Genoprotective and neuroprotective effects of Daphne gnidium leaf methanol extract,tested on male mice

Methanol extract of Daphne gnidium leaves was assessed for its antigenotoxic and neuroprotective effects through antioxidant and antibutyrylcholinesterase activities. Antigenotoxic activity was evaluated against methyl methanesulfonate injected intraperitoneally to mice, using the comet assay. The protective effect of D. gnidium reached 99.12%, at the lowest tested dose (44?mg/kg b.w.) in kidney cells, and 92.16% at the dose of 88?mg/kg b.w. in blood cells. The extract was dissolved in water and administrated to mice by intraperitoneal injection. Antioxidant activity was tested against DPPH radicals. It reached a maximum of 74.52% with an IC₅₀ value of 45?µg/ml. Anticholinesterase activity was determined against butyrylcholinesterase, an enzyme linked to Alzheimer disease. The extract exhibited antibutyrylcholinestrase effect with an inhibition percentage of 35.82% at the lowest tested dose (44?mg/kg b.w.).     

Honey and quercetin reduce ochratoxin A-induced DNA damage in the liver and the kidney through the modulation of intestinal microflora

This study was conducted to evaluate the interactions between the gut microbiota, ochratoxin A and functional food such as honey and quercetin, and the consequences of these interactions on ochratoxin-induced DNA damage in blood, liver and kidney cells. Honey (2?g?kg^?1) or Quercetin (50?mg?kg^?1) was applied to mice by intragastric application every day for 15 days, immediately before ochratoxin treatment (100?µg?kg^?1). We investigated colonic probiotic bacteria count, β-glucuronidase activity, the alkaline comet assay in blood, liver and kidney, the number of cells in the peritoneal cavity, macrophage spreading index and hematological and biochemical parameters. Honey and QU may reduce ochratoxin-induced DNA damage in the liver and kidney, β-glucuronidase activity and inflammation, partly through increasing the colon Bifidobacteria and Lactobacilli counts. The obtained results suggest that honey and QU counteracted the OTA-induced toxicity due to their bifidogenic activity and antigenotoxic activity.     

Cancer Chemoprevention: Tea Polyphenol Induced Cellular and Molecular Responses

Genetic polymorphisms may modify the effects of environmental risk factors on cancer occurence. We have recentlylaunched a comprehensive epidemiologic project, HERPACC II (Hospital-based Epidemiologic Research Programat Aichi Cancer Center II), including both lifestyle and polymorphism data, following HERPACC-I which solelyconcentrated on lifestyle data. As of April 2001, about 3000 samples of DNA are being stored to conduct case-controlstudies. Genotyping of 46 polymorphisms has been conducted at the laboratory of the Division of Epidemiology andPrevention. Twelve case-control studies and two papers on a new PCR method, PCR-CTPP (polymerase chain reactionwith confronting two-pair primers), have been accepted for publication. Significant findings in Japanese were foundfor 1) gene-environment interaction for esophageal cancer between heavy drinking and aldehyde dehydrogenase 2(ALDH2), 2) malignant lymphoma risk with methylenetetrahydrofalate reductase (MTHFR) and methionine synthase(MS), 3) interactions between smoking and two polymorphisms, interleukin 1B (IL-1B) and myeloperoxidase (MPO)for Helicobacter pylori infection, and 4) smoking habits with dopamine receptor D2 (DRD2) and IL-1B. Furtherstudies on interactions with polymorphisms will continue to be conducted for Japanese, using larger sizes of samples.     

Absence of genotoxic effects of the coumarin derivative 4‐methylesculetin in vivo and its potential chemoprevention against doxorubicin‐induced DNA damage

4‐Methylesculetin (4‐ME) is a synthetic derivative of coumarin that displays a potent reactive oxygen species (ROS) scavenger and metal chelating agent and therefore has been produced to help reduce the risk of human disease. The main objective of this study was to investigate the in vivo genotoxicity of 4‐ME and initially to verify its potential antigenotoxicity on doxorubicin (DXR)‐induced DNA damage. Different doses of 4‐ME (500, 1000 and 2000 mg kg^–1 body weight) were administered by gavage only or with a simultaneous intraperitoneal (i.p.) injection of DXR (80 mg kg^–1). The following endpoints were analyzed: DNA damage in peripheral blood, liver, bone marrow, brain and testicle cells according to an alkaline (pH > 13) comet assay and micronucleus induction in bone marrow cells. Cytotoxicity was assessed by scoring polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE/NCE ratio). No differences were observed between the negative control and the groups treated with a 4‐ME dose for any of the endpoints analyzed, indicating that it lacks genotoxic and cytotoxic effects. Moreover, 4‐ME demonstrated protective effects against DXR‐induced DNA damage at all tested doses and in all analyzed cell types, which ranged from 34.1% to 93.3% in the comet assay and 54.4% to 65.9% in the micronucleus test. Copyright © 2012 John Wiley & Sons, Ltd.     

