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Oxidative DNA lesions cause significant detrimental effects on a living species. Two major DNA lesions resulting from dG oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo) and formamidopyrimidine (Fapy·dG), are produced from a common chemical intermediate. Fapy·dG is formed in comparable yields under oxygen-deficient conditions. Replicative bypass of Fapy·dG in human cells is more mutagenic than that of 8-OxodGuo. Despite the biological importance of transcriptional mutagenesis, there are no reports of the effects of Fapy·dG on RNA polymerase II (Pol II) activity. Here we perform comprehensive kinetic studies to investigate the impact of Fapy·dG on three key transcriptional fidelity checkpoint steps by Pol II: insertion, extension, and proofreading steps. The ratios of error-free versus error-prone incorporation opposite Fapy·dG are significantly reduced in comparison with undamaged dG. Similarly, Fapy·dG:A mispair is extended with comparable efficiency as that of the error-free, Fapy·dG:C base pair. The α- and β-configurational isomers of Fapy·dG have distinct effects on Pol II insertion and extension. Pol II can preferentially cleave error-prone products by proofreading. To further understand the structural basis of transcription processing of Fapy·dG, five different structures were solved, including Fapy·dG template-loading state (apo), error-free cytidine triphosphate (CTP) binding state (prechemistry), error-prone ATP binding state (prechemistry), error-free Fapy·dG:C product state (postchemistry), and error-prone Fapy·dG:A product state (postchemistry), revealing distinctive nucleotide binding and product states. Taken together, our study provides a comprehensive mechanistic framework for better understanding how Fapy·dG lesions impact transcription and subsequent pathological consequences.

One of the most distinguished features in biological effects of heavy ions would be the decrease of oxygen effect in the high-LET region. This feature has been referred to as the radiobiological basis for the control of hypoxic fraction in cancer radiotherapy. However, mechanisms to explain this phenomenon have not been fully understood. One of the explanations was given by the oxygen in the track hypothesis, which proposes that oxygen is produced along ion tracks even in the hypoxic irradiation condition. In the present study, we designed an experimental approach to support this hypothesis by using 8-hydroxy-2'-deoxyguanosine (8-OHdG) as DNA damage requiring oxygen to produce. The LET dependence of 8-OHdG under hypoxic condition revealed that with increasing LET 8-OHdG yield seems to increase, despite that the yield of OH radical, which is also required for the production of 8-OHdG, decreases in the high-LET region. This result is consistent with the explanation that the local generation of oxygen along ion tracks contributes to the increase of 8-OHdG yield., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

In recent years, research has shown that oxidative stress plays a significant role in chronic inflammatory conditions. The alteration of the oxidant/antioxidant balance leads to the appearance of free radicals, important molecules involved in both diabetes mellitus and periodontal disease. Diabetes is considered to be one of the major risk factors of periodontal disease and the inflammation characterizing this condition is associated with oxidative stress, implicitly resulting in oxidative damage to DNA. 8-Hydroxydeoxyguanosine (8-OHdG) is the most common stable product of oxidative DNA damage caused by reactive oxygen species, and its levels have been reported to increase in body fluids and tissues during inflammatory conditions. 8-OHdG emerges as a pivotal biomarker for assessing oxidative DNA damage, demonstrating its relevance across diverse health conditions, including neurodegenerative disorders, cancers, inflammatory conditions, and periodontal disease. Continued research in this field is crucial for developing more precise treatments and understanding the detailed link between oxidative stress and the progression of periodontitis. The use of the 8-OHdG biomarker in assessing and managing chronic periodontitis is an area of increased interest in dental research, with the potential to provide crucial information for diagnosis and treatment.

In this study, experimental studies were carried out to explore the action mechanism of the anti-cancer drug Azacitidine on the double-stranded DNA (dsDNA). The drug binding constant (K b ) was found to be 4.13 ± 0.23 × 10 5 M -1 using voltammetric measurements and 1.67 ± 0.24 × 10 5 M -1 using the fluorescence spectroscopy. Both values are close to the values of 2.04 ± 0.30 × 10 5 M -1 for deoxyguanosine (dGuO) and 1.23 ± 0.30 × 10 5 M -1 for deoxyadenosine (dAdo). In the displacement studies, the ethidium bromide, strong DNA intercalator, was replaced by the Azacitidine, hence caused a decrease on the fluorescence emission intensity. In thermal denaturation studies, the increase of 8.60 °C in the melting temperature upon introduction of the Azacitidine into the dsDNA solution cleary indicated intercalation binding mode of the drug. The experimental and theoretical IR spectra of Azacitidine, dsDNA and their H-bonded complex were confirmed the Azacitidine's intercalation ability to induce cytotoxicity. We also developed a method for the detection of Azacitidine at low concentrations using the differential pulse voltammetry (DPV). The peak current decreases in the oxidation signals of the deoxyguanosine obtained voltammetrically upon the interaction of Azacitidine and dsDNA allowed a sensitive determination of Azacitidine in pH 4.80 acetate buffer. A linear dependence of the deoxyguanosine oxidation signals was observed within the range of 2-20 µM Azacitidine, with a limit of detection (LOD) 0.62 µM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships., (Copyright © 2023. Published by Elsevier B.V.)

Sucrose and high-fructose corn syrup comprise nearly equal amounts of glucose and fructose. With the use of high-fructose corn syrup in the food industry, consumption of fructose, which may be a tumor promoter, has increased dramatically. We examined fructose-induced oxidative DNA damage in the presence of Cu(II), with or without the addition of H 2 O 2 . With isolated DNA, fructose induced Cu(II)-mediated DNA damage, including formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), to a greater extent than did glucose, and H 2 O 2 enhanced the damage. In cultured human cells, 8-oxodG formation increased significantly following treatment with fructose and the H 2 O 2 -generating enzyme glucose oxidase. Fructose may play an important role in oxidative DNA damage, suggesting a possible mechanism for involvement of fructose in carcinogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The International Agency for Research on Cancer has classified arsenic as a class I carcinogen. Oxidative DNA damage is a typical early precursor to recognized malignancies. The most sensitive early independent marker of oxidative DNA damage is believed to be 8-hydroxy-2 deoxyguanosine (8-OHdG). To date, research on the link between urinary arsenic and 8-OHdG has not been consistent., Objective: This study was aimed at exploring the effects of urinary arsenic on 8-OHdG in human urine., Methods: A literature search until January 2023 was performed on the PubMed, Cochrane Library, Web of Science, Embase, and Scopus databases through a combination of computer and manual retrieval. Stata 12.0 was used to examine the degree of heterogeneity among included studies. The percentage change and 95 % confidence interval (95 % CI) of 8-OHdG were calculated between populations exposed to different doses. We used a random effect model because the degree of heterogeneity exceeded 50 %. Sensitivity analysis and testing for publication bias were performed., Results: This meta-analysis included nine studies, most of which were performed in China. After exposure to arsenic, urinary arsenic (per 10 μg/g creatinine increase) was associated with the increased 8-OHdG (% change = 41.49 %, 95 % CI: 19.73 %, 63.25 %). Subgroup analysis indicated that the percentage change in 8-OHdG in urine was more pronounced in people exposed to arsenic <50 μg/L (% change = 24.60 %, 95 % CI: 17.35 %, 37.85 %). In studies using total urinary arsenic content as an indicator, the percentage change in 8-OHdG in urine was more significant (% change = 60.38 %, 95 % CI: 15.08 %, 105.68 %)., Conclusion: The 8-OHdG levels in human urine significantly increased after exposure to environmental arsenic, thus suggesting that arsenic exposure is correlated with oxidative DNA damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationship., (Copyright © 2023. Published by Elsevier B.V.)

