Deoxyribonucleic Acid Strand Breaks Research Articles

Ongoing Phase III Randomized Trial of Salvage DFP-10917 Vs. Non-Intensive Reinduction or Intensive Reinduction for Acute Myelogenous Leukemia (AML)

Background: DFP-10917 is a deoxycytidine analogue with a novel structure. It contains a side chain cyanide (CN) group at the 2 carbon of deoxyribose that induces DNA damage in a manner unique from structurally related nucleoside analogues (eg, cytarabine, decitabine, or gemcitabine). When administered at high doses, DFP-10917 inactivates deoxyribonucleic acid (DNA) polymerase leading to S-phase arrest similar to cytarabine. When administered at low concentrations by continuous infusion, it displays an alternative, potentially advantageous, mechanism of action - DNA strand breakage leading to G2/M phase arrest and ultimately cell apoptosis. The strand breakage occurs via a spontaneous beta elimination reaction that requires no additional enzymatic activity. There is no current standard treatment for patients with relapsed/refractory (R/R) AML. Results of a completed Phase I/II study in R/R AML (D11-11002; NCT01702155) demonstrated preliminary efficacy of DFP-10917 in this indication, with a ~50% complete response (CR) rate in Phase II. Five of 14 patients who achieved CR proceeded to stem cell transplantation. Based on completed studies, risks associated with DFP-10917 are predominantly hematological (eg, neutropenia, anemia, febrile neutropenia, leukopenia, lymphopenia, thrombocytopenia). Study Design and Methods: Based on promising Phase II results, the Sponsor initiated Study D18-11141 (NCT03926624), a Phase III, randomized, controlled study to compare the rate and duration of CR in patients with AML R/R to 2-4 prior induction regimens. Patients receive either DFP-10917 or non-intensive reinduction (low-dose cytarabine [LoDAC], azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive reinduction (high and intermediate dose cytarabine regimens). Patients assigned to DFP-10917 receive 6 mg/m 2/day by continuous infusion for 14 days followed by a 14-day rest period. Control treatment is administered per physician's decision. Adults aged ≥18 years with histologically or pathologically confirmed diagnosis of AML based on World Health Organization classification and adequate performance status (≤2) and organ function are eligible. Study Status: The study is ongoing at 34 study centers in the United States. As of July 2023, 162 patients were enrolled, with 82 assigned to DFP-10917. A majority of the patients are male (57.4%) and aged <75 years (83.3%). Overall, 44% have AML with myelodysplasia-related changes; 36% have AML not otherwise specified; and <20% have AML with recurrent genetic abnormalities or therapy-related myeloid neoplasms. Enrollment and management of patients were affected from 2020 to 2021 by COVID-19 restrictions. A prospectively-planned interim analysis will occur after the 150 th patient randomized is followed for >2 months. Based on recruitment projections, this analysis is scheduled for 09/2023. At that time, the Data Safety Monitoring Board will review an unblinded estimate of the treatment effect for the primary endpoint of CR, with the study either stopped for superiority or futility or continuing to a final analysis. If continued, the number of patients required for the final analysis will range from 300 to 450, in increments of 50, with the number determined based on the size of the interim treatment effect for the primary endpoint of CR or the secondary endpoint of overall survival.

Azadirachta indica A. Juss (neem) phenolic extract inhibits human B-lymphoblastoid cells growth via cell cycle arrest, apoptosis induction, and DNA damage

