RESUMO
BACKGROUND: The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison with non-EAOC. METHODS: After we searched an electronic search to identify relevant studies published online between January 1990 and December 2012, we found 20 case-control and 15 cohort studies including 444,255 patients from 1,625 potentially relevant studies. In the meta-analysis, ovarian cancer risk by endometriosis and clinicopathologic characteristics were evaluated using risk ratio (RR) or standard incidence ratio (SIR), and prognosis was investigated using hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was evaluated using Higgins I(2) to select fixed-effect (I(2) ≤50%) or random effects models (I(2)>50%), and found no publication bias using funnel plots with Egger's test (P>0.05). Furthermore, we performed subgroup analyses based on study design, assessment of endometriosis, histology, disease status, quality of study and adjustment for potential confounding factors to minimise bias. RESULTS: Endometriosis increased ovarian cancer risk in case-control or two-arm cohort studies (RR, 1.265; 95% CI, 1.214-1.318) and single-arm cohort studies (SIR, 1.797; 95% CI, 1.276-2.531), which were similar in subgroup analyses. Although progression-free survival was not different between EAOC and non-EAOC (HR, 1.023; 95% CI, 0.712-1.470), EAOC was associated with better overall survival than non-EAOC in crude analyses (HR, 0.778; 95% CI, 0.655-0.925). However, progression-free survival and overall survival were not different between the two groups in subgroup analyses. Stage I-II disease, grade 1 disease and nulliparity were more common in EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367-2.807, 1.149-1.514 and 1.245-1.415), whereas probability of optimal debulking surgery was not different between the two groups (RR, 1.403; 95% CI, 0.915-2.152). Furthermore, endometrioid and clear cell carcinomas were more common in EAOC (RRs, 1.759 and 2.606; 95% CIs, 1.551-1.995 and 2.225-3.053), whereas serous carcinoma was less frequent in EAOC than in non-EAOC (RR, 0.733; 95% CI, 0.617-0.871), and there was no difference in the risk of mucinous carcinoma between the two groups (RR, 0.805; 95% CI, 0.584-1.109). These clinicopathologic characteristics were also similar in subgroup analyses. CONCLUSIONS: Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma. However, endometriosis may not affect disease progression after the onset of ovarian cancer.
Assuntos
Endometriose/epidemiologia , Neoplasias Ovarianas/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Prognóstico , Fatores de RiscoRESUMO
Syringaldehyde is one of the active principles from the stems of Hibiscus taiwanensis (Malvaceae) that has been mentioned to lower hyperglycemia. However, the potential mechanisms for this action of syringaldehyde remain obscure. In the present study, we used streptozotocin to induce diabetic rats (STZ-diabetic rats) as type 1-like diabetic rats and fed fructose-rich chow to rats as type 2-like diabetic rats. Then, we performed the postprandial glucose test and applied the hyperinsulinemic euglycemic clamp to investigate the actions of syringaldehyde. Also, the changes of gene expressions of enzyme relating to glucose homeostasis in muscle and liver were characterized. Syringaldehyde significantly decreased the postprandial plasma glucose in rats, while the plasma insulin was not modified by syringaldehyde. The glucose infusion rate (GIR) in fructose chow-fed rats using hyperinsulinemic euglycemic clamp was markedly improved by syringaldehyde. Additionally, repeated administration of syringaldehyde for 3 days in STZ-diabetic rats resulted in a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Our results suggest that syringaldehyde may increase glucose utilization to lower hyperglycemia in diabetic rats.
Assuntos
Benzaldeídos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Período Pós-Prandial , Animais , Benzaldeídos/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/enzimologia , Frutose , Técnica Clamp de Glucose , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/sangue , Hiperglicemia/complicações , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Imidazoline I1-receptor (I1R) is known to regulate the blood pressure, and rilmenidine, as the agonist, is used to treat hypertension in clinics. However, the role of I1R in obesity is still unclear. In the present study, we investigated the changes of obesity by activation of I1R in high fat diet (HFD)-fed mice. Chronic administration of rilmenidine into HFD-fed mice for 8 weeks significantly reduced body weight, which was reversed by efaroxan at the dose sufficient to block I1R. Also, rilmenidine significantly decreased the energy intake of HFD-fed mice. This reduction of energy intake was abolished by efaroxan at the same dosing for blockade of I1R. However, hypothalamic I1R protein expression in HFD-fed mice was markedly lower than that in normal chow-fed mice. In addition, epididymal white adipose tissue (eWAT) cell size in HFD-fed mice was decreased by rilmenidine via the activation of I1R. Moreover, effect of rilmenidine on appetite disappeared in db/db mice. Taken together, we suggest that rilmenidine can improve obesity in HFD-fed mice through an activation of I1R to ameliorate energy intake and eWAT accumulation.
Assuntos
Receptores de Imidazolinas/metabolismo , Obesidade/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Humanos , Receptores de Imidazolinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/genética , Oxazóis/administração & dosagem , RilmenidinaRESUMO
Recent work using radioactive tracer indicates that activation of imidazoline I2 receptor (I2R) by guanidinium derivatives may increase the glucose uptake in the skeletal muscle. However, the effect of I2R activation on nonradioactive glucose uptake is still unknown. The ability of glucose uptake in cultured L6 cells is then determined using 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) as a fluorescence indicator. The changes in 5'-AMP-activated protein kinase (AMPK) expression were also identified by Western blot analysis. In the present study, 2-(2-benzofuranyl)-2-imidazoline (2-BFI) is used to stimulate I2R while 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) is applied to activate AMPK directly. Both compounds can increase 2-NBDG in L6 cells in a concentration-dependent manner. Meanwhile, compound C at concentrations sufficient to inhibit AMPK blocked this increase of glucose uptake by 2-BFI or AICAR. However, only 2-BFI-induced glucose uptake action was dose-dependently blocked by BU224, a specific I2R antagonist, in L6 cells. Moreover, AMPK phosphorylation was markedly increased by 2-BFI or AICAR in L6 cells. Similarly, only the effect of 2-BFI was attenuated by BU224 in L6 cells. Thus, we suggest that AMPK is mediated in I2R activation for increase of glucose uptake in the skeletal muscle cell and I2R will be a new target for diabetic therapy.
Assuntos
Adenilato Quinase/metabolismo , Glucose/metabolismo , Receptores de Imidazolinas/metabolismo , Células Musculares/enzimologia , Adenilato Quinase/antagonistas & inibidores , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Benzofuranos/farmacologia , Linhagem Celular , Imidazóis/farmacologia , Receptores de Imidazolinas/antagonistas & inibidores , Metformina/farmacologia , Células Musculares/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ribonucleotídeos/farmacologiaRESUMO
Insulin resistance (IR) is known as a main problem in diabetic disorders. Some animal models for research in IR have been mentioned. Each model shows merit with some disadvantages. Thus, a new animal model for IR is required. The present study used zymosan, a mixture of cell-wall particles from the yeast named Saccharomyces cerevisiae, to establish a new model of IR in mice. Also, we compared the difference of this model with fructose-rich chow-induced model and found some merits of this model. Moreover, we identified that this model induced by zymosan is reversible and IR can be reversed gradually after termination of treatment. Taken together, we suggest zymosan as a useful agent to induce IR through inflammatory pathway in mice.
Assuntos
Modelos Animais de Doenças , Resistência à Insulina , Camundongos , Zimosan/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Dieta/efeitos adversos , Frutose/efeitos adversos , Masculino , Camundongos Endogâmicos BALB C , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/reabilitação , Recuperação de Função FisiológicaRESUMO
Imidazoline I1-receptors (I1R) are known to regulate blood pressure and rilmenidine, an agonist, is widely used as antihypertensive agent in clinic. However, the role of I1R in feeding behavior is still unclear. In the present study, we used the agonist of I1R to investigate the effect on hyperphagia in streptozotocin (STZ)-induced diabetic mice. Rilmenidine decreased the food intake of STZ-diabetic mice in a dose-dependent manner. The reduction of food intake was abolished by pretreatment with efaroxan at the dose sufficient to block I1R. Intracerebroventricular (icv) administration of rilmenidine into STZ-diabetic mice also significantly reduced hyperphagia, which was reversed by icv administration of efaroxan. In addition, similar results were observed in STZ-diabetic mice, which received chronic treatment with rilmenidine 3 times daily (t.i.d.) for 7 days. Moreover, the hypothalamic neuropeptide Y (NPY) level was reduced by rilmenidine that was also reversed by pretreatment with efaroxan. In conclusion, the obtained results suggest that rilmenidine can decrease food intake in STZ-diabetic mice through an activation of I1R to lower hypothalamic NPY level.
