Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49
Filtrar
1.
Cancer Immunol Immunother ; 71(9): 2067-2075, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35092481

RESUMO

Programmed death-1 (PD-1) is a cell surface receptor that functions as a T cell checkpoint and plays a central role in regulating T cell collapse. The binding of PD-1 to its ligand programmed death-ligand 1 (PD-L1) activates downstream signaling pathways and inhibits T cell activation in the perspective of immune system mechanism and regulation in tumor progression. It is well reported that tumors adopt certain immune-checkpoint pathways as a mechanism of resistance against immune cells such as T cells that are specific for tumor antigens. Indeed, the PD-1/PD-L1 pathway controls the induction and maintenance of immune tolerance within the tumor microenvironment. Thus, the PD-1/PD-L1 checkpoint regulation appears to be of extreme importance as well as the immunotherapy targeting that via and the using of PD-1/PD-L1 inhibitors that have changed the scenario of brain cancer treatment and survival. Here, we review the mechanism of action of PD-1 and PD-L1, the PD/PDL-1 signaling pathway involved in the progression of brain tumors, and its application as cancer immunotherapy counteracting tumor escape in central nervous system.


Assuntos
Antígeno B7-H1 , Neoplasias Encefálicas , Proteínas de Checkpoint Imunológico , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/terapia , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunoterapia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral
2.
J Endocrinol Invest ; 43(10): 1373-1389, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32358737

RESUMO

AIM: Over the last decades, the shift in age distribution towards older ages and the progressive ageing which has occurred in most populations have been paralleled by a global epidemic of obesity and its related metabolic disorders, primarily, type 2 diabetes (T2D). Dysfunction of the adipose tissue (AT) is widely recognized as a significant hallmark of the ageing process that, in turn, results in systemic metabolic alterations. These include insulin resistance, accumulation of ectopic lipids and chronic inflammation, which are responsible for an elevated risk of obesity and T2D onset associated to ageing. On the other hand, obesity and T2D, the paradigms of AT dysfunction, share many physiological characteristics with the ageing process, such as an increased burden of senescent cells and epigenetic alterations. Thus, these chronic metabolic disorders may represent a state of accelerated ageing. MATERIALS AND METHODS: A more precise explanation of the fundamental ageing mechanisms that occur in AT and a deeper understanding of their role in the interplay between accelerated ageing and AT dysfunction can be a fundamental leap towards novel therapies that address the causes, not just the symptoms, of obesity and T2D, utilizing strategies that target either senescent cells or DNA methylation. RESULTS: In this review, we summarize the current knowledge of the pathways that lead to AT dysfunction in the chronological ageing process as well as the pathophysiology of obesity and T2D, emphasizing the critical role of cellular senescence and DNA methylation. CONCLUSION: Finally, we highlight the need for further research focused on targeting these mechanisms.


Assuntos
Tecido Adiposo/fisiopatologia , Envelhecimento/fisiologia , Doenças Metabólicas , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/patologia , Senescência Celular/genética , Doença Crônica , Metilação de DNA/fisiologia , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
3.
Mult Scler Relat Disord ; 26: 46-51, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30223228

RESUMO

BACKGROUND: The computerized stabilometric platform can be used and privileged over clinical scales, as self-administered questionnaires to asses postural control and balance evaluation in Multiple sclerosis (MS). Aim of our study was to evaluate static postural control assessed by Neurocom Balance Manager® through the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) in relapsing-remitting MS (RRMS), progressive MS (PMS) and CIS, compared to healthy controls (HC). METHODS: We screened MS patients consecutively referring to our MS Center at University of Catania, during July 2013-June 2014 diagnosed as CIS, RRMS and PMS. All MS patients underwent clinical and neurological evaluations and a complete postural exam by Neurocom Balance Manager® in order to evaluate Center of Pressure (COP), through mCTSIB. We evaluated the following parameters: Total Path Length-open eyes (TPL-OE), Total Path Length-closed eyes (TPL-CE), Sway Area-open eyes (SA-OE), Sway Area-closed eyes (SA-CE), Mean sway velocity-open eyes (MSV-OE), Mean sway velocity-closed eyes (MSV-CE). Additionally, patients were tested by Berg balance scale (BBS) for balance and Barthel Index (BI) for disability outcomes. RESULTS: Out of 170 MS patients assessed for eligibility, 163 met the inclusion/exclusion criteria and were finally enrolled. All balance parameters were found more impaired in MS group compared to controls and CIS. Moreover, no differences in terms of balance assessment were found between HC and CIS. The correlation analysis showed that BBS was strongly associated to SA-OE, SA-CE, TPL-OE and MSV-OE. We also found a correlation between BI and SA-CE. CONCLUSION: Our study revealed significant differences among HCs, CIS and MS. MS, especially PMS, exhibit the worst balance performances especially in EC trials. The higher correlation between balance parameters, especially sway area, and BBS score confirmed the reliability and sensibility of mCTSIB assessment in evaluating static postural control in MS patients.


