RESUMO
This study examined whether the forkhead transcription factors of O group 1 (FoxO1) might be involved in telomere biology during calorie restriction (CR). We used FoxO1-knockout heterozygous mice (FoxO1(+/-)) and wild-type mice (WT) as a control. Both WT and FoxO1(+/-) were subjected to ad libitum (AL) feeding or 30% CR compared to AL for 20 weeks from 15 weeks of age. The heart-to-body weight ratio, blood glucose, and serum lipid profiles were not different among all groups of mice at the end of the study. Telomere size was significantly lower in the FoxO1(+/-)-AL than the WT-AL, and telomere attrition was not observed in either WT-CR or FoxO1(+/-)-CR. Telomerase activity was elevated in the heart and liver of WT-CR, but not in those of FoxO1(+/-)-CR. The phosphorylation of Akt was inhibited and Sirt 1 was activated in heart tissues of WT-CR and FoxO1(+/-)-CR. However, the ratio of conjugated to cytosolic light chain 3 increased and the level of p62 decreased in WT-CR, but not in FoxO1(+/-)-CR. A marker of oxidative DNA damage, 8-OhdG, was significantly lower in WT-CR only. The level of MnSOD and eNOS increased, and the level of cleaved caspase-3 decreased in WT-CR, but not FoxO1(+/-)-CR. Echocardiography showed that the left ventricular end-diastolic and systolic dimensions were significantly lower in WT-CR or FoxO1(+/-)-CR than WT-AL or FoxO1(+/-)-AL, respectively. The present studies suggest that FoxO1 plays beneficial roles by inducing genes involved in telomerase activity, as well as anti-oxidant, autophagic, and anti-apoptotic genes under conditions of CR, and suggest that FoxO1 signaling may be an important mediator of metabolic equilibrium during CR.
Assuntos
Restrição Calórica , Fatores de Transcrição Forkhead/metabolismo , Miocárdio/metabolismo , Transdução de Sinais , Telômero , Animais , Peso Corporal , Caspase 3/metabolismo , Dano ao DNA , Proteína Forkhead Box O1 , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho do Órgão , Estresse Oxidativo , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: This study aimed to investigate the function of tissue plasminogen activator in the olfactory epithelium of mice following neural injury. METHOD: Transmission electron microscopy was used to study the changes in the morphology of the olfactory epithelium 1-7 days after surgical ablation of the olfactory bulb (bulbectomy). RESULTS: Prior to bulbectomy, a uniformly fine material was observed within some regions of the olfactory epithelium of mice deficient in tissue plasminogen activator. At 2-3 days after bulbectomy, there were degenerative changes in the olfactory epithelium. At 5-7 days after bulbectomy, we noted drastic differences in olfactory epithelium morphology between mice deficient in tissue plasminogen activator and wild-type mice (comparisons were made using findings from a previous study). The microvilli seemed to be normal and olfactory vesicles and receptor neuron dendrites were largely intact in the olfactory epithelium of mice deficient in tissue plasminogen activator. CONCLUSION: The tissue plasminogen activator plasmin system may inhibit the regeneration of the olfactory epithelium in the early stages following neural injury.
Assuntos
Bulbo Olfatório/fisiologia , Bulbo Olfatório/cirurgia , Mucosa Olfatória/fisiologia , Regeneração/fisiologia , Ativador de Plasminogênio Tecidual/deficiência , Animais , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mucosa Olfatória/citologia , Ativador de Plasminogênio Tecidual/fisiologiaRESUMO
OBJECTIVE: This study investigated the correlation between the chronological age, telomere length in peripheral blood leukocytes and blood laboratory data of female patients with mild hypertension to identify laboratory data that reflect the biological aging of individuals. DESIGN: Cross-sectional population-based study. SETTING: Outpatient clinic of the Department of Cardiovascular, Respiratory, and Geriatric Medicine Kyushu University Hospital at Beppu in Japan. PARTICIPANTS: Outpatients with mild hypertension treated with a low dose of amlodipine. MEASUREMENTS: The laboratory data of female patients were collected and the telomere length parameters in their peripheral blood leukocytes were determined by Southern blotting. Any correlations between the laboratory data and the telomere length parameters were assessed. RESULTS: The patients showed a positive correlation between the telomere length and the high density lipoprotein, albumin, creatinine, hemoglobin levels, red blood cell counts, and a negative correlation with the globulin level. The extent of subtelomeric methylation of long telomeres tended to correlate negatively with the telomeric attrition. Only the creatinine level correlated with subtelomeric methylation, but not with telomeric length. CONCLUSION: HDL and the albumin/globulin ratio were potential indicators for individual somatic genomic aging. Creatinine may therefore be a useful indicator for a predisposition for telomeric attrition.
