scholarly journals Evaluation of Genotoxic Effects of New Molecules with Possible Trypanocidal Activity for Chagas Disease Treatment

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Francisco V. C. Mello ◽  
Alcione S. Carvalho ◽  
Mônica M. Bastos ◽  
Nubia Boechat ◽  
Claudia A. F. Aiub ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
New Drugs ◽  
Disease Treatment ◽  
Structural Modifications ◽  
Serovar Typhimurium ◽  
Mutagenic Response ◽  
Human Infections

Chagas disease is responsible for a large number of human infections and many are also at risk of infection. There is no effective drug for Chagas disease treatment. The Institute of Pharmaceutical Technology at Fiocruz, Brazil, has designed three nitro analogs of the nitroimidazole-thiadiazole, megazol: two triazole analogs PTAL 05-02 and PAMT 09 and a pyrazole analog PTAL 04-09. A set ofSalmonella entericaserovar Typhimurium strains were used in the bacterial reverse mutation test (Ames test) to determine the mutagenicity and cytotoxicity of megazol and its nitro analogs. Megazol presented positive mutagenic activity at very low concentration, either with or without metabolic activation S9 mix. The mutagenic response of the analogs was detected at higher concentration than the lowest megazol concentration to yield mutagenic activity showing that new advances can be made to develop new analogs. The micronucleus test with rat macrophage cells was used in the genotoxic evaluation. The analogs were capable of inducing micronucleus formation and showed cytotoxic effects. PTAL 04-09 structural modifications might be better suitable for the design of promising new drugs candidate for Chagas’ disease treatment.

Genetic Toxicity Studies of the Ketogenic Ester Bis Hexanoyl (R)-1,3-Butanediol

2021 ◽  
pp. 109158182199177
Author(s):  
Brianna J. Stubbs ◽  
Andrey I. Nikiforov ◽  
Marisa O. Rihner ◽  
Sari Weston ◽  
Nancy Higley ◽  
...  
Keyword(s):  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
Coli Strain ◽  
Control Group ◽  
Sprague Dawley ◽  
Genetic Toxicity ◽  
Polychromatic Erythrocytes

A series of studies was conducted to assess the genetic toxicity of a novel ketone ester, bis hexanoyl (R)-1,3-butanediol (herein referred to as BH-BD), according to Organization for Economic Co-operation and Development testing guidelines under the standards of Good Laboratory Practices. In bacterial reverse mutation tests, there was no evidence of mutagenic activity in any of the Salmonella typhimurium strains tested or in Escherichia coli strain WP2 uvrA, at dose levels up to 5,000 μg/plate in the presence or absence of Aroclor 1254-induced rat liver (S9 mix) for metabolic activation. In the in vitro micronucleus test using human TK6 cells, BH-BD did not show a statistically significant increase in the number of cells containing micronuclei when compared with concurrent control cultures at all time points and at any of the concentrations analyzed (up to 100 μg/mL, final concentration in culture medium), with and without S9 mix activation. In the in vivo micronucleus test using Sprague Dawley rats, BH-BD did not show a statistically significant increase in the incidence of micronucleated polychromatic erythrocytes relative to the vehicle control group. Therefore, BH-BD was concluded to be negative in all 3 tests. These results support the safety assessment of BH-BD for potential use in food.

scholarly journals Mutagenic activation of CL64,855, an anti-Trypanosoma cruzi nitroderivant, by bacterial nitroreductases

1998 ◽  
Vol 21 (4) ◽  
pp. 567-572 ◽  
Author(s):  
Marcos Antonio de Morais Jr. ◽  
Rita de Cássia Café Ferreira ◽  
Luiz Carlos de Souza Ferreira
Keyword(s):  
Trypanosoma Cruzi ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
Extreme Resistance ◽  
Serum Samples ◽  
Killing Effect ◽  
Mutagenic Response ◽  
Induced Mutagenesis