Assuntos
Teste de Esforço/instrumentação , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Equilíbrio Postural/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
J Endocrinol Invest ; 39(10): 1095-103, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27180180

RESUMO

Type 2 diabetes (T2D) and obesity are the major public health problems. Substantial efforts have been made to define loci and variants contributing to the individual risk of these disorders. However, the overall risk explained by genetic variation is very modest. Epigenetics is one of the fastest growing research areas in biomedicine as changes in the epigenome are involved in many biological processes, impact on the risk for several complex diseases including diabetes and may explain susceptibility. In this review, we focus on the role of DNA methylation in contributing to the risk of T2D and obesity.


Assuntos
Diabetes Mellitus Tipo 2/genética , Epigênese Genética/genética , Obesidade/genética , Humanos
5.
Int J Obes (Lond) ; 40(6): 929-37, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26980478

RESUMO

BACKGROUND/OBJECTIVES: The genomic bases of the adipose tissue abnormalities induced by chronic positive calorie excess have been only partially elucidated. We adopted a genome-wide approach to directly test whether long-term high-fat diet (HFD) exposure affects the DNA methylation profile of the mouse adipose tissue and to identify the functional consequences of these changes. SUBJECTS/METHODS: We have used epididymal fat of mice fed either high-fat (HFD) or regular chow (STD) diet for 5 months and performed genome-wide DNA methylation analyses by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mouse Homeobox (Hox) Gene DNA Methylation PCR, RT-qPCR and bisulphite sequencing analyses were then performed. RESULTS: Mice fed the HFD progressively expanded their adipose mass accompanied by a significant decrease in glucose tolerance (P<0.001) and insulin sensitivity (P<0.05). MeDIP-seq data analysis revealed a uniform distribution of differentially methylated regions (DMR) through the entire adipocyte genome, with a higher number of hypermethylated regions in HFD mice (P<0.005). This different methylation profile was accompanied by increased expression of the Dnmt3a DNA methyltransferase (Dnmt; P<0.05) and the methyl-CpG-binding domain protein Mbd3 (P<0.05) genes in HFD mice. Gene ontology analysis revealed that, in the HFD-treated mice, the Hox family of development genes was highly enriched in differentially methylated genes (P=0.008). To validate this finding, Hoxa5, which is implicated in fat tissue differentiation and remodeling, has been selected and analyzed by bisulphite sequencing, confirming hypermethylation in the adipose tissue from the HFD mice. Hoxa5 hypermethylation was associated with downregulation of Hoxa5 mRNA and protein expression. Feeding animals previously exposed to the HFD with a standard chow diet for two further months improved the metabolic phenotype of the animals, accompanied by return of Hoxa5 methylation and expression levels (P<0.05) to values similar to those of the control mice maintained under standard chow. CONCLUSIONS: HFD induces adipose tissue abnormalities accompanied by epigenetic changes at the Hoxa5 adipose tissue remodeling gene.


Assuntos
Tecido Adiposo/metabolismo , Metilação de DNA , Dieta Hiperlipídica , Regulação para Baixo , Proteínas de Homeodomínio/genética , Fosfoproteínas/genética , Transcrição Gênica , Animais , Modelos Animais de Doenças , Epigênese Genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Fatores de Transcrição
6.
J Neurosci Res ; 93(3): 521-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25388553