The oxidative balance score (OBS), wherein higher OBSs indicate lower oxidative stress, was designed to assess a composite measure of multiple pro-oxidant and antioxidant effects on an individual's oxidative stress status. This study aimed to evaluate whether OBSs were inversely associated with urinary levels of 8-hydroxydeoxyguanosine (8-OHdG)-an oxidative stress marker-among Japanese adults. This cross-sectional study was based on data obtained during 2010-2012. Overall, 7552 participants from the J-MICC Study Saga who answered a self-administered food frequency questionnaire were recruited for the final analysis. OBSs were calculated from 11 pro-oxidant and antioxidant lifestyle factors, including dietary intake, physical activity, and alcohol and smoking status. Urinary 8-OHdG values were corrected by creatinine level (ng/mg creatinine). Our findings revealed a higher total OBS was significantly associated with lower urinary 8-OHdG/creatinine levels after adjustment for covariates in men and women ( p for trend < 0.01 in both sexes). We performed a multiple regression analysis of the association between OBSs and urinary 8-OHdG/creatinine levels stratified by age, body mass index (BMI), and menopausal status and found consistent negative associations in most groups for both sexes. No significant differences in the 60-64 age group for women (standardized β = -0.09, p = 0.13) or BMI < 18.5 kg/m 2 for men (standardized β = -0.18, p = 0.17) were observed. A higher OBS had a strong inverse association with urinary 8-OHdG/creatinine levels in men and women among Japanese adults. The OBS might be a useful tool for evaluating the roles of oxidative stress-related lifestyle factors, including diet.

Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase that exists in monomeric, dimeric, and tetrameric forms. It is activated by GTP binding to an A1 allosteric site on each monomer subunit, which induces dimerization, a prerequisite for dNTP-induced tetramerization. SAMHD1 is a validated drug target stemming from its inactivation of many anticancer nucleoside drugs leading to drug resistance. The enzyme also possesses a single-strand nucleic acid binding function that promotes RNA and DNA homeostasis by several mechanisms. To discover small molecule inhibitors of SAMHD1, we screened a custom ∼69 000-compound library for dNTPase inhibitors. Surprisingly, this effort yielded no viable hits and indicated that exceptional barriers for discovery of small molecule inhibitors existed. We then took a rational fragment-based inhibitor design approach using a deoxyguanosine (dG) A1 site targeting fragment. A targeted chemical library was synthesized by coupling a 5'-phosphoryl propylamine dG fragment (dGpC 3 NH 2 ) to 376 carboxylic acids (RCOOH). Direct screening of the products (dGpC 3 NHCO-R) yielded nine initial hits, one of which (R = 3-(3'-bromo-[1,1'-biphenyl]), 5a ) was investigated extensively. Amide 5a is a competitive inhibitor against GTP binding to the A1 site and induces inactive dimers that are deficient in tetramerization. Surprisingly, 5a also prevented ssDNA and ssRNA binding, demonstrating that the dNTPase and nucleic acid binding functions of SAMHD1 can be disrupted by a single small molecule. A structure of the SAMHD1- 5a complex indicates that the biphenyl fragment impedes a conformational change in the C-terminal lobe that is required for tetramerization.

To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: r s  = 0.912, P < 0.01; GR: r s  = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (r s  = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: r s  = - 0.855, P < 0.01; 8-OHDG:r s  = - 0.412, P < 0.05, DNA adduct: γ s  = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship., (© 2023. Springer Nature Limited.)

There is accumulating evidence that pro-inflammatory features are inherent to mitochondrial DNA and oxidized DNA species. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is the most frequently studied oxidatively generated lesion. Modified DNA reaches the circulation upon cell apoptosis, necrosis or neutrophil extracellular trap (NET) formation. Standard chromatography-based techniques for the assessment of 8-oxodGuo imply degradation of DNA to a single base level, thus precluding the attribution to a nuclear or mitochondrial origin. We therefore aimed to establish a protocol for the concomitant assessment of oxidized mitochondrial and nuclear DNA from human plasma samples. We applied immunoprecipitation (IP) for 8-oxodGuo to separate oxidized from non-oxidized DNA species and subsequent quantitative polymerase chain reaction (qPCR) to assign them to their subcellular source. The IP procedure failed when applied directly to plasma samples, i.e. isotype control precipitated similar amounts of DNA as the specific 8-oxodGuo antibody. In contrast, DNA isolation from plasma prior to the IP process provided assay specificity with little impact on DNA oxidation status. We further optimized sensitivity and efficiency of qPCR analysis by reducing amplicon length and targeting repetitive nuclear DNA elements. When the established protocol was applied to plasma samples of abdominal aortic aneurysm (AAA) patients and control subjects, the AAA cohort displayed significantly elevated circulating non-oxidized and total nuclear DNA and a trend for increased levels of oxidized mitochondrial DNA. An enrichment of mitochondrial versus nuclear DNA within the oxidized DNA fraction was seen for AAA patients. Regarding the potential source of circulating DNA, we observed a significant correlation of markers of neutrophil activation and NET formation with nuclear DNA, independent of oxidation status. Thus, the established method provides a tool to detect and distinguish the release of oxidized nuclear and mitochondrial DNA in human plasma and offers a refined biomarker to monitor disease conditions of pro-inflammatory cell and tissue destruction., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitamin B 12 (cyano- or hydroxo-cobalamin) acts, via its coenzymes, methyl- and adenosyl-cobalamin, as a partner for enzymatic reactions in humans catalysed by methionine synthase and methylmalonyl-CoA mutase. As well as its association with pernicious anaemia, human B 12 deficiency may also be a risk factor for neurological illnesses, heart disease and cancer. In the present work the effect of vitamin B 12 (hydroxocobalamin) on the formation of DNA adducts by the epoxide phenyloxirane (styrene oxide), a genotoxic metabolite of phenylethene (styrene), has been studied using an in vitro model system. Styrene was converted to its major metabolite styrene oxide as a mixture of enantiomers using a microsomal fraction from the livers of Sprague-Dawley rats with concomitant inhibition of epoxide hydrolase. However, microsomal oxidation of styrene in the presence of vitamin B 12 gave diastereoisomeric 2-hydroxy-2-phenylcobalamins. The quantitative formation of styrene oxide-DNA adducts was investigated using 2-deoxyguanosine or calf thymus DNA in the presence or absence of vitamin B 12 . Microsomal incubations containing either deoxyguanosine or DNA in the absence of vitamin B 12 gave 2-amino-7-(2-hydroxy-1-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-1-phenylethyl)-guanine], and 2-amino-7-(2-hydroxy-2-phenylethyl)-1,7-dihydro-6H-purin-6-one [N7-(2-hydroxy-2-phenylethyl)guanine] as the principal adducts. With deoxyguanosine the level of formation of guanine adducts was ca. 150 adducts/10 6 unmodified nucleoside. With DNA the adduct level was 36 pmol/mg DNA (ca. 1 adduct/0.83 × 10 5 nucleotides). Styrene oxide adducts from deoxyguanosine or DNA were not detected in microsomal incubations of styrene in the presence of vitamin B 12 . These results suggest that vitamin B 12 could protect DNA against genotoxicity due to styrene oxide and other xenobiotic metabolites. However, this potential defence mechanism requires that the 2-hydroxyalkylcobalamins derived from epoxides are not 'anti-vitamins' and ideally liberate, and therefore, recycle vitamin B 12 . Otherwise, depletion of vitamin B 12 leading to human deficiency could increase the risk of carcinogenesis initiated by genotoxic epoxides., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Modified nucleotides often hinder and/or decrease the fidelity of DNA polymerases. Tandem lesions, which are comprised of DNA modifications at two contiguous nucleotide positions, can be even more detrimental to genome stability. Recently, tandem lesions containing 5-formyl-2'-deoxyuridine (5fdU) flanked at the 5'-position by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo) or N-(2-deoxy-α,β-D-erythropentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy•dG) were discovered. We examined the replication of 5'- 8-OxodGuo-5fdU and 5'-Fapy•dG-5fdU tandem lesions in HEK 293T cells and several polymerase deficient variants by transfecting single-stranded vectors containing them. The local sequence of the tandem lesions encompasses the 273 codon of the p53 gene, a mutational hot-spot. The bypass efficiency and mutation spectra of the tandem lesions were compared to those of the isolated lesions. Replication of weakly mutagenic 5-fdU is little changed when part of the 5'- 8-OxodGuo-5fdU tandem lesion. G → T transversions attributable to 8-OxodGuo increase > 10-fold when the tandem lesion is bypassed. 5'-Fapy•dG-5fdU has a synergistic effect on the error-prone bypass of both lesions. The mutation frequency (MF) of 5'-Fapy•dG-5fdU increases 3-fold compared to isolated Fapy•dG. In addition, a 5'-adjacent Fapy•dG significantly increases the MF of 5fdU. The major mutation, G → T transversions, decrease by almost a third in hPol κ - cells, which is the opposite effect when isolated Fapy•dG in the same sequence context is replicated in HEK 293T cells in the same sequence. Steady-state kinetics indicate that hPol κ contributes to greater G → T transversions by decreasing the specificity constant for dCTP compared to an isolated Fapy•dG. The greater conformational freedom of Fapy•dG compared to 8-OxodGuo and its unusual ability to epimerize at the anomeric center is believed to be the source of the complex effects of 5'-Fapy•dG-5fdU on replication., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