CL64,855 is a nitroimidazole-thiodiazole derivate with high anti-Trypanosoma cruzi activity. CL64,855-induced mutagenesis in the Salmonella/microsome test was detected by TA98 and TA98dnp6 strains, but not by the nitroreductase I-deficient TA98nr strain. The lack of mutagenic response of TA98nr was connected with its extreme resistance to the killing effect of the drug. Presence of S9 mix did not restore mutagenic activity of CL64,855 to the TA98nr strain. Additionally, CL64,855 was reduced in vitro by the nitroreductase I-proficient TA98 strain, mainly in the presence of oxygen, but not by the TA98nr strain. Mutagenic activity was detected in serum samples of treated guinea pigs by nitroreductase-proficient strains TA98 and TA98dnp6, but not by nitroductase-deficient strain TA98nr. In the case of urine, mutagenic activity was observed with all three tested strains, suggesting an in vivo metabolic activation of the drug by a distinct metabolic pathway.

scholarly journals Origanum majoranaEssential Oil Lacks Mutagenic Activity in theSalmonella/Microsome and Micronucleus Assays

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Andrea dos Santos Dantas ◽  
Luiz Carlos Klein-Júnior ◽  
Miriana S. Machado ◽  
Temenouga N. Guecheva ◽  
Luciana D. dos Santos ◽  
...  
Keyword(s):  
Essential Oil ◽  
Salmonella Typhimurium ◽  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Chinese Hamster ◽  
Metabolic Activation ◽  
Lung Fibroblasts ◽  
Chromosome Mutation ◽  
Origanum Majorana

The present study aimed to investigate thein vitromutagenic activity ofOriganum majoranaessential oil. The most abundant compounds identified by GC-MS wereγ-terpinene (25.73%),α-terpinene (17.35%), terpinen-4-ol (17.24%), and sabinene (10.8%). Mutagenicity was evaluated by theSalmonella/microsome test using the preincubation procedure on TA98, TA97a, TA100, TA102, and TA1535Salmonella typhimuriumstrains, in the absence or in the presence of metabolic activation. Cytotoxicity was detected at concentrations higher than 0.04 μL/plate in the absence of S9 mix and higher than 0.08 μL/plate in the presence of S9 mix and no gene mutation increase was observed. For thein vitromammalian cell micronucleus test, V79 Chinese hamster lung fibroblasts were used. Cytotoxicity was only observed at concentrations higher than or equal to 0.05 μg/mL. Moreover, when tested in noncytotoxic concentrations,O. majoranaessential oil was not able to induce chromosome mutation. The results from this study therefore suggest thatO. majoranaessential oil is not mutagenic at the concentrations tested in theSalmonella/microsome and micronucleus assays.

The Effect of Ergothioneine on Clastogenic Potential and Mutagenic Activity

2011 ◽  
Vol 30 (4) ◽  
pp. 405-409 ◽  
Author(s):  
Alexander G. Schauss ◽  
Erzsébet Béres ◽  
Adél Vértesi ◽  
Zsuzsanna Frank ◽  
Ilona Pasics ◽  
...  
Keyword(s):  
Dietary Supplement ◽  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
Chromosome Aberration Assay ◽  
Mammalian Erythrocyte ◽  
Polychromatic Erythrocytes ◽  
Structural Chromosome

L-(+)-ergothioneine has antioxidant and anti-inflammatory properties in vitro and in vivo and has uses as a dietary supplement and as an ingredient in foods, cosmetics, and as a pharmaceutical additive. The clastogenic potential and mutagenic of ergothioneine were assessed in vitro and in vivo. Ergothioneine concentrations up to 5000 μg/mL, with and without metabolic activation, was tested in the chromosome aberration assay with CHL cells and found not to induce structural chromosome aberrations. In the in vivo mammalian erythrocyte micronucleus test, ergothioneine was administered orally to male mice at doses up to 1500 mg/kg for potential genotoxic activity. No increase in the frequency of micronucleated polychromatic erythrocytes was observed.  Overall, ergothioneine was not genotoxic in these studies and provides additional experimental evidence supporting the safety of its use as a potential dietary supplement.

scholarly journals Mutagenic activity of airborne particulate matter from the urban area of Porto Alegre, Brazil

