Intermediate filament cytoskeleton of the liver in health and disease

Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising ~70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Probing the water phases and microstructure in a model cement blend matrix used for the encapsulation of intermediate level nuclear wastes

The changes in microstructure and content of water phases during hydration of a 3:1 BFS:OPC blend are investigated by Mercury Intrusion Porosimetry (MIP), freeze-drying, Thermal Gravimetric Analysis (TGA) and 1H Nuclear Magnetic Resonance (NMR) relaxometry. MIP indicates that during the blend hydration, a reduction in the population of capillary pores (larger than about 100 nm) occurs while the population of gel pores (smaller than few tens of nanometres) increases. Between 3 and 90 days, the porosity estimated by MIP decreases from about 36% down to 18% while the median pore size decreases from about 140 nm down to 6 nm. 1HNMR relaxometry shows that after 1 day of hydration, nearly 70% of the evaporable water is held in capillary pores while about 30% is present in gel pores. After two weeks, most of the evaporable water (90%) is found in pores smaller than few tens of nanometres. : The amount of evaporable water detected by freeze drying decreases from less than 20 wt.% after one week of hydration down to about 16.3 wt.% after 90 days while the amount of chemical ly bound water related to the degree of advancement of the cement hydration and detected by TGA increases from 8 wt.% to 10.3 wt.%. During hydration the BFS:OPC blend matrix evolves from an open microporous network to one of a poorly connected network of water rich nanopores with increasing amounts of chemically bound water. © 2006 Materials Research Society