipídeos , Fígado/patologia , Masculino , Obesidade/metabolismo , Estresse Oxidativo , Distribuição Aleatória , Ratos
17.
Gastroenterology ; 139(2): 644-52, 652.e1, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20381490

RESUMO

BACKGROUND & AIMS: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein with pleotropic functions, including clearance of hepatic insulin. We investigated the functions of the related protein CEACAM2, which has tissue-specific distribution (kidney, uterus, and crypt epithelia of intestinal tissues), in genetically modified mice. METHODS: Ceacam2-null mice (Cc2-/-) were generated from a 129/SvxC57BL/6J background. Female mice were assessed by hyperinsulinemic-euglycemic clamp analysis and indirect calorimetry and body fat composition was measured. Cc2-/- mice and controls were fed as pairs, given insulin tolerance tests, and phenotypically characterized. RESULTS: Female, but not male Cc2-/- mice exhibited obesity that resulted from hyperphagia and reduced energy expenditure. Pair feeding experiments showed that hyperphagia led to peripheral insulin resistance. Insulin action was normal in liver but compromised in skeletal muscle of female Cc2-/- mice; the mice had incomplete fatty acid oxidation and impaired glucose uptake and disposal. The mechanism of hyperphagia in Cc2-/- mice is not clear, but appears to result partly from increased hyperinsulinemia-induced hypothalamic fatty acid synthase levels and activity. Hyperinsulinemia was caused by increased insulin secretion. CONCLUSIONS: In mice, CEACAM2 is expressed by the hypothalamus. Cc2-/- mice develop obesity from hyperphagia and reduced energy expenditure, indicating its role in regulating energy balance and insulin sensitivity.


Assuntos
Metabolismo Energético , Glicoproteínas/metabolismo , Hiperinsulinismo/metabolismo , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Insulina/sangue , Obesidade/metabolismo , Fatores Etários , Animais , Glicemia/metabolismo , Composição Corporal , Calorimetria Indireta , Moléculas de Adesão Celular , Ácido Graxo Sintase Tipo I/metabolismo , Ácidos Graxos/metabolismo , Comportamento Alimentar , Feminino , Genótipo , Técnica Clamp de Glucose , Glicoproteínas/deficiência , Glicoproteínas/genética , Homeostase , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatologia , Hiperfagia/genética , Hiperfagia/fisiopatologia , Hipotálamo/fisiopatologia , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/fisiopatologia , Oxirredução , Fenótipo , Fatores Sexuais
18.
Endocrinology ; 151(7): 3225-36, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20427484

RESUMO

Although FK506-binding protein 52 (FKBP52) is an established positive regulator of glucocorticoid receptor (GR) activity, an in vivo role for FKBP52 in glucocorticoid control of metabolism has not been reported. To address this question, FKBP52(+/-) mice were placed on a high-fat (HF) diet known to induce obesity, hepatic steatosis, and insulin resistance. Tissue profiling of wild-type mice showed high levels of FKBP52 in the liver but little to no expression in muscle or adipose tissue, predicting a restricted pattern of FKBP52 effects on metabolism. In response to HF, FKBP52(+/-) mice demonstrated a susceptibility to hyperglycemia and hyperinsulinemia that correlated with reduced insulin clearance and reduced expression of hepatic CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a mediator of clearance. Livers of HF-fed mutant mice had high lipid content and elevated expression of lipogenic genes (peroxisome proliferator-activated receptor gamma, fatty acid synthase, and sterol regulatory element-binding protein 1c) and inflammatory markers (TNFalpha). Interestingly, mutant mice under HF showed elevated serum corticosterone, but their steatotic livers had reduced expression of gluconeogenic genes (phosphoenolpyruvate carboxy kinase, glucose 6 phosphatase, and pyruvate dehydrogenase kinase 4), whereas muscle and adipose expressed normal to elevated levels of glucocorticoid markers. These data suggest a state of glucocorticoid resistance arising from liver-specific loss of GR activity. Consistent with this hypothesis, reduced expression of gluconeogenic genes and CEACAM1 was observed in dexamethasone-treated FKBP52-deficient mouse embryonic fibroblast cells. We propose a model in which FKBP52 loss reduces GR control of gluconeogenesis, predisposing the liver to steatosis under HF-diet conditions attributable to a shunting of metabolism from glucose production to lipogenesis.


Assuntos
Fígado Gorduroso/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/fisiologia , Animais , Antígenos CD/genética , Western Blotting , Moléculas de Adesão Celular/genética , Células Cultivadas , Corticosterona/sangue , Gorduras na Dieta/farmacologia , Suscetibilidade a Doenças , Fígado Gorduroso/induzido quimicamente , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/genética , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Receptores de Glucocorticoides/genética , Proteínas de Ligação a Tacrolimo/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Hepat Med ; 2010(2): 69-78, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-21949477

RESUMO

Transgenic liver-specific inactivation of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) impairs hepatic insulin clearance and causes hyperinsuline-mia, insulin resistance, elevation in hepatic and serum triglyceride levels, and visceral obesity. It also predisposes to nonalchoholic steatohepatitis (NASH) in response to a high-fat diet. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we investigated whether Ceacam1 (gene encoding CEACAM1 protein) null mice with impaired insulin clearance also develop a NASH-like phenotype on a prolonged high-fat diet. Three-month-old male null and wild-type mice were fed a high-fat diet for 3 months and their NASH phenotype was examined. While high-fat feeding elevated hepatic triglyceride content in both strains of mice, it exacerbated macrosteatosis and caused NASH-characteristic fibrogenic changes and inflammatory responses more intensely in the null mouse. This demonstrates that CEACAM1-dependent insulin clearance pathways are linked with NASH pathogenesis.

20.
Diabetes ; 57(9): 2296-303, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18544705

RESUMO

OBJECTIVE: Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (l-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene (Cc1(-/-)). RESEARCH DESIGN AND METHODS: Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the Cc1(-/-) and wild-type Cc1(+/+) groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels. RESULTS: Like l-SACC1, Cc1(-/-) mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5-6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred Cc1(-/-) mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic beta-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in Cc1(-/-) mice (inbred and outbred strains). CONCLUSIONS: Intact insulin secretion in response to glucose and impairment of insulin clearance in l-SACC1 and Cc1(-/-) mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver.


Assuntos
Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Animais , Peso Corporal , Células Cultivadas , Genes Dominantes , Técnica Clamp de Glucose , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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