RESUMO

Astrocyte activity may be modulated by steroid hormones and GFs. This study investigates the interaction between glucocorticoids or estrogens and GFs on the expression of heme oxygenase-1 (HO-1) and cyclin D1 in astrocyte cultures at 14 days treated for 48 or 60 hr with dexamethasone (DEX) or 48 hr with 17ß-estradiol (E2) alone or with GFs added only in the last 12 or 24 hr. Twelve- or twenty-four-hour epidermal growth factor (EGF) treatment significantly enhanced HO-1 expression in astrocyte cultures pretreated for 48 hr with DEX. A highly significant increase in HO-1 expression was obtained after the last-12-hr EGF treatment in 48-hr E2-pretreated astrocyte cultures; this enhancement was particularly significant in 48-hr E2-pretreated cultures as well as in the last-12-hr insulin-treated ones pretreated for 48 hr with E2. Sixty-hour DEX-alone pretreatment as well as the last-12-hr EGF treatment in 60-hr DEX-pretreated astrocyte cultures showed a significant increase of cyclin D1 expression. A significant decrease of cyclin D1 expression in the last-12-hr insulin-like growth factor-I (IGF-1)-treated cultures pretreated for 60 hr with DEX was observed. A highly significant enhancement in cyclin D1 expression in 14 days in vitro astrocyte cultures pretreated with E2 alone for 48 hr and treated in the last 12 hr with IGF-1 in 48-hr E2-pretreated cultures was found. Finally, the data highlight an interactive dialogue between the growth factors and glucocorticoids or estrogens during the maturation of astroglial cells in culture that may control the HO-1 and cyclin D1 expression as well as proliferating astroglial cells during the cell cycle.


Assuntos
Astrócitos/efeitos dos fármacos , Ciclina D1/metabolismo , Dexametasona/farmacologia , Estradiol/farmacologia , Glucocorticoides/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Animais , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Esquema de Medicação , Ratos , Ratos Wistar
7.
G Chir ; 35(3-4): 75-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24841683

RESUMO

OBJECTIVE: Multiple and bilateral ovarian dermoid cysts constitute a very unusual report. We report an rare case of a woman with three ovarian dermoid cyst, two localized in the same ovary, detected by US examination and removed by laparoscopy. CASE REPORT: A patient aged 29 years, para 0, gravida 0, was referred to our hospital with pain of the right adnexal region. Gynaecological examination showed an antiverted uterus with normal volume; on the right side a mobile mass approximately 7 cms in diameter was palpable, moreover the left ovary was normal. Ultrasound examination showed a normal uterus. The right ovary presented two complex masses of 7 and 3 cm in diameter, respectively; moreover, the left ovary showed a hyperechogenic complex mass of 3 cm in diameter. The ultrasound pattern was compatible with bilateral ovarian dermoid cysts. On laparoscopy abdominal cavity and uterus were normal, while the right ovary presented two masses and the left ovary a small mass which were enucleated and removed. The patient had an uncomplicated postoperative recovery and was discharged two day after laparoscopy. Pathologic examination confirmed the diagnosis of ovarian dermoid cysts. A one year follow-up showed no evidence of recurrence. CONCLUSION: The case reported shows that exceptionally multiple and bilateral dermoid cysts may be detected underlining the importance of an accurate preoperative diagnostic imaging. Some recurrence of ovarian dermoid cysts may be due to undiagnosed small dermoid cists during preoperative imaging and/or surgical exploration.


Assuntos
Cisto Dermoide/diagnóstico por imagem , Cisto Dermoide/cirurgia , Laparoscopia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/cirurgia , Adulto , Cisto Dermoide/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia , Doenças Raras , Resultado do Tratamento , Ultrassonografia
8.
Phys Med Biol ; 57(22): 7651-71, 2012 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-23123643

RESUMO

Nuclear fragmentation measurements are necessary when using heavy-ion beams in hadrontherapy to predict the effects of the ion nuclear interactions within the human body. Moreover, they are also fundamental to validate and improve the Monte Carlo codes for their use in planning tumor treatments. Nowadays, a very limited set of carbon fragmentation cross sections are being measured, and in particular, to our knowledge, no double-differential fragmentation cross sections at intermediate energies are available in the literature. In this work, we have measured the double-differential cross sections and the angular distributions of the secondary fragments produced in the (12)C fragmentation at 62 A MeV on a thin carbon target. The experimental data have been used to benchmark the prediction capability of the Geant4 Monte Carlo code at intermediate energies, where it was never tested before. In particular, we have compared the experimental data with the predictions of two Geant4 nuclear reaction models: the Binary Light Ions Cascade and the Quantum Molecular Dynamic. From the comparison, it has been observed that the Binary Light Ions Cascade approximates the angular distributions of the fragment production cross sections better than the Quantum Molecular Dynamic model. However, the discrepancies observed between the experimental data and the Monte Carlo simulations lead to the conclusion that the prediction capability of both models needs to be improved at intermediate energies.


