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Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole-exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double-strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR-induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end-resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR-mediated DNA double-strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development.
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Proteínas Cromosómicas no Histona/metabolismo , Neoplasias Gástricas , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Roturas del ADN de Doble Cadena , Daño del ADN , Reparación del ADN , Inestabilidad Genómica , Recombinación Homóloga , Humanos , Recombinasa Rad51/metabolismo , Reparación del ADN por Recombinación , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Anti-heat shock protein (HSP) autoantibodies are detected in autoimmune diseases. We sought to ascertain whether anti-HSP10 IgG is present in patients with CSU and to elucidate the role of HSP10 in CSU pathogenesis. METHOD: Using a human proteome microarray, six potential autoantibodies had higher expression in 10 CSU samples compared with 10 normal controls (NCs). Among them, HSP10 IgG autoantibody was quantified by immune dot-blot assay in sera from 86 CSU patients and 44 NCs. The serum levels of HSP10 and microRNA-101-5p were measured in CSU patients and NCs. The effects of HSP10 and miR-101-5p on mast cell degranulation in response to IgE, compound 48/80, and platelet-activating factor (PAF) were investigated. RESULTS: CSU patients had higher IgG positivity to HSP10 (40.7% vs. 11.4%, p = .001), lower serum HSP10 levels (5.8 ± 3.6 vs. 12.2 ± 6.6 pg/mL, p < .001) than in NCs, and their urticaria severity was associated with anti-HSP10 IgG positivity, while HSP10 levels were related to urticaria control status. MiR-101-5p was increased in CSU patients. PAF enhanced IL4 production in PBMCs from CSU patients. IL-4 upregulated miR-101-5p and reduced HSP10 expression in keratinocytes. Transfection of miR-101-5p reduced HSP10 expression in keratinocytes. MiR-101-5p promoted PAF-induced mast cell degranulation, while HSP10 specifically prevented it. CONCLUSION: A new autoantibody, anti-HSP10 IgG was detected in CSU patients, which showed a significant correlation with UAS7 scores. A decreased serum HSP10 level was associated with upregulation of miR-101-5p due to increased IL-4 and PAF in CSU patients. Modulation of miR-101-5p and HSP10 may be a novel therapeutic approach for CSU.
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Urticaria Crónica , MicroARNs , Urticaria , Humanos , MicroARNs/genética , Factor de Activación Plaquetaria , Interleucina-4 , Enfermedad Crónica , Autoanticuerpos , Inmunoglobulina GRESUMEN
BACE1 is the rate-limiting enzyme for amyloid-ß peptides (Aß) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aß production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aß production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.
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Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Trastornos del Conocimiento/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/genética , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Isotiocianatos/farmacología , Ratones , Ratones Transgénicos , Factor 2 Relacionado con NF-E2/biosíntesis , Regiones Promotoras Genéticas , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Sulfóxidos , Transcripción GenéticaRESUMEN
INTRODUCTION: Chronic spontaneous urticaria (CSU) is a common cutaneous disease caused by mast-cell degranulation. Human ß-defensin 2 (HBD2) is a well-known antimicrobial peptide that is also a pruritogen inducing vascular permeability via non-IgE-mediated mast-cell degranulation. OBJECTIVE: We investigated the associations between serum HBD2 levels and the clinical characteristics of CSU patients. METHODS: Serum samples from 124 CSU patients and 56 healthy controls were screened for the levels of HBD2 and translationally controlled tumor protein (TCTP)_ by using ELISA. The urticaria activity score over 7 days (UAS7) was used to measure disease activity in CSU patients. Accompanying angioedema was self-reported. RESULTS: Serum HBD2 levels were higher in the CSU group than in healthy subjects (median [interquartile range], 84.1 [43.5, 142.5] vs. 59.5 [26.7, 121.5], p = 0.034). In CSU patients, serum HBD2 level was negatively correlated with the peripheral basophil percentages (Spearman's rho = -0.229, p = 0.01) and vitamin D levels (-0.262, p = 0.02), but positively correlated with TCTP levels (0.252, p = 0.006). In CSU patients, HBD2 level was higher in those with than without angioedema (101.7 [50.9, 184.2] vs. 66.7 [37.9, 132.0], p = 0.019). It did not differ by aspirin hypersensitivity or atopy status, or autologous serum skin test positivity. CONCLUSION: A known mast-cell degranulator, HBD2 was elevated in the sera from CSU patients compared to healthy controls and may be involved in the pathogenesis of accompanying angioedema.
