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Li M, Shao G. Senataxin Attenuates DNA Damage Response Activation and Suppresses Senescence. Antioxidants (Basel) 2024; 13:1337. [PMID: 39594478 PMCID: PMC11591223 DOI: 10.3390/antiox13111337] [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: 09/14/2024] [Revised: 10/25/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Oxidative stress, driven by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), induces DNA double-strand breaks (DSBs) that compromise genomic integrity. The DNA Damage Response (DDR), primarily mediated by ATM and ATR kinases, is crucial for recognizing and repairing DSBs. Senataxin (SETX), a DNA/RNA helicase, is critical in resolving R-loops, with mutations in SETX associated with neurodegenerative diseases. This study uncovers a novel function of senataxin in modulating DDR and its impact on cellular senescence. Senataxin is shown to be crucial not only for DSB repair but also for determining cell fate under oxidative stress. SETX knockout cells show impaired DSB repair and prolonged ATM/ATR signaling detected by Western blotting, leading to increased senescence, as indicated by elevated β-galactosidase activity following H2O2 exposure and I-PpoI-induced DSBs. Wild-type cells exhibit higher apoptosis levels compared to SETX knockout cells under H2O2 treatment, suggesting that senataxin promotes apoptosis over senescence in oxidative stress. This indicates that senataxin plays a protective role against the accumulation of senescent cells, potentially mitigating age-related cellular decline and neurodegenerative disease progression. These findings highlight senataxin as a critical mediator in DDR pathways and a potential therapeutic target for conditions where cellular senescence contributes to disease pathology.
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Affiliation(s)
| | - Genbao Shao
- Department of Basic Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China;
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2
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Davies JG, Menzies GE. Utilizing biological experimental data and molecular dynamics for the classification of mutational hotspots through machine learning. BIOINFORMATICS ADVANCES 2024; 4:vbae125. [PMID: 39239360 PMCID: PMC11377099 DOI: 10.1093/bioadv/vbae125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 08/06/2024] [Accepted: 08/23/2024] [Indexed: 09/07/2024]
Abstract
Motivation Benzo[a]pyrene, a notorious DNA-damaging carcinogen, belongs to the family of polycyclic aromatic hydrocarbons commonly found in tobacco smoke. Surprisingly, nucleotide excision repair (NER) machinery exhibits inefficiency in recognizing specific bulky DNA adducts including Benzo[a]pyrene Diol-Epoxide (BPDE), a Benzo[a]pyrene metabolite. While sequence context is emerging as the leading factor linking the inadequate NER response to BPDE adducts, the precise structural attributes governing these disparities remain inadequately understood. We therefore combined the domains of molecular dynamics and machine learning to conduct a comprehensive assessment of helical distortion caused by BPDE-Guanine adducts in multiple gene contexts. Specifically, we implemented a dual approach involving a random forest classification-based analysis and subsequent feature selection to identify precise topological features that may distinguish adduct sites of variable repair capacity. Our models were trained using helical data extracted from duplexes representing both BPDE hotspot and nonhotspot sites within the TP53 gene, then applied to sites within TP53, cII, and lacZ genes. Results We show our optimized model consistently achieved exceptional performance, with accuracy, precision, and f1 scores exceeding 91%. Our feature selection approach uncovered that discernible variance in regional base pair rotation played a pivotal role in informing the decisions of our model. Notably, these disparities were highly conserved among TP53 and lacZ duplexes and appeared to be influenced by the regional GC content. As such, our findings suggest that there are indeed conserved topological features distinguishing hotspots and nonhotpot sites, highlighting regional GC content as a potential biomarker for mutation. Availability and implementation Code for comparing machine learning classifiers and evaluating their performance is available at https://github.com/jdavies24/ML-Classifier-Comparison, and code for analysing DNA structure with Curves+ and Canal using Random Forest is available at https://github.com/jdavies24/ML-classification-of-DNA-trajectories.
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Affiliation(s)
- James G Davies
- Molecular Bioscience Division, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom
| | - Georgina E Menzies
- Molecular Bioscience Division, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom
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3
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Marcolungo L, Bellamoli F, Cecchin M, Lopatriello G, Rossato M, Cosentino E, Rombauts S, Delledonne M, Ballottari M. Haematococcus lacustris genome assembly and annotation reveal diploid genetic traits and stress-induced gene expression patterns. ALGAL RES 2024; 80:103567. [PMID: 39717182 PMCID: PMC7617258 DOI: 10.1016/j.algal.2024.103567] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024]
Abstract
The green alga Haematococcus lacustris (formerly Haematococcus pluvialis) is a primary source of astaxanthin, a ketocarotenoid with high antioxidant activity and several industrial applications. Here, the Haematococcus lacustris highly repetitive genome was reconstructed by exploiting next-generation sequencing integrated with Hi-C scaffolding, obtaining a 151 Mb genome assembly in 32 scaffolds at a near-chromosome level with high continuity. Surprisingly, the distribution of the single-nucleotide-polymorphisms identified demonstrates a diploid configuration for the Haematococcus genome, further validated by Sanger sequencing of heterozygous regions. Functional annotation and RNA-seq data enabled the identification of 13,946 nuclear genes, with >5000 genes not previously identified in this species, providing insights into the molecular basis for metabolic rear-rangement in stressing conditions such as high light and/or nitrogen starvation, where astaxanthin biosynthesis is triggered. These data constitute a rich genetic resource for biotechnological manipulation of Haematococcus lacustris highlighting potential targets to improve astaxanthin and carotenoid productivity.
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Affiliation(s)
- Luca Marcolungo
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Francesco Bellamoli
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Michela Cecchin
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Giulia Lopatriello
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Marzia Rossato
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Emanuela Cosentino
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Stephane Rombauts
- Bioinformatics and Evolutionary Genomics, University of Ghent, Technologiepark 927, B-9052Gent, Belgium
| | - Massimo Delledonne
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
| | - Matteo Ballottari
- Dipartimento di Biotecnologie, Università di Verona, Strada Le Grazie 15, 37134Verona, Italy
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4
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Thakur M, Muniyappa K. Macrophage activation highlight an important role for NER proteins in the survival, latency and multiplication of Mycobacterium tuberculosis. Tuberculosis (Edinb) 2023; 138:102284. [PMID: 36459831 DOI: 10.1016/j.tube.2022.102284] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/14/2022] [Accepted: 11/20/2022] [Indexed: 11/27/2022]
Abstract
Nucleotide excision repair (NER) is one of the most extensively studied DNA repair processes in both prokaryotes and eukaryotes. The NER pathway is a highly conserved, ATP-dependent multi-step process involving several proteins/enzymes that function in a concerted manner to recognize and excise a wide spectrum of helix-distorting DNA lesions and bulky adducts by nuclease cleavage on either side of the damaged bases. As such, the NER pathway of Mycobacterium tuberculosis (Mtb) is essential for its survival within the hostile environment of macrophages and disease progression. This review focuses on present published knowledge about the crucial roles of Mtb NER proteins in the survival and multiplication of the pathogen within the macrophages and as potential targets for drug discovery.
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Affiliation(s)
- Manoj Thakur
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India.
| | - K Muniyappa
- Department of Biochemistry, Indian Institute of Science, Bangalore, 560012, India
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5
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Jiang X, Jiang Z, Jiang M, Sun Y. Berberine as a Potential Agent for the Treatment of Colorectal Cancer. Front Med (Lausanne) 2022; 9:886996. [PMID: 35572960 PMCID: PMC9096113 DOI: 10.3389/fmed.2022.886996] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/29/2022] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.
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Affiliation(s)
- Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhongxiu Jiang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Yan Sun
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6
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El-Saadi MW, Tian X, Grames M, Ren M, Keys K, Li H, Knott E, Yin H, Huang S, Lu XH. Tracing brain genotoxic stress in Parkinson's disease with a novel single-cell genetic sensor. SCIENCE ADVANCES 2022; 8:eabd1700. [PMID: 35427151 PMCID: PMC9012470 DOI: 10.1126/sciadv.abd1700] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 03/01/2022] [Indexed: 05/06/2023]
Abstract
To develop an in vivo tool to probe brain genotoxic stress, we designed a viral proxy as a single-cell genetic sensor termed PRISM that harnesses the instability of recombinant adeno-associated virus genome processing and a hypermutable repeat sequence-dependent reporter. PRISM exploits the virus-host interaction to probe persistent neuronal DNA damage and overactive DNA damage response. A Parkinson's disease (PD)-associated environmental toxicant, paraquat (PQ), inflicted neuronal genotoxic stress sensitively detected by PRISM. The most affected cell type in PD, dopaminergic (DA) neurons in substantia nigra, was distinguished by a high level of genotoxic stress following PQ exposure. Human alpha-synuclein proteotoxicity and propagation also triggered genotoxic stress in nigral DA neurons in a transgenic mouse model. Genotoxic stress is a prominent feature in PD patient brains. Our results reveal that PD-associated etiological factors precipitated brain genotoxic stress and detail a useful tool for probing the pathogenic significance in aging and neurodegenerative disorders.
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Affiliation(s)
- Madison Wynne El-Saadi
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Xinli Tian
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Mychal Grames
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Michael Ren
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Kelsea Keys
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Hanna Li
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Erika Knott
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Hong Yin
- Feist-Weiller Cancer Center and Department of Medicine, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
| | - Xiao-Hong Lu
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health, Shreveport, Shreveport, LA 71103, USA
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Neri S, Guidotti S, Bini C, Pelotti S, D'Adamo S, Minguzzi M, Platano D, Santi S, Mariani E, Cattini L, Borzì RM. Oxidative stress-induced DNA damage and repair in primary human osteoarthritis chondrocytes: focus on IKKα and the DNA Mismatch Repair System. Free Radic Biol Med 2021; 166:212-225. [PMID: 33636333 DOI: 10.1016/j.freeradbiomed.2021.02.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/12/2021] [Accepted: 02/13/2021] [Indexed: 12/15/2022]
Abstract
During osteoarthritis development, chondrocytes are subjected to a functional derangement. This increases their susceptibility to stressful conditions such as oxidative stress, a characteristic of the aging tissue, which can further provoke extrinsic senescence by DNA damage responses. It was previously observed that IκB kinase α knockdown increases the replicative potential of primary human OA chondrocytes cultured in monolayer and the survival of the same cells undergoing hypertrophic-like differentiation in 3-D. In this paper we investigated whether IKKα knockdown could modulate oxidative stress-induced senescence of OA chondrocytes undergoing a DDR and particularly the involvement in this process of the DNA mismatch repair system, the principal mechanism for repair of replicative and recombinational errors, devoted to genomic stability maintenance in actively replicating cells. This repair system is also implicated in oxidative stress-mediated DNA damage repair. We analyzed microsatellite instability and expression of the mismatch repair components in human osteoarthritis chondrocytes after IKKα knockdown and H2O2 exposure. Only low MSI levels and incidence were detected and exclusively in IKKα proficient cells. Moreover, we found that IKKα proficient and deficient chondrocytes differently regulated MMR proteins after oxidative stress, both at mRNA and protein level, suggesting a reduced susceptibility of IKKα deficient cells. Our data suggest an involvement of the MMR system in the response to oxidative stress that tends to be more efficient in IKKαKD cells. This argues for a partial contribution of the MMR system to the better ability to recover DNA damage already observed in these cells.
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Affiliation(s)
- Simona Neri
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Serena Guidotti
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Carla Bini
- Department of Medical and Surgical Sciences, (DIMEC), Unit of Legal Medicine, University of Bologna, Via Irnerio, 49, 40126, Bologna, Italy.
| | - Susi Pelotti
- Department of Medical and Surgical Sciences, (DIMEC), Unit of Legal Medicine, University of Bologna, Via Irnerio, 49, 40126, Bologna, Italy.
| | - Stefania D'Adamo
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Manuela Minguzzi
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
| | - Daniela Platano
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
| | - Spartaco Santi
- CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna at IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Erminia Mariani
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy; Department of Medical and Surgical Sciences, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
| | - Luca Cattini
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy.
| | - Rosa Maria Borzì
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Immunorheumatology and Tissue Regeneration, Via di Barbiano 1/10, 40136, Bologna, Italy.
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8
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Persi E, Wolf YI, Horn D, Ruppin E, Demichelis F, Gatenby RA, Gillies RJ, Koonin EV. Mutation-selection balance and compensatory mechanisms in tumour evolution. Nat Rev Genet 2020; 22:251-262. [PMID: 33257848 DOI: 10.1038/s41576-020-00299-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/11/2022]
Abstract
Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mutations to whole-genome duplications, in tumour initiation and progression is lacking. We posit that different genomic aberrations generally exhibit a temporal order, shaped by a balance between the levels of mutations and selective pressures. Repeat instability emerges first, followed by larger aberrations, with compensatory effects leading to robust tumour fitness maintained throughout the tumour progression. A better understanding of the interplay between genetic aberrations, the microenvironment, and epigenetic and metabolic cellular states is essential for early detection and prevention of cancer as well as development of efficient therapeutic strategies.
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Affiliation(s)
- Erez Persi
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
| | - Yuri I Wolf
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - David Horn
- School of Physics and Astronomy, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv, Israel
| | - Eytan Ruppin
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Francesca Demichelis
- Department for Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy.,Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
| | - Robert A Gatenby
- Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Robert J Gillies
- Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| | - Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
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Sudharshan SJ, Dyavaiah M. Astaxanthin protects oxidative stress mediated DNA damage and enhances longevity in Saccharomyces cerevisiae. Biogerontology 2020; 22:81-100. [PMID: 33108581 DOI: 10.1007/s10522-020-09904-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/21/2020] [Indexed: 10/23/2022]
Abstract
Reactive oxygen species (ROS) have long been found to play an important role in oxidative mediated DNA damage. Fortunately, cells possess an antioxidant system that can neutralize ROS. However, oxidative stress occurs when antioxidants are overwhelmed by ROS or impaired antioxidant pathways. This study was carried out to find the protective effect of astaxanthin on the yeast DNA repair-deficient mutant cells under hydrogen peroxide stress. The results showed that astaxanthin enhances the percent cell growth of rad1∆, rad51∆, apn1∆, apn2∆ and ogg1∆ cells. Further, the spot test and colony-forming unit count results confirmed that astaxanthin protects DNA repair mutant cells from oxidative stress. The DNA binding property of astaxanthin studied by in silico and in vitro methods indicated that astaxanthin binds to the DNA in the major and minor groove, and that might protect DNA against oxidative stress induced by Fenton's reagent. The intracellular ROS, 8-OHdG level and the DNA fragmentation as measured by comet tail was reduced by astaxanthin under oxidative stress. Similarly, reduced nuclear fragmentation and chromatin condensation results suggest that astaxanthin might reduce apoptosis. Finally, we show that astaxanthin decreases the accumulation of mutation rate and enhances the longevity of DNA repair-deficient mutants' cells during a chronological lifespan.
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Affiliation(s)
- S J Sudharshan
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, 605014, India
| | - Madhu Dyavaiah
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, 605014, India.
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10
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Zhen W, Hu W, Dong L, An S, Jiang X. Nanomaterials for the regulation of the tumor microenvironment and theranostics. NANOSCALE ADVANCES 2020; 2:1395-1409. [PMID: 36132317 PMCID: PMC9417269 DOI: 10.1039/c9na00816k] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 02/08/2020] [Indexed: 05/22/2023]
Abstract
Cancer has become one of the primary threats to human beings, and traditional therapies (including surgery, chemotherapy and radiotherapy) show limited therapeutic efficacy due to the complexity of tumor biology. Furthermore, determining how to utilize the differences between the tumor microenvironment (TME) and healthy tissues and exploring new nanoplatforms that can realize early diagnosis and effective and non-toxic therapy are challenges in cancer theranostics. Numerous researchers have designed multifunctional nanomaterials and investigated their personalized therapy and regulation abilities toward TME, including oxygen generation, glutathione consumption and the production of reactive oxygen species and multi-model imaging effects. This review will introduce the latest progress in the design of multi-functional nanomedicines for the regulation of TME and their theranostics, and it will provide a critical angle for the future development of nanomedicine.
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Affiliation(s)
- Wenyao Zhen
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun 130022 Jilin China
- University of Science and Technology of China Hefei 230026 Anhui China
| | - Wenxue Hu
- Department of Materials Science and Engineering, Shenyang University of Chemical Technology Shenyang 110142 Liaoning China
| | - Liang Dong
- School of Chemistry and Molecular Engineering, East China Normal University Shanghai 200241 China
| | - Shangjie An
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun 130022 Jilin China
- University of Science and Technology of China Hefei 230026 Anhui China
| | - Xiue Jiang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun 130022 Jilin China
- University of Science and Technology of China Hefei 230026 Anhui China
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11
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Abstract
Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life, suggesting that aging may play an active role in pathogenesis. Cellular aging is defined as the slow decline in stress resistance and accumulation of damage over time. While different cells and tissues can age at different rates, 9 hallmarks of aging have emerged to better define the cellular aging process. Strikingly, many of the hallmarks of aging are also hallmarks of HD pathology. Models of HD and HD patients possess markers of accelerated aging, and processes that decline during aging also decline at a more rapid rate in HD, further implicating the role of aging in HD pathogenesis. Furthermore, accelerating aging in HD mouse and patient-derived neurons unmasks HD-specific phenotypes, suggesting an active role for the aging process in the onset and progression of HD. Here, we review the overlap between the hallmarks of aging and HD and discuss how aging may contribute to pathogenesis in HD.
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Affiliation(s)
- Emily Machiela
- University of Central Florida, College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
| | - Amber L. Southwell
- University of Central Florida, College of Medicine, Burnett School of Biomedical Sciences, Orlando, FL, USA
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12
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Nohmi T, Matsumoto K. Effects of DNA polymerase kappa and mismatch repair on dose-responses of chromosome aberrations induced by three oxidative genotoxins in human cells. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2020; 61:193-199. [PMID: 31294882 DOI: 10.1002/em.22315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/25/2019] [Accepted: 06/27/2019] [Indexed: 06/09/2023]
Abstract
Genotoxic carcinogens are regulated under the policy that there is no threshold or safe dose. It has been pointed out, however, that self-defense mechanisms, such as detoxification, DNA repair, and error-free translesion synthesis, may protect chromosome DNA from genotoxic insults, thereby constituting practical threshold. In this study, we examined dose responses of chromosome aberrations induced by three oxidative genotoxins, that is, hydrogen peroxide (H2 O2 ), menadione and paraquat, with or without DNA polymerase kappa (Polκ) activities and mismatch repair capacities in human cells. Polκ is involved in translesion synthesis across DNA damage and mismatch repair is responsible for correction of base-base mismatch in DNA. Polκ activity of the cells was inactivated either by point mutations in the catalytically essential amino acids (catalytically dead or CD) or by deletion of the POLK gene (knockout or KO). In the absence of mismatch repair, frequencies of chromosome aberrations induced by H2 O2 and menadione were not significantly different among CD, KO, and the wild type (WT) cells. In the presence of mismatch repair, however, cytotoxicity and clastogenicity were enhanced and Polκ modulated the sensitivity of the cells. No-observed-genotoxic-effect-levels (NOGELs) for H2 O2 and menadione were CD = KO < WT cells. In contrast, the sensitivities of the cells to paraquat were not significantly affected by the status of mismatch repair or Polκ activity. The results suggest that mismatch repair and Polκ coordinately modulate NOGELs for the clastogenicity of H2 O2 and menadione and also that DNA lesion(s) responsible for paraquat-induced chromosome aberrations are different from those induced by H2 O2 and menadione. Environ. Mol. Mutagen. 61:193-199, 2020. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- Takehiko Nohmi
- Biological Safety Research Center, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan
| | - Kyomu Matsumoto
- Toxicology Division, The Institute of Environmental Toxicology, Joso-shi, Ibaraki, Japan
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13
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Liu T, Song X, Khan S, Li Y, Guo Z, Li C, Wang S, Dong W, Liu W, Wang B, Cao H. The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing. Int J Cancer 2019; 146:1780-1790. [DOI: 10.1002/ijc.32563] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Tianyu Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Samiullah Khan
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Yun Li
- Department of Pharmacy, General HospitalTianjin Medical University Tianjin China
| | - Zixuan Guo
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Chuqiao Li
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Sinan Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Wenxiao Dong
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Wentian Liu
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, General HospitalTianjin Medical University Tianjin China
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14
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Olsen KC, Moscoso JA, Levitan DR. Somatic Mutation Is a Function of Clone Size and Depth in Orbicella Reef-Building Corals. THE BIOLOGICAL BULLETIN 2019; 236:1-12. [PMID: 30707605 DOI: 10.1086/700261] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
In modular organisms, the propagation of genetic variability within a clonal unit can alter the scale at which ecological and evolutionary processes operate. Genetic variation within an individual primarily arises through the accretion of somatic mutations over time, leading to genetic mosaicism. Here, we assess the prevalence of intraorganismal genetic variation and potential mechanisms influencing the degree of genetic mosaicism in the reef corals Orbicella franksi and Orbicella annularis. Colonies of both species, encompassing a range of coral sizes and depths, were sampled multiple times and genotyped at the same microsatellite loci to detect intraorganismal genetic variation. Genetic mosaicism was detected in 38% of corals evaluated, and mutation frequency was found to be positively related with clonal size and negatively associated with coral depth. We suggest that larger clones experience a greater number of somatic cell divisions and consequently have an elevated potential to accumulate mutations. Furthermore, corals at shallower depths may be exposed to abiotic conditions such as elevated thermal regimes, which promote increased mutation rates. The results highlight the pervasiveness of intraorganismal genetic variation in reef-building corals and emphasize potential mechanisms generating somatic mutations in modular organisms.
