-
Dalton Transactions (Cambridge, England... Aug 2023The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, -[Pt(N)(OH)(py)] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence...
The interaction of a photoactivatable diazidodihydroxido Pt(IV) prodrug, -[Pt(N)(OH)(py)] (py = pyridine; 1), with a hexamer straight human telomeric DNA unit sequence (5'-TTAGGG-3', I) upon light irradiation was investigated by electrospray ionization mass spectroscopy (ESI-MS). In the primary mass spectrum, two major mono-platinated I adducts with the bound Pt moieties, -[Pt(N)(py)] (1') and -[Pt(py)] (1''), respectively, were detected. It is rare to observe such high abundance and nearly equal intensity platinated DNA adducts formed by these two Pt species because 1' is usually the only major reduced Pt(II) species produced by the photodecomposition of complex 1 in the presence of DNA while 1'' was rarely detected as the major reduced Pt species reported previously. Subsequent tandem mass spectrometric analysis by collision-induced dissociation (CID) showed that in the former adduct {I + 1'}, G and A were the platination sites. While in the latter adduct {I + 1''}, a potential intrastrand crosslink was speculated after G and G sites were identified. Additionally, other minor platinated adducts like di-platinated I adduct by 1' with platination sites at G and G and mono-platinated I adducts containing base oxidation were also detected by mass spectrometry. Due to the rich guanines and their sensitivity to oxidation, the oxidation induced by 1 most probably occurred at guanine. The oxidation adducts were proposed as 8-hydroxyl guanine, spiroiminodihydantoin (Sp), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), 5-guanidinohydantoin (Gh), and/or dehydroguanidinohydantoin (DGh) referring to previous reports. The obtained results provide useful chemical information about the photoreaction between photoactivatable Pt(IV) anticancer prodrugs and human telomeric DNA. Such special damages of Pt(IV) prodrugs on human telomeric DNA implicate its active role in the mechanism of Pt(IV) prodrugs and further support the unique sequence-dependent photointeraction profile of complex 1 reacting with DNA.
Topics: Humans; Antineoplastic Agents; Prodrugs; Organoplatinum Compounds; DNA; DNA Adducts; Guanine
PubMed: 37581306
DOI: 10.1039/d3dt01643a -
Chemical Research in Toxicology Aug 2023Human exposure to known carcinogen 1,3-butadiene (BD) is common due to its high concentrations in automobile exhaust, cigarette smoke, and forest fires, as well as its...
Human exposure to known carcinogen 1,3-butadiene (BD) is common due to its high concentrations in automobile exhaust, cigarette smoke, and forest fires, as well as its widespread use in the polymer industry. The adverse health effects of BD are mediated by epoxide metabolites such as 3,4-epoxy-1-butene (EB), which reacts with DNA to form 1-hydroxyl-3-buten-1-yl adducts on DNA nucleobases. EB-derived mercapturic acids (1- and 2-(-acetyl-l-cysteine--yl)-1-hydroxybut-3-ene (MHBMA) and -acetyl--(3,4-dihydroxybutyl)-l-cysteine (DHBMA)) and urinary N7-(1-hydroxyl-3-buten-1-yl) guanine DNA adducts (EB-GII) have been used as biomarkers of BD exposure and cancer risk in smokers and occupationally exposed workers. However, low but significant levels of MHBMA, DHBMA, and EB-GII have been reported in unexposed cultured cells, animals, and humans, suggesting that these metabolites and adducts may form endogenously and complicate risk assessment of butadiene exposure. In the present work, stable isotope labeling in combination with high-resolution mass spectrometry was employed to accurately quantify endogenous and exogenous butadiene metabolites and DNA adducts in vivo. Laboratory rats were exposed to 0.3, 0.5, or 3 ppm of BD- by inhalation, and the amounts of endogenous () and exogenous () DNA adducts and metabolites were quantified in tissues and urine by isotope dilution capillary liquid chromatography/high resolution electrospray ionization tandem mass spectrometry (capLC-ESI-HRMS/MS). Our results reveal that EB-GII adducts and MHBMA originate exclusively from exogenous exposure to BD, while substantial amounts of DHBMA are formed endogenously. Urinary EB-GII concentrations were associated with genomic EB-GII levels in tissues of the same animals. Our findings confirm that EB-GII and MHBMA are specific biomarkers of exposure to BD, while endogenous DHBMA predominates at sub-ppm exposures to BD.
Topics: Rats; Animals; Humans; DNA Adducts; Butadienes; Isotope Labeling; Mass Spectrometry; DNA; Acetylcysteine; Biomarkers; Epoxy Compounds
PubMed: 37477250
DOI: 10.1021/acs.chemrestox.3c00141 -
Redox Biology Jun 2024The explosive compound 2,4,6-trinitrotoluene (TNT) is well known as a major component of munitions. In addition to its potential carcinogenicity and mutagenicity in... (Review)
Review
The explosive compound 2,4,6-trinitrotoluene (TNT) is well known as a major component of munitions. In addition to its potential carcinogenicity and mutagenicity in humans, recent reports have highlighted TNT toxicities in diverse organisms due to its occurrence in the environment. These toxic effects have been linked to the intracellular metabolism of TNT, which is generally characterised by redox cycling and the generation of noxious reactive molecules. The reactive intermediates formed, such as nitroso and hydroxylamine compounds, also interact with oxygen molecules and cellular components to cause macromolecular damage and oxidative stress. The current review aims to highlight the crucial role of TNT metabolism in mediating TNT toxicity, via increased generation of reactive oxygen species. Cellular proliferation of reactive species results in depletion of cellular antioxidant enzymes, DNA and protein adduct formation, and oxidative stress. While TNT toxicity is well known, its ability to induce oxidative stress, resulting from its reductive activation, suggests that some of its toxic effects may be caused by its reactive metabolites. Hence, further research on TNT metabolism is imperative to elucidate TNT-induced toxicities.
Topics: Trinitrotoluene; Humans; Reactive Oxygen Species; Oxidative Stress; Activation, Metabolic; Animals; Explosive Agents; Oxidation-Reduction
PubMed: 38527399
DOI: 10.1016/j.redox.2024.103082 -
Biomolecules Aug 2023High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of...
High mobility group box 1 (HMGB1) is secreted from activated immune cells, necrotic cells, and certain cancers. Previous studies have reported that different patterns of post-translational modification, particularly acetylation and oxidation, mediate HMGB1 release and confer distinct extracellular HMGB1 signaling activity. Here we report that cisplatin but not carboplatin induces secretion of HMGB1 from human A549 non-small cell lung cancer (NSCLC) cells. Cisplatin-mediated HMGB1 secretion was dose-dependent and was regulated by nuclear exportin 1 (XPO1) also known as chromosomal maintenance 1 (CRM1) rather than adenosine diphosphate (ADP)-ribosylation, acetylation, or oxidation. HMGB1, as well as lysine acetylation and cysteine disulfide oxidation of secreted HMGB1, were monitored by sensitive and specific assays using immunoprecipitation, stable isotope dilution, differential alkylation, and nano liquid chromatography parallel reaction monitoring/high-resolution mass spectrometry (nano-LC-PRM/HRMS). A major fraction of the HMGB1 secreted by low-dose cisplatin treatment of A549 NSCLC cells was found to be in the fully reduced form. In contrast, mainly oxidized forms of HMGB1 were secreted by dimethyl sulfoxide (DMSO)-mediated apoptosis. These findings suggest that inhibition of XPO1 could potentiate the anti-tumor activity of cisplatin by increasing the nuclear accumulation of HMGB1 protein, an inhibitor of cisplatin DNA-adduct repair. Furthermore, low-dose cisplatin therapy could modulate the immune response in NSCLC through the established chemokine activity of extracellular reduced HMGB1. This could potentially enhance the efficacy of subsequent immunotherapy treatment.
Topics: Humans; Cisplatin; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; HMGB1 Protein; Immunity
PubMed: 37759736
DOI: 10.3390/biom13091335 -
Journal of the American Chemical Society May 2024Here, we present a cross-linking approach to covalently functionalize and stabilize DNA origami structures in a one-pot reaction. Our strategy involves adding nucleotide...
