Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the “Two Hit Theory” to the “Multiple Hit Theory”. However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first “Achilles’ heel” of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.
BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-κB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-κB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.BAG3 | IKK-gamma | apoptosis
Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms.
ABSTRACT1. The Pelagos Sanctuary is the largest marine protected area of the Mediterranean Sea (87 500 km 2 ), and is located in the north-west part of the basin. The presence of the bottlenose dolphin in this area is well documented but its distribution and abundance are not well known.2. The present study collected and analysed data from 10 different research groups operating in the Pelagos Sanctuary from 1994 to 2007. Photo-identification data were used to analyse the displacement behaviour of the dolphins and to estimate their abundance through mark-recapture modelling.3. Results show that the distribution of bottlenose dolphin is confined to the continental shelf within the 200 m isobath, with a preference for shallow waters of less than 100 m depth.4. Bottlenose dolphins seem to be more densely present in the eastern part of the sanctuary and along the north-west coast of Corsica.5. Bottlenose dolphins show a residential attitude with excursions usually within a distance of 80 km (50 km on average). A few dolphins exhibit more wide-ranging journeys, travelling up to 427 km between sub-areas.6. The displacement analysis identified two (sub)populations of bottlenose dolphins, one centred on the eastern part of the sanctuary and the other one around the west coast of Corsica.7. In 2006, the eastern (sub)population was estimated to comprise 510-552 individuals, while 368-429 individuals were estimated in the Corsican (sub)population. It was estimated that in total, 884 -1023 bottlenose dolphins were living in the Pelagos Sanctuary MPA in the same year.8. The designation of a number of Special Areas of Conservation (SACs) under the Habitats Directive is discussed as a possible tool to protect the bottlenose dolphin in the Pelagos Sanctuary and in the whole of the Mediterranean Sea.
We examined the peroxisome proliferator-activated receptor ␥ (PPARG) locus in an attempt to identify expressed sequence tags and/or conserved non-coding sequences in the intron sequences containing open reading frames and potentially able to encode new proteins. We identified a new PPARG transcript, defined ␥ORF4, which harbors a readthrough in intron 4. The expected translated protein lacks the ligand-binding domain encoded by exons 5 and 6. We identified the transcript in human tumor cell lines and tissues, synthesized the cDNA, and cloned it in expression vectors. Using transient transfections, we found that ␥ORF4 cDNA is translated into a predominantly nuclear protein that does not transactivate a reporter gene. Moreover, the isoform is dominant negative versus PPAR␥. Interestingly, ␥ORF4 was expressed in vivo in a series of sporadic colorectal cancers. In some cases, it was expressed, albeit at lower levels, also in the mucosa adjacent to the tumors, suggesting that it may be related to tumorigenesis. A tumorigenic effect of ␥ORF4 is in line with our finding that ␥ORF4 has not only lost the capacity to restrain cell growth but has acquired the potential to stimulate it. In conclusion, this study demonstrates that ␥ORF4 is expressed in vivo, that it has lost some PPAR␥ properties, and that it affects PPAR␥ functioning. The ability to counteract PPAR␥ suggests that ␥ORF4 plays a role in the pathogenesis of colorectal cancers.
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