Assuntos
Envelhecimento/sangue , Hipertensão/genética , Telômero/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Southern Blotting , Creatinina/sangue , Estudos Transversais , Feminino , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Japão , Leucócitos , Metilação , Pessoa de Meia-Idade , Telômero/genéticaRESUMO
OBJECTIVE: To elucidate the correlation between the telomere length and subtelomeric methylated status in peripheral leukocytes and the laboratory data of inpatients with brain infarction and metabolic disorders. This is the first report describing a link between routine clinical laboratory data and genomic aging. DESIGN: Cross-sectional population-based study. SETTING: Chronic disease ward of Kyushu University Hospital at Beppu in Japan. PARTICIPANTS: Inpatients with brain infarction and metabolic disorders. MEASUREMENTS: The laboratory data of male patients were collected and the telomeric parameters in their peripheral leukocytes were determined by a Southern blot analysis with methylation-sensitive and insensitive isoschizomers. Any correlations between the laboratory data and the telomeric parameters were assessed. RESULTS: The patients revealed a significant correlation among the fasting blood sugar, HbA1c, serum creatinine and urea nitrogen levels with the mean telomere length, expression of long telomeres ( > 9.4 kb), or the subtelomeric hypermethylation status of long telomeres. CONCLUSION: Our results suggested that the hyperglycemia and renal function of patients with metabolic disorders correlated positively with the aging-associated telomeric changes.
Assuntos
Infarto Encefálico/metabolismo , Metilação de DNA , Hiperglicemia/metabolismo , Rim/metabolismo , Leucócitos/metabolismo , Doenças Metabólicas/metabolismo , Telômero/metabolismo , Idoso , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Infarto Encefálico/complicações , Senescência Celular , Creatinina/sangue , Estudos Transversais , Hemoglobinas Glicadas/metabolismo , Humanos , Leucócitos/ultraestrutura , Masculino , Doenças Metabólicas/complicações , Pessoa de Meia-Idade , Telômero/ultraestruturaRESUMO
SUMMARY BACKGROUND: Hemophilia A is a congenital bleeding disorder caused by a deficiency of coagulation factor VIII. Approximately 30% of hemophilia A patients develop inhibitors against FVIII following replacement therapy. We have reported that neonatal exposure of FVIII antigen can induce antigen-specific immune tolerance by interferon-gamma (IFN-gamma)-dependent T-cell anergy in hemophilia A mice. OBJECTIVE: The thymus plays crucial roles in self-tolerance, with negative selection of self-reactive effector T cells and positive selection of self-reactive regulatory T cells. We investigated the possibility of the induction of antigen-specific immune tolerance by intrathymic injection of FVIII in hemophilia A mice. METHODS: Hemophilia A mice were injected with recombinant FVIII into the thymus under real-time high-resolution image guidance. RESULTS: Anti-FVIII inhibitory antibody titers in mice challenged with intravenous administration of FVIII were significantly lower in mice (n = 22) that had received thymic FVIII injection than in mice (n = 18) without thymic injection (9.4 +/- 2.3 vs. 122.5 +/- 27.6 BU mL(-1), respectively, P = 0.00078). The CD4(+) T cells from thymic-injected mice could not proliferate or produce interleukin (IL)-2, IL-12 and IFN-gamma in response to FVIII. The CD4(+)CD25(+) T cells generated from thymic-treated mice but not from naïve mice efficiently suppressed the in vitro proliferative response of CD4(+) T cells and blocked the in vivo development of anti-FVIII antibodies in the adoptive transfer. CONCLUSION: These data suggest that intrathymic administration of FVIII could result in immune tolerance by induction of FVIII-specific regulatory T cells.