2'-deoxyguanosine is a key medicinal intermediate that could be used to synthesize anti-cancer drug and biomarker in type 2 diabetes. In this study, an enzymatic cascade using thymidine phosphorylase from Escherichia coli (EcTP) and purine nucleoside phosphorylase from Brevibacterium acetylicum (BaPNP) in a one-pot whole cell catalysis was proposed for the efficient synthesis of 2'-deoxyguanosine. BaPNP was semi-rationally designed to improve its activity, yielding the best triple variant BaPNP-Mu3 (E57A/T189S/L243I), with a 5.6-fold higher production of 2'-deoxyguanosine than that of wild-type BaPNP (BaPNP-Mu0). Molecular dynamics simulation revealed that the engineering of BaPNP-Mu3 resulted in a larger and more flexible substrate entrance channel, which might contribute to its catalytic efficiency. Furthermore, by coordinating the expression of BaPNP-Mu3 and EcTP, a robust whole cell catalyst W05 was created, capable of producing 14.8 mM 2'-deoxyguanosine (74.0% conversion rate) with a high time-space yield (1.32 g/L/h) and therefore being very competitive for industrial applications., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Acrylamide, a common food contaminant, is metabolically activated to glycidamide, which reacts with DNA at the N7 position of dG, forming N7-(2-carbamoyl-2-hydroxyethyl)-dG (GA 7 dG). Owing to its chemical lability, the mutagenic potency of GA 7 dG has not yet been clarified. We found that GA 7 dG undergoes ring-opening hydrolysis to form N 6 -(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-[N-(2-carbamoyl-2-hydroxyethyl)formamido]pyrimidine (GA-FAPy-dG), even at neutral pH. Therefore, we aimed to examine the effects of GA-FAPy-dG on the efficiency and fidelity of DNA replication using an oligonucleotide carrying GA-FAPy-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)guanine (dfG), a 2'-fluorine substituted analog of GA-FAPy-dG. GA-FAPy-dfG inhibited primer extension by both human replicative DNA polymerase ε and the translesion DNA synthesis polymerases (Polη, Polι, Polκ, and Polζ) and reduced the replication efficiency by less than half in human cells, with single base substitution at the site of GA-FAPy-dfG. Unlike other formamidopyrimidine derivatives, the most abundant mutation was G:C > A:T transition, which was decreased in Polκ- or REV1-KO cells. Molecular modeling suggested that a 2-carbamoyl-2-hydroxyethyl group at the N 5 position of GA-FAPy-dfG can form an additional H-bond with thymidine, thereby contributing to the mutation. Collectively, our results provide further insight into the mechanisms underlying the mutagenic effects of acrylamide., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Radon gas inhalation is the main source of exposure to ionizing radiation by humans. There is still lack in knowledge concerning the chronic and indirect effects of exposure to this carcinogenic factor. Therefore, the aim of this work is to analyze the levels of oxidative genomic damage in inhabitants of a medium-high background radiation area (HBRA) (N = 82) in Northeastern Brazil and compare them with people living in a low background radiation area (LBRA) (N = 46). 8-hydroxy-2-deoxyguanosine (8-OHdG) was quantified in urine, Ser326Cys polymorphism was determined in the hOGG1 gene and indoor radon was measured. HBRA houses had 6.5 times higher indoor radon levels than those from LBRA (p-value < 0.001). The 8-OHdG mean (95% confidence interval) were significantly different, 8.42 (5.98-11.9) ng/mg creatinine and 29.91 (23.37-38.30) ng/mg creatinine for LBRA and HBRA, respectively. The variables representing lifestyle and environmental and occupational exposures did not have a significant association with oxidized guanosine concentrations. On the other hand, lower 8-OHdG values were observed in subjects that had one mutant allele (326Cys) in the hOGG1 gene than those who had both wild alleles (Ser/Ser (p-value < 0.05). It can be concluded that high radon levels have significantly influenced the genome oxidative metabolism and hOGG1 gene polymorphism would mediate the observed biological response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To explore the impact of modernization on oxidative stress during a momentous health transition process, we investigated differences in oxidative stress among the indigenous populations of villages in northern Laos with different levels of modernization., Methods: We conducted a cross-sectional study of 380 adults in three villages with different levels of modernization. Three biomarkers related to oxidative stress were measured: urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane concentrations (both measured by liquid chromatography-tandem mass spectrometry), and blood telomere length (measured with qPCR). We examined associations between village-level modernization and oxidative stress-related biomarkers in a multilevel analysis including a random effect and covariates., Results: The geometric means of urinary 8-OHdG and 8-isoprostane concentrations were 2.92 and 0.700 μg/g creatinine, respectively, in our study population. Higher urinary 8-OHdG concentrations and shorter telomeres were observed in participants from the more modernized villages, whereas urinary 8-isoprostane concentrations did not differ significantly among villages., Conclusions: Our findings imply that modernization-induced changes in lifestyle may increase oxidative DNA damage. Baseline levels of oxidative lipid damage are expected to be high in the indigenous populations of northern Laos. Assessments of oxidative stress may provide valuable insights into the mechanisms of health transition in specific populations., (© 2023 The Authors. American Journal of Biological Anthropology published by Wiley Periodicals LLC.)

Excessive exposure of fluoride not only leads to damage on bone, but also has an adverse effect on soft tissues. Oxidative DNA damage induced by fluoride is thought to be one of the toxic mechanisms of fluoride effect. However, the dose-response of fluoride on oxidative DNA damage is barely studied in organisms. This study investigated the concentration of fluoride in rat blood, kidney, liver, and brain as well as the dose-time effect of fluoride on the expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the above tissues. Rats were exposed to 0 mg/L, 25 mg/L, 50 mg/L, and 100 mg/L of fluorine ion and treated for one and three months. The results showed that the accumulation of fluoride in soft tissues was very different. At the first month, blood fluoride was increased, liver and brain fluoride showed a U-shaped change, and kidney fluoride was not significant. At the third month, blood fluoride was altered with an inverted U-shaped change, kidney and brain fluoride increased, but liver fluoride decreased. Both the exposure concentration and the time of exposure had a significant effect on the expression of 8-OHdG in the above tissues. However, the effect patterns of fluoride on these tissues were notably different at different times. At the first month of fluoride treatment, blood, kidney, and liver 8-OHdG decreased with the increasing fluoride concentration. At the third month, blood 8-OHdG showed a U-shaped change, but kidney 8-OHdG altered with an inverted U-shaped change. Liver 8-OHdG increased, while brain 8-OHdG decreased at the third month. Correlation analysis showed that only blood 8-OHdG was significantly inversely correlated with blood fluoride and dental fluorosis grade in both the first and third months. Liver 8-OHdG was negatively and significantly correlated with liver fluoride. There was a weak but nonsignificant correlation between kidney and brain 8-OHdG and fluoride in both tissues. Additionally, blood 8-OHdG was positively correlated with kidney and liver 8-OHdG at the first month and positively correlated with brain 8-OHdG at the third month. Taken together, our data suggests that concentration and time of fluoride exposure had a significant effect on 8-OHdG, but the effect patterns of fluoride on 8-OHdG were different in the tissues, which suggests that the impact of fluoride on 8-OHdG may be a tissue-specific, as well as a non-monotonic positive correlation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Taking soy-based food supplements for menopausal symptoms by women may reduce the risk of cancer. Therefore, the interaction between nucleic acids (or their constituents) and ingredients of the supplements, e. g., isoflavone glucosides, on the molecular level, has been of interest with respect to cancer therapy. In this work, the interaction between isoflavone glucosides and G-tetrads, namely [4G+Na] + ions (G stands for guanosine or deoxyguanosine), were analyzed by using electrospray ionization-collision induced dissociation-mass spectrometry (ESI-CID-MS) and survival yields method. The strength of isoflavone glucosides-[4G+Na] + interaction in the gas phase was determined from E com50 - the energy required to fragment 50 % of selected precursor ions. Glycitin-[4G+Na] + interaction was found to be the strongest, and the interaction between isoflavone glucosides and guanosine tetrad was established to be stronger than that between isoflavone glucosides and deoxyguanosine tetrad., (© 2023 Wiley-VCH GmbH.)