Assuntos
Carbono/uso terapêutico , Radioterapia com Íons Pesados/métodos , Método de Monte Carlo , Carbono/química , Humanos
9.
Diabetologia ; 54(11): 2911-22, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21842266

RESUMO

AIMS/HYPOTHESIS: ANKRD26 is a newly described gene located at 10p12 in humans, a locus that has been identified with some forms of hereditary obesity. Previous studies have shown that partial inactivation of Ankrd26 in mice causes hyperphagia, obesity and gigantism. Hypothesising that Ankrd26 mutant (MT) mice could develop diabetes, we sought to establish whether the observed phenotype could be (1) solely related to the development of obesity or (2) caused by a direct action of ankyrin repeat domain 26 (ANKRD26) in peripheral tissues. METHODS: To test the hypothesis, we did a full metabolic characterisation of Ankrd26 MT mice that had free access to chow or were placed under two different energy-restricted dietary regimens. RESULTS: Highly obese Ankrd26 MT mice developed an unusual form of diabetes in which white adipose tissue is insulin-sensitive, while other tissues are insulin-resistant. When obese MT mice were placed on a food-restricted diet, their weight and glucose homeostasis returned to normal. In addition, when young MT mice were placed on a pair-feeding diet with normal mice, they maintained normal body weight, but showed better glucose tolerance than normal mice, an increased responsiveness of white adipose tissue to insulin and enhanced phosphorylation of the insulin receptor. CONCLUSIONS/INTERPRETATION: These findings show that the ANKRD26 protein has at least two functions in mice. One is to control the response of white adipose tissue to insulin; the other is to control appetite, which when Ankrd26 is mutated, leads to hyperphagia and diabetes in an obesity-dependent manner.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteínas de Ligação a DNA/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Insulina/metabolismo , Obesidade/fisiopatologia , Receptor de Insulina/metabolismo , Transdução de Sinais , Fatores de Transcrição/fisiologia , Animais , Regulação do Apetite , Restrição Calórica , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Modelos Animais de Doenças , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Mutantes/fisiologia , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/prevenção & controle , Especificidade de Órgãos , Fosforilação , Processamento de Proteína Pós-Traducional , Distribuição Aleatória , Fatores de Transcrição/genética
10.
Diabetologia ; 54(7): 1879-87, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21461637

RESUMO

AIMS/HYPOTHESIS: We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. METHODS: Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. RESULTS: Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. CONCLUSIONS/INTERPRETATION: Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.


Assuntos
Resistência à Insulina/fisiologia , Proteínas Nucleares/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adolescente , Adulto , Idoso , Animais , Western Blotting , Linhagem Celular , Feminino , Células Hep G2 , Humanos , Técnicas In Vitro , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Obesidade/genética , Fosfoproteínas Fosfatases/genética , Ratos , Adulto Jovem
11.
Diabetologia ; 53(7): 1482-92, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20396999

RESUMO

AIMS/HYPOTHESIS: Overexpression of PED (also known as PEA15) determines insulin resistance and impaired insulin secretion and may contribute to progression toward type 2 diabetes. Recently, we found that the transcription factor hepatocyte nuclear factor (HNF)-4alpha binds to PED promoter and represses its transcription. However, the molecular details responsible for regulation of PED gene remain unclear. METHODS: Here we used gain and loss of function approaches to investigate the hypothesis that HNF-4alpha controls chromatin remodelling at the PED promoter in human cell lines. RESULTS: HNF-4alpha production and binding induce chromatin remodelling at the -250 to 50 region of PED, indicating that remodelling is limited to two nucleosomes located at the proximal promoter. Chromatin immunoprecipitation assays also revealed concomitant HNF-4alpha-induced deacetylation of histone H3 at Lys9 and Lys14, and increased dimethylation of histone H3 at Lys9. The latter was followed by reduction of histone H3 Lys4 dimethylation. HNF-4alpha was also shown to target the histone deacetylase complex associated with silencing mediator of retinoic acid and thyroid hormone receptor, both at the PED promoter, and at GRB14 and USP21 regulatory regions, leading to a reduction of mRNA levels. Moreover, HNF-4alpha silencing and PED overexpression were accompanied by a significant reduction of hepatic glycogen content. CONCLUSIONS/INTERPRETATION: These results show that HNF-4alpha serves as a scaffold protein for histone deacetylase activities, thereby inhibiting liver expression of genes including PED. Dysregulation of these mechanisms may lead to upregulation of the PED gene in type 2 diabetes.