Assuntos
Fator VIII/imunologia , Hemofilia A/imunologia , Timo/metabolismo , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Fator VIII/administração & dosagem , Citometria de Fluxo , CamundongosRESUMO
High glucose (HG) concentrations are toxic to various cells in vivo, but cells become insensitive to HG toxicity when they are subcultured serially in vitro. Oxidative stress is involved in HG toxicity, and metal ions, especially iron, mediate some oxidative stress. To investigate mechanisms involved in the insensitiveness of cultured cells to HG toxicity, we focused on the level of intracellular iron. Freshly prepared human umbilical vein endothelial cells contained a substantial amount of iron, whereas its level decreased rapidly during the course of culture (to less than 10%). The iron content was restored by incubation of the cells with Fe(III)/8-hydroxyquinoline, and the iron-supplemented cells were more susceptible to both oxidant- and HG-induced injury. Under the HG conditions, the iron-loaded cells were subjected to higher levels of oxidative stress. The enhanced HG toxicity by iron was attenuated by the treatment with several antioxidants including catalase, ascorbic acid, and pyruvate. These data suggested that the insensitiveness of subcultured cells to HG toxicity is, at least in part, due to rapid and dramatic loss of intracellular iron. Supplementation with iron is useful to restore the vulnerability of cultured cells to HG that is normally observed in in vivo situations.
Assuntos
Técnicas de Cultura de Células/métodos , Diabetes Mellitus/metabolismo , Angiopatias Diabéticas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Glucose/farmacologia , Ferro/farmacologia , Aerobiose , Apoptose , Contagem de Células , Hipóxia Celular , Sobrevivência Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Ferro/metabolismo , Estresse Oxidativo , Veias Umbilicais/citologiaRESUMO
The present study was undertaken to determine the effects of AT1 receptor blockade which occurred in response to losartan, on the extracellular matrix (ECM) degradation process in the Bio 14.6 (n = 12) and Bio 53.58 (n = 12) strains which are referred as models of hypertrophic and dilated cardiomyopathy, respectively. The administration of losartan (30 mg/kg/day) in hamsters from 10-20 weeks of age reduced the accumulation of the left ventricular collagen matrix in both of the Bio 14.6 and the Bio 53.58 strains. According to the RT-PCR, the levels of mRNA for matrix metalloproteinase (MMP) and the tissue inhibitor of MMP (TIMP) were examined. MMP-1, -2, -3, and -9 were more enhanced in both myopathic strains than in the control F1beta, strains. With losartan, the levels of MMP-1, -2, -9, TIMP-1 and -2 decreased in the both strains but those for MMP-3 did not in Bio 14.6 strains. TIMP-3 and -4 mRNA levels did not change in any of the experimental hamsters, whether treated or untreated with losartan. The Western blots also showed similar observations in the both strains as seen in mRNA expressions although MMP-2 in the Bio 53.58 strains did not differ between treated and untreated with losartan. Although losartan has an inhibitory effect on collagen accumulation in the development of cardiomyopathy, MMPs (-1, -2, -9) and TIMPs (-1, -2) seem to be susceptible to responding to losartan in Bio cardiomyopathic hamsters.