Assuntos
Cérebro/metabolismo , Diabetes Mellitus Tipo 1/genética , Hiperfagia/genética , Receptores de Imidazolinas/genética , Animais , Benzofuranos/administração & dosagem , Cérebro/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Humanos , Hiperfagia/tratamento farmacológico , Hiperfagia/metabolismo , Hiperfagia/fisiopatologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Imidazóis/administração & dosagem , Receptores de Imidazolinas/agonistas , Receptores de Imidazolinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuropeptídeo Y/metabolismo , Oxazóis/administração & dosagem , Rilmenidina , Estreptozocina/efeitos adversosRESUMO
Allantoin, an active principle of the yam, belongs to the group of guanidinium derivatives and has been reported to lower plasma glucose in diabetic animals. Recent evidence indicates that activation of the imidazoline I(2B) receptor (I(2B)R) by guanidinium derivatives also increases glucose uptake; however, the effect of allantoin on I(2B)R is still unknown. Glucose uptake into cultured C2C12 cells was determined using 2-[¹4C]-deoxy-D-glucose as a tracer. The changes in 5'-AMP-activated protein kinase (AMPK) expression were also identified by Western blotting analysis. The allantoin-induced glucose uptake action was dose-dependently blocked by BU224, a specific I2R antagonist, in C2C12 cells. Moreover, AMPK phosphorylation by allantoin was found to be dose-dependently increased in C2C12 cells using AICAR treatment as a reference. In addition, both actions of allantoin, the increases in glucose uptake and AMPK phosphorylation, were dose-dependently attenuated by amiloride in C2C12 cells. Moreover, compound C at concentrations sufficient to inhibit AMPK blocked the allantoin-induced glucose uptake and AMPK phosphorylation. Thus, we suggest that allantoin can activate I(2B)R to increase glucose uptake into cells, and propose I(2B)R as a new target for diabetic therapy.
Assuntos
Alantoína/farmacologia , Glucose/metabolismo , Receptores de Imidazolinas/metabolismo , Extratos Vegetais/farmacologia , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Dioscorea/química , Humanos , Receptores de Imidazolinas/genética , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismoRESUMO
Allantoin is known as the agonist of imidazoline receptor, especially the I2 subtype. Effect of allantoin on imidazoline I1 receptor (I1R) relating to reduction of blood pressure and its merit in steatosis are still obscure. Also, farnesoid X receptor (FXR) plays an important role in lipid homeostasis related to I1R activation. Thus, we administered allantoin into high fat diet (HFD)-fed mice showing hypertriglyceridemia and hypercholesterolemia. Allantoin significantly improved hyperlipidemia in HFD mice after 4 weeks of administration. Pretreatment with efaroxan, at a dose sufficient to inhibit I1R activation, attenuated the action of allantoin. In addition, in cultured HepG2 cells, allantoin increased the expression of farnesoid X receptor (FXR). The allantoin-induced FXR expression was blocked by efaroxan. Similar changes were observed in the expressions of FXR-targeted genes. Otherwise, allantoin also lowered systolic blood pressure (SBP) in HFD mice that can be blocked by efaroxan. Taken together, allantoin has an ability to activate I1R for improvement of metabolic disorders.
