scholarly journals Diallyl Sulfide Attenuation of Carcinogenesis in Mammary Epithelial Cells through the Inhibition of ROS Formation, and DNA Strand Breaks

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1313
Author(s):  
Selina F. Darling-Reed ◽  
Yasmeen Nkrumah-Elie ◽  
Dominique T. Ferguson ◽  
Hernan Flores-Rozas ◽  
Patricia Mendonca ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Dna Strand Breaks ◽  
Diallyl Sulfide ◽  
Extracellular Medium ◽  
Strand Breaks ◽  
Ros Formation ◽  
Dna Strand

Garlic has long been used medicinally for many diseases, including cancer. One of the active garlic components is diallyl sulfide (DAS), which prevents carcinogenesis and reduces the incidence rate of several cancers. In this study, non-cancerous MCF-10A cells were used as a model to investigate the effect of DAS on Benzo (a)pyrene (BaP)-induced cellular carcinogenesis. The cells were evaluated based on changes in proliferation, cell cycle arrest, the formation of peroxides, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, the generation of DNA strand breaks, and DNA Polymerase β (Pol β) expression. The results obtained indicate that when co-treated with BaP, DAS inhibited BaP-induced cell proliferation (p < 0.05) to levels similar to the negative control. BaP treatment results in a two-fold increase in the accumulation of cells in the G2/M-phase of the cell cycle, which is restored to baseline levels, similar to untreated cells and vehicle-treated cells, when pretreated with 6 μM and 60 μM DAS, respectively. Co-treatment with DAS (60 μM and 600 μM) inhibited BaP-induced reactive oxygen species (ROS) formation by 132% and 133%, respectively, as determined by the accumulation of H2O2 in the extracellular medium and an increase in 8-OHdG levels of treated cells. All DAS concentrations inhibited BaP-induced DNA strand breaks through co-treatment and pre-treatment methods at all time points evaluated. Co-Treatment with 60 μM DAS increased DNA Pol β expression in response to BaP-induced lipid peroxidation and oxidative DNA damage. These results indicate that DAS effectively inhibited BaP-induced cell proliferation, cell cycle transitions, ROS, and DNA damage in an MCF-10A cell line. These results provide more experimental evidence for garlic’s antitumor abilities and corroborate many epidemiological studies regarding the association between the increased intake of garlic and the reduced risk of several types of cancer.

scholarly journals Repair of DNA Strand Breaks by the Overlapping Functions of Lesion-Specific and Non-Lesion-Specific DNA 3′ Phosphatases

2001 ◽  
Vol 21 (21) ◽  
pp. 7191-7198 ◽  
Author(s):  
John R. Vance ◽  
Thomas E. Wilson
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Synthetic Lethality ◽  
Dna Strand Breaks ◽  
Triple Mutant ◽  
Phosphatase Domain ◽  
Strand Breaks ◽  
Alternative Pathways ◽  
Processing Enzymes ◽  
Dna Strand

ABSTRACT In Saccharomyces cerevisiae, the apurinic/apyrimidinic (AP) endonucleases Apn1 and Apn2 act as alternative pathways for the removal of various 3′-terminal blocking lesions from DNA strand breaks and in the repair of abasic sites, which both result from oxidative DNA damage. Here we demonstrate that Tpp1, a homologue of the 3′ phosphatase domain of polynucleotide kinase, is a third member of this group of redundant 3′ processing enzymes. Unlike Apn1 and Apn2, Tpp1 is specific for the removal of 3′ phosphates at strand breaks and does not possess more general 3′ phosphodiesterase, exonuclease, or AP endonuclease activities. Deletion ofTPP1 in an apn1 apn2 mutant background dramatically increased the sensitivity of the double mutant to DNA damage caused by H2O2 and bleomycin but not to damage caused by methyl methanesulfonate. The triple mutant was also deficient in the repair of 3′ phosphate lesions left by Tdp1-mediated cleavage of camptothecin-stabilized Top1-DNA covalent complexes. Finally, the tpp1 apn1 apn2 triple mutation displayed synthetic lethality in combination with rad52, possibly implicating postreplication repair in the removal of unrepaired 3′-terminal lesions resulting from endogenous damage. Taken together, these results demonstrate a clear role for the lesion-specific enzyme, Tpp1, in the repair of a subset of DNA strand breaks.

scholarly journals Cylindrospermopsin-Microcystin-LR Combinations May Induce Genotoxic and Histopathological Damage in Rats

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 348 ◽  
Author(s):  
Leticia Díez-Quijada ◽  
Concepción Medrano-Padial ◽  
María Llana-Ruiz-Cabello ◽  
Giorgiana M. Cătunescu ◽  
Rosario Moyano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Fatty Degeneration ◽  
Dna Strand Breaks ◽  
Histopathological Study ◽  
Strand Breaks ◽  
Dna Strand

Cylindrospermopsin (CYN) and microcystins (MC) are cyanotoxins that can occur simultaneously in contaminated water and food. CYN/MC-LR mixtures previously investigated in vitro showed an induction of micronucleus (MN) formation only in the presence of the metabolic fraction S9. When this is the case, the European Food Safety Authority recommends a follow up to in vivo testing. Thus, rats were orally exposed to 7.5 + 75, 23.7 + 237, and 75 + 750 μg CYN/MC-LR/kg body weight (b.w.). The MN test in bone marrow was performed, and the standard and modified comet assays were carried out to measure DNA strand breaks or oxidative DNA damage in stomach, liver, and blood cells. The results revealed an increase in MN formation in bone marrow, at all the assayed doses. However, no DNA strand breaks nor oxidative DNA damage were induced, as shown in the comet assays. The histopathological study indicated alterations only in the highest dose group. Liver was the target organ showing fatty degeneration and necrotic hepatocytes in centrilobular areas, as well as a light mononuclear inflammatory periportal infiltrate. Additionally, the stomach had flaking epithelium and mild necrosis of epithelial cells. Therefore, the combined exposure to cyanotoxins may induce genotoxic and histopathological damage in vivo.

Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans

2001 ◽  
Vol 15 (7) ◽  
pp. 1181-1186 ◽  
Author(s):  
PETER MØLLER ◽  
STEFFEN LOFT ◽  
CARSTEN LUNDBY ◽  
NIELS VIDIENDAL OLSEN
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Acute Hypoxia ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Dna Strand ◽  
Hypoxic Exercise

6-Gingerol prevents MEHP-induced DNA damage in human umbilical vein endothelia cells

2016 ◽  
Vol 36 (11) ◽  
pp. 1177-1185 ◽  
Author(s):  
G Yang ◽  
X Gao ◽  
L Jiang ◽  
X Sun ◽  
X Liu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Umbilical Vein ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Human Umbilical Vein ◽  
Associated Proteins ◽  
Dna Strand ◽  
Umbilical Vein Endothelial Cells ◽  
Ethylhexyl Phthalate

Mono (2-ethylhexyl) phthalate (MEHP) is the principal metabolite of di (2-etylhexyl) phthalate, which is widely used as a plasticizer, especially in medical devices. MEHP has toxic effects on cardiovascular system. The aim of this study was to investigate the possibility that 6-gingerol may inhibit the oxidative DNA damage of MEHP in human umbilical vein endothelial cells (HUVECs) and the potential mechanism. The comet assay was used to monitor DNA strand breaks. We have shown that 6-gingerol significantly reduced the DNA strand breaks caused by MEHP. MEHP increased the levels of reactive oxygen species and malondialdehyde, decreased the level of glutathione and activity of superoxide dismutase, and altered the mitochondrial membrane potential. In addition, DNA damage-associated proteins (p53 and p-Chk2 (T68)) were significantly increased by the treatment of MEHP. Those effects can all be protected by 6-gingerol. The results firmly indicate that 6-gingerol may have a strong protective ability against the DNA damage caused by MEHP in HUVECs, and the mechanism may relate to the antioxidant activity.

scholarly journals Evaluation of the Protective Effects of Quercetin, Rutin, Naringenin, Resveratrol and Trolox Against Idarubicin-Induced DNA Damage

2010 ◽  
Vol 13 (2) ◽  
pp. 231 ◽  
Author(s):  
Haydar Çelik ◽  
Emel Arinç
Keyword(s):  
Dna Damage ◽  
Cytochrome P450 ◽  
Mitomycin C ◽  
Dna Strand Breaks ◽  
Protective Effects ◽  
Cytochrome P450 Reductase ◽  
Strand Breaks ◽  
P450 Reductase ◽  
Nadph Cytochrome P450 Reductase ◽  
Dna Strand

PURPOSE. Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Çelik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation. METHODS. DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method. RESULTS. Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 μM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. CONCLUSION. We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.

KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells

1997 ◽  
Vol 272 (6) ◽  
pp. L1174-L1180 ◽  
Author(s):  
M. Takeoka ◽  
W. F. Ward ◽  
H. Pollack ◽  
D. W. Kamp ◽  
R. J. Panos
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Dna Polymerase ◽  
Dna Polymerases ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Alveolar Epithelial ◽  
Radiation Induced ◽  
Dna Strand

Administration of exogenous keratinocyte growth factor (KGF) prevents or attenuates several forms of oxidant-mediated lung injury. Because DNA damage in epithelial cells is a component of radiation pneumotoxicity, we determined whether KGF ameliorated DNA strand breaks in irradiated A549 cells. Cells were exposed to 137Cs gamma rays, and DNA damage was measured by alkaline unwinding and ethidium bromide fluorescence after a 30-min recovery period. Radiation induced a dose-dependent increase in DNA strand breaks. The percentage of double-stranded DNA after exposure to 30 Gy increased from 44.6 +/- 3.5% in untreated control cells to 61.6 +/- 5.0% in cells cultured with 100 ng/ml KGF for 24 h (P < 0.05). No reduction in DNA damage occurred when the cells were cultured with KGF but maintained at 0 degree C during and after irradiation. The sparing effect of KGF on radiation-induced DNA damage was blocked by aphidicolin, an inhibitor of DNA polymerases-alpha, -delta, and -epsilon and by butylphenyl dGTP, which blocks DNA polymerase-alpha strongly and polymerases-delta and -epsilon less effectively. However, dideoxythymidine triphosphate, a specific inhibitor of DNA polymerase-beta, did not abrogate the KGF effect. Thus KGF increases DNA repair capacity in irradiated pulmonary epithelial cells, an effect mediated at least in part by DNA polymerases-alpha, -delta, and -epsilon. Enhancement of DNA repair capability after cell damage may be one mechanism by which KGF is able to ameliorate oxidant-mediated alveolar epithelial injury.

scholarly journals The role of Sp1 in the detection and elimination of cells with persistent DNA strand breaks

NAR Cancer ◽  
2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Polina S Loshchenova ◽  
Svetlana V Sergeeva ◽  
Sally C Fletcher ◽  
Grigory L Dianov
Keyword(s):  
Dna Damage ◽  
Cancer Therapy ◽  
Genome Stability ◽  
Dna Strand Breaks ◽  
Dna Lesions ◽  
Exogenous Dna ◽  
Strand Breaks ◽  
Specificity Factor ◽  
Dna Strand

Abstract Maintenance of genome stability suppresses cancer and other human diseases and is critical for organism survival. Inevitably, during a life span, multiple DNA lesions can arise due to the inherent instability of DNA molecules or due to endogenous or exogenous DNA damaging factors. To avoid malignant transformation of cells with damaged DNA, multiple mechanisms have evolved to repair DNA or to detect and eradicate cells accumulating unrepaired DNA damage. In this review, we discuss recent findings on the role of Sp1 (specificity factor 1) in the detection and elimination of cells accumulating persistent DNA strand breaks. We also discuss how this mechanism may contribute to the maintenance of physiological populations of healthy cells in an organism, thus preventing cancer formation, and the possible application of these findings in cancer therapy.

scholarly journals Influence of Acute Exercise on DNA Repair and PARP Activity before and after Irradiation in Lymphocytes from Trained and Untrained Individuals

2019 ◽  
Vol 20 (12) ◽  
pp. 2999 ◽  
Author(s):  
Maria Moreno-Villanueva ◽  
Andreas Kramer ◽  
Tabea Hammes ◽  
Maria Venegas-Carro ◽  
Patrick Thumm ◽  
...  
Keyword(s):  
Physical Activity ◽  
Dna Damage ◽  
Dna Repair ◽  
Immune Cells ◽  
Acute Exercise ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Before And After ◽  
Radiation Induced ◽  
Dna Strand

Several studies indicate that acute exercise induces DNA damage, whereas regular exercise increases DNA repair kinetics. Although the molecular mechanisms are not completely understood, the induction of endogenous reactive oxygen species (ROS) during acute exhaustive exercise due to metabolic processes might be responsible for the observed DNA damage, while an adaptive increase in antioxidant capacity due to regular physical activity seems to play an important protective role. However, the protective effect of physical activity on exogenously induced DNA damage in human immune cells has been poorly investigated. We asked the question whether individuals with a high aerobic capacity would have an enhanced response to radiation-induced DNA damage. Immune cells are highly sensitive to radiation and exercise affects lymphocyte dynamics and immune function. Therefore, we measured endogenous and radiation-induced DNA strand breaks and poly (ADP-ribose) polymerase-1 (PARP1) activity in peripheral blood mononuclear cells (PBMCs) from endurance-trained (maximum rate of oxygen consumption measured during incremental exercise V’O2max > 55 mL/min/kg) and untrained (V’O2max < 45 mL/min/kg) young healthy male volunteers before and after exhaustive exercise. Our results indicate that: (i) acute exercise induces DNA strand breaks in lymphocytes only in untrained individuals, (ii) following acute exercise, trained individuals repaired radiation-induced DNA strand breaks faster than untrained individuals, and (iii) trained subjects retained a higher level of radiation-induced PARP1 activity after acute exercise. The results of the present study indicate that increased aerobic fitness can protect immune cells against radiation-induced DNA strand breaks.

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