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15
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Qin H, Wang F, Liu H, Zeng Z, Wang S, Pan X, Gao H. New advances in immunotherapy for non-small cell lung cancer. Am J Transl Res 2018; 10:2234-2245. [PMID: 30210667 PMCID: PMC6129543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/29/2018] [Indexed: 06/08/2023]
Abstract
Immunotherapy is one of the methods that can change the survival rate of patients with malignant tumors, in addition to surgery therapy, radiotherapy, chemotherapy and targeted therapy. Among various immunotherapy methods, immunoprecipitation inhibitors have been the most effective medications developed in recent years. At present, more in-depth studies have been conducted for two immune checkpoint inhibitor pathways, programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and a variety of medications for those above mentioned. The present study briefly reviews the results of clinical trials for relevant immune checkpoint inhibitors in lung cancer.
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Affiliation(s)
- Haifeng Qin
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Fang Wang
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Hui Liu
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Zhen Zeng
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Shasha Wang
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Xin Pan
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
| | - Hongjun Gao
- Department of Lung Cancer, 307th Hospital of Chinese People's Liberation Army Beijing 100071, China
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16
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Kluckova K, Tennant DA. Metabolic implications of hypoxia and pseudohypoxia in pheochromocytoma and paraganglioma. Cell Tissue Res 2018; 372:367-378. [PMID: 29450727 PMCID: PMC5915505 DOI: 10.1007/s00441-018-2801-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 01/17/2018] [Indexed: 12/13/2022]
Abstract
Hypoxia is a critical driver of cancer pathogenesis, directly inducing malignant phenotypes such as epithelial-mesenchymal transition, stem cell-like characteristics and metabolic transformation. However, hypoxia-associated phenotypes are often observed in cancer in the absence of hypoxia, a phenotype known as pseudohypoxia, which is very well documented in specific tumour types, including in paraganglioma/pheochromocytoma (PPGL). Approximately 40% of the PPGL tumours carry a germ line mutation in one of a number of susceptibility genes of which those that are found in succinate dehydrogenase (SDH) or in von Hippel-Lindau (VHL) genes manifest a strong pseudohypoxic phenotype. Mutations in SDH are oncogenic, forming tumours in a select subset of tissues, but the cause for this remains elusive. Although elevated succinate levels lead to increase in hypoxia-like signalling, there are other phenotypes that are being increasingly recognised in SDH-mutated PPGL, such as DNA hypermethylation. Further, recently unveiled changes in metabolic re-wiring of SDH-deficient cells might help to decipher cancer related roles of SDH in the future. In this review, we will discuss the various implications that the malfunctioning SDH can have and its impact on cancer development.
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Affiliation(s)
- Katarina Kluckova
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Daniel A Tennant
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
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17
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Function and Regulation of Protein Kinase D in Oxidative Stress: A Tale of Isoforms. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2138502. [PMID: 29854077 PMCID: PMC5944262 DOI: 10.1155/2018/2138502] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/19/2018] [Indexed: 12/17/2022]
Abstract
Oxidative stress is a condition that arises when cells are faced with levels of reactive oxygen species (ROS) that destabilize the homeostatic redox balance. High levels of ROS can cause damage to macromolecules including DNA, lipids, and proteins, eventually resulting in cell death. Moderate levels of ROS however serve as signaling molecules that can drive and potentiate several cellular phenotypes. Increased levels of ROS are associated with a number of diseases including neurological disorders and cancer. In cancer, increased ROS levels can contribute to cancer cell survival and proliferation via the activation of several signaling pathways. One of the downstream effectors of increased ROS is the protein kinase D (PKD) family of kinases. In this review, we will discuss the regulation and function of this family of ROS-activated kinases and describe their unique isoform-specific features, in terms of both kinase regulation and signaling output.
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18
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Lin LS, Song J, Song L, Ke K, Liu Y, Zhou Z, Shen Z, Li J, Yang Z, Tang W, Niu G, Yang HH, Chen X. Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2
-Based Nanoagent to Enhance Chemodynamic Therapy. Angew Chem Int Ed Engl 2018. [DOI: 10.1002/ange.201712027] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Li-Sen Lin
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Jibin Song
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Liang Song
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Kaimei Ke
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Yijing Liu
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Zijian Zhou
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Zheyu Shen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Juan Li
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Zhen Yang
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Wei Tang
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Gang Niu
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Huang-Hao Yang
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Xiaoyuan Chen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
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19
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Lin LS, Song J, Song L, Ke K, Liu Y, Zhou Z, Shen Z, Li J, Yang Z, Tang W, Niu G, Yang HH, Chen X. Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2
-Based Nanoagent to Enhance Chemodynamic Therapy. Angew Chem Int Ed Engl 2018; 57:4902-4906. [DOI: 10.1002/anie.201712027] [Citation(s) in RCA: 754] [Impact Index Per Article: 107.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/13/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Li-Sen Lin
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Jibin Song
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Liang Song
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Kaimei Ke
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Yijing Liu
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Zijian Zhou
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Zheyu Shen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Juan Li
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Zhen Yang
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Wei Tang
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Gang Niu
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
| | - Huang-Hao Yang
- MOE key laboratory for analytical science of food safety and biology; College of Chemistry; Fuzhou University; Fuzhou 350108 China
| | - Xiaoyuan Chen
- Laboratory of Molecular Imaging and Nanomedicine (LOMIN); National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); Bethesda MD 20892 USA
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20
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Complete sequence of the ATP6 and ND3 mitochondrial genes in breast cancer tissue of postmenopausal women with different body mass indexes. Ann Diagn Pathol 2018; 32:23-27. [DOI: 10.1016/j.anndiagpath.2017.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 05/24/2017] [Accepted: 09/08/2017] [Indexed: 12/11/2022]
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21
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TIF1β is phosphorylated at serine 473 in colorectal tumor cells through p38 mitogen-activated protein kinase as an oxidative defense mechanism. Biochem Biophys Res Commun 2017; 492:310-315. [DOI: 10.1016/j.bbrc.2017.08.117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 08/27/2017] [Indexed: 11/30/2022]
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22
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Dowling ME, Schnabel G, Boatwright HG, Everhart SE. Novel gene-sequence markers for isolate tracking within Monilinia fructicola lesions. PEST MANAGEMENT SCIENCE 2017; 73:1822-1829. [PMID: 28160377 DOI: 10.1002/ps.4544] [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: 10/05/2016] [Revised: 12/19/2016] [Accepted: 02/01/2017] [Indexed: 06/06/2023]
Abstract
BACKGROUND Monilinia fructicola is a diverse pathogen of pome and stone fruits that causes severe economic losses each year. However, little is known about inoculum flow within or between orchards and pathogen establishment in an orchard, because few methods exist for detecting diversity or tracking isolates over time. SSR loci are an effective option, but may be confounded by a high degree of mutability and potential sensitivity to abiotic stress. RESULTS Through transcriptome analysis, we identified novel markers mrr1, DHFR and MfCYP01 and validated stability of these markers under fungicide stress in natural infection sites. Nucleotide variation within mrr1, DHFR and MfCYP01 sequences differentiated isolates at all spatial scales: within the same infection site, between trees and between two farms. Sequenced regions were also effective for matching isolates collected from blossoms at the beginning of the season to progeny in cankers obtained at the end of the season. CONCLUSIONS Collectively, results show that mrr1, DHFR and MfCYP01 are able to accurately differentiate M. fructicola isolates at the population level, can be used to track isolates over time, and are more stable than SSRs under external stresses. Either by themselves or combined with SSR markers, these gene-encoding regions are a much-needed tool for better understanding M. fructicola population dynamics. © 2017 Society of Chemical Industry.
