Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-kB-dependent manner

Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-κB-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.status: publishe

Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62–Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62–Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15–85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

A constitutive representation for linear aging, environmental-dependent viscoelastic materials

This study is concerned with developing a constitutive law for aging and environmental-dependent materials. The development rests on the assumption that the mechanical properties of the aforementioned materials can be mathematically represented by a functional of the strain and environmental histories, and this functional depends on the present time and the time the material is created. This constitutive assumption leads to two equivalent integral forms of the constitutive law after asserting that the functional is linear in the strain history. The first form of the integral law contains a material response functional analogous to the creep and relaxation functions of classical linear viscoelasticity. The second integral law has the same basic mathematical form but the physical interpretation of the mechanical response functional is different. It is demonstrated that both forms of the aging law reduce to the same non-aging law which is the usual starting for an analysis of only environmental-dependent materials. In the Appendix an operator algebra is presented for convenience in manipulating the integral laws for aging materials. Diese Untersuchung beschäftigt sich mit der Darstellung eines Werkstoffgesetzes für Altern und für umgebungsabhängige Stoffe. Die Entwicklung beruht auf der Annahme, daß die mechanischen Eigenschaften der oben erwähnten Stoffe mathematisch durch ein Funktional der Verzerrungs- und der Umgebungsgeschichten dargestellt werden kann und daß dieses Funktional von der augenblicklichen Zeit und der Zeit der Erzeugung des Stoffes abhängt. Diese Werkstoffannahme führt, unter der Voraussetzung einer linearen Abhängigkeit des Funktionals von der Verzerrungsgeschichte, auf zwei äquivalente Integraldarstellungen des Werkstoffgesetzes. Die erste Darstellung des Integralgesetzes enthält ein Materialantwort-Funktional analog der Kriech- und Relaxationsfunktionen der klassischen linearen Viskoelastizität. Das zweite Gesetz hat die gleiche mathematische Gestalt, aber verschiedene physikalische Interpretation des mechanischen Antwort-Funktionals. Es wird gezeigt, daß für nicht-alternde Stoffe beide Darstellungen dasselbe Gesetz, das der übliche Ausgangspunkt einer Untersuchung umgebungsbeeinflußter Stoffe ist, ergeben. Im Anhang werden einige für das Rechnen mit den Integralgesetzen alternder Stoffe handliche Sätze der Operatorenrechnung angegeben.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41700/1/707_2005_Article_BF01179657.pd

A brave new world of RNA-binding proteins

RNA-binding proteins (RBPs) are typically thought of as proteins that bind RNA through one or multiple globular RNA-binding domains (RBDs) to change the fate or function of the bound RNAs. Several hundreds of such RBPs have been discovered and investigated over the years. Recent proteome-wide studies have more than doubled the number of proteins implicated in RNA binding and uncovered hundreds of additional RBPs lacking classical RBDs. This review integrates these new RBPs and discusses their possible functions, including the notion that some may be regulated by RNA rather than exerting control over it

PREPARATION AND STRUCTURE OF THIN Fe1-xBx SPUTTER FILMS

No abstract availabl