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Vasquez C, Osgood NB, Zepeda M, Sandel D, Cowan Q, Peiris M, Donoghue D, Komor A. Precision genome editing and in-cell measurements of oxidative DNA damage repair enable functional and mechanistic characterization of cancer-associated MUTYH variants. Nucleic Acids Res 2025; 53:gkaf037. [PMID: 40156857 PMCID: PMC11952967 DOI: 10.1093/nar/gkaf037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 01/08/2025] [Accepted: 01/16/2025] [Indexed: 04/01/2025] Open
Abstract
Functional characterization of genetic variants has the potential to advance the field of precision medicine by enhancing the efficacy of current therapies and accelerating the development of new approaches to combat genetic diseases. MUTYH is a DNA repair enzyme that recognizes and repairs oxidatively damaged guanines [8-oxoguanine (8-oxoG)] mispaired with adenines (8-oxoG·A). While some mutations in the MUTYH gene are associated with colorectal cancer, most MUTYH variants identified in sequencing databases are classified as variants of uncertain significance. Convoluting clinical classification is the absence of data directly comparing homozygous versus heterozygous MUTYH mutations. In this study, we present the first effort to functionally characterize MUTYH variants using precision genome editing to generate heterozygous and homozygous isogenic cell lines. Using a MUTYH-specific lesion reporter in which we site-specifically incorporate an 8-oxoG·A lesion in a fluorescent protein gene, we measure endogenous MUTYH enzymatic activity and classify them as pathogenic or benign. Further, we modify this reporter to incorporate the MUTYH repair intermediate (8-oxoG across from an abasic site) and validate it with co-immunoprecipitation experiments to demonstrate its ability to characterize the mechanism by which MUTYH mutants are defective at DNA repair.
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Affiliation(s)
- Carlos A Vasquez
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Nicola R B Osgood
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Marcanthony U Zepeda
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Dominika K Sandel
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Quinn T Cowan
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Malalage N Peiris
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
| | - Daniel J Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, San Diego, CA 92093, United States
| | - Alexis C Komor
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, San Diego, CA 92093, United States
- Sanford Stem Cell Institute, University of California San Diego, La Jolla, CA 92037, United States
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2
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Aleksič S, Podbevšek P, Plavec J. Oxidative events in a double helix system promote the formation of kinetically trapped G-quadruplexes. Nucleic Acids Res 2025; 53:gkaf260. [PMID: 40183633 PMCID: PMC11969667 DOI: 10.1093/nar/gkaf260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/05/2025] Open
Abstract
Guanine-rich oligonucleotide sequences can adopt four-stranded G-quadruplex structures. These sequences are highly susceptible to oxidative damage due to the low redox potential of their constituent guanine nucleotides. Oxidative lesions of guanine residue exhibit perturbations in the position of hydrogen-bond donors and acceptors, which can impair the formation of G-quadruplexes. Here we studied the effect of guanine oxidation in model systems comprised of a G-rich as well as a complementary C-rich DNA strand to discern how oxidative damage can destabilize double-stranded DNA and promote G-quadruplex formation. Our data show that G-rich strands containing oxidative lesions can still adopt the G-quadruplex fold due to the presence of spare G-tracts, which rescue the damaged G-tracts via either full or partial replacement. However, most of the observed G-quadruplexes are kinetically trapped structures and the preferred equilibrium state of the two-stranded constructs is double-stranded DNA.
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Affiliation(s)
- Simon Aleksič
- Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Peter Podbevšek
- Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
| | - Janez Plavec
- Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
- EN-FIST Centre of Excellence, Trg OF 13, 1000 Ljubljana, Slovenia
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3
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Fujikawa Y, Suzuki T, Kawai H, Kamiya H. NEIL1: The second DNA glycosylase involved in action-at-a-distance mutations induced by 8-oxo-7,8-dihydroguanine. Free Radic Biol Med 2025; 229:374-383. [PMID: 39848343 DOI: 10.1016/j.freeradbiomed.2025.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/21/2024] [Accepted: 01/20/2025] [Indexed: 01/25/2025]
Abstract
8-Oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine), an oxidatively damaged base, induces mutations and is involved in cancer initiation. In addition to G:C→T:A transversions at the damaged site, it causes untargeted base substitution (action-at-a-distance) mutations at the G bases of 5'-GpA-3' sites in human cells. Paradoxically, OGG1, a DNA glycosylase involved in the base excision repair (BER) pathway, enhances the action-at-a-distance mutations by GO. In this study, other DNA glycosylases, potential repair enzymes for the GO base, were knocked down, and their effects on the untargeted mutations were examined using the supF reporter gene. The knockdown of NEIL1 decreased such mutations, while those of NTH1, NEIL2, and NEIL3 had no effects. The double knockdown of OGG1 and NEIL1 additively affected the mutation frequency. These results indicated that NEIL1 is another BER protein involved in the action-at-a-distance mutations triggered by the oxidized guanine base.
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Affiliation(s)
- Yoshihiro Fujikawa
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Tetsuya Suzuki
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Hidehiko Kawai
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Hiroyuki Kamiya
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
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Jaruga P, Kant M, Dizdaroglu M. Production, Isolation, and Characterization of Stable Isotope-Labeled Standards for Mass Spectrometric Measurements of Oxidatively-Damaged Nucleosides in RNA. ACS OMEGA 2025; 10:1519-1530. [PMID: 39829548 PMCID: PMC11740632 DOI: 10.1021/acsomega.4c09310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/02/2024] [Accepted: 12/12/2024] [Indexed: 01/22/2025]
Abstract
RNA undergoes oxidatively induced damage in living organisms analogous to DNA. RNA is even more vulnerable to damage than DNA due to its greater abundance, single-strandedness, lack of repair and chromatin proteins shield, and instability, among other effects. RNA damage can adversely affect gene expression, leading to protein synthesis alterations, cell death, and other detrimental biological consequences. Growing indications suggest the involvement of oxidatively induced RNA damage in the pathogenesis of various human diseases, aging, and age-related diseases. Oxidatively induced damage can cause modifications to all four heterocyclic bases in RNA. Precise measurement of such modifications in RNA is essential for understanding the biological effects of oxidatively induced RNA damage. In the past, mass spectrometry has been used for this purpose. In mass spectrometric measurements, the use of stable isotope-labeled analogues of analytes as internal standards is essential for accurate quantifications. Past work utilized a stable isotope-labeled analogue of 8-hydroxyguanosine only as an internal standard. Thus, far, no stable isotope-labeled analogues of other oxidatively modified RNA nucleosides were available. In the present work, we report on the preparation, isolation, and characterization of the 13C- and 15N-labeled analogues of a variety of modified pyrimidine- and purine-derived RNA nucleosides. We also show the application of these internal standards for the measurement of oxidatively induced RNA damage in several commercially available RNA samples and in DNA along with DNA damage.
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Affiliation(s)
- Pawel Jaruga
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States
| | | | - Miral Dizdaroglu
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States
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Darwish IA, Zhang D, Al-Qaaneh AM, Alahmad W. A Prototype of Ultrasensitive Time-Resolved Fluoroimmunoassay with Enhanced Fluorescence System for the Trace Determination of Urinary 8-Hydroxy-2`-Deoxyguanosine, the DNA Oxidative Stress Biomarker. J Fluoresc 2025:10.1007/s10895-024-04099-5. [PMID: 39806235 DOI: 10.1007/s10895-024-04099-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 12/27/2024] [Indexed: 01/16/2025]
Abstract
This study presents a new highly sensitive and specific time-resolved fluoroimmunoassay (TRFIA) for the measurement of trace amounts of the urinary 8-hydroxy-2`-deoxyguanosine (8-OHdG) which is a biomarker for oxidative stress on DNA. The assay relied on a competitive binding approach and a mouse monoclonal antibody which recognized 8-OHdG with high specificity. In this assay, 8-OHdG conjugated with bovine serum albumin protein (8-OHdG-BSA) was employed as a solid phase antigen. The competition occurred between the 8-OHdG present in the sample solutions and the assay plate-coated 8-OHdG-BSA for a limited quantity of the anti-8-OHdG antibody labeled with a chelate of europium of ethylenediaminetetraacetic acid. The fluorescence signal of the europium chelate-labeled antibody was enhanced by a solution composed of thenoyltrifluoroacetone, trioctylphosphine oxide, and Triton X-100. The validation demonstrated a working range of 10-600 pg mL-1 and a limit of quantitation of 10 pg mL-1. When applied to urine samples, the assay exhibited satisfactory accuracy and precision in quantifying 8-OHdG. In summary, this study introduces the first TRFIA capable of detecting urinary levels of 8-OHdG at picogram levels. The assay outperforms existing analytical techniques for 8-OHdG in terms of sensitivity, convenience, and analysis throughput.
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Affiliation(s)
- Ibrahim A Darwish
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
| | - Daohong Zhang
- College of Food Engineering, Ludong University, Yantai, 264025, Shandong, China
| | - Ayman M Al-Qaaneh
- Department of Allied Health Sciences, Al-Balqa Applied University (BAU), Al-Salt, 19117, Jordan
| | - Waleed Alahmad
- Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Phayathai Road Pathumwan, 10330, Thailand
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Kamala KA, Sankethguddad S. P53 and Ki67 Biomarkers are Predictors for Malignant Transformation in Oral Submucous Fibrosis: A Prospective Study. Asian Pac J Cancer Prev 2024; 25:4129-4136. [PMID: 39733401 PMCID: PMC12008325 DOI: 10.31557/apjcp.2024.25.12.4129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 12/20/2024] [Indexed: 12/31/2024] Open
Abstract
OBJECTIVES Oral submucous fibrosis (OSMF) is a potentially malignant disorder (PMD) characterized by a high rate of malignant transformation (MT). OSMF exhibits atrophic epithelium yet has a high proliferation rate. Both p53 and Ki67 are nuclear proteins associated with cell proliferation, detectable in the early stages of oral cancer (OC). This study aimed to analyze the efficacy of p53 and Ki67 immuno-expression as tools for predicting malignant transformation in OSMF cases. The objective was to correlate the expression of p53 and Ki67 with demographic and chewing habits data. MATERIALS AND METHODS The study group consisted of 60 histopathologically diagnosed cases of OSMF, 60 cases of OC as positive controls, and 60 cases of NOM as negative controls. Immunohistochemistry was performed on neutral-buffered formalin-fixed, paraffin-embedded tissue sections of 3 μm thickness, using ready-to-use anti-human p53 protein (clone DO-7) and monoclonal antibody for Ki67 antigen (clone MIB-1). Statistical analysis was conducted using SPSS software version 21, employing the chi-square test (p < 0.05). RESULTS The expression of p53 and Ki67 was significantly higher in OSMF samples compared to NOM samples, but lower than in OC samples. When the expression levels of both p53 and Ki67 were correlated with demographic and chewing habits data, the results were statistically significant. CONCLUSION The overexpression of p53 and Ki67 may contribute to the progression of MT in OSM. Early detection of these biomarkers is crucial for preventing MT, which also helps reduce the morbidity and mortality of OC. Therefore, both p53 and Ki67 can serve as predictive biomarkers for the early detection of MT in high-risk OSMF patients.
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Affiliation(s)
- KA. Kamala
- Department of Oral Medicine and Radiology. School of Dental Sciences, KIMSDU, Karad, Pin code -415110, District- Satara, Maharashtra, India.
| | - S Sankethguddad
- Department of Periodontology, HKDET’S Dental College, Hospital and Reaserch Institute, Humnadad, Karnataka, India.
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Cadet J, Angelov D, Di Mascio P, Wagner JR. Contribution of oxidation reactions to photo-induced damage to cellular DNA. Photochem Photobiol 2024; 100:1157-1185. [PMID: 38970297 DOI: 10.1111/php.13990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/14/2024] [Accepted: 06/15/2024] [Indexed: 07/08/2024]
Abstract
This review article is aimed at providing updated information on the contribution of immediate and delayed oxidative reactions to the photo-induced damage to cellular DNA/skin under exposure to UVB/UVA radiations and visible light. Low-intensity UVC and UVB radiations that operate predominantly through direct excitation of the nucleobases are very poor oxidizing agents giving rise to very low amounts of 8-oxo-7,8-dihydroguanine and DNA strand breaks with respect to the overwhelming bipyrimidine dimeric photoproducts. The importance of these two classes of oxidatively generated damage to DNA significantly increases together with a smaller contribution of oxidized pyrimidine bases upon UVA irradiation. This is rationalized in terms of sensitized photooxidation reactions predominantly mediated by singlet oxygen together with a small contribution of hydroxyl radical that appear to also be implicated in the photodynamic effects of the blue light component of visible light. Chemiexcitation-mediated formation of "dark" cyclobutane pyrimidine dimers in UVA-irradiated melanocytes is a recent major discovery that implicates in the initial stage, a delayed generation of reactive oxygen and nitrogen species giving rise to triplet excited carbonyl intermediate and possibly singlet oxygen. High-intensity UVC nanosecond laser radiation constitutes a suitable source of light to generate pyrimidine and purine radical cations in cellular DNA via efficient biphotonic ionization.
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Affiliation(s)
- Jean Cadet
- Département de Médecine nucléaire et Radiobiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Dimitar Angelov
- Laboratoire de Biologie et de Modélisation de la Cellule LMBC, Ecole Normale Supérieure de Lyon, CNRS, Université de Lyon, Lyon, France
- Izmir Biomedicine and Genome Center IBG, Dokuz Eylul University, Balçova, Izmir, Turkey
| | - Paolo Di Mascio
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - J Richard Wagner
- Département de Médecine nucléaire et Radiobiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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8
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Ahmad MM, Hassan HA, Saadawy SF, Ahmad EA, Elsawy NAM, Morsy MM. Antox targeting AGE/RAGE cascades to restore submandibular gland viability in rat model of type 1 diabetes. Sci Rep 2024; 14:18160. [PMID: 39103403 PMCID: PMC11300852 DOI: 10.1038/s41598-024-68268-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 07/22/2024] [Indexed: 08/07/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic disorder of glucose metabolism that threatens several organs, including the submandibular (SMG) salivary glands. Antox (ANX) is a strong multivitamin with significant antioxidant benefits. The goal of this study was to demonstrate the beneficial roles of ANX supplementation in combination with insulin in alleviating diabetic SMG changes. For four weeks, 30 rats were divided into equal five groups (n = 6): (1) control group; (2) diabetic group (DM), with DM induced by streptozotocin (STZ) injection (50 mg/kg i.p.); (3) DM + ANX group: ANX was administrated (10 mg/kg/day/once daily/orally); (4) DM + insulin group: insulin was administrated 1U once/day/s.c.; and (5) DM + insulin + ANX group: co-administrated insulin. The addition of ANX to insulin in diabetic rats alleviated hyposalivation and histopathological alterations associated with diabetic rats. Remarkably, combined ANX and insulin exerted significant antioxidant effects, suppressing inflammatory and apoptotic pathways associated with increased salivary advanced glycation end-product (AGE) production and receptor for advanced glycation end-product expression (RAGE) activation in diabetic SMG tissues. Combined ANX and insulin administration in diabetic rats was more effective in alleviating SMG changes (functions and structures) than administration of insulin alone, exerting suppressive effects on AGE production and frustrating RAGE downstream pathways.
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Affiliation(s)
- Marwa M Ahmad
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| | - Heba A Hassan
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, 45519, Egypt
- Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, 61710, Jordan
| | - Sara F Saadawy
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Enssaf Ahmad Ahmad
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Manal Mohammad Morsy
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Ye X, Li Z, Ye S, Liang X, Bao C, He M, Wang H, Xia L, Cao X. Accurate identification of 8-oxoguanine in RNA with single-nucleotide resolution using ligase-dependent qPCR. Org Biomol Chem 2024; 22:5629-5635. [PMID: 38912549 DOI: 10.1039/d4ob00786g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2024]
Abstract
8-oxoguanine (o8G), a prevalent oxidative modification in RNA induced by reactive oxygen species (ROS), plays a pivotal role in regulating RNA functions. Accurate detection and quantification of o8G modifications is critical to understanding their biological significance and potential as disease biomarkers, but effective detection methods remain limited. Here, we have developed a highly specific T3 DNA ligase-dependent qPCR assay that exploits the enzyme's ability to discriminate o8G from guanine (G) with single-nucleotide resolution. This method can detect o8G in RNA at levels as low as 500 fM, with an up to 18-fold higher selectivity for discriminating o8G from G. By simulating oxidative stress conditions in SH-SY5Y and HS683 cell lines treated with rotenone, we successfully identified site-specific o8G modifications in key miRNAs associated with neuroprotective responses, including miR-124, let-7a and miR-29a. The developed assay holds significant promise for the practical identification of o8G, facilitating its potential for detailed studies of o8G dynamics in various biological contexts and diseases.
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Affiliation(s)
- Xidong Ye
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Zengguang Li
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Shangde Ye
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Xinqi Liang
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Chenyu Bao
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Mingyang He
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Hailan Wang
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Laixin Xia
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Xin Cao
- Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
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De Silva WGM, Sequeira VB, Yang C, Dixon KM, Holland AJA, Mason RS, Rybchyn MS. 1,25-Dihydroxyvitamin D 3 Suppresses UV-Induced Poly(ADP-Ribose) Levels in Primary Human Keratinocytes, as Detected by a Novel Whole-Cell ELISA. Int J Mol Sci 2024; 25:5583. [PMID: 38891771 PMCID: PMC11171802 DOI: 10.3390/ijms25115583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Photoprotective properties of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to reduce UV-induced DNA damage have been established in several studies. UV-induced DNA damage in skin such as single or double strand breaks is known to initiate several cellular mechanisms including activation of poly(ADP-ribose) (pADPr) polymerase-1 (PARP-1). DNA damage from UV also increases extracellular signal-related kinase (ERK) phosphorylation, which further increases PARP activity. PARP-1 functions by using cellular nicotinamide adenine dinucleotide (NAD+) to synthesise pADPr moieties and attach these to target proteins involved in DNA repair. Excessive PARP-1 activation following cellular stress such as UV irradiation may result in excessive levels of cellular pADPr. This can also have deleterious effects on cellular energy levels due to depletion of NAD+ to suboptimal levels. Since our previous work indicated that 1,25(OH)2D3 reduced UV-induced DNA damage in part through increased repair via increased energy availability, the current study investigated the effect of 1,25(OH)2D3 on UV-induced PARP-1 activity using a novel whole-cell enzyme- linked immunosorbent assay (ELISA) which quantified levels of the enzymatic product of PARP-1, pADPr. This whole cell assay used around 5000 cells per replicate measurement, which represents a 200-400-fold decrease in cell requirement compared to current commercial assays that measure in vitro pADPr levels. Using our assay, we observed that UV exposure significantly increased pADPr levels in human keratinocytes, while 1,25(OH)2D3 significantly reduced levels of UV-induced pADPr in primary human keratinocytes to a similar extent as a known PARP-1 inhibitor, 3-aminobenzamide (3AB). Further, both 1,25(OH)2D3 and 3AB as well as a peptide inhibitor of ERK-phosphorylation significantly reduced DNA damage in UV-exposed keratinocytes. The current findings support the proposal that reduction in pADPr levels may be critical for the function of 1,25(OH)2D3 in skin to reduce UV-induced DNA damage.
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Affiliation(s)
| | - Vanessa Bernadette Sequeira
- Department of Physiology, School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Chen Yang
- Department of Physiology, School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Katie Marie Dixon
- Department of Anatomy and Histology and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia;
| | - Andrew J. A. Holland
- Douglas Cohen Department of Paediatric Surgery, The Children’s Hospital at Westmead Clinical School, The Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Rebecca Sara Mason
- Department of Physiology, School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Mark Stephen Rybchyn
- Department of Physiology, School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
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Ramamurthy K, Priya PS, Murugan R, Arockiaraj J. Hues of risk: investigating genotoxicity and environmental impacts of azo textile dyes. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2024; 31:33190-33211. [PMID: 38676865 DOI: 10.1007/s11356-024-33444-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 04/19/2024] [Indexed: 04/29/2024]
Abstract
The textile industry, with its extensive use of dyes and chemicals, stands out as a significant source of water pollution. Exposure to certain textile dyes, such as azo dyes and their breakdown products like aromatic amines, has been associated with health concerns like skin sensitization, allergic reactions, and even cancer in humans. Annually, the worldwide production of synthetic dyes approximates 7 × 107 tons, of which the textile industry accounts for over 10,000 tons. Inefficient dyeing procedures result in the discharge of 15-50% of azo dyes, which do not adequately bind to fibers, into wastewater. This review delves into the genotoxic impact of azo dyes, prevalent in the textile industry, on aquatic ecosystems and human health. Examining different families of textile dye which contain azo group in their structure such as Sudan I and Sudan III Sudan IV, Basic Red 51, Basic Violet 14, Disperse Yellow 7, Congo Red, Acid Red 26, and Acid Blue 113 reveals their carcinogenic potential, which may affect both industrial workers and aquatic life. Genotoxic and carcinogenic characteristics, chromosomal abnormalities, induced physiological and neurobehavioral changes, and disruptions to spermatogenesis are evident, underscoring the harmful effects of these dyes. The review calls for comprehensive investigations into the toxic profile of azo dyes, providing essential insights to safeguard the aquatic ecosystem and human well-being. The importance of effective effluent treatment systems is underscored to mitigate adverse impacts on agricultural lands, water resources, and the environment, particularly in regions heavily reliant on wastewater irrigation for food production.
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Affiliation(s)
- Karthikeyan Ramamurthy
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulatur, 603203, Tamil Nadu, India
| | - Peter Snega Priya
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulatur, 603203, Tamil Nadu, India
| | - Raghul Murugan
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulatur, 603203, Tamil Nadu, India
| | - Jesu Arockiaraj
- Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulatur, 603203, Tamil Nadu, India.
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12
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Fukushima R, Suzuki T, Kobayakawa A, Kamiya H. Action-at-a-distance mutations induced by 8-oxo-7,8-dihydroguanine are dependent on APOBEC3. Mutagenesis 2024; 39:24-31. [PMID: 37471265 DOI: 10.1093/mutage/gead023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023] Open
Abstract
DNA oxidation is a serious threat to genome integrity and is involved in mutations and cancer initiation. The G base is most frequently damaged, and 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) is one of the predominant damaged bases. In human cells, GO causes a G:C→T:A transversion mutation at the modified site, and also induces untargeted substitution mutations at the G bases of 5'-GpA-3' dinucleotides (action-at-a-distance mutations). The 5'-GpA-3' sequences are complementary to the 5'-TpC-3' sequences, the preferred substrates for apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) cytosine deaminases, and thus their contribution to mutagenesis has been considered. In this study, APOBEC3B, the most abundant APOBEC3 protein in human U2OS cells, was knocked down in human U2OS cells, and a GO-shuttle plasmid was then transfected into the cells. The action-at-a-distance mutations were reduced to ~25% by the knockdown, indicating that GO-induced action-at-a-distance mutations are highly dependent on APOBEC3B in this cell line.
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Affiliation(s)
- Ruriko Fukushima
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Tetsuya Suzuki
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Akari Kobayakawa
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Hiroyuki Kamiya
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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13
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Ohno M, Takano N, Hidaka K, Sasaki F, Yamauchi K, Aoki Y, Nohmi T, Nakabeppu Y, Nakatsu Y, Tsuzuki T. Oxidative stress accelerates intestinal tumorigenesis by enhancing 8-oxoguanine-mediated mutagenesis in MUTYH-deficient mice. Genome Res 2024; 34:47-56. [PMID: 38290979 PMCID: PMC10904009 DOI: 10.1101/gr.278326.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 01/02/2024] [Indexed: 02/01/2024]
Abstract
Oxidative stress-induced DNA damage and its repair systems are related to cancer etiology; however, the molecular basis triggering tumorigenesis is not well understood. Here, we aimed to explore the causal relationship between oxidative stress, somatic mutations in pre-tumor-initiated normal tissues, and tumor incidence in the small intestines of MUTYH-proficient and MUTYH-deficient mice. MUTYH is a base excision repair enzyme associated with human colorectal cancer. Mice were administered different concentrations of potassium bromate (KBrO3; an oxidizing agent)-containing water for 4 wk for mutagenesis studies or 16 wk for tumorigenesis studies. All Mutyh -/- mice treated with >0.1% KBrO3 developed multiple tumors, and the average tumor number increased dose dependently. Somatic mutation analysis of Mutyh -/-/rpsL transgenic mice revealed that G:C > T:A transversion was the only mutation type correlated positively with KBrO3 dose and tumor incidence. These mutations preferentially occurred at 5'G in GG and GAA sequences in rpsL This characteristic mutation pattern was also observed in the genomic region of Mutyh -/- tumors using whole-exome sequencing. It closely corresponded to signature 18 and SBS36, typically caused by 8-oxo-guanine (8-oxoG). 8-oxoG-induced mutations were sequence context dependent, yielding a biased amino acid change leading to missense and stop-gain mutations. These mutations frequently occurred in critical amino acid codons of known cancer drivers, Apc or Ctnnb1, known for activating Wnt signal pathway. Our results indicate that oxidative stress contributes to increased tumor incidence by elevating the likelihood of gaining driver mutations by increasing 8-oxoG-mediated mutagenesis, particularly under MUTYH-deficient conditions.
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Affiliation(s)
- Mizuki Ohno
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan;
| | - Noriko Takano
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Kyoko Hidaka
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
- Center for Fundamental Education, The University of Kitakyushu, Kitakyushu, Fukuoka 802-8577, Japan
| | - Fumiko Sasaki
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Kazumi Yamauchi
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
- Department of Radiobiology, Institute for Environmental Sciences, Kamikita, Aomori 039-3212, Japan
| | - Yasunobu Aoki
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
| | - Takehiko Nohmi
- Division of Genetics and Mutagenesis, National Institute of Health Sciences, Kawasaki, Kanagawa 210-9501, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
- Japan Society for the Promotion of Science, San Francisco Office, Berkeley, California 94704, USA
| | - Yoshimichi Nakatsu
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
| | - Teruhisa Tsuzuki
- Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
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14
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Suzuki T, Yoshida S, Kamiya H. Inhibition of Uracil DNA Glycosylase Alters Frequency and Spectrum of Action-at-a-Distance Mutations Induced by 8-Oxo-7,8-dihydroguanine. Biol Pharm Bull 2024; 47:1275-1281. [PMID: 38987176 DOI: 10.1248/bpb.b24-00258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
The generation of DNA damage causes mutations and consequently cancer. Reactive oxygen species are important sources of DNA damage and some mutation signatures found in human cancers. 8-Oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine) is one of the most abundant oxidized bases and induces a G→T transversion mutation at the modified site. The damaged G base also causes untargeted base substitution mutations at the G bases of 5'-GpA-3' dinucleotides (action-at-a-distance mutations) in human cells, and the cytosine deaminase apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) is involved in the mutation process. The deaminated cytosine, i.e., uracil, bases are expected to be removed by uracil DNA glycosylase. Most of the substitution mutations at the G bases of 5'-GpA-3' might be caused by abasic sites formed by the glycosylase. In this study, we expressed the uracil DNA glycosylase inhibitor from Bacillus subtilis bacteriophage PBS2 in human U2OS cells and examined the effects on the GO-induced action-at-a-distance mutations. The inhibition of uracil DNA glycosylase increased the mutation frequency, and in particular, the frequency of G→A transitions. These results indicated that uracil DNA glycosylase, in addition to APOBEC3, is involved in the untargeted mutation process induced by GO.
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Affiliation(s)
- Tetsuya Suzuki
- Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Saho Yoshida
- Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Hiroyuki Kamiya
- Graduate School of Biomedical and Health Sciences, Hiroshima University
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15
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Chen YN, Chan YH, Shiau JP, Farooqi AA, Tang JY, Chen KL, Yen CY, Chang HW. The neddylation inhibitor MLN4924 inhibits proliferation and triggers apoptosis of oral cancer cells but not for normal cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:299-313. [PMID: 37705323 DOI: 10.1002/tox.23951] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/26/2023] [Accepted: 08/13/2023] [Indexed: 09/15/2023]
Abstract
Increased neddylation benefits the survival of several types of cancer cells. The inhibition of neddylation has the potential to exert anticancer effects but is rarely assessed in oral cancer cells. This study aimed to investigate the antiproliferation potential of a neddylation inhibitor MLN4924 (pevonedistat) for oral cancer cells. MLN4924 inhibited the cell viability of oral cancer cells more than that of normal oral cells (HGF-1) with 100% viability, that is, IC50 values of oral cancer cells (CAL 27, OC-2, and Ca9-22) are 1.8, 1.4, and 1.9 μM. MLN4924 caused apoptotic changes such as the subG1 accumulation, activation of annexin V, pancaspase, and caspases 3/8/9 of oral cancer cells at a greater rate than in normal oral cells. MLN4924 induced greater oxidative stress in oral cancer cells compared to normal cells by upregulating reactive oxygen species and mitochondrial superoxide and depleting the mitochondrial membrane potential and glutathione. In oral cancer cells, preferential inductions also occurred for DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine). Therefore, this investigation demonstrates that MLN4924 is a potential anti-oral-cancer agent showing preferential inhibition of apoptosis and promotion of DNA damage with fewer cytotoxic effects on normal cells.
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Affiliation(s)
- Yan-Ning Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Hsuan Chan
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jun-Ping Shiau
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Jen-Yang Tang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuan-Liang Chen
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Ching-Yu Yen
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan, Taiwan
- School of Dentistry, Taipei Medical University, Taipei, Taiwan
| | - Hsueh-Wei Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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16
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Jiang Y, Clavaguéra C, Indrajith S, Houée-Levin C, Berden G, Oomens J, Scuderi D. OH Radical-Induced Oxidation in Nucleosides and Nucleotides Unraveled by Tandem Mass Spectrometry and Infrared Multiple Photon Dissociation Spectroscopy. Chemphyschem 2023; 24:e202300534. [PMID: 37713246 DOI: 10.1002/cphc.202300534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 09/16/2023]
Abstract
OH⋅-induced oxidation products of DNA nucleosides and nucleotides have been structurally characterized by collision-induced dissociation tandem mass spectrometry (CID-MS2 ) and Infrared Multiple Photon Dissociation (IRMPD) spectroscopy. CID-MS2 results have shown that the addition of one oxygen atom occurs on the nucleobase moiety. The gas-phase geometries of +16 mass increment products of 2'-deoxyadenosine (dA(O)H+ ), 2'-deoxyadenosine 5'-monophosphate (dAMP(O)H+ ), 2'-deoxycytidine (dC(O)H+ ), and 2'-deoxycytidine 5'-monophosphate (dCMP(O)H+ ) are extensively investigated by IRMPD spectroscopy and quantum-chemical calculations. We show that a carbonyl group is formed at the C8 position after oxidation of 2'-deoxyadenosine and its monophosphate derivative. For 2'-deoxycytidine and its monophosphate derivative, the oxygen atom is added to the C5 position to form a C-OH group. IRMPD spectroscopy has been employed for the first time to provide direct structural information on oxidative lesions in DNA model systems.
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Affiliation(s)
- Yining Jiang
- Université Paris-Saclay, CNRS, Institut de Chimie Physique, 91405, Orsay, France
| | - Carine Clavaguéra
- Université Paris-Saclay, CNRS, Institut de Chimie Physique, 91405, Orsay, France
| | - Suvasthika Indrajith
- Stockholm University, Roslagstullsbacken 21 C, plan 4, Albano, Fysikum, 106 91, Stockholm, Sweden
| | - Chantal Houée-Levin
- Université Paris-Saclay, CNRS, Institut de Chimie Physique, 91405, Orsay, France
| | - Giel Berden
- Radboud University, Institute for Molecules and Materials, FELIX Laboratory, Toernooiveld 7, Nijmegen, 6525 ED, The Netherlands
| | - Jos Oomens
- Radboud University, Institute for Molecules and Materials, FELIX Laboratory, Toernooiveld 7, Nijmegen, 6525 ED, The Netherlands
- Van't Hoff Institute for Molecular Sciences, University of Amsterdam, P.O. Box, 94157, Amsterdam, 1090 GD, The Netherlands
| | - Debora Scuderi
- Université Paris-Saclay, CNRS, Institut de Chimie Physique, 91405, Orsay, France
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17
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Krasuska U, Wal A, Staszek P, Ciacka K, Gniazdowska A. Do Reactive Oxygen and Nitrogen Species Have a Similar Effect on Digestive Processes in Carnivorous Nepenthes Plants and Humans? BIOLOGY 2023; 12:1356. [PMID: 37887066 PMCID: PMC10604543 DOI: 10.3390/biology12101356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 10/28/2023]
Abstract
Carnivorous plants attract animals, trap and kill them, and absorb nutrients from the digested bodies. This unusual (for autotrophs) type of nutrient acquisition evolved through the conversion of photosynthetically active leaves into specialised organs commonly called traps. The genus Nepenthes (pitcher plants) consists of approximately 169 species belonging to the group of carnivorous plants. Pitcher plants are characterised by specialised passive traps filled with a digestive fluid. The digestion that occurs inside the traps of carnivorous plants depends on the activities of many enzymes. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) also participate in the digestive process, but their action is poorly recognised. ROS and RNS, named together as RONS, exhibit concentration-dependent bimodal functions (toxic or signalling). They act as antimicrobial agents, participate in protein modification, and are components of signal transduction cascades. In the human stomach, ROS are considered as the cause of different diseases. RNS have multifaceted functions in the gastrointestinal tract, with both positive and negative impacts on digestion. This review describes the documented and potential impacts of RONS on the digestion in pitcher plant traps, which may be considered as an external stomach.
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Affiliation(s)
| | - Agnieszka Wal
- Department of Plant Physiology, Institute of Biology, Warsaw University of Life Sciences-SGGW, 02-776 Warsaw, Poland; (U.K.); (P.S.); (K.C.); (A.G.)
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18
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Andrés CMC, de la Lastra JMP, Juan CA, Plou FJ, Pérez-Lebeña E. Chemical Insights into Oxidative and Nitrative Modifications of DNA. Int J Mol Sci 2023; 24:15240. [PMID: 37894920 PMCID: PMC10607741 DOI: 10.3390/ijms242015240] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
This review focuses on DNA damage caused by a variety of oxidizing, alkylating, and nitrating species, and it may play an important role in the pathophysiology of inflammation, cancer, and degenerative diseases. Infection and chronic inflammation have been recognized as important factors in carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from inflammatory and epithelial cells, and result in the formation of oxidative and nitrative DNA lesions, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine. Cellular DNA is continuously exposed to a very high level of genotoxic stress caused by physical, chemical, and biological agents, with an estimated 10,000 modifications occurring every hour in the genetic material of each of our cells. This review highlights recent developments in the chemical biology and toxicology of 2'-deoxyribose oxidation products in DNA.
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Affiliation(s)
| | - José Manuel Pérez de la Lastra
- Institute of Natural Products and Agrobiology, CSIC-Spanish Research Council, Avda. AstrofísicoFco. Sánchez, 3, 38206 La Laguna, Spain
| | - Celia Andrés Juan
- Cinquima Institute and Department of Organic Chemistry, Faculty of Sciences, Valladolid University, Paseo de Belén, 7, 47011 Valladolid, Spain;
| | - Francisco J. Plou
- Institute of Catalysis and Petrochemistry, CSIC-Spanish Research Council, 28049 Madrid, Spain;
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19
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Montes M, Huarte M. 8G modifications rewire tumoral microRNAs. Nat Cell Biol 2023; 25:1243-1244. [PMID: 37696948 DOI: 10.1038/s41556-023-01179-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Affiliation(s)
- Marta Montes
- DNA and RNA Medicine Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdISNA), Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Maite Huarte
- DNA and RNA Medicine Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
- Instituto de Investigación Sanitaria de Navarra (IdISNA), Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain.
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20
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Eom S, Peak J, Park J, Ahn SH, Cho YK, Jeong Y, Lee HS, Lee J, Ignatova E, Lee SE, Hong Y, Gu D, Kim GWD, Lee DC, Hahm JY, Jeong J, Choi D, Jang ES, Chi SW. Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development. Nat Cell Biol 2023; 25:1369-1383. [PMID: 37696949 DOI: 10.1038/s41556-023-01209-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 07/19/2023] [Indexed: 09/13/2023]
Abstract
Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o8G) can change RNA-RNA interactions via o8G•A base pairing, but its regulatory roles remain elusive. Here, on the basis of o8G-induced guanine-to-thymine (o8G > T) variations featured in sequencing, we discovered widespread position-specific o8Gs in tumour microRNAs, preferentially oxidized towards 5' end seed regions (positions 2-8) with clustered sequence patterns and clinically associated with patients in lower-grade gliomas and liver hepatocellular carcinoma. We validated that o8G at position 4 of miR-124 (4o8G-miR-124) and 4o8G-let-7 suppress lower-grade gliomas, whereas 3o8G-miR-122 and 4o8G-let-7 promote malignancy of liver hepatocellular carcinoma by redirecting the target transcriptome to oncogenic regulatory pathways. Stepwise oxidation from tumour-promoting 3o8G-miR-122 to tumour-suppressing 2,3o8G-miR-122 occurs and its specific modulation in mouse liver effectively attenuates diethylnitrosamine-induced hepatocarcinogenesis. These findings provide resources and insights into epitranscriptional o8G regulation of microRNA functions, reprogrammed by redox changes, implicating its control for cancer treatment.
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Affiliation(s)
- Sangkyeong Eom
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Jongjin Peak
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Jongyeun Park
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Seung Hyun Ahn
- Department of Life Sciences, Korea University, Seoul, Korea
| | - You Kyung Cho
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Yeahji Jeong
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Hye-Sook Lee
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Jung Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea
| | | | - Sung Eun Lee
- Department of Life Sciences, Korea University, Seoul, Korea
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Yunji Hong
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Dowoon Gu
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Geun-Woo D Kim
- Department of Life Sciences, Korea University, Seoul, Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea
| | - Dong Chan Lee
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Ja Young Hahm
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Jaemin Jeong
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Eun-Sook Jang
- Department of Life Sciences, Korea University, Seoul, Korea
| | - Sung Wook Chi
- Department of Life Sciences, Korea University, Seoul, Korea.
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea.
- Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, Korea.
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21
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Ding Y, Gui X, Chu X, Sun Y, Zhang S, Tong H, Ju W, Li Y, Sun Z, Xu M, Li Z, Andrews RK, Gardiner EE, Zeng L, Xu K, Qiao J. MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis. Nat Commun 2023; 14:4829. [PMID: 37563135 PMCID: PMC10415391 DOI: 10.1038/s41467-023-40600-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collagen-related peptide (CRP) along with decreased mitochondrial ATP production. Thrombin but not CRP induced Ca2+-dependent mitochondria reactive oxygen species generation. Mechanistically, MTH1 deficiency caused mitochondrial DNA oxidative damage and reduced the expression of cytochrome c oxidase 1. Furthermore, MTH1 exerts a similar role in human platelet function. Our study suggests that MTH1 exerts a protective function against oxidative stress in platelets and indicates that MTH1 could be a potential therapeutic target for the prevention of thrombotic diseases.
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Affiliation(s)
- Yangyang Ding
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Xiang Gui
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Xiang Chu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Yueyue Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Sixuan Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Huan Tong
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Yue Li
- School of Medical Technology, Xuzhou Medical University, Xuzhou, China
| | - Zengtian Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Mengdi Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China
| | - Robert K Andrews
- Division of Genome Science and Cancer, John Curtin School of Medical Research, Australian National University, Canberra, Australia
| | - Elizabeth E Gardiner
- Division of Genome Science and Cancer, John Curtin School of Medical Research, Australian National University, Canberra, Australia
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China.
- School of Medical Technology, Xuzhou Medical University, Xuzhou, China.
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China.
| | - Jianlin Qiao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
- Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu Province, China.
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22
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De Silva WGM, McCarthy BY, Han J, Yang C, Holland AJA, Stern H, Dixon KM, Tang EKY, Tuckey RC, Rybchyn MS, Mason RS. The Over-Irradiation Metabolite Derivative, 24-Hydroxylumister-ol 3, Reduces UV-Induced Damage in Skin. Metabolites 2023; 13:775. [PMID: 37512482 PMCID: PMC10383208 DOI: 10.3390/metabo13070775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 07/30/2023] Open
Abstract
The hormonal form of vitamin D3, 1,25(OH)2D3, reduces UV-induced DNA damage. UV exposure initiates pre-vitamin D3 production in the skin, and continued UV exposure photoisomerizes pre-vitamin D3 to produce "over-irradiation products" such as lumisterol3 (L3). Cytochrome P450 side-chain cleavage enzyme (CYP11A1) in skin catalyzes the conversion of L3 to produce three main derivatives: 24-hydroxy-L3 [24(OH)L3], 22-hydroxy-L3 [22(OH)L3], and 20,22-dihydroxy-L3 [20,22(OH)L3]. The current study investigated the photoprotective properties of the major over-irradiation metabolite, 24(OH)L3, in human primary keratinocytes and human skin explants. The results indicated that treatment immediately after UV with either 24(OH)L3 or 1,25(OH)2D3 reduced UV-induced cyclobutane pyrimidine dimers and oxidative DNA damage, with similar concentration response curves in keratinocytes, although in skin explants, 1,25(OH)2D3 was more potent. The reductions in DNA damage by both compounds were, at least in part, the result of increased DNA repair through increased energy availability via increased glycolysis, as well as increased DNA damage recognition proteins in the nucleotide excision repair pathway. Reductions in UV-induced DNA photolesions by either compound occurred in the presence of lower reactive oxygen species. The results indicated that under in vitro and ex vivo conditions, 24(OH)L3 provided photoprotection against UV damage similar to that of 1,25(OH)2D3.
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Affiliation(s)
| | - Bianca Yuko McCarthy
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Jeremy Han
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Chen Yang
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Andrew J A Holland
- Douglas Cohen Department of Paediatric Surgery, The Children's Hospital at Westmead Clinical School, The Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Harvey Stern
- Department of Plastic and Constructive Surgery, The Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
- Strathfield Private Hospital, Sydney, NSW 2042, Australia
| | - Katie Marie Dixon
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Edith Kai Yan Tang
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Robert Charles Tuckey
- School of Molecular Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Mark Stephen Rybchyn
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Rebecca Sara Mason
- School of Medical Sciences and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
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23
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Nishi R, Harada A, Hori K, Maeda S, Momoi Y, Yonezawa T. 8-Hydroxy-2'-deoxyguanosine and malondialdehyde in plasma and their association with disease severity in 20 cats with chronic kidney disease. J Feline Med Surg 2023; 25:1098612X231173519. [PMID: 37318844 PMCID: PMC10811979 DOI: 10.1177/1098612x231173519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
OBJECTIVES Oxidative stress is associated with the development and progression of chronic kidney disease (CKD) in humans. The aim of this study was to evaluate the concentrations of oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA), in the plasma and urine of cats with different stages of CKD. METHODS Plasma and urine samples were collected from cats with CKD that were referred to the Veterinary Medical Center of the University of Tokyo between April 2019 and October 2022. Plasma and urine samples were collected from healthy cats (n = 6 at most), cats with stage 2 CKD (n = 8) and stage 3-4 CKD (n = 12), and cats with idiopathic cystitis (disease control, n = 5). Plasma and urine concentrations of 8-OHdG and MDA were measured using ELISA and thiobarbituric acid reactive substances assay kits, respectively. RESULTS The median plasma 8-OHdG concentrations were 0.156 ng/ml (<0.125-0.210 ng/ml) in the healthy group, <0.125 ng/ml (range <0.125 ng/ml) in the idiopathic cystitis group, 0.246 ng/ml (range 0.170-0.403 ng/ml) in cats with stage 2 CKD and 0.433 ng/ml (range 0.209-1.052 ng/ml) in cats with stage 3-4 CKD. Concentrations in stage 3-4 CKD were significantly higher than those in the healthy and disease control groups. Plasma MDA concentrations were low in the healthy and disease control groups and significantly higher in cats with stage 3-4 CKD. In every cat with CKD, plasma 8-OHdG and MDA concentrations were positively correlated with plasma creatinine concentrations (8-OHdG, rs = 0.68; MDA, rs = 0.67). Urinary 8-OHdG/urinary creatinine (u-CRE) and urinary MDA/u-CRE levels did not differ significantly between the groups; however, it was difficult to evaluate them because of the small sample size. CONCLUSIONS AND RELEVANCE This report shows that plasma 8-OHdG and MDA concentrations increase with the severity of feline CKD. These markers may be useful for assessing oxidative stress in cats with CKD.