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Affiliation(s)
- Madeline E Dowling
- Department of Plant and Environmental Sciences, Clemson University, Clemson, SC, USA
| | - Guido Schnabel
- Department of Plant and Environmental Sciences, Clemson University, Clemson, SC, USA
| | - Harriet G Boatwright
- Department of Plant and Environmental Sciences, Clemson University, Clemson, SC, USA
| | - Sydney E Everhart
- Department of Plant Pathology, University of Nebraska, Lincoln, NE, USA
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23
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Sha Y, Minko IG, Malik CK, Rizzo CJ, Lloyd RS. Error-prone replication bypass of the imidazole ring-opened formamidopyrimidine deoxyguanosine adduct. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2017; 58:182-189. [PMID: 28436537 PMCID: PMC5476229 DOI: 10.1002/em.22089] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 03/21/2017] [Accepted: 03/24/2017] [Indexed: 06/07/2023]
Abstract
Addition of hydroxyl radicals to the C8 position of 2'-deoxyguanosine generates an 8-hydroxyguanyl radical that can be converted into either 8-oxo-7,8-dihydro-2'-deoxyguanosine or N-(2-deoxy-d-pentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine) (Fapy-dG). The Fapy-dG adduct can adopt different conformations and in particular, can exist in an unnatural α anomeric configuration in addition to canonical β configuration. Previous studies reported that in 5'-TGN-3' sequences, Fapy-dG predominantly induced G → T transversions in both mammalian cells and Escherichia coli, suggesting that mutations could be formed either via insertion of a dA opposite the 5' dT due to primer/template misalignment or as result of direct miscoding. To address this question, single-stranded vectors containing a site-specific Fapy-dG adduct were generated to vary the identity of the 5' nucleotide. Following vector replication in primate cells (COS7), complex mutation spectra were observed that included ∼3-5% G → T transversions and ∼14-21% G → A transitions. There was no correlation apparent between the identity of the 5' nucleotide and spectra of mutations. When conditions for vector preparation were modified to favor the β anomer, frequencies of both G → T and G → A substitutions were significantly reduced. Mutation frequencies in wild-type E. coli and a mutant deficient in damage-inducible DNA polymerases were significantly lower than detected in COS7 and spectra were dominated by deletions. Thus, mutagenic bypass of Fapy-dG can proceed via mechanisms that are different from the previously proposed primer/template misalignment or direct misinsertions of dA or dT opposite to the β anomer of Fapy-dG. Environ. Mol. Mutagen. 58:182-189, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Yan Sha
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, USA
| | - Irina G. Minko
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, USA
| | - Chanchal K. Malik
- Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - Carmelo J. Rizzo
- Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA
| | - R. Stephen Lloyd
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, USA
- Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA
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24
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Neri S, Guidotti S, Lilli NL, Cattini L, Mariani E. Infrapatellar fat pad-derived mesenchymal stromal cells from osteoarthritis patients: In vitro genetic stability and replicative senescence. J Orthop Res 2017; 35:1029-1037. [PMID: 27334047 DOI: 10.1002/jor.23349] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/21/2016] [Indexed: 02/04/2023]
Abstract
Different sources of mesenchymal stromal cells can be considered for regenerative medicine applications. Here we analyzed human adipose-derived stromal cells from infrapatellar fat pad (IFPSC) of osteoarthritis patients, representing a very interesting candidate for cartilage regeneration. No data are available concerning IFPSC stability after in vitro expansion. Indeed, replicative potential and multipotency progressively decrease during culture passages while DNA damage and cell senescence increase, thus possibly affecting clinical applications. To investigate whether in vitro expansion influences the genetic stability and replicative senescence of IFPSC, we performed long-term cultures and comparatively analyzed cells at different culture passages. Stromal vascular fraction was harvested from infrapatellar fat pad of 11 osteoarthritis patients undergoing knee replacement surgery. Cell recovery, growth kinetics, surface marker profile, and differentiation ability in inductive culture conditions were recorded. Genetic integrity maintenance was estimated by microsatellite instability analysis and mismatch repair gene expression, whereas telomere length and telomerase activity were assessed to evaluate replicative senescence. Anchorage-dependent growth was tested by soft agar culture. IFPSC displayed a phenotype similar to mesenchymal stromal cells from subcutaneous fat and showed differentiation ability. No microsatellite instability was documented even at advanced culture times in accordance to a sustained expression of mismatch repair genes, thus highlighting stability of short repeated sequences in the genome. No significant telomere attrition nor telomerase activity were documented during culture and cells did not lose anchorage-dependent growth ability. The presented data support the suitability and safety of in vitro expanded IFPSC from osteoarthritis patients for applications in regenerative medicine approaches. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1029-1037, 2017.
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Affiliation(s)
- Simona Neri
- Immunorheumatology and Tissue Regeneration Laboratory, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy
| | - Serena Guidotti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Nicoletta Libera Lilli
- Immunorheumatology and Tissue Regeneration Laboratory, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy
| | - Luca Cattini
- Immunorheumatology and Tissue Regeneration Laboratory, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy
| | - Erminia Mariani
- Immunorheumatology and Tissue Regeneration Laboratory, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, Bologna, 40136, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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25
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Dowling ME, Bryson PK, Boatwright HG, Wilson JR, Fan Z, Everhart SE, Brannen PM, Schnabel G. Effect of Fungicide Applications on Monilinia fructicola Population Diversity and Transposon Movement. PHYTOPATHOLOGY 2016; 106:1504-1512. [PMID: 27452900 DOI: 10.1094/phyto-03-16-0127-r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
In this study, we investigated whether fungicide-induced mutagenesis previously reported in Monilinia fructicola could accelerate genetic changes in field populations. Azoxystrobin and propiconazole were applied to nectarine trees at weekly intervals for approximately 3 months between bloom and harvest in both 2013 and 2014. Fungicides were applied at half-label rate to allow recovery of isolates and to increase chances of sublethal dose exposure. One block was left unsprayed as a control. In total, 608 single-spore isolates were obtained from blighted blossoms, cankers, and fruit to investigate phenotypic (fungicide resistance) and genotypic (simple-sequence repeat [SSR] loci and gene region) changes. In both years, populations from fungicide-treated and untreated fruit were not statistically different in haploid gene diversity (P = 0.775 for 2013 and P = 0.938 for 2014), allele number (P = 0.876 for 2013 and P = 0.406 for 2014), and effective allele number (P = 0.861 for 2013 and P = 0.814 for 2014). Isolates from blossoms and corresponding cankers of fungicide treatments revealed no changes in SSR analysis or evidence for induced Mftc1 transposon translocation. No indirect evidence for increased genetic diversity in the form of emergence of reduced sensitivity to azoxystrobin, propiconazole, iprodione, and cyprodinil was detected. High levels of population diversity in all treatments provided evidence for sexual recombination of this pathogen in the field, despite apparent absence of apothecia in the orchard. Our results indicate that fungicide-induced, genetic changes may not occur or not occur as readily in field populations as they do under continuous exposure to sublethal doses in vitro.
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Affiliation(s)
- Madeline E Dowling
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Patricia K Bryson
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Harriet G Boatwright
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Jennifer R Wilson
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Zhen Fan
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Sydney E Everhart
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Phillip M Brannen
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
| | - Guido Schnabel
- First, second, third, fourth, fifth, and eighth authors: Department of Agricultural and Environmental Sciences, Clemson University, Clemson, SC 29634; sixth author: Department of Plant Pathology, University of Nebraska, Lincoln 68583; and seventh author: Plant Pathology Department, University of Georgia, Athens 30602
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Ryu S, Chang Y, Yun KE, Jung HS, Shin JH, Shin H. Gallstones and the Risk of Gallbladder Cancer Mortality: A Cohort Study. Am J Gastroenterol 2016; 111:1476-1487. [PMID: 27575712 DOI: 10.1038/ajg.2016.345] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 07/02/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Despite epidemiologic data, definitive evidence for the role of gallstones as a cause for gallbladder cancer is lacking. The goal of this study was to evaluate the association between gallstones, determined by ultrasound, and the risk of gallbladder cancer mortality in a large study of Korean men and women. In addition, the association between gallstones and cholecystectomy, and risk of hepatobiliary cancer mortality was investigated. METHODS A cohort study was performed for 396,720 South Korean men and women who underwent a health checkup from 2002 to 2012. Hazard ratios for mortality outcomes were estimated using Cox-proportional hazards regression analysis. Vital status and cause of death assignment were based on linkage to the National Death Index of death certificate records. RESULTS From a total of 2,158,906.2 person-years of follow-up (median follow-up of 5.4 years), we identified 224 deaths from hepatobiliary cancer, comprising 174 cases of liver/intrahepatic bile ducts cancer, 20 cases of gallbladder cancer, and 30 cases of biliary tract cancer. Gallstones were significantly associated with increased risk of hepatobiliary cancer mortality, especially liver/intrahepatic biliary cancer, and gallbladder cancer mortality. The multivariable-adjusted hazard ratios (95% confidence intervals) for hepatobiliary cancer, liver/intrahepatic biliary cancer, and gallbladder cancer mortality comparing subjects having gallstones with those without gallstone disease were 2.74 (1.83-4.10), 2.34 (1.45-3.77), and 7.35 (2.60-20.8), respectively. Cholecystectomy was not significantly associated with hepatobiliary cancer mortality. CONCLUSIONS In this large cohort study, gallstones were associated with increased risk of hepatobiliary cancer mortality, especially liver/intrahepatic cancer, and gallbladder cancer mortality independent of potential confounders. Future studies with longer follow-up periods that include data on incident cancer cases should provide a more comprehensive view of the role of gallstones in cancer development.
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Affiliation(s)
- Seungho Ryu
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Yoosoo Chang
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
| | - Kyung Eun Yun
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hyun-Suk Jung
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jun Ho Shin
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hocheol Shin
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Canto P, Benítez Granados J, Martínez Ramírez MA, Reyes E, Feria-Bernal G, García-García E, Tejeda ME, Zavala E, Tapia A, Rojano-Mejía D, Méndez JP. Genetic variants in ATP6 and ND3 mitochondrial genes are not associated with aggressive prostate cancer in Mexican-Mestizo men with overweight or obesity. Aging Male 2016; 19:187-191. [PMID: 27187822 DOI: 10.1080/13685538.2016.1185409] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Mitochondrial defects have been related to obesity and prostate cancer. We investigated if Mexican-Mestizo men presenting this type of cancer, exhibited somatic mutations of ATP6 and/or ND3.Body mass index (BMI) was determined; the degree of prostate cancer aggressiveness was demarcated by the Gleason score. DNA from tumor tissue and from blood leukocytes was amplified by the polymerase chain reaction and ATP6 and ND3 were sequenced. We included 77 men: 20 had normal BMI, 38 were overweight and 19 had obesity; ages ranged from 52 to 83. After sequencing ATP6 and ND3, from DNA obtained from leukocytes and tumor tissue, we did not find any somatic mutations. All changes observed, in both genes, were polymorphisms. In ATP6 we identified, in six patients, two non-synonymous nucleotide changes and in ND3 we observed that twelve patients presented non-synonymous polymorphisms. To our knowledge, this constitutes the first report where the complete sequences of the ATP6 and ND3 have been analyzed in Mexican-Mestizo men with prostate cancer and diverse BMI. Our results differ with those reported in Caucasian populations, possibly due to ethnic differences.
