Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats.
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ABSTRACT:
SUBMITTER: Miller DB
PROVIDER: S-EPMC4765366 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
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Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats.
Miller Desinia B DB Karoly Edward D ED Jones Jan C JC Ward William O WO Vallanat Beena D BD Andrews Debora L DL Schladweiler Mette C MC Snow Samantha J SJ Bass Virginia L VL Richards Judy E JE Ghio Andrew J AJ Cascio Wayne E WE Ledbetter Allen D AD Kodavanti Urmila P UP
Toxicology and applied pharmacology 20150331 2
Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.5 ...[more]
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Project description:Long-term exposure to particulate air pollutants has been linked to increased incidence of Type 2 Diabetes (T2DM). Recently, we showed that the gaseous pollutant, O3, induced glucose intolerance, and increased serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause broad scale changes in metabolic homeostasis involving liver, muscle and adipose tissues, and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights into pollutant-induced metabolic alterations. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.00 ppm, 6h/day for two consecutive days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0 ppm O3, 6h/day for either one day or two consecutive days and systemic metabolic responses were determined immediately after each exposure or after an 18h recovery period. In WKY rats, O3 increased serum fasting glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h post second exposure. O3 exposure increased circulating metabolites of glycolysis, long-chain free fatty acids, branched chain amino acids (BCAA) and cholesterol while 1,5- anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, muscle proteolysis and adipose lipolysis. Liver gene expression profile after O3 exposure reflected a response to the serum metabolite changes, as evidenced by increased expression of genes for glycolysis, TCA cycle and gluconeogenesis, and decreased expression of genes involved in steroid and fat biosynthesis. In conclusion, short-term O3 exposure induced hormonal changes and global metabolic disorder reflective of changes in peripheral glucose, lipid, and amino acid metabolism, representative of a stress-response. It remains to be examined if these metabolic alterations contribute to insulin resistance upon chronic exposure. Rats were exposed to filtered air (FA) or Ozone at 1 ppm, 6h/day for two consecutive days to establish ozone-exposure related effects on transcriptomic profiles. Samples were taken at three time points: 1 day (1day0hrs) - at the end of the 6 hour exposure period, 2 days (2day0hrs) - at the end of the of the second day 6 hour exposure period) and 2 days 18 hours (2day18hrs) - 18 hours after the 6 hour exposure period on the second day. Total liver RNA was isolated from ~20 mg tissue with a commercially available RNeasy mini kit (Qiagen, Valencia, CA) using silica gel membrane purification. Liver RNA was resuspended in 30μl of RNAse- free water. RNAse inhibitor was added and RNA yield was determined spectrophotometrically on a NanoDrop 1000 (Thermo Scientific, Wilmington, DE). RNA integrity was assessed by the RNA 6000 LabChip® kit using a 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). We examined global gene expression changes using the Affymetrix platform (RG- 230 PM Array strip). Biotin-labeled cRNA was produced from total RNA using an Affymetrix “IVT-express labeling kit “(cat# 901229).
2015-01-31 | E-GEOD-59329 | biostudies-arrayexpress
Project description:Long-term exposure to particulate air pollutants has been linked to increased incidence of Type 2 Diabetes (T2DM). Recently, we showed that the gaseous pollutant, O3, induced glucose intolerance, and increased serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause broad scale changes in metabolic homeostasis involving liver, muscle and adipose tissues, and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights into pollutant-induced metabolic alterations. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.00 ppm, 6h/day for two consecutive days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0 ppm O3, 6h/day for either one day or two consecutive days and systemic metabolic responses were determined immediately after each exposure or after an 18h recovery period. In WKY rats, O3 increased serum fasting glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h post second exposure. O3 exposure increased circulating metabolites of glycolysis, long-chain free fatty acids, branched chain amino acids (BCAA) and cholesterol while 1,5- anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, muscle proteolysis and adipose lipolysis. Liver gene expression profile after O3 exposure reflected a response to the serum metabolite changes, as evidenced by increased expression of genes for glycolysis, TCA cycle and gluconeogenesis, and decreased expression of genes involved in steroid and fat biosynthesis. In conclusion, short-term O3 exposure induced hormonal changes and global metabolic disorder reflective of changes in peripheral glucose, lipid, and amino acid metabolism, representative of a stress-response. It remains to be examined if these metabolic alterations contribute to insulin resistance upon chronic exposure.
