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The Science of the Total Environment Sep 2023Terrestrial ecosystems store large amounts of mercury (Hg), which may be subject to methylation, mobilization and uptake into downstream aquatic ecosystems. Mercury...
Terrestrial ecosystems store large amounts of mercury (Hg), which may be subject to methylation, mobilization and uptake into downstream aquatic ecosystems. Mercury concentrations, methylation and demethylation potentials are not well characterized simultaneously across different habitats in boreal forest ecosystems, particularly not so in stream sediment, leading to uncertainties about the importance of various habitats as primary production areas of the bioaccumulative neurotoxin methylmercury (MeHg). In this study, we collected soil and sediment samples from 17 undisturbed, central Canadian boreal forested watersheds during spring, summer and fall to robustly characterize the spatial (upland and riparian/wetland soils, and stream sediment) and seasonal patterns of total Hg (THg) and MeHg concentrations. Mercury methylation and MeHg demethylation potentials (K and K) in the soils and sediment were also assessed using enriched stable Hg isotope assays. We found the highest K and %-MeHg in stream sediment. In both riparian and wetland soils, Hg methylation was lower and less seasonally variable compared to stream sediment, but had comparable MeHg concentrations, suggesting longer-term storage of MeHg produced in these soils. Soil and sediment carbon content, and THg and MeHg concentrations were strong covariates across habitats. Additionally, sediment carbon content was important for delineating between stream sediment with relatively high vs. relatively low Hg methylation potential, which generally separated between different landscape physiographies. Broadly, this large and spatiotemporally diverse dataset is an important baseline for understanding Hg biogeochemistry in boreal forests both in Canada and possibly in many other boreal systems globally. This work is particularly important with respect to future possible impacts from natural and anthropogenic perturbations, which are increasingly straining boreal ecosystems in various parts of the world.
Topics: Mercury; Ecosystem; Soil; Methylation; Seasons; Canada; Water Pollutants, Chemical; Environmental Monitoring; Methylmercury Compounds; Demethylation
PubMed: 37245803
DOI: 10.1016/j.scitotenv.2023.164447 -
Current Opinion in Clinical Nutrition... Jul 2016The activation of inflammatory response is dependent upon genetic factors and epigenetic control mechanisms. This overview will highlight recent advances in the... (Review)
Review
PURPOSE OF REVIEW
The activation of inflammatory response is dependent upon genetic factors and epigenetic control mechanisms. This overview will highlight recent advances in the understanding of epigenetic dynamics during cellular inflammation.
RECENT FINDINGS
There is a growing body of evidence indicating that alterations of the chromatin state associate with an increased risk of chronic disease development and inflammation. Epigenetic alterations respond rapidly to environmental changes and have a profound effect on gene regulatory cross-wirings and transcriptional regulation.
SUMMARY
Systematic dissection of the mechanisms underlying epigenetic effects during inflammatory response is a critical step toward elucidation of the cell's molecular processes and holds potential for the development of novel therapies for the treatment of chronic diseases.
Topics: Acetylation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; DNA Methylation; Demethylation; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histones; Humans; Immune System Diseases; Immunity, Innate; Methylation; Protein Processing, Post-Translational
PubMed: 27116713
DOI: 10.1097/MCO.0000000000000281 -
The New England Journal of Medicine Aug 2022
Topics: Azacitidine; Demethylation; Humans; Myelodysplastic Syndromes; Oncogenes; Up-Regulation
PubMed: 35921465
DOI: 10.1056/NEJMc2208134 -
Future Medicinal Chemistry May 2018
Topics: Demethylation; Enzyme Inhibitors; Histone Demethylases; Histones; Humans; Patents as Topic; Virus Diseases; Virus Replication
PubMed: 29787289
DOI: 10.4155/fmc-2018-0065 -
European Journal of Pharmaceutical... Jul 2018Metamizole is an old analgesic used frequently in some countries. Active metabolites of metamizole are the non-enzymatically generated N-methyl-4-aminoantipyrine (4-MAA)...
