Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction.

Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9ppm as sodium arsenite) for 10weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects.

Chronic Alcohol Exposure Enhances Lipopolysaccharide-Induced Lung Injury in Mice: Potential Role of Systemic Tumor Necrosis Factor-Alpha.

BACKGROUND: It is well known that liver and lung injury can occur simultaneously during severe inflammation (e.g., multiple organ failure). However, whether these are parallel or interdependent (i.e., liver-lung axis) mechanisms is unclear. Previous studies have shown that chronic ethanol (EtOH) consumption greatly increases mortality in the setting of sepsis-induced acute lung injury (ALI). The potential contribution of subclinical liver disease in driving this effect of EtOH on the lung remains unknown. Therefore, the purpose of this study was to characterize the impact of chronic EtOH exposure on concomitant liver and lung injury. METHODS: Male mice were exposed to EtOH-containing Lieber-DeCarli diet or pair-fed control diet for 6 weeks. Some animals were administered lipopolysaccharide (LPS) 4 or 24 hours prior to sacrifice to mimic sepsis-induced ALI. Some animals received the tumor necrosis factor-alpha (TNF-α)-blocking drug, etanercept, for the duration of alcohol exposure. The expression of cytokine mRNA in lung and liver tissue was determined by quantitative PCR. Cytokine levels in the bronchoalveolar lavage fluid and plasma were determined by Luminex assay. RESULTS: As expected, the combination of EtOH and LPS caused liver injury, as indicated by significantly increased levels of the transaminases alanine aminotransferase/aspartate aminotransferase in the plasma and by changes in liver histology. In the lung, EtOH preexposure enhanced pulmonary inflammation and alveolar hemorrhage caused by LPS. These changes corresponded with unique alterations in the expression of pro-inflammatory cytokines in the liver (i.e., TNF-α) and lung (i.e., macrophage inflammatory protein-2 [MIP-2], keratinocyte chemoattractant [KC]). Systemic depletion of TNF-α (etanercept) blunted injury and the increase in MIP-2 and KC caused by the combination of EtOH and LPS in the lung. CONCLUSIONS: Chronic EtOH preexposure enhanced both liver and lung injury caused by LPS. Enhanced organ injury corresponded with unique changes in the pro-inflammatory cytokine expression profiles in the liver and the lung.

Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced Fatty liver disease.

Arsenic is a widely distributed environmental component that is associated with a variety of cancer and non-cancer adverse health effects. Additional lifestyle factors, such as diet, contribute to the manifestation of disease. Recently, arsenic was found to increase inflammation and liver injury in a dietary model of fatty liver disease. The purpose of the present study was to investigate potential mechanisms of this diet-environment interaction via a high-throughput metabolomics approach. GC×GC-TOF MS was used to identify metabolites that were significantly increased or decreased in the livers of mice fed a Western diet (a diet high in fat and cholesterol) and co-exposed to arsenic-contaminated drinking water. The results showed that there are distinct hepatic metabolomic profiles associated with eating a high fat diet, drinking arsenic-contaminated water, and the combination of the two. Among the metabolites that were decreased when arsenic exposure was combined with a high fat diet were short-chain and medium-chain fatty acid metabolites and the anti-inflammatory amino acid, glycine. These results are consistent with the observed increase in inflammation and cell death in the livers of these mice and point to potentially novel mechanisms by which these metabolic pathways could be altered by arsenic in the context of diet-induced fatty liver disease.

MetPP: a computational platform for comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry-based metabolomics.

