Oxidative stress induced by intermittent hypoxia exacerbates lipid accumulation and inflammation in a cell model of non-alcoholic steatohepatitis

Oral PresentationBackground/Aims: The prevalence of obstructive sleep apnea (OSA) is high in patients with non-alcoholic fatty liver disease (NAFLD) and NASH is a progressive hallmark of the pathogenesis of NAFLD. Chronic intermittent hypoxia is associated with recurrent episodes of oxygen desaturation and reoxygenation in OSA patients, leading to excessive production of reactive oxygen species (ROS). The causal link between OSA and NAFLD is not known and the mechanistic effect of intermittent hypoxia (IH) on the pathogenesis of NAFLD remains elusive. Here we tested the hypothesis that IH-induced oxidative stress aggravates lipid accumulation and inflammation induced by sodium palmitate in HepG2 cells. Materials and Methods: HepG2 cells were treated with sodium palmitate or vehicle under normoxia (Nx) or IH condition for 72 hours in the present or absence of a ROS scavenger MnTBAP. Cell viability was detected by MTT assay and intracellular lipid deposit was examined by oil red staining. Lipid peroxidation was measured by malondialdehyde (MDA) assay and levels of reactive oxygen species (ROS) were detected by CM-H2DCFDA staining. The expressions of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), fatty acid uptake-associated genes (caveolin-1 and FATP5), fatty acid synthesis genes (SREBP1 and ACC1) and fatty acid β-oxidation gene ACOX were determined by real-time PCR. Results: Results showed that sodium palmitate increased lipid deposit in the cells and it also decreased cell viability. The effect of sodium palmitate was more prominent in the group co-treated with hypoxia. Levels of MDA and ROS and the expressions of IL-1β, TNF-α, IL-6 and caveolin-1, but not FATP5, were significantly increased in the palmitate- or hypoxia-treated group and were remarkably elevated in the co-treated group. These effects were abolished by MnTBAP treatment. In addition, levels of the expression of ACOX, SREBP1 and ACC1 were significantly lowered in the cells treated with palmitate or hypoxia and the expressions were much less in the cotreated group. Treatment of MnTBAP prevented the decreased expression of ACOX but had no effect on the SREBP1 and ACC1 expression. Conclusion: IH-induced oxidative stress exacerbates lipid accumulation and inflammation induced by sodium palmitate in HepG2 cells, probably mediated by an increase in lipid uptake and a decrease in the fatty acid β-oxidation.published_or_final_versio

Cordycepin enhances cisplatin apoptotic effect through caspase/MAPK pathways in human head and neck tumor cells

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The iron-chelating drug M30 down-regulates carbon tetrachloride (CCI4)-induced hepatic oxidative stress, inflammation and apoptosis in vitro

Topic: 2 Acute Liver FailureThis journal suppl. entitled: APASL Liver Week 2013BACKGROUND/AIMS: The novel multifunctional brain permeable ironchelator M30 possesses neuroprotective activities against several insults applicable to various neurodegenerative diseases. However, the effect of M30 on CCl4 induced acute liver damage is still unknown. The aim of this study is to investigate whether the multifunctional drug M30 could ameliorate CCl4 induced hepatic injury in human HepG2 cell line. METHODS: HepG2 cells were grown in DMEM supplemented with ...postprin

Intermittent hypoxia aggravates early pathogenesis of non-alcoholic fatty liver disease in rats

BACKGROUND/AIMS: Chronic intermittent hypoxia (CIH) is associated with recurrent episodes of oxygen desaturation and reoxygenation in obstructive sleep apnea (OSA) patients. The prevalence of OSA is high in patients with non-alcoholic fatty liver disease (NAFLD). The mechanistic effect of CIH on the early pathogenesis of NAFLD remains elusive. Here we tested the hypothesis that IH aggravates oxidative stress and inflammation induced by high fat diet at an initial stage of pathogenesis ...postprin

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

An Obligatory Role of Mind Bomb-1 in Notch Signaling of Mammalian Development

Background. The Notch signaling pathway is an evolutionarily conserved intercellular signaling module essential for cell fate specification that requires endocytosis of Notch ligands. Structurally distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), cooperatively regulate the endocytosis of Notch ligands in Drosophila. However, the respective roles of the mammalian E3 ubiquitin ligases, Neur1, Neur2, Mib1, and Mib2, in mammalian development are poorly understood. Methodology/Principal Findings. Through extensive use of mammalian genetics, here we show that Neur1 and Neur2 double mutants and Mib2-1- mice were viable and grossly normal. In contrast, conditional inactivation of MW in various tissues revealed the representative Notch phenotypes: defects of arterial specification as deltalike4 mutants, abnormal cerebellum and skin development as jagged1 conditional mutants, and syndactylism as jagged2 mutants. Conclusions/Significance. Our data provide the first evidence that Mib1 is essential for Jagged as well as Deltalike ligand-mediated Notch signaling in mammalian development, while Neur1, Neur2, and Mib2 are dispensable.open504

Is an ecosystem services-based approach developed for setting specific protection goals for plant protection products applicable to other chemicals?

Clearly defined protection goals specifying what to protect, where and when, are required for designing scientifically sound risk assessments and effective risk management of chemicals. Environmental protection goals specified in EU legislation are defined in general terms, resulting in uncertainty in how to achieve them. In 2010, the European Food Safety Authority (EFSA) published a framework to identify more specific protection goals based on ecosystem services potentially affected by plant protection products. But how applicable is this framework to chemicals with different emission scenarios and receptor ecosystems? Four case studies used to address this question were: (i) oil refinery waste water exposure in estuarine environments; (ii) oil dispersant exposure in aquatic environments; (iii) down the drain chemicals exposure in a wide range of ecosystems (terrestrial and aquatic); (iv) persistent organic pollutant exposure in remote (pristine) Arctic environments. A four-step process was followed to identify ecosystems and services potentially impacted by chemical emissions and to define specific protection goals. Case studies demonstrated that, in principle, the ecosystem services concept and the EFSA framework can be applied to derive specific protection goals for a broad range of chemical exposure scenarios. By identifying key habitats and ecosystem services of concern, the approach offers the potential for greater spatial and temporal resolution, together with increased environmental relevance, in chemical risk assessments. With modifications including improved clarity on terminology/definitions and further development/refinement of the key concepts, we believe the principles of the EFSA framework could provide a methodical approach to the identification and prioritization of ecosystems, ecosystem services and the service providing units that are most at risk from chemical exposure