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SignificanceHepatic fibrosis is the common pathophysiologic process resulting from chronic liver injury, characterized by the accumulation of an excessive extracellular matrix. Multiple lines of evidence indicate that oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to phagocytic NOX2, there are six nonphagocytic NOX proteins.Recent advancesIn the liver, NOX is functionally expressed both in the phagocytic form and in the nonphagocytic form. NOX-derived ROS contributes to various kinds of liver disease caused by alcohol, hepatitis C virus, and toxic bile acids. Recent evidence indicates that both phagocytic NOX2 and nonphagocytic NOX isoforms, including NOX1 and NOX4, mediate distinct profibrogenic actions in hepatic stellate cells, the main fibrogenic cell type in the liver. The critical role of NOX in hepatic fibrogenesis provides a rationale to assess pharmacological NOX inhibitors that treat hepatic fibrosis in patients with chronic liver disease.Critical issuesAlthough there is compelling evidence indicating a crucial role for NOX-mediated ROS generation in hepatic fibrogenesis, little is known about the expression, subcellular localization, regulation, and redox signaling of NOX isoforms in specific cell types in the liver. Moreover, the exact mechanism of NOX-mediated fibrogenic signaling is still largely unknown.Future directionsA better understanding through further research about NOX-mediated fibrogenic signaling may enable the development of novel anti-fibrotic therapy using NOX inhibition strategy. Antio

Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-[A.sup.y] mice, an animal model of metabolic syndrome. Twelve-week-old male KK-[A.sup.y] and C57B1/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun N[H.sub.2]-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-[A.sup.y] mice than in C57B1/6 mice and significantly increased serum alanine aminotransferase levels in KK-[A.sup.y] mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-[A.sup.y] mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-[A.sup.y] mice. Exposure to 20 [micro]M tert-butyl hydroperoxide did not kill hepatocytes isolated from C57B1/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-[A.sup.y] mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-[A.sup.y] mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury. drug-induced liver injury; metabolic syndrome; steatohepatitis; oxidative stress; hepatotoxicity doi: 10.1152/ajpgi.00361.2009.

The study report of the impact of polarity of gate bias and Hf concentration on HfSiON/Si[O.sub.2] gate dielectric breakdown (DB) with time-zero DB (TZDB) and time-dependent DB (TDDB) is presented.

The article analyzed the gate depletion in poly-Si/HfSiON stacks by the C-V differentiation analysis.

In order to elucidate influences of nitrogen on the change of effective work function (Δ[uppercase_phi_synonym]eff) with impurity segregation, we systematically investigated the Δ[uppercase_phi_synonym]eff at arsenic (As) and boron (B) segregated NiSi/SiO2 and NiSi/SiON interfaces. These impurities are introduced to NiSi/SiON (SiO2) interfaces by using the conventional predoping process. It was found that increase in [uppercase_phi_synonym]eff with B segregation is suppressed as low as Δ[uppercase_phi_synonym]eff=+0.05 eV at NiSi/SiON interface compared to Δ[uppercase_phi_synonym]eff=+0.14 eV at NiSi/SiO2 interface, though there is little change in decrease of [uppercase_phi_synonym]eff with As segregation. Moreover, the opposite (negative) [uppercase_phi_synonym]eff modulation occurred at NiSi/SiON interface in the case of low B dose. We also performed the B postdoping process, in which B atoms were introduced after Ni silicide gate formation with lower thermal process (∼500 °C) than conventional predoping process (∼1000 °C). A large Δ[uppercase_phi_synonym]eff of +0.2 eV occurred even at NiSi/SiON system in the postdoping process. Based on the results of backside x-ray photoelectron spectroscopy (XPS), we revealed that most of B atoms were segregated at SiON side of the interface, which was similar to the case of NiSi/SiO2 interface, and the B concentration increases with N ratio in SiON in the predoping process. The backside XPS analysis also clarified that the formation of thermally stable B–N bonds in SiON was suppressed in the case of the postdoping process compared to that in the predoping process. The degree of suppression of Δ[uppercase_phi_synonym]eff is proportional to the B–N state intensity. From these experimental results, we conclude that generation of B–N bonds positively charged in SiON counteracts and suppresses the interface dipole effect of segregated B at NiSi/SiON interface. The large Δ[uppercase_phi_synonym]eff at the B postdoped NiSi/SiON interface seems to be owing to low density of charged B–N bonds, because of suppression of B infiltration into SiON layer with low annealing temperature. [ABSTRACT FROM AUTHOR]