Motivation: From the scientific community, a lot of effort has been spent on the correct identification of gene and protein names in text, while less effort has been spent on the correct ...identification of chemical names. Dictionary-based term identification has the power to recognize the diverse representation of chemical information in the literature and map the chemicals to their database identifiers. Results: We developed a dictionary for the identification of small molecules and drugs in text, combining information from UMLS, MeSH, ChEBI, DrugBank, KEGG, HMDB and ChemIDplus. Rule-based term filtering, manual check of highly frequent terms and disambiguation rules were applied. We tested the combined dictionary and the dictionaries derived from the individual resources on an annotated corpus, and conclude the following: (i) each of the different processing steps increase precision with a minor loss of recall; (ii) the overall performance of the combined dictionary is acceptable (precision 0.67, recall 0.40 (0.80 for trivial names); (iii) the combined dictionary performed better than the dictionary in the chemical recognizer OSCAR3; (iv) the performance of a dictionary based on ChemIDplus alone is comparable to the performance of the combined dictionary. Availability: The combined dictionary is freely available as an XML file in Simple Knowledge Organization System format on the web site http://www.biosemantics.org/chemlist. Contact: k.hettne@erasmusmc.nl Supplementary information: Supplementary data are available at Bioinformatics online.
IntroductionIn the European Exposome Project for Health and Occupational Research (EPHOR), a working life exposome toolbox is developed to support evidence-based and cost-effective prevention to ...improve health at work. Our narrative synthesis showed the potential of using non-invasive sampling for the occupational exposome. This pilot study aims to develop, optimise and validate methods, for collection, storage, detection, and quantification of biomarkers in non-invasive matrices, as alternatives to e.g. whole blood collection via phlebotomy.Materials and MethodsThis study was approved by the Ethics Committee Research UZ/KU Leuven (S64599). Nineteen healthy participants were included after filling in informed consent. At two visits to the lab, exhaled breath (EB), EB condensate, lung volumes (spirometry), peripheral blood via phlebotomy, dried blood spots (DBS), saliva and urine were collected and questionnaires were filled in. For a third sampling at home, participants were asked to use instructions for self-sampling of DBS, saliva and urine and bring the samples back to the lab. Each sampling was approximately six months apart. DBS from the first visit and home sampling were stored at room temperature (RT), while those from the second visit were stored at -80° C until analysis. Saliva was collected by chewing a cotton swab for one minute.ResultsBy comparing biomarkers in samples of the three timepoints within individuals, we will be able to evaluate the stability and quality of non-invasive samples with different storage times and conditions. We will explore the potential of self-sampling, which can ease sampling in large groups of participants, in shift work, remote areas and during pandemics.ConclusionThis pilot study will allow us to investigate the quality and stability of non-invasive samples, as well as their potential usage in research.EPHOR is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement number 874703.
Toxicogenomics is a novel approach integrating the expression analysis of thousands of genes (transcriptomics) or proteins (proteomics) with classical methods in toxicology. Effects at the molecular ...level are related to pathophysiological changes of the organisms, enabling detailed comparison of mechanisms and early detection and prediction of toxicity. This report addresses the value of the combined use of transcriptomics and proteomics technologies in toxicology. Acute hepatotoxicity was induced in rats by bromobenzene administration resulting in depleted glutathione levels and reduced average body weights, 24
hr after dosage. These physiological symptoms coincided with many changes of hepatic mRNA and protein content. Gene induction confirmed involvement of glutathione-
S-transferase isozymes and epoxide hydrolase in bromobenzene metabolism and identified many genes possibly relevant in bromobenzene toxicity. Observed glutathione depletion coincided with induction of the key enzyme in glutathione biosynthesis, γ-glutamylcysteine synthetase. Oxidative stress was apparent from strong upregulation of heme oxygenase, peroxiredoxin 1 and other genes. Bromobenzene-induced protein degradation was suggested from two-dimensional gel electrophoresis, upregulated mRNA levels for proteasome subunits and lysosomal cathepsin L, whereas also genes were upregulated with a role in protein synthesis. Both protein and gene expression profiles from treated rats were clearly distinct from controls as shown by principal component analysis, and several proteins found to significantly change upon bromobenzene treatment were identified by mass spectrometry. A modest overlap in results from proteomics and transcriptomics was found. This work indicates that transcriptomics and proteomics technologies are complementary to each other and provide new possibilities in molecular toxicology.
Many different mechanisms are involved in nutrient-related prevention of colon cancer. In this study, a comprehensive assessment of the spectrum of possible biological actions of the bioactive ...compound quercetin is made using multiple gene expression analysis. Quercetin is a flavonoid that can inhibit proliferation of tumor cells and reduce the number of aberrant crypt foci, although increase of number of colon tumors was also reported.
In order to elucidate possible mechanisms involved in its mode of action the effect of quercetin on expression of 4000 human genes in Caco-2 cells was studied and related to functional effects.
Caco-2 cells were exposed to 5 or 50 microM quercetin for 48 hours, differential expression of 4000 human genes was studied using microarrays and related to functional effects. Differentially expressed genes were categorized in seven functional groups: cell cycle and differentiation, apoptosis, tumor suppressor genes and oncogenes, cell adhesion and cell-cell interaction, transcription, signal transduction and energy metabolism. Also, cell proliferation and cell cycle distribution were measured.
Quercetin (5 microM) downregulated expression of cell cycle genes (for example CDC6, CDK4 and cyclin D1), downregulated cell proliferation and induced cell cycle arrest in Caco-2 cells. After exposure to 50 microM quercetin cell proliferation decreased to 51.3% of control, and further decrease of the percentage of cells in the G1 phase coincided with an increase of the percentage of cells in the sub-G1 phase. Quercetin upregulated expression of several tumor suppressor genes. In addition, genes involved in signal transduction pathways like beta catenin/TCF signalling and MAPK signal transduction were influenced by quercetin.
This study shows that large-scale gene expression analysis in combination with functional assays yields a considerable amount of information on (anti-)carcinogenic potential of food components like quercetin.
Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests ...for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight.
To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers.
Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2g dose) and oxidative stress responses (4g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level.
'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites.
► 'Omics techniques outperformed classic clinical chemistry tests. ► Metabolomic analyses led to the detection of five new acetaminophen metabolites. ► Low dose APAP changed immune and oxidative stress related gene expression in blood. ► APAP-induced full-genome human blood miRNA profiles were assessed for the first time.
The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies ...extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo.
Abstract Introduction Inhalation is an important route wherethrough occupational exposure can reach and potentially affect pulmonary function. Recently, there is a shift towards using less invasive ...matrices. We investigated quality and stability of exhaled breath condensate (EBC) as a minimally invasive matrix to identify lung-related biomarkers. Methods EBC and lung function measurements were collected, from twelve healthy participants twice six months apart (T1,T2) using Medivac® TurboDECCS System and spirometry. Cytokines, MMP-1, 2, 7, and 9, VEGF/Flt1, E- and P-selectin, α-amylase activity, proteomics, CysLTs, LTB4, and TXB2 were measured in EBC. This study was approved by the Ethics Committee Research UZ/KU Leuven (S64599). Results Only two out of twenty-four EBC samples exhibited detectable α-amylase activity. Proteomics showed presence of proteins involved in several biological processes, originating from different cellular components, with different molecular functions. Negative associations were shown between forced expiratory flow (FEF) 25% and TXB2(T2), and FEF 75% and forced expiratory volume within the first second (FEV1) and IFNγ(T1). Peak expiratory flow positively associated with CysLTs(T1) and IL6(T2), FEF 25% with CysLTs(T1), FEF 75% with IL8(T1), FEV1 with IL2 and IL6(T2), and forced vital capacity with IL1β, IL2, and IL6(T2). Discussion With only limited saliva contamination, the collection procedure for EBC is robust. Several associations were shown between spirometry parameters and various markers, suggesting the potential of EBC as alternative minimally invasive matrix. Conclusion So far, these results support the usage of EBC to identify biomarkers for lung function. EPHOR is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement number 874703.
Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by ...next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles.
We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals.
Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals.
Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect.
The effect of the flavonoid quercetin and its conjugate rutin was investigated on (biomarkers of) colorectal cancer (CRC). Male F344 rats (n = 42/group) were fed 0, 0.1, 1, or 10 g quercetin/kg diet ...or 40 g rutin/kg diet. Two wk after initial administration of experimental diets, rats were given 2 weekly subcutaneous injections with 15 mg/kg body wt azoxymethane (AOM). At wk 38 post-AOM, quercetin dose dependently (P < 0.05) decreased the tumor incidence, multiplicity, and size, whereas tumor incidences were comparable in control (50%) and rutin (45%) groups. The number of aberrant crypt foci (ACF) in unsectioned colons at wk 8 did not correlate with the tumor incidence at wk 38. Moreover, at wk 8 post-AOM, the number and multiplicity of ACF with or without accumulation of β-catenin were not affected by the 10 g quercetin/kg diet. In contrast, another class of CRC-biomarkers, β-catenin accumulated crypts, contained less β-catenin than in controls (P < 0.05). After enzymatic deconjugation, the plasma concentration of 3'-O-methyl-quercetin and quercetin at wk 8 was inversely correlated with the tumor incidence at wk 38 (r = -0.95, P <= 0.05). Rats supplemented with 40 g rutin/kg diet had only 30% of the (3'-O-methyl-) quercetin concentration of 10 g quercetin/kg diet-fed rats (P < 0.001). In conclusion, quercetin, but not rutin, at a high dose reduced colorectal carcinogenesis in AOM-treated rats, which was not reflected by changes in ACF-parameters. The lack of protection by rutin is probably due to its low bioavailability.
Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies ...(transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic substances in relation to structure and activity of the genome. The advantages and limitations of the different technologies are evaluated, and the prospects for integration of the technologies into a systems biology or systems toxicology approach are discussed. Applications of toxicogenomics in various laboratories around the world show that the crucial steps and sequence of events at the molecular level can be studied to provide detailed insights into mechanisms of toxic action. Toxicogenomics allowed for more sensitive and earlier detection of adverse effects in (animal) toxicity studies. Furthermore, the effects of exposure to mixtures could be studied in more detail. This review argues that in the (near) future, human health risk assessment will truly benefit from toxicogenomics (systems toxicology).
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