AP-1 (Activating Protein1The members of the Fos, Jun, ATF (Activating Transcription Factor), and MAF (Musculo Aponeurotic Fibrosarcoma) protein families are components of the dimeric AP-1 (Activating Protein 1) transcription factor complex. AP-1 participates in the regulation of a variety of cellular processes, such as cell proliferation, cell differentiation, neoplastic transformation, and apoptosis (Angel and Karin 1991; Karin et al. 1997;Eferl and Wagner 2003). AP-1 transcription factor activity is regulated at multiple levels, including transcriptional control, post-translational modifications, dimer composition, and interactions with many structurally divergent regulatory proteins. AP-1 proteins are prototype transcription factors that harbor several functional domains: (1) several transactivation regions, (2) a basic domain that interacts with sequence elements in the promoters and enhancers of target genes, and (3) the adjacent leucine-zipper domain (ZIP) required for dimerization, a prerequisite for AP-1 DNA-binding activity and for transcriptional regulation of target genes (Angel and Karin 1991;Karin et al. 1997;Eferl and Wagner 2003).The importance of protein-protein interactions in the control of AP-1 function is suitably illustrated by the participation of Fos and Jun in multiple dimeric transcription complexes including: (1) Jun/Jun homodimers, (2) Fos/Jun heterodimers, (3) heterodimers between Fos or Jun and other "basic-ZIP" (bZIP) family proteins (e.g., ATF, MAF, Nrf-1, Nrf-2), and (4)

There are no effective antifibrotic therapies for patients with liver diseases. We performed an experimental and translational study to investigate whether ghrelin, an orexigenic hormone with pleiotropic properties, modulates liver fibrogenesis. Recombinant ghrelin was administered to rats with chronic (bile duct ligation) and acute (carbon tetrachloride) liver injury. Hepatic gene expression was analyzed by way of microarray analysis and quantitative polymerase chain reaction. The hepatic response to chronic injury was also evaluated in wild-type and ghrelin-deficient mice. Primary human hepatic stellate cells were used to study the effects of ghrelin in vitro. Ghrelin hepatic gene expression and serum levels were assessed in patients with chronic liver diseases. Ghrelin gene polymorphisms were analyzed in patients with chronic hepatitis C. Recombinant ghrelin treatment reduced the fibrogenic response, decreased liver injury and myofibroblast accumulation, and attenuated the altered gene expression profile in bile duct-ligated rats. Moreover, ghrelin reduced the fibrogenic properties of hepatic stellate cells. Ghrelin also protected rats from acute liver injury and reduced the extent of oxidative stress and inflammation. Ghrelin-deficient mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis, and ghrelin gene hepatic expression correlated with expression of fibrogenic genes. In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (؊994CT and ؊604GA) influenced the progression of liver fibrosis. Conclusion: Ghrelin exerts antifibrotic effects in the liver and may represent a novel antifibrotic therapy. (HEPATOLOGY 2010;51:974-985.) H epatic fibrosis is the progressive accumulation of extracellular matrix that occurs in most types of chronic liver diseases. In patients with advanced fibrosis, liver cirrhosis ultimately develops. Currently, the only effective therapy to treat liver fibrosis is to eliminate the causative agent (e.g. successful antiviral therapy in patients with chronic hepatitis C). For those patients in whom the underlying cause cannot be removed, there are no effective antifibrotic therapies. During recent years, research has focused on molecular and cellular mechanisms involved in liver fibrosis, and many pharmacological interventions have been successfully tested in experimental models of liver fibrosis. 1 However, most of the information derives from the experimental setting,

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G 1 cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27Kip1 and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27Kip1 at the level of transcription. We further show that BCR-ABL also regulates p27Kip1 protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27Kip1 by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27Kip1 . We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27Kip1 mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27Kip1 contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27Kip1 and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias. (Cancer Res 2005; 65(8): 3264-72)

BackgroundLow birth weight has been linked to an increased risk to develop obesity, type 2 diabetes, and hypertension in adult life, although the mechanisms underlying the association are not well understood. The objective was to determine whether the metabolomic profile of plasma from umbilical cord differs between low and normal birth weight newborns.MethodsFifty healthy pregnant women and their infants were selected. The eligibility criteria were being born at term and having a normal pregnancy. Pairs were grouped according to their birth weight: low birth weight (LBW, birth weight < 10th percentile, n = 20) and control (control, birth weight between the 75th-90th percentiles, n = 30). Nuclear Magnetic Resonance (NMR) was used to generate metabolic fingerprints of umbilical cord plasma samples. Simultaneously, the metabolomic profiles of the mothers were analysed. The resulting data were subjected to chemometric, principal component and partial least squares discriminant analyses.ResultsUmbilical cord plasma from LBW and control newborns displayed a clearly differentiated metabolic profile. Seven metabolites were identified that discriminate the LBW from the control group. LBW newborns had lower levels of choline, proline, glutamine, alanine and glucose than did the control newborns, while plasma levels of phenylalanine and citrulline were higher in LBW newborns (p < 0.05). No significant differences were found between the two groups of mothers.ConclusionsLow birth weight newborns display a differential metabolomic profile than those of normal birth weight, a finding not present in the mothers. The meaning and the potential utility of the findings as biomarkers of risk need to be addressed in future studies.