Antigenotoxic activity of naturally occurring furanocoumarins

This study was designed to investigate the antigenotoxic effects of a series of naturally occurring furanocoumarins (NOFs) including isoimperatorin, imperatorin, (+)-oxypeucedanin, (+)-byakangelicol, and (+)-byakangelicine on antigenotoxic activities against genotoxicity induced by carcinogens [furylfuramide and N-methyl-N'-nitro-N-nitrosoguanidine], and procarcinogens 2-[2-(acetylamino)-4-amino-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-4) and 2-amino-3,4-dimethyl-3H-imidazo-[4,5-f] quinoline (MeIQ)] to genotoxic metabolites catalyzed by rat S9 or rat and human recombinant cytochrome P450 (CYP) 1As by using the umu test based on SOS response. Five different NOFs, which were found in the human diets, strongly inhibited the umuC induction by procarcinogens, but did not be affected by carcinogens. Notably, isoimperatorin and (+)-byakangelicol were found to be potent inhibitors on the metabolic activation of PBTA-4 and MeIQ to genotoxic metabolites catalyzed by rat and human CYP1A1, or rat and human CYP1A2, respectively. In addition, to elucidate the mechanism of their antigenotoxic effects against procarcinogens, the effects of NOFs on rat and human CYP1A1- or rat and human CYP1A2-related enzyme activities of 7-ethoxyresorufin-O-deethylase (EROD) were also investigated. Reduction of the EROD activities by some of the NOFs with IC(50) values of 0.23-20.64 μM was found to be due to strong inhibition of CYP1A1 and CYP1A2 dependent monooxygenases. Furthermore, the mechanism of inhibitions by NOFs on human CYP1A1 and CYP1A2 was analyzed by means of Dixon plots plus Cornish-Bowden plots. The kinetic studies of inhibition types revealed that these compounds inhibited the human CYP1A1 and CYP1A2 a variety of modes rather than by a uniform one. Moreover, experiments with a two-stage incubation indicated that NOFs, except for imperatorin, inhibited human CYP1A1 in a mechanism-based manner, but directly inhibited human CYP1A2. This data suggest that certain NOFs, to which humans are exposed in the diet, may be capable of affecting the metabolic activation of procarcinogens due to inhibitions of CYP1A1 and CYP1A2 enzymes.     

Cell protection induced by Acacia salicina extracts: Inhibition of genotoxic damage and determination of its antioxidant capacity

Antioxidant activity of Acacia salicina extracts was determined by the ability of each extract to inhibit lipid peroxidation, to protect against DNA strand scission induced by hydroxyl radicals, and to scavenge the free radical, 2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS^?+). The IC₅₀ values of the inhibitory activity toward lipid peroxidation of total oligomer flavonoids (TOF), methanol, ethyl acetate, and aqueous extracts were respectively 28, 52, 472, and 480 μg/mL. All extracts have the ability to scavenge the ABTS^?+ radical by a hydrogen-donating mechanism and to protect pKS plasmid DNA against hydroxyl radicals- induced DNA damage. An assay for the ability of A. salicina extracts to prevent mutations induced by various mutagens in Salmonella typhimurium TA102 and TA104 cells was conducted. TOF, methanol, ethyl acetate, and aqueous extracts from leaf parts of A. salicina showed no mutagenicity either with or without the metabolic enzymes preparation (S9). Protection against methylmethanesulfonate-induced mutagenicity was observed for TOF, methanol, and ethyl acetate extracts. Likewise, all extracts exhibited a high inhibition level of the Ames response induced by the indirect mutagen, 2-aminoanthracene. The antigenotoxic activity could be ascribed, at least in part, to their antioxidant properties, but we cannot exclude additionally mechanisms. Thus, A. salicina may serve as an ideal candidate for a cost- effective, readily exploitable natural phytochemical compound.     

Antigenotoxic studies of different substances to reduce the DNA damage induced by aflatoxin B(1) and ochratoxin A

Mycotoxins are produced mainly by the mycelial structure of filamentous fungi, or more specifically, molds. These secondary metabolites are synthesized during the end of the exponential growth phase and appear to have no biochemical significance in fungal growth and development. The contamination of foods and feeds with mycotoxins is a significant problem for the adverse effects on humans, animals, and crops that result in illnesses and economic losses. The toxic effect of the ingestion of mycotoxins in humans and animals depends on a number of factors including intake levels, duration of exposure, toxin species, mechanisms of action, metabolism, and defense mechanisms. In general, the consumption of contaminated food and feed with mycotoxin induces to neurotoxic, immunosuppressive, teratogenic, mutagenic, and carcinogenic effect in humans and/or animals. The most significant mycotoxins in terms of public health and agronomic perspective include the aflatoxins, ochratoxin A (OTA), trichothecenes, fumonisins, patulin, and the ergot alkaloids. Due to the detrimental effects of these mycotoxins, several strategies have been developed in order to reduce the risk of exposure. These include the degradation, destruction, inactivation or removal of mycotoxins through chemical, physical and biological methods. However, the results obtained with these methods have not been optimal, because they may change the organoleptic characteristics and nutritional values of food. Another alternative strategy to prevent or reduce the toxic effects of mycotoxins is by applying antimutagenic agents. These substances act according to several extra- or intracellular mechanisms, their main goal being to avoid the interaction of mycotoxins with DNA; as a consequence of their action, these agents would inhibit mutagenesis and carcinogenesis. This article reviews the main strategies used to control AFB(1) and ochratoxin A and contains an analysis of some antigenotoxic substances that reduce the DNA damage caused by these mycotoxins.     