Aim: As far as is known, the pharmaceutical effects of neem on human B-lymphoblastoid (TK6) cells have not been studied until now. Hence, the present study aimed to obtain neem phenolic extracts for inhibits the proliferation of TK6 cells and explore some possible underlying mechanisms involved in these effects. Methods: Hexane extract (HE) was obtained in the first step. After that, the residual hexane was removed from the neem. The dried neem sample was used in a new extraction for obtaining the ethyl acetate extract (EAE). Total phenolic compounds (TPC) and total flavonoid contents (TFC) were determined by spectrophotometric methods. Lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to evaluate the cytotoxicity in TK6 cells. The stop at G0/G1 cell cycle and inducing apoptosis in the TK6 cells were analyzed by flow cytometry. For deoxyribonucleic acid (DNA) damage evaluation, the alkaline comet test was used. Results: The higher TFC (65.50 mg/g of extract ± 1.17 mg/g of extract) and TPC (52.08 mg of extract ± 0.88 mg of extract) were obtained in EAE compared to HE that was obtained TFC of 14.61 mg/g of extract ± 0.60 mg/g of extract and TPC of 3.20 mg/g of extract ± 1.20 mg/g of extract. EAE was more significantly cytotoxic to TK6 cells than HE. The apoptosis induction was higher after exposure to 15.0 µg/mL of EAE (11.29%) in comparison to 15.0 µg/mL of HE (2.52%). The G0/G1 phase increased from 72% negative control (NC) to 83% after treatment with neem extracts (15 µg/mL). Neem extracts were also able to cause DNA strand breaks in TK6 cells. Conclusions: The extraction residue from neem leaf after hexane extraction is a source important of cytotoxic and genotoxic molecules against TK6 cells, the results also can suggest that the toxic effects in TK6 cells can be provided most likely due to the presence of high content of TPC from neem extracts.

In vitro assessment of the severity of deoxyribonucleic acid damage in different types of cataracts directly in lens epithelial cells.

This study aimed to assess the severity of deoxyribonucleic acid (DNA) damage in lens epithelial cells (LECs) of senile cortical, nuclear, and posterior subcapsular cataracts. LECs were obtained from senile cortical, nuclear, and subcapsular types of cataracts after surgery. DNA damage in the cells was immediately assessed quantitatively using the CometScore™ software. Comets were found in cataractous LECs. The formation of "comets" in the DNA of LECs can be visualized using single-cell gel electrophoresis and indicates DNA strand breaks because the damaged DNA migrates at a different rate than the nondamaged DNA. Maximal damage was observed in Grade 3 cortical, nuclear, and subcapsular forms of cataracts. Statistically significant DNA damage was seen between grades 1 and 3 of cortical type of cataract, grades 1 and 3 of nuclear type of cataract, and grades 2 and 3 and grades 1 and 3 of posterior subcapsular type of cataract. In patients with senile cataract, DNA of LECs was randomly damaged, and this type of damage was possibly caused by reactive oxygen species (ROS). Maximum DNA damage was found in patients with Grade 3 senile cortical, nuclear, and subcapsular type cataracts. The pathogenesis of senile cataracts is multifactorial and includes continuous molecular stress resulting from photooxidative stress, UV irradiation, and oxidative reactions.

Model of Streptozotocin-nicotinamide Induced Type 2 Diabetes: a Comparative Review.

The aim of the present study was to review the streptozotocin-nicotinamide (STZ-NA) diabetes model. Type 2 diabetes is more prevalent (90-95%) in adults than type 1. Experimentally- induced diabetes models may be established by chemicals, viral agents, insulin antibodies, surgery, etc. The most advisable and prompt method to induce diabetes is using chemicals, and STZ and alloxan are widely used chemicals. STZ has proven to be a better diabetogenic agent than alloxan because alloxan has many drawbacks, as it induces only type 1 diabetes, has a high mortality rate in rats, and causes ketosis in animals. Moreover, it has lesser selectivity towards β-cells, and the diabetes-induced is reversible. STZ can be used to induce both type 1 and type 2 diabetes. It is noted that the genotoxic behavior of STZ in animals is accomplished through a reduction of nicotinamide adenine dinucleotide (NAD+) in pancreatic β-cells via the GLUT2 (Glucose transporter 2), which can cause cellular damage by DNA (Deoxyribonucleic acid) strand breaks that lead to cell death. NA is a biochemical precursor of NAD+, and it is a poly-ADP-ribose-polymerase-1 (PARP- 1) inhibitor. NAD+ is an important redox reaction co-enzyme for the production of adenosine triphosphate (ATP) and many other metabolic pathways. Extreme DNA damage contributes to the over-activation of PARP-1, loss of cellular resources, and necrotic cells death. Some studies have expressed that NA can protect pancreatic β-cells against the severe cytotoxicity of STZ. The review concluded that the STZ-NA model is dependent on the competency of NA to attain partial protection against the β-cytotoxic essence of STZ to induce type-2 diabetes.