Assuntos
Epigênese Genética/fisiologia , Fator 4 Nuclear de Hepatócito/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/metabolismo , Acetilação , Animais , Proteínas Reguladoras de Apoptose , Western Blotting , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/fisiologia , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Células Hep G2 , Fator 4 Nuclear de Hepatócito/genética , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Transgênicos , Nucleossomos/genética , Fosfoproteínas/genética , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Diabetologia ; 53(5): 955-65, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20165829

RESUMO

AIMS/HYPOTHESIS: Glucosamine, generated during hyperglycaemia, causes insulin resistance in different cells. Here we sought to evaluate the possible role of endoplasmic reticulum (ER) stress in the induction of insulin resistance by glucosamine in skeletal muscle cells. METHODS: Real-time RT-PCR analysis, 2-deoxy-D: -glucose (2-DG) uptake and western blot analysis were carried out in rat and human muscle cell lines. RESULTS: In both rat and human myotubes, glucosamine treatment caused a significant increase in the expression of the ER stress markers immunoglobulin heavy chain-binding protein/glucose-regulated protein 78 kDa (BIP/GRP78 [also known as HSPA5]), X-box binding protein-1 (XBP1) and activating transcription factor 6 (ATF6). In addition, glucosamine impaired insulin-stimulated 2-DG uptake in both rat and human myotubes. Interestingly, pretreatment of both rat and human myotubes with the chemical chaperones 4-phenylbutyric acid (PBA) or tauroursodeoxycholic acid (TUDCA), completely prevented the effect of glucosamine on both ER stress induction and insulin-induced glucose uptake. In both rat and human myotubes, glucosamine treatment reduced mRNA and protein levels of the gene encoding GLUT4 and mRNA levels of the main regulators of the gene encoding GLUT4 (myocyte enhancer factor 2 a [MEF2A] and peroxisome proliferator-activated receptor-gamma coactivator 1alpha [PGC1alpha]). Again, PBA or TUDCA pretreatment prevented glucosamine-induced inhibition of GLUT4 (also known as SLC2A4), MEF2A and PGC1alpha (also known as PPARGC1A). Finally, we showed that overproduction of ATF6 is sufficient to inhibit the expression of genes GLUT4, MEF2A and PGC1alpha and that ATF6 silencing with a specific small interfering RNA is sufficient to completely prevent glucosamine-induced inhibition of GLUT4, MEF2A and PGC1alpha in skeletal muscle cells. CONCLUSIONS/INTERPRETATION: In this work we show that glucosamine-induced ER stress causes insulin resistance in both human and rat myotubes and impairs GLUT4 production and insulin-induced glucose uptake via an ATF6-dependent decrease of the GLUT4 regulators MEF2A and PGC1alpha.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Retículo Endoplasmático/metabolismo , Glucosamina/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fator 6 Ativador da Transcrição/genética , Análise de Variância , Animais , Western Blotting , Linhagem Celular , Células Cultivadas , Imunoprecipitação da Cromatina , Relação Dose-Resposta a Droga , Retículo Endoplasmático/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Glucosamina/farmacologia , Glucose/metabolismo , Glucose/farmacologia , Transportador de Glucose Tipo 4/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Insulina/metabolismo , Insulina/farmacologia , Resistência à Insulina/fisiologia , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Fatores de Transcrição MEF2 , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fatores de Regulação Miogênica/genética , Fatores de Regulação Miogênica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Phys Rev Lett ; 102(15): 152701, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19518626

RESUMO

The A/Z dependence of projectile fragmentation at relativistic energies has been studied with the ALADIN forward spectrometer at SIS. A stable beam of (124)Sn and radioactive beams of (124)La and (107)Sn at 600 MeV per nucleon have been used in order to explore a wide range of isotopic compositions. Chemical freeze-out temperatures are found to be nearly invariant with respect to the A/Z of the produced spectator sources, consistent with predictions for expanded systems. Small Coulomb effects (DeltaT approximately 0.6 MeV) appear for residue production near the onset of multifragmentation.