Copper oxide nanoparticles and copper sulphate act as antigenotoxic agents in drosophila melanogaster

The biological reactivity of metal and metal oxide nanomaterials is attributed to their redox properties, which would explain their pro‐ or anti‐cancer properties depending on exposure circumstances. In this sense, copper oxide nanoparticles (CuONP) have been proposed as a potential anti‐tumoral agent. The aim of this study was to assess if CuONP can exert antigenotoxic effects using Drosophila melanogaster as an in vivo model. Genotoxicity was induced by two well‐known genotoxic compounds, namely potassium dichromate (PD) and ethyl methanesulfonate (EMS). The wing‐spot assay and the comet assay were used as biomarkers of genotoxic effects. In addition, changes in the expression of Ogg1 and Sod genes were determined. The effects of CuONP cotreatment were compared with those induced by copper sulfate (CS), an agent releasing copper ions. Using the wing‐spot assay, CuONP and CS were not able to reduce the genotoxic effects of EMS exposure, but had the ability to decrease the effects induced by PD, reducing the frequency of mutant twin‐spots that arise from mitotic recombination. In addition, CuONP and CS were able to reduce the DNA damage induced by PD as determined by the comet assay. In general, similar qualitative antigenotoxic effects were obtained with both copper compounds. The antigenotoxic effects of environmentally relevant and non‐toxic doses of CuONP and CS may be explained by their ability to partially restore the expression levels of the repair gene Ogg1 and the antioxidant gene Cu,ZnSod, both of which are inhibited by PD treatment. Environ. Mol. Mutagen. 58:46–55, 2017. © 2016 Wiley Periodicals, Inc.     

Antigenotoxic activities of crude extracts from Acacia salicina leaves

For centuries, plants have been used in traditional medicines and there has been recent interest in the chemopreventive properties of compounds derived from plants. In the present study, we investigated the effects of extracts of Acacia salicina leaves on the genotoxicity of benzo[a]pyrene (B(a)P) and nifuroxazide in the SOS Chromotest. Aqueous, total oligomers flavonoids (TOF)-enriched, petroleum ether, chloroform, ethyl acetate, and methanol extracts were prepared from powdered Acacia leaves, and characterized qualitatively for the presence of tannins, flavonoids, and sterols. All the extracts significantly decreased the genotoxicity induced by 1 microg B(a)P (+S9) and 10 microg nifuroxazide (-S9). The TOF-enriched and methanol extracts decreased the SOS response induced by B(a)P to a greater extent, whereas the TOF-enriched and the ethyl acetate extracts exhibited increased activity against the SOS response produced by nifuroxazide. In addition, the aqueous, ethyl acetate, and methanol extracts showed increased activity in scavenging the 1,1-diphenyl- 2-picrylhydrazyl (DPPH) free radical, while 100-300 microg/ml of all the test extracts were active in inhibiting O2-production in a xanthine/xanthine oxidase system. In contrast, only the petroleum ether extract was effective at inhibiting nitroblue tetrazolium reduction by the superoxide radical in a nonenzymatic O2- -generating system. The present study indicates that extracts of A. salicina leaves are a significant source of compounds with antigenotoxic and antioxidant activity (most likely phenolic compounds and sterols), and thus may be useful for chemoprevention.     

Recombinant human erythropoietin prevents cisplatin-induced genotoxicity in rat liver and heart tissues via an antioxidant process

Cisplatin (Cisp) is one of the most effective chemotherapeutic agents. However, at higher doses, liver and heart injuries may occur. Recombinant human erythropoietin (rhEPO) has recently been shown to exert an important cytoprotective effect in many tissues. For that reason, we tried to check the protective effect of rhEPO against Cisp-induced genotoxicity and oxidative stress in liver and heart tissues. Our experiments were performed using six groups of adult male Wistar rats. The control group was treated only with saline solution. The rhEPO group was given a single dose of rhEPO. The Cisp group was given a single injection of Cisp. The rhEPO+Cisp groups were given rhEPO simultaneously, 24 hours before, and 5 days after Cisp injection. Our results clearly showed that Cisp induced noticeable DNA damage in the liver and heart, accompanied by a significant increase in protein carbonyl level, reduced glutathione (GSH) depletion, and a decrease in catalase activity. Rats treated with rhEPO, simultaneously, before, or after Cisp injection, remarkably decreased DNA damage. It decreased also the protein carbonyl level, restored GSH depletion, and enhanced catalase activity. Our results highlight an interesting cytoprotective strategy using rhEPO against Cisp-induced liver and heart injuries.