1998 ◽  
Vol 21 (2) ◽  
pp. 247-253 ◽  
Author(s):  
Vera Maria Ferrão Vargas ◽  
Rubem Cesar Horn ◽  
Régis Rolim Guidobono ◽  
Ana Beatriz Mittelstaedt ◽  
Irascema Girardi de Azevedo
Keyword(s):  
Particulate Matter ◽  
Salmonella Typhimurium ◽  
Urban Area ◽  
Mutagenic Activity ◽  
Airborne Particulate Matter ◽  
Metabolic Activation ◽  
Polar Fraction ◽  
Airborne Particulate ◽  
Porto Alegre ◽  
Mutagenic Response

The mutagenic activity of airborne particulate matter collected from three different sites within the urban area of Porto Alegre, Brazil, was investigated using a Salmonella/microsome assay. Samples were extracted by sonication, sequentially, with cyclohexane (CX), and dichloromethane (DCM), for a rough fractionation by polarity. The different fractions were tested for mutagenicity using Salmonella typhimurium strains TA98, with and without metabolic activation (S9 mix fraction), and TA98NR and TA98/1,8-DNP6, without metabolic activation. Mutagenic response was observed for frameshift strain TA98 in assays with and without metabolization for two sites (sites 2 and 3), which had considerable risk of environmental contamination by nonpolar (CX) and/or moderately polar (DCM) compounds. However, the values of revertants/m3 (rev/m3) were highest on the site subject to automobile exhaust (site 3) in assays without (9.56 rev/m3) and with metabolization (5.08 rev/m3). Maximum mutagenic activity was detected in the moderately polar fraction, decreasing after metabolization. Nevertheless, the nonpolar fractions (CX) gave higher mutagenic activity in the presence of metabolization than in the absence of the S9 mix fraction. The responses observed for TA98NR and TA98/1,8-DNP6 strains suggest the activity of nitrocompounds.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Antiproliferative and Genotoxic Action of an Underexploited Organoteluran Derivative on Sarcoma 180 Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Maria L.L. Barreto do Nascimento ◽  
Antonielly Campinho dos Reis ◽  
José V.O. Santos ◽  
Helber A. Negreiros ◽  
Felipe C. Carneiro da Silva ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Nuclear Division ◽  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Chemical Compounds ◽  
Negative Control ◽  
Nuclear Division Index ◽  
Apoptosis And Necrosis ◽  
Genotoxicity Tests ◽  
Genotoxic Action

Background: The search for novel metallic chemical compounds with toxicogenic effects have been of great importance for more efficient cancer treatment. Objective: The study evaluated the cytotoxic, genotoxic and mutagenic activity of organoteluran RF07 in S-180 cell line. Methods: The bioassays used were cell viability with 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test, evaluation of apoptosis and necrosis using fluorescence and flow cytometry, cytokinesis-block micronucleus test and comet assay. The compound was tested at 1; 2.5 and 5 µM. Results: The results showed the cytotoxicity of RF07 at concentrations of 2.5, 5, 10 and 20 µM when compared to the negative control. For genotoxicity tests, RF07 showed effects in all concentrations assessed by increased index and frequencies of damage and mutagenic alterations. The compound was also cytotoxic due to the significant decrease in nuclear division index, with significant values of apoptosis and necrosis. The results of fluorescence and flow cytometry showed apoptosis as the main type of cell death caused by RF07 at 5 µM, which is thought to avoid an aggressive immune response of the organism. Conclusion: In addition to cytotoxic and genotoxic effects, RF07 creates good perspectives for future antitumor formulations.

scholarly journals N-Nitroso Compounds and Mutagens in Chinese Fermented (Sour) Corn Pancakes

2002 ◽  
Vol 85 (5) ◽  
pp. 1052-1056 ◽  
Author(s):  
Frank D Groves ◽  
Haleem Issaq ◽  
Stephen Fox ◽  
Alan M Jeffrey ◽  
John Whysner ◽  
...  
Keyword(s):  
Stomach Cancer ◽  
Ames Test ◽  
Energy Analysis ◽  
Case Control Study ◽  
Mutagenic Activity ◽  
Nitroso Compounds ◽  
Positive Trend ◽  
Mutagenic Response ◽  
Control Study ◽  
Volatile Nitrosamines