2015-01-31 | GSE59329 | GEO
Project description:Air pollutant exposures have been linked to systemic disease; however, underlying mechanisms between single-tissue exposures and systemic responses are poorly understood. A prototypic inducer of stress, ozone causes respiratory and systemic, multiorgan effects through neuroendocrine stress response activation. The goal of the presented study was to assess transcriptomic signatures of multiple tissues and serum metabolomics to understand how neuroendocrine and adrenal-derived stress hormones contribute to multiorgan health outcomes. Male Wistar Kyoto rats (12-13 weeks old) were exposed to filtered air or 0.8 ppm ozone for 4-hours, and blood/tissues were collected immediately post-exposure. Each tissue had distinct expression profile at baseline. Ozone changed (adjusted p-value < .1, absolute fold-change > 50%) 5,102 genes in muscle, 2,516 in adrenals, 1,640 in lung, 1,333 in liver, 1,242 in adrenals and 274 in hypothalamus. Serum metabolomic analysis identified 863 metabolites, of which 447 were significantly altered in ozone-exposed rats (adjusted p-value < .1, absolute fold change > 20%). Although overall hypoxia, GPCR signaling and glucocorticoid signaling pathways were commonly changed in most tissues, gene signatures within overrepresented pathways showed limited overlap between tissues. This pattern suggested the distribution of receptors and transcriptional mechanisms for stress hormones are likely tissue-specific and involve induction of different gene sets with shared initiating triggers. Metabolomic analysis suggested major changes in lipids, amino acids and metabolites linked to gut microbiome, which correlated with transcriptional changes identified through pathway analysis within liver, muscle, and adipose tissues. Systems-level examination of tissue-specific biological mechanisms could further understanding of air pollution-related health consequences.
2024-04-23 | GSE234042 | GEO
Project description:The increasing world population is driving demand for improved efficiency of feed resources of livestock. However, the molecular mechanisms behind various feed efficiency traits and their regulation by nutrition remain poorly understood. Here, we aimed to identify differentially expressed (DE) genes in the liver tissues of fattening Merino lambs and differences in metabolites accumulated in plasma to identify modified metabolic pathways as a consequence of milk restriction during the suckling period. Twenty-four male Merino lambs (4.81 ± 0.256 kg) were divided into 2 groups (n = 12 per dietary treatment). The first group (ad libitum, ADL) was kept permanently with the dams, whereas the other group (restricted, RES) was milk restricted. When they reached 15 kg of live body weight (LBW), all the animals were offered the same complete pelleted diet at the same level (35 g DM/kg LBW per day) to ensure no differences in dry matter intake. All the lambs were harvested when they reached 27 kg of LBW. For transcriptomic analysis, 4 liver samples from each group (8 samples in total) were selected for RNA sequencing (RNA-seq), and plasma samples from all animals (24 samples in total) were used to perform a nontargeted metabolomic analysis on a hybrid quadrupole-time-of-flight mass spectrometer coupled to an ultra-high performance liquid chromatographic system (UHPLC/QTOF-MS). Thirty-eight DE annotated genes were identified by RNA-seq, with 23 DE genes being down-regulated and 15 up-regulated in the liver of RES lambs relative to the ADL group (P < 0.10). Also, the metabolomic assay identified 38 differentially accumulated compounds (P < 0.10). In general, those genes and pathways involved in protein synthesis or protease inhibitors were down-regulated in the RES group, whereas those related to proteolytic degradation were up-regulated, thus suggesting a higher catabolism of proteins in these lambs. RES lambs showed over-expression of xenobiotic metabolism pathways, whereas those genes related to β-oxidation of fatty acids were down-regulated. According to the data obtained, early feed restriction during the suckling period of Merino lambs promoted long-term effects on both the hepatic transcriptomic profile and plasma metabolic profile, which might have modified fatty acids metabolism, catabolism of proteins, and detoxification of xenobiotics, thus reducing feed efficiency during the fattening period.