7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-OxodGuo) is a ubiquitous DNA damage formed by oxidation of 2'-deoxyguanosine. In this study, plasmid DNA containing 8-OxodGuo located in three mutational hot spots of human cancers, codons 248, 249, and 273 of the Tp53 tumor suppressor gene, was replicated in HEK 293T cells. 8-OxodGuo was only a weak block of replication, and the bypass was largely error-free. The mutations (1-5%) were primarily G → T transversions, and the mutation frequency was generally lower than that of the chemically related Fapy·dG. A unique 8-OxodGuo mutation spectrum was observed at each site, as reflected by replication in translesion synthesis (TLS) polymerase- or hPol λ-deficient cells. In codon 248 (CG*G) and 249 (AG*G), where G* denotes 8-OxodGuo, hPol η and hPol ζ carried out largely error-free bypass of the lesion, whereas hPol κ and hPol ι were involved mostly in error-prone TLS, resulting in G → T mutations. 8-OxodGuo bypass in codon 273 (CG*T) was unlike the other two sites, as hPol κ participated in the mostly error-free bypass of the lesion. Yet, in all three sites, including codon 273, simultaneous deficiency of hpol κ and hPol ι resulted in reduction of G → T transversions. This indicates a convincing role of these two TLS polymerases in error-prone bypass of 8-OxodGuo. Although the dominant mutation was G → T in each site, in codon 249, and to a lesser extent in codon 248, significant semi-targeted single-base deletions also occurred, which suggests that 8-OxodGuo can initiate slippage of a base near the lesion site. This study underscores the importance of sequence context in 8-OxodGuo mutagenesis in human cells. It also provides a more comprehensive comparison between 8-OxodGuo and the sister lesion, Fapy·dG. The greater mutagenicity of the latter in the same sequence contexts indicates that Fapy·dG is a biologically significant lesion and biomarker on par with 8-OxodGuo.

Genetic information stored in a DNA base sequence is continuously exposed to harmful factors. It has been determined that 9 × 10 4 different DNA damage events occur in a single human cell every 24 h. Of these, 7,8-dihydro-8-oxo-guanosine ( OXO G) is one of the most abundant and can undergo further transformations towards spirodi(iminohydantoin) (Sp). Sp is highly mutagenic in comparison to its precursor if not repaired. In this paper, the influence of both Sp diastereomers 4 R and 4 S as well as their anti and syn conformers on charge transfer through the double helix was taken into theoretical consideration. In addition, the electronic properties of four modelled double-stranded oligonucleotides (ds-oligos) were also discussed, i.e., d[A 1 Sp 2 A 3 oxo G 4 A 5 ] * [T 5 C 4 T 3 C 2 T 1 ]. Throughout the study, the M06-2X/6-31++G** level theory was used. Solvent-solute non-equilibrated and equilibrated interactions were also considered. The subsequent results elucidated that the 7,8-dihydro-8-oxo-guanosine:cytidine ( OXO GC) base pair is the settled point of a migrated radical cation in each of the discussed cases, due to its low adiabatic ionization potential, i.e., ~ 5.55 [eV]. The opposite was noted for excess electron transfer through ds-oligos containing anti ( R )-Sp or anti ( S )-Sp. The radical anion was found on the OXO GC moiety, whereas in the presence of syn ( S )-Sp or syn ( R )-Sp, an excess electron was found on the distal A 1 T 5 or A 5 T 1 base pair, respectively. Furthermore, a spatial geometry analysis of the discussed ds-oligos revealed that the presence of syn ( R )-Sp in the ds-oligo caused only a slight deformation to the double helix, while syn ( S )-Sp formed an almost ideal base pair with a complementary dC. The above results are in strong agreement with the final charge transfer rate constant, as calculated according to Marcus' theory. In conclusion, DNA damage such as spirodi(iminohydantoin), especially when becoming part of clustered DNA damage, can affect the effectiveness of other lesion recognition and repair processes. This can lead to the acceleration of undesired and deleterious processes such as carcinogenesis or aging. However, in terms of anticancer radio-/chemo- or combined therapy, the slowing down of the repair machinery can result in increased effectiveness. With this in mind, the influence of clustered damage on charge transfer and its subsequent effect on single-damage recognition by glycosylases justifies future investigation.

Modification of DNA aptamers is aimed at increasing their thermodynamic stability, and improving affinity and resistance to biodegradation. G-quadruplex DNA aptamers are a family of affinity ligands that form non-canonical DNA assemblies based on a G-tetrads stack. Modification of the quadruplex core is challenging since it can cause complete loss of affinity of the aptamer. On the other hand, increased thermodynamic stability could be a worthy reward. In the current paper, we developed new three- and four-layer modified analogues of the thrombin binding aptamer with high thermal stability, which retain anticoagulant activity against alpha-thrombin. In the modified aptamers, one or two G-tetrads contained non-natural anti-preferred alpha-deoxyguanosines at specific positions. The use of this nucleotide analogue made it possible to control the topology of the modified structures. Due to the presence of non-natural tetrads, we observed some decrease in the anticoagulant activity of the modified aptamers compared to the natural prototype. This negative effect was completely compensated by conjugation of the aptamers with optimized tripeptide sequences.