Here, we present a cross-linking approach to covalently functionalize and stabilize DNA origami structures in a one-pot reaction. Our strategy involves adding nucleotide sequences to adjacent staple strands, so that, upon assembly of the origami structure, the extensions form short hairpin duplexes targetable by psoralen-labeled triplex-forming oligonucleotides bearing other functional groups (pso-TFOs). Subsequent irradiation with UVA light generates psoralen adducts with one or both hairpin staples leading to site-specific attachment of the pso-TFO (and attached group) to the origami with ca. 80% efficiency. Bis-adduct formation between strands in proximal hairpins further tethers the TFO to the structure and generates "superstaples" that improve the structural integrity of the functionalized complex. We show that directing cross-linking to regions outside of the origami core dramatically reduces sensitivity of the structures to thermal denaturation and disassembly by T7 RNA polymerase. We also show that the underlying duplex regions of the origami core are digested by DNase I and thus remain accessible to read-out by DNA-binding proteins. Our strategy is scalable and cost-effective, as it works with existing DNA origami structures, does not require scaffold redesign, and can be achieved with just one psoralen-modified oligonucleotide.
Topics: DNA; Nucleic Acid Conformation; Cross-Linking Reagents; Ultraviolet Rays; Photochemical Processes; Ficusin
PubMed: 38695163
DOI: 10.1021/jacs.4c03413 -
Biological Trace Element Research Oct 2023The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these...
Examining the Potential Formation of Ternary DNA Complexes with Chromium‑Cysteine, Chromium-Ascorbate, and Chromium-Glutathione and Implications for Their Carcinogenicity.
The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories' efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-cysteine-DNA, Cr(III)-ascorbate-DNA, and Cr(III)-glutathione-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "pre-reacted" chromium cysteinate and chromium glutathione. Neither of these complexes nor "chromium ascorbate" form ternary complexes with DNA as previously proposed. In fact, these Cr(III) compounds do not measurably bind to DNA and cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-cysteine-DNA and Cr(III)-ascorbate-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), cysteine, glutathione, or ascorbate and DNA were made from "pre-reacted" chromium cysteinate or chromium glutathione or from "chromium ascorbate" must, therefore, be interpreted with caution.
Topics: Cysteine; Chromium; DNA; DNA Adducts; DNA Damage; Carcinogens; Glutathione
PubMed: 36662348
DOI: 10.1007/s12011-023-03573-8 -
Diabetes Apr 2024More than 30% of patients with type 1 diabetes develop diabetic kidney disease (DKD), which significantly increases mortality risk. The Diabetes Control and...
More than 30% of patients with type 1 diabetes develop diabetic kidney disease (DKD), which significantly increases mortality risk. The Diabetes Control and Complications Trial (DCCT) and follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC), established that glycemic control measured by HbA1c predicts DKD risk. However, the continued high incidence of DKD reinforces the urgent need for additional biomarkers to supplement HbA1c. Here, we assessed biomarkers induced by methylglyoxal (MG), a metabolic by-product that forms covalent adducts on DNA, RNA, and proteins, called MG adducts. Urinary MG adducts were measured in samples from patients with type 1 diabetes enrolled in DCCT/EDIC who did (case patients; n = 90) or did not (control patients; n = 117) develop DKD. Univariate and multivariable analyses revealed that measurements of MG adducts independently predict DKD before established DKD biomarkers such as glomerular filtration rate and albumin excretion rate. Elevated levels of MG adducts bestowed the greatest risk of developing DKD in a multivariable model that included HbA1c and other clinical covariates. Our work establishes a novel class of biomarkers to predict DKD risk and suggests that inclusion of MG adducts may be a valuable tool to improve existing predictors of complications like DKD prior to overt disease, and to aid in identifying at-risk individuals and personalized risk management.
Topics: Humans; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Pyruvaldehyde; Follow-Up Studies; Prognosis; Glycated Hemoglobin; Biomarkers; Glomerular Filtration Rate
PubMed: 37967313
DOI: 10.2337/db23-0277 -
Journal of Agricultural and Food... Oct 2023Benzo[a]pyrene (B[a]P) is a genotoxic polycyclic aromatic hydrocarbon that is metabolized by cytochrome P450 family 1 enzymes (CYP 1s) and can bind to DNA to form DNA...