Evaluation of Spontaneous DNA Damage Using the Alkaline Comet Assay in Lymphocyte Cells of Humans Living in the High Level Natural Radiation Area of Mamuju, Indonesia

To evaluate the biological impacts of high background radiation exposures that are represented by spontaneous deoxyribonucleic acid (DNA) damage, an evaluation on lymphocyte cells from residents of Mamuju, West Sulawesi, Indonesia was tested. The mean annual dose received by individuals in this area is about 10.40 mSv. Of the 177 adult subjects studied, 102 were from high-level natural radiation areas of Mamuju and 75 subjects were from a nearby normal-level natural radiation area. Both areas are similar in living situations. DNA strand breaks and other parameters of study and control group were determined using a standardized comet assay. Our results showed that chronic low-level natural radiation had resulted in significantly higher (p<0.001) DNA damage based on the three parameters of the assay (tail length, tail DNA, and tail moment) compared to those of control. There was a positive correlation between the level of DNA damage and age, where people aged 40 years and older had a higher level of DNA damage than those under 40 year. The level of DNA damage was also found to be higher in females compared to that of males. It was concluded that chronic exposure to natural radiation in Mamuju had induced spontaneous DNA damage in human cells after long-term exposure which was dependent on age and sex.

Simulation of Proton-Induced DNA Damage Patterns Using an Improved Clustering Algorithm.

Simulations of deoxyribonucleic acid (DNA) molecular damage use the traversal algorithm that has the disadvantages of being time-consuming, slowly converging, and requiring high-performance computer clusters. This work presents an improved version of the algorithm, "density-based spatial clustering of applications with noise" (DBSCAN), using a KD-tree approach to find neighbors of each point for calculating clustered DNA damage. The resulting algorithm considers the spatial distributions for sites of energy deposition and hydroxyl radical attack, yielding the statistical probability of (single and double) DNA strand breaks. This work achieves high accuracy and high speed at calculating clustered DNA damage that has been induced by proton treatment at the molecular level while running on an i7 quad-core CPU. The simulations focus on the indirect effect generated by hydroxyl radical attack on DNA. The obtained results are consistent with those of other published experiments and simulations. Due to the array of chemical processes triggered by proton treatment, it is possible to predict the effects that different track structures of various energy protons produce on eliciting direct and indirect damage of DNA.

Effects of DNA Damage and Oxidative Stress in Human Bronchial Epithelial Cells Exposed to PM2.5 from Beijing, China, in Winter.

Epidemiological studies have corroborated that respiratory diseases, including lung cancer, are related to fine particulate matter (<2.5 μm) (PM2.5) exposure. The toxic responses of PM2.5 are greatly influenced by the source of PM2.5. However, the effects of PM2.5 from Beijing on bronchial genotoxicity are scarce. In the present study, PM2.5 from Beijing was sampled and applied in vitro to investigate its genotoxicity and the mechanisms behind it. Human bronchial epithelial cells 16HBE were used as a model for exposure. Low (67.5 μg/mL), medium (116.9 μg/mL), and high (202.5 μg/mL) doses of PM2.5 were used for cell exposure. After PM2.5 exposure, cell viability, oxidative stress markers, DNA (deoxyribonucleic acid) strand breaks, 8-OH-dG levels, micronuclei formation, and DNA repair gene expression were measured. The results showed that PM2.5 significantly induced cytotoxicity in 16HBE. Moreover, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and cellular heme oxygenase (HO-1) were increased, and the level of glutathione (GSH) was decreased, which represented the occurrence of severe oxidative stress in 16HBE. The micronucleus rate was elevated, and DNA damage occurred as indicators of the comet assay, γ-H2AX and 8-OH-dG, were markedly enhanced by PM2.5, accompanied by the influence of 8-oxoguanine DNA glycosylase (OGG1), X-ray repair cross-complementing gene 1 (XRCC1), and poly (ADP-ribose) polymerase-1 (PARP1) expression. These results support the significant role of PM2.5 genotoxicity in 16HBE cells, which may occur through the combined effect on oxidative stress and the influence of DNA repair genes.

Highly standardized multicolor femtosecond fiber system for selective microphotomanipulation of deoxyribonucleic acid and chromatin.

We present a three-color femtosecond Er/Yb:fiber laser enabling highly specific and standardized nonlinear optical manipulation of live cells. The system simultaneously provides bandwidth-limited 80-fs pulses with identical intensity envelope centered at wavelengths of 515, 775, and 1035nm in the focus of a confocal microscope. We achieve this goal by combining high-order dispersion control via, for example, chirped fiber Bragg gratings with proper bandwidth management in each nonlinear conversion step. Wavelength-selective and noninterfering induction of deoxyribonucleic acid (DNA) photoproducts and DNA strand breaks, as well as fluorescence photoactivation of a photoactivatable green fluorescent protein (PA-GFP)-histone fusion protein, are demonstrated. The capability to introduce different types of DNA lesions and perform photoswitching experiments in a selective manner is essential for quantitative studies on DNA repair and chromatin dynamics.

Influence of plasma-generated reactive species on the plasmid DNA structure and plasmid-mediated transformation of Escherichia coli cells

The influence of plasma-generated reactive species on the conformation of plasmid DNA (pDNA) and the transformation efficiency of Escherichia coli cells were studied. An atmospheric-pressure plasma jet (APPJ) was used to generate reactive oxygen and nitrogen species (RONS) in an aqueous solution. When E. coli cells were transformed, the transformation efficiency of E. coli with the APPJ-treated plasmid was lower than with the APPJ-untreated plasmid. Transformation efficiency was reduced due to structural modification and degradation of the pDNA by the APPJ. Plasma treatment caused structural modification of the plasmid from the supercoiled form to the linear form, and also decreased the amount of plasmid by degrading the deoxyribonucleic acid (DNA) structure accompanied by disruption of nucleobases and DNA strand breakage. The formation of linear plasmid from supercoiled plasmid by the APPJ treatment was verified through electrophoretic analysis of the NdeI restriction enzyme-cut supercoiled plasmid. The structural modification and/or decrease in the amount of pDNA are attributed to the RONS from the plasma itself and to those derived from the interaction of plasma radicals with the aqueous solution. The effect of plasma treatment on the transformation efficiency of E. coli cells was more pronounced with the linear plasmid than with the supercoiled plasmid, indicating that the linear plasmid is more vulnerable to RONS. Overall, these results revealed that plasma-generated RONS can modify the structural and optical properties of bacterial pDNA, thus affecting its biological function.

Exercise and Oxidative Damage in Nucleoid DNA Quantified Using Single Cell Gel Electrophoresis: Present and Future Application.

High intensity exercise can enhance the production of reactive oxygen and nitrogen free radical species, which may cause a number of perturbations to cellular integrity, including deoxyribonucleic acid (DNA) modification. In the absence of adequate DNA repair, it is theoretically possible that several biological disorders may ensue, in addition to premature aging. This striking hypothesis and supposition can only be realized in the presence of sound methodology for the quantification of DNA damage and repair. The alkaline single-cell gel electrophoresis or “comet assay” is a simple and reliable method for measuring the components of DNA stability in eukaryotic cells. The assay is commonly used in research associated with genotoxicology and in human bio-monitoring studies concerned with gene-environment interactions; but is currently less appreciated and under-utilized in the domain of exercise science. No exercise related study for example, has incorporated the comet assay combined with fluorescent in situ hybridization methodology to detect and investigate whole genome, telomeric DNA, or gene region-specific DNA damage and repair in cells. Our laboratory and others have used the comet assay in conjunction with lesion-specific endonucleases to measure DNA strand breaks and oxidized bases to confirm that high intensity exercise can damage and destabilize DNA. Thus, the primary function of this review is to highlight recent advances and innovation with the comet assay, in order to enhance our future understanding of the complex interrelationship between exercise and DNA modification in eukaryotic cells. A brief synopsis of the current literature addressing DNA stability as a function of continuous aerobic exercise is also included.