Objective: Oxidative DNA damage has been associated with the pathophysiology of bipolar disorder (BD) as one of the common pathways between increased medical comorbidity and premature aging in BD. Previous evidence shows increased levels of oxidatively induced DNA damage markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) or its tautomer 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), in patients with BD in comparison to healthy individuals. With the current research, we aim to analyze data on peripheral (blood or urine) 8-OHdG/8-oxo-dG levels across mood states of BD using a meta-analytical approach., Method: A literature search was conducted using the databases PubMed, Scopus, and Web of Science to identify eligible studies (January 1989 to July 2022). Relevant studies were systematically reviewed; a random-effects meta-analysis and a meta-regression analysis were conducted., Results: The current meta-analysis included 12 studies consisting of 808 BD patients (390 in euthymia, 156 in mania, 137 in depression, 16 in mixed episode, 109 not specified) and 563 healthy controls. BD patients that were currently depressed had significantly higher levels of 8-OHdG/8-oxo-dG than healthy controls, while euthymic or manic patients did not differ from healthy controls. A meta-regression analysis showed sex distribution (being female) and older age to be significantly related to increased 8-OHdG/8-oxo-dG levels., Conclusion: Our findings suggest that 8-OHdG/8-oxo-dG may be a state-related marker of depression in BD and may be affected by older age and female gender., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Selenium is an element present in trace amounts and different chemical forms. It may exert both beneficial and adverse effects on cellular redox status and on the generation of reactive oxygen species. 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG) is an oxidized derivative of deoxyguanosine, and a sensitive biomarker of oxidative stress and genotoxicity. The present study assessed the extent to which selenium status was associated with urinary 8-oxodG concentrations in a Northern Italian population. We recruited healthy, non-smoking blood donors living in the Reggio Emilia province during 2017-2019. We measured urinary 8-oxodG concentrations and used restricted cubic spline regression analyses to investigate the association between selenium status (estimated using food frequency questionnaires, urinary concentrations, and serum concentrations of selenium and selenium species) and 8-oxodG/g creatinine. Among 137 participants aged 30-60 years, median urinary selenium and 8-oxodG concentrations were 22.02 μg/L and 3.21 μg/g creatinine, respectively. Serum samples and selenium speciation analyses were available for 104 participants. Median total serum selenium levels and dietary intake were 116.5 μg/L and 78.7 μg/day, respectively. In spline regression analysis, there was little association between dietary, serum, or urinary selenium with 8-oxodG concentrations. In sex-specific analyses, urinary selenium showed a positive association with the endpoint among males. For single selenium species, we observed positive associations with urinary 8-oxodG for serum organic selenium species, and negative associations for inorganic selenium forms. In the most adjusted analysis, urinary 8-oxodG concentrations showed a strong positive association with selenomethione-bound selenium (Se-Met) and a negative association with inorganic tetravalent selenium, selenite. In sex-specific analyses, these associations were considerably stronger in males than in females. Overall, study findings indicate that selenium species exhibited very different patterns of associations with the biomarker of oxidative stress, and that these associations also depended on sex. Background exposure to Se-Met appears to be strongly and positively associated with oxidative stress., Competing Interests: Declaration of competing interest Dr. Lauren A. Wise is supported by grants from the National Institutes of Health. She also serves as a fibroid consultant on for AbbVie, Inc. She also receives in-kind donations for primary data collection in Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility apps). All of these relationships are for work unrelated to this manuscript. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Beneficial microorganisms play essential roles in plant growth and induced systemic resistance (ISR) by releasing signaling molecules. Our previous study obtained the crude extract from beneficial endophyte Paecilomyces variotii, termed ZNC (ZhiNengCong), which significantly enhanced plant resistance to pathogen even at 100 ng/ml. However, the immunoreactive components of ZNC remain unclear. Here, we further identified one of the immunoreactive components of ZNC is a nucleoside 2'-deoxyguanosine (2-dG)., Objectives: This paper intends to reveal the molecular mechanism of microbial-derived 2'-deoxyguanosine (2-dG) in activating plant immunity, and the role of plant-derived 2-dG in plant immunity., Methods: The components of ZNC were separated using a high-performance liquid chromatography (HPLC), and 2-dG is identified using a HPLC-mass spectrometry system (LC-MS). Transcriptome analysis and genetic experiments were used to reveal the immune signaling pathway dependent on 2-dG activation of plant immunity., Results: This study identified 2'-deoxyguanosine (2-dG) as one of the immunoreactive components from ZNC. And 2-dG significantly enhanced plant pathogen resistance even at 10 ng/ml (37.42 nM). Furthermore, 2-dG-induced resistance depends on NPR1, pattern-recognition receptors/coreceptors, ATP receptor P2K1 (DORN1), ethylene signaling but not salicylic acid accumulation. In addition, we identified Arabidopsis VENOSA4 (VEN4) was involved in 2-dG biosynthesis and could convert dGTP to 2-dG, and vne4 mutant plants were more susceptible to pathogens., Conclusion: In summary, microbial-derived 2-dG may act as a novel immune signaling molecule involved in plant-microorganism interactions, and VEN4 is 2-dG biosynthesis gene and plays a key role in plant immunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Purpose: To compare the aqueous humor (AH) and serum levels of 4-hydroxynenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OhdG) in patients with pseudoexfoliation syndrome (PES) and pseudoexfoliation glaucoma (PEG) with each other and with age- and sex-matched control group., Methods: This prospective study included 66 patients divided into three groups: PES (n = 24), PEG (n = 21), and a control group (n = 21). 4-HNE and 8-OhdG levels were analyzed using the enzyme-linked immunosorbent assay., Results: Aqueous and serum 4-HNE levels were significantly higher in the PEG (466.52 ± 62.12 pg/mL and 313.47 ± 47.41 pg/mL) and PES (290.69 ± 63.63 pg/mL and 201.53 ± 39.57 pg/mL) groups than the control group (144.02 ± 39.58 pg/mL and 99.10 ± 16.96 pg/mL; p < 0.001, for all). Both aqueous and serum levels of 4-HNE in the PEG group were significantly higher than in the PES group (p < 0.001, for both). Similar to 4-HNE, the AH 8-OhdG levels were higher in the PEG group (21.18 ± 2.23 ng/mL) compared to the PES (14.90 ± 3.37 ng/mL) and control (4.86 ± 1.94 ng/mL) groups (p < 0.001, for all). Serum 8-OhdG levels were significantly higher in the PEG and PES groups than the control (p < 0.001, for both); however, there was no significant difference between the PES and PEG groups (p = 0.097). There were strong significant correlations between the aqueous and serum levels of 4-HNE (p < 0.001, r = 0.857) and 8-OhdG (p < 0.001, r = 0.807) among all the patients., Conclusions: Aqueous humor and serum levels of 4-HNE and 8-OhdG increased in the PES and PEG patients. These findings are potentially significant and add to the growing body of evidence concerning oxidative stress in PES and PEG., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

This article describes procedures for preparation of deoxyguanosine and guanosine derivatives in which the guanine N 2 contains a thiopropyl tether, protected as a tert-butyl disulfide. After incorporation into a DNA or RNA fragment, this tether allows site-specific cross-linking to a thiol of a protein or another nucleic acid. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Preparation of diisopropyl-1-(tert-butylthio)-1,2-hydrazinedicarboxylate (4) Basic Protocol 2: Preparation of the 2'-deoxyguanosine N 2 -propyl-tert-butyl disulfide phosphoramidite (12) Basic Protocol 3: Preparation of the guanosine N 2 -propyl-tert-butyl disulfide phosphoramidite (20) Basic Protocol 4: Preparation of DNA fragments containing N 2 -propyl-tert-butyl disulfide guanine Alternate Protocol: Preparation of RNA fragments containing N 2 -propyl-tert-butyl disulfide guanine Basic Protocol 5: Conversion of N 2 -propyl-tert-butyl disulfide to the free thiol, disulfide 5-thio-2-nitrobenzoic acid disulfide, or ethylamine disulfide., (© 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.)

Background: Frequent heavy air pollution occurred during the winter heating season of northern China. Particulate air pollution is a serious concern in Urumqi during heating season. Exposure to air pollution is known to increase adverse health outcomes, particularly oxidative damage. This study aimed to evaluate the impact of air pollution on oxidative damage around pregnant women and newborns in Urumqi., Methods: This prospective observational study enrolled pregnant women in the Fifth Affiliated Hospital of Xinjiang Medical University between January 2019 and October 2019. Pregnant women and newborns were allocated into a heating season group (January - end of April 2019, October 2019) or non-heating season group (June 2019 - end of September) according to the specific delivery time. Venous blood, urine from the women and cord blood from their newborns were collected to measure the levels of PAHs and 8-deoxyguanosine (8-OHdG), a measure of oxidative stress., Results: A total of 200 pregnant women and newborns were enrolled, with 100 pregnant women and newborns in the heating season group. Compared to the non-heating season group, the total contents of 8-OHdG in maternal urine, PAHs and 8-OHdG in maternal plasma and neonatal cord blood were higher in the heating season group (all P < 0.001). The average values for AQI, PM 2.5 , PM 10 , SO 2 , NO 2 , and CO were higher in the heating season group (all P < 0.001). Maternal and neonatal PAHs were correlated with 8-OHdG measurements in maternal urine (r = 0.288, P < 0.001 and r = 0.336, P < 0.001) and neonatal umbilical cord blood (r = 0.296, P < 0.001 and r = 0.252, P < 0.001). There was also a positive relationship between PAHs, 8-OHdG levels in pregnant women and their newborns and proximate air pollutant concentrations (all P < 0.05). Based on the results of multiple linear regression analysis, it was found that air pollutants(PM 10 , 0 3 ) had a great influence on the level of 8-OHdG in neonatal cord blood, and the contribution rate was high(R 2  = 0.320). Based on the epidemiological questionnaire, a multiple linear regression model was established(R 2  = 0.496). We found that 8-OHdG levels in neonatal umbilical cord blood were mainly affected by two aspects: (1) Biological samples collected during heating had higher levels of 8-OHdG in neonatal umbilical cord blood. (2) Study may suggest that in neonates, males are more sensitive to oxidative damage., Conclusion: Particulate air pollution may increase PAHs exposure and oxidative DNA damage in pregnant women and newborns., (© 2023. The Author(s).)

Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF. These adducts can be considered biomarkers of exposure for effects of endoF and exogF on DNA that may be part of the mechanism of tumor formation. We describe a computational model linking CFD-predicted flux of formaldehyde from air into tissue, and the intracellular production of endoF, with the formation of DPX and DG adducts. We assumed that, like exogF, endoF can produce DPX. The model accurately reproduces exogDPX, exogDG, and endoDG data after inhalation from 0.7 to 15 ppm. The dose-dependent concentrations of exogDPX and exogDG are predicted to exceed the concentrations of their endogenous counterparts at about 2 and 6 ppm exogF, respectively. At all concentrations examined, the concentrations of endoDPX and exogDPX were predicted to be at least 10-fold higher than that of their DG counterparts. The modeled dose-dependent concentrations of these adducts are suitable to be used together with data on the dose-dependence of cell proliferation to conduct quantitative modeling of formaldehyde-induced rat nasal carcinogenicity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

The guanine base in nucleic acids is, among the other bases, the most susceptible to being converted into 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) when exposed to reactive oxygen species. In double-helix DNA, 8-oxodG can pair with adenine; hence, it may cause a G > T (C > A) mutation; it is frequently referred to as a form of DNA damage and promptly corrected by DNA repair mechanisms. Moreover, 8-oxodG has recently been redefined as an epigenetic factor that impacts transcriptional regulatory elements and other epigenetic modifications. It has been proposed that 8-oxodG exerts epigenetic control through interplay with the G-quadruplex (G4), a non-canonical DNA structure, in transcription regulatory regions. In this review, we focused on the epigenetic roles of 8-oxodG and the G4 and explored their interplay at the genomic level.

Z-DNA structure is a noncanonical left-handed alternative form of DNA, which has been suggested to be biologically important and is related to several genetic diseases and cancer. Therefore, investigation of Z-DNA structure associated with biological events is of great importance to understanding the functions of these molecules. Here, we described the development of a trifluoromethyl labeled deoxyguanosine derivative and employed it as a 19 F NMR probe to study Z-form DNA structure in vitro and in living cells., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Carbon material derived from the waste-based biomass human hair (H), which is naturally rich in pyridinic nitrogen, provides a significant benefit in biosensor applications with its dominant conductivity character. The carbon material was synthesized from human hair waste by the hydrothermal carbonization (HTC) method, which is a promising green synthesis. A morphological characterization of the carbon materials was performed. In this study, H and amine-functionalized multi-walled carbon nanotubes (NH 2 -MWCNT) were combined for the first time as a modifier, which enhanced the glassy carbon electrode (GCE) surface area for deoxyribonucleic acid (DNA) biosensor studies. Palbociclib (PLB) is clinically used in the treatment of breast cancer. The novel electrochemical nanobiosensor was used to investigate the dsDNA-PLB interaction to evaluate the possibility that PLB causes conformational changes in DNA structure and/or oxidative damage. The interaction was conducted based on the voltammetric signals of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) by differential pulse voltammetry (DPV) on a bare and H + NH 2 -MWCNT modified GCE. The proposed analytical method was applied to a pharmaceutical dosage form with a satisfactory recovery of 98.25 %. The nanobiosensor was tested in the presence of some interfering agents. The binding mechanism of dsDNA-PLB was also evaluated by spectroscopic and theoretical calculations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Inhibition of the activation of the NLR family pyrin domain‑containing 3 (NLRP3) inflammasome has previously been reported to confer protection against post‑infectious irritable bowel syndrome (PI‑IBS). Coptisine, the second most abundant isoquinoline alkaloid in Coptis chinensis , can inhibit NLRP3 inflammasome activation; however, whether coptisine exhibits protective effects against PI‑IBS remains unclear. In the present study, coptisine significantly reduced gastrointestinal motility and abdominal withdrawal reflex scores in a PI‑IBS rat model that was induced using intragastric administration of Trichinella spiralis larvae. Coptisine treatment significantly decreased the protein levels of oxidative stress markers, 4‑hydroxynonenal, protein carbonyl and 8‑hydroxy‑2'deoxyguanosine, and proinflammatory cytokines, TNF‑α, IL‑1β and IL‑18 in the colon of PI‑IBS rats. Moreover, coptisine treatment significantly increased nuclear factor erythroid 2‑related factor 2 (Nrf2) nuclear translocation and heme oxygenase‑1 protein expression levels, while significantly downregulating the protein expression levels of NLRP3, apoptosis‑associated speck‑like protein containing a CARD and caspase‑1 in the colons of PI‑IBS rats. It is important to note that the anti‑inflammatory effects of coptisine were blocked by the Nrf2 inhibitor ML385. In summary, the present study indicated that coptisine potentially attenuated PI‑IBS in rats via Nrf2‑dependent inhibition of the NLPR3 inflammasome.

Urinary artificial sweeteners (ASs) have been proved to be useful biomarkers for assessing their dietary intakes; however, it is unclear how well a spot urine sample may represent a longer-term exposure. Therefore, a longitudinal study was designed and six ASs and two oxidative stress biomarkers, namely, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), were determined. Acesulfame (ACE) and saccharin (SAC) were detected in most urines with concentration ranges of

This study aimed to investigate the effect of biomarkers of oxidative stress (OS) in 8-isoprostane (8-iso) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) on mild cognitive impairment (MCI) during a 12-week Ruesi Dadton (RD) exercise. A total of 274 enrolled participants were classified into blocks based on age and formal educational years, and randomly assigned into two groups: RD and control (CON). The participants' cognitive functions were tested using Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores to screen for MCI. Urine samples of approximately 30 mL were collected from both groups pre- and post-intervention. All participants signed consent forms before participating in the program. Participants in the RD group were instructed to perform 15 postures of RD exercise in 60 min, three times a week for 12 weeks. A 2 × 2 (group × time) repeated multivariate analysis, with MoCA score, 8-iso, and 8-OH-dG as covariates, was performed to analyze the between-subject differences across group [ V = 0.143, F(2,60) = 5.020, p = 0.010, d = 0.209] and within-subject differences across interaction between group [ V = 0.143, F(2,60) = 5.020, p = 0.010, d = 0.408]. There were significant differences from univariate data regarding both 8-iso (F1,61 = 10.081, P = 0.002, d = 0.406) and 8-OH-dG (F(1,61) = 5.965, P = 0.018, d = 0.312) levels. Moreover, results from both biomarkers in the RD group revealed significant improvements in 8-iso ( p < 0.001) and 8-OH-dG ( p = 0.003), whereas there were no improvements in the CON group. In conclusion, RD decreased biomarkers of OS during 12 weeks of RD exercise in MCI. These results indicate that in MCI, RD could improve lipid peroxidation and DNA oxidation by 8-iso and 8-OH-dG, respectively.

Objectives: Semen comprises prostatic fluid and seminal vesicle fluid, and seminal vesicle fluid contains various factors such as prostaglandin E2 (PGE2), zinc, and testosterone, which play important roles in sperm motility. It is not known whether these factors affect erectile function. In this study, we investigated factors in seminal vesicle fluid that may affect erectile function., Methods: After receiving institutional review board approval, we collected seminal vesicle fluid samples from 134 Japanese patients with localized prostate cancer who underwent robot-assisted radical prostatectomy. We examined the relationship between the results of the Sexual Health Inventory for Men (SHIM), erection hardness score, an original questionnaire on the presence or absence of sexual desire, and concentrations of several factors in seminal vesicle fluid (testosterone, PGE2, transforming growth factor β1, and 8-hydroxy-2-deoxyguanosine), as well as the serum testosterone level., Results: Median participant age was 67 (range 51-77) years. Median concentrations were as follows: seminal vesicle testosterone 1.85 (range 0.17-4.32) ng/ml and serum testosterone 4.60 (range 1.75-10.82) ng/ml. When the SHIM score was divided into two groups, seminal vesicle testosterone concentration was significantly increased (p = 0.002) in participants with a SHIM score ≥17, and no significant difference was observed in serum testosterone levels (p = 0.661). Multivariate analysis revealed that seminal vesicle testosterone was significantly correlated with the SHIM score (≥17 vs. <17; odds ratio 2.137, 95% confidence interval 1.148-3.978, p = 0.016)., Conclusions: Testosterone levels in seminal vesicle fluid can reflect erectile function in patients with prostate cancer, suggesting that seminal vesicle testosterone is very important for male erectile function., (© 2022 The Japanese Urological Association.)