Assuntos
Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Hipertrófica/enzimologia , Colágeno/metabolismo , Losartan/farmacologia , Antagonistas de Receptores de Angiotensina , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Cricetinae , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Cinética , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Miocárdio/enzimologia , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Angiotensina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
Deletions of the long arm of chromosome 6 (6q) are one of the most common chromosomal abnormalities in multiple human malignancies. Previously, we have identified three commonly deleted regions on 6q (6q21, 6q23-q24, and 6q26) in pancreatic cancer by loss of heterozygosity studies, suggesting the presence of one or more tumor suppressor genes on this chromosome arm. Using a combination of database search and cDNA library screening, we successfully isolated a transcript from 6q24. This mRNA encodes a protein consisting of 543 amino acids with homology to the Drosophila headcase (hdc) gene and, thus, is designated as hHDC. Northern analysis identified a ubiquitously expressed 5.6-kb transcript. Seventeen (81%) of 21 pancreatic cancer cell lines and four (80%) of five renal cell carcinoma cell lines showed low level expression, suggesting that the hHDC gene may play an important role in some human cancers.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6 , Proteínas de Drosophila/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar , Drosophila melanogaster/genética , Humanos , Dados de Sequência Molecular , RNA Mensageiro , Homologia de Sequência de Aminoácidos , Células Tumorais CultivadasRESUMO
Alpha1-adrenergic stimulation, coupled to Gq, has been shown to promote heart failure. However, the role of alpha1-adrenergic signaling in the regulation of myocardial contractility in failing myocardium is still poorly understood. To investigate this, we observed 1) the effect of phenylephrine on myofibrillar Ca2+ sensitivity in alpha-toxin-skinned cardiomyocytes, and 2) protein expression of Gq, RhoA, and myosin light chain phosphorylation using tachypacing-induced canine failing hearts. Phenylephrine significantly increased myofibrillar Ca2+ sensitivity in failing but not in normal cardiomyocytes. Whereas Y-27632 (Rho kinase inhibitor) blocked the phenylephrine-induced Ca2+ sensitization in the failing myocytes, calphostin C (protein kinase C inhibitor) had no effect on Ca2+ sensitization. The protein expression of Galpha(q) and RhoA and the phosphorylation level of regulatory myosin light chain significantly increased in the failing myocardium. Our results suggest that alpha1-adrenoceptor-Gq signaling is upregulated in the failing myocardium to increase the myofibrillar Ca2+ sensitivity mainly through the RhoA-Rho kinase pathway rather than through the protein kinase C pathway.
Assuntos
Cálcio/fisiologia , Insuficiência Cardíaca/fisiopatologia , Transdução de Sinais , Amidas/farmacologia , Animais , Cães , Inibidores Enzimáticos/farmacologia , Proteínas de Ligação ao GTP/fisiologia , Coração/fisiopatologia , Contração Miocárdica , Fosforilação , Piridinas/farmacologia , Receptores Adrenérgicos alfa 1/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologiaRESUMO
Prostaglandin (PG) F(2)a is known to initiate luteal cell apoptosis in the bovine corpus luteum (CL) via its specific receptor (FP) on the luteal membrane by inducing intracellular Ca(2+) mobilization and the activation of PKC. In order to identify the signaling components involved in cell apoptosis, mRNA levels and activities of antioxidative enzymes were analyzed using bovine CL at different stages of the estrous cycle. Northern blot analysis revealed that the levels of two isozymes of superoxide dismutase (SOD), the Mn and Cu/Zn types, and catalase are highly enriched in the middle estrous phase, whereas glutathione peroxidase (GPx) levels gradually decrease as the estrous cycle progresses. The incubation of bovine luteal cells with H(2)O(2) and mercaptosuccinate (MS), a specific inhibitor of GPx, resulted in an increase in chromatin DNA condensation and apoptotic DNA fragmentation. Analyses of the enzymatic activities of GPx and catalase support the RNA data, indicating that H(2)O(2) produced due to the lack of GPx is a potent inducer of luteal cell apoptosis.
Assuntos
Apoptose , Corpo Lúteo/citologia , Corpo Lúteo/enzimologia , Regulação para Baixo , Glutationa Peroxidase/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Catalase/genética , Catalase/metabolismo , Bovinos , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Estro/efeitos dos fármacos , Estro/metabolismo , Feminino , Glutationa Peroxidase/genética , Peróxido de Hidrogênio/farmacologia , Isoenzimas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Superóxido Dismutase/genéticaRESUMO
AIMS: Patients with NIDDM have excessive cardiovascular morbidity and mortality, even in the absence of hypertension. Left ventricular hypertrophy (LVH), which is an ominous prognostic sign and an independent risk factor for cardiac events, is often present in NIDDM patients. METHODS AND RESULTS: NIDDM male patients with (n=10) and without (n=12) hypertension, all of whom had been diagnosed over 10 years ago, were examined in the present study. Normotensive NIDDM patients had not received any anti-hypertensive drugs. All patients were classified according to the left ventricular mass (LVM) index by using M-mode echocardiography and were assessed regarding their systolic (fractional shortening) and diastolic function, which included the maximal early flow velocity (MFV), the mitral valve deceleration time (DT), and the isovolumic relaxation time (IRT) as determined by Doppler indices. Troglitazone (TRO), an antidiabetic drug, was administered to both groups at a dose of 400 mg/day for 6 months. After TRO treatment, a reduction in the LVM index and an improvement in the diastolic function were observed in the normotensive but not in the hypertensive patients. CONCLUSION: The TRO treatment was sensitive for cardiac regression in those normotensive patients. These results suggest that LVH and the diastolic function in NIDDM patients without hypertension may be associated with elevated insulin resistance because TRO has a pharmacological function to increase the insulin sensitivity and to decrease insulin resistance.