Metamizole is an old analgesic used frequently in some countries. Active metabolites of metamizole are the non-enzymatically generated N-methyl-4-aminoantipyrine (4-MAA) and its demethylation product 4-aminoantipyrine (4-AA). Previous studies suggested that 4-MAA demethylation can be performed by hepatic cytochrome P450 (CYP) 3A4, but the possible contribution of other CYPs remains unclear. Using human liver microsomes (HLM), liver homogenate and HepaRG cells, we could confirm 4-MAA demethylation by CYPs. Based on CYP induction (HepaRG cells) and CYP inhibition (HLM) we could identify CYP2B6, 2C8, 2C9 and 3A4 as major contributors to 4-MAA demethylation. The 4-MAA demethylation rate by HLM was 280 pmol/mg protein/h, too low to account for in vivo 4-MAA demethylation in humans. Since peroxidases can perform N-demethylation, we investigated horseradish peroxidase and human myeloperoxidase (MPO). Horse radish peroxidase efficiently demethylated 4-MAA, depending on the hydrogen peroxide concentration. This was also true for MPO; this reaction was saturable with a K of 22.5 μM and a maximal velocity of 14 nmol/min/mg protein. Calculation of the entire body MPO capacity revealed that the demethylation capacity by granulocyte/granulocyte precursors was approximately 600 times higher than the liver capacity and could account for 4-MAA demethylation in humans. 4-MAA demethylation could also be demonstrated in MPO-expressing granulocyte precursor cells (HL-60). In conclusion, 4-MAA can be demethylated in the liver by several CYPs, but hepatic metabolism cannot fully explain 4-MAA demethylation in humans. The current study suggests that the major part of 4-MAA is demethylated by circulating granulocytes and granulocyte precursors in bone marrow.
Topics: Activation, Metabolic; Analgesics; Antipyrine; Cytochrome P-450 Enzyme System; Demethylation; Dipyrone; Granulocytes; HL-60 Cells; Hepatocytes; Humans; Kinetics; Microsomes, Liver; Peroxidase; Substrate Specificity
PubMed: 29746911
DOI: 10.1016/j.ejps.2018.05.003 -
The European Journal of Neuroscience Jul 2023It has been confirmed that BTB domain and CNC homologue 1 (BACH1) are involved in ferroptosis-related diseases. However, the function of BACH1 in cerebral...
It has been confirmed that BTB domain and CNC homologue 1 (BACH1) are involved in ferroptosis-related diseases. However, the function of BACH1 in cerebral ischemia-reperfusion injury (CIRI)-induced ferroptosis remains to be largely unrevealed. First, analysis of differentially expressed genes in CIRI based on the GEO dataset GSE119121 revealed that BACH1 was upregulated in CIRI. BACH1 level was prominently increased in middle cerebral artery occlusion (MCAO)/reperfusion model and oxygen-glucose deprivation/reoxygenation cell model. Further, knock-down of BACH1 markedly reduced iron ion concentration, ROS production, 4-HNE and lipid peroxidation levels and facilitated GSH content, cell viability and protein levels of GPX4 and SLC7A11, while an pcDNA-KDM4C or pcDNA-COX2 combined with BACH1 siRNA could not enhance this effect. Mechanistically, BACH1 bound on the KDM4C promoter to transcriptionally activate its expression. Besides, KDM4C could occupy the promoter locus of the COX2 gene, promoting the COX2 expression by eliminating H3K9me3. Overexpression of KDM4C or COX2 overturned the effects of BACH1 inhibition. In vivo findings displayed that brain infraction, pathological damage and neuronal loss rate in MCAO mice were conspicuously decreased after BACH1 knock-down. This study reveals that BACH1 encourages ferroptosis in neuroblastoma cells and CIRI mouse brain tissues by activating KDM4C-mediated COX2 demethylation.
Topics: Animals; Mice; BTB-POZ Domain; Cyclooxygenase 2; Ferroptosis; Reperfusion Injury; Cinacalcet; Demethylation; Brain Ischemia; Infarction, Middle Cerebral Artery
PubMed: 37161649
DOI: 10.1111/ejn.16035 -
Proceedings of the National Academy of... Feb 2024Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the...
Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting by this strategy provides an attractive therapeutic approach for cancer.
Topics: Animals; Genes, MHC Class I; Histocompatibility Antigens Class I; Trans-Activators; Neoplasms; Demethylation
PubMed: 38300873
DOI: 10.1073/pnas.2310821121 -
Methods in Enzymology 2018Dimethylsulfoniopropionate (DMSP) demethylase is a tetrahydrofolate-dependent enzyme that initiates the DMSP demethylation pathway in marine bacteria. This enzyme is...