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Angioedema/sangre , Urticaria Crónica/sangre , beta-Defensinas/sangre , Adulto , Biomarcadores de Tumor/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Tumoral Controlada Traslacionalmente 1RESUMEN
Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-ß (Aß) in neurons and neuropathology and cognitive functions in Aß precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in Aß-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aß deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aß-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.SIGNIFICANCE STATEMENT Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-ß (Aß)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aß deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.
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Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Trastornos del Conocimiento/fisiopatología , Dinaminas/metabolismo , Depresión Sináptica a Largo Plazo , Mitocondrias/metabolismo , Neuronas/metabolismo , Enfermedad de Alzheimer/complicaciones , Animales , Encéfalo/fisiopatología , Trastornos del Conocimiento/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición NeuralRESUMEN
The simultaneous detection of hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface (anti-HBs) is unusual in chronic hepatitis B virus (HBV) infection, but may be related with more advanced liver diseases. This retrospective long-term cohort study was aimed to investigate whether coexistence of HBsAg and anti-HBs may increase the risk of hepatocellular carcinoma (HCC) in chronic HBV infection. A total of 1,042 non-HCC patients were recruited and followed up for a median 4.3 years (range 1.0-22 years). Univariate and multivariate analyses were performed to identify the risk factors for HCC development. The prevalence of coexistence of HBsAg and anti-HBs was 7.0% (73/1,042). In univariate analysis, the 5-, 10-, and 15-year cumulative incidences of HCC were significantly higher in coexistence group than in HBsAg only group (12.7%, 23.4%, 69.4% vs. 4.9%, 13%, 20.6%, respectively; P = 0.008). In multivariate analysis, coexistence of HBsAg and anti-HBs [Hazard ratio (HR), 2.001; 95% confidence interval (CI), 1.023-3.912; P = 0.043] as well as male gender [HR, 1.898; 95% CI, 0.31-0.896; P = 0.018], age over 40 years [HR, 14.56; 95% CI, 4.499-47.08; P = 0.0001], and cirrhosis [HR, 7.995; 95% CI, 4.756-13.439; P = 0.0001] was identified as the independent factor for HCC development. Also, the cumulative incidence of HCC increased in proportion to the number of the risk factors. In conclusion, coexistence of HBsAg and anti-HBs may increase independently the risk of HCC development in chronic HBV infection. Therefore, consideration of HCC development is required in patients with coexistence of HBsAg and anti-HBs.
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Carcinoma Hepatocelular/epidemiología , Anticuerpos contra la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Vertical transmission from mother to child, the main route of chronic hepatitis B virus (HBV) infection in the East Asia, is considered one of the most important predictors for the response to antiviral therapies as well as its complications such as cirrhosis and hepatocellular carcinoma. Therefore, it is critical in both etiologic and prognostic aspects to confirm whether or not chronic HBV infection is acquired vertically. This study investigated whether mother-to-child infection could be proved by the phylogenetic analyses of HBV pre-S/S genes ever since several decades have elapsed in mother-child pairs with presumed vertical transmission. The pre-S and S regions of HBVs were compared and analyzed phylogenetically in a total of 36 adults (18 mother-child pairs) with chronic HBV infection. All of the isolates of HBV were genotype C and serotype adr. The divergence between mothers and offsprings was 0 to 1.5%. Phylogenetic trees revealed that 17 of 18 pairs (94%) with presumed vertical transmission were grouped into the same cluster. Vertical transmission from mother to child could be strongly suggested even in adults with a history of several decades of HBV infection using the phylogenetic analyses of pre-S and S genes.