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Affiliation(s)
- Reo Nishi
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Airi Harada
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Koji Hori
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Shingo Maeda
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Yasuyuki Momoi
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Tomohiro Yonezawa
- Department of Veterinary Clinical Pathobiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
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24
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Wang Q, Qi H, Wu Y, Yu L, Bouchareb R, Li S, Lassén E, Casalena G, Stadler K, Ebefors K, Yi Z, Shi S, Salem F, Gordon R, Lu L, Williams RW, Duffield J, Zhang W, Itan Y, Böttinger E, Daehn I. Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR. Nat Metab 2023; 5:607-625. [PMID: 37024752 PMCID: PMC10821741 DOI: 10.1038/s42255-023-00776-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/07/2023] [Indexed: 04/08/2023]
Abstract
The lifetime risk of kidney disease in people with diabetes is 10-30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we identify an expression quantitative trait loci (QTLs) in the cis-acting regulatory region of the xanthine dehydrogenase, or xanthine oxidoreductase (Xor), a binding site for C/EBPβ, to be associated with diabetes-induced podocyte loss in DKD in male mice. We examine mouse inbred strains that are susceptible (DBA/2J) and resistant (C57BL/6J) to DKD, as well as a panel of recombinant inbred BXD mice, to map QTLs. We also uncover promoter XOR orthologue variants in humans associated with high risk of DKD. We introduced the risk variant into the 5'-regulatory region of XOR in DKD-resistant mice, which resulted in increased Xor activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium, which increase further with type 1 diabetes, high-fat diet and ageing. Therefore, differential regulation of Xor contributes to phenotypic consequences with diabetes and ageing.
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Affiliation(s)
- Qin Wang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pharmacy, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Haiying Qi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yiming Wu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Liping Yu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rihab Bouchareb
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shuyu Li
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emelie Lassén
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gabriella Casalena
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Krisztian Stadler
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Kerstin Ebefors
- Department of Neuroscience and Physiology, Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Zhengzi Yi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shaolin Shi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fadi Salem
- Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ronald Gordon
- Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Robert W Williams
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuval Itan
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Erwin Böttinger
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Hasso Plattner Institute for Digital Heath at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Digital Health Center, Hasso Plattner Institut, University of Potsdam, Potsdam, Germany
| | - Ilse Daehn
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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25
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Li J, Zhang H, Wang ZH, Li YX, Zhang LQ, Cui J, Li DN, Wang ZH, Liu Q, Liu Z, Iwakuma T, Cai JP. 8-oxo-dGTP curbs tumor development via S phase arrest and AIF-mediated apoptosis. Free Radic Biol Med 2023; 196:53-64. [PMID: 36640852 DOI: 10.1016/j.freeradbiomed.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/19/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1-knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1-knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development.
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Affiliation(s)
- Jin Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China
| | - He Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, PR China
| | - Zhen-He Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China
| | - Yun-Xuan Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China
| | - Li-Qun Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China
| | - Dan-Ni Li
- Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
| | - Zi-Hui Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China
| | - Qian Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China
| | - Zhen Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China
| | - Tomoo Iwakuma
- Children's Mercy Research Institute, Kansas City, MO, 64108, USA
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, PR China.
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26
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Li C, Xue Y, Ba X, Wang R. The Role of 8-oxoG Repair Systems in Tumorigenesis and Cancer Therapy. Cells 2022; 11:cells11233798. [PMID: 36497058 PMCID: PMC9735852 DOI: 10.3390/cells11233798] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/09/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
Tumorigenesis is highly correlated with the accumulation of mutations. The abundant and extensive DNA oxidation product, 8-Oxoguanine (8-oxoG), can cause mutations if it is not repaired by 8-oxoG repair systems. Therefore, the accumulation of 8-oxoG plays an essential role in tumorigenesis. To avoid the accumulation of 8-oxoG in the genome, base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase1 (OGG1), is responsible for the removal of genomic 8-oxoG. It has been proven that 8-oxoG levels are significantly elevated in cancer cells compared with cells of normal tissues, and the induction of DNA damage by some antitumor drugs involves direct or indirect interference with BER, especially through inducing the production and accumulation of reactive oxygen species (ROS), which can lead to tumor cell death. In addition, the absence of the core components of BER can result in embryonic or early post-natal lethality in mice. Therefore, targeting 8-oxoG repair systems with inhibitors is a promising avenue for tumor therapy. In this study, we summarize the impact of 8-oxoG accumulation on tumorigenesis and the current status of cancer therapy approaches exploiting 8-oxoG repair enzyme targeting, as well as possible synergistic lethality strategies involving exogenous ROS-inducing agents.
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Affiliation(s)
- Chunshuang Li
- Center for Cell Structure and Function, Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, China
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun 130024, China
| | - Yaoyao Xue
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun 130024, China
| | - Xueqing Ba
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun 130024, China
- Correspondence: (X.B.); (R.W.)
| | - Ruoxi Wang
- Center for Cell Structure and Function, Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Sciences, Shandong Normal University, Jinan 250014, China
- Correspondence: (X.B.); (R.W.)
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27
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Hahm JY, Park J, Jang ES, Chi SW. 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification. Exp Mol Med 2022; 54:1626-1642. [PMID: 36266447 PMCID: PMC9636213 DOI: 10.1038/s12276-022-00822-z] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/06/2022] [Accepted: 05/26/2022] [Indexed: 12/29/2022] Open
Abstract
In pathophysiology, reactive oxygen species control diverse cellular phenotypes by oxidizing biomolecules. Among these, the guanine base in nucleic acids is the most vulnerable to producing 8-oxoguanine, which can pair with adenine. Because of this feature, 8-oxoguanine in DNA (8-oxo-dG) induces a G > T (C > A) mutation in cancers, which can be deleterious and thus actively repaired by DNA repair pathways. 8-Oxoguanine in RNA (o8G) causes problems in aberrant quality and translational fidelity, thereby it is subjected to the RNA decay pathway. In addition to oxidative damage, 8-oxo-dG serves as an epigenetic modification that affects transcriptional regulatory elements and other epigenetic modifications. With the ability of o8G•A in base pairing, o8G alters structural and functional RNA-RNA interactions, enabling redirection of posttranscriptional regulation. Here, we address the production, regulation, and function of 8-oxo-dG and o8G under oxidative stress. Primarily, we focus on the epigenetic and epitranscriptional roles of 8-oxoguanine, which highlights the significance of oxidative modification in redox-mediated control of gene expression.
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Affiliation(s)
- Ja Young Hahm
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Jongyeun Park
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Eun-Sook Jang
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Sung Wook Chi
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02481 Republic of Korea
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28
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Lodato MA, Ziegenfuss JS. The two faces of DNA oxidation in genomic and functional mosaicism during aging in human neurons. FRONTIERS IN AGING 2022; 3:991460. [PMID: 36313183 PMCID: PMC9596766 DOI: 10.3389/fragi.2022.991460] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
Abstract
Maintaining genomic integrity in post-mitotic neurons in the human brain is paramount because these cells must survive for an individual's entire lifespan. Due to life-long synaptic plasticity and electrochemical transmission between cells, the brain engages in an exceptionally high level of mitochondrial metabolic activity. This activity results in the generation of reactive oxygen species with 8-oxo-7,8-dihydroguanine (8-oxoG) being one of the most prevalent oxidation products in the cell. 8-oxoG is important for the maintenance and transfer of genetic information into proper gene expression: a low basal level of 8-oxoG plays an important role in epigenetic modulation of neurodevelopment and synaptic plasticity, while a dysregulated increase in 8-oxoG damages the genome leading to somatic mutations and transcription errors. The slow yet persistent accumulation of DNA damage in the background of increasing cellular 8-oxoG is associated with normal aging as well as neurological disorders such as Alzheimer's disease and Parkinson's disease. This review explores the current understanding of how 8-oxoG plays a role in brain function and genomic instability, highlighting new methods being used to advance pathological hallmarks that differentiate normal healthy aging and neurodegenerative disease.
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Affiliation(s)
- Michael A. Lodato
- University of Massachusetts Chan Medical School, Worcester, MA, United States
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29
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Liu F, Last KS, Henry TB, Reinardy HC. Interspecific differences in oxidative DNA damage after hydrogen peroxide exposure of sea urchin coelomocytes. Mutagenesis 2022; 38:13-20. [PMID: 36130095 PMCID: PMC9897020 DOI: 10.1093/mutage/geac018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Interspecific comparison of DNA damage can provide information on the relative vulnerability of marine organisms to toxicants that induce oxidative genotoxicity. Hydrogen peroxide (H2O2) is an oxidative toxicant that causes DNA strand breaks and nucleotide oxidation and is used in multiple industries including Atlantic salmon aquaculture to treat infestations of ectoparasitic sea lice. H2O2 (up to 100 mM) can be released into the water after sea lice treatment, with potential consequences of exposure in nontarget marine organisms. The objective of the current study was to measure and compare differences in levels of H2O2-induced oxidative DNA damage in coelomocytes from Scottish sea urchins Echinus esculentus, Paracentrotus lividus, and Psammechinus miliaris. Coelomocytes were exposed to H2O2 (0-50 mM) for 10 min, cell concentration and viability were quantified, and DNA damage was measured by the fast micromethod, an alkaline unwinding DNA method, and the modified fast micromethod with nucleotide-specific enzymes. Cell viability was >92% in all exposures and did not differ from controls. Psammechinus miliaris coelomocytes had the highest oxidative DNA damage with 0.07 ± 0.01, 0.08 ± 0.01, and 0.07 ± 0.01 strand scission factors (mean ± SD) after incubation with phosphate-buffered saline, formamidopyrimidine-DNA glycosylase, and endonuclease-III, respectively, at 50 mM H2O2. Exposures to 0.5 mM H2O2 (100-fold dilution from recommended lice treatment concentration) induced oxidative DNA damage in all three species of sea urchins, suggesting interspecific differences in vulnerabilities to DNA damage and/or DNA repair mechanisms. Understanding impacts of environmental genotoxicants requires understanding species-specific susceptibilities to DNA damage, which can impact long-term stability in sea urchin populations in proximity to aquaculture farms.
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Affiliation(s)
- Fengjia Liu
- The Scottish Association for Marine Science, Oban, United Kingdom
| | - Kim S Last
- The Scottish Association for Marine Science, Oban, United Kingdom
| | - Theodore B Henry
- Institute of Earth and Life Sciences, School of Energy, Geoscience, Infrastructure and Society, Heriot-Watt University, Edinburgh, United Kingdom,Center for Environmental Biotechnology, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Helena C Reinardy
- Corresponding author. Scottish Association for Marine Science, Oban, Argyll PA37 1QA, UK. E-mail: ;
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30
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Zhao Q, Chen S, Wang G, Du Y, Zhang Z, Yu G, Ren C, Zhang Y, Du J. Exogenous melatonin enhances soybean (Glycine max (L.) Merr.) seedling tolerance to saline-alkali stress by regulating antioxidant response and DNA damage repair. PHYSIOLOGIA PLANTARUM 2022; 174:e13731. [PMID: 35717632 DOI: 10.1111/ppl.13731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/13/2022] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
Saline-alkali (SA) stress induces excessive reactive oxygen species (ROS) accumulation in plant cells, resulting in oxidative damages of membranes, lipids, proteins, and nucleic acids. Melatonin has antioxidant protection effects in living organisms and thus has received a lot of attention. This study aimed to investigate the effect and regulating mechanism of melatonin treatment on soybean tolerance to SA stress. In this study, cultivars Heihe 49 (HH49, SA-tolerant) and Henong 95 (HN95, SA-sensitive) were pot-cultured in SA soil, then treated with MT (0-300 μM) at V1 stage. SA stress induced ROS accumulation and DNA damage in the seedling roots of both cultivars, causing G1/S arrest in HN95 and G2/M arrest in HH49. Melatonin treatment enhanced the activity of antioxidant enzymes in soybean seedling roots and reduced ROS accumulation. Additionally, melatonin treatment upregulated DNA damage repair genes, thus enhancing the reduction of DNA oxidative damage under SA stress. The effects of melatonin treatment were manifested as decreased RAPD polymorphism, 8-hydroxy-2'-deoxyguanine (8-OH-dG) level, and relative density of apurinic sites (AP-sites). Meanwhile, melatonin treatment partially alleviated the SA-induced G1/S arrest in HN95 and G2/M arrest in HH49, thus enhancing soybean seedling tolerance to SA stress.