Assuntos
Cromanos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipoglicemiantes/uso terapêutico , Contração Miocárdica/efeitos dos fármacos , Tiazóis/uso terapêutico , Tiazolidinedionas , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Ecocardiografia Doppler , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/prevenção & controle , Insulina/sangue , Pessoa de Meia-Idade , TroglitazonaRESUMO
This study was designed to determine changes in expression of heme oxygenase (HO)-1, the stress-inducible and carbon monoxide-producing enzyme, in normotensive and portal hypertensive human livers. GTS-1, a monoclonal antibody against rat HO-1 cross-reacted with the human HO-1 and blocked its enzyme activity, allowing us to examine the activity and localization of HO-1. In controls, approximately 50% of the total HO activity was from HO-1 as judged by the sensitivity to GTS-1, while the rest of activity was from other isozymes such as HO-2. HO-1 was expressed mainly in a subpopulation of Kupffer cells, and the expression in hepatic stellate cells, sinusoidal endothelial cells, and hepatocytes was little, if any. The HO-1 expression exhibited quite different pictures in the livers of portal hypertensive diseases. In cirrhotic livers, which undergo portal hypertension through increases in intrasinusoidal resistance and regenerative changes in the parenchyma, HO-1 occurred in a majority of Kupffer cells and was also observed in hepatocytes. Consequently, the total HO-1 activities became significantly greater in these tissues than those from normal individuals. By contrast, livers of idiopathic portal hypertension that are characterized by an increase in presinusoidal resistance displayed a significant decrease in the HO-1 expression in Kupffer cells, and its hepatocellular expression was not detectable. Although factors involved in altered HO-1 expression in these cells remain unknown, the results suggest that Kupffer cells could alter their expression of HO-1 in response to local hemodynamic changes associated with chronic portal hypertension in humans.
Assuntos
Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Portal/enzimologia , Fígado/enzimologia , Anticorpos Monoclonais , Heme Oxigenase-1 , Humanos , Hipertensão Portal/patologia , Imuno-Histoquímica/métodos , Fígado/patologia , Cirrose Hepática/enzimologia , Proteínas de Membrana , Valores de Referência , Baço/enzimologia , Distribuição TecidualRESUMO
The intracellular mechanisms of cGMP, a major intracellular mediator of nitric oxide that regulates the contractility of cardiac muscle, are still to some extent unknown. To investigate these mechanisms, we observed the effects of 8-bromo-cyclic GMP (8br-cGMP) on myofibrillar Ca2+ sensitivity and Ca2+ handling of the sarcoplasmic reticulum (SR) using beta-escin-skinned preparations from Wistar rat hearts. Both low (1 microM) and high doses (100 microM) of 8br-cGMP significantly decreased the myofibrillar Ca2+ sensitivity obtained from pCa-tension relationships to a similar extent (pCa50; from 6.04 to 5.95 by 1 microM 8br-cGMP and 6.00 to 5.89 by 100 microM 8br-cGMP, respectively, n = 9 each). Whereas this Ca2+ desensitization induced by 100 microM 8br-cGMP was blocked by 1 microM KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG), not induced by 1 microM 8br-cGMP was not effected by KT5823. When the amount of Ca2+ released from the SR was estimated by the peak amplitude of 25 mM caffeine-induced contractions after constant Ca2+-loading by pCa 6, both doses of 8br-cGMP significantly augmented the caffeine-induced peak force to a similar extent (125 +/- 5.8% by 1 microM 8br-cGMP and 116 +/- 5.1% by 100 microM 8br-cGMP, respectively, n = 6 each). The two observed effects of cGMP (a decrease in myofibrillar Ca2+ sensitivity and an increase in Ca2+ uptake by the SR) may participate in regulating myocardial contraction via nitric oxide. Low and high doses of cGMP seem to work mainly via PKG-independent and PKG-dependent pathways, respectively.