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

DNA viruses and retroviruses consume large quantities of deoxynucleotides (dNTPs) when replicating. The human antiviral factor SAMHD1 takes advantage of this vulnerability in the viral lifecycle, and inhibits viral replication by degrading dNTPs into their constituent deoxynucleosides and inorganic phosphate. Here, we report that bacteria use a similar strategy to defend against bacteriophage infection. We identify a family of defensive bacterial deoxycytidine triphosphate (dCTP) deaminase proteins that convert dCTP into deoxyuracil nucleotides in response to phage infection. We also identify a family of phage resistance genes that encode deoxyguanosine triphosphatase (dGTPase) enzymes, which degrade dGTP into phosphate-free deoxyguanosine and are distant homologues of human SAMHD1. Our results suggest that bacterial defensive proteins deplete specific deoxynucleotides (either dCTP or dGTP) from the nucleotide pool during phage infection, thus starving the phage of an essential DNA building block and halting its replication. Our study shows that manipulation of the dNTP pool is a potent antiviral strategy shared by both prokaryotes and eukaryotes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Methoxychlor (MXC) is an organopesticide classified as a "Proposed Persistent Organic Pollutant" in the Stockholm Convention, and recent studies revealed that MXC could induce DNA strand breaks, whereas its underlying mechanisms were underinvestigated. Here, we first reported that hydroxymethoxychlor (HPTE), one of MXC's active metabolites, could be oxidized in vivo to form quinone intermediate, which attacked N7 position of 2'-deoxyguanosine to form N7-HPTE-deoxyguanosine (N7-HPTE-dG), followed by depurination to produce N7-HPTE-guanine (N7-HPTE-Gua) in MXC-treated mammalian cells and tissues from mice fed with MXC, employing an ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method. We observed a positive correlation between the doses of MXC exposure and the levels of N7-HPTE-Gua and N7-HPTE-dG in cytoplasm and genomic DNA, respectively. Furthermore, after removal of exogenous MXC, the amount of genomic N7-HPTE-dG was significantly decreased during 24 h, while the level of cytoplasmic N7-HPTE-Gua was elevated during first 12 h, indicating the accumulation of the N7-HPTE-Gua in cells. Additionally, for animal experiment, genomic N7-HPTE-dG was observed in livers and cortexes from female C57BL/6 mice fed with MXC, suggesting a potential mechanism of its hepatoxicity and neurotoxicity. Overall, our study provides new understanding about the formation of MXC-induced DNA adducts in mammalian cells and animal models., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The popularity of engineered stone (ES) has been associated with a global increase in occupational lung disease in workers exposed to respirable dust during the fabrication of benchtops and other ES products. In this study, the reactivity and subsequent oxidative reduction potential of freshly generated ES dusts were evaluated by (i) comparing different engineered and natural stones, (ii) comparing settled and respirable stone dust fractions and (iii) assessing the effect of ageing on the reactivity of freshly generated stone dust. An established cell-free deoxyguanosine hydroxylation assay was used to assess the potential for oxidative DNA damage. ES dust exhibited a higher relative reactivity than two of the three natural stones tested. Respirable dust fractions were found to be significantly more reactive than their corresponding settled fraction (ANOVA, p < 0.05) across all stone types and samples. However, settled dust still displayed high relative reactivity. The lower reactivity of the settled dust was not due to decay in reactivity of the respirable dust when it settled but rather a result of the admixture of larger nonrespirable particles. No significant change in respirable dust reactivity was observed for three ES samples over a 21-day time period, whereas a significant decrease in reactivity was observed in the natural stone studied. This study has practical implications for dust control and housekeeping in industry, risk assessment and hazard management.

N 6-(2-Deoxy-α,β-d- erythro -pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido pyrimidine (Fapy•dG) is a prevalent form of genomic DNA damage. Fapy•dG is formed in greater amounts under anoxic conditions than the well-studied, chemically related 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodGuo). Fapy•dG is more mutagenic in mammalian cells than 8-oxodGuo. A distinctive property of Fapy•dG is facile epimerization, but prior works with Fapy•dG analogues have precluded determining its effect on chemistry. We present crystallographic characterization of natural Fapy•dG in duplex DNA and as the template base for DNA polymerase β (Pol β). Fapy•dG adopts the β-anomer when base paired with cytosine but exists as a mixture of α- and β-anomers when promutagenically base paired with adenine. Rotation about the bond between the glycosidic nitrogen atom and the pyrimidine ring is also affected by the opposing nucleotide. Sodium cyanoborohydride soaking experiments trap the ring-opened Fapy•dG, demonstrating that ring opening and epimerization occur in the crystalline state. Ring opening and epimerization are facilitated by propitious water molecules that are observed in the structures. Determination of Fapy•dG mutagenicity in wild type and Pol β knockdown HEK 293T cells indicates that Pol β contributes to G → T transversions but also suppresses G → A transitions. Complementary kinetic studies have determined that Fapy•dG promotes mutagenesis by decreasing the catalytic efficiency of dCMP insertion opposite Fapy•dG, thus reducing polymerase fidelity. Kinetic studies have determined that dCMP incorporation opposite the β-anomer is ∼90 times faster than the α-anomer. This research identifies the importance of anomer dynamics, a feature unique to formamidopyrimidines, when considering the incorporation of nucleotides opposite Fapy•dG and potentially the repair of this structurally unusual lesion.

Deoxyguanosine kinase (dGK) is reported responsible for the phosphorylation of deoxyadenosine (dA) and deoxyguanosine (dG) in the mitochondrial purine salvage pathway. Antiviral nucleoside analogs known as nucleoside reverse transcriptase inhibitors (NRTIs) must be phosphorylated by host enzymes for the analog to become active. We address the possibility that NRTI purine analogs may be competitive inhibitors of dGK. From a group of such analogs, we demonstrate that entecavir (ETV) competitively inhibited the phosphorylation of dG and dA in rat mitochondria. Mitochondria from the brain, heart, kidney, and liver showed a marked preference for phosphorylation of dG over dA (10-30-fold) and ETV over dA (2.5-4-fold). We found that ETV inhibited the phosphorylation of dG with an IC 50 of 15.3 ± 2.2 μM and that ETV and dG were both potent inhibitors of dA phosphorylation with IC 50s of 0.034 ± 0.007 and 0.028 ± 0.006 μM, respectively. In addition, the phosphorylation of dG and ETV followed Michaelis-Menten kinetics and each competitively inhibited the phosphorylation of the other. We observed that the kinetics of dA phosphorylation were strikingly different from those of dG phosphorylation, with an exponentially lower affinity for dGK and no effect of dA on dG or ETV phosphorylation. Finally, in an isolated heart perfusion model, we demonstrated that dG, dA, and ETV were phosphorylated and dG phosphorylation was inhibited by ETV. Taken together, these data demonstrate that dGK is inhibited by ETV and that the primary role of dGK is in the phosphorylation of dG rather than dA., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The identification of the position of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA is important to clarify the pathogenesis of many diseases. We herein developed a purine-1,3-diazaphenoxazine triphosphate (dPdapTP) and described the first example of detecting the presence of 8-oxo-dG by amplifying it several hundred times after the multiple-turnover single nucleotide primer extension reactions.