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Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Adulto , Anciano , ADN Viral/análisis , Femenino , Genotipo , Antígenos de Superficie de la Hepatitis B/clasificación , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/metabolismo , Hepatitis B Crónica/diagnóstico , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Persona de Mediana Edad , Madres , Filogenia , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Serotipificación , Adulto JovenRESUMEN
BACKGROUND/AIMS: The clinical course of acute viral hepatitis A (AHA) is highly variable. Serum alphafetoprotein (AFP) level is often elevated in various types of acute liver injuries, indicating active liver regeneration. This study was aimed to investigate the clinical significance of serum AFP level in the aspect of the early recovery in AHA. METHODOLOGY: A total of 238 patients with AHA, confirmed by IgM anti-hepatitis A virus, were included. The patients were classified according to serum AFP level. Multivariate analysis by Cox proportional hazards model using dichotomized clinical variables was performed to identify the independent predictors for early recovery (ALT normalization within 2 weeks). RESULTS: The median age (range) was 30 (17-50) years and male dominant (62%, 147/238). Compared to low AFP group, high AFP group (>10 ng/mL) had significantly lower platelet counts (p <0.0001), lower albumin (p =0.003), lower AST (p <0.001), lower ALT (p = 0.001), higher total bilirubin level (p <0.0001) on univariate analysis. On Cox regression analysis, high AFP level (>10 ng/mL) was the only independent predictor for early recovery (Hazard ratio (HR); 2.392, 95% CI; 1.564-3.659, p = 0.0001). CONCLUSIONS: High serum AFP level (>10 ng/mL) may indicate the already-started recovery through active liver regeneration or the early recovery within 2 weeks in AHA.
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Hepatitis A/sangre , alfa-Fetoproteínas/análisis , Enfermedad Aguda , Adolescente , Adulto , Femenino , Hepatitis A/diagnóstico , Hepatitis A/fisiopatología , Anticuerpos de Hepatitis A/sangre , Humanos , Estimación de Kaplan-Meier , Regeneración Hepática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Tiempo , Regulación hacia Arriba , Adulto JovenRESUMEN
CCN family members are matricellular proteins with diverse roles in cell function. The differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. We aimed to evaluate the role of CCN2 and CCN5 in the development of cardiac hypertrophy and fibrosis. In isolated cardiomyocytes, overexpression of CCN2 induced hypertrophic growth, whereas the overexpression of CCN5 inhibited both phenylephrine (PE)- and CCN2-induced hypertrophic responses. Deletion of the C-terminal (CT) domain of CCN2 transformed CCN2 into a CCN5-like dominant negative molecule. Fusion of the CT domain to the Carboxy-terminus of CCN5 transformed CCN5 into a CCN2-like pro-hypertrophic molecule. CCN2 transgenic (TG) mice did not develop cardiac hypertrophy at baseline but showed significantly increased fibrosis in response to pressure overload. In contrast, hypertrophy and fibrosis were both significantly inhibited in CCN5 TG mice. CCN2 TG mice showed an accelerated deterioration of cardiac function in response to pressure overload, whereas CCN5 TG mice showed conserved cardiac function. TGF-beta-SMAD signaling was elevated in CCN2 TG mice, but was inhibited in CCN5 TG mice. CCN2 is pro-hypertrophic and -fibrotic, whereas CCN5 is anti-hypertrophic and -fibrotic. CCN5 lacking the CT domain acts as a dominant negative molecule. CCN5 may provide a novel therapeutic target for the treatment of cardiac hypertrophy and heart failure.
