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BioRxiv : the Preprint Server For... Mar 2024Certain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well...
Certain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well as RNA. Indeed, most of the nucleic acid adducts (>90%) formed due to these chemicals, such as alkylating agents, occur in RNA . However, compared to the well-studied mechanisms for DNA alkylation repair, the biological consequences of RNA damage are largely unexplored. Here, we demonstrate that RNA damage can directly result in loss of genome integrity. Specifically, we show that a human YTH domain-containing protein, YTHDC1, regulates alkylation damage responses in association with the THO complex (THOC) . In addition to its established binding to 6-methyladenosine (m6A)-containing RNAs, YTHDC1 binds to 1-methyladenosine (m1A)-containing RNAs upon alkylation. In the absence of YTHDC1, alkylation damage results in increased alkylation damage sensitivity and DNA breaks. Such phenotypes are fully attributable to RNA damage, since an RNA-specific dealkylase can rescue these phenotypes. These R NA d amage-induced DNA b reaks (RDIBs) depend on R-loop formation, which in turn are processed by factors involved in transcription-coupled nucleotide excision repair. Strikingly, in the absence of YTHDC1 or THOC, an RNA m1A methyltransferase targeted to the nucleus is sufficient to induce DNA breaks. Our results uncover a unique role for YTHDC1-THOC in base damage responses by preventing RDIBs, providing definitive evidence for how damaged RNAs can impact genomic integrity.
PubMed: 38559256
DOI: 10.1101/2024.03.14.585107 -
Journal of Medicinal Chemistry Apr 2024DNA adducting drugs, including alkylating agents and platinum-containing drugs, are prominent in cancer chemotherapy. Their mechanisms of action involve direct... (Review)
Review
DNA adducting drugs, including alkylating agents and platinum-containing drugs, are prominent in cancer chemotherapy. Their mechanisms of action involve direct interaction with DNA, resulting in the formation of DNA addition products known as DNA adducts. While these adducts are well-accepted to induce cancer cell death, understanding of their specific chemotypes and their role in drug therapy response remain limited. This perspective aims to address this gap by investigating the metabolic activation and chemical characterization of DNA adducts formed by the U.S. FDA-approved drugs. Moreover, clinical studies on DNA adducts as potential biomarkers for predicting patient responses to drug efficacy are examined. The overarching goal is to engage the interest of medicinal chemists and stimulate further research into the use of DNA adducts as biomarkers for guiding personalized cancer treatment.
Topics: Humans; DNA Adducts; DNA; Neoplasms; Platinum; Biomarkers
PubMed: 38552031
DOI: 10.1021/acs.jmedchem.3c02476 -
Archives of Toxicology Jun 2024Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and...
Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.
Topics: Animals; Acetaminophen; Male; Chemical and Drug Induced Liver Injury; Mice, Inbred C57BL; Thrombopoietin; Liver; Liver Regeneration; Mice; Acetylcysteine; Pyrazoles; Hepatocytes; Oxidative Stress; Receptors, Thrombopoietin; Cell Proliferation
PubMed: 38551724
DOI: 10.1007/s00204-024-03725-2 -
Chemical Research in Toxicology Apr 2024Accumulated evidence has shown that Balkan endemic nephropathy (BEN) is a multifactorial environmental disease, with exposure to aristolochic acids (AA), and the...
Accumulated evidence has shown that Balkan endemic nephropathy (BEN) is a multifactorial environmental disease, with exposure to aristolochic acids (AA), and the associated DNA adduct formation, as a key causative factor of BEN development. Here, we show that coexposure to arsenic, cadmium, and iron increases the DNA adduct formation of AA in cultured kidney cells, while exhibiting both an exposure concentration and duration dependence. In contrast, coexposure to calcium and copper showed a decreasing DNA adduct formation. Because DNA damage is responsible for both the nephrotoxicity and carcinogenicity of AA, these results shed greater light on the endemic nature of BEN.
Topics: Humans; DNA Adducts; Aristolochic Acids; Balkan Nephropathy; Metals, Heavy
PubMed: 38551460
DOI: 10.1021/acs.chemrestox.4c00045 -
Asian Pacific Journal of Cancer... Mar 2024Gastric cancer (GC) is one of the most common malignancies and ranks third in terms of cancer-related mortality. This study aims to identify the hub genes and potential...
OBJECTIVE
Gastric cancer (GC) is one of the most common malignancies and ranks third in terms of cancer-related mortality. This study aims to identify the hub genes and potential mechanisms in GC using a bioinformatics approach.
METHODS
Microarray data GSE54129, GSE79973, GSE55696 were extracted from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) was identified using Benjamini-Hochberg method in the limma package. GO and KEGG pathway enrichment analyses of the DEGs were conducted. Furthermore, protein-protein interaction network was constructed the STRING platform, and the hub genes were discovered using Maximal Clique Centrality method via cytoHubba. The predictive significance of hub genes was evaluated through GSE15459 dataset.