14.
Clin Exp Hypertens ; 30(8): 798-807, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19021029

RESUMO

The aim of the present investigation was to study the effects of choline and choline-containing phospholipids CDP-choline (CDPC) and L-alpha-glyceryl-phosphorylcholine (AGPC) on transglutaminase (TG) activity and expression in primary astrocyte cultures. TG is an important Ca(2+)-dependent protein that represents a normal constituent of nervous systems during fetal stages of development, playing a role in cell signal transduction, differentiation, and apoptosis. Confocal laser scanning microscopy (CLSM) analysis showed an increase of TG activity in astrocyte cultures treated with choline, CDPC, or AGPC at 0.1 microM or 1 microM concentrations. Comparatively, AGPC induced the most conspicuous effects enhancing monodansyl-cadaverine fluorescence both in cytosol and in nuclei, supporting the evidence of the important role played by AGPC throughout differentiation processes tightly correlated to nucleus-cytosol cross- talk during astroglial cells proliferation and development. Western blot analysis showed that in 24h 1 microM AGPC and choline-treated astrocytes increased TG-2, whereas no effect was observed in 24h 1 microM CDP-choline treated astrocytes. Our data suggest a crucial role of choline precursors during different stages of astroglial cell proliferation and differentiation in cultures.


Assuntos
Astrócitos/enzimologia , Citidina Difosfato Colina/farmacologia , Glicerilfosforilcolina/farmacologia , Nootrópicos/farmacologia , Transglutaminases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ratos , Ratos Wistar
15.
Neurochem Res ; 33(12): 2601-8, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18841472

RESUMO

Effects of acetylcholine and of the cholinergic precursors choline, cytidine 5'-diphosphocholine (CDP-choline) and alpha-glyceryl-phosphorylcholine (alpha-GPC) on transglutaminase (TG) and cyclin D1 expression were studied in primary astrocyte cultures by confocal laser microscopy (CLSM) with monodansyl-cadaverine uptake as a marker of enzyme activity and by immunochemistry (Western blotting). CLSM analysis showed an increased cytofluorescence in 0.1 microM choline-treated astrocytes. Treatment with CDP-choline dose-dependently increased TG. A total of 1 microM CDP-choline exposure in 14 days in vitro (DIV) astrocyte cultures increased cytofluorescence. A total of 1 microM alpha-GPC 24 h-treated cultures revealed increased cytofluorescence both in cytosol and nuclei. Western blot analysis showed an increased TG expression in cultures exposed for 24 h to 1 microM choline or alpha-GPC, whereas in 24 h 1 microM CDP-choline and acetylcholine-treated astrocytes TG expression was unaffected. Treatment with 1 microM acetylcholine reduced TG expression at 21 DIV. In cultures at 14 and 35 DIV cholinergic precursor treatment for 24 h induced a marked down-regulation of cyclin D1 expression, with reduced cyclin D1 expression in 1 microM alpha-GPC treated astrocytes. Our data suggest a role of cholinergic precursors investigated independent from acetylcholine on maturation and differentiation of astroglial cells in vitro, rather than on their growth, proliferation and development in culture.


Assuntos
Acetilcolina/farmacologia , Astrócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Acetilcolina/química , Animais , Astrócitos/citologia , Western Blotting , Células Cultivadas , Ratos , Ratos Wistar
16.
Phys Rev Lett ; 100(19): 192503, 2008 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-18518446

RESUMO

Two-proton decay from (18)Ne excited states has been studied by complete kinematical reconstruction of the decay products. The (18)Ne nucleus has been produced as a radioactive beam by (20)Ne primary projectile fragmentation at 45 AMeV incident energy on a Be target. The (18)Ne at 33 AMeV incident energy has been excited via Coulomb excitation on a (nat)Pb target. The obtained results unambiguously show that the 6.15 MeV (18)Ne state two-proton decay proceeds through a (2)He diproton resonance (31%) and democratic or virtual sequential decay (69%). The quoted branching ratio has been deduced from relative angle and momentum correlations of the emitted proton pairs.

17.
J Neurosci Res ; 86(6): 1297-305, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18041095

RESUMO

Type-2 transglutaminase (TG-2) is a multifunctional enzyme involved in the regulation of cell differentiation and survival that recently has been shown to play an emerging role in astrocytes, where it is involved in both proliferation and differentiation processes. Growth factors (GFs) such as EGF, basic fibroblast growth factor, insulin-like growth factor-I (IGF-I), and insulin (INS) are trophic and mitogenic peptides that participate in neuron-glia interactions and stimulate neuronal and astroglial proliferation and differentiation. Steroid hormones such as glucocorticoids and estrogens also play a pivotal role in neuronal and astroglial proliferation and differentiation and are key hormones in neurodegenerative and neuroprotective processes. We investigated the effects of the interaction of GFs with dexamethasone (DEX) or 17beta-estradiol (E(2)) on TG-2 activity and their expression in cultured astrocytes. We observed a significant increase in TG-2 activity and expression in astroglial cells treated for 24 hr with IGF-I, EGF, or INS. Priming of the cells with DEX or E(2), for 48 hr also led to an increase in TG-2 levels. When growth factors were present in the last 24 hr of the steroid treatment, a reduction in TG-2 expression and activity and a different subcellular TG-2 distribution were found. Our data indicate that steroid hormone-GF interaction may play an important role in astroglial function. The effect on TG-2 could be part of the regulation of intracellular pathways associated with the astrocyte response observed in physiological conditions and, possibly, also in neuropathological diseases.


Assuntos
Astrócitos/metabolismo , Dexametasona/metabolismo , Estradiol/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Transglutaminases/metabolismo , Animais , Western Blotting , Células Cultivadas , Imunofluorescência , Microscopia Confocal , Proteína 2 Glutamina gama-Glutamiltransferase , Ratos , Esteroides/metabolismo
18.
Diabetologia ; 49(12): 3058-66, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17021921

RESUMO

AIMS/HYPOTHESIS: Overexpression of the gene encoding phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED), causes insulin resistance and diabetes in transgenic mice and has been observed in type 2 diabetic individuals. The aim of this study was to investigate whether PEA15 overexpression occurs in individuals at high risk of diabetes and whether it is associated with specific type 2 diabetes subphenotypes. SUBJECTS AND METHODS: We analysed PEA15 expression in euglycaemic first-degree relatives (FDR) of type 2 diabetic subjects. RESULTS: The expression of PEA15 in peripheral blood leucocytes (PBLs) paralleled that in fat and skeletal muscle tissues. In PBLs from the FDR, PEA15 expression was two-fold higher than in euglycaemic individuals with no family history of diabetes (control subjects), both at the protein and the mRNA level (p < 0.001). The expression of PEA15 was comparable in FDR and type 2 diabetic subjects and in each group close to one-third of the subjects expressed PEA15 levels more than 2 SD higher than the mean of control subjects. Subjects with IFG with at least one type 2 diabetes-affected FDR also overexpressed PEA15 (p < 0.05). In all the groups analysed, PEA15 expression was independent of sex and unrelated to age, BMI, waist circumference, systolic and diastolic BP, and fasting cholesterol, triacylglycerol and glucose levels. However, in euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r = -557, p = 0.01). CONCLUSIONS/INTERPRETATION: We conclude that PEA15 overexpression represents a common defect in FDR of patients with type 2 diabetes and is correlated with reduced insulin sensitivity in these individuals.


Assuntos
Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Resistência à Insulina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/genética , Adulto , Proteínas Reguladoras de Apoptose , Glicemia/metabolismo , Primers do DNA , Diabetes Mellitus Tipo 2/fisiopatologia , Família , Feminino , Humanos , Masculino , Fosfoproteínas/metabolismo , RNA/genética , RNA/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Phys Rev Lett ; 94(16): 162701, 2005 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15904219

RESUMO

Isotopic effects in the fragmentation of excited target residues following collisions of 12C on (112,124)Sn at incident energies of 300 and 600 MeV per nucleon were studied with the INDRA 4pi detector. The measured yield ratios for light particles and fragments with atomic number Z < or = 5 obey the exponential law of isotopic scaling. The deduced scaling parameters decrease strongly with increasing centrality to values smaller than 50% of those obtained for the peripheral event groups. Symmetry-term coefficients, deduced from these data within the statistical description of isotopic scaling, are near gamma = 25 MeV for peripheral and gamma < 15 MeV for central collisions.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...