Electrochemical and spectroscopic studies of ssDNA damage induced by hydrogen peroxide using graphene based nanomaterials

The oxidative damage of deoxyribonucleic acid (DNA) has been intensively studied due to its role in the occurrence of some diseases. The hydrogen peroxide (H2O2) is one of the reactive oxygen species (ROS). It can induce oxidation of DNA bases, sugar lesions or DNA strand breaks. The Pt/Gr–Au-3 modified electrode was employed for the analysis of four ssDNA samples: single-stranded DNA (ssDNA), ssDNA pre-treated with hydrogen peroxide (ssDNA–H2O2), ssDNA pre-treated with graphene–gold nanoparticles (ssDNA–Gr–Au) and ssDNA–Gr–Au complex pre-treated with hydrogen peroxide (ssDNA–Gr–Au–H2O2). By monitoring the changes of the purine oxidation peaks currents, we obtained valuable information about the damage induced by the hydrogen peroxide onto the un-treated or graphene pre-treated ssDNA and also about the interaction between ssDNA and graphene-based nanomaterial. The FTIR analysis has been also used to obtain information about the ssDNA damage. These findings allowed us to prove the utility of graphene-based nanomaterials (mainly Gr–Au-3) not only for the investigation of the oxidative damage induced by a non-radical oxidant, but also for the determination of the type of interaction between ssDNA and graphene surface. The stability of the ssDNA–Gr–Au-3 complex against the damage induced by H2O2, in the absence of reduced transition metals, was also established.

The role of epigenetics in spermatogenesis.

Male germ cells have a unique morphology and function to facilitate fertilization. Sperm deoxyribonucleic acid (DNA) is highly condensed to protect the paternal genome during transfer from male to oocyte. Sperm cells undergo extensive epigenetic modifications during differentiation to become a mature spermatozoon. Epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodeling are substantial regulators of spermatogenesis. DNA hypermethylation is associated with gene silencing. Meanwhile, hypomethylation is associated with gene expression. In sperm cells, promoters of developmental genes are highly hypomethylated. Proper DNA methylation is essential for embryo development. Histone modifications are chemical modifications that change the DNA-binding capacity of histones and the accessibility of regulatory factors to the DNA, thereby altering gene expression. Phosphorylation, methylation, acetylation, and ubiquitination are primary modifications of lysine and serine residues on histone tails. In addition to somatic histones, testis-specific histone variants are expressed, including histone H2B in mature sperm. The replacement of histones with protamines is a crucial step in spermatogenesis. Histone hyper-acetylation induces a loose chromatin structure and facilitates topoisomerase-induced DNA strand breaks. As a result, histones are replaced with transition proteins. Next, the transition proteins are replaced with protamines that induce compaction of sperm DNA. This review provides an overview of epigenetic changes during spermatogenesis.

The comet assay a method to measure DNA damage in oral submucous fibrosis patients: A case-control study

Context: Oral submucous fibrosis (OSF) is a chronic, progressive condition and rise in incidence of this disease has been attributed to an increased uptake of betel nut and its products, especially among young people. Due to its potential for malignant transformation, easy and reliable techniques for its early detection are needed. Comet assay is a simple technique to detect and quantify single strand breaks, double strand breaks and alkali labile damages. Aims: The present pilot study was undertaken to assess the deoxyribonucleic acid (DNA) damage in OSF and healthy groups using comet assay. Settings and Design: The hospital-based study was conducted by evaluating buccal mucosal cells of 50 individuals in the age range of 16-47 years and comet assay was carried out for all the two groups under alkali conditions. Materials and Methods: Oral epithelial cells were obtained from buccal mucosa of each 25 cases of healthy and OSF groups were subjected to comet assay. DNA damage was evaluated by measuring the tail length. Statistical Analysis Used: Student's t-test and Turkeys-multiple post-hoc procedures were used to statistically analyze the obtained data. Results: Increase in the tail length in buccal epithelial cells of OSF group when compared with the healthy group was noted. Furthermore, there was a significant increase in the DNA damage with duration of habits. Conclusions: We conclude that increase in the tail length formation in OSF groups when compared to healthy groups; this indicates DNA damage in the oral epithelial cells. The comet assay is a relatively simple, but sensitive and well-validated tool for measuring strand breaks in DNA in single cells.

Detection of low level microwave radiation induced deoxyribonucleic acid damage vis-à-vis genotoxicity in brain of fischer rats

Background:Non-ionizing radiofrequency radiation has been increasingly used in industry, commerce, medicine and especially in mobile phone technology and has become a matter of serious concern in present time.Objective:The present study was designed to investigate the possible deoxyribonucleic acid (DNA) damaging effects of low-level microwave radiation in brain of Fischer rats.Materials and Methods:Experiments were performed on male Fischer rats exposed to microwave radiation for 30 days at three different frequencies: 900, 1800 and 2450 MHz. Animals were divided into 4 groups: Group I (Sham exposed): Animals not exposed to microwave radiation but kept under same conditions as that of other groups, Group II: Animals exposed to microwave radiation at frequency 900 MHz at specific absorption rate (SAR) 5.953 × 10−4 W/kg, Group III: Animals exposed to 1800 MHz at SAR 5.835 × 10−4 W/kg and Group IV: Animals exposed to 2450 MHz at SAR 6.672 × 10−4 W/kg. At the end of the exposure period animals were sacrificed immediately and DNA damage in brain tissue was assessed using alkaline comet assay.Results:In the present study, we demonstrated DNA damaging effects of low level microwave radiation in brain.Conclusion:We concluded that low SAR microwave radiation exposure at these frequencies may induce DNA strand breaks in brain tissue.

Evaluation of Deoxyribonucleic Acid Toxicity Induced by the Radiopharmaceutical 99mTechnetium-Methylenediphosphonic Acid and by Stannous Chloride in Wistar Rats

Radiopharmaceuticals are employed in patient diagnostics and disease treatments. Concerning the diagnosis aspect, technetium-99m (99mTc) is utilized to label radiopharmaceuticals for single photon computed emission tomography (SPECT) due to its physical and chemical characteristics. 99mTc fixation on pharmaceuticals depends on a reducing agent, stannous chloride (SnCl2) being the most widely-utilized. The genotoxic, clastogenic and anegenic properties of the 99mTc-MDP(methylene diphosphonate used for bone SPECT) and SnCl2 were evaluated in Wistar rat blood cells using the Comet assay and micronucleus test. The experimental approach was to endovenously administer NaCl 0.9% (negative control), cyclophosphamide 50 mg/kg b.w. (positive control), SnCl2 500 μg/mL or 99mTc-MDP to animals and blood samples taken immediately before the injection, 3, and 24 h after (in the Comet assay) and 36 h after, for micronucleus test. The data showed that both SnCl2 and 99mTc-MDP-induced deoxyribonucleic acid (DNA) strand breaks in rat total blood cells, suggesting genotoxic potential. The 99mTc-MDP was not able to induce a significant DNA strand breaks increase in in vivo assays. Taken together, the data presented here points to the formation of a complex between SnCl2 in the radiopharmaceutical 99mTc-MDP, responsible for the decrease in cell damage, compared to both isolated chemical agents. These findings are important for the practice of nuclear medicine.

Short-term uptake of microcystin-LR by Coregonus lavaretus: GST activity and genotoxicity

In the present study, juvenile whitefish weighing 2 g were exposed by force-feeding to two ecologically relevant doses (0.05 and 0.5 μg per fish) of microcystin-LR (MC-LR). Then over 96 h the MC uptake in fish liver and muscle was measured, as the activity of the detoxification enzyme glutathione S-transferase (GST) in the liver, and the genotoxicity impact on red blood cells. Results show that (1) the MC-LR equivalent concentrations increased for both doses and in both organs of whitefish with approximately threefold lower concentrations for the low dose compared to the high dose in both organs and threefold lower concentrations in the muscle compared to the liver for each dose (2) the liver GST activity increased during the first 48 h of exposure with fivefold higher GST activity for the highest dose at 48 h compared to control and (3) MC-LR leads to deoxyribonucleic acid strand breaks that were detected by the comet assay and shown to be partially repaired. This work demonstrates that European whitefish could be impacted by cyanobacteria toxins due to rapid microcystin uptake, especially in the context of chronic contamination, which can occur during long bloom episodes.