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Affiliation(s)
- Patricia Canto
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - Jesús Benítez Granados
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - Mónica Adriana Martínez Ramírez
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - Edgardo Reyes
- c Departamento de Patología , Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - Guillermo Feria-Bernal
- d Departamento de Urología , Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México , and
| | - Eduardo García-García
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - María Elena Tejeda
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - Esperanza Zavala
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - André Tapia
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
| | - David Rojano-Mejía
- e Unidad de Medicina Física y Rehabilitación Centro, UMAE, Hospital de Traumatología y Ortopedia "Lomas Verdes", Instituto Mexicano del Seguro Social , México, D.F , México
| | - Juan Pablo Méndez
- a Facultad de Medicina , Unidad de Investigación en Obesidad, Universidad Nacional Autónoma de México , México, D.F , México
- b Clínica de Obesidad, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" , México, D.F , México
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Docosahexaenoic Acid Induces Oxidative DNA Damage and Apoptosis, and Enhances the Chemosensitivity of Cancer Cells. Int J Mol Sci 2016; 17:ijms17081257. [PMID: 27527148 PMCID: PMC5000655 DOI: 10.3390/ijms17081257] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/16/2016] [Accepted: 07/27/2016] [Indexed: 12/11/2022] Open
Abstract
The human diet contains low amounts of ω-3 polyunsaturated fatty acids (PUFAs) and high amounts of ω-6 PUFAs, which has been reported to contribute to the incidence of cancer. Epidemiological studies have shown that a high consumption of fish oil or ω-3 PUFAs reduced the risk of colon, pancreatic, and endometrial cancers. The ω-3 PUFA, docosahexaenoic acid (DHA), shows anticancer activity by inducing apoptosis of some human cancer cells without toxicity against normal cells. DHA induces oxidative stress and oxidative DNA adduct formation by depleting intracellular glutathione (GSH) and decreasing the mitochondrial function of cancer cells. Oxidative DNA damage and DNA strand breaks activate DNA damage responses to repair the damaged DNA. However, excessive DNA damage beyond the capacity of the DNA repair processes may initiate apoptotic signaling pathways and cell cycle arrest in cancer cells. DHA shows a variable inhibitory effect on cancer cell growth depending on the cells’ molecular properties and degree of malignancy. It has been shown to affect DNA repair processes including DNA-dependent protein kinases and mismatch repair in cancer cells. Moreover, DHA enhanced the efficacy of anticancer drugs by increasing drug uptake and suppressing survival pathways in cancer cells. In this review, DHA-induced oxidative DNA damage, apoptotic signaling, and enhancement of chemosensitivity in cancer cells will be discussed based on recent studies.
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Mesenchymal Stem/Stromal Cells in Stromal Evolution and Cancer Progression. Stem Cells Int 2015; 2016:4824573. [PMID: 26798356 PMCID: PMC4699086 DOI: 10.1155/2016/4824573] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/27/2015] [Accepted: 09/01/2015] [Indexed: 01/14/2023] Open
Abstract
The study of cancer biology has mainly focused on malignant epithelial cancer cells, although tumors also contain a stromal compartment, which is composed of stem cells, tumor-associated fibroblasts (TAFs), endothelial cells, immune cells, adipocytes, cytokines, and various types of macromolecules comprising the extracellular matrix (ECM). The tumor stroma develops gradually in response to the needs of epithelial cancer cells during malignant progression initiating from increased local vascular permeability and ending to remodeling of desmoplastic loosely vascularized stromal ECM. The constant bidirectional interaction of epithelial cancer cells with the surrounding microenvironment allows damaged stromal cell usage as a source of nutrients for cancer cells, maintains the stroma renewal thus resembling a wound that does not heal, and affects the characteristics of tumor mesenchymal stem/stromal cells (MSCs). Although MSCs have been shown to coordinate tumor cell growth, dormancy, migration, invasion, metastasis, and drug resistance, recently they have been successfully used in treatment of hematopoietic malignancies to enhance the effect of total body irradiation-hematopoietic stem cell transplantation therapy. Hence, targeting the stromal elements in combination with conventional chemotherapeutics and usage of MSCs to attenuate graft-versus-host disease may offer new strategies to overcome cancer treatment failure and relapse of the disease.
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Schweinsberg M, Weiss LC, Striewski S, Tollrian R, Lampert KP. More than one genotype: how common is intracolonial genetic variability in scleractinian corals? Mol Ecol 2015; 24:2673-85. [DOI: 10.1111/mec.13200] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/26/2015] [Accepted: 04/02/2015] [Indexed: 01/01/2023]
Affiliation(s)
- Maximilian Schweinsberg
- Department of Animal Ecology, Evolution and Biodiversity; University of Bochum; 44780 Bochum Germany
| | - Linda C. Weiss
- Department of Animal Ecology, Evolution and Biodiversity; University of Bochum; 44780 Bochum Germany
| | - Sebastian Striewski
- Department of Animal Ecology, Evolution and Biodiversity; University of Bochum; 44780 Bochum Germany
| | - Ralph Tollrian
- Department of Animal Ecology, Evolution and Biodiversity; University of Bochum; 44780 Bochum Germany
| | - Kathrin P. Lampert
- Department of Animal Ecology, Evolution and Biodiversity; University of Bochum; 44780 Bochum Germany
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Song M, Nishihara R, Wu K, Qian ZR, Kim SA, Sukawa Y, Mima K, Inamura K, Masuda A, Yang J, Fuchs CS, Giovannucci EL, Ogino S, Chan AT. Marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability. J Natl Cancer Inst 2015; 107:djv007. [PMID: 25810492 DOI: 10.1093/jnci/djv007] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. METHODS We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study. We documented and classified 1125 CRC cases into either MSI-high tumors, in which 30% or more of the 10 microsatellite markers demonstrated instability, or microsatellite-stable (MSS) tumors. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MSS tumors and MSI-high tumors in relation to marine ω-3 PUFA intake. All statistical tests were two-sided. RESULTS Marine ω-3 PUFA intake was not associated with overall incidence of CRC. However, a statistically significant difference was detected by MSI status (P heterogeneity = .02): High marine ω-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing ≥0.30g/d with <0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P linearity = .03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P linearity = .28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status. CONCLUSIONS High marine ω-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of ω-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms.
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Affiliation(s)
- Mingyang Song
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Reiko Nishihara
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kana Wu
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Zhi Rong Qian
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Sun A Kim
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Yasutaka Sukawa
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kosuke Mima
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kentaro Inamura
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Atsuhiro Masuda
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Juhong Yang
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Charles S Fuchs
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Edward L Giovannucci
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Shuji Ogino
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Andrew T Chan
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
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Fattorini P, Previderè C, Sorçaburu-Cigliero S, Marrubini G, Alù M, Barbaro AM, Carnevali E, Carracedo A, Casarino L, Consoloni L, Corato S, Domenici R, Fabbri M, Giardina E, Grignani P, Baldassarra SL, Moratti M, Nicolin V, Pelotti S, Piccinini A, Pitacco P, Plizza L, Resta N, Ricci U, Robino C, Salvaderi L, Scarnicci F, Schneider PM, Seidita G, Trizzino L, Turchi C, Turrina S, Vatta P, Vecchiotti C, Verzeletti A, De Stefano F. The molecular characterization of a depurinated trial DNA sample can be a model to understand the reliability of the results in forensic genetics. Electrophoresis 2014; 35:3134-44. [PMID: 25176610 DOI: 10.1002/elps.201400141] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Revised: 07/31/2014] [Accepted: 08/12/2014] [Indexed: 11/09/2022]
Abstract
The role of DNA damage in PCR processivity/fidelity is a relevant topic in molecular investigation of aged/forensic samples. In order to reproduce one of the most common lesions occurring in postmortem tissues, a new protocol based on aqueous hydrolysis of the DNA was developed in vitro. Twenty-five forensic laboratories were then provided with 3.0 μg of a trial sample (TS) exhibiting, in mean, the loss of 1 base of 20, and a molecular weight below 300 bp. Each participating laboratory could freely choose any combination of methods, leading to the quantification and to the definition of the STR profile of the TS, through the documentation of each step of the analytical approaches selected. The results of the TS quantification by qPCR showed significant differences in the amount of DNA recorded by the participating laboratories using different commercial kits. These data show that only DNA quantification "relative" to the used kit (probe) is possible, being the "absolute" amount of DNA inversely related to the length of the target region (r(2) = 0.891). In addition, our results indicate that the absence of a shared stable and certified reference quantitative standard is also likely involved. STR profiling was carried out selecting five different commercial kits and amplifying the TS for a total number of 212 multiplex PCRs, thus representing an interesting overview of the different analytical protocols used by the participating laboratories. Nine laboratories decided to characterize the TS using a single kit, with a number of amplifications varying from 2 to 12, obtaining only partial STR profiles. Most of the participants determined partial or full profiles using a combination of two or more kits, and a number of amplifications varying from 2 to 27. The performance of each laboratory was described in terms of number of correctly characterized loci, dropped-out markers, unreliable genotypes, and incorrect results. The incidence of unreliable and incorrect genotypes was found to be higher for participants carrying out a limited number of amplifications, insufficient to define the correct genotypes from damaged DNA samples such as the TS. Finally, from a dataset containing about 4500 amplicons, the frequency of PCR artifacts (allele dropout, allele drop-in, and allelic imbalance) was calculated for each kit showing that the new chemistry of the kits is not able to overcome the concern of template-related factors. The results of this collaborative exercise emphasize the advantages of using a standardized degraded DNA sample in the definition of which analytical parameters are critical for the outcome of the STR profiles.
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Affiliation(s)
- Paolo Fattorini
- Department of Medicine, Surgery and Health, University of Trieste, Trieste, Italy*
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Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, Angriman I. Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol 2014; 20:6774-6785. [PMID: 24944468 PMCID: PMC4051917 DOI: 10.3748/wjg.v20.i22.6774] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colonic Neoplasms/etiology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- DNA Methylation
- Disease Progression
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators/metabolism
- Neoplasm Grading
- Oncogenes
- Oxidative Stress
- Risk Factors
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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Strickertsson JAB, Desler C, Rasmussen LJ. Impact of bacterial infections on aging and cancer: impairment of DNA repair and mitochondrial function of host cells. Exp Gerontol 2014; 56:164-74. [PMID: 24704713 DOI: 10.1016/j.exger.2014.03.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Revised: 03/19/2014] [Accepted: 03/26/2014] [Indexed: 02/06/2023]
Abstract
The commensal floras that inhabit the gastrointestinal tract play critical roles in immune responses, energy metabolism, and even cancer prevention. Pathogenic and out of place commensal bacteria, can however have detrimental effects on the host, by introducing genomic instability and mitochondrial dysfunction, which are hallmarks of both aging and cancer. Helicobacter pylori and Enterococcus faecalis are bacteria of the gastrointestinal tract that have been demonstrated to affect these two hallmarks. These, and other bacteria, have been shown to decrease the transcription and translation of essential DNA repair subunits of major DNA repair pathways and increase production of reactive oxygen species (ROS). Defects in DNA repair cause mutations and genomic instability and are found in several cancers as well as in progeroid syndromes. This review describes our contemporary view on how bacterial infections impact DNA repair and damage, and the consequence on the mitochondrial and nuclear genomes. We argue that in the gastrointestinal tract, these mechanisms can contribute to tumorigenesis as well as cellular aging of the digestive system.
