Early Mechanistic Events Induced by Secondhand Smoke Prevalent Low Molecular Weight Polycyclic Aromatic Hydrocarbons in Mouse Lung Epithelial Cells (part-I)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Epithelial Cells
DISEASE(S): Lung Disease
PROVIDER: ST001094 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description: Not available
| ST001124 | MetabolomicsWorkbench
Project description:Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are under regulated environmental contaminants (eg, secondhand smoke) that lead to gap junction dysregulation, p38 MAPK activation, and increased mRNA production of inflammatory mediators, such as cytokines and cyclooxygenase (COX2), in lung epithelial cells. However, the early mechanisms involving lipid signaling through the arachidonic acid pathway and subsequent eicosanoid production leading to these downstream events are not known. Common human exposures are to mixtures of LMW PAHs, thus C10 cells (a mouse lung epithelial cell line) were exposed to a representative binary PAH mixture, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), for 30 min-24 h with and without p38 and cytosolic phospholipase A2 (cPLA2) inhibitors. Cytosolic phospholipase A2 inhibition reversed PAH-induced phospho-p38 MAPK activation and gap junction dysregulation at 30 min. A significant biphasic increase in cPLA2 protein was observed at 30 min, 2, and 4 h, as well as COX2 protein at 2 and 8 h. Untargeted metabolomics demonstrated a similar trend with significantly changing metabolites at 30 min and 4 h of exposure relative to 1 h; a "cPLA2-like" subset of metabolites within the biphasic response were predominately phospholipids. Targeted metabolomics showed several eicosanoids (eg, prostaglandin D2 (PGD2), PGE2α) were significantly increased at 4, 8, and 12 h following exposure to the binary PAH mixture and this effect was p38-dependent. Finally, PAH metabolism was not observed until after 8 h. These results indicate an early lipid signaling mechanism of LMW PAH toxicity in lung epithelial cells due to parent PAH compounds.
| S-EPMC6484882 | biostudies-literature
Project description:Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.
| S-EPMC5808746 | biostudies-literature
Project description:Low molecular weight polyethylenimine (1800 Da, also referred to as oligoethylenimines, OEI) was modified with amino acids, including two aromatic amino acids (tryptophan, phenylalanine) and an aliphatic amino acid (leucine). The substitution degree of amino acids could be controlled by adjusting the feeding mole ratio of the reactants. Fluorescence spectroscopy and circular dichroism experiments demonstrated that the indole ring of tryptophan may intercalate into the DNA base pairs and contribute to efficient DNA condensation. In vitro gene expression results revealed that the modified OEIs (OEI-AAs) may provide higher transfection efficiency even than high molecular weight polyethylenimine (25 kDa, PEI), especially the aromatic tryptophan substituted OEI. Moreover, OEI-AAs exhibited excellent serum tolerance, and up to 137 times higher transfection efficiency than PEI 25 kDa that was obtained in the presence of serum. The cytotoxicity of OEI-AAs is much lower than PEI 25 kDa. This study may afford a new method for the development of low molecular weight oligomeric non-viral gene vectors with both high efficiency and biocompatibility.
| S-EPMC6418655 | biostudies-literature
Project description:Beta-glucans are widely used in treatment, cosmetics, and the food industry. Glucans play a significant role in activation of the immune and antioxidant system and inhibiting tumor proliferation. In the current study the antitumor activities of new high and low molecular weight beta-glucan derived from oats were investigated in two human lung cancer cell line (A549, H69AR) and normal keratinocytes (HaCaT). The effect of high and low molecular weight beta-glucan from oat was evaluated by cellular viability assessment, lipid peroxidation and manganese superoxide dismutase evaluation and cytoskeleton visualisation. Additionally the level of red blood cells hemolysis was performed. Our results indicate strong anti-tumor properties of new beta-glucan from oat and at the same time no toxicity for normal cells.
| S-EPMC5972159 | biostudies-literature
Project description:The bronchial epithelium plays a key role in providing a protective barrier against many environmental substances of anthropogenic or natural origin which enter the lungs during breathing. Appropriate responses to these agents are critical for regulation of tissue homeostasis, while inappropriate responses may contribute to disease pathogenesis. Here, we compared epithelial barrier responses to different pollen species, characterized the active pollen components and the signaling pathways leading to epithelial activation. Polarized bronchial cells were exposed to extracts of timothy grass (Phleum pratense), ragweed (Ambrosia artemisifolia), mugwort (Artemisia vulgaris), birch (Betula alba) and pine (Pinus sylvestris) pollens. All pollen species caused a decrease in ionic permeability as monitored trans-epithelial electrical resistance (TER) and induced polarized release of mediators analyzed by ELISA, with grass pollen showing the highest activity. Ultrafiltration showed that the responses were due to components <3kDa. However, lipid mediators, including phytoprostane E1, had no effect on TER, and caused only modest induction of mediator release. Reverse-phase chromatography separated 2 active fractions: the most hydrophilic maximally affected cytokine release whereas the other only affected TER. Inhibitor studies revealed that JNK played a more dominant role in regulation of barrier permeability in response to grass pollen exposure, whereas ERK and p38 controlled cytokine release. Adenosine and the flavonoid isorhamnetin present in grass pollen contributed to the overall effect on airway epithelial barrier responses. In conclusion, bronchial epithelial barrier functions are differentially affected by several low molecular weight components released by pollen. Furthermore, ionic permeability and innate cytokine production are differentially regulated.
| S-EPMC4574901 | biostudies-literature
Project description:Low-molecular-weight (LMW) aromatics are crucial in meditating fungal processes for plant biomass decomposition. Some LMW compounds are employed as electron donors for oxidative degradation in brown rot (BR), an efficient wood-degrading strategy in fungi that selectively degrades carbohydrates but leaves modified lignins. Previous understandings of LMW aromatics were primarily based on "bulk extraction", an approach that cannot fully reflect their real-time functions during BR. Here, we applied an optimized molecular imaging method that combines matrix-assisted laser desorption ionization (MALDI) with Fourier-transform ion cyclotron resonance mass spectrometry (FTICR-MS) to directly measure the temporal profiles of BR aromatics as Rhodonia placenta decayed a wood wafer. We found that some phenolics were pre-existing in wood, while some (e.g., catechin-methyl ether and dihydroxy-dimethoxyflavan) were generated immediately after fungal activity. These pinpointed aromatics might be recruited to drive early BR oxidative mechanisms by generating Fenton reagents, Fe2+ and H2O2. As BR progressed, ligninolytic products were accumulated and then modified into various aromatic derivatives, confirming that R. placenta depolymerizes lignin. Together, this work confirms aromatic patterns that have been implicated in BR fungi, and it demonstrates the use of MALDI-FTICR-MS imaging as a new approach to monitor the temporal changes of LMW aromatics during wood degradation.
| S-EPMC8397067 | biostudies-literature
Project description:BackgroundMurine models of Helicobacter pylori infection are used to study host-pathogen interactions, but lack of severe gastritis in this model has limited its usefulness in studying pathogenesis. We compared the murine gastric epithelial cell line GSM06 to the human gastric epithelial AGS cell line to determine whether similar events occur when cultured with H. pylori.Materials and methodsThe lysates of cells infected with H. pylori isolates or an isogenic cagA-deficient mutant were assessed for translocation and phosphorylation of CagA and for activation of stress pathway kinases by immunoblot.ResultsPhosphorylated CagA was detected in both cell lines within 60 minutes. Phospho-ERK 1/2 was present within several minutes and distinctly present in GSM06 cells at 60 minutes. Similar results were obtained for phospho-JNK, although the 54 kDa phosphoprotein signal was dominant in AGS, whereas the lower molecular weight band was dominant in GSM06 cells.ConclusionThese results demonstrate that early events in H. pylori pathogenesis occur within mouse epithelial cells similar to human cells and therefore support the use of the mouse model for the study of acute CagA-associated host cell responses. These results also indicate that reduced disease in H. pylori-infected mice may be due to lack of the Cag PAI, or by differences in the mouse response downstream of the initial activation events.
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Project description:Agarwood is known to have a sedative effect and the less studied volatile aromatic constituents it contains may have contribution to the activity. In this study, two Kyara grade (highest-grade agarwood in Japan) samples were extracted using headspace-solid phase microextraction (HS-SPME) and analyzed through gas chromatography-mass spectrometry (GC-MS). Six low molecular weight aromatic compounds (LACs) and one structurally simple compound (diethylene glycol monoethyl ether) present in the aromas were individually evaluated for inhalational sedative activity in mice through open field test. Doses of 0.0001 g/L to 1 g/L were prepared for each compound and administered to mice (n = 6/dose/compound). Results revealed all compounds decreased spontaneous motor activity at almost all doses. Strongest sedative activity of each compound reduced total spontaneous motor activity by more than half against control, demonstrating their contribution to agarwood aroma and potential as independent sedating agents. Mixtures of compounds using their most effective dose were made and evaluated again for inhalational sedative effect. Interestingly, the combination of all compounds showed no significant effect and even caused stimulation in mice movements. This result suggests antagonistic-like interaction between the compounds, which is probably due to structural similarities. Consequently, it implies the other constituents present in agarwood, along with LACs, are also important to the overall sedative activity.
| S-EPMC7958121 | biostudies-literature
Project description:Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.
| S-EPMC3670909 | biostudies-literature