scholarly journals Mutagenicity of carcinogenic heterocyclic amines in Salmonella typhimurium YG strains and transgenic rodents including gpt delta

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Takehiko Nohmi ◽  
Masahiko Watanabe
Keyword(s):  
Salmonella Typhimurium ◽  
Ames Test ◽  
Point Mutations ◽  
High Sensitivity ◽  
Metabolic Activation ◽  
Reporter Genes ◽  
Heterocyclic Amines ◽  
In Vivo Mutagenicity

AbstractChemical carcinogens to humans have been usually identified by epidemiological studies on the relationships between occupational or environmental exposure to the agents and specific cancer induction. In contrast, carcinogenic heterocyclic amines were identified under the principle that mutagens in bacterial in the Ames test are possible human carcinogens. In the 1970s to 1990s, more than 10 heterocyclic amines were isolated from pyrolysates of amino acids, proteins, meat or fish as mutagens in the Ames test, and they were demonstrated as carcinogens in rodents. In the 1980s and 1990s, we have developed derivatives of the Ames tester strains that overexpressed acetyltransferase of Salmonella typhimurium. These strains such as Salmonella typhimurium YG1024 exhibited a high sensitivity to the mutagenicity of the carcinogenic heterocyclic amines. Because of the high sensitivity, YG1024 and other YG strains were used for various purposes, e.g., identification of novel heterocyclic amines, mechanisms of metabolic activation, comparison of mutagenic potencies of various heterocyclic amines, and the co-mutagenic effects. In the 1990s and 2000s, we developed transgenic mice and rats for the detection of mutagenicity of chemicals in vivo. The transgenics were generated by the introduction of reporter genes for mutations into fertilized eggs of mice and rats. We named the transgenics as gpt delta because the gpt gene of Escherichia coli was used for detection of point mutations such as base substitutions and frameshifts and the red/gam genes of λ phage were employed to detect deletion mutations. The transgenic rodents gpt delta and other transgenics with lacI or lacZ as reporter genes have been utilized for characterization of mutagenicity of heterocyclic amines in vivo. In this review, we summarized the in vitro mutagenicity of heterocyclic amines in Salmonella typhimurium YG strains and the in vivo mutagenicity in transgenic rodents. We discussed the relationships between in vitro and in vivo mutagenicity of the heterocyclic amines and their relations to the carcinogenicity.

scholarly journals Evaluation of mutagenic activity of the pesticides: actara, sencor, mospilan, pencozeb, fastac in the Ames test

2008 ◽  
Vol 6 (4) ◽  
pp. 29-33 ◽  
Author(s):  
Nazira S Karamova ◽  
Alexandra P Denisova ◽  
Zenon Stasevski
Keyword(s):  
Salmonella Typhimurium ◽  
Rat Liver ◽  
Potato Plant ◽  
Ames Test ◽  
Mutagenic Activity ◽  
Metabolic Activation ◽  
Mutagenic Effect ◽  
Toxic Concentrations ◽  
S9 Fraction

The mutagenic activity of five pesticides actara, sencor, mospilan, pencozeb, fastac widely used for treatment of potato plant lands in Tatarstan was tested in the Ames test. The non toxic concentrations of the pesticides determined in preliminary cytotoxicty test were used in the Ames assay. Pesticides actara, mospilan, pencozeb, fastac did not show mutagenic effect in Salmonella typhimurium TA 100 without rat liver S9 fraction. The weak mutagenic effect of herbicide sencor was established at concentration 1 ug/plate. Metabolic activation in vitro using rat liver S9 fraction decreased the mutagenic activity of sencor and did not alter the mutagenicity rate of the pesticides actara, mospilan, pencozeb and fastac.

scholarly journals Antimutagenic Effects of Polymethoxy Flavonoids of Citrus unshiu