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Affiliation(s)
- Jesper A B Strickertsson
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Claus Desler
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Lene Juel Rasmussen
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark.
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35
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Li IC, Chiu CY, Wu CL, Chi JY, Jian SR, Wang SW, Chang CL. A dual-fluorescent reporter facilitates identification of thiol compounds that suppress microsatellite instability induced by oxidative stress. Free Radic Biol Med 2014; 69:86-95. [PMID: 24412704 DOI: 10.1016/j.freeradbiomed.2013.12.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/13/2013] [Accepted: 12/19/2013] [Indexed: 01/22/2023]
Abstract
The DNA mismatch-repair (MMR) system corrects replicative errors and minimizes mutations that occur at a high rate in microsatellites. Patients with chronic inflammation or inflammation-associated cancer display microsatellite instability (MSI), indicating a possible MMR inactivation. In fact, H2O2-generated oxidative stress inactivates the MMR function and increases mutation accumulation in a reporter microsatellite. However, it remains unclear whether MSI induced by oxidative stress is preventable because of the lack of a sufficiently sensitive detection assay. Here, we developed and characterized a dual-fluorescent system, utilizing DsRed harboring the (CA)13 microsatellite as a reporter and GFP for normalization, in near-isogenic human colorectal cancer cell lines. Via flow cytometry, this reporter sensitively detected H2O2-generated oxidative microsatellite mutations in a dose-dependent manner. The reporter further revealed that glutathione or N-acetylcysteine was better than aspirin and ascorbic acid for suppressing oxidative microsatellite mutations. These two thiol compounds also partially suppressed oxidative frameshift mutations in the coding microsatellites of the hMSH6 and CHK1 genes based on a fluoresceinated PCR-based assay. MSI suppression by N-acetylcysteine appears to be mediated through reduction of oxidative frameshift mutations in the coding microsatellite of hMSH6 and protection of hMSH6 and other MMR protein levels from being decreased by H2O2. Our findings suggest a linkage between oxidative damage, MMR deficiency, and MSI. The two thiol compounds are potentially valuable for preventing inflammation-associated MSI. The dual-fluorescent reporter with improved features will facilitate identification of additional compounds that modulate MSI, which is relevant to cancer initiation and progression.
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Affiliation(s)
- I-Chen Li
- Institute of Molecular Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chien-Yuan Chiu
- Institute of Oral Medicine, and National Cheng Kung University, Tainan 70101, Taiwan
| | - Chang-Lin Wu
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan
| | - Jhih-Ying Chi
- Institute of Molecular Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Siao-Ru Jian
- Institute of Oral Medicine, and National Cheng Kung University, Tainan 70101, Taiwan
| | - Shainn-Wei Wang
- Institute of Molecular Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan
| | - Christina L Chang
- Institute of Molecular Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Institute of Oral Medicine, and National Cheng Kung University, Tainan 70101, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan.
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36
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Devi SP, Kumaria S, Rao SR, Tandon P. Single primer amplification reaction (SPAR) methods reveal subsequent increase in genetic variations in micropropagated plants of Nepenthes khasiana Hook. f. maintained for three consecutive regenerations. Gene 2014; 538:23-9. [PMID: 24440289 DOI: 10.1016/j.gene.2014.01.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 01/09/2014] [Accepted: 01/10/2014] [Indexed: 11/17/2022]
Abstract
The genetic fidelity of in vitro-raised plants of three successive regenerations of Nepenthes khasiana Hook. f. was assessed using three different single primer amplification reaction (SPAR) methods, viz., random amplified polymorphic DNA (RAPD), inter-simple sequence repeat (ISSR) and direct amplification of minisatellite DNA region (DAMD) markers. Out of 80 RAPD primers screened, 14 primers reflected a genetic variation of 4.1% in the first regeneration which was increased to 9.4% in the third regeneration. In the case of ISSR, out of 36 primers screened for assessment of genetic homogeneity of the regenerated plantlets, 12 primers showed an increase of genetic variation from 4.3% to 10% from the first to the third regenerations. In DAMD profiling, 15 primers were used for the evaluation of genetic fidelity where 8.47% of polymorphism was observed in the first regeneration which was increased to 13.33% in the third regeneration. The cumulative analysis reflected a genetic variation of 5.65% in the first regeneration which increased subsequently to 7.77% in the second regeneration and 10.87% in the third regeneration. The present study demonstrates SPAR technique to be an efficient tool for the assessment of clonal fidelity of in vitro-raised plants.
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Affiliation(s)
| | - Suman Kumaria
- Department of Botany, North-Eastern Hill University, Shillong 793022, India.
| | - Satyawada Rama Rao
- Department of Biotechnology & Bioinformatics, North-Eastern Hill University, Shillong 793022, India
| | - Pramod Tandon
- Department of Botany, North-Eastern Hill University, Shillong 793022, India
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37
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Neri S, Bourin P, Peyrafitte JA, Cattini L, Facchini A, Mariani E. Human adipose stromal cells (ASC) for the regeneration of injured cartilage display genetic stability after in vitro culture expansion. PLoS One 2013; 8:e77895. [PMID: 24205017 PMCID: PMC3810264 DOI: 10.1371/journal.pone.0077895] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 09/05/2013] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells are emerging as an extremely promising therapeutic agent for tissue regeneration due to their multi-potency, immune-modulation and secretome activities, but safety remains one of the main concerns, particularly when in vitro manipulation, such as cell expansion, is performed before clinical application. Indeed, it is well documented that in vitro expansion reduces replicative potential and some multi-potency and promotes cell senescence. Furthermore, during in vitro aging there is a decrease in DNA synthesis and repair efficiency thus leading to DNA damage accumulation and possibly inducing genomic instability. The European Research Project ADIPOA aims at validating an innovative cell-based therapy where autologous adipose stromal cells (ASCs) are injected in the diseased articulation to activate regeneration of the cartilage. The primary objective of this paper was to assess the safety of cultured ASCs. The maintenance of genetic integrity was evaluated during in vitro culture by karyotype and microsatellite instability analysis. In addition, RT-PCR array-based evaluation of the expression of genes related to DNA damage signaling pathways was performed. Finally, the senescence and replicative potential of cultured cells was evaluated by telomere length and telomerase activity assessment, whereas anchorage-independent clone development was tested in vitro by soft agar growth. We found that cultured ASCs do not show genetic alterations and replicative senescence during the period of observation, nor anchorage-independent growth, supporting an argument for the safety of ASCs for clinical use.
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Affiliation(s)
- Simona Neri
- Laboratory of Immunorheumatology and Tissue Regeneration/RAMSES, Rizzoli Orthopedic Institute, Bologna, Italy
- * E-mail:
| | - Philippe Bourin
- Etablissement Français du Sang Pyrénées Méditerranée (EFS-PM), Toulouse, France
- CSA21, Toulouse, France
| | - Julie-Anne Peyrafitte
- Etablissement Français du Sang Pyrénées Méditerranée (EFS-PM), Toulouse, France
- STROMALAB, UMR 5273 Centre national de la Recherche Scientifique (CNRS)/Université Paul Sabatier, U1031 Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France
| | - Luca Cattini
- Laboratory of Immunorheumatology and Tissue Regeneration/RAMSES, Rizzoli Orthopedic Institute, Bologna, Italy
| | - Andrea Facchini
- Laboratory of Immunorheumatology and Tissue Regeneration/RAMSES, Rizzoli Orthopedic Institute, Bologna, Italy
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Erminia Mariani
- Laboratory of Immunorheumatology and Tissue Regeneration/RAMSES, Rizzoli Orthopedic Institute, Bologna, Italy
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
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38
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Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome. Leuk Res 2013; 38:95-102. [PMID: 23958061 DOI: 10.1016/j.leukres.2013.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 07/01/2013] [Indexed: 12/28/2022]
Abstract
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it has been suggested that additional mutations lead to progression of MDS to AML, the causative agent(s) for such mutations remains unclear. Oxidative stress is a potential cause, therefore, we evaluated levels of reactive oxygen species (ROS) in NUP98-HOXD13 (NHD13) transgenic mice, a murine model for MDS. Increased levels of ROS were detected in bone marrow nucleated cells (BMNC) that express CD71, a marker for cell proliferation, as well as immature, lineage negative bone marrow nucleated cells from NHD13 mice. In addition to the increase in ROS, increased DNA double strand breaks and activation of a G2/M phase cell cycle checkpoint were noted in NHD13 BMNC. Finally, using an in vivo assay for mutation frequency, we detected an increased mutation frequency in NHD13 BMNC. These results suggest that oxidative stress may contribute to disease progression of MDS to AML through ineffective repair of DNA damage and acquisition of oncogenic mutations.
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Conde-Pérezprina JC, Luna-López A, González-Puertos VY, Zenteno-Savín T, León-Galván MÁ, Königsberg M. DNA MMR systems, microsatellite instability and antioxidant activity variations in two species of wild bats: Myotis velifer and Desmodus rotundus, as possible factors associated with longevity. AGE (DORDRECHT, NETHERLANDS) 2012; 34:1473-1492. [PMID: 22453932 PMCID: PMC3528369 DOI: 10.1007/s11357-012-9399-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 02/22/2012] [Indexed: 05/31/2023]
Abstract
The accumulation of oxidative damage to biomolecules, such as DNA, is known to induce alterations in the cell's mechanisms and structure that might lead to the aging process. DNA mismatch repair system (MMR) corrects base mismatches generated during DNA replication that have escaped the proofreading process. In addition, antioxidant enzymes can reduce reactive oxygen species effects in order to protect cells from oxidizing damage. In order to determine the importance of these associated factors during the aging process, in this study, levels of MMR proteins MSH2 and MLH1, as well as microsatellite markers, were compared in liver, lung, and brain of juvenile, adult, and old, both female and male, individuals from two species of wild bats: the short-lived Myotis velifer and the longer lived Desmodus rotundus. Catalase, glutathione peroxidase, and superoxide dismutase were also analyzed to determine if the antioxidant protection correlates negatively with DNA damage. Antioxidant activities were higher in the longer lived D. rotundus than in M. velifer. Furthermore, old M. velifer but not old D. rotundus bats had reduced MMR levels and increased microsatellite instability. Therefore, although our results correlate the reduced MMR efficiency, the deficient antioxidant activity, and the increase in DNA damage with the aging process, this is not always true for all living organisms.