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Cardiomegalia/complicaciones , Cardiomegalia/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miocardio/metabolismo , Miocardio/patología , Animales , Cardiomegalia/patología , Células Cultivadas , Factor de Crecimiento del Tejido Conjuntivo/química , Fibrosis , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/prevención & control , Péptidos y Proteínas de Señalización Intracelular/química , Ratones , Ratones Transgénicos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenilefrina , Presión , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
PURPOSE: CD44 isoforms are highly expressed in cancer stem cells, initiating tumor growth and sustaining tumor self-renewal. Among these isoforms, CD44 variant 9 (CD44v9) is overexpressed in chronic inflammation-induced cancer. CD44 and the mesenchymal-to-epithelial transition (MET) receptor tyrosine kinase are coactivated in some gastric cancers (GCs). In this study, we characterized MET and CD44 expression and signaling in human GC cell lines and analyzed differences in the susceptibility of these lines to foretinib. PATIENTS AND METHODS: We analyzed cell viability and the rate of apoptotic cells using MTS assays and flow cytometry, respectively. Gene and protein expression were assessed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting, respectively. RESULTS: Foretinib treatment resulted in dose-dependent inhibition of growth in c-MET-amplified MKN45 and SNU620 cells with concomitant induction of apoptosis, but not in c-MET-reduced MKN28 and AGS cells. Foretinib treatment also significantly reduced phosphor-c-MET, phosphor-AKT, beta-catenin, and COX-2 protein expression in MKN45 and SNU620 cells. Interestingly, foretinib significantly reduced CD44, CD44v9, COX-2, OCT3/4, CCND1, c-MYC, VEGFA, and HIF-1a gene expression in CD44 and MET coactivated MKN45 cells and increased CD44s gene expression; in contrast, these drugs were only slightly active against SNU620 cells. CONCLUSION: The results of this study indicate that foretinib could be a therapeutic agent for the prevention or treatment of GCs positive for CD44v9 and c-MET.
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Eyes absent 2 (Eya2) is a transcription factor involved in a number of cellular and developmental processes. We have previously shown that Eya2 is up-regulated during regression of cardiac hypertrophy and blocks phenylephrine-induced development of cardiomyocyte hypertrophy in vitro, suggesting that Eya2 is a negative regulator of cardiac hypertrophy. In this study, we generated transgenic mice with cardiac-specific overexpression of Eya2 to elucidate the in vivo function of Eya2 in cardiac remodeling. Mild cardiac hypertrophy developed in Eya2 transgenic mice under baseline conditions with no obvious structural or functional defects. Eya2 overexpression inhibited development of cardiac hypertrophy as judged by the abrogation of increases in heart weight and cross-sectional cell surface areas and re-activation of fetal genes under pressure overload (4 weeks). Eya2 overexpression also prevented wall thinning, ventricular dilation, and deterioration of cardiac function as well as fibrosis and inflammation in the heart under long-term pressure overload (12 weeks). Gene expression profiling using the parametric analysis of gene set enrichment (PAGE) method revealed that gene sets related to mitochondrial biogenesis and metabolism were elevated in the Eya2 transgenic mice. We also observed that the PI3K/Akt/mTOR signaling cascade was preserved in the Eya2 transgenic mice, while it was significantly reduced in the wild type littermates under pressure overload. These results demonstrate that Eya2 prevents adverse cardiac remodeling under pressure overload partly through altering metabolic gene expression and preserving PI3K/Akt/mTOR signaling pathway.
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Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Presión , Proteínas Tirosina Fosfatasas/metabolismo , Estrés Fisiológico , Factores de Transcripción/metabolismo , Remodelación Ventricular , Animales , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/enzimología , Cardiomegalia/fisiopatología , Cardiomegalia/prevención & control , Fibrosis , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Ratones , Ratones Transgénicos , Especificidad de Órganos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR , Factores de Tiempo , UltrasonografíaRESUMEN
Reactive oxygen species (ROS) are chemically reactive oxygen containing molecules. ROS consist of radical oxygen species including superoxide anion (O2 â¢-) and hydroxyl radical (â¢OH) and non-radical oxygen species such as hydrogen peroxide (H2O2), singlet oxygen (O2). ROS are generated by mitochondrial oxidative phosphorylation, environmental stresses including UV or heat exposure, and cellular responses to xenobiotics ( Ray et al., 2012 ). Excessive ROS production over cellular antioxidant capacity induces oxidative stress which results in harmful effects such as cell and tissue damage. Sufficient evidence suggests that oxidative stresses are involved in cancers, cardiovascular disease, and neurodegenerative diseases including Alzheimer's disease and Parkinson disease (Waris and Ahsan, 2006). Though excessive level of ROS triggers detrimental effects, ROS also have been implicated to regulate cellular processes. Since ROS function is context dependent, measurement of ROS level is important to understand cellular processes (Finkel, 2011). This protocol describes how to detect intracellular and mitochondrial ROS in live cells using popular chemical fluorescent dyes.