| S-EPMC6140908 | biostudies-other
Project description:Coronavirus disease 2019 (COVID-19) has become a global public health concern. We aimed to study the cytokine profile during the convalescent phase and its association with liver functions. We performed a retrospective study to investigate the longitudinal dynamic serum cytokine, liver function, and metabolomic profiles, as well as their potential correlations, from the viral replication phase to early convalescence. Our results demonstrated that liver injury was common. Liver injury was significantly associated with higher levels of interleukin (IL)-6 and IL-10 (p < 0.05). However, alanine aminotransferase levels decreased during the first week after hospital discharge (p < 0.01). In parallel, T-cell and B-cell immune response-stimulating cytokine IL-4, but not IL-2, was significantly elevated (p < 0.05). Furthermore, interferon-γ (IFN-γ) and tumor necrosis factor-α (TFN-α) levels increased, in contrast to the decrease in IL-6 and IL-10 levels; liver function returned to normal. The metabolomic analysis supported active recovery during early convalescence of COVID-19 patients that had distinct metabolic profiles associated with the hepatic tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. In addition, we identified a metabolomic association of IL-4 with liver repair. Our findings suggest that discharged patients continue to recover from the physiological effects of COVID-19, and the association of IL-4, IL-6, and IL-10 levels with metabolic changes and liver function repair may have important implications for clinical manifestations and treatment of COVID-19.
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Project description:This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC) from malignant diseases, such as biliary tract cancer (BTC), intraductal papillary mucinous carcinoma (IPMC), and various benign pancreaticobiliary diseases. Capillary electrophoresismass spectrometry was used to analyze charged metabolites. We repeatedly analyzed serum samples (n = 41) of different storage durations to identify metabolites showing high quantitative reproducibility, and subsequently analyzed all samples (n = 140). Overall, 189 metabolites were quantified and 66 metabolites had a 20% coefficient of variation and, of these, 24 metabolites showed significant differences among control, benign, and malignant groups (p < 0.05; Steel-Dwass test). Four multiple logistic regression models (MLR) were developed and one MLR model clearly discriminated all disease patients from healthy controls with an area under receiver operating characteristic curve (AUC) of 0.970 (95% confidential interval (CI), 0.946-0.994, p < 0.0001). Another model to discriminate PC from BTC and IPMC yielded AUC = 0.831 (95% CI, 0.650-1.01, p = 0.0020) with higher accuracy compared with tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), pancreatic cancer-associated antigen (DUPAN2) and s-pancreas-1 antigen (SPAN1). Changes in metabolomic profiles might be used to screen for malignant cancers as well as to differentiate between PC and other malignant diseases.
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Project description:The incidence of Alzheimer's disease (AD) increases with age and is becoming a significant cause of worldwide morbidity and mortality. However, the metabolic perturbation behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of 6 metabolites, glycolithocholate (GLCA), petroselinic acid, linoleic acid, myristic acid, palmitic acid, palmitoleic acid and the deoxycholate/cholate (DCA/CA) ratio, along with the dysregulation scores of 3 metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences across both brain and serum diagnostic groups (P-value < 0.05). Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models, respectively, that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median area under the receiver operating characteristic curve (AUC) = 0.772 for the metabolite level model; median AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline in the later years (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials. Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.
| S-EPMC7441317 | biostudies-literature
Project description:Acute exposure to inhaled ozone causes oxidative stress, lung injury, and inflammation. Activated macrophages play a key role in both the initiation and resolution of the inflammatory response to inhaled ozone; this activity is mediated by distinct subsets, broadly classified as proinflammatory (M1) and anti-inflammatory/pro-resolution (M2) macrophages. Successful resolution of inflammation and tissue repair require balanced activity of M1 and M2 macrophages. In this context, overactivation of M1 macrophages or inadequate activation of M2 macrophages results in a failure to resolve inflammation and prolonged injury. Thus, identifying signaling mechanisms contributing to aberrant activation of lung macrophages is critical to mitigating lung injury and decrements in pulmonary function caused by this ubiquitous air pollutant. The purpose of the present study was to identify mechanisms regulating macrophage activation in response to acute exposure to ozone by characterizing global transcriptional profiles using RNA-seq. We hypothesized that gene expression patterns would be distinctly regulated at 24 and 72 hr post exposure to ozone as these time points reflect different phases of the inflammatory response, namely initiation and resolution, when macrophage subpopulations derived from different origins would predominate. We identified significant enrichment of pathways involved in innate immune signaling and cytokine production among differentially expressed genes at 24 and 72 hr post exposure. In addition, we observed a preponderance of pathways involved in cell cycle regulation at 24 hr and intracellular metabolism at 72 hr post exposure. These studies are significant as they permit the identification of signaling pathways representing prospective therapeutic targets to fine tune macrophage responses and limit ozone-induced lung injury.