Assuntos
Cálcio/metabolismo , Carbazóis , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , Coração/fisiologia , Indóis , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Alcaloides/farmacologia , Animais , GMP Cíclico/farmacologia , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Retículo Sarcoplasmático/metabolismo , Troponina I/metabolismoAssuntos
Cardiomegalia/fisiopatologia , Cromanos/uso terapêutico , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Diástole/fisiologia , Hipertensão/fisiopatologia , Hipoglicemiantes/uso terapêutico , Tiazóis/uso terapêutico , Tiazolidinedionas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diástole/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Troglitazona , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
We compared the findings of high-resolution MR imaging and standard MR imaging in the detection of tears of the triangular fibrocartilage in 33 patients with chronic wrist pain on the ulnar side. With arthroscopy as the standard of reference, sensitivity was 100%, specificity 53%, and accuracy 79% with the high-resolution MR imaging, against 83%, 67%, and 76% with the standard MR imaging. High-resolution MR imaging showed a higher sensitivity, but a decreased specificity in the assessment of the triangular fibrocartilage. The results showed that diagnosis of tears in the triangular fibrocartilage by MR imaging, even high-resolution MR imaging, is unsatisfactory, although further technological advances may well improve the accuracy.
Assuntos
Cartilagem Articular/patologia , Ligamentos Articulares/patologia , Imageamento por Ressonância Magnética/métodos , Traumatismos do Punho/diagnóstico , Articulação do Punho/patologia , Punho/patologia , Adulto , Cartilagem Articular/lesões , Feminino , Humanos , Ligamentos Articulares/lesões , Masculino , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Myocardial ischemia-reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. Injury of myocardium due to ischemia-reperfusion includes cardiac contractile dysfunction, arrhythmias as well as irreversible myocyte damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. OBSERVATIONS: An increase in the formation of reactive oxygen species during ischemia-reperfusion and the adverse effects of oxyradicals on myocardium have now been well established by both direct and indirect measurements. Although several experimental studies as well as clinical trials have demonstrated the cardioprotective effects of antioxidants, some studies have failed to substantiate the results. Nonetheless, it is becoming evident that some of the endogenous antioxidants such as glutathione peroxidase, superoxide dismutase, and catalase act as a primary defense mechanism whereas the others including vitamin E may play a secondary role for attenuating the ischemia-reperfusion injury. The importance of various endogenous antioxidants in suppressing oxidative stress is evident from the depression in their activities and the inhibition of cardiac alterations which they produce during ischemia-reperfusion injury. The effects of an antioxidant thiol containing compound, N-acetylcysteine, and ischemic preconditioning were shown to be similar in preventing changes in the ischemic-reperfused hearts. CONCLUSIONS: The available evidence support the role of oxidative stress in ischemia-reperfusion injury and emphasize the importance of antioxidant mechanisms in cardioprotection.
Assuntos
Antioxidantes/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Acetilcisteína/metabolismo , Animais , Apoptose , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Precondicionamento Isquêmico Miocárdico , Contração Miocárdica , Superóxido Dismutase/metabolismo , Vitamina E/metabolismoRESUMO
Nitric oxide (NO) shows cytotoxicity, and its reaction products with reactive oxygen species, such as peroxynitrite, are potentially more toxic. To examine the role of O2 in the NO toxicity, we have examined the proliferation of cultured human umbilical vein endothelial cells in the presence or absence of NO donor, ((Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-++ +ium-1,2-diolate) (DETA-NONOate) (100-500 microM), under normoxia (air), hypoxia (< 0.04% O2) or hyperoxia (88-94% O2). It was found that the dose dependency on NONOate was little affected by the ambient O2 concentration, showing no apparent synergism between the two treatments. We have also examined the effects of exogenous NO under normoxia and hyperoxia on the cellular activities of antioxidant enzymes involved in the H2O2 elimination, since many of them are known to be inhibited by NO or peroxynitrite in vitro. Under normoxia DETA-NONOate (500 microM) caused 25% decrease in catalase activity and 30% increases in glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in 24h. Under hyperoxia NO caused about 25% decreases in activities of catalase, glutathione reductase and glucose-6-phosphate dehydrogenase. The H2O2 removal rate by NO-treated cells was computed on the mathematical model for the enzyme system. It was concluded that the cellular antioxidant function is little affected by NO under normoxia but that it is partially impaired when the cells are exposed to NO under hyperoxia.