DNA is a fractal antenna in electromagnetic fields

Purpose: To review the responses of deoxyribonucleic acid (DNA) to electromagnetic fields (EMF) in different frequency ranges, and characterise the properties of DNA as an antenna.Materials and methods: We examined published reports of increased stress protein levels and DNA strand breaks due to EMF interactions, both of which are indicative of DNA damage. We also considered antenna properties such as electronic conduction within DNA and its compact structure in the nucleus.Results: EMF interactions with DNA are similar over a range of non-ionising frequencies, i.e., extremely low frequency (ELF) and radio frequency (RF) ranges. There are similar effects in the ionising range, but the reactions are more complex.Conclusions: The wide frequency range of interaction with EMF is the functional characteristic of a fractal antenna, and DNA appears to possess the two structural characteristics of fractal antennas, electronic conduction and self symmetry. These properties contribute to greater reactivity of DNA with EMF in the environment, and the DNA damage could account for increases in cancer epidemiology, as well as variations in the rate of chemical evolution in early geologic history.

Azidothymidine Enhances Fluorodeoxyuridine-Mediated Radiosensitization

To examine the role of DNA repair and altered thymidine analogues in altering the response to radiation during thymidine deprivation. Mismatch repair-deficient and -proficient cell lines HEC59 and HC-2.4 were treated with fluorodeoxyuridine (FUdR), azidothymidine (AZT), and irradiation either alone or in combination, and outcomes of clonogenic survival and cell-cycle distributions were determined. Survival outcomes for all treatments were similar for both cell lines, suggesting that hMSH2 does not significantly influence thymidine deprivation toxicity or radiosensitization. The chain-terminating thymidine analogue AZT increased the toxicity of FUdR and increased DNA fragmentation. The combination of FUdR and AZT afforded greater radiosensitization than either drug alone. Drug enhancement ratios, the degree of excess radiation-induced cell death in drug-treated cultures compared with radiation alone for HEC59, were 1.2, 1.4, and 1.8 for AZT, FUdR, and the combination, respectively. Enhancement ratios for HC-2.4 were 1.3, 1.5, and 1.8 for AZT, FUdR, and the combination, respectively. Azidothymidine, a chain-terminating thymidine analogue, can enhance the radiosensitizing affects of thymidine deprivation. Deoxyribonucleic acid strand breaks may play an important role in the mechanism of thymidine deprivation-induced radiosensitization.

New evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regions.

Deoxyribonucleic acid (DNA) conformation and stability play an important role in brain function. Earlier studies reported alterations in DNA integrity in the brain regions of neurological disorders like Parkinson’s and Alzheimer’s diseases. However, there are only limited studies on DNA stability in an aging brain and the factors responsible for genomic instability are still not clear. In this study, we assess the levels of Copper (Cu), Iron (Fe) and Zinc (Zn) in three age groups (Group I: below 40 years), Group II: between 41-60 years) and Group III: above 61 years) in hippocampus and frontal cortex regions of normal brains. The number of samples in each group was eight. Genomic DNA was isolated and DNA integrity was studied by nick translation studies and presented as single and double strand breaks. The number of single strand breaks correspondingly increased with aging compared to double strand breaks. The strand breaks were more in frontal cortex compared to hippocampus. We observed that the levels of Cu and Fe are significantly elevated while Zn is significantly depleted as one progresses from Group I to Group III, indicating changes with aging in frontal cortex and hippocampus. But the elevation of metals was more in frontal cortical region compared to hippocampal region. There was a clear correlation between Cu and Fe levels versus strand breaks in aging brain regions. This indicates that genomic instability is progressive with aging and this will alter the gene expressions. To our knowledge, this is a new comprehensive database to date, looking at the levels of redox metals and corresponding strand breaks in DNA in two brain regions of the aging brain. The biological significance of these findings with relevance to mental health will be discussed.

The ability of Warburgia salutaris extracts to protect against crystalline silica-induced cell injury

In Southern Africa, the medicinal plant Warburgia salutaris is commonly used for the treatment of inflammatory and other diseases. The methanol extracts of W. salutaris were investigated with regard to a) production of proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma; b) activation of the transcription factor nuclear factor kappa B; and c) induction of deoxyribonucleic acid (DNA) damage and lipid peroxidation in the presence of crystalline silica particles. Due to its antioxidant properties, extracts of W. salutaris showed protective effects against crystalline silica-induced inflammatory cytokine expression, activation of nuclear transcription factor-kappaB, DNA strand breakage, and lipid peroxidation. Hence, W. salutaris may be a potential therapeutic agent against the fibrogenic and carcinogenic effects of crystalline silica.