Predicting molecular mechanisms, pathways, and health outcomes induced by Juul e-cigarette aerosol chemicals using the comparative toxicogenomics database

: Over the past 20 years, the prevalence of obesity has risen dramatically worldwide, with an increase in occurrence among women in their reproductive age. Obesity during pregnancy is associated with significantly increased maternal and fetal morbidity and mortality. In addition to the short-term adverse health outcomes, both mother and the child are prone to develop cardiovascular, metabolic and neurological disorders. Although associations between obesity during pregnancy and adverse maternalfetal health outcomes are clear, the complex molecular mechanisms underlying maternal obesity remain largely unknown. This review describes multimeric self-assembling protein complexes, namely inflammasomes, as potential molecular targets in the pathophysiology of maternal obesity. Inflammasomes are implicated in both normal physiological and in pathophysiological processes that occur in response to an inflammatory milieu throughout gestation. This review highlights the current knowledge of inflammasome expression and its activity in pregnancies affected by maternal obesity. Key discussions in defining pharmacological inhibition of upstream as well as downstream targets of the inflammasome signaling cascade; and the inflammasome platform, as a potential therapeutic strategy in attenuating the pathophysiology underpinning inflammatory component in maternal obesity are presented herein.

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Placenta DNA methylation at ZNF300 is associated with fetal sex and placental morphology

10.1101/2021.03.05.433992 ◽

2021 ◽

Cited By ~ 1

Author(s):

Christine Ladd-Acosta ◽

Shan V. Andrews ◽

Kelly M. Bakulski ◽

Jason I. Feinberg ◽

Rakel Tryggvadottir ◽

...

Keyword(s):

Dna Methylation ◽

Health Outcomes ◽

Molecular Mechanisms ◽

Female Offspring ◽

Specific Pattern ◽

Fetal Sex ◽

Adverse Health Outcomes ◽

Wide Range ◽

Significant Difference ◽

Genome Bisulfite Sequencing

AbstractFetal sex-specific differences in placental morphology and physiology have been associated with sexually dimorphic health outcomes. However, the molecular mechanisms underlying these sex differences are not well understood. We performed whole genome bisulfite sequencing in 133 placenta samples and discovered a significant difference in DNA methylation (DNAm) at the ZNF300 gene locus between male and female offspring and replicated this result in 6 independent datasets. Additionally, the sex-specific pattern appears to be placenta-specific, is robust to a wide range of gestational ages and adverse health outcomes and is present in sorted placenta villous cytotrophoblast cells. Integration of DNAm, genetic, and placental morphology data from the same individuals revealed ZNF300 methylation is also associated with placenta area, perimeter, and max diameter, genetic variants on chromosomes 5 and X, and may mediate the effects of genetic variation on placental area.

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Comparative Toxicogenomics Database (CTD): update 2021

Nucleic Acids Research ◽

10.1093/nar/gkaa891 ◽

2020 ◽

Vol 49 (D1) ◽

pp. D1138-D1143

Author(s):

Allan Peter Davis ◽

Cynthia J Grondin ◽

Robin J Johnson ◽

Daniela Sciaky ◽

Jolene Wiegers ◽

...

Keyword(s):

Amino Acid ◽

Environmental Health ◽

Human Health ◽

Molecular Mechanisms ◽

Heterogeneous Data ◽

Comparative Toxicogenomics Database ◽

The Public ◽

Chemical Exposures ◽

Digital Ecosystem ◽

New Literature

Abstract The public Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is an innovative digital ecosystem that relates toxicological information for chemicals, genes, phenotypes, diseases, and exposures to advance understanding about human health. Literature-based, manually curated interactions are integrated to create a knowledgebase that harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions. In this biennial update, we report a 20% increase in CTD curated content and now provide 45 million toxicogenomic relationships for over 16 300 chemicals, 51 300 genes, 5500 phenotypes, 7200 diseases and 163 000 exposure events, from 600 comparative species. Furthermore, we increase the functionality of chemical–phenotype content with new data-tabs on CTD Disease pages (to help fill in knowledge gaps for environmental health) and new phenotype search parameters (for Batch Query and Venn analysis tools). As well, we introduce new CTD Anatomy pages that allow users to uniquely explore and analyze chemical–phenotype interactions from an anatomical perspective. Finally, we have enhanced CTD Chemical pages with new literature-based chemical synonyms (to improve querying) and added 1600 amino acid-based compounds (to increase chemical landscape). Together, these updates continue to augment CTD as a powerful resource for generating testable hypotheses about the etiologies and molecular mechanisms underlying environmentally influenced diseases.

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Mechanism of Action of Dengzhan Shengmai in Regulating Stroke from an Inflammatory Perspective: A Preliminary Analysis of Network Pharmacology

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6138854 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yiqi Yan ◽

Chao Sun ◽

Xiaoting Rong ◽

Rui Han ◽

Shan Zhu ◽

...

Keyword(s):

Signaling Pathway ◽

Mechanism Of Action ◽

Molecular Mechanisms ◽

Animal Experiments ◽

Disease Process ◽

Network Pharmacology ◽

Chemical Components ◽

Reference Database ◽

Therapeutic Effects ◽

Comparative Toxicogenomics Database

Stroke is a complicated disease with an increasing incidence and a very high mortality rate. A classical Chinese herbal medicine, Dengzhan Shengmai (DZSM), has shown to have therapeutic effects on stroke; however, its chemical basis and molecular mechanism are still unclear. In this study, a systems biology approach was applicable to elucidate the underlying mechanism of action of DZSM on stroke. All the compounds were obtained from databases, and pendant-related targets were obtained from various data platforms, including the TCM Systematic Pharmacology (TCMSP) database, TCM Integrated Database (TCMIP), High Throughput Experimental Reference Database (HERB), Comparative Toxicogenomics Database (CTD), SwissTargetPredicition, and SymMap, The Human Gene Database (GENECARD) and Comparative Toxicogenomics Database (CTD) were used for stroke disease target data, followed by network pharmacology analysis to predict the potential effect of DZSM on stroke. Animal experiments were intended to validate the underlying mechanisms. A total of 846 chemical components were compiled for the targets of DZSM drug, and quercetin, kaempferol, and Wuweizisu C are the highest chemical components compiled from DZSM. Overlapping with 375 disease-specific targets and 149 core targets, the core targets include TNF, IL-6, ALB, and AKT1, which are shown to regulate the disease process from an anti-inflammatory perspective. 198 enrichment messages were obtained by KEGG enrichment analysis, and we believe that the role of the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and IL-17 signaling pathway is more important. Based on rat experiments, we also demonstrated that DZSM could effectively modulate the inflammation level of brain infarct tissues and effectively alleviate behavioral characteristics. Grouped together, our study suggests that the combination of network pharmacology prediction and experimental validation can provide a useful tool to describe the molecular mechanisms of DZSM in Chinese medicine (TCM).

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S-Glutathionylation: From Molecular Mechanisms to Health Outcomes

Antioxidants and Redox Signaling ◽

10.1089/ars.2010.3540 ◽

2011 ◽

Vol 15 (1) ◽

pp. 233-270 ◽

Cited By ~ 144

Author(s):

Ying Xiong ◽

Joachim D. Uys ◽

Kenneth D. Tew ◽

Danyelle M. Townsend

Keyword(s):

Health Outcomes ◽

Molecular Mechanisms

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APPLYING „IN SILICO“ TOXICOGENOMIC DATA MINING TO PREDICT MOLECULAR MECHANISMS AND PATHWAYS AGAINST CARCINOMA: IMMUNOMODULATOR SULFORAPHANE AS A CASE STUDY

10.46793/iccbi21.470b ◽

2021 ◽

Author(s):

Dragica Božić ◽

◽

Katarina Živančević ◽

Katarina , Baralić ◽

Dragana Javorac ◽

...

Keyword(s):

Data Mining ◽

Tumor Cells ◽

In Silico ◽

Molecular Mechanisms ◽

Antioxidative Activity ◽

Biological Processes ◽

Comparative Toxicogenomics Database ◽

Oxidoreductase Activity ◽

Different Types

The aim of this study was to predict the molecular mechanisms and pathways of immunomodulator sulforaphane (SFN) against carcinoma using in silico toxicogenomic data mining. Three key tools applied in our analysis were Comparative Toxicogenomics Database (CTD; http://CTD.mdibl. org), ToppGene Suite portal (https://toppgene.cchmc.org) and Reactome Knowledgebase (https://reactome.org). Sulforaphane interacted with a total of 1896, among which NFE2L2, NQO1, HMOX1, GCLC, TXNRD1, IL1B, IFNG, AGT, KEAP1, and CASP3 had the highest number of interactions. In the CTD, there were direct evidences that SFN interacts with a total of 169 genes to express a therapeutic effect against different types of cancer such as: hepatocellular carcinoma (113), colorectal neoplasms (67), uterine cervical neoplasms (10), and adenomatous polyposis coli (4). This set of genes was further uploaded into the Gene Mania software, ToppGene Suite portal, and Reactome Knowledgebase, which confirmed that molecular functions, biological processes and pathways of SFN-affected genes were mostly related to oxidoreductase activity, regulation of immune system, and apoptosis. In conclusion, we may suggest that SFN interacts with host immunity to enhance the eradication of tumor cells mainly by inducing immune-response and stimulating apoptotic process of tumor cells. Moreover, its antioxidative activity could contribute to better anti-cancerogenic effects.

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Identification of Biomarkers and Study of Mechanisms Related to Metastatic of Osteosarcoma Based on Integrated Bioinformatics Analyses

10.21203/rs.3.rs-136142/v1 ◽

2020 ◽

Author(s):

Guangzhi Wu ◽

Minglei Zhang

Keyword(s):

Clinical Characteristics ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Gene Expression Omnibus ◽

Receptor Interaction ◽

High Morbidity ◽

Comparative Toxicogenomics Database ◽

Bioinformatics Analyses ◽

Kegg Pathways ◽

Geo Database

Abstract BackgroundOsteosarcoma (OS) is a serious threat to public health. Because of high morbidity and fairly complicated pathogenesis. The study aim to identify candidate biomarkers and research the molecular mechanisms correlated of patients with metastatic OS. MethodsThe GSE21257 was downloaded from Gene Expression Omnibus(GEO) database, and the differentially expressed RNAs (DERs) were identified and functional enriched analysis by statistical soft-ware in R. Subsequently, the co-expression modules and its clinical characteristics of OS were identified by weighted gene co-expression network analysis (WGCNA) Following, the KEGG pathways directly related to metastatic OS was to researched by the Comparative Toxicogenomics Database 2019 update (CTD). Finally, the “survival” package in R was used to survival analysis and the DERs were verified using another independent profiling GSE14827. ResultsA total of 1,464 DERs were classified including 702 up-regulated and 762 down-regulated. In addition, a total of 1248 DERs were obtained by WGCNA analysis, the blue modules is the highest negative correlation (P=0) and the turquoise modules is highest positive correlation (P=3E-196) among all correlations with OS metastatic. The lncRNA-mRNA co-expression network including 4 lncRNAs and 507 mRNAs, and the cytokine-cytokine receptor interaction and JAK-STAT signaling pathway were found significantly correlation with metastatic. Finally, the increased expression levels of IFNGR1, lower DLEU1 and DLEU2 related to better prognosis. Which were significantly consistent in the another independent profiling GSE14827. ConclusionsA bioinformatics analysis related to the IFNGR1, DLEU1 and DLEU2 may as candidate biomarkers for metastatic OS.