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Affiliation(s)
- Qiang Zhao
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Suyu Chen
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Guangda Wang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Yanli Du
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Zhaoning Zhang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Gaobo Yu
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Chunyuan Ren
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Yuxian Zhang
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
| | - Jidao Du
- Heilongjiang Bayi Agricultural University, Key Laboratory of Ministry of Agriculture and Rural Affairs of Soybean Mechanized Production, Daqing, People's Republic of China
- Research Center of Saline and Alkali Land Improvement Engineering Technology in Heilongjiang Province, Daqing, People's Republic of China
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Thredgold L, Ramkissoon C, Kumarasamy C, Gun R, Rowett S, Gaskin S. Rapid Assessment of Oxidative Damage Potential: A Comparative Study of Engineered Stone Dusts Using a Deoxyguanosine Assay. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:6221. [PMID: 35627757 PMCID: PMC9140999 DOI: 10.3390/ijerph19106221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/09/2022] [Accepted: 05/16/2022] [Indexed: 11/21/2022]
Abstract
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.
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Affiliation(s)
- Leigh Thredgold
- Adelaide Exposure Science and Health, School of Public Health, University of Adelaide, Adelaide, SA 5005, Australia; (L.T.); (C.R.); (C.K.); (R.G.)
| | - Chandnee Ramkissoon
- Adelaide Exposure Science and Health, School of Public Health, University of Adelaide, Adelaide, SA 5005, Australia; (L.T.); (C.R.); (C.K.); (R.G.)
| | - Chellan Kumarasamy
- Adelaide Exposure Science and Health, School of Public Health, University of Adelaide, Adelaide, SA 5005, Australia; (L.T.); (C.R.); (C.K.); (R.G.)
| | - Richard Gun
- Adelaide Exposure Science and Health, School of Public Health, University of Adelaide, Adelaide, SA 5005, Australia; (L.T.); (C.R.); (C.K.); (R.G.)
| | - Shelley Rowett
- SafeWork SA, Government of South Australia, Adelaide, SA 5035, Australia;
| | - Sharyn Gaskin
- Adelaide Exposure Science and Health, School of Public Health, University of Adelaide, Adelaide, SA 5005, Australia; (L.T.); (C.R.); (C.K.); (R.G.)
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Cadet J, Angelov D, Wagner JR. Hydroxyl radical is predominantly involved in oxidatively generated base damage to cellular DNA exposed to ionizing radiation. Int J Radiat Biol 2022; 98:1684-1690. [PMID: 35475423 DOI: 10.1080/09553002.2022.2067363] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/29/2022] [Accepted: 04/06/2022] [Indexed: 12/28/2022]
Affiliation(s)
- Jean Cadet
- Département de Médecine Nucléaire et Radiobiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada
| | - Dimitar Angelov
- Laboratoire de Biologie et de Modélisation de la Cellule LBMC, Ecole Normale Supérieure de Lyon, CNRS, Université de Lyon, Lyon, France
- Izmir Biomedicine and Genome Center IBG, Dokuz Eylul University Health Campus, Balçova, Izmir, Turkey
| | - J Richard Wagner
- Département de Médecine Nucléaire et Radiobiologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Canada
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Chitosan Oligosaccharides Alleviate H2O2-stimulated Granulosa Cell Damage via HIF-1α Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4247042. [PMID: 35401926 PMCID: PMC8993563 DOI: 10.1155/2022/4247042] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/02/2022] [Accepted: 03/02/2022] [Indexed: 12/23/2022]
Abstract
Oocyte maturation disorder and decreased quality are the main causes of infertility in women, and granulosa cells (GCs) provide the only microenvironment for oocyte maturation through autocrine and paracrine signaling by steroid hormones and growth factors. However, chronic inflammation and oxidative stress caused by ovarian hypoxia are the largest contributors to ovarian aging and GC dysfunction. Therefore, the amelioration of chronic inflammation and oxidative stress is expected to be a pivotal method to improve GC function and oocyte quality. In this study, we detected the protective effect of chitosan oligosaccharides (COS), on hydrogen peroxide- (H2O2-) stimulated oxidative damage in a human ovarian granulosa cell line (KGN). COS significantly increased cell viability, mitochondrial function, and the cellular glutathione (GSH) content and reduced apoptosis, reactive oxygen species (ROS) content, and the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial-derived growth factor (VEGF) in H2O2-stimulated KGN cells. COS treatment significantly increased levels of the TGF-β1 and IL-10 proteins and decreased levels of the IL-6 protein. Compared with H2O2-stimulated KGN cells, COS significantly increased the levels of E2 and P4 and decreased SA-β-gal protein expression. Furthermore, COS caused significant inactivation of the HIF-1α-VEGF pathway in H2O2-stimulated KGN cells. Moreover, inhibition of this pathway enhanced the inhibitory effects of COS on H2O2-stimulated oxidative injury and apoptosis in GCs. Thus, COS protected GCs from H2O2-stimulated oxidative damage and apoptosis by inactivating the HIF-1α-VEGF signaling pathway. In the future, COS might represent a therapeutic approach for ameliorating disrupted follicle development.
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Lin R, Zhou S, Zhao H, Lin H, Wang L, Hu W, Gao H, Qiu B. A novel signal enhancement strategy for the detection of DNA oxidative damage biomarker 8-OHdG based on the synergy between β-CD-CuNCs and multi-walled carbon nanotubes. Am J Transl Res 2022; 14:740-751. [PMID: 35273682 PMCID: PMC8902525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 12/29/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To propose a novel signal enhancement strategy based on the synergy between β-CD-CuNCs and multi-walled carbon nanotubes (MWCNTs) for the detection of DNA oxidative damage biomarker 8-Hydroxy-2'-deoxyguanosine (8-OHdG). METHODS The sensor was constructed with the β-CD-CuNCs-MWCNTs-nafion film and successfully used for the quantitative detection of 8-OhdG in the presence of biomolecules such as ascorbic acid (AA) and uric acid (UA). To investigate the surface morphology of the modified electrode, Transmission Electron Microscopy (TEM), Cyclic Voltammetry (CV) and Electrochemical Impedance Spectroscopy (EIS) were performed on bare and modified electrodes. RESULTS According to Differential Pulse Voltammetry (DPV) results, there was a linear relationship between peak current and concentration of 8-OhdG, ranging from 1.0×10-7 to 1.0×10-6 mol/L (R2=0.9926) and 1.0×10-6 to 2.0×10-5 mol/L (R2=0.9933). The detection limit (S/N=3) was 33 nmol/L. CONCLUSIONS The proposed sensor had been successfully applied to the determination of 8-OHdG in human urine samples with high recovery rates.
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Affiliation(s)
- Ruoting Lin
- Department of Neurology, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Shuang Zhou
- Clinical Center of Molecular Diagnosis and Therapy, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Huanan Zhao
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, Fuzhou UniversityFuzhou 350108, Fujian, China
| | - Huasong Lin
- Department of Neurology, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Lixing Wang
- Clinical Center of Molecular Diagnosis and Therapy, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Weipeng Hu
- Department of Neurosurgery, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Hongzhi Gao
- Clinical Center of Molecular Diagnosis and Therapy, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
- Department of Neurosurgery, Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000, Fujian, China
| | - Bin Qiu
- Ministry of Education Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection for Food Safety, Fuzhou UniversityFuzhou 350108, Fujian, China
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Suzuki T, Zaima Y, Fujikawa Y, Fukushima R, Kamiya H. Paradoxical role of the major DNA repair protein, OGG1, in action-at-a-distance mutation induction by 8-oxo-7,8-dihydroguanine. DNA Repair (Amst) 2022; 111:103276. [DOI: 10.1016/j.dnarep.2022.103276] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 12/21/2022]
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36
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Tsegay PS, Hernandez D, Brache C, Chatgilialoglu C, Krokidis MG, Chapagain P, Liu Y. Incorporation of 5',8-cyclo-2'deoxyadenosines by DNA repair polymerases via base excision repair. DNA Repair (Amst) 2022; 109:103258. [PMID: 34871863 PMCID: PMC9884144 DOI: 10.1016/j.dnarep.2021.103258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 10/30/2021] [Accepted: 11/18/2021] [Indexed: 01/31/2023]
Abstract
5',8-cyclo-2-deoxy nucleosides (cdPus) are the smallest tandem purine lesions including 5',8-cyclo-2'-deoxyadenosine (cdA) and 5',8-cyclo-2'-deoxyguanosine (cdG). They can inhibit DNA and RNA polymerases causing mutations, DNA strand breaks, and termination of DNA replication and gene transcription. cdPus can be removed by nucleotide excision repair with low efficiency allowing them to accumulate in the genome. Recent studies suggest that cdPus can be induced in damaged nucleotide pools and incorporated into the genome by DNA polymerases. However, it remains unknown if and how DNA polymerases can incorporate cdPus. In this study, we examined the incorporation of cdAs by human DNA repair polymerases, DNA polymerases β (pol β), and pol η during base excision repair. We then determined the efficiency of cdA incorporation by the polymerases using steady-state kinetics. We found that pol β and pol η incorporated cdAs opposite dT and dC with low efficiency, and incorporated cdAs were readily extended and ligated into duplex DNA. Using molecular docking analysis, we found that the 5',8-covalent bond in cdA disrupted its hydrogen bonding with a template base suggesting that the phosphodiester bond between the 3'-terminus nucleotide and the α-phosphate of cdATP were generated in the absence of hydrogen bonding. The enzyme kinetics analysis further suggests that pol β and pol η increased their substrate binding to facilitate the enzyme catalysis for cdA incorporation. Our study reveals unique mechanisms underlying the accumulation of cdPu lesions in the genome resulting from nucleotide incorporation by repair DNA polymerases.