Individuals who get involved in the disinfection of public settings using sodium hypochlorite might suffer adverse health effects. However, scarce information is available on the potential oxidative stress damage caused at low concentrations typically used for disinfection. We aimed to assess whether exposure to sodium hypochlorite during the COVID-19 pandemic causes oxidative stress damage in workers engaged in disinfection tasks. 75 operators engaged in the disinfection of public places were recruited as the case group, and 60 individuals who were not exposed to disinfectant were chosen as the control group. Spot urine samples were collected before (BE) and after exposure (AE) to disinfectants in the case group. Likewise, controls provided two spot urine samples in the same way as the case group. Urinary malondialdehyde (MDA) levels were quantified by forming thiobarbituric acid reactive substances in the urine. In addition, the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the urine was determined using an ELISA kit. Results showed significant differences in the urinary levels of oxidative stress markers, where median 8-OHdG (AE case: 3.84 ± 2.89 μg/g creatinine vs AE control 2.54 ± 1.21 μg/g creatinine) and MDA (AE case: 169 ± 89 μg/g creatinine vs AE control 121 ± 47 μg/g creatinine) levels in case group AE samples were 1.55 and 1.35-times higher than the control group AE samples (P < 0.05), respectively. Besides, urinary levels of oxidative stress markers in AE samples of the case group were significantly higher than in BE samples (8-OHdG BE 3.40 ± 1.95 μg/g creatinine, MDA BE 136 ± 51.3 μg/g creatinine, P < 0.05). Our results indicated that exposure to even low levels of sodium hypochlorite used in disinfection practices might cause oxidative stress related damage. With this in mind, implementing robust protective measures, such as specific respirators, is crucial to reduce the health burdens of exposure to disinfectants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adenosine synthase A (AdsA) is a key virulence factor of Staphylococcus aureus , a dangerous microbe that causes fatal diseases in humans. Together with staphylococcal nuclease, AdsA generates deoxyadenosine (dAdo) from neutrophil extracellular DNA traps thereby igniting caspase-3-dependent cell death in host immune cells that aim at penetrating infectious foci. Powered by a multi-technological approach, we here illustrate that the enzymatic activity of AdsA in abscess-mimicking microenvironments is not restricted to the biogenesis of dAdo but rather comprises excessive biosynthesis of deoxyguanosine (dGuo), a cytotoxic deoxyribonucleoside generated by S. aureus to eradicate macrophages of human and animal origin. Based on a genome-wide CRISPR-Cas9 knock-out screen, we further demonstrate that dGuo-induced cytotoxicity in phagocytes involves targeting of the mammalian purine salvage pathway-apoptosis axis, a signaling cascade that is concomitantly stimulated by staphylococcal dAdo. Strikingly, synchronous targeting of this route by AdsA-derived dGuo and dAdo boosts macrophage cell death, indicating that S. aureus multiplexes death-effector deoxyribonucleosides to maximize intra-host survival. Overall, these data provide unique insights into the cunning lifestyle of a deadly pathogen and may help to design therapeutic intervention strategies to combat multidrug-resistant staphylococci., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tantawy, Schwermann, Ostermeier, Garbe, Bähre, Vital and Winstel.)

Small structural alterations of the purine/pyrimidine core have been related to important photophysical changes, such as the loss of photostability. Similarly to canonical nucleobases, solute-solvent interactions can lead to a change in the excited state lifetimes and/or to the interplay of different states in the photophysics of these modified nucleobases. To shed light on both effects, we here report a complete picture of the absorption spectra and excited state deactivation of deoxyguanosine and its closely related derivative, deoxydeazaguanosine, in water and methanol through the mapping of the excited state potential energy surfaces and molecular dynamics simulations at the TD-DFT level of theory. We show that the N by CH exchange in the imidazole ring of deoxyguanosine translates into a small red-shift of the bright states and slightly faster dynamics. In contrast, changing solvent from water to methanol implies the opposite, i.e., that the deactivation of both systems to the ground state is significantly hindered.

Introduction: Recently, it was revealed that uric acid is a photosensitizer of reactions of nucleosides on irradiation with UV light at wavelengths longer than 300 nm, and two products generated from 2'-deoxycytidine were identified. In the present study, UV reactions of acetylated derivatives of 2'-deoxyguansoine and 2'-deoxyadenosine were conducted and their products were identified., Findings: Each reaction of 3',5'-di-O-acetyl-2'-deoxyguansoine or 3',5'-di-O-acetyl-2'-deoxyadenosine with UV light at wavelengths longer than 300 nm in the presence of uric acid generated several products. The products were separated by HPLC and identified by comparing UV and MS spectra of the products with previously reported values. The major products were spiroiminodihydantoin, imidazolone, and dehydro-iminoallantoin nucleosides for 3',5'-di-O-acetyl-2'-deoxyguansoine, and an adenine base and a formamidopyrimidine nucleoside for 3',5'-di-O-acetyl-2'-deoxyadenosine., Conclusions: If these damages caused by uric acid with sunlight occur in DNA of skin cells, mutations may arise. We should pay attention to the genotoxicity of uric acid in terms of DNA damage to dGuo and dAdo sites mediated by sunlight., (© 2022. The Author(s).)

Nucleoside-lipid conjugates are very useful supramolecular building blocks to construct self-assembled architectures suited for biomedical and material applications. Such nucleoside derivatives can be further synthetically manipulated to endow additional functionalities that could augment the assembling process and impart interesting properties. Here, we report the design, synthesis and self-assembling process of multifunctional supramolecular nucleolipid synthons containing an environment-sensitive fluorescent guanine. The amphiphilic synthons are composed of an 8-(2-(benzofuran-2-yl)vinyl)-guanine core and alkyl chains attached to 3'-O and 5'-O-positions of 2'-deoxyguanosine. The 2-(benzofuran-2-yl)vinyl (BFV) moiety attached at the C8 position of the nucleobase adopted a syn conformation about the glycosidic bond, which facilitated the self-assembly process through the formation of a G-tetrad as the basic unit. While 3',5'-diacylated BFV-modified dG analog stabilized the guanosine hydrogel by hampering the crystallization process and imparted fluorescence, BFV-modified dGs containing longer alkyl chains formed a green fluorescent organogel, which transformed into a yellow fluorescent gel in the presence of a complementary non-fluorescent cytidine nucleolipid. The ability of the dG analog containing short alkyl chains to modulate the mechanical property of a gel, and interesting fluorescence properties and self-assembling behavior exhibited by the dG analogs containing long alkyl chains in response to heat and complementary base underscore the potential use of these new supramolecular synthons in material applications., (© 2021 Wiley-VCH GmbH.)

Fetal thymic organ culture (FTOC) provides a method for analyzing T cell development in a physiological context outside the animal. This technique enables studies of genetically altered mice that are embryonic or neonatal lethal, in addition to bypassing the complication of migration of successive waves of T cells out of the thymus. The hanging drop method involves depletion of thymocytes from host lobes using deoxyguanosine, followed by reconstitution with hematopoietic progenitors. This method has become standard for analysis of fetal liver precursors, bone marrow precursors, and early thymocytes. However, difficulties are encountered in the analysis of γδ T cell precursors using this method. We have developed a modification of FTOC in which partial depletion of hematopoietic precursors by shortened deoxyguanosine treatment, coupled with the use of TCRδ-deficient host lobes, enables engraftment and development of fetal γδTCR+ thymocytes. This method allows comparisons of development and functional differentiation of γδ T cell precursors between cells of different genotypes or treatments, in the context of a permissive thymic microenvironment., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

An efficient synthetic method has been developed for the synthesis of 2'-deoxyguanosine from the more commercially available 2'-deoxyadenosine via late-stage C2 nitration in 48.7% total yield by a 5-step synthetic procedure. Crucially, 2'-deoxyadenosine was fully protected by bennzoyl groups and then nitrated at C2 by tetrabutylammonium nitrate/trifluoroacetic anhydride. The resulting 2-NO 2 moiety was converted into 2-NH 2 by Ni-catalyzed hydrogenolysis. Finally, 2'-deoxyguanosine was obtained from the diaminopurine intermediate by deaminase-catalyzed reaction. Furthermore, the 2-NO 2 moiety also appeared to be a versatile handle to introduce a variety of functional groups, resulting in a divergent access to 2-substituted 2'-deoxyadenosine analogues.

Background: Reactive oxygen species released on stimulation by periodontal pathogens cause oxidation of biomolecules and play significant role in periodontal disease pathogenesis., Aim: This study aimed to evaluate the levels of oxidative by-products malondialdehyde (MDA) and 8-hydroxy deoxyguanosine (8-OHdG) as biomarkers in chronic periodontitis patients compared to healthy as well as before and after nonsurgical periodontal therapy. The correlation between biomarkers and clinical attachment level was also evaluated., Settings and Design: A total of 112 subjects were included in this study. The subjects were divided into two groups (Group I included 56 healthy subjects and Group II constituted 56 chronic periodontitis patients) on the basis of clinical periodontal parameters., Materials and Methods: Group I subjects received no treatment and were evaluated once only for clinical and oxidative stress biomarker parameters. Nonsurgical periodontal therapy was carried out in Group II patients and they were evaluated at baseline and 3 months after therapy., Results: Both salivary and serum levels of MDA and 8-OHdG were found to be increased in chronic periodontitis patients as compared to healthy subjects. After nonsurgical periodontal therapy, the levels of MDA and 8-OHdG significantly reduced. Linear correlation between clinical attachment level and oxidative stress parameters was found to be positive and highly significant., Conclusion: It can be concluded that periodontal therapy is effective in improving the oxidative stress condition., Competing Interests: None