Dimethylsulfoniopropionate (DMSP) demethylase is a tetrahydrofolate-dependent enzyme that initiates the DMSP demethylation pathway in marine bacteria. This enzyme is important for understanding of organic sulfur flux from the oceans because it directs the sulfur from DMSP away from dimethylsulfide. This enzyme has been purified and characterized from two marine bacteria from different ecological niches. Both enzymes were confirmed to catalyze the tetrahydrofolate-dependent demethylation of DMSP and possessed similar properties. In this chapter a description of the steps for performing enzyme assays and measuring enzyme activity is provided.
Topics: Aquatic Organisms; Bacteria; Bacterial Proteins; Chemical Fractionation; Chromatography, High Pressure Liquid; Demethylation; Enzyme Assays; Methyltransferases; Sulfonium Compounds; Tetrahydrofolates
PubMed: 29909830
DOI: 10.1016/bs.mie.2018.03.001 -
Environmental Science & Technology Feb 2021Toxicity of methylmercury (MeHg) to wildlife and humans results from its binding to cysteine residues of proteins, forming MeHg-cysteinate (MeHgCys) complexes that...
Toxicity of methylmercury (MeHg) to wildlife and humans results from its binding to cysteine residues of proteins, forming MeHg-cysteinate (MeHgCys) complexes that hinder biological functions. MeHgCys complexes can be detoxified , yet how this occurs is unknown. We report that MeHgCys complexes are transformed into selenocysteinate [Hg(Sec)] complexes in multiple animals from two phyla (a waterbird, freshwater fish, and earthworms) sampled in different geographical areas and contaminated by different Hg sources. In addition, high energy-resolution X-ray absorption spectroscopy (HR-XANES) and chromatography-inductively coupled plasma mass spectrometry of the waterbird liver support the binding of Hg(Sec) to selenoprotein P and biomineralization of Hg(Sec) to chemically inert nanoparticulate mercury selenide (HgSe). The results provide a foundation for understanding mercury detoxification in higher organisms and suggest that the identified MeHgCys to Hg(Sec) demethylation pathway is common in nature.
Topics: Animals; Birds; Demethylation; Humans; Mercury; Methylmercury Compounds; Oligochaeta
PubMed: 33476127
DOI: 10.1021/acs.est.0c04948 -
Translational Research : the Journal of... Oct 2023Neointimal hyperplasia is a major clinical complication of coronary artery bypass graft and percutaneous coronary intervention. Smooth muscle cells (SMCs) play a vital...
Neointimal hyperplasia is a major clinical complication of coronary artery bypass graft and percutaneous coronary intervention. Smooth muscle cells (SMCs) play a vital roles in neointimal hyperplasia development and undergo complex phenotype switching. Previous studies have linked glucose transporter member 10(Glut10) to the phenotypic transformation of SMCs. In this research, we reported that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via promotion of mtDNA demethylation in SMCs. Glut10 is significantly downregulated in both human and mouse restenotic arteries. Global Glut10 deletion or SMC-specific Glut10 ablation in the carotid artery of mice accelerated neointimal hyperplasia, while Glut10 overexpression in the carotid artery triggered the opposite effects. All of these changes were accompanied by a significant increase in vascular SMCs migration and proliferation. Mechanistically, Glut10 is expressed primarily in the mitochondria after platelet-derived growth factor-BB (PDGF-BB) treatment. Glut10 ablation induced a reduction in ascorbic acid (VitC) concentrations in mitochondria and mitochondrial DNA (mtDNA) hypermethylation by decreasing the activity and expression of the Ten-eleven translocation (TET) protein family. We also observed that Glut10 deficiency aggravated mitochondrial dysfunction and decreased the adenosinetriphosphate (ATP) content and the oxygen consumption rate, which also caused SMCs to switch their phenotype from contractile to synthetic phenotype. Furthermore, mitochondria-specific TET family inhibition partially reversed these effects. These results suggested that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via the promotion of mtDNA demethylation in SMCs.
Topics: Animals; Humans; Mice; Carotid Arteries; Cell Movement; Cell Proliferation; Cells, Cultured; Demethylation; DNA, Mitochondrial; Hyperplasia; Mitochondria; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima
PubMed: 37220836
DOI: 10.1016/j.trsl.2023.05.001