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1.
Sub-optimal Application of a High SPF Sunscreen Prevents Epidermal DNA Damage in Vivo.
Young, AR, Greenaway, J, Harrison, GI, Lawrence, KP, Sarkany, R, Douki, T, Boyer, F, Josse, G, Questel, E, Monteil, C, et al
Acta dermato-venereologica. 2018;(9):880-887
Abstract
The cyclobutane pyrimidine dimer (CPD) is a potentially mutagenic DNA photolesion that is the basis of most skin cancers. There are no data on DNA protection by sunscreens under typical conditions of use. The study aim was to determine such protection, in phototypes I/II, with representative sunscreen-user application. A very high SPF formulation was applied at 0.75, 1.3 and 2.0 mg/cm2. Unprotected control skin was exposed to 4 standard erythema doses (SED) of solar simulated UVR, and sunscreen-treated sites to 30 SED. Holiday behaviour was also simulated by UVR exposure for 5 consecutive days. Control skin received 1 SED daily, and sunscreen-treated sites received 15 (all 3 application thicknesses) or 30 (2.0 mg/cm2) SED daily. CPD were assessed by quantitative HPLC-tandem mass spectrometry (HPLC-MS/MS) and semi-quantitative immunostaining. In comparison with unprotected control sites, sunscreen significantly (p ≤ 0.001-0.05) reduced DNA damage at 1.3 and 2.0 mg/cm2 in all cases. However, reduction with typical sunscreen use (0.75 mg/cm2) was non-significant, with the exception of HPLC-MS/MS data for the 5-day study (p <0.001). Overall, these results support sunscreen use as a strategy to reduce skin cancer, and demonstrate that public health messages must stress better sunscreen application to get maximal benefit.
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2.
Mediterranean diet supplemented with coenzyme Q10 induces postprandial changes in p53 in response to oxidative DNA damage in elderly subjects.
Gutierrez-Mariscal, FM, Perez-Martinez, P, Delgado-Lista, J, Yubero-Serrano, EM, Camargo, A, Delgado-Casado, N, Cruz-Teno, C, Santos-Gonzalez, M, Rodriguez-Cantalejo, F, Castaño, JP, et al
Age (Dordrecht, Netherlands). 2012;(2):389-403
Abstract
Coenzyme Q10 (CoQ) is a powerful antioxidant that reduces oxidative stress. We explored whether the quality of dietary fat alters postprandial oxidative DNA damage and whether supplementation with CoQ improves antioxidant capacity by modifying the activation/stabilization of p53 in elderly subjects. In this crossover study, 20 subjects were randomly assigned to receive three isocaloric diets during 4 weeks each: (1) Mediterranean diet (Med diet), (2) Mediterranean diet supplemented with CoQ (Med+CoQ diet), and (3) saturated fatty acid-rich diet (SFA diet). Levels of mRNAs were determined for p53, p21, p53R2, and mdm2. Protein levels of p53, phosphorylated p53 (Ser20), and monoubiquitinated p53 were also measured, both in cytoplasm and nucleus. The extent of DNA damage was measured as plasma 8-OHdG. SFA diet displayed higher postprandial 8-OHdG concentrations, p53 mRNA and monoubiquitinated p53, and lower postprandial Mdm2 mRNA levels compared with Med and Med+CoQ diets (p < 0.05). Moreover, Med+CoQ diet induced a postprandial decrease of cytoplasmatic p53, nuclear p-p53 (Ser20), and nuclear and cytoplasmatic monoubiquitinated p53 protein (p < 0.05). In conclusion, Med+CoQ diet improves oxidative DNA damage in elderly subjects and reduces processes of cellular oxidation. Our results suggest a starting point for the prevention of oxidative processes associated with aging.
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3.
Effect of dark chocolate on plasma epicatechin levels, DNA resistance to oxidative stress and total antioxidant activity in healthy subjects.
Spadafranca, A, Martinez Conesa, C, Sirini, S, Testolin, G
The British journal of nutrition. 2010;(7):1008-14
Abstract
Dark chocolate (DC) may be cardioprotective by antioxidant properties of flavonoids. We investigated the effect of DC (860 mg polyphenols, of which 58 mg epicatechin) compared with white chocolate (WC; 5 mg polyphenols, undetectable epicatechin) on plasma epicatechin levels, mononuclear blood cells (MNBC) DNA damage and plasma total antioxidant activity (TAA). Twenty healthy subjects followed a balanced diet (55 % of energy from carbohydrates, 30 % from fat and 1 g protein/kg body weight) for 4 weeks. Since the 14th day until the 27th day, they introduced daily 45 g of either WC (n 10) or DC (n 10). Whole experimental period was standardised in antioxidant intake. Blood samples were collected at T(0), after 2 weeks (T(14)), 2 h and 22 h after the first chocolate intake (T(14+2 h) and T(14+22 h)), and at 27th day, before chocolate intake (T(27)), 2 h and 22 h after (T(27+2 h) and T(27+22 h)). Samples, except for T(14+2 h) and T(27+2 h), were fasting collected. Detectable epicatechin levels were observed exclusively 2 h after DC intake (T(14+2 h) = 0.362 (se 0.052) micromol/l and T(27+2 h) = 0.369 (se 0.041) micromol/l); at the same times corresponded lower MNBC DNA damages (T(14+2 h) = - 19.4 (se 3.4) % v. T(14), P < 0.05; T(27+2 h) = - 24 (se 7.4) % v. T(27), P < 0.05; T(14+2 h) v. T(27+2 h), P = 0.7). Both effects were no longer evident after 22 h. No effect was observed on TAA. WC did not affect any variable. DC may transiently improve DNA resistance to oxidative stress, probably for flavonoid kinetics.
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4.
A nanodosimetric model of radiation-induced clustered DNA damage yields.
Garty, G, Schulte, R, Shchemelinin, S, Leloup, C, Assaf, G, Breskin, A, Chechik, R, Bashkirov, V, Milligan, J, Grosswendt, B
Physics in medicine and biology. 2010;(3):761-81
Abstract
We present a nanodosimetric model for predicting the yield of double strand breaks (DSBs) and non-DSB clustered damages induced in irradiated DNA. The model uses experimental ionization cluster size distributions measured in a gas model by an ion counting nanodosimeter or, alternatively, distributions simulated by a Monte Carlo track structure code developed to simulate the nanodosimeter. The model is based on a straightforward combinatorial approach translating ionizations, as measured or simulated in a sensitive gas volume, to lesions in a DNA segment of one-two helical turns considered equivalent to the sensitive volume of the nanodosimeter. The two model parameters, corresponding to the probability that a single ion detected by the nanodosimeter corresponds to a single strand break or a single lesion (strand break or base damage) in the equivalent DNA segment, were tuned by fitting the model-predicted yields to previously measured double-strand break and double-strand lesion yields in plasmid DNA irradiated with protons and helium nuclei. Model predictions were also compared to both yield data simulated by the PARTRAC code for protons of a wide range of different energies and experimental DSB and non-DSB clustered DNA damage yield data from the literature. The applicability and limitations of this model in predicting the LET dependence of clustered DNA damage yields are discussed.
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5.
Direct-oxidative DNA damage and apoptosis induction in different human respiratory cells exposed to low concentrations of sodium chromate.
Cavallo, D, Ursini, CL, Fresegna, AM, Ciervo, A, Maiello, R, Rondinone, B, D'Agata, V, Iavicoli, S
Journal of applied toxicology : JAT. 2010;(3):218-25
Abstract
The mechanism of Cr(VI) genotoxicity has still not been elucidated. We used Fpg-modified comet assay to assess direct-oxidative DNA damage on human lung (A549) and bronchial (BEAS-2B) cells exposed to 0.1, 0.5, 1.0 and 10 microm sodium chromate for 0.5, 1 and 4 h. Moreover we evaluated apoptosis by morphological analysis and caspase-3 activity, also after 24 h. On A549 cells a time-dependent DNA damage, expressed as tail DNA%, beginning from 0.5 microm was found. For oxidative DNA damage an induction after 30 min to 0.5 microm decreasing with time, and a time-dependent increase at 10 microm was found, indicating for low Cr(VI) concentration the oxidative stress as the first event followed by direct DNA damage and for the highest concentration a time-dependent increase in oxidative DNA damage. On BEAS-2B cells DNA damage was induced within 1 h at 0.5-10 microm, without changes with time, showing that BEAS-2B cells are able to resist to Cr(VI) genotoxicity. Early oxidative DNA damage at 0.1 microm decreasing with time was also found. Significant apoptosis was observed by morphological analysis in A549 cells and to a lower extent in BEAS-2B at 10 microm. The exposure to 10 microm induced caspase-3 activity after 4 h in BEAS-2B and after 24 h in A549 cells. The findings show a higher responsiveness of A549 cells to genotoxic effect of Cr(VI) and early transient oxidative DNA damage in BEAS-2B. The results emphasize the suitability of this experimental model to evaluate the early genotoxic response of different cells to non-cytotoxic concentrations of Cr(VI) on target organ.
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6.
Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers.
Dziaman, T, Huzarski, T, Gackowski, D, Rozalski, R, Siomek, A, Szpila, A, Guz, J, Lubinski, J, Wasowicz, W, Roszkowski, K, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009;(11):2923-8
Abstract
Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy.
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7.
High dosage of ascorbic acid and alpha-tocopherol is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults.
Retana-Ugalde, R, Casanueva, E, Altamirano-Lozano, M, González-Torres, C, Mendoza-Núñez, VM
Annals of nutrition & metabolism. 2008;(2):167-73
Abstract
AIM: To determine the useful dosage of ascorbic acid and alpha-tocopherol against oxidative stress and DNA damage in the elderly. METHODS A double-blind controlled clinical assay carried out in a sample of 66 healthy subjects divided into three age-paired random groups with 22 subjects in each group. Group A received placebo and group B was administered 500 mg of ascorbic acid and 400 IU of alpha-tocopherol, whereas group C received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol for a 6-month period. The following measurements were performed before and after the 6-month treatment period: thiobarbituric acid reactive substances (TBARS); total antioxidant status (TAS); superoxide dismutase (SOD), and glutation peroxidase (GPx) and DNA damage by comet assay. RESULTS After 6 months, group B subjects exhibited an increase in SOD and GPx enzyme levels; however, this was not statistically significant (p > 0.05). Likewise, TBARS and TAS concentrations remained unchanged (p > 0.05). In addition, in group C the decrease in TBARS and increase in SOD, GPx, and TAS were not statistically significant (p > 0.05). Similarly, average DNA migration showed no significant differences with high-dosage ascorbic acid and alpha-tocopherol. CONCLUSION These findings suggest that administration of 1,000 mg of ascorbic acid plus 400 IU of alpha-tocopherol for 6 months is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults.
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8.
Orange juice vs vitamin C: effect on hydrogen peroxide-induced DNA damage in mononuclear blood cells.
Guarnieri, S, Riso, P, Porrini, M
The British journal of nutrition. 2007;(4):639-43
Abstract
The intake of fruits rich in vitamin C seems to increase the antioxidant defence of the organism. However, it is still not clear whether vitamin C alone is responsible for this effect. The aim of the present investigation was to study the effect of the intake of a single portion of blood orange juice (BOJ, 300 ml, providing 150 mg vitamin C) on mononuclear blood cell (MNBC) DNA damage, compared with a drink supplemented with the same amount of vitamin C (C-drink) or sugars (S-drink). Seven young healthy subjects were randomised in a repeated-measures design in which they received each drink on different occasions, 2 weeks apart. Blood samples were collected at baseline, every hour for 8 h, and at 24 h after the intake of each drink. Vitamin C was analysed at each time point by HPLC, whereas H2O2-induced MNBC DNA damage was evaluated at 0, 3 and 24 h by means of the comet assay. Plasma vitamin C concentration increased similarly following BOJ or C-drink intake and was not affected by the S-drink. DNA damage significantly decreased 3 h after BOJ intake (about 18 %; P < 0.01) and remained constant at 24 h (about 16 %; P < 0.01). No effect of the C-drink and S-drink was observed. In conclusion, the intake of a single portion of BOJ provided an early protection of MNBC against oxidative DNA damage; however, the protective effect of BOJ was not explained by vitamin C alone, thus other phytochemicals could be involved.
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9.
Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes.
Hauser, JE, Kadekaro, AL, Kavanagh, RJ, Wakamatsu, K, Terzieva, S, Schwemberger, S, Babcock, G, Rao, MB, Ito, S, Abdel-Malek, ZA
Pigment cell research. 2006;(4):303-14
Abstract
Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.
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10.
Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage.
Sundheim, O, Vågbø, CB, Bjørås, M, Sousa, MM, Talstad, V, Aas, PA, Drabløs, F, Krokan, HE, Tainer, JA, Slupphaug, G
The EMBO journal. 2006;(14):3389-97
Abstract
Methylating agents are ubiquitous in the environment, and central in cancer therapy. The 1-methyladenine and 3-methylcytosine lesions in DNA/RNA contribute to the cytotoxicity of such agents. These lesions are directly reversed by ABH3 (hABH3) in humans and AlkB in Escherichia coli. Here, we report the structure of the hABH3 catalytic core in complex with iron and 2-oxoglutarate (2OG) at 1.5 A resolution and analyse key site-directed mutants. The hABH3 structure reveals the beta-strand jelly-roll fold that coordinates a catalytically active iron centre by a conserved His1-X-Asp/Glu-X(n)-His2 motif. This experimentally establishes hABH3 as a structural member of the Fe(II)/2OG-dependent dioxygenase superfamily, which couples substrate oxidation to conversion of 2OG into succinate and CO2. A positively charged DNA/RNA binding groove indicates a distinct nucleic acid binding conformation different from that predicted in the AlkB structure with three nucleotides. These results uncover previously unassigned key catalytic residues, identify a flexible hairpin involved in nucleotide flipping and ss/ds-DNA discrimination, and reveal self-hydroxylation of an active site leucine that may protect against uncoupled generation of dangerous oxygen radicals.