RESULTS
A total of 73 genes was identified as DEGs in GC. Volcano plots and heatmaps of DEGs were visualized. Functional enrichment analysis revealed that the genes were mostly enriched in response to xenobiotic stimulus, digestion, cellular hormone metabolic process, extracellular matrix structural constituent, calcium-dependent cysteine-type endopeptidase activity, aromatase activity, apical part of cell, basal part of cell, and apical plasma membrane. Regarding KEGG pathway-enrichment, the genes were mainly involved in Drug metabolism-cytochrome P450, Retinol metabolism, Chemical carcinogenesis-DNA adducts, Gastric acid secretion, and Metabolism of xenobiotics by cytochrome P450. By combining the results of Cytohubba, the top five intersecting genes identified were SPP1, INHBA, MMP7, THBS2 and FAP. Kapplan-Meier analysis results showed that these 5 hub genes were highly related to the overall survival of patients.
CONCLUSION
SPP1, INHBA, MMP7, THBS2, and FAP were identified as prospective biomarkers and therapeutic targets for GC that might be utilized for prognostic evaluation and scheme selection.
Topics: Humans; Transcriptome; Stomach Neoplasms; Matrix Metalloproteinase 7; Biomarkers, Tumor; Gene Expression Profiling; Computational Biology; Cytochrome P-450 Enzyme System
PubMed: 38546071
DOI: 10.31557/APJCP.2024.25.3.885 -
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 -
Biochemical Genetics Mar 2024XRCC1 is involved in repair of single-strand breaks generated by mutagenic exposure. Polymorphisms within XRCC1 affect its ability to efficiently repair DNA damage....
XRCC1 is involved in repair of single-strand breaks generated by mutagenic exposure. Polymorphisms within XRCC1 affect its ability to efficiently repair DNA damage. Polycyclic aromatic hydrocarbons or PAHs are genotoxic compounds which form bulky DNA adducts that are linked with infertility. Few reports suggest combined role of XRCC1 polymorphisms and PAHs in infertility. Present study investigates association of three XRCC1 polymorphisms (p.Arg194Trp, p.Arg280His, p.Arg399Gln) with male and female infertility in a North-West Indian population using case-control approach. Additionally, in silico approach has been used to predict whether XRCC1 polymorphisms effect interaction of XRCC1 with different PAHs. For case-control study, XRCC1 polymorphisms were screened in peripheral blood samples of age- and gender-matched 201 infertile cases (♂-100, ♀-101) and 201 fertile controls (♂-100, ♀-101) using PCR-RFLP method. For in silico study, AutoDock v4.2.6 was used for molecular docking of B[a]P, BPDE-I, ( ±)-anti-BPDE, DB[a,l]P, 1-N, 2-N, 1-OHP, 2-OHF with XRCC1 and assess effect of XRCC1 polymorphisms on their interaction. In case-control study, statistical analysis showed association of XRCC1 p.Arg280His GA genotype (p = 0.027), A allele (p = 0.019) with reduced risk of male infertility. XRCC1 p.Arg399Gln AA genotype (p = 0.021), A allele (p = 0.014) were associated with reduced risk for female primary infertility. XRCC1 p.Arg194Trp T allele was associated with increased risk for female infertility (p = 0.035). In silico analysis showed XRCC1-PAH interaction with non-significant effect of XRCC1 polymorphisms on predicted binding. Therefore, present study concludes that XRCC1 polymorphism-modified risk for male and female infertility in North-West Indians without significant effect on predicted XRCC1-PAH interactions. This is the first report on XRCC1 in female infertility.
PubMed: 38514504
DOI: 10.1007/s10528-024-10743-3 -
Talanta Jun 2024Current genotoxicity assessment methods are mainly employed to verify the genotoxic safety of drugs, but do not allow for rapid screening of specific genotoxic...
Current genotoxicity assessment methods are mainly employed to verify the genotoxic safety of drugs, but do not allow for rapid screening of specific genotoxic impurities (GTIs). In this study, a new approach for the recognition of GTIs has been proposed. It is to expose the complex samples to an in vitro nucleoside incubation model, and then draw complete DNA adduct profiles to infer the structures of potential genotoxic impurities (PGIs). Subsequently, the genotoxicity is confirmed in human by 3D bioprinted human liver organoids. To verify the feasibility of the approach, lansoprazole chloride compound (Lanchlor), a PGI during the synthesis of lansoprazole, was selected as the model drug. After confirming genotoxicity by Comet assay, it was exposed to different models to map and compare the DNA adduct profiles by LC-MS/MS. The results showed Lanchlor could generate diverse DNA adducts, revealing firstly its genotoxicity at molecular mechanism of action. Furthermore, the largest variety and content of DNA adducts were observed in the nucleoside incubation model, while the human liver organoids exhibited similar results with rats. The results showed that the combination of DNA adductomics and 3D bioprinted organoids were useful for the rapid screening of GTIs.
