Publications by authors named "Roberta Meschini"

31 Publications

DNA integrity and ecophysiological responses of Spanish populations of Ulmus glabra to increasing ozone levels.

Ecotoxicology 2021 Jun 10. Epub 2021 Jun 10.

DEB, University of Tuscia, Viterbo, Italy.

Ulmus glabra is a deciduous tree with a wide distribution in the Eurosiberian region. The southernmost populations, in the Mediterranean area, are fragmented in mountain areas which act as a refugium. These small relict populations can act as sentinel of global change, including climate change and impacts of human activities such as air pollution. Besides, tropospheric ozone (O) is an additional stress factor in the Mediterranean region affecting plant physiology and health. Moreover, oxidative stress caused by O could increase DNA damage in plants cells. U. glabra 4-year-old seedlings originated from a natural population growing in the Guadarrama mountain range (central Spain), were exposed in Open Top Chambers to four O treatments: charcoal filtered air, non-filtered air reproducing ambient levels, non-filtered air supplemented with 15 nl l O and non- filtered air supplemented with 30 nl l O. Ozone effects on the DNA integrity through Comet assay were evaluated and eco-physiological responses were explored as well as. Comet assay showed a significant increase of DNA damage with increasing levels of O after only one-month exposure, when no eco-physiological symptoms of damage could be detected. Comet assay could thus be suggested as a predictive test to detect DNA damage induced in plants by other abiotic stresses as well as to identify tolerant and sensitive species or in preservation strategies of small relict populations. The discovery of a test for an early identification of stressed plants could be important to speed the selection of tolerant individuals for breeding programmes.
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http://dx.doi.org/10.1007/s10646-021-02436-zDOI Listing
June 2021

RENEB Inter-Laboratory comparison 2017: limits and pitfalls of ILCs.

Int J Radiat Biol 2021 May 25:1-18. Epub 2021 May 25.

Agenzia Nazionale per le Nuove Tecnologie, L´Energia e lo Sviluppo Economico Sostenibile, Rome, Italy.

Purpose: In case of a mass-casualty radiological event, there would be a need for networking to overcome surge limitations and to quickly obtain homogeneous results (reported aberration frequencies or estimated doses) among biodosimetry laboratories. These results must be consistent within such network. Inter-laboratory comparisons (ILCs) are widely accepted to achieve this homogeneity. At the European level, a great effort has been made to harmonize biological dosimetry laboratories, notably during the MULTIBIODOSE and RENEB projects. In order to continue the harmonization efforts, the RENEB consortium launched this intercomparison which is larger than the RENEB network, as it involves 38 laboratories from 21 countries. In this ILC all steps of the process were monitored, from blood shipment to dose estimation. This exercise also aimed to evaluate the statistical tools used to compare laboratory performance.

Materials And Methods: Blood samples were irradiated at three different doses, 1.8, 0.4 and 0 Gy (samples A, C and B) with 4-MV X-rays at 0.5 Gy min, and sent to the participant laboratories. Each laboratory was requested to blindly analyze 500 cells per sample and to report the observed frequency of dicentric chromosomes per metaphase and the corresponding estimated dose.

Results: This ILC demonstrates that blood samples can be successfully distributed among laboratories worldwide to perform biological dosimetry in case of a mass casualty event. Having achieved a substantial harmonization in multiple areas among the RENEB laboratories issues were identified with the available statistical tools, which are not capable to advantageously exploit the richness of results of a large ILCs. Even though - and -tests are accepted methods for biodosimetry ILCs, setting the number of analyzed metaphases to 500 and establishing a tests' common threshold for all studied doses is inappropriate for evaluating laboratory performance. Another problem highlighted by this ILC is the issue of the dose-effect curve diversity. It clearly appears that, despite the initial advantage of including the scoring specificities of each laboratory, the lack of defined criteria for assessing the robustness of each laboratory's curve is a disadvantage for the 'one curve per laboratory' model.

Conclusions: Based on our study, it seems relevant to develop tools better adapted to the collection and processing of results produced by the participant laboratories. We are confident that, after an initial harmonization phase reached by the RENEB laboratories, a new step toward a better optimization of the laboratory networks in biological dosimetry and associated ILC is on the way.
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http://dx.doi.org/10.1080/09553002.2021.1928782DOI Listing
May 2021

Synthesis and Evaluation of Artemisinin-Based Hybrid and Dimer Derivatives as Antimelanoma Agents.

ACS Omega 2020 Jan 27;5(1):243-251. Epub 2019 Dec 27.

Department of Ecological and Biological Sciences, University of Tuscia, via S. C. De Lellis 44, 01100, Viterbo, Italy.

A library of hybrid and dimer compounds based on the natural scaffold of artemisinin was synthesized. These derivatives were obtained by coupling of artemisinin derivatives, artesunate, and dihydroartemisinin with a panel of phytochemical compounds. The novel artemisinin-based hybrids and dimers were evaluated for their anticancer activity on a cervical cancer cell line (HeLa) and on three complementary metastatic melanoma cancer cell lines (SK-MEL3, SK-MEL24, and RPMI-7951). Two hybrid compounds obtained by coupling of artesunate with eugenol and tyrosol, and one of the dimer compounds containing curcumin, emerged as the most active and cancer-selective derivatives.
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http://dx.doi.org/10.1021/acsomega.9b02600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964273PMC
January 2020

In vitro evaluation of cytotoxic and genotoxic effects of Di(2-ethylhexyl)-phthalate (DEHP) on European sea bass (Dicentrarchus labrax) embryonic cell line.