MOTIVATION: Due to the high complexity of metabolome, the comprehensive 2D gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS) is considered as a powerful analytical platform for metabolomics study. However, the applications of GC×GC-TOF MS in metabolomics are not popular owing to the lack of bioinformatics system for data analysis. RESULTS: We developed a computational platform entitled metabolomics profiling pipeline (MetPP) for analysis of metabolomics data acquired on a GC×GC-TOF MS system. MetPP can process peak filtering and merging, retention index matching, peak list alignment, normalization, statistical significance tests and pattern recognition, using the peak lists deconvoluted from the instrument data as its input. The performance of MetPP software was tested with two sets of experimental data acquired in a spike-in experiment and a biomarker discovery experiment, respectively. MetPP not only correctly aligned the spiked-in metabolite standards from the experimental data, but also correctly recognized their concentration difference between sample groups. For analysis of the biomarker discovery data, 15 metabolites were recognized with significant concentration difference between the sample groups and these results agree with the literature results of histological analysis, demonstrating the effectiveness of applying MetPP software for disease biomarker discovery. AVAILABILITY: The source code of MetPP is available at http://metaopen.sourceforge.net CONTACT: xiang.zhang@louisville.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Olanzapine activates hepatic mammalian target of rapamycin: new mechanistic insight into metabolic dysregulation with atypical antipsychotic drugs.

Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.

Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice.

Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations.

Xanthohumol Protects Morphology and Function in a Mouse Model of Retinal Degeneration.

Purpose: To investigate whether treatment with xanthohumol (XN), the principal prenylated chalconoid from Humulus lupulus (hops), is protective in a mouse model of light-induced retinal degeneration (LIRD). Methods: Mice (129S2/SvPasCrl) were intraperitoneally injected with vehicle or XN prior to toxic light exposure and every 3 days thereafter. Retinal function was assessed by electroretinograms at 1, 2, and 4 weeks following toxic light exposure. Visual acuity was tested by optokinetic tracking 1 week and 4 weeks after toxic light exposure. Retina sections were stained with hematoxylin and eosin for morphologic analysis or by TUNEL. Redox potentials were assessed in retinal tissue by measuring levels of cysteine (CYS), cystine (CYSS), glutathione (GSH), and glutathione disulfide (GSSG) using HPLC with fluorescence detection. Results: Toxic light significantly suppressed retinal function and visual acuity, severely disrupted the photoreceptor cell layer, and significantly decreased the number of nuclei and increased the accumulation of TUNEL-labeled cells in the outer nuclear layer. These effects were prevented by XN treatment. Treatment with XN also maintained GSSG and CYSS redox potentials and the total CYS pool in retinas of mice undergoing toxic light exposure. Conclusions: XN treatment partially preserved visual acuity and retinal function in the LIRD mouse. Preservation of retinal CYS and of GSSG and CYSS redox potentials may indicate that XN treatment induces an increased antioxidant response, but further experiments are needed to verify this potential mechanism. To our knowledge, this is the first study to report protective effects of XN in a model of retinal degeneration.

Exercise as Gene Therapy: BDNF and DNA Damage Repair.

DNA damage is a common feature of neurodegenerative illnesses, and the ability to repair DNA strand breaks and lesions is crucial for neuronal survival, reported by Jeppesen et al (Prog Neurobiol. 2011;94:166-200) and Shiwaku et al (Curr Mol Med. 2015;15:119-128). Interventions aimed at repairing these lesions, therefore, could be useful for preventing or delaying the progression of disease. One potential strategy for promoting DNA damage repair (DDR) is exercise. Although the role of exercise in DDR is not understood, there is increasing evidence that simple physical activity may impact clinical outcomes for neurodegeneration. Here, we discuss what is currently known about the molecular mechanisms of brain-derived neurotrophic factor and how these mechanisms might influence the DDR process.

Potential Role of Exercise in Retinal Health.

For many patients suffering vision loss due to retinal degeneration, the potential exists for therapeutic intervention to halt or delay disease progression. Proposed molecular, pharmacological, and surgical treatments are expensive and complicated. Finding low-cost interventions to sustain vision and thereby quality of life is vitally important. This chapter reviews findings from animal model and human subject studies indicating that physical exercise has direct, beneficial effects on regions of the central nervous system and is protective against neurodegenerative disease, including recent data from animal models showing similar effects for retina and vision. Potential local and systemic mechanistic pathways for exercise-induced retinal neuroprotection are discussed.