Topics: Humans; Rats; Animals; DNA Adducts; Nucleosides; Chromatography, Liquid; Tandem Mass Spectrometry; DNA Damage; Liver; DNA; Organoids; Lansoprazole
PubMed: 38508126
DOI: 10.1016/j.talanta.2024.125902 -
Biomarkers : Biochemical Indicators of... May 2024Exocyclic DNA adducts have been shown to be potential biomarkers of cancer risk related to oxidative stress and exposure to aldehydes in smokers. In fact, aldehydes...
CONTEXT
Exocyclic DNA adducts have been shown to be potential biomarkers of cancer risk related to oxidative stress and exposure to aldehydes in smokers. In fact, aldehydes potentially arise from tobacco combustion directly and endogenously through lipid peroxidation.
OBJECTIVE
This study aims to investigate the relationship between a profile of nine aldehydes-induced DNA adducts and antioxidant activities, in order to evaluate new biomarkers of systemic exposure to aldehydes.
METHODS
Using our previously published UPLC-MS/MS method, adducts levels were quantified in the blood DNA of 34 active smokers. The levels of antioxidant vitamins (A, C and E), coenzyme Q10, β-carotene, superoxide dismutase (SOD) and autoantibodies against oxidized low-density lipoprotein were measured.
RESULTS
Adducts induced by tobacco smoking-related aldehydes were quantified at levels reflecting an oxidative production from lipid peroxidation. A significant correlation between SOD and crotonaldehyde-induced adducts ( = 0.0251) was also observed. β-Carotene was negatively correlated with the adducts of formaldehyde ( 0.0351) and acetaldehyde ( 0.0413). Vitamin C tended to inversely correlate with acetaldehyde-induced adducts ( = 0.0584).
CONCLUSION
These results are promising, and the study is now being conducted on a larger cohort with the aim of evaluating the impact of smoking cessation programs on the evolution of adducts profile and antioxidants activities.
Topics: Humans; DNA Adducts; Smokers; Biological Monitoring; Antioxidants; beta Carotene; Chromatography, Liquid; Tandem Mass Spectrometry; Aldehydes; Oxidative Stress; Biomarkers; Acetaldehyde; Superoxide Dismutase
PubMed: 38506499
DOI: 10.1080/1354750X.2024.2333361 -
Cell Biochemistry and Function Mar 2024The majority of adenocarcinoma lung cancer is found in nonsmokers. A history of tobacco use is more common in squamous cell carcinoma of the lung. The aim of this study...
The majority of adenocarcinoma lung cancer is found in nonsmokers. A history of tobacco use is more common in squamous cell carcinoma of the lung. The aim of this study is to identify the cisplatin (CDDP)-resistance that promotes lung squamous carcinoma cell growth through nicotine-mediated HDAC1/7nAchR/E2F/pRb cell cycle activation. Squamous cell carcinoma (NCI-H520 and NCI-H157) cells were examined after cisplatin and nicotine treatment by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell migration assay, immunofluorescence staining, western blot analysis, and immunoprecipitation analysis. Consequently, CDDP is released from DNA and Rb phosphorylated pRb as a result of nicotine-induced cancer cell proliferation through 7nAchR, which then triggers the opening of the HDAC1 cell cycle. The cell cycle is stopped when CDDP adducts are present. Nicotine exerts cancer cytoprotective effects by allowing HDAC1 repair mechanisms to re-establish E2F promoting DNA stimulation cell cycle integrity in the cytosol and preventing potential CDDP and HDAC1 suppressed in the nuclear. Concentration expression of nicotine causes squamous carcinoma cell carcinogens to emerge from inflammation. COX2, NF-KB, and NOS2 increase as a result of nicotine-induced squamous carcinoma cell inflammation. Nicotine enhanced the cell growth-related proteins such as α7nAchR, EGFR, HDAC1, Cyclin D, Cyclin E, E2F, Rb, and pRb by western blot analysis. It also induced cancer cell inflammation and growth. As a result, we suggest that nicotine will increase the therapeutic resistance effects of CDDP. This has the potential to interact with nicotine through α7nAchR receptors and HDAC1/Cyclin D/E2F/pRb potentially resulting in CDDP therapy resistance, as well as cell cycle-induced cancer cell growth.
Topics: Humans; Cisplatin; Nicotine; alpha7 Nicotinic Acetylcholine Receptor; Cyclin D1; Cell Cycle; Carcinoma, Squamous Cell; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Lung Neoplasms; Lung; DNA; Inflammation; Cell Line, Tumor; Histone Deacetylase 1
PubMed: 38504444
DOI: 10.1002/cbf.3990