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Affiliation(s)
- Juan C. Conde-Pérezprina
- />Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Iztapalapa, A.P. 55–535, 09340 México, DF Mexico
| | | | - Viridiana Y. González-Puertos
- />Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Iztapalapa, A.P. 55–535, 09340 México, DF Mexico
| | - Tania Zenteno-Savín
- />Programa de Planeación Ambiental y Conservación, Centro de Investigaciones Biológicas del Noroeste, S.C., La Paz, Baja California Sur Mexico
| | - Miguel Ángel León-Galván
- />Departamento de Biología, DCBS, Universidad Autónoma Metropolitana Iztapalapa, A.P. 55–535, 09340 México, DF Mexico
| | - Mina Königsberg
- />Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Iztapalapa, A.P. 55–535, 09340 México, DF Mexico
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40
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Novel checkpoint pathway organization promotes genome stability in stationary-phase yeast cells. Mol Cell Biol 2012; 33:457-72. [PMID: 23149941 DOI: 10.1128/mcb.05831-11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Most DNA alterations occur during DNA replication in the S phase of the cell cycle. However, the majority of eukaryotic cells exist in a nondividing, quiescent state. Little is known about the factors involved in preventing DNA instability within this stationary-phase cell population. Previously, we utilized a unique assay system to identify mutations that increased minisatellite alterations specifically in quiescent cells in Saccharomyces cerevisiae. Here we conducted a modified version of synthetic genetic array analysis to determine if checkpoint signaling components play a role in stabilizing minisatellites in stationary-phase yeast cells. Our results revealed that a subset of checkpoint components, specifically MRC1, CSM3, TOF1, DDC1, RAD17, MEC3, TEL1, MEC1, and RAD53, prevent stationary-phase minisatellite alterations within the quiescent cell subpopulation of stationary-phase cells. Pathway analysis revealed at least three pathways, with MRC1, CSM3, and TOF1 acting in a pathway independent of MEC1 and RAD53. Overall, our data indicate that some well-characterized checkpoint components maintain minisatellite stability in stationary-phase cells but are regulated differently in those cells than in actively growing cells. For the MRC1-dependent pathway, the checkpoint itself may not be the important element; rather, it may be loss of the checkpoint proteins' other functions that contributes to DNA instability.
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41
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Linde CC, Selmes H. Genetic diversity and mating type distribution of Tuber melanosporum and their significance to truffle cultivation in artificially planted truffieres in Australia. Appl Environ Microbiol 2012; 78:6534-9. [PMID: 22773652 PMCID: PMC3426713 DOI: 10.1128/aem.01558-12] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 06/28/2012] [Indexed: 11/20/2022] Open
Abstract
Tuber melanosporum is a truffle native to Europe and is cultivated in countries such as Australia for the gastronomic market, where production yields are often lower than expected. We assessed the genetic diversity of T. melanosporum with six microsatellite loci to assess the effect of genetic drift on truffle yield in Australia. Genetic diversity as assessed on 210 ascocarps revealed a higher allelic diversity compared to previous studies from Europe, suggesting a possible genetic expansion and/or multiple and diverse source populations for inoculum. The results also suggest that the single sequence repeat diversity of locus ME2 is adaptive and that, for example, the probability of replication errors is increased for this locus. Loss of genetic diversity in Australian populations is therefore not a likely factor in limiting ascocarp production. A survey of nursery seedlings and trees inoculated with T. melanosporum revealed that <70% of seedlings and host trees were colonized with T. melanosporum and that some trees had been contaminated by Tuber brumale, presumably during the inoculation process. Mating type (MAT1-1-1 and MAT1-2-1) analyses on seedling and four- to ten-year-old host trees found that 100% of seedlings but only approximately half of host trees had both mating types present. Furthermore, MAT1-1-1 was detected significantly more commonly than MAT1-2-1 in established trees, suggesting a competitive advantage for MAT1-1-1 strains. This study clearly shows that there are more factors involved in ascocarp production than just the presence of both mating types on host trees.
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Affiliation(s)
- C C Linde
- Evolution, Ecology, and Genetics, Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
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42
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Medina-Arana V, Delgado L, Bravo A, Martín J, Fernández-Peralta AM, González-Aguilera JJ. Tumor spectrum in lynch syndrome, DNA mismatch repair system and endogenous carcinogens. J Surg Oncol 2012; 106:10-6. [PMID: 22275225 DOI: 10.1002/jso.23054] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 01/11/2012] [Indexed: 01/08/2023]
Abstract
Inactivation of Mismatch Repair genes in Lynch Syndrome, caused by inherited mutations, decreases the ability to repair DNA errors throughout life. This deficit may allow the development of any tumor type. Nevertheless, the Syndrome develops a specific tumor spectrum associated with the disease. We think that such spectrum of tumors would be related to the action of certain endogenous carcinogens such as bile acids and estrogens that aggravate the inherited defect.
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Affiliation(s)
- Vicente Medina-Arana
- Servicio de Cirugía General y Digestiva, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
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Abstract
Reactive oxygen species (ROS) are produced by living organisms as a result of normal cellular metabolism and environmental factors, such as air pollutants or cigarette smoke. ROS are highly reactive molecules and can damage cell structures such as carbohydrates, nucleic acids, lipids, and proteins and alter their functions. The shift in the balance between oxidants and antioxidants in favor of oxidants is termed “oxidative stress.” Regulation of reducing and oxidizing (redox) state is critical for cell viability, activation, proliferation, and organ function. Aerobic organisms have integrated antioxidant systems, which include enzymatic and nonenzymatic antioxidants that are usually effective in blocking harmful effects of ROS. However, in pathological conditions, the antioxidant systems can be overwhelmed. Oxidative stress contributes to many pathological conditions and diseases, including cancer, neurological disorders, atherosclerosis, hypertension, ischemia/perfusion, diabetes, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. In this review, we summarize the cellular oxidant and antioxidant systems and discuss the cellular effects and mechanisms of the oxidative stress.
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Fattorini P, Marrubini G, Sorçaburu-Cigliero S, Pitacco P, Grignani P, Previderè C. CE analysis and molecular characterisation of depurinated DNA samples. Electrophoresis 2011; 32:3042-52. [PMID: 22002769 DOI: 10.1002/elps.201100130] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 05/06/2011] [Accepted: 05/31/2011] [Indexed: 11/08/2022]
Abstract
A DNA sample was partially degraded by scalar heat-acid treatments to study the extent of apurinic-apyrimidinic (A-P) lesions produced along the molecule. A CE-UV method allowed us to measure the rate of depurination at pH 5.0 and 70°C which was calculated to be 5.41×10(-6) s(-1) for adenine and 6.27×10(-6) s(-1) for guanine. CE identified depurination on treated samples when it occurred with a loss of >4% of the basic moieties. The molecular features of the A-P enriched samples were investigated by using molecular assays (agarose gel electrophoresis, UV spectrophotometry and quantitative PCR) and the consistency of the results of the STR typing were compared with the degree of depurination of the PCR template. The treated DNA samples showed molecular features such as fragmentation, altered OD(260) /OD(280) ratios and decreased ability of the quantitative PCR to synthesise the human target, related to the severity of depurination. A satisfactory correlation between the degree of damage and the amount of residual PCR-sensitive target sequences was also demonstrated (r(2) =0.9717). The conventional and mini-STR typing of the samples showed that the genetic outcome was influenced by a depurination damage that exceeded 4% when locus drop-outs and artefactual PCR results were evident. As the success of STR typing depends on the integrity of the DNA recovered from the samples, the CE-UV, physical and molecular assays described here are proposed as a set of useful methods in the analysis of certain forensic and clinical samples, for a critical evaluation of the outcome of the genetic testing.
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Affiliation(s)
- Paolo Fattorini
- Department of Medicine, Surgery and Health, University of Trieste, Italy.
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45
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Neri S, Mariani E, Cattini L, Facchini A. Long-term in vitro expansion of osteoarthritic human articular chondrocytes do not alter genetic stability: a microsatellite instability analysis. J Cell Physiol 2011; 226:2579-85. [PMID: 21792915 DOI: 10.1002/jcp.22603] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In this study, we investigated genetic damage acquisition during in vitro culture of human osteoarthritic (OA) chondrocytes to evaluate their safety for use in regenerative medicine clinical applications. In particular, we have addressed the impact of long-term in vitro culture on simple sequence repeat stability, to evaluate the involvement of the mismatch repair system (MMR) in the accumulation of genetic damage. MMR, the main post-replicative correction pathway, has a fundamental role in maintaining genomic stability and can be monitored by assessing microsatellite instability (MSI). MMR activity has been reported to decrease with age not only in vivo, but also in vitro in relationship to culture passages. OA chondrocytes from seven donors were cultured corresponding to 13-29 population doublings. Aliquots of the cells were collected and analyzed for MSI at five DNA loci (CD4, VWA, FES, TPOX, and P53) and for MMR gene expression at each subculture. Genetic stability was confirmed throughout the culture period. MMR genes demonstrated a strong coordination at the transcriptional level among the different components; expression levels were very low, in accordance with the observed genetic stability. The reduced expression of MMR genes might underline no need for increasing DNA repair control in the culture conditions tested, in which no genetic damage was evidenced. These data argue for the safety of chondrocytes for cellular therapies and are encouraging for the potential use of in vitro expanded OA chondrocytes, supporting the extension of autologous cell therapy procedures to degenerative articular diseases.
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Affiliation(s)
- Simona Neri
- SC Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, Istituto di Ricerca Codivilla Putti, Istituto Ortopedico Rizzoli, Bologna, Italy.