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Affiliation(s)
- Pawlos S. Tsegay
- Biochemistry Ph.D. Program, Florida International University, Miami, FL, USA
| | - Daniela Hernandez
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
| | - Christopher Brache
- Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA
| | | | - Marios G. Krokidis
- Institute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos,” 15341, Agia Paraskevi, Athens, Greece
| | - Prem Chapagain
- Department of Physics, Florida International University, Miami, FL, USA,Biomolecular Sciences Institute, Florida International University, Miami, Florida, USA
| | - Yuan Liu
- Biochemistry Ph.D. Program, Florida International University, Miami, FL, USA,Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA,Biomolecular Sciences Institute, Florida International University, Miami, Florida, USA,Correspondence:
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37
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Sleight TW, Sexton CN, Mpourmpakis G, Gilbertson LM, Ng CA. A Classification Model to Identify Direct-Acting Mutagenic Polycyclic Aromatic Hydrocarbon Transformation Products. Chem Res Toxicol 2021; 34:2273-2286. [PMID: 34662518 DOI: 10.1021/acs.chemrestox.1c00187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are a complex group of environmental contaminants, many having long environmental half-lives. As these compounds degrade, the changes in their structure can result in a substantial increase in mutagenicity compared to the parent compound. Over time, each individual PAH can potentially degrade into several thousand unique transformation products, creating a complex, constantly evolving set of intermediates. Microbial degradation is the primary mechanism of their transformation and ultimate removal from the environment, and this process can result in mutagenic activation similar to the metabolic activation that can occur in multicellular organisms. The diversity of the potential intermediate structures in PAH-contaminated environments renders hazard assessment difficult for both remediation professionals and regulators. A mixture of structural and energetic descriptors has proven effective in existing studies for classifying which PAH transformation products will be mutagenic. However, most existing studies of environmental PAH mutagens primarily focus on nitrogenated derivatives, which are prevalent in the atmosphere and not as relevant in soil. Additionally, PAH products commonly found in the environment can range from as large as five rings to as small as a single ring, requiring a broadly inclusive methodology to comprehensively evaluate mutagenic potential. We developed a combination of supervised and unsupervised machine learning methods to predict environmentally induced PAH mutagenicity with improved performance over currently available tools. K-means clustering with principal component analysis allows us to identify molecular clusters that we hypothesize to have similar mechanisms of action. Recursive feature elimination identifies the most influential descriptors. The cluster-specific regression outperforms available classifiers in predicting direct-acting mutagens resulting from the microbial biodegradation of PAHs and provides direction for future studies evaluating the environmental hazards resulting from PAH biodegradation.
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Affiliation(s)
- Trevor W Sleight
- Civil & Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Caitlin N Sexton
- Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Giannis Mpourmpakis
- Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Leanne M Gilbertson
- Civil & Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.,Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Carla A Ng
- Civil & Environmental Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.,Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
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38
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Wang D, Nambu T, Tanimoto H, Iwata N, Yoshikawa K, Okinaga T, Yamamoto K. Interdental Plaque Microbial Community Changes under In Vitro Violet LED Irradiation. Antibiotics (Basel) 2021; 10:antibiotics10111348. [PMID: 34827286 PMCID: PMC8614803 DOI: 10.3390/antibiotics10111348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 12/23/2022] Open
Abstract
Oral microbiome dysbiosis has important links to human health and disease. Although photodynamic therapy influences microbiome diversity, the specific effect of violet light irradiation remains largely unknown. In this study, we analyzed the effect of violet light-emitting diode (LED) irradiation on interdental plaque microbiota. Interdental plaque was collected from 12 human subjects, exposed to violet LED irradiation, and cultured in a specialized growth medium. Next-generation sequencing of the 16S ribosomal RNA genes revealed that α-diversity decreased, whereas β-diversity exhibited a continuous change with violet LED irradiation doses. In addition, we identified several operational taxonomic units that exhibited significant shifts during violet LED irradiation. Specifically, violet LED irradiation led to a significant reduction in the relative abundance of Fusobacterium species, but a significant increase in several species of oral bacteria, such as Veillonella and Campylobacter. Our study provides an overview of oral plaque microbiota changes under violet LED irradiation, and highlights the potential of this method for adjusting the balance of the oral microbiome without inducing antibiotic resistance.
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Affiliation(s)
- Dan Wang
- Department of Operative Dentistry, Graduate School of Dentistry, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan;
| | - Takayuki Nambu
- Department of Bacteriology, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan
- Correspondence: (T.N.); (T.O.)
| | - Hiroaki Tanimoto
- Department of Operative Dentistry, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan; (H.T.); (N.I.); (K.Y.); (K.Y.)
| | - Naohiro Iwata
- Department of Operative Dentistry, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan; (H.T.); (N.I.); (K.Y.); (K.Y.)
| | - Kazushi Yoshikawa
- Department of Operative Dentistry, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan; (H.T.); (N.I.); (K.Y.); (K.Y.)
| | - Toshinori Okinaga
- Department of Bacteriology, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan
- Correspondence: (T.N.); (T.O.)
| | - Kazuyo Yamamoto
- Department of Operative Dentistry, Osaka Dental University, 8-1, Kuzuha-Hanazono, Hirakata, Osaka 573-1121, Japan; (H.T.); (N.I.); (K.Y.); (K.Y.)
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39
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Foo BJA, Eu JQ, Hirpara JL, Pervaiz S. Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1341604. [PMID: 34777681 PMCID: PMC8580634 DOI: 10.1155/2021/1341604] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 02/06/2023]
Abstract
Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
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Affiliation(s)
- Brittney Joy-Anne Foo
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Jie Qing Eu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Cancer Science Institute, NUS, Singapore, Singapore
| | | | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore, Singapore
- NUS Medicine Healthy Longevity Program, Yong Loo Lin School of Medicine, NUS, Singapore, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, NUS, Singapore, Singapore
- National University Cancer Institute, National University Health System, Singapore, Singapore
- Faculté de Médicine, Université de Paris, Paris, France
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40
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Onetto CA, Costello PJ, Kolouchova R, Jordans C, McCarthy J, Schmidt SA. Analysis of Transcriptomic Response to SO 2 by Oenococcus oeni Growing in Continuous Culture. Microbiol Spectr 2021; 9:e0115421. [PMID: 34612664 PMCID: PMC8510247 DOI: 10.1128/spectrum.01154-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 08/31/2021] [Indexed: 01/01/2023] Open
Abstract
To successfully complete malolactic fermentation (MLF), Oenococcus oeni must overcome wine stress conditions of low pH, high ethanol, and the presence of SO2. Failure to complete MLF may result in detrimental effects to the quality and stability of the resulting wines. Research efforts to date have focused on elucidating the mechanisms and genetic features that confer the ability to withstand low pH and high ethanol concentrations on O. oeni; however, the responses to SO2 stress are less well defined. This study focused on characterizing the transcriptional response of O. oeni to SO2 challenge during cultivation in a continuous system at wine-like pH (3.5). This experimental design allowed the precise discrimination of transcriptional changes linked to SO2 stress from responses associated with growth stage and cultivation parameters. Differential gene expression analysis revealed major transcriptional changes following SO2 exposure and suggested that this compound primarily interacts with intracellular proteins, DNA, and the cell envelope of O. oeni. The molecular chaperone hsp20, which has a demonstrated function in the heat, ethanol, and acid stress response, was highly upregulated, confirming its additional role in the response of this species to SO2 stress. This work also reports the first nanopore-based complete genome assemblies for O. oeni. IMPORTANCE Malolactic fermentation is an indispensable step in the elaboration of most wines and is generally performed by Oenococcus oeni, a Gram-positive heterofermentative lactic acid bacterium species. While O. oeni is tolerant to many of the wine stresses, including low pH and high ethanol concentrations, it has high sensitivity to SO2, an antiseptic and antioxidant compound regularly used in winemaking. Understanding the physiological changes induced in O. oeni by SO2 stress is essential for the development of more robust starter cultures and methods for their use. This study describes the main transcriptional changes induced by SO2 stress in the wine bacterium O. oeni and provides foundational understanding on how this compound interacts with the cellular components and the induced protective mechanisms of this species.
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Affiliation(s)
- Cristobal A. Onetto
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
| | - Peter J. Costello
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
| | - Radka Kolouchova
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
| | - Charlotte Jordans
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
| | - Jane McCarthy
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
| | - Simon A. Schmidt
- The Australian Wine Research Institute, Glen Osmond, South Australia, Australia
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41
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Jamsen JA, Sassa A, Perera L, Shock DD, Beard WA, Wilson SH. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair. Nat Commun 2021; 12:5055. [PMID: 34417448 PMCID: PMC8379156 DOI: 10.1038/s41467-021-24486-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 05/11/2021] [Indexed: 01/09/2023] Open
Abstract
Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.
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Affiliation(s)
- Joonas A Jamsen
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Akira Sassa
- Laboratory of Chromatin Metabolism and Epigenetics, Graduate School of Science, Chiba University, Chiba, Japan
| | - Lalith Perera
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - David D Shock
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - William A Beard
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - Samuel H Wilson
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
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42
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Sun M, Wang W, Liu X, Wang Y, Cui H, Liu S, Cao L. Total cholesterol, alanine aminotransferase and the risk of primary liver cancer: A population-based prospective study. Medicine (Baltimore) 2021; 100:e25746. [PMID: 33950959 PMCID: PMC8104288 DOI: 10.1097/md.0000000000025746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 04/07/2021] [Indexed: 01/04/2023] Open
Abstract
Previous studies have shown that serum total cholesterol (TC) and serum alanine aminotransferase (ALT) are associated with liver cancer risk. However, the common contribution of TC and normal-high ALT to primary liver cancer (PLC) has not been reported. We aim to assess the separate and joint effect of low TC level and normal-high ALT level on the risk of PLC, a large prospective cohort was conducted in our study.The participants were divided into 4 groups via the cross-matching method according to TC [low level (-)/non-low level (+)] and ALT [normal level (-)/normal-high level(+)] status, and using the lower quartile value of TC and the upper quartile value of ALT as a threshold, respectively. Incident PLC was confirmed by review of medical records. Cox proportional hazards regression models and interactive additive models were used to evaluate whether the joint effect of low TC level and normal-high ALT level is associated with the risk of PLC.During 1,248,895 person-years follow-up, 298 participants were diagnosed with PLC among 114,972 subjects. In male population, TC < 4.24 mmol/L was group "TC (-)"; TC ≥ 4.24 mmol/L was group "TC (+)"; ALT < 23 U/L was group "ALT (-)": 33 U/L ≥ ALT ≥ 23 U/L was group "ALT (+)". Compared with the group "TC (+)", group "ALT (-)", respectively, the adjusted hazard ratio (HR) and 95% confidence interval (95%CI) for PLC risk was 1.74 (1.36-2.25) in group "TC (-)" and 1.49 (1.15-1.94) in group "ALT (+)". In combinatorial analysis, compared with group "TC (+) and ALT (-)", the significant increased risk of PLC were observed in group "TC (+) and ALT (+)" (HR = 1.41; 95% confidence intervals [CI]: 1.02-1.95), group "TC (-) and ALT (-)" (HR = 1.67; 95%CI: 1.24-2.27) and group "TC (-) and ALT (+)" (HR = 2.72; 95%CI: 1.81-4.09), respectively. However, no statistical significance was found among female.The separate and joint effect of low TC level and normal-high ALT level was observed for PLC risk in males. When combined, individuals with coexistence of low TC level and normal-high ALT level significantly increase the risk of PLC.
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Affiliation(s)
- Miaomiao Sun
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
- Department of Graduate School, North China University of Science and Technology, Tangshan, Hebei, China
| | - Wanchao Wang
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Xining Liu
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Yiming Wang
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Haozhe Cui
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
- Department of Graduate School, North China University of Science and Technology, Tangshan, Hebei, China
| | - Siqing Liu
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
| | - Liying Cao
- Department of Hepatobiliary Surgery, Kailuan General Hospital Affiliated to North China University of Science and Technology
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Oka S, Leon J, Sakumi K, Abolhassani N, Sheng Z, Tsuchimoto D, LaFerla FM, Nakabeppu Y. MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis. Sci Rep 2021; 11:5819. [PMID: 33758207 PMCID: PMC7988129 DOI: 10.1038/s41598-021-84640-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 02/16/2021] [Indexed: 02/06/2023] Open
Abstract
8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.