Toxicol In Vitro 2019 Apr 24;56:118-125. Epub 2019 Jan 24.

Department of Ecological and Biological Sciences, Ichthyogenic Experimental Marine Center (CISMAR), University of Tuscia, Borgo Le Saline, 01016 Tarquinia, VT, Italy.

Marine litter is extensively distributed in the marine environment, and plastic debris, of which litter is mostly composed, can be a major source of pollutants. Among them, Di(2-ethylhexyl)-phthalate (DEHP) is the most abundantly used plastic additive, and it has been reported to affect biochemical processes both in humans and wildlife; however, studies on its toxicological effects on marine organisms are still scarce. In this survey, we studied the cytotoxic, genotoxic, and mutagenic effects of DEHP in European sea bass embryonic cell line (DLEC) by applying specific in vitro tests. Results showed a significant decrease in cell viability starting at 0.01 mM of DEHP after 24 h together with a significant increase in apoptosis and necrosis, morphological changes and cell detachment. Consistently, we detected a moderate increase in DNA strand breaks from 0.02 mM, and a dose-dependent increase in of micronucleus frequency from 0.01 mM, accompanied by a significant inhibition of cell proliferation, which suggested a possible aneugenic effect of this phthalate. Our results demonstrate that in vitro exposure to DEHP had a dose-dependent cytotoxic and genotoxic effects in DLEC cell line, encouraging further investigation into its effects in in vivo and/or ex vivo cell systems of marine organisms.
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http://dx.doi.org/10.1016/j.tiv.2019.01.017DOI Listing
April 2019

Oxidative nucleophilic substitution selectively produces cambinol derivatives with antiproliferative activity on bladder cancer cell lines.

Bioorg Med Chem Lett 2019 01 7;29(1):78-82. Epub 2018 Nov 7.

Department of Biological and Ecological Sciences, University of Tuscia, Largo dell'Università, Viterbo 01100, Italy.

Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.006DOI Listing
January 2019

Influence of chromatin remodeling in the removal of UVC-induced damage in TCR proficient and deficient Chinese hamster cells.

Mutat Res Genet Toxicol Environ Mutagen 2018 Dec 28;836(Pt A):124-131. Epub 2018 Aug 28.

Department of Ecological & Biological Sciences (DEB), University of Tuscia, Viterbo, Italy.

In mammalian cells, nucleotide excision repair system is constituted of two sub-pathways, global genomic repair (GGR) and transcription coupled repair (TCR). Deficiency of TCR pathway leads to Cockyane syndrome (CS) which is a rare human autosomal recessive disorder. Owing to the pivotal role of CSB gene in TCR, it's mutation causes severe repair and transcriptional defects in CSB patients. CSB protein belongs to the ATP chromatin remodeling complex, hence presumably an improper chromatin remodeling in CSB cells could be at the source of inefficient removal of pyrimidine dimers (CPDs) after UVC exposure in these patients. In this study, we evaluated the role of chromatin remodeling process on UVC induced CPDs and the ensuing effect on chromosomal aberrations in UV61 cells (TCR deficient) and its parental cell line, AA8 (TCR proficient). We observed that post 2 h UVC irradiation, both cell lines underwent pronounced chromatin relaxation but was lower in CSB deficient UV61 cells. Since the deficiency in chromatin remodeling in CSB-mutated cells was accompanied by a decrease in the histone acetylation level, the histone deacetylase inhibitor trichostatin A (TSA) was employed to improve the removal of UVC-induced lesions by increasing the histone acetylation level. Contrary to expectations, TSA increased the induction of chromosomal aberrations and apoptotic cells along with amounts of CPDs after UVC-irradiation, indicating that changes in histone acetylation levels might contribute to the failure in the removal of UVC-induced lesions. Also, it has been shown earlier that the expression of genes regulated by CSB is affected by the increase in the acetylation level produced by TSA. Taken all together, we hypothesize that failure in the removal of UVC induced lesions in CSB-deficient cells can be caused by an imbalance in histone acetylation levels leading to chromatin conformation changes and hence interaction defects among repair proteins and DNA lesions.
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http://dx.doi.org/10.1016/j.mrgentox.2018.08.003DOI Listing
December 2018

Modulation of chromatin conformation by the histone deacetylase inhibitor trichostatin A promotes the removal of radiation-induced lesions in ataxia telangiectasia cell lines.

Mutat Res Genet Toxicol Environ Mutagen 2018 Dec 15;836(Pt A):109-116. Epub 2018 Jun 15.