Assuntos
Endotélio Vascular/enzimologia , Doadores de Óxido Nítrico/toxicidade , Oxirredutases/metabolismo , Oxigênio/toxicidade , Catalase/metabolismo , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Glucosefosfato Desidrogenase/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Hiperóxia/enzimologia , Hipóxia/enzimologia , Compostos Nitrosos/toxicidade , Fosfogluconato Desidrogenase/metabolismoRESUMO
High-density lipoproteins (HDL) levels have been shown to be inversely correlated with coronary heart disease, but the mechanisms of the direct protective effect of HDL on endothelial cells are not fully understood. The apoptosis of endothelial cells induced by cytokines and/or oxidized low-density lipoproteins, etc. may provide a mechanistic clue to the "response-to-injury" hypothesis of atherogenesis. Here we report that HDL prevent the apoptosis of human umbilical venous endothelial cells (HUVECs) induced by tumor necrosis factor-alpha (TNF-alpha) via an inhibition of CPP32-like protease activity. The incubation of HUVECs with TNF-alpha significantly increased the CPP32-like protease activity, and induced apoptosis. Preincubation of HUVECs with HDL before incubation with TNF-alpha significantly suppressed the increase in the CPP32-like protease activity, preventing apoptosis in a concentration-dependent manner. These results suggest that HDL prevent the suicide pathway leading to apoptosis of endothelial cells by decreasing the CPP32-like protease activity and that HDL thus play a protective role against the "response-to-injury" hypothesis of atherogenesis.
Assuntos
Apoptose/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Lipoproteínas HDL/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia , Apolipoproteína A-I/farmacologia , Apolipoproteína A-II/farmacologia , Caspase 3 , Caspases/metabolismo , Extratos Celulares/química , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/citologia , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Indução Enzimática/efeitos dos fármacos , Humanos , Lipoproteínas HDL/isolamento & purificação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Veias Umbilicais , Receptor fas/metabolismoRESUMO
OBJECTIVE: The exact role of angiotensinogen (AGT) in vascular remodeling has yet to be determined. In the present study, we examined the effects of reducing plasma AGT by intravenous injections with antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on vascular remodeling in spontaneously hypertensive rats (SHRs). DESIGN AND METHODS: The ODNs against rat AGT were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression. Male SHRs (n = 18) and age-matched male Wistar- Kyoto (WKY) rats (n = 4) were used for this study. All animals were fed a standard rat diet throughout the experiment At 10 weeks of age, the SHRs were divided into three groups (n = 6); systolic blood pressure (SBP) was similar in each group. The control group received saline, the sense group was injected with the sense ODN complex and the antisense group was injected with the antisense ODN complex. WKY rats were fed for the same period of time. The ASOR-poly(L)lysine-ODN complex was injected into the tail veins twice a week. RESULTS: At the end of the treatment, a reduction in AGT mRNA levels in the liver and plasma AGT was observed only in the animals injected with antisense ODNs. Antisense ODNs significantly reduced the plasma angiotensin II (Ang II) concentrations to levels similar to those observed in WKY rats. Antisense ODNs significantly reduced the SBP (180.7 +/- 4.4 mmHg) and media cross-sectional areas of the aorta (1.11 +/- 0.02 mm2), which were still larger than those seen in WKY rats (140.3 +/- 2.1 mmHg, 0.84 +/- 0.02 mm2), compared with the SHRs injected with sense ODNs (225.2 +/- 4.4 mmHg, 1.24 +/- 0.02 mm2) and control SHRs (223.7 +/- 4.8 mmHg, 1.25 +/- 0.02 mm2). The aortic angiotensin-converting enzyme (ACE) activity and collagen concentrations, which were significantly higher than those seen in WKY rats, did not significantly change among the SHR groups. The aortic AGT, ACE, angiotensin II type 1 (AT1) receptor and angiotensin II type 2 (AT2) receptor mRNA also did not significantly change among the SHR groups. CONCLUSION: On the basis of these findings, plasma AGT is thus considered to play a role in the development of hypertrophy of smooth muscle in the aorta of SHRs, it is thought to have only a slight effect, however, on the remodeling of the matrix tissue when the suppression of hypertension is insufficient.