Behavioral alterations and Fos protein immunoreactivity in brain regions of bile duct-ligated cirrhotic rats

Hepatic encephalopathy (HE) encompasses a variety of neuropsychiatric symptoms, including anxiety and psychomotor dysfunction. Although HE is a frequent complication of liver cirrhosis, the neurobiological substrates responsible for its clinical manifestations are largely unclear. In the present study, male Wistar rats were bile duct-ligated (BDL), a procedure which induces liver cirrhosis, and on the 21st day after surgery tested in the elevated plus-maze (EPM) and in an open field for anxiety and locomotor activity measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to better understand the neurobiological alterations present in BDL animals. Plasma levels of ammonia were quantified and histopathological analysis of the livers was performed. BDL rats showed a significant decrease in the percentage of entries and time spent in the open arms of the EPM, an anxiogenic effect. These animals also presented significant decreases in Fos-ir in the lateral septal nucleus and medial amygdalar nucleus. Their ammonia plasma levels were significantly higher when compared to the sham group and the diagnosis of cirrhosis was confirmed by histopathological analysis. These results indicate that the BDL model induces anxiogenic results, possibly related to changes in the activation of anxiety-mediating circuitries and to increases in ammonia plasma levels.A Encefalopatia hepática (HE) engloba uma variedade de sintomas neuropsiquiátricos, incluindo ansiedade e disfunção psicomotora. Embora seja uma complicação frequente da cirrose hepática, os substratos neurobiológicos responsáveis por suas manifestações clínicas são em grande parte desconhecidos. No presente estudo, ratos Wistar machos foram submetidos ao procedimento cirúrgico de ligação e secção do ducto biliar (BDL; bile-duct ligation), para indução da cirrose hepática e, no 21º dia após a cirurgia, submetidos aos testes comportamentais no labirinto em cruz elevado (LCE) e campo aberto para avaliação da ansiedade e atividade locomotora. A análise da imunorreatividade à proteína Fos (Fos-ir) foi utilizada para melhor compreender as alterações neurobiológicas presentes nos animais do grupo BDL. Foi realizada a quantificação da concentração de amônia plasmática e análise histopatológica dos fígados. Os ratos do grupo BDL mostraram diminuição significativa na porcentagem de entradas e tempo gasto nos braços abertos do LCE, caracterizando efeito ansiogênico. Estes animais também apresentaram redução significativa na Fos-ir no núcleo septal lateral e núcleo medial da amígdala. A concentração plasmática de amônia foi significativamente mais elevada que a do grupo sham e o diagnóstico de cirrose foi confirmado por análise histopatológica. Estes resultados indicam que o modelo de HE induzido por BDL induz efeito ansiogênico possivelmente relacionado à ativação de circuitos mediadores da ansiedade e à hiperamonemia.Universidade Federal de São Paulo (UNIFESP) Departamento de BiociênciasUniversidade de São Paulo Instituto de Ciências Biomédicas Departamento de AnatomiaUNIFESP, Depto. de BiociênciasSciEL

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G1 phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL

Genomics and epidemiology for gastric adenocarcinomas (GE4GAC): a Brazilian initiative to study gastric cancer

Abstract Gastric cancer (GC) is the fifth most common type of cancer worldwide with high incidences in Asia, Central, and South American countries. This patchy distribution means that GC studies are neglected by large research centers from developed countries. The need for further understanding of this complex disease, including the local importance of epidemiological factors and the rich ancestral admixture found in Brazil, stimulated the implementation of the GE4GAC project. GE4GAC aims to embrace epidemiological, clinical, molecular and microbiological data from Brazilian controls and patients with malignant and pre-malignant gastric disease. In this letter, we summarize the main goals of the project, including subject and sample accrual and current findings

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification