RESUMEN
Major depressive disorder (MDD) and suicidal behavior have been associated with structural and functional changes in the brain. However, little is known regarding alterations of brain networks in MDD patients with suicidal ideation. We investigated whether or not MDD patients with suicidal ideation have different topological organizations of white matter networks compared with MDD patients without suicidal ideation. Participants consisted of 24 patients with MDD and suicidal ideation, 25 age- and gender-matched MDD patients without suicidal ideation and 31 healthy subjects. A network-based statistics (NBS) and a graph theoretical analysis were performed to assess differences in the inter-regional connectivity. Diffusion tensor imaging (DTI) was performed to assess topological changes according to suicidal ideation in MDD patients. The Scale for Suicide Ideation (SSI) and the Korean version of the Barrett Impulsiveness Scale (BIS) were used to assess the severity of suicidal ideation and impulsivity, respectively. Reduced structural connectivity in a characterized subnetwork was found in patients with MDD and suicidal ideation by utilizing NBS analysis. The subnetwork included the regions of the frontosubcortical circuits and the regions involved in executive function in the left hemisphere (rostral middle frontal, pallidum, superior parietal, frontal pole, caudate, putamen and thalamus). The graph theoretical analysis demonstrated that network measures of the left rostral middle frontal had a significant positive correlation with severity of SSI (r=0.59, P=0.02) and BIS (r=0.59, P=0.01). The total edge strength that was significantly associated with suicidal ideation did not differ between MDD patients without suicidal ideation and healthy subjects. Our findings suggest that the reduced frontosubcortical circuit of structural connectivity, which includes regions associated with executive function and impulsivity, appears to have a role in the emergence of suicidal ideation in MDD patients.
Asunto(s)
Encéfalo/fisiopatología , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Imagen de Difusión por Resonancia Magnética , Red Nerviosa/fisiopatología , Ideación Suicida , Sustancia Blanca/fisiopatología , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Trastorno Depresivo Mayor/diagnóstico por imagen , Dominancia Cerebral/fisiología , Función Ejecutiva/fisiología , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Conducta Impulsiva/fisiología , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Valores de Referencia , Encuestas y Cuestionarios , Sustancia Blanca/diagnóstico por imagenRESUMEN
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1α stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1α regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1α under hypoxic conditions, whereas HIF-1α protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1α and deacetylated Lys709 of HIF-1α. Deacetylation of HIF-1α by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1α stability, and increased HIF-1α hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1α by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1α deacetylation is critical for the destablization of HIF-1α and the hypoxic response of tumour cells.
Asunto(s)
Hipoxia de la Célula/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sirtuina 2/metabolismo , Animales , Línea Celular Tumoral , Metabolismo Energético/genética , Femenino , Células HeLa , Humanos , Hidroxilación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , NAD/metabolismo , Prolil Hidroxilasas/metabolismo , Unión Proteica , Estabilidad Proteica , Interferencia de ARN , ARN Interferente Pequeño , Sirtuina 2/genética , UbiquitinaciónRESUMEN
The oncogenic human papillomavirus (HPV) E6/E7 proteins are essential for the onset and maintenance of HPV-associated malignancies. Here, we report that activation of the cellular ubiquitin-proteasome system (UPS) by the omega-3 fatty acid, docosahexaenoic acid (DHA), leads to proteasome-mediated degradation of E6/E7 viral proteins and the induction of apoptosis in HPV-infected cancer cells. The increases in UPS activity and degradation of E6/E7 oncoproteins were associated with DHA-induced overproduction of mitochondrial reactive oxygen species (ROS). Exogenous oxidative stress and pharmacological induction of mitochondrial ROS showed effects similar to those of DHA, and inhibition of ROS production abolished UPS activation, E6/E7 viral protein destabilization, and apoptosis. These findings identify a novel role for DHA in the regulation of UPS and viral proteins, and provide evidence for the use of DHA as a mechanistically unique anticancer agent for the chemoprevention and treatment of HPV-associated tumors.
Asunto(s)
Antivirales/farmacología , Proteínas de Unión al ADN/metabolismo , Ácidos Docosahexaenoicos/farmacología , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Represoras/metabolismo , Activación Enzimática/efectos de los fármacos , Regulación de la Expresión Génica , Células HeLa , Interacciones Huésped-Patógeno , Papillomavirus Humano 16/efectos de los fármacos , Papillomavirus Humano 16/fisiología , Papillomavirus Humano 18/efectos de los fármacos , Papillomavirus Humano 18/fisiología , Humanos , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
SUMMARY The dynamics of influenza A viral load in respiratory samples collected from adult A(H1N1)pdm09 influenza patients were investigated. Three respiratory specimens were obtained every 2-4 days and clinical findings were recorded at the time each specimen was collected. A total of 105 serial specimens were collected from 35 patients. Viral clearance was more rapid in patients aged 15-29 years than patients aged 30-49 years (P < 0.01) or ≥ 50 years (P < 0.01). Hospitalized patients showed slow viral clearance compared to outpatients (P < 0.01). Resolution of cough and headache was correlated with viral load reduction in respiratory specimens. Viral shedding was found in 17 patients (48.6%) 5 days after symptom onset. Time to hospital visit after symptom onset was significantly correlated with prolonged viral shedding (odds ratio 9.0, 95% confidence interval 1.56-51.87, P = 0.01). These findings will contribute to infection control aspects with respect to managing patients with influenza virus infections.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/epidemiología , Gripe Humana/virología , Carga Viral/fisiología , Adolescente , Adulto , Femenino , Humanos , Gripe Humana/fisiopatología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Faringe/virología , Estudios Prospectivos , Estadísticas no Paramétricas , Esparcimiento de Virus/fisiología , Adulto JovenRESUMEN
Two cases of late postoperative capsular block syndrome that occurred 4 and 8.5 years, respectively, were encountered. One case underwent phacoemulsification after continuous curvilinear capsulorhexis in his left eye. The other case had a can opener type capsulorhexis and underwent extracapsular cataract extraction with trabeculectomy. One-piece posterior chamber lenses were implanted in both cases. Upon slit-lamp examination, the posterior capsules were found distorted posteriorly; the capsular openings were apparently sealed by the lens optic. A whitish material existed between the intraocular lens optic and posterior capsule, with thick aggregation in a lower fifth space in case 1. After Nd:YAG laser anterior capsulotomy in case 1, the thick aggregate spread diffusely on the posterior capsule which was sunken completely for 4 weeks. After Nd:YAG capsulotomy, the distorted posterior capsule disappeared and the best corrected visual acuity was restored to 20/20 in both cases.
Asunto(s)
Cápsula del Cristalino/patología , Complicaciones Posoperatorias , Capsulorrexis , Humanos , Terapia por Láser , Cápsula del Cristalino/cirugía , Implantación de Lentes Intraoculares , Masculino , Persona de Mediana Edad , Facoemulsificación , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/cirugía , Reoperación , Síndrome , Factores de Tiempo , Agudeza VisualRESUMEN
Numerous controlled studies have shown that nitrates, beta blockers, and calcium antagonists are effective in the treatment of stable angina pectoris. The pharmacokinetics, pharmacodynamics, and hemodynamic effects of these agents are different, and thus combination therapy offers additive improvement and also counterbalancing of the undesirable side effects of each drug. The choice of therapy depends on the severity of symptoms, associated diseases, compliance, side effects, and status of left ventricular function. The main mechanism of improvement is a decrease in myocardial oxygen consumption, though an increase in coronary blood flow is another potential reason for the use of calcium blockers. This review considers the properties of these drugs, their mechanism of action, and the results of randomized studies.