2017 ◽  
Vol 12 (1) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Takahiro Matsumoto ◽  
Taisuke Nishikawa ◽  
Ayano Furukawa ◽  
Saki Itano ◽  
Yuka Tamura ◽  
...  
Keyword(s):  
Salmonella Typhimurium ◽  
Traditional Medicine ◽  
Ames Test ◽  
Micronucleus Test ◽  
Ethanolic Extract ◽  
Citrus Unshiu ◽  
Citrus Fruits ◽  
Edible Fruit

Citrus fruits have been used as edible fruit and traditional medicine for various diseases such as cancer. In the courses of our study to find antimutagens, we have found that the ethanolic extract of the peel of Citrus unshiu Marc showed antimutagenic effects against several mutagens in the Ames test using Salmonella typhimurium TA98 strain. Three polymethoxy flavonoids, nobiletin, 3,5,6,7,8,3′,4′-heptamethoxyflavone, and tangeretin, were identified in the extract as major constituents. These three polymethoxy flavonoids showed antimutagenic effects in the Ames test in vitro and in the micronucleus test in vivo.

scholarly journals Testing of the mutagenic potential of N-(γ-aminobuturyl)-1-aza-15-crown-5 hydrochloride in Ames test microplate modification

2019 ◽  
pp. 81-87
Author(s):  
M. Ya. Golovenko ◽  
V. B. Larionov ◽  
S. S. Basok ◽  
A. S. Reder
Keyword(s):  
Salmonella Typhimurium ◽  
Sodium Azide ◽  
Anticonvulsant Activity ◽  
Ames Test ◽  
Point Mutations ◽  
Gene Mutations ◽  
Metabolic Activation ◽  
Chemical Mutagenesis ◽  
Mutagenic Potential ◽  
Significant Development

In recent years, studies in the field of chemical mutagenesis have undergone significant development, due to the introduction of a large number of different chemicals and scientific advances in the creation and use of new test systems, allowing a complete assessment of both mutagens themselves and their metabolites. The aim of the work was to determine possible induction of gene mutations under influence of hydrochloride N-(γ-aminobuturil)-1-aza-4,7,10,13-tetraozacyclopentadecan (TOCPD), which has nootropic, anxiolytic and anticonvulsant activity. The ability of TOCPD to induce gene mutations was evaluated in Ames test on strains Salmonella typhimurium ТА 98 (frame shift mutations) and ТА 100 (substitution point mutations). The compound was used at concentrations of 10, 100, 250, 500 and 1000 μg/ml. Standard mutagens were 2-nitrofluoren for Salmonella typhimurium ТА 98 and sodium azide for Salmonella typhimurium ТА 100 in test without metabolic activation. In an activation variant a microsomal activating mixture was used (S9 mix). In tests with activation for both strains, 2-aminoantracene was used. The µAmes kit, Moltox (USA) and Muta-ChromoPlate kit (Canada) were used in the work. The results were evaluated by the number of wells with mutated cells with medium color changing from purple to yellow. The obtained data showed that in the control and according to the action of corresponding mutagens, the percentage of wells with mutated cells corresponded to the standard parameters determined by protocol of the microplate test. For the action of TOCPD compound, no gene mutations were detected in both S. typhimurium ТА 98 and ТА 100 strains within the concentrations used.

scholarly journals Compensatory mechanisms in resistant Anopheles gambiae AcerKis and KdrKis neurons modulate insecticide-based mosquito control

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Stéphane Perrier ◽  
Eléonore Moreau ◽  
Caroline Deshayes ◽  
Marine El-Adouzi ◽  
Delphine Goven ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Anopheles Gambiae ◽  
Calcium Concentration ◽  
Mosquito Control ◽  
Point Mutations ◽  
Resting Membrane Potential ◽  
Compensatory Mechanisms ◽  
Pyrethroid Insecticides