Assuntos
Alantoína/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Receptores de Imidazolinas/agonistas , Fígado/efeitos dos fármacos , Alantoína/antagonistas & inibidores , Alantoína/farmacologia , Animais , Anticolesterolemiantes/antagonistas & inibidores , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Anti-Hipertensivos/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Benzofuranos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Células Hep G2 , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipercolesterolemia/patologia , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/patologia , Hipolipemiantes/antagonistas & inibidores , Hipolipemiantes/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/antagonistas & inibidores , Receptores de Imidazolinas/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i. c. v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K (ATP) channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i. c. v. pretreatment with insulin antibody or glibenclamide. Also, i. c. v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K (ATP) channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Insulisina/antagonistas & inibidores , Tiorfano/análogos & derivados , Animais , Anticorpos/imunologia , Glicemia/efeitos dos fármacos , Glibureto/administração & dosagem , Glibureto/farmacologia , Injeções Intravenosas , Injeções Intraventriculares , Insulina/imunologia , Insulina/metabolismo , Insulisina/metabolismo , Canais KATP/metabolismo , Masculino , Ratos , Ratos Wistar , Tiorfano/administração & dosagem , Tiorfano/farmacologia , Extratos de Tecidos , Vagotomia , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
Metformin (dimethylbiguanide) belongs to guanidinium-derivative and is widely used for treatment of diabetic disorders in clinic. Metformin lowers blood glucose in diabetic animals through increase of glucose uptake into skeletal muscle. Recent evidence indicates that activation of imidazoline I2B receptor (I2BR) by guanidinium-derivatives also increased glucose uptake; however, the effect of metformin on I2BR is still unknown. The blood glucose levels were determined by a glucose kit. The ability of glucose uptake into isolated skeletal muscle or cultured C2C12 cells was determined using 2-[14C]-deoxyglucose as tracer. The expressions of 5' AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT-4) were identified by Western blotting analysis. The metformin-induced blood glucose-lowering action was dose-dependently blocked by BU224, a specific I2R antagonist, in Wistar rats. Also, similar reversion by BU224 was observed in isolated skeletal muscle regarding the metformin-induced glucose uptake. Moreover, AMPK phosphorylation by metformin was concentration-dependently reduced by BU224 in isolated skeletal muscle. In addition, signals for metformin increased glucose uptake were identified via I2R/PI3K/PKC/AMPK dependent pathway in C2C12 cells. Thus, we suggest that metformin can activate I2BR to increase glucose uptake and I2BR will be a new target for diabetic therapy.
Assuntos
Glucose/metabolismo , Receptores de Imidazolinas/antagonistas & inibidores , Metformina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/metabolismo , Linhagem Celular , Imidazóis/farmacologia , Receptores de Imidazolinas/metabolismo , Masculino , Músculo Esquelético/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
The present study is designed to investigate the role of peroxisome proliferator-activated receptors delta (PPARdelta) in the action of digoxin in diabetic rats showing cardiac hypertrophy. We used Wistar rats to induce diabetes by injection of streptozotocin (STZ-rat) and examined the effect of digoxin on PPARdelta expression in these hyperglycemic rats (STZ-rat) at 10 weeks later. We measured the changes of body weight, water intake, and food intake in three groups of age-matched rats; the vehicle treated normal control (Wistar rats), the vehicle treated STZ-rats, and the digoxin-treated STZ-rats. Cardiac output, heart rate, and blood pressure in addition to plasma insulin or glucose level were also determined. The mRNA and protein levels of PPARdelta were measured using Northern and Western blotting, respectively. Cardiac output, heart rate, and blood pressure were markedly reduced while food intake, water intake, and blood glucose were raised in STZ-rats showing lower body weight and plasma insulin as compared with the vehicle-treated controls. After a 20-day of digoxin treatment, cardiac output was raised in STZ-rats but the diabetic parameters were not modified. The PPARdelta expressions, both mRNA and protein, were markedly elevated in the hearts of STZ-rats by digoxin treatment. The related signals with PPARdelta, such as carnitine palmitoyltransferase 1B (CPT1B), acetyl-coenzyme A, carboxylase alpha (ACC1), fatty acid synthase (FAS), and troponin I, were also raised. The increase of cardiac output by digoxin was reversed by the combined treatment with PPARdelta antagonist GSK0660. Thus, we suggest a new finding that PPARdelta is involved in digoxin induced cardiac inrotropic action.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Digoxina/farmacologia , Miocárdio/metabolismo , Miocárdio/patologia , PPAR delta/metabolismo , Animais , Débito Cardíaco/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Digoxina/administração & dosagem , Masculino , PPAR delta/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina , Sulfonas/farmacologia , Tiofenos/farmacologia , Troponina I/metabolismoRESUMO
Mutations in Ras protein at positions Gly12 and Gly13 (phosphate-binding loop L1) and at positions Ala59, Gly60, and Gln61 (loop L4) are commonly associated with oncogenic activation. The structural and catalytic roles of these residues were probed with a series of unnatural amino acids that have unusual main chain conformations, hydrogen bonding abilities, and steric features. The properties of wild-type and transforming Ras proteins previously thought to be uniquely associated with the structure of a single amino acid at these positions were retained by mutants that contained a variety of unnatural amino acids. This expanded set of functional mutants provides new insight into the role of loop L4 residues in switch function and suggests that loop L1 may participate in the activation of Ras protein by effector molecules.
Assuntos
Genes ras , Conformação Proteica , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Sequência de Aminoácidos , Animais , Clonagem Molecular/métodos , Escherichia coli/genética , Escherichia coli/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas Ativadoras de GTPase , Ligação de Hidrogênio , Metionina/genética , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fosforilação , Plasmídeos , Regiões Promotoras Genéticas , Proteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Ativadoras de ras GTPaseRESUMO
Recently, we reported that the histone methyltransferase, EZH2, controls leukocyte migration through interaction with the cytoskeleton remodeling effector, VAV, and direct methylation of the cytoskeletal regulatory protein, Talin. However, it is unclear whether this extranuclear, epigenetic-independent function of EZH2 has a profound impact on the initiation of cellular transformation and metastasis. Here, we show that EZH2 increases Talin1 methylation and cleavage, thereby enhancing adhesion turnover and promoting accelerated tumorigenesis. This transforming capacity is abolished by targeted disruption of EZH2 interaction with VAV. Furthermore, our studies demonstrate that EZH2 in the cytoplasm is closely associated with cancer stem cell properties, and that overexpression of EZH2, a mutant EZH2 lacking its nuclear localization signal (EZH2ΔNLS), or a methyl-mimicking Talin1 mutant substantially promotes JAK2-dependent STAT3 activation and cellular transformation. Taken together, our results suggest a critical role for the VAV interaction-dependent, extranuclear action of EZH2 in neoplastic transformation.
Assuntos
Transformação Celular Neoplásica/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-vav/metabolismo , Animais , Adesão Celular/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Citoplasma/genética , Citoplasma/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/isolamento & purificação , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Células Jurkat , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Mutagênese Sítio-Dirigida , Neoplasias/genética , Sinais de Localização Nuclear/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Talina/genética , Talina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Diagnostic laparoscopy is a useful tool, especially when there is no definite anatomical abnormality visible on imaging modalities. We assess the role and clinical impact of diagnostic laparoscopy in the management of women with chronic pelvic pain. METHODS: Clinical data of 3,068 cases of diagnostic laparoscopy performed for chronic pelvic pain from June 1994 to August 2005 were analyzed. We compared the diagnoses after diagnostic laparoscopy and those after pelvic examination and imaging modalities such as ultrasound or computed tomography (CT), and we then checked the final pathologic diagnoses after operation. RESULTS: Pelvic endometriosis was the most common (60.2%) laparoscopic finding in patients with chronic pelvic pain in this study, followed by normal pelvic findings (21.2%) and pelvic congestion (13.0%). Diagnostic laparoscopy had an influence on correcting previous plans based on imaging modalities in 42.7% of patients such as discarding unnecessary procedures or introducing new diagnostic or therapeutic plans. There were 3 cases of major complications requiring immediate correction. CONCLUSIONS: Diagnostic laparoscopy is a useful diagnostic tool for of women with chronic pelvic pain and can be used as a guideline for individualized treatment.
Assuntos
Laparoscopia , Dor Pélvica/etiologia , Adolescente , Adulto , Idoso , Doença Crônica , Endometriose , Feminino , Humanos , Pessoa de Meia-Idade , Exame Físico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Caspase plays an important role in apoptosis. We report here that farnesyltransferase/geranylgeranyltransferase (FTase/GGTase)-alpha, a common subunit of FTase (alpha/beta(FTase)) and GGTase I (alpha/beta(GGTase)), was cleaved by caspase-3 during apoptosis. FTase/GGTase-alpha (49 kDa) was cleaved to 35 kDa (p35) in the Rat-2/H-ras, W4 and Rat-1 cells treated with FTase inhibitor (LB42708), anti-Fas antibody and etoposide, respectively. This cleavage was inhibited by caspase-inhibitors (YVAD-cmk, DEVD-cho). Serial N-terminal deletions and site-directed mutagenesis showed that Asp59 of FTase/GGTase-alpha was cleaved by caspase-3. The common FTase/GGTase-alpha subunit, but not the beta subunits, of the FTase or GGTase I protein complexes purified from baculovirus-infected SF-9 cells was cleaved to be inactivated by purified caspase-3. In contrast, FTase mutant protein complex [(D(59)A)alpha/beta(FTase)] was resistant to caspase-3. Expression of either the cleavage product (60-379) or anti-sense of FTase/GGTase-alpha induced cell death in Rat-2/H-ras cells. Furthermore, expression of (D(59)A)FTase/GGTase-alpha mutant significantly desensitized cells to etoposide-induced death. Taken together, we suggest that cleavage of prenyltransferase by caspase contributes to the progression of apoptosis.
Assuntos
Alquil e Aril Transferases/metabolismo , Apoptose/fisiologia , Caspases/metabolismo , Alquil e Aril Transferases/efeitos dos fármacos , Alquil e Aril Transferases/genética , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ácido Aspártico/metabolismo , Caspase 3 , Inibidores de Caspase , Sobrevivência Celular/genética , Células Cultivadas , Inibidores de Cisteína Proteinase/farmacologia , Ativação Enzimática , Farnesiltranstransferase , Fibroblastos/metabolismo , Fibroblastos/patologia , Linfoma/metabolismo , Mutação , Oligopeptídeos/farmacologia , Mapeamento de Peptídeos , Prenilação de Proteína , Subunidades ProteicasRESUMO
In contrast to all cellular ras oncogenes which carry a single activating mutation at codon 12, 13 or 61, all known retroviral ras oncogenes have two mutations at codons 12 and 59. To understand the role of the mutation at codon 59, we have constructed plasmids containing genes for Harvey ras: p21(Gly-12,Thr-59) and p21(Val-12,Thr-59). Escherichia coli expressed proteins and their respective phosphorylated (Pi) and non-phosphorylated (non-Pi) proteins were purified to 95% homogeneity by ion-exchange chromatography and gel filtration. GTPase, autophosphorylation and nucleotide exchange activities of the mutants were studied. When the mutants were microinjected into Xenopus oocytes, the non-phosphorylated forms of p21(Gly-12,Thr-59) and p21(Val-12,Thr-59) showed high activity. Surprisingly, their phosphorylated forms were inactive. These results suggest that threonine at position 59 endows the protein with transforming activity but that phosphorylation of the residue inhibits biological activity. A structural interpretation of the observation is presented.
Assuntos
Mutação , Proteína Oncogênica p21(ras)/metabolismo , Animais , Sequência de Bases , Cromatografia em Gel , Cromatografia por Troca Iônica , Eletroforese em Gel de Poliacrilamida , Escherichia coli/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Expressão Gênica , Guanosina Trifosfato/metabolismo , Cinética , Dados de Sequência Molecular , Fosforilação , Plasmídeos , XenopusRESUMO
AIM: The aim of this study was to evaluate the effects of adherence to National Comprehensive Cancer Network (NCCN) guidelines on survival outcomes in patients with early-stage epithelial ovarian cancer. METHODS: Our institutional cancer registry data on 266 patients with Stage I epithelial ovarian cancer was reviewed retrospectively and compliance with treatment guidelines for surgery and adjuvant treatment was determined. Patients were categorized according to adherence or non-adherence. The primary endpoints were recurrence-free survival and disease-specific survival. Hazard ratios (HRs) for survival were estimated with a Cox proportional hazards model. RESULTS: Of the 266 patients, 71 (26.7%) underwent adequate surgical staging in accordance with the guidelines. The guidelines for adjuvant chemotherapy were followed adequately in all 71 patients that were adherent to surgical staging and in 163 of the 195 patients with non-adherence to surgical staging (83.6%). Multivariate analysis, adjusted for prognostic factors, identified higher recurrence-free survival (HR, 0.36; 95% CI, 0.15-0.88) and disease-specific survival (HR, 0.42; 95% CI, 0.16-1.12) among patients whose treatment adhered to both surgical and chemotherapy guidelines, although disease-specific survival was not statistically significant. When excluding clear cell histology from the cohort, the guideline-adherent group had significantly better disease-specific survival than the non-adherent group (HR, 0.13; 95% CI, 0.02-0.94). CONCLUSION: The results of this study suggest that adherence to NCCN guidelines may improve survival outcomes in patients with early-stage epithelial ovarian cancer, particularly in cases other than clear cell histology.