Benzo[a]pyrene (B[a]P) is a genotoxic polycyclic aromatic hydrocarbon that is metabolized by cytochrome P450 family 1 enzymes (CYP 1s) and can bind to DNA to form DNA adducts, leading to DNA damage and increased colorectal cancer risk. Previous studies have shown polymethoxyflavones to have a high potential for anticancer effects by regulating CYP 1s, especially nobiletin (NBT) and 5-demethylnobiletin (5-DMNB). However, the effects of NBT and 5-DMNB on B[a]P metabolism remain unclear. Therefore, this study aimed to clarify the effects of NBT and 5-DMNB on B[a]P-induced DNA damage and . In NCM460 cells, 5-DMNB and NBT appeared to reduce the metabolic conversion of B[a]P by regulating the aryl hydrocarbon receptor (AhR)/CYP 1s signaling pathway. This process protected NCM460 cells from B[a]P's cytotoxic effects by decreasing DNA damage and suppressing B[a]P diol-epoxide-DNA adduct formation. In BALB/c mice, 5-DMNB and NBT also protected against B[a]P-induced DNA damage. Altogether, these findings indicate that 5-DMNB and NBT attenuate B[a]P-induced DNA damage by modulating biotransformation, highlighting their chemopreventive potential against B[a]P-induced carcinogenesis. Therefore, 5-DMNB and NBT are promising agents for colorectal cancer chemoprevention in the future.
Topics: Mice; Animals; Benzo(a)pyrene; Xenobiotics; DNA Damage; DNA Adducts; Colorectal Neoplasms
PubMed: 37610775
DOI: 10.1021/acs.jafc.3c03347 -
Molecular Biology Reports Oct 2023Fanconi anemia (FA) is a devastating hereditary disorder for which we desperately need a novel therapeutic strategy. It is caused by mutations in one of at least 22...
BACKGROUND
Fanconi anemia (FA) is a devastating hereditary disorder for which we desperately need a novel therapeutic strategy. It is caused by mutations in one of at least 22 genes in the FA pathway and is characterized by developmental abnormalities, bone marrow failure, and cancer predisposition. The FA pathway is required for the efficient repair of damaged DNA, including interstrand cross-links (ICL). Recent studies indicate formaldehyde as an ultimate endogenous cause of DNA damage in FA pathophysiology. Formaldehyde can form DNA adducts as well as ICLs by inducing covalent linkages between opposite strands of double-stranded DNA.
METHODS AND RESULTS
In this study, we generated a disease model of FA in zebrafish by disrupting the ube2t or fancd2 gene, which resulted in a striking phenotype of female-to-male sex reversal. Since formaldehyde is detoxified from the body by alcohol dehydrogenase 5 (ADH5), we generated fancd2/adh5 zebrafish. We observed a body size reduction and a lower number of mature spermatozoa than wild-type or single knockout zebrafish. To evaluate if increased activity in ADH5 can affect the FA phenotype, we overexpressed human ADH5 in fancd2 zebrafish. The progress of spermatogenesis seemed to be partially recovered due to ADH5 overexpression.
CONCLUSIONS
Our results suggest potential utility of an ADH5 enzyme activator as a therapeutic measure for the clearance of formaldehyde and treatment of FA.
Topics: Animals; Male; Humans; Female; Zebrafish; Fanconi Anemia; DNA Damage; DNA Repair; Phenotype; Formaldehyde
PubMed: 37615925
DOI: 10.1007/s11033-023-08696-8 -
PeerJ 2023We were curious if the urinary proteome could reflect the effects of e-cigarettes on the organism.
BACKGROUND
We were curious if the urinary proteome could reflect the effects of e-cigarettes on the organism.
METHODS
Urine samples were collected from a rat e-cigarette model before, during, and after two weeks of e-cigarette smoking. Urine proteomes before and after smoking of each rat were compared individually, while the control group was set up to rule out differences caused by rat growth and development.
RESULTS
Fetuin-B, a biomarker of chronic obstructive pulmonary disease (COPD), and annexin A2, which is recognized as a multiple tumour marker, were identified as differential proteins in five out of six smoking rats on day 3. To our surprise, odourant-binding proteins expressed in the olfactory epithelium were also found and were significantly upregulated. Pathways enriched by the differential proteins include the apelin signalling pathway, folate biosynthesis pathway, arachidonic acid metabolism, chemical carcinogenesis-DNA adducts and chemical carcinogenesis-reactive oxygen species. They have been reported to be associated with immune system, cardiovascular system, respiratory system,
CONCLUSIONS
Urinary proteome could reflect the effects of e-cigarettes in rats.
Topics: Animals; Rats; Electronic Nicotine Delivery Systems; Proteome; Proteomics; Urinalysis; Carcinogenesis
PubMed: 37753171
DOI: 10.7717/peerj.16041