Department of Ecological and Biological Sciences (DEB), University of Tuscia, Via San Camillo de Lellis snc, 01100, Viterbo, Italy. Electronic address:

Ataxia telangiectasia is a rare autosomal recessive genome instability syndrome caused by mutations in the Ataxia Telangiectasia Mutated gene and characterized by a very high sensitivity to agents inducing double strand breaks such as ionizing radiation. In cells derived from ataxia telangiectasia patients a prominent enhancement of chromosomal aberrations is revealed as a consequence of this radiosensitivity characteristic, arising from defective DNA repair for a small fraction of breaks localized in the less accessible heterochromatin. Moreover, the signaling mediated by ataxia telangiectasia protein kinase also modifies chromatin structure. Even if there is a lot of knowledge concerning biochemical aspects of repair of double strand breaks, no conclusive results on radiosensitivity of structurally- and functionally-different chromatin are available, particularly in ataxia telangiectasia cells. Thus, a wild-type cell line and two ataxia telangiectasia patient derived ones could represent a suitable model to study the possible relationship between chromatin conformation and sensitivity to ionizing radiation. In this context, the effects of both cytosine arabinoside, an inhibitor of DNA repair synthesis, and trichostatin A, a histone deacetylase inhibitor, were tested in normal and ataxia telangiectasia lymphoblastoid cell lines carrying different mutation in the Ataxia Telangiectasia Mutated gene. The response to both inhibitors was investigated analyzing two endpoints, namely, chromosomal aberrations and the removal of DNA lesions by Comet assay, after exposure to X-rays. Results obtained suggest that the modulation of chromatin structure by trichostatin A leading to a more open conformation, decreases radiation-induced chromosomal aberrations in ataxia telangiectasia cells. The reduction in chromosomal instability can be attributed to an enhancement in DNA repair occurring in the presence of the histone deacetylase inhibitor, as its abolishment by the known inhibitor of DNA repair synthesis cytosine arabinoside clearly demonstrates. Data obtained could indicate a pivotal role of chromatin conformation in the radiosensitivity of ataxia telangiectasia cells.
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http://dx.doi.org/10.1016/j.mrgentox.2018.06.016DOI Listing
December 2018

Tyrosinase-Treated Hydroxytyrosol-Enriched Olive Vegetation Waste with Increased Antioxidant Activity Promotes Autophagy and Inhibits the Inflammatory Response in Human THP-1 Monocytes.

J Agric Food Chem 2018 Nov 7;66(46):12274-12284. Epub 2018 Nov 7.

Department of Ecological and Biological Sciences (DEB) , University of Tuscia , Viterbo , Italy.

Treatment of olive vegetation waste with tyrosinase immobilized on multiwalled carbon nanotubes increased the antioxidant activity as a consequence of the conversion of phenols to corresponding catechol derivatives, as evaluated by DPPH, Comet assay, and micronucleus analyses. During this transformation, 4-hydroxyphenethyl alcohol (tyrosol) was quantitatively converted to bioactive 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol). The hydroxytyrosol-enriched olive vegetation waste also promoted autophagy and inhibited the inflammatory response in human THP-1 monocytes.
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http://dx.doi.org/10.1021/acs.jafc.8b03630DOI Listing
November 2018

Laccase-Mediated Enhancement of the Antioxidant Activity of Propolis and Poplar Bud Exudates.

ACS Omega 2017 Jun 6;2(6):2515-2523. Epub 2017 Jun 6.

Department of Biological and Ecological Sciences, University of Tuscia, Via S. Camillo de Lellis snc, I-01100 Viterbo, Italy.

The treatment of propolis and poplar bud exudates with laccase from and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical increased the antioxidant activity, as evaluated by the 2,2'-diphenyl picrylhydrazyl (DPPH)- and -butyl-OOH-induced DNA breakage comet assay analyses. The effect was highest for shorter reaction times. Propolis showed the highest antioxidant activity in the DPPH test, whereas poplar bud exudates were more active in reducing the -butyl-OOH-induced lesions in the Chinese hamster ovary cell line. Even if the concentration of polyphenols decreased during the oxidation, the formation of low-molecular-weight phenols phloroglucinol (1,3,5-trihydroxy benzene), hydroquinone (1,4-dihydroxy benzene), and catechol (1,2-dihydroxy benzene), characterized by the radical-scavenging activity, can account for the observed increase in the antioxidant activity.
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http://dx.doi.org/10.1021/acsomega.7b00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044900PMC
June 2017

Graphene-Based Raman Spectroscopy for pH Sensing of X-rays Exposed and Unexposed Culture Media and Cells.

Sensors (Basel) 2018 Jul 12;18(7). Epub 2018 Jul 12.

Dipartimento di Medicina Sperimentale, Università della Campania "L. Vanvitelli", 80138 Naples, Italy.

Graphene provides a unique way of sensing the local pH level of substances on the micrometric scale, with important implications for the monitoring of cellular metabolic activities where proton excretion could occur. Accordingly, an innovative biosensing approach for the quantification of the pH value of biological fluids, to be used also with small amounts of fluids, was realized and tested. It is based on the use of micro-Raman spectroscopy to detect the modifications of the graphene doping level induced by the contact of the graphene with the selected fluids. The approach was preliminarily tested on aqueous solutions of known pH values. It was then used to quantify the pH values of cell culture media directly exposed to different doses of X-ray radiation and to media exposed to X-ray-irradiated cells. The Raman response of cells placed on graphene layers was also examined.
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http://dx.doi.org/10.3390/s18072242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069167PMC
July 2018

Genetic effects in Helix aspersa near a coal plant revealed by the micronucleus test.

Ecotoxicology 2018 Mar 5;27(2):234-243. Epub 2018 Feb 5.

Department of Ecological and Biological Sciences, Tuscia University, Largo dell'Università snc, 01100, Viterbo, Italy.