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Zhu X, Chen L, Fan W, Lin MCM, Tian L, Wang M, Lin S, Wang Z, Zhang J, Wang J, Yao H, Kung H, Li D. An intronic variant in the GRP78, a stress-associated gene, improves prediction for liver cirrhosis in persistent HBV carriers. PLoS One 2011; 6:e21997. [PMID: 21779363 PMCID: PMC3136490 DOI: 10.1371/journal.pone.0021997] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Accepted: 06/10/2011] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Our previous study indicated that a common variant (rs430397 G>A) in the intron 5 of glucose-regulated protein 78 (GRP78) gene was associated with risk and prognosis of primary hepatocellular carcinoma (HCC), including HBV- and cirrhosis-related HCC. rs430397 polymorphism may be a contributing factor or biomarker of HBV infection or HBV-related cirrhosis. METHODOLOGY/PRINCIPAL FINDINGS 539 non-HBV-infected individuals, 205 self-limited infection and 496 persistent HBV infection were recruited between January 2001 and April 2005 from the hospitals in Southern China. Genomic DNA was genotyped for rs430397. The associations between the variation and susceptibility to liver cirrhosis (LC) in persistent HBV infection were examined. We observed that individuals carrying allele rs430397A were more likely to become HBV-related LC. When persistently infected patients were divided into four subgroups, patients with phase IV had an increased allele A and genotype AG compared with phase I and/or phase III. Decreased serum albumin and prolonged plasma prothrombin time (PT) were showed in LC patients carrying genotype AA. Furthermore, rs430397 genotype had an increased susceptibility to LC with dose-dependent manners (P-trend = 0.005), and the genotype did constitute a risk factor for the development of advanced LC (Child-Pugh classification C and B, P-trend = 0.021). CONCLUSIONS/SIGNIFICANCE rs430397 polymorphism may be a contributing factor to LC in persistent HBV carriers.
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Affiliation(s)
- Xiao Zhu
- Cancer Institute, Affiliated Tumor Hospital, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Molecular Diagnosis, Institute of Biochemistry and Molecular Biology, Guangdong Medical College, Dongguan, China
- * E-mail: (XZ); (DL)
| | - Lianzhou Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenguo Fan
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Marie C. M. Lin
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Linwei Tian
- Department of Epidemiology, School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Min Wang
- Cancer Institute, Affiliated Tumor Hospital, Guangzhou Medical University, Guangzhou, China
| | - Sheng Lin
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Zifeng Wang
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinfang Zhang
- Stanley Ho Center for Emerging Infectious Diseases, and Li Ka Shing Institute of Medical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinlong Wang
- Cancer Institute, Affiliated Tumor Hospital, Guangzhou Medical University, Guangzhou, China
| | - Hong Yao
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Stanley Ho Center for Emerging Infectious Diseases, and Li Ka Shing Institute of Medical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Hsiangfu Kung
- Stanley Ho Center for Emerging Infectious Diseases, and Li Ka Shing Institute of Medical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Dongpei Li
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- * E-mail: (XZ); (DL)
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Karpinets T, Greenwood D, Pogribny I, Samatova N. Bacterial stationary-state mutagenesis and Mammalian tumorigenesis as stress-induced cellular adaptations and the role of epigenetics. Curr Genomics 2011; 7:481-96. [PMID: 18369407 DOI: 10.2174/138920206779315764] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2006] [Revised: 11/11/2006] [Accepted: 11/23/2006] [Indexed: 01/16/2023] Open
Abstract
Mechanisms of cellular adaptation may have some commonalities across different organisms. Revealing these common mechanisms may provide insight in the organismal level of adaptation and suggest solutions to important problems related to the adaptation. An increased rate of mutations, referred as the mutator phenotype, and beneficial nature of these mutations are common features of the bacterial stationary-state mutagenesis and of the tumorigenic transformations in mammalian cells. We argue that these commonalities of mammalian and bacterial cells result from their stress-induced adaptation that may be described in terms of a common model. Specifically, in both organisms the mutator phenotype is activated in a subpopulation of proliferating stressed cells as a strategy to survival. This strategy is an alternative to other survival strategies, such as senescence and programmed cell death, which are also activated in the stressed cells by different subpopulations. Sustained stress-related proliferative signalling and epigenetic mechanisms play a decisive role in the choice of the mutator phenotype survival strategy in the cells. They reprogram cellular functions by epigenetic silencing of cell-cycle inhibitors, DNA repair, programmed cell death, and by activation of repetitive DNA elements. This reprogramming leads to the mutator phenotype that is implemented by error-prone cell divisions with the involvement of Y family polymerases. Studies supporting the proposed model of stress-induced cellular adaptation are discussed. Cellular mechanisms involved in the bacterial stress-induced adaptation are considered in more detail.
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Affiliation(s)
- Tv Karpinets
- Computational Biology Institute, Computer Science and Mathematics Division, Oak Ridge National Laboratory, P.O. Box 2008, MS6164, Oak Ridge, TN 37831, USA
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Shi MM, Michalski SG, Chen XY, Durka W. Isolation by elevation: genetic structure at neutral and putatively non-neutral loci in a dominant tree of subtropical forests, Castanopsis eyrei. PLoS One 2011; 6:e21302. [PMID: 21701584 PMCID: PMC3118804 DOI: 10.1371/journal.pone.0021302] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 05/24/2011] [Indexed: 11/18/2022] Open
Abstract
Background The distribution of genetic diversity among plant populations growing along elevational gradients can be affected by neutral as well as selective processes. Molecular markers used to study these patterns usually target neutral processes only, but may also be affected by selection. In this study, the effects of elevation and successional stage on genetic diversity of a dominant tree species were investigated controlling for neutrality of the microsatellite loci used. Methodology/Principal Findings Diversity and differentiation among 24 populations of Castanopsis eyrei from different elevations (251–920 m) and successional stages were analysed by eight microsatellite loci. We found that one of the loci (Ccu97H18) strongly deviated from a neutral model of differentiation among populations due to either divergent selection or hitchhiking with an unknown selected locus. The analysis showed that C. eyrei populations had a high level of genetic diversity within populations (AR = 7.6, HE = 0.82). Genetic variation increased with elevation for both the putatively selected locus Ccu97H18 and the neutral loci. At locus Ccu97H18 one allele was dominant at low elevations, which was replaced at higher elevations by an increasing number of other alleles. The level of genetic differentiation at neutral loci was similar to that of other Fagaceae species (FST = 0.032, = 0.15). Population differentiation followed a model of isolation by distance but additionally, strongly significant isolation by elevation was found, both for neutral loci and the putatively selected locus. Conclusions/Significance The results indicate higher gene flow among similar elevational levels than across different elevational levels and suggest a selective influence of elevation on the distribution of genetic diversity in C. eyrei. The study underlines the importance to check the selective neutrality of marker loci in analyses of population structure.
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Affiliation(s)
- Miao-Miao Shi
- Helmholtz Centre for Environmental Research - UFZ, Department of Community Ecology (BZF), Halle, Germany.
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Mahlke MA, Cortez LA, Ortiz MA, Rodriguez M, Uchida K, Shigenaga MK, Lee S, Zhang Y, Tominaga K, Hubbard GB, Ikeno Y. The anti-tumor effects of calorie restriction are correlated with reduced oxidative stress in ENU-induced gliomas. PATHOBIOLOGY OF AGING & AGE RELATED DISEASES 2011; 1:PBA-1-7189. [PMID: 22953030 PMCID: PMC3417672 DOI: 10.3402/pba.v1i0.7189] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 05/10/2011] [Accepted: 05/10/2011] [Indexed: 11/17/2022]
Abstract
The anti-tumor effects of calorie restriction (CR) and the possible underlying mechanisms were investigated using ethylnitrosourea (ENU)-induced glioma in rats. ENU was given transplacentally at gestational day 15, and male offspring were used in this experiment. The brain from 4-, 6-, and 8-month-old rats fed either ad libitum (AL) or calorie-restricted diets (40% restriction of total calories compared to AL rats) was studied. Tumor burden was assessed by comparing the number and size of gliomas present in sections of the brain. Immunohistochemical analysis was used to document lipid peroxidation [4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)], protein oxidation (nitrotyrosine), glycation and AGE formation [methylglyoxal (MG) and carboxymethyllysine (CML)], cell proliferation activity [proliferating cell nuclear antigen (PCNA)], cell death [single-stranded DNA (ssDNA)], presence of thioredoxin 1 (Trx1), and presence of heme oxygenase-1 (HO-1) associated with the development of gliomas. The results showed that the number of gliomas did not change with age in the AL groups; however, the average size of the gliomas was significantly larger in the 8-month-old group compared to that of the younger groups. Immunopositivity was observed mainly in tumor cells and reactive astrocytes in all histological types of ENU-induced glioma. Immunopositive areas for HNE, MDA, nitrotyrosine, MG, CML, HO-1, and Trx1 increased with the growth of gliomas. The CR group showed both reduced number and size of gliomas, and tumors exhibited less accumulation of oxidative damage, decreased formation of glycated end products, and a decreased presence of HO-1 and Trx1 compared to the AL group. Furthermore, gliomas of the CR group showed less PCNA positive and more ssDNA positive cells, which are correlated to the retarded growth of tumors. Interestingly, we also discovered that the anti-tumor effects of CR were associated with decreased hypoxia-inducible factor-1α (HIF-1α) levels in normal brain tissue. Our results are very exciting because they not only demonstrate the anti-tumor effects of CR in gliomas, but also indicate the possible underlying mechanisms, i.e. anti-tumor effects of CR observed in this investigation are associated with reduced accumulation of oxidative damage, decreased formation of glycated end products, decreased presence of HO-1 and Trx1, reduced cell proliferation and increased apoptosis, and decreased levels of HIF-1α.
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Affiliation(s)
- Megan A Mahlke
- Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, TX, USA
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Genomic instability after allogeneic hematopoietic cell transplantation is frequent in oral mucosa, particularly in patients with a history of chronic graft-versus-host disease, and rare in nasal mucosa. Blood 2010; 116:1803-6. [PMID: 20548092 DOI: 10.1182/blood-2009-10-249201] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Genomic instability (GI) of cells may lead to their malignant transformation. Carcinoma after hematopoietic cell transplantation (HCT) frequently involves some (eg, oral) but not other (eg, nasal) epithelia. We examined GI in oral and nasal mucosal specimens from 105 subjects, including short-term (7-98 days, n = 32) and long-term (4-22 yrs, n = 25) allogeneic HCT survivors. Controls included autologous HCT survivors (n = 11), patients treated with chemotherapy without HCT (n = 9) and healthy controls (n = 27). GI was detected in 60% oral versus only 4% nasal specimens in long-term allogeneic HCT survivors (P < .001). None of the controls showed GI. In oral specimens, GI was significantly associated with history of oral chronic graft-versus-host disease (cGVHD). We conclude that GI after HCT is frequent in some (oral) but rare in other (nasal) epithelia. This may explain why some epithelia (especially those involved with cGVHD) are prone to develop cancer.
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