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Affiliation(s)
- Sugako Oka
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.,Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66010, USA
| | - Julio Leon
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.,Laboratory for Advanced Genomics Circuit, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan
| | - Kunihiko Sakumi
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Nona Abolhassani
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Zijing Sheng
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Daisuke Tsuchimoto
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
| | - Frank M LaFerla
- Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
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Zheng Y, Haratipour P, Kashemirov BA, McKenna CE. Synthesis of 8-oxo-dGTP and its β,γ-CH 2-, β, γ-CHF-, and β, γ-CF 2- analogues. Tetrahedron Lett 2021; 67:152890. [PMID: 33716328 PMCID: PMC7951955 DOI: 10.1016/j.tetlet.2021.152890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Three novel 8-oxo-dGTP bisphosphonate analogues of 3 in which the bridging β,γ-oxygen is replaced by a methylene, fluoromethylene or difluoromethylene group (4-6, respectively) have been synthesized from 8-oxo-dGMP 2 by reaction of its morpholine 5'-phosphoramidate 14 or preferably, its N-methylimidazole 5'-phosphoramidate 15 with n-tributylammonium salts of the appropriate bisphosphonic acids, 11-13. The latter method also provides a convenient new route to 3. Analogues 4-6 may be useful as mechanistic probes for the role of 3 in abnormal DNA replication and repair.
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Affiliation(s)
- Yiying Zheng
- Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
| | - Pouya Haratipour
- Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
| | - Boris A. Kashemirov
- Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
| | - Charles E. McKenna
- Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA
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Design, Synthesis, and Evaluation of Novel 3-Carboranyl-1,8-Naphthalimide Derivatives as Potential Anticancer Agents. Int J Mol Sci 2021; 22:ijms22052772. [PMID: 33803403 PMCID: PMC7967199 DOI: 10.3390/ijms22052772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/04/2021] [Accepted: 03/06/2021] [Indexed: 12/11/2022] Open
Abstract
We synthesized a series of novel 3-carboranyl-1,8-naphthalimide derivatives, mitonafide and pinafide analogs, using click chemistry, reductive amination and amidation reactions and investigated their in vitro effects on cytotoxicity, cell death, cell cycle, and the production of reactive oxygen species in a HepG2 cancer cell line. The analyses showed that modified naphthalic anhydrides and naphthalimides bearing ortho- or meta-carboranes exhibited diversified activity. Naphthalimides were more cytotoxic than naphthalic anhydrides, with the highest IC50 value determined for compound 9 (3.10 µM). These compounds were capable of inducing cell cycle arrest at G0/G1 or G2M phase and promoting apoptosis, autophagy or ferroptosis. The most promising conjugate 35 caused strong apoptosis and induced ROS production, which was proven by the increased level of 2′-deoxy-8-oxoguanosine in DNA. The tested conjugates were found to be weak topoisomerase II inhibitors and classical DNA intercalators. Compounds 33, 34, and 36 fluorescently stained lysosomes in HepG2 cells. Additionally, we performed a similarity-based assessment of the property profile of the conjugates using the principal component analysis. The creation of an inhibitory profile and descriptor-based plane allowed forming a structure–activity landscape. Finally, a ligand-based comparative molecular field analysis was carried out to specify the (un)favorable structural modifications (pharmacophoric pattern) that are potentially important for the quantitative structure–activity relationship modeling of the carborane–naphthalimide conjugates.
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MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model. Sci Rep 2021; 11:3599. [PMID: 33574380 PMCID: PMC7878918 DOI: 10.1038/s41598-021-83138-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 01/29/2021] [Indexed: 12/24/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh+/+), heterozygous (Mutyh+/-), and MUTYH-null (Mutyh-/-) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh-/- mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.
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Altıngöz SM, Kurgan Ş, Önder C, Serdar MA, Ünlütürk U, Uyanık M, Başkal N, Tatakis DN, Günhan M. Salivary and serum oxidative stress biomarkers and advanced glycation end products in periodontitis patients with or without diabetes: A cross-sectional study. J Periodontol 2021; 92:1274-1285. [PMID: 33277933 DOI: 10.1002/jper.20-0406] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/09/2020] [Accepted: 11/03/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Non-invasive methods for periodontitis diagnosis would be a clinically important tool. This cross-sectional study aimed to investigate the association between oxidative stress, glycation, and inflammation markers and periodontal clinical parameters in periodontitis and periodontally healthy patients with type 2 diabetes and corresponding systemically healthy controls. METHODS Sixty-seven periodontally healthy (DM-H, n = 32) and periodontitis (DM-P, n = 35) patients with type 2 diabetes, and 54 systemically healthy periodontitis (H-P, n = 26) and periodontally healthy (H-H, n = 28) controls were included. Clinical periodontal parameters, body mass index, fasting glucose, hemoglobin A1c (HbA1c), along with saliva and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), advanced glycation end products (AGE), AGE receptor (RAGE) and high sensitivity C-reactive protein (hsCRP) levels were recorded and analyzed. RESULTS Salivary 8-OHdG levels were significantly higher in periodontitis compared to periodontally healthy patients, regardless of systemic status (P < 0.001). Salivary MDA levels were significantly higher in all disease groups compared to H-H group (P ≤ 0.004). Serum AGE levels were significantly higher in diabetic groups than systemically healthy groups (P < 0.001) and in H-P compared to H-H (P < 0.001). Bleeding on probing (BOP) and clinical attachment level (CAL) strongly correlated with salivary 8-OHdG and serum hsCRP (P < 0.001). In systemically healthy patients, salivary 8-OHdG was the most accurate marker to differentiate periodontitis from controls (AUC = 0.84). In diabetics salivary 4-HNE and RAGE were the most accurate (AUC = 0.85 for both). CONCLUSION Salivary 8-OHdG alone or in combination with 4-HNE, AGE and RAGE for diabetics, and salivary 8-OHdG alone or in combination with MDA and hsCRP for systemically healthy persons, could potentially serve as non-invasive screening marker(s) of periodontitis.
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Affiliation(s)
- Sema Merve Altıngöz
- Department of Periodontology, Faculty of Dentistry, Lokman Hekim University, Ankara, Turkey
| | - Şivge Kurgan
- Department of Periodontoloy, Faculty of Dentistry, Ankara University, Ankara, Turkey
| | - Canan Önder
- Department of Periodontoloy, Faculty of Dentistry, Ankara University, Ankara, Turkey
| | - Muhittin A Serdar
- Department of Medical Biochemistry, School of Medicine, Acıbadem University, Ankara, Turkey
| | - Uğur Ünlütürk
- Department of Endocrinology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Metin Uyanık
- Department of Medical Biochemistry, School of Medicine, Namık Kemal University, Tekirdağ, Turkey
| | - Nilgün Başkal
- Department of Endocrinology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Dimitris N Tatakis
- Division of Periodontology, College of Dentistry, The Ohio State University, Columbus, Ohio, USA
| | - Meral Günhan
- Department of Periodontoloy, Faculty of Dentistry, Ankara University, Ankara, Turkey
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Watanabe S, Li Y, Kawasaki Y, Ootsuyama Y, Kawai K. Health examination results and work environment factors affecting urinary 8-hydroxy-2'-deoxyguanosine levels. J Occup Health 2021; 63:e12210. [PMID: 33689200 PMCID: PMC7945954 DOI: 10.1002/1348-9585.12210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Oxidative stress is considered to cause lifestyle-related diseases, including cancer. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is widely analyzed as an oxidative stress marker. We extensively scrutinized the relationships between 8-OHdG levels and lifestyle choices as carcinogenic factors. METHODS In this study, we investigated health examination results and working conditions affecting urinary 8-OHdG levels in 503 male workers. RESULTS The urinary 8-OHdG level was positively associated with high blood sugar and leanness in smokers. In addition, urinary 8-OHdG tended to increase with organic solvent or hydrochloric acid exposure, as well as long working hours. On the other hand, the urinary 8-OHdG level was negatively associated with high plasma LDL-cholesterol levels in non-smokers and anemia. CONCLUSION According to the results, anemia decreased the oxidative stress, regardless of smoking status, while leanness or high blood sugar increased the oxidative stress in smokers, and the presence of plasma cholesterol contributed to the lower oxidative stress in non-smokers. Certain types of occupational exposure may cause oxidative stress. The measurement of urinary 8-OHdG at annual health checks may be a useful biomarker for preventing lifestyle- and work-related diseases.
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Affiliation(s)
- Sintaroo Watanabe
- Department of Environmental OncologyInstitute of Industrial Ecological SciencesUniversity of Occupational and Environmental Health JapanKitakyushuJapan
- Japan Marine United Corporation Kure ShipyardHiroshimaJapan
| | - Yun‐Shan Li
- Department of Environmental OncologyInstitute of Industrial Ecological SciencesUniversity of Occupational and Environmental Health JapanKitakyushuJapan
| | - Yuya Kawasaki
- Department of Environmental OncologyInstitute of Industrial Ecological SciencesUniversity of Occupational and Environmental Health JapanKitakyushuJapan
| | - Yuko Ootsuyama
- Department of Environmental OncologyInstitute of Industrial Ecological SciencesUniversity of Occupational and Environmental Health JapanKitakyushuJapan
| | - Kazuaki Kawai
- Department of Environmental OncologyInstitute of Industrial Ecological SciencesUniversity of Occupational and Environmental Health JapanKitakyushuJapan
- Center for Stress‐related Disease Control and PreventionUniversity of Occupational and Environmental Health JapanKitakyushuJapan
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Barguilla I, Peremartí J, Bach J, Marcos R, Hernández A. Role of As3mt and Mth1 in the genotoxic and carcinogenic effects induced by long-term exposures to arsenic in MEF cells. Toxicol Appl Pharmacol 2020; 409:115303. [DOI: 10.1016/j.taap.2020.115303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/13/2020] [Accepted: 10/21/2020] [Indexed: 11/30/2022]
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Matsuda R, Miyasaka Y, Yamada Y, Kawata J, Sakihama K, Yamamoto T, Saeki K, Yamamoto H, Ohishi Y, Koga Y, Nakamura M, Oda Y. Chronic inflammatory changes and oxidative stress in the background of "pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm". Virchows Arch 2020; 477:799-806. [PMID: 32468246 DOI: 10.1007/s00428-020-02844-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/02/2020] [Accepted: 05/07/2020] [Indexed: 12/27/2022]
Abstract
Cases of "pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm" (IPMN) have multiple PDAC lesions more frequently than cases of "PDAC without IPMN". However, the mechanism of carcinogenesis in this former disease category remains unknown. The main objective of this work was thus to investigate the effects of chronic inflammation on carcinogenesis in PDAC cases. We selected 31 "PDAC concomitant with IPMN" patients and 58 "PDAC without IPMN" patients and pathologically evaluated their background pancreatic parenchyma. Fibrosis and inflammation scores of background pancreas were higher in "PDAC concomitant with IPMN" than in "PDAC without IPMN" (P < 0.0001 and P < 0.0001, respectively), whereas the fatty infiltration score of background pancreas was high in "PDAC without IPMN" (P = 0.0024). Immunohistochemically, the expression of 8-hydroxy-2'-deoxyguanosine (8-OHDG), an oxidative stress marker, in the background pancreas was high in "PDAC concomitant with IPMN" compared with that in "PDAC without IPMN" (P < 0.0001). Chronic inflammation activates oxidative stress in tissue throughout the pancreas and probably confers susceptibility to tumorigenesis in "PDAC concomitant with IPMN".
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Affiliation(s)
- Ryota Matsuda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Miyasaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Yuichi Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Kawata
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kukiko Sakihama
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kiyoshi Saeki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ohishi
- Department of Diagnostic Pathology, Iizuka Hospital, Iizuka, Japan
| | - Yutaka Koga
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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