2024-09-13 | GSE237594 | GEO
Project description:BACKGROUND: Clostridium thermocellum is a candidate consolidated bioprocessing biocatalyst, which is a microorganism that expresses enzymes for both cellulose hydrolysis and its fermentation to produce fuels such as lignocellulosic ethanol. However, C. thermocellum is relatively sensitive to ethanol compared to ethanologenic microorganisms such as yeast and Zymomonas mobilis that are used in industrial fermentations but do not possess native enzymes for industrial cellulose hydrolysis. RESULTS: In this study, C. thermocellum was grown to mid-exponential phase and then treated with ethanol to a final concentration of 3.9 g/L to investigate its physiological and regulatory responses to ethanol stress. Samples were taken pre-shock and 2, 12, 30, 60, 120, and 240 min post-shock, and from untreated control fermentations for systems biology analyses. Cell growth was arrested by ethanol supplementation with intracellular accumulation of carbon sources such as cellobiose, and sugar phosphates, including fructose-6-phosphate and glucose-6-phosphate. The largest response of C. thermocellum to ethanol shock treatment was in genes and proteins related to nitrogen uptake and metabolism, which is likely important for redirecting the cells physiology to overcome inhibition and allow growth to resume. CONCLUSION: This study suggests possible avenues for metabolic engineering and provides comprehensive, integrated systems biology datasets that will be useful for future metabolic modeling and strain development endeavors.
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Project description:The recruitment and subsequent polarization of inflammatory monocytes/macrophages in the perivascular regions of pulmonary arteries is a key feature of pulmonary hypertension (PH). However, the mechanisms driving macrophage polarization within the adventitial microenvironment during PH progression remain unclear. We previously established that reciprocal interactions between fibroblasts and macrophages are essential in driving the activated phenotype of both cell types although the signals involved in these interactions remain undefined. We sought to test the hypothesis that adventitial fibroblasts produce a complex array of metabolites and proteins that coordinately direct metabolomic and transcriptomic re-programming of naïve macrophages to recapitulate the pathophysiologic phenotype observed in PH. Media conditioned by pulmonary artery adventitial fibroblasts isolated from pulmonary hypertensive (PH-CM) or age-matched control (CO-CM) calves were used to activate bone marrow derived macrophages. RNA-Seq and mass spectrometry-based metabolomics analyses were performed. Fibroblast conditioned medium from patients with idiopathic pulmonary arterial hypertension or controls were used to validate transcriptional findings. The microenvironment was targeted in vitro using a fibroblast-macrophage co-culture system and in vivo in a mouse model of hypoxia-induced PH. Both CO-CM and PH-CM actively, yet distinctly regulated macrophage transcriptomic and metabolomic profiles. Network integration revealed coordinated rewiring of pro-inflammatory and pro-remodeling gene regulation in concert with altered mitochondrial and intermediary metabolism in response to PH-CM. Pro-inflammation and metabolism are key regulators of macrophage phenotype in vitro, and are closely related to in vivo flow sorted lung interstitial/perivascular macrophages from hypoxic mice. Metabolic changes are accompanied by increased free NADH levels and increased expression of a metabolic sensor and transcriptional co-repressor, C-terminal binding protein 1 (CtBP1), a mechanism shared with adventitial PH-fibroblasts. Targeting the microenvironment created by both cell types with the CtBP1 inhibitor MTOB, inhibited macrophage pro-inflammatory and metabolic re-programming both in vitro and in vivo. In conclusion, coordinated transcriptional and metabolic reprogramming is a critical mechanism regulating macrophage polarization in response to the complex adventitial microenvironment in PH. Targeting the adventitial microenvironment can return activated macrophages toward quiescence and attenuate pathological remodeling that drives PH progression.
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