Abstract Stomach cancer rates in rural Linqu County, Shandong Province, China, are exceptionally high. A previous case-control study revealed that the risk of stomach cancer was 30%higher among those who consumed sour (fermented) corn pancakes at least daily. A previous study of the sour pancakes reported volatile nitrosamines in most specimens, and almost half reportedly showed mutagenic activity. Few households currently consume sour pancakes, and the duration of fermentation has been shortened. We tested specimens of pancake batter and sour pancakes from Linqu County for mutagenic activity using the Ames test; for N-nitroso compounds (NOC) we used the Nitrolite–thermal energy analysis (TEA) method. Results of the Ames test were inconclusive: only 1 out of 15 cooked pancakes showed a positive mutagenic response, and all 15 batter specimens were negative; however, several batter specimens showed a weakly positive trend of mutagenicity with extract concentration. Our assay for total nitroso compounds was weakly positive in only 1 out of 15 specimens of sour pancake batter. That specimen was also tested by gas chromatography–TEA for nitrosaminoacids and volatile nitrosamines, but none were detected. It seems unlikely that the Chinese sour pancakes are significantly contaminated by NOC or other mutagens.

scholarly journals Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi, the Etiological Agent of Chagas' Disease

2010 ◽  
Vol 54 (9) ◽  
pp. 3738-3745 ◽  
Author(s):  
Sharon King-Keller ◽  
Minyong Li ◽  
Alyssa Smith ◽  
Shilong Zheng ◽  
Gurpreet Kaur ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Catalytic Domain ◽  
Polypeptide Chain ◽  
Inflammatory Diseases ◽  
New Drugs ◽  
Volume Recovery ◽  
Chronic Pulmonary Diseases ◽  
Potential Inhibitors

ABSTRACT Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.

Genotoxicity Studies on Sel-Plex®, a Standardized, Registered High-Selenium Yeast

2006 ◽  
Vol 25 (6) ◽  
pp. 477-485 ◽  
Author(s):  
James C. Griffiths ◽  
Ray A. Matulka ◽  
Ronan Power
Keyword(s):  
Chromosome Aberration ◽  
Micronucleus Test ◽  
Mutagenic Activity ◽  
Human Lymphocytes ◽  
Selenium Yeast ◽  
Yeast Saccharomyces Cerevisiae ◽  
Reverse Mutation ◽  
High Selenium ◽  
Chromosome Aberration Test

Selenium, recognized as an essential nutrient for human health, is a component of proteins and enzymes required for various biological functions and is currently being used as a feed supplement for livestock in geographical areas that are naturally low in selenium. Selenium is structurally similar to sulfur, replacing the sulfur atom in stoichiometric amounts and thus functions through an association with proteins, termed selenoproteins. In geographic areas low in selenium, there is the potential for animals (including humans) to become selenium deficient and this potential deficiency can be remedied by consumption of exogenous selenium, including selenium-enriched yeast ( Saccharomyces cerevisiae) that contains high levels of organic selenium (e.g., selenized yeast). A unique, standardized, registered high selenium food-grade baker’s yeast ( S. cerevisiae; Sel-Plex®), was tested in the following battery of Genotoxicity assays; (1) a bacterial reverse mutation test (Ames test); (2) an in vitro mammalian chromosome aberration test; and (3) a mouse micronucleus test. Under the conditions of this assay, Sel-Plex® showed no evidence of mutagenic activity in Salmonella typhimurium, in the bacterial reverse mutation test. Sel-Plex® did not induce significant chromosomal aberrations in cultured human lymphocytes in the in vitro mammalian chromosome aberration test. Sel-Plex® did not statistically increase the frequency or proportion of micronucleated immature erythrocytes in the mouse micronucleus test. Thus, from the studies presented here, the authors conclude that Sel-Plex® is nongenotoxic.

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