Liver-specific activation of AMPK prevents steatosis on a high fructose diet

AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the γ1 subunit (γ1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma)

Oxidative discolouration in whole-head and cut lettuce: biochemical and environmental influences on a complex phenotype and potential breeding strategies to improve shelf-life

Lettuce discolouration is a key post-harvest trait. The major enzyme controlling oxidative discolouration has long been considered to be polyphenol oxidase (PPO) however, levels of PPO and subsequent development of discolouration symptoms have not always correlated. The predominance of a latent state of the enzyme in plant tissues combined with substrate activation and contemporaneous suicide inactivation mechanisms are considered as potential explanations for this phenomenon. Leaf tissue physical properties have been associated with subsequent discolouration and these may be influenced by variation in nutrient availability, especially excess nitrogen and head maturity at harvest. Mild calcium and irrigation stress has also been associated with a reduction in subsequent discolouration, although excess irrigation has been linked to increased discolouration potentially through leaf physical properties. These environmental factors, including high temperature and UV light intensities, often have impacts on levels of phenolic compounds linking the environmental responses to the biochemistry of the PPO pathway. Breeding strategies targeting the PALand PPOpathway biochemistry and environmental response genes are discussed as a more cost-effective method of mitigating oxidative discolouration then either modified atmosphere packaging or post-harvest treatments, although current understanding of the biochemistry means that such programs are likely to be limited in nature and it is likely that they will need to be deployed alongside other methods for the foreseeable future

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Aspirin activates the NF-kappa B signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer

Substantial evidence indicates that aspirin has antitumour activity against large bowel cancer and modulation of the NF-kappaB (NF-kappa B) signalling pathway has been identified as a key mechanism in this effect. However, studies examining how aspirin affects the NF-kappa B pathway to promote apoptosis have been restricted to in vitro analysis in tissue culture systems and have produced contrasting results. Here, we employed two animal models of human colorectal cancer to determine aspirin effects on the NF-kappa B pathway in colorectal neoplasia in vivo, and the relationship of such effects to the induction of apoptosis. We demonstrate that aspirin induces phosphorylation and degradation of cytoplasmic I kappa B alpha in xenografted HT-29 tumours and in adenomas from APC(Min+/-) mice. Furthermore, we show that this response occurs in a time-dependent manner and is paralleled by nuclear translocation of p65 and caspase activation. Using high performance liquid chromatography analysis, we demonstrate that > 0.5 mM salicylate levels are achievable in xenografted tumours after low-dose aspirin (40 mg/kg) treatment and that these levels, which are pharmacologically relevant to humans, are sufficient to stimulate an NF-kappa B and apoptotic response. We demonstrate that activation of the NF-kappa B pathway is associated with increased apoptosis in neoplastic epithelial cells, but found that aspirin has a minimal effect on nuclear p65 and apoptosis in normal intestinal mucosa from APC(Min+/-) mice. These in vivo findings further establish that aspirin induces activation of the NF-kappa B pathway in neoplastic epithelial cells and provide further support that this effect is important for the antitumour activity of the agent. These data have considerable relevance to cancer prevention and therapy