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Transcription factor/DNA interactions visualized by electron spectroscopic imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122654 ◽

1992 ◽

Vol 50 (1) ◽

pp. 450-451

Author(s):

David P. Bazett-Jones ◽

Mark L. Brown

Keyword(s):

Transcription Factor ◽

Dna Sequences ◽

Transcription Initiation ◽

Molecular Mechanisms ◽

Phosphorus Content ◽

Spectroscopic Imaging ◽

Electron Spectroscopic Imaging ◽

Dna Backbone ◽

Two Parameters ◽

High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

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Dissection of the molecular mechanisms of protein targeting to the peroxisome using immunofluorescence and immunocryoelectron microscopies

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100157760 ◽

1990 ◽

Vol 48 (3) ◽

pp. 44-45

Author(s):

G-A. Keller ◽

S. J. Gould ◽

S. Subramani ◽

S. Krisans

Keyword(s):

Mammalian Cells ◽

Molecular Mechanisms ◽

Protein Targeting ◽

Firefly Luciferase ◽

Peroxisomal Enzyme ◽

Transfected Cells ◽

Peroxisomal Targeting ◽

Targeting Signal ◽

Series Of Experiments ◽

Peroxisomal Targeting Signal

Subcellular compartments within eukaryotic cells must each be supplied with unique sets of proteins that must be directed to, and translocated across one or more membranes of the target organelles. This transport is mediated by cis- acting targeting signals present within the imported proteins. The following is a chronological account of a series of experiments designed and carried out in an effort to understand how proteins are targeted to the peroxisomal compartment.-We demonstrated by immunocryoelectron microscopy that the enzyme luciferase is a peroxisomal enzyme in the firefly lantern. -We expressed the cDNA encoding firefly luciferase in mammalian cells and demonstrated by immunofluorescence that the enzyme was transported into the peroxisomes of the transfected cells. -Using deletions, linker insertions, and gene fusion to identify regions of luciferase involved in its transport to the peroxisomes, we demonstrated that luciferase contains a peroxisomal targeting signal (PTS) within its COOH-terminal twelve amino acid.

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High resolution mapping of nucleic acid containing complexes in vitro and in situ

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162703 ◽

1996 ◽

Vol 54 ◽

pp. 48-49

Author(s):

D. P. Bazett-Jones ◽

M. J. Hendzel

Keyword(s):

Nucleic Acid ◽

High Resolution ◽

Transcription Initiation ◽

Molecular Mechanisms ◽

Heavy Atom ◽

Regulation Of Transcription ◽

High Exposure ◽

Resolution Mapping ◽

Tata Sequence

Structural analysis of combinations of nucleosomes and transcription factors on promoter and enhancer elements is necessary in order to understand the molecular mechanisms responsible for the regulation of transcription initiation. Such complexes are often not amenable to study by high resolution crystallographic techniques. We have been applying electron spectroscopic imaging (ESI) to specific problems in molecular biology related to transcription regulation. There are several advantages that this technique offers in studies of nucleoprotein complexes. First, an intermediate level of spatial resolution can be achieved because heavy atom contrast agents are not necessary. Second, mass and stoichiometric relationships of protein and nucleic acid can be estimated by phosphorus detection, an element in much higher proportions in nucleic acid than protein. Third, wrapping or bending of the DNA by the protein constituents can be observed by phosphorus mapping of the complexes. Even when ESI is used with high exposure of electrons to the specimen, important macromolecular information may be provided. For example, an image of the TATA binding protein (TBP) bound to DNA is shown in the Figure (top panel). It can be seen that the protein distorts the DNA away from itself and much of its mass sits off the DNA helix axis. Moreover, phosphorus and mass estimates demonstrate whether one or two TBP molecules interact with this particular promoter TATA sequence.

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