Assuntos
Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Fidelidade a Diretrizes , Excisão de Linfonodo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Adenocarcinoma de Células Claras/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Aorta , Carcinoma Epitelial do Ovário , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ovariectomia , Lavagem Peritoneal , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Salpingectomia , Taxa de Sobrevida , Adulto JovemRESUMO
A case-control study was performed to assess the potential influence of catechol O-methyl transferase (COMT) genotype on the risk of breast cancer in Korean women. One hundred and sixty-three histologically confirmed incident breast cancer cases and 163 age- and menopausal status-matched control individuals with no present or previous history of cancer were selected as study subjects. COMT genetic polymorphism was determined by gel electrophoresis after NlaIII enzyme digestion of amplified DNA. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Women with at least one COMT lower enzyme activity associated allele (COMT-L) were at elevated risk for breast cancer (OR = 1.7, 95% CI = 1.04-2.78) compared with those homozygous for high enzyme activity associated COMT-H alleles. Among women with low (> or = 23.1) body mass index the COMT-L allele containing genotypes posed a marginally significant increased risk of breast cancer compared to the COMT-HH genotype (OR = 1.8, 95% CI = 0.95-3.48). Women with at least one COMT-L allele who had experienced a full-term pregnancy when aged over 30 years or were nulliparous had 2.7-fold increased risk; however, this increase did not reach statistical significance (OR = 2.7, 95% CI = 0.64-11.35). Furthermore, never-drinking and never-smoking women with at least one COMT-L allele were at increased risk of breast cancer compared to those with COMT-HH genotype with ORs of 2.0 (95% CI = 1.23-3.38) and 1.7 (95% CI = 1.04-2.62), respectively. These results are consistent with studies showing that COMT genotype of lower enzyme activity might be related to increase in risk of breast cancer, and extend this finding to Korean women.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Catecol O-Metiltransferase/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Estrogênios/metabolismo , Feminino , Genótipo , Humanos , Coreia (Geográfico) , Menopausa , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias Hormônio-Dependentes/genética , Fatores de RiscoRESUMO
It is known that reperfusion of the ischemic myocardium may intensify damage and increase the extent of myocardial necrosis. Oxygen free radicals and their metabolites have been implicated as possible elements in myocardial ischemia-reperfusion injury. In this study in cyanotic patients undergoing open heart operation for tetralogy of Fallot, the myocardial tissue activities of catalase, superoxide dismutase, glutathione peroxidase, and lactate dehydrogenase were determined together with the tissue contents of malondialdehyde, oxidized glutathione, and total glutathione using the spectrophotometric assay method. The tissue activities of catalase, superoxide dismutase, and glutathione peroxidase increased significantly after myocardial reperfusion (p < 0.05) when compared with the tissue activities of the control group (myocardial tissue taken immediately after aortic cross-clamping). The tissue content of malondialdehyde increased significantly after reperfusion (p < 0.05), but the tissue activity of lactate dehydrogenase and the ratio of oxidized glutathione to total glutathione showed an insignificant difference after reperfusion. These data suggest that peroxidation of the cardiac lipids was triggered by the reperfusion of the hypoxic heart, but the myocardial cellular damage was not significant enough to decrease the myocardial lactate dehydrogenase and total glutathione levels. These results also suggest that oxygen free radicals may play an important role in in-vivo myocardial reperfusion stress, but endogenous self-defensive enzyme systems to protect the cell against the cytotoxic oxygen metabolites also were triggered, and the resulting myocardial cellular damage was insignificant.