82 research outputs found
Noxa mediates hepatic stellate cell apoptosis by proteasome inhibition.
Aim: Induction of hepatic stellate cell (HSC) apoptosis is a viable therapeutic strategy to reduce liver fibrogenesis. Although BH3-only proteins of the Bcl-2 family trigger pro-apoptotic pathways, the BH3-only proteins mediating HSC apoptosis have not been well defined. Our aim, using proteasome inhibition as a model to induce HSC apoptosis, was to examine the BH3-only proteins contributing to cell death of this key liver cell subtype. Methods: Apoptosis was induced by treating LX-2 cells, an immortalized human hepatic stellate cell line, and primary rat stellate cells with the proteasome inhibitor MG-132. Results: Treatment with proteasome inhibitors increased expression of Noxa both at the mRNA (16-fold) and protein (22-fold) levels indicating that both transcriptional and post-translational mechanisms contributed to the increase in cellular Noxa levels. Knockdown of Noxa by siRNA significantly attenuated cell death, mechanistically implicating Noxa as a key apoptotic mediator of proteasome inhibitor-induced cell death. Given the pivotal role for the anti-apoptotic Bcl-2 protein A1 in activated HSC survival, we determined if Noxa bound to this survival protein. Noxa was shown to physically bind the anti-apoptotic Bcl-2 protein A1 by co-immunoprecipitation. Conclusions: Noxa contributes to proteasome inhibitor-induced apoptosis of stellate cells likely by binding A1. Strategies to therapeutically increase Noxa expression may be useful for inducing HSC apoptosis
TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouse.
The contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand expressed by cells of the innate immune system, to cholestatic liver injury has not been explored. Our aim was to ascertain if TRAIL contributes to liver injury in the bile duct-ligated (BDL) mouse. C57/BL6 wild-type (wt), TRAIL heterozygote (TRAIL(+/-)), and TRAIL knockout (TRAIL(-/-)) mice were used for these studies. Liver injury and fibrosis were examined 7 and 14 days after BDL, respectively. Hepatic TRAIL messenger RNA (mRNA) was 6-fold greater in BDL animals versus sham-operated wt animals (P \u3c 0.01). The increased hepatic TRAIL expression was accompanied by an increase in liver accumulation of natural killer 1.1 (NK 1.1)-positive NK and natural killer T (NKT) cells, the predominant cell types expressing TRAIL. Depletion of NK 1.1-positive cells reduced hepatic TRAIL mRNA expression and serum alanine aminotransferase (ALT) values. Consistent with a role for NK/NKT cells in this model of liver injury, stress ligands necessary for their recognition of target cells were also up-regulated in hepatocytes following BDL. Compared to sham-operated wt mice, BDL mice displayed a 13-fold increase in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and an 11-fold increase in caspase 3/7-positive hepatocytes (P \u3c 0.01). The number of TUNEL and caspase 3/7-positive cells was reduced by \u3e80% in BDL TRAIL knockout animals (P \u3c 0.05). Likewise, liver histology, number of bile infarcts, serum ALT values, hepatic fibrosis, and animal survival were also improved in BDL TRAIL(-/-) animals as compared to wt animals. Conclusion: These observations support a pivotal role for TRAIL in cholestatic liver injury mediated by NK 1.1-positive NK/NKT cells
Overexpression of mcl-1 attenuates liver injury and fibrosis in the bile duct-ligated mouse.
Hepatocyte apoptosis contributes to liver injury and fibrosis after cholestatic injury. Our aim was to ascertain if the anti-apoptotic protein Mcl-1 alters liver injury or fibrosis in the bile duct-ligated mouse. Markers of apoptosis and fibrosis were compared in wild-type and transgenic mice expressing human Mcl-1 after bile duct ligation. Compared to hMcl-1 transgenic animals, ligated wild-type mice displayed a significant increase in TUNEL-positive cells and in caspase 3/7-positive hepatocytes. Consistent with apoptotic injury, the pro-apoptotic protein Bak underwent a conformational change to an activated form upon cholestatic injury, a change mitigated by hMcl-1 overexpression. Likewise, liver histology, number of bile infarcts, serum ALT values, markers of hepatic fibrosis, and animal survival were improved in bile duct-ligated mice transgenic for hMcl-1 as compared to wild-type mice. In conclusion, increased Mcl-1 expression plays a role in hepatoprotection upon cholestatic liver injury
Intercrop of sunflower hybrids. A strategy for an agroecological resource management
La siembra de intercultivos permite mejorar el uso de recursos y la biodiversidad. El objetivo del trabajo fue evaluar en tres híbridos de girasol sembrados puros y mezclados de a dos, las características asociadas al aprovechamiento de la luz, como posible determinante de una mejor productividad de la mezcla. Se realizó un ensayo a campo, en La Plata, Argentina con los híbridos de girasol DK4040, DK4050 y Jagüel puros y en mezcla de a dos, con una relación 1:1. Se evaluó cobertura del suelo (%CRG), altura de planta e índice de área foliar (IAF) en diferentes estados de desarrollo y en madurez: rendimiento, biomasa aérea, índice de cosecha, rendimiento relativo total (RYT) para grano y biomasa. No hubo diferencias significativas entre tratamientos en %CRG, altura ni IAF. La productividad y los rendimientos relativos de los híbridos fueron diferentes encontrándose una relación funcional entre el rendimiento potencial y la tolerancia a la competencia. Los valores de RYT grano y RYT biomasa de las mezclas fueron cercanos a 1 y sólo la mezcla DK4050 + Jagüel superó ligeramente la unidad, lo que permite considerar a la mezcla de híbridos de girasol una alternativa de producción con ventajas asociadas a su mayor diversidad.Intercropping can improve resource use and biodiversity. The aim of this study was to evaluate, in three sunflower hybrids sown as pure crop or two hybrid intercrop, traits associate with light use as possible determinants of the higher intercrop productivity. A field experiment was carried out in La Plata, Argentina. Sunflower DK 4040, DK 4050 and Jagüel were sowing pure or mixed in 1:1 ratio. Soil cover (%CGR), plant height and leaf area index (IAF) were evaluated at different development stages, and at maturity, yield, total above ground biomass, harvest index, seed and biomass relative yield total (RYT) were evaluated. Plant height, %CGR and IAF did not differ significantly between treatments. Productivity and relative yields were different between hybrids and a functional relationship was found between potential yield and tolerance to competence. Relative yield total seed and relative yield total biomass values were near 1 and only DK4050 + Jagüel intercrop surpassed lightly the unity that allows to consider sunflower hybrids mixture as a production alternative with advantages related to the higher divertsity.Facultad de Ciencias Agrarias y Forestale
Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage
Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis-inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro-apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim-deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death
De la quinta a la mesa: experiencias en escuelas primarias de La Plata
Este trabajo recoge la experiencia de un proyecto de extensión de la Universidad Nacional de La Plata (UNLP) que comenzó en el año 2012. Sus integrantes son profesionales y estudiantes de distintas carreras de grado y unidades académicas. La propuesta constituye una iniciativa para el abordaje interdisciplinario del consumo responsable de frutas y hortalizas en niños de nivel primario.Facultad de Ciencias Agrarias y Forestale
Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells
Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells
Homogeneidade e heterogeneidade nos sistemas educacionais: Argentina, Brasil, Chile e México
- …