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Inhibition of Notch signalling has shown anti-inflammatory properties in vivo and in vitro models of rheumatoid arthritis (RA). The objective of this study was to determine whether Notch1 might play a role in regulating T-regulatory cells (Tregs) in animal models of RA. Methods: Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) were induced in C57BL/6, Notch1 antisense transgenic (NAS) or DBA1/J mice. We examined whether pharmacological inhibitors of γ-secretase (an enzyme required for Notch1 activation) and antisense-mediated knockdown of Notch1 could attenuate the severity of inflammatory arthritis in CIA and CAIA mice. Proportions of CD4+CD25+Foxp3+ Treg cells were measured by flow cytometry. To assess the suppressive capacity of Treg toward responder cells, CFSE-based suppression assay of Treg was performed. Results: γ-secretase inhibitors and antisense-mediated knockdown of Notch1 reduced the severity of inflammatory arthritis in both CIA and CAIA mice. Pharmacological and genetic inhibition of Notch1 signalling induced significant elevation of Treg cell population in CIA and CAIA mice. We also demonstrated that inhibition of Notch signalling suppressed the progression of inflammatory arthritis through modulating the expansion and suppressive function of regulatory T (Treg) cells. Conclusion: Pharmacological and genetic inhibition of Notch1 signalling suppresses the progression of inflammatory arthritis through modulating the population and suppressive function of Treg cells in animal models of RA.
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Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Receptor Notch1/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Artritis Reumatoide/inducido químicamente , Modelos Animales de Enfermedad , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Transducción de SeñalRESUMEN
Regression of cardiac hypertrophy and improvement of the functional capacity of failing hearts have reportedly been achieved by mechanical unloading in cardiac work. In this study, cardiac hypertrophy was first induced in rats by transverse aortic constriction and then mechanically unloaded by relieving the constriction after significant cardiac hypertrophy had developed. Hypertrophy was significantly regressed at the cellular and molecular levels at day 1, 3, and 7 after constriction relief. Gene profiling analysis revealed that 52 genes out of 9,911 genes probed on a gene array were specifically upregulated during the early regression period. Among these regression-induced genes, Eyes absent 2 (eya2) was of particular interest because it is a transcriptional cofactor involved in mammalian organogenesis as well as Drosophila eye development. Adenovirus-mediated overexpression of eya2 in rat neonatal cardiomyocytes completely abrogated phenylephrine-induced development of cardiomyocyte hypertrophy as determined by cell size, sarcomere rearrangement and fetal gene re-expression. Our data strongly suggest that transcriptional programs distinct from those mediating cardiac hypertrophy may be operating during the regression of hypertrophy, and eya2 may be a key regulator of one of these programs.
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Cardiomegalia/genética , Perfilación de la Expresión Génica/métodos , Miocitos Cardíacos/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Línea Celular , Células Cultivadas , Análisis por Conglomerados , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fenilefrina/farmacología , Presión , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet -fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosis.
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Ácidos Grasos/metabolismo , Hígado Graso/genética , Hígado Graso/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Oxidación-Reducción , Receptor Notch1/deficiencia , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Línea Celular , Dieta/efectos adversos , Hígado Graso/patología , Técnicas de Silenciamiento del Gen , Humanos , Resistencia a la Insulina/genética , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Obesidad/genética , Obesidad/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo , Interferencia de ARN , Receptor Notch1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Right ventricular dysfunction (RVD) is associated with poor prognosis in patients with acute pulmonary embolism (APE). Echocardiography and computed tomography (CT)-angiography may be difficult to perform in a serial follow up, unlike electrocardiography (ECG). Many ECG findings specific for APE have been reported, and many studies have found that negative T-waves (NTW) in precordial leads are most frequently observed in patients with APE. We analyzed serial changes in precordial NTW to detect RVD and predict the recovery of RVD in patients with APE. METHODS: We examined 81 consecutive patients diagnosed with APE using CT-angiography or echocardiography. ECG, transthoracic echocardiography, and laboratory tests were performed within 24 hours of admission, and daily ECG follow-up was performed. Precordial NTWs were defined by the new development of pointed and symmetrical inverted T-waves in at least three leads. Recovery of NTW was defined as flattening or upright inverted T-waves in more than two leads. RESULTS: Of the 81 patients with APE, 52 (64%) had RVD according to echocardiography. Among the patients with RVD, 33 (63%) showed precordial NTW. The multivariate logistic regression analysis revealed that NTW was the strongest independent predictor for RVD (odds ratio, 22.8; 95% confidence interval, 2.4 to 221.4; p = 0.007). Time to normalization of NTW was associated with improvement of RVD on echocardiography (r = 0.84, p < 0.01). CONCLUSIONS: Precordial NTW was a reliable finding to identify RVD in patients with APE. Improvements in RVD can be predicted by normalizing precordial NTW.
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Electrocardiografía , Embolia Pulmonar/diagnóstico , Disfunción Ventricular Derecha/diagnóstico , Función Ventricular Derecha , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Ecocardiografía , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Embolia Pulmonar/complicaciones , Recuperación de la Función , República de Corea , Factores de Tiempo , Tomografía Computarizada por Rayos X , Disfunción Ventricular Derecha/complicaciones , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
Although the adrenal gland is a common site of metastasis from hepatocellular carcinoma (HCC), adrenal metastases are rarely seen in clinical practice because of its lower metastatic potential compared to the other malignancies. Adrenal metastases usually were detected at the time of diagnosis of primary HCC or simultaneously with intrahepatic recurrence after curative management of HCC. It is very rare that only metastatic HCC is detected without evidence of intrahepatic recurrence. Hereby, we report two cases of adrenal metastasis from HCC without intrahepatic recurrence after hepatic resection.
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Neoplasias de las Glándulas Suprarrenales/diagnóstico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/secundario , Anciano de 80 o más Años , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND/AIMS: The tumor-node-metastasis (TNM) staging is an useful system to assess the prognosis of any solid cancer. As new TNM staging classification of 7th stomach cancer was revised in 2009, we evaluated the prognostic predictability of the 7th International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM classification compared to 6th UICC/AJCC TNM classification in gastric cancer. METHODS: From January 2000 to December 2009, 5-year survival rates of 266 patients with gastric cancer were calculated by the 6th and 7th UICC/AJCC TNM classification. RESULTS: Using the 7th UICC/AJCC TNM classification, there was no significant difference in the 5-year cumulative survival rates (5 YSR) between stage IIA and IIB, IIB and IIIA, and IIIA and IIIB (70% vs. 71%, p=0.530; 71% vs. 80%, p=0.703; 80% vs. 75%, p=0.576, respectively) though significant differences of the survival rates were observed among stages of 6th edition. Using T stage of 7th edition, 5 YSR was not different between T2 and T3 (86% vs. 82%, p=0.655). Using N stage of 7th edition, 5 YSR were not different between N1 and N2, N3a and N3b (79% vs. 81%, p=0.506; 41% vs. 17%, p=0.895, respectively). CONCLUSIONS: The 7th UICC/AJCC TNM classification had poor prognostic predictability in gastric cancer compared to the 6th edition.