Coal plants can be a major source of mutagenic pollutants. In this study we used the common land snail Helix aspersa, to detect the mutagenic effect of pollution from a coal plant in central Italy applying the micronucleus test (MN) on snail's haemocytes and evaluating trace elements concentration (As Cd, Pb, Hg, and Zn) in soil and snails. Snails from a biological farm were exposed for 13 days in five locations at different distances from the plant. Wild snails collected in the same locations were also analysed. MN frequency in exposed snails was significantly higher in four locations within 10 km from to the plant, with respect to the control and the farthest location. Comparing the MN frequency between farmed and wild snails, a significantly higher frequency emerged for the exposed snails in all locations except the farthest, likely indicating adaptation or selection of the wild organisms due to chronic exposure to pollutants. In natural snails significantly higher MN frequencies with near the plant emerged as well. Trace elements analysis showed significant correlations between MN frequencies and both Zn and As concentrations in soil, for both exposed and wild snails, and Zn and Pb concentrations in exposed snails. Our results were consistent with those previously obtained when evaluating primary DNA damage in natural snails from the same area and show that the snails near the plant were affected by a permanent cytogenetic damage. Moreover, they confirm the suitability of snails for biomonitoring the presence of pollutants with mutagenic effect.
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http://dx.doi.org/10.1007/s10646-018-1906-8DOI Listing
March 2018

Novel compound heterozygous mutations in a child with Ataxia-Telangiectasia showing unrelated cerebellar disorders.

J Neurol Sci 2016 Dec 13;371:48-53. Epub 2016 Oct 13.

Unit of Child Neurology and Psychiatry, Spedali Civili and University of Brescia, Brescia, Italy.

We report the case of a 6-year-old female patient with Ataxia Telangiectasia, an extremely rare condition, who developed in addition a left cerebellar astrocytoma and a right cerebellar infarction, considered as two independent events. Children with AT have an increased risk of developing cancer, but only few cases of glioma are reported and, at our knowledge, no other case of unrelated cerebellar glioma and cerebellar infarction in with the same AT patient have been described. The molecular analysis of ATM (Ataxia Telangiectasia Mutated) gene showed that the patient is compound heterozygote for two previously unreported mutations: c.3291delC (p.Phe1097fs) at exon 25 and c.8198A>C (p.Gln2733Pro) at exon 58. The role of the identified ATM gene mutations in the pathogenesis of Ataxia Telangiectasia and the coexisting cerebellar disorders is discussed.
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http://dx.doi.org/10.1016/j.jns.2016.10.014DOI Listing
December 2016

Dose assessment intercomparisons within the RENEB network using G-lymphocyte prematurely condensed chromosomes (PCC assay).

Int J Radiat Biol 2017 01 4;93(1):48-57. Epub 2016 Nov 4.

j Stockholm University, Institute Molecular Biosciences , Stockholm , Sweden.

Purpose: Dose assessment intercomparisons within the RENEB network were performed for triage biodosimetry analyzing G-lymphocyte PCC for harmonization, standardization and optimization of the PCC assay.

Materials And Methods: Comparative analysis among different partners for dose assessment included shipment of PCC-slides and captured images to construct dose-response curves for up to 6 Gy γ-rays. Accident simulation exercises were performed to assess the suitability of the PCC assay by detecting speed of analysis and minimum number of cells required for categorization of potentially exposed individuals.

Results: Calibration data based on Giemsa-stained fragments in excess of 46 PCC were obtained by different partners using galleries of PCC images for each dose-point. Mean values derived from all scores yielded a linear dose-response with approximately 4 excess-fragments/cell/Gy. To unify scoring criteria, exercises were carried out using coded PCC-slides and/or coded irradiated blood samples. Analysis of samples received 24 h post-exposure was successfully performed using Giemsa staining (1 excess-fragment/cell/Gy) or centromere/telomere FISH-staining for dicentrics.

Conclusions: Dose assessments by RENEB partners using appropriate calibration curves were mostly in good agreement. The PCC assay is quick and reliable for whole- or partial-body triage biodosimetry by scoring excess-fragments or dicentrics in G-lymphocytes. Particularly, analysis of Giemsa-stained excess PCC-fragments is simple, inexpensive and its automation could increase throughput and scoring objectivity of the PCC assay.
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http://dx.doi.org/10.1080/09553002.2016.1234725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495998PMC
January 2017

RENEB intercomparisons applying the conventional Dicentric Chromosome Assay (DCA).

Int J Radiat Biol 2017 01 21;93(1):20-29. Epub 2016 Oct 21.

y Radiation and Nuclear Safety Authority , Helsinki , Finland.

Purpose: Two quality controlled inter-laboratory exercises were organized within the EU project 'Realizing the European Network of Biodosimetry (RENEB)' to further optimize the dicentric chromosome assay (DCA) and to identify needs for training and harmonization activities within the RENEB network.

Materials And Methods: The general study design included blood shipment, sample processing, analysis of chromosome aberrations and radiation dose assessment. After manual scoring of dicentric chromosomes in different cell numbers dose estimations and corresponding 95% confidence intervals were submitted by the participants.

Results: The shipment of blood samples to the partners in the European Community (EU) were performed successfully. Outside the EU unacceptable delays occurred. The results of the dose estimation demonstrate a very successful classification of the blood samples in medically relevant groups. In comparison to the 1st exercise the 2nd intercomparison showed an improvement in the accuracy of dose estimations especially for the high dose point.

Conclusions: In case of a large-scale radiological incident, the pooling of ressources by networks can enhance the rapid classification of individuals in medically relevant treatment groups based on the DCA. The performance of the RENEB network as a whole has clearly benefited from harmonization processes and specific training activities for the network partners.
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http://dx.doi.org/10.1080/09553002.2016.1233370DOI Listing
January 2017

Investigation of the influence of calibration practices on cytogenetic laboratory performance for dose estimation.

Int J Radiat Biol 2017 01 13;93(1):118-126. Epub 2016 Oct 13.

f Stockholm University , Department of Molecular Biosciences , Stockholm , Sweden.

Purpose: In the frame of the QA program of RENEB, an inter-laboratory comparison (ILC) of calibration sources used in biological dosimetry was achieved to investigate the influence of calibration practices and protocols on the results of the dose estimation performance as a first step to harmonization and standardization of dosimetry and irradiation practices in the European biological dosimetry network.

Materials And Methods: Delivered doses by irradiation facilities used by RENEB partners were determined with EPR/alanine dosimetry system. Dosimeters were irradiated in the same conditions as blood samples. A short survey was also performed to collect the information needed for the data analysis and evaluate the diversity of practices.

Results: For most of partners the deviation of delivered dose from the targeted dose remains below 10%. Deviations larger than 10% were observed for five facilities out of 21. Origins of the largest discrepancies were identified. Correction actions were evaluated as satisfactory. The re-evaluation of some ILC results for the fluorescence in situ hybridization (FISH) and premature chromosome condensation (PCC) assays has been performed leading to an improvement of the overall performances.

Conclusions: This work has shown the importance of dosimetry in radiobiology studies and the needs of harmonization, standardization in irradiation and dosimetry practices and educational training for biologists using ionizing radiation.
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http://dx.doi.org/10.1080/09553002.2016.1213455DOI Listing
January 2017

RENEB - Running the European Network of biological dosimetry and physical retrospective dosimetry.

Int J Radiat Biol 2017 01 6;93(1):2-14. Epub 2016 Oct 6.

a Bundesamt für Strahlenschutz , Department Radiation Protection and Health , Oberschleissheim , Germany.

Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios.

Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015.

Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.
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http://dx.doi.org/10.1080/09553002.2016.1230239DOI Listing
January 2017

Isolation of Mesophyll Protoplasts from Mediterranean Woody Plants for the Study of DNA Integrity under Abiotic Stress.

Front Plant Sci 2016 15;7:1168. Epub 2016 Aug 15.

Laboratory of Forest Biotechnology, Department for Innovation in Biological, Agro-food and Forest systems, University of Tuscia Viterbo, Italy.

Abiotic stresses have considerable negative impact on Mediterranean plant ecosystems and better comprehension of the genetic control of response and adaptation of trees to global changes is urgently needed. The single cell gel electrophoresis (SCGE) assay could be considered a good estimator of DNA damage in an individual eukaryotic cell. This method has been mainly employed in animal tissues, because the plant cell wall represents an obstacle for the extraction of nuclei; moreover, in Mediterranean woody species, especially in the sclerophyll plants, this procedure can be quite difficult because of the presence of sclerenchyma and hardened cells. On the other hand, these plants represent an interesting material to be studied because of the ability of these plants to tolerate abiotic stress. For instance, holm oak (Quercus ilex L.) has been selected as the model plant to identify critical levels of O3 for Southern European forests. Consequently, a quantitative method for the evaluation of cell injury of leaf tissues of this species is required. Optimal conditions for high-yield nuclei isolation were obtained by using protoplast technology and a detailed description of the method is provided and discussed. White poplar (Populus alba L.) was used as an internal control for protoplast isolation. Such a method has not been previously reported in newly fully developed leaves of holm oak. This method combined with SCGE assay represents a new tool for testing the DNA integrity of leaf tissues in higher plants under stress conditions.
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http://dx.doi.org/10.3389/fpls.2016.01168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983556PMC
August 2016

RENEB accident simulation exercise.

Int J Radiat Biol 2017 01 25;93(1):75-80. Epub 2016 Aug 25.

t National Centre for Scientific Research Demokritos , Athens , Greece.

Purpose: The RENEB accident exercise was carried out in order to train the RENEB participants in coordinating and managing potentially large data sets that would be generated in case of a major radiological event.

Materials And Methods: Each participant was offered the possibility to activate the network by sending an alerting email about a simulated radiation emergency. The same participant had to collect, compile and report capacity, triage categorization and exposure scenario results obtained from all other participants. The exercise was performed over 27 weeks and involved the network consisting of 28 institutes: 21 RENEB members, four candidates and three non-RENEB partners.

Results: The duration of a single exercise never exceeded 10 days, while the response from the assisting laboratories never came later than within half a day. During each week of the exercise, around 4500 samples were reported by all service laboratories (SL) to be examined and 54 scenarios were coherently estimated by all laboratories (the standard deviation from the mean of all SL answers for a given scenario category and a set of data was not larger than 3 patient codes).

Conclusions: Each participant received training in both the role of a reference laboratory (activating the network) and of a service laboratory (responding to an activation request). The procedures in the case of radiological event were successfully established and tested.
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http://dx.doi.org/10.1080/09553002.2016.1206230DOI Listing
January 2017

Capabilities of the RENEB network for research and large scale radiological and nuclear emergency situations.

Int J Radiat Biol 2017 01 4;93(1):136-141. Epub 2016 Oct 4.

o Hospital Universitario y Politécnico La Fe , Valencia , Spain.

Purpose: To identify and assess, among the participants in the RENEB (Realizing the European Network of Biodosimetry) project, the emergency preparedness, response capabilities and resources that can be deployed in the event of a radiological or nuclear accident/incident affecting a large number of individuals. These capabilities include available biodosimetry techniques, infrastructure, human resources (existing trained staff), financial and organizational resources (including the role of national contact points and their articulation with other stakeholders in emergency response) as well as robust quality control/assurance systems.

Materials And Methods: A survey was prepared and sent to the RENEB partners in order to acquire information about the existing, operational techniques and infrastructure in the laboratories of the different RENEB countries and to assess the capacity of response in the event of radiological or nuclear accident involving mass casualties. The survey focused on several main areas: laboratory's general information, country and staff involved in biological and physical dosimetry; retrospective assays used, the number of assays available per laboratory and other information related to biodosimetry and emergency preparedness. Following technical intercomparisons amongst RENEB members, an update of the survey was performed one year later concerning the staff and the available assays.

Conclusions: The analysis of RENEB questionnaires allowed a detailed assessment of existing capacity of the RENEB network to respond to nuclear and radiological emergencies. This highlighted the key importance of international cooperation in order to guarantee an effective and timely response in the event of radiological or nuclear accidents involving a considerable number of casualties. The deployment of the scientific and technical capabilities existing within the RENEB network members seems mandatory, to help other countries with less or no capacity for biological or physical dosimetry, or countries overwhelmed in case of a radiological or nuclear accident involving a large number of individuals.
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http://dx.doi.org/10.1080/09553002.2016.1227107DOI Listing
January 2017

Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons.

Int J Radiat Biol 2017 01 20;93(1):99-109. Epub 2016 Jul 20.

q National Center of Radiobiology and Radiation Protection (NCRRP) , Bulgaria.

Purpose: RENEB, 'Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,' is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation.

Materials And Methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones.

Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques.

Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios.
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http://dx.doi.org/10.1080/09553002.2016.1206233DOI Listing
January 2017

The micronucleus assay in mammalian cells in vitro to assess health benefits of various phytochemicals.

Mutat Res Genet Toxicol Environ Mutagen 2015 Nov 30;793:79-85. Epub 2015 Jun 30.

Department of Ecological and Biological Sciences, University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy.

We evaluated the protective effects of Gentiana lutea extracts (GLEx) and 6-Gingerol (6-G) on clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 7,12-dimethylbenz(α) anthracene (DMBA) in vitro on HepG2 cells using the frequencies of induced micronuclei (MN) as the end point. Pre-, post- and simultaneous treatments with GLEx or 6-G and the carcinogens were carried out. Both GLEx post- and simultaneous treatments reduced the frequencies of MN induced by MNNG and DMBA. Probably this effect is due to an increase of cytostasis and a physico-chemical interaction between GLEx and DMBA under simultaneous treatment. Pre- and simultaneous treatments with 6-G significantly reduced the yield of MNNG-induced micronuclei without affecting % of cytostasis. Simultaneous treatment with 6-G plus DMBA resulted in reduction in the frequency of MN and an increase in cytotoxicity compared to sample treated alone with DMBA, whereas a post-treatment, caused a significant decrease in the yield of MN compared with DMBA alone without any cytotoxic effect. These results are compared with our earlier data obtained in the same system with other phytochemicals. It is concluded that for a critical evaluation of the protective effects of phytochemicals, both the influence on the induced MN and induced cytostasis have to be considered.
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http://dx.doi.org/10.1016/j.mrgentox.2015.06.016DOI Listing
November 2015

Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.

Oncotarget 2015 Nov;6(34):36098-112

Division of Health Protection Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy.

The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.
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http://dx.doi.org/10.18632/oncotarget.5553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742164PMC
November 2015

Pasta containing tartary buckwheat sprouts prevents DNA damage in spontaneously hypertensive rats.

Int J Food Sci Nutr 2015 11;66(5):574-8. Epub 2015 Jun 11.

Department of Ecological and Biological Sciences (DEB), Laboratory of Cellular and Molecular Nutrition, Tuscia University , Viterbo , Italy and.

Recent studies have shown that DNA damage occurs more often in hypertensive patients than non-hypertensive individuals. Here, we analyzed the in vivo effect of pasta containing 30% of tartary buckwheat sprouts (TBSP) on spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKY) to elucidate if TBSP could have an anti-genotoxic effect in hypertensive animal models. Both SHRs and WKY rats were divided into two groups and fed for six weeks with 5 g of TBSP and durum wheat flour commercial pasta, respectively. Our results showed that a diet rich in TBSP has anti-genotoxic effect. Indeed, SHRs fed with TBSP exhibited a significant decrease in DNA damage (38%) and more efficient DNA repair (84%) compared to SHRs fed with commercial pasta.
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http://dx.doi.org/10.3109/09637486.2015.1052378DOI Listing
May 2016

Role of chromatin structure modulation by the histone deacetylase inhibitor trichostatin A on the radio-sensitivity of ataxia telangiectasia.

Mutat Res 2015 Jul 20;777:52-9. Epub 2015 Apr 20.

Department of Ecological and Biological Sciences (DEB), University of Tuscia, Via San Camillo de Lellis snc, 01100 Viterbo, Italy.

At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post-treatment is favouring the slow component of DSB repair pathway, the one impaired in absence of a functionally ATM protein. Data obtained suggest a fundamental role of chromatin compaction on chromosomal instability in A-T cells.
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http://dx.doi.org/10.1016/j.mrfmmm.2015.04.009DOI Listing
July 2015

Evaluation of the effects of ellagic acid (EA) on 7,12-dimethylbenz(α) anthracene (DMBA) induced micronuclei in mammalian cells in vitro and in vivo.

Toxicol Lett 2014 Jan 1;224(2):240-5. Epub 2013 Nov 1.

Department of Ecological and Biological Sciences, Università degli Studi della Tuscia, Largo dell'Università, snc, I-01100 Viterbo, Italy.

We evaluated the protective effects of EA, a promising dietary constituent against degenerative diseases, on the clastogenic action of the model carcinogen DMBA in vitro on human hepatoma cells (HepG2) and in vivo on bone marrow of mice, using the frequencies of induced micronuclei as the end point. Pre-, post- and simultaneous treatments with EA and the carcinogen were carried out in vitro. Simultaneous treatment with EA caused a statistically significant increase of DMBA induced MN, suggesting a direct interaction between the two agents. No significant reduction in DMBA induced MN was found by pre- or post treatment with EA. Similar effects were observed in the toxicity assay. In in vivo experiments, EA pre-treatment did not affect the frequencies of MN in PCEs of bone marrow induced by DMBA. A good correlation was found between in vitro and in vivo experiments. Our results did not reveal any clear indication on the efficacy of EA on the induction of micronuclei by DMBA. EA by itself did not show any harmful effects.
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http://dx.doi.org/10.1016/j.toxlet.2013.10.012DOI Listing
January 2014

Study on X-ray-induced apoptosis and chromosomal damage in G2 human lymphocytes in the presence of pifithrin-α, an inhibitor of p53.

Mutat Res 2011 Nov 26;726(1):29-35. Epub 2011 Aug 26.

Department of Ecology and Biology, University of Tuscia, Viterbo, Italy.

The aim of this study is to investigate the role of the cell-cycle phase in cells exposed to radiation and chemicals in relation to the cellular response. The analysis was focused on the G2 cell-cycle phase, exploring the impact of p53 inhibition in human lymphocytes irradiated with X-rays in the presence or absence of pifithrin-α (PFT-α), a p53-specific inhibitor. Lymphocytes, 44h after stimulation to proliferate, were X-irradiated with 0.5Gy both in the presence or the absence of PFT-α and post-treated with a pulse of 5-bromodeoxyuridine (BrdUrd) to distinguish cells in the S- or G2-phase at the moment of irradiation. At early sampling times after X-ray exposure the following parameters were analysed: cellular proliferation, apoptosis, chromosomal aberrations and p53 expression. The results show an enhancement of apoptotic cells in G2 at early sampling times after irradiation and no differences in terms of chromosomal aberration induction both in cells treated with X-rays alone and in cells treated with X-rays plus PFT-α. Expression of p53 was not detectable at all recovery times. The results suggest a p53-independent apoptotic pathway acting at early times after X-ray exposure in G2 lymphocytes. Furthermore, the same yield of X-ray-induced chromatid breaks was observed both in the presence or absence of PFT-α implying that in G2 X-irradiated lymphocytes this inhibitor of the p53 protein does not affect DNA repair.
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http://dx.doi.org/10.1016/j.mrgentox.2011.07.013DOI Listing
November 2011

Kinetics of gamma-H2AX induction and removal in bone marrow and testicular cells of mice after X-ray irradiation.

Mutagenesis 2011 Jul 15;26(4):563-72. Epub 2011 Apr 15.

Unit of Radiation Biology and Human Health, Laboratory of Toxicology, ENEA CR Casaccia, Via Anguillarese 301, 00123, Rome, Italy.

Male germ cells have been shown to differ in their DNA damage response (DDR) with respect to somatic cells. In addition, DDR pathways are modulated along spermatogenesis, accompanying profound chromatin modifications. Histone H2AX phosphorylation is a fundamental step of DDR. Few data are available on the long-term kinetics of phosphorylated H2AX (γ-H2AX) after in vivo irradiation. We have investigated, by microscopic and flow cytometric immunochemistry, γ-H2AX induction and removal in testicular cells of irradiated mice, in comparison with bone marrow cells. In unirradiated testicular cells, much higher levels of γ-H2AX were measured by flow cytometry with respect to bone marrow cells. Irradiation induced a redistribution of γ-H2AX into discrete foci detectable by microscopy. In irradiated bone marrow, the percentage of labelled cells peaked at 1 h and rapidly declined, in agreement with data on in vitro cell lines. In contrast, spermatocytes and round spermatids showed persistent labelling until 48 h. During this time, in spermatids, topological changes were observed in γ-H2AX foci from a pattern of many uncountable dots to a pattern of few large spots. Observations of testicular sections confirmed this trend in the reduction of foci number in spite of substantially invariable percentages of labelled cells in the analysed timeframe. To assess whether γ-H2AX persistence in testicular cells was due to unrepaired DNA breaks, we performed comet assay and immunofluorescence analysis of Mdc1, a marker of DDR different from γ-H2AX. Comet assay showed that most breaks were repaired within 2 h. Forty-eight hours after irradiation, contrary to γ-H2AX foci that remained detectable in 80% of initially labelled cells, Mdc1 foci were observed in only 20-30% of cells. These data suggest that, at long times after irradiation, mechanisms additional to impairment of DNA break repair may account for the long persistence of γ-H2AX foci in male germ cells.
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http://dx.doi.org/10.1093/mutage/ger017DOI Listing
July 2011

Relation between DNA repair, apoptosis and chromosomal aberrations in presence of pifithrin-alpha, an inhibitor of p53.

Mutat Res 2010 Aug 27;701(1):92-7. Epub 2010 Mar 27.

Agrobiology and Agrochemistry Department, University of Tuscia, Viterbo, Italy.

The aim of this study was to investigate the impact of inhibition of p53 in X-irradiated human peripheral blood lymphocytes (HPBL) in the G0 phase of the cell cycle in the presence or absence of pifithrin-alpha (PFT-alpha), a specific inhibitor of p53, on repair of DNA damage or induced apoptosis. Lymphocyte (HPBL) cultures were X-irradiated with 3 Gy in the absence or presence of PFT-alpha. In order to distinguish the effects of PFT-alpha either on DNA repair or on apoptosis, PFT-alpha was added to the cultures employing different protocols namely, a) "continuous treatment", where PFT-alpha was added four hours before X-irradiation and left until the end of the experiment, b) "pre-treatment", where PFT-alpha was added four hours before X-irradiation and removed by washing the cells with phosphate buffered saline (PBS) four hours after irradiation and c) "post-treatment", where PFT-alpha was added four hours after irradiation and left in the medium until the harvest. At various times after irradiation of lymphocytes, Single Cell Gel Electrophoresis was performed to detect DNA damage in individual cells. Apoptosis and chromosomal aberrations were quantified at later sampling times following irradiation. The results presented here strengthen the known role of p53 protein in priming apoptotic cell death in HPBL following X-irradiation. Furthermore, our data suggest that the inhibition of p53 by PFT-alpha affects the repair kinetics of X-ray induced DNA lesions leading to mis-repair events and consequently to an enhancement of cytogenetic damage in HPBL.
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http://dx.doi.org/10.1016/j.mrgentox.2010.03.017DOI Listing
August 2010

Effects of storage conditions of human whole blood on the viability of lymphocytes.

Int J Radiat Biol 2008 Jul;84(7):613-9

Department of Agrobiology and Agrochemistry, University of Tuscia, Viterbo, Italy.

Purpose: To investigate the optimal storage conditions of human whole blood to retain viability of lymphocytes.

Material And Methods: Phytohaemagglutinin (PHA) stimulated and unstimulated human whole blood samples were stored for 48-96 h up to one week at 4 degrees C, 20 degrees C and 37 degrees C and were analysed for apoptosis. After 96 h and one week of storage unstimulated cultures were stimulated to proliferate. These cultures and samples stimulated immediately before storing were incubated at 37 degrees C for 56 h and analysed for mitotic index (MI).

Results: Lymphocytes undergo apoptosis during storage and this loss of viability is accelerated by increasing both temperature and storage time. In the presence of PHA, incubation at both 4 degrees C and 20 degrees C for 48 h resulted in low percentages of apoptotic cells and after incubation at 4 degrees C for 96 h the cultures grown for 56 h at 37 degrees C revealed the highest percentage of MI.

Conclusions: The storage conditions affect lymphocytes in terms of both cell viability and proliferation. Storage at 4 degrees C for 96 h in presence of PHA was found optimal.
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http://dx.doi.org/10.1080/09553000802203630DOI Listing
July 2008

L-carnitine enhances resistance to oxidative stress by reducing DNA damage in Ataxia telangiectasia cells.

Mutat Res 2008 Feb 8;650(2):165-74. Epub 2007 Dec 8.

Department of Agrobiology and Agrochemistry, University of Tuscia, Via San Camillo de Lellis snc, Viterbo, Italy.

In this study, the modulating effect of L-carnitine on tert-butyl-hydroperoxide-induced DNA damage was compared with that of mannitol, a well known scavenger of hydroxyl radicals, both in normal and Ataxia telangiectasia mutated (ATM)-deficient lymphoblastoid cell lines established from A. telangiectasia (A-T) patients. The alkaline version of the comet assay was employed to measure the frequency of single-strand breaks (SSBs) and alkali-labile sites induced by t-butyl-OOH immediately after treatment and at different recovery times in normal and A-T cell lines, with and without pre-treatment with L-carnitine. In addition, both the yield of induced chromosomal damage and the effect on cell proliferation were evaluated. Our results show that pre-treatment of cells with L-carnitine produced an enhancement of the rate and extent of DNA repair in A-T cell lines at early recovery time; furthermore, in samples pre-treated with L-carnitine a reduction of all types of chromosomal aberration was observed, both in A-T and in wild-type cell lines. The reducing effect of L-carnitine pre-treatment on oxidative DNA damage was more prominent than that of pre-treatment with mannitol. In conclusion, we demonstrated a protective effect of L-carnitine on oxidative stress-induced DNA damage in A-T cells, suggesting its possible role in future pharmacological applications in A-T therapy.
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http://dx.doi.org/10.1016/j.mrgentox.2007.11.008DOI Listing
February 2008