AbstractIn the malaria vector Anopheles gambiae, two point mutations in the acetylcholinesterase (ace-1R) and the sodium channel (kdrR) genes confer resistance to organophosphate/carbamate and pyrethroid insecticides, respectively. The mechanisms of compensation that recover the functional alterations associated with these mutations and their role in the modulation of insecticide efficacy are unknown. Using multidisciplinary approaches adapted to neurons isolated from resistant Anopheles gambiae AcerKis and KdrKis strains together with larval bioassays, we demonstrate that nAChRs, and the intracellular calcium concentration represent the key components of an adaptation strategy ensuring neuronal functions maintenance. In AcerKis neurons, the increased effect of acetylcholine related to the reduced acetylcholinesterase activity is compensated by expressing higher density of nAChRs permeable to calcium. In KdrKis neurons, changes in the biophysical properties of the L1014F mutant sodium channel, leading to enhance overlap between activation and inactivation relationships, diminish the resting membrane potential and reduce the fraction of calcium channels available involved in acetylcholine release. Together with the lower intracellular basal calcium concentration observed, these factors increase nAChRs sensitivity to maintain the effect of low concentration of acetylcholine. These results explain the opposite effects of the insecticide clothianidin observed in AcerKis and KdrKis neurons in vitro and in vivo.

scholarly journals Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

2021 ◽  
Vol 14 (1) ◽  
pp. 38
Author(s):  
Hyo Jeong Lee ◽  
Pyeonghwa Jeong ◽  
Yeongyu Moon ◽  
Jungil Choi ◽  
Jeong Doo Heo ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Carcinoma Cells ◽  
Medullary Thyroid ◽  
Potent Inhibition ◽  
Kinase Inhibitory Activity

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

scholarly journals Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

2021 ◽  
Vol 22 (1) ◽  
pp. 434
Author(s):  
Yuria Jang ◽  
Hong Moon Sohn ◽  
Young Jong Ko ◽  
Hoon Hyun ◽  
Wonbong Lim
Keyword(s):  
Nuclear Translocation ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Point Mutations ◽  
Tartrate Resistant Acid Phosphatase ◽  
Mice Model ◽  
Gsk 3Β ◽  
Rank Signaling

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.

scholarly journals Biological nanoscale fluorescent probes: From structure and performance to bioimaging

2020 ◽  
Vol 39 (1) ◽  
pp. 209-221
Author(s):  
Jiafeng Wan ◽  
Xiaoyuan Zhang ◽  
Kai Zhang ◽  
Zhiqiang Su
Keyword(s):  
Fluorescent Probes ◽  
Organic Dyes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
High Sensitivity ◽  
Biological Imaging ◽  
Fluorescent Materials ◽  
And Performance

Abstract In recent years, nanomaterials have attracted lots of attention from researchers due to their unique properties. Nanometer fluorescent materials, such as organic dyes, semiconductor quantum dots (QDs), metal nano-clusters (MNCs), carbon dots (CDs), etc., are widely used in biological imaging due to their high sensitivity, short response time, and excellent accuracy. Nanometer fluorescent probes can not only perform in vitro imaging of organisms but also achieve in vivo imaging. This provides medical staff with great convenience in cancer treatment. Combined with contemporary medical methods, faster and more effective treatment of cancer is achievable. This article explains the response mechanism of three-nanometer fluorescent probes: the principle of induced electron transfer (PET), the principle of fluorescence resonance energy transfer (FRET), and the principle of intramolecular charge transfer (ICT), showing the semiconductor QDs, precious MNCs, and CDs. The excellent performance of the three kinds of nano fluorescent materials in biological imaging is highlighted, and the application of these three kinds of nano fluorescent probes in targeted biological imaging is also introduced. Nanometer fluorescent materials will show their significance in the field of biomedicine.

scholarly journals Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected withPlasmodium falciparum Malaria Parasites

1998 ◽  
Vol 42 (7) ◽  
pp. 1811-1814 ◽  
Author(s):  
Leonardo K. Basco ◽  
Rachida Tahar ◽  
Pascal Ringwald
Keyword(s):  
Dihydrofolate Reductase ◽  
Point Mutations ◽  
Gene Mutations ◽  
Adult Patients ◽  
Wild Type ◽  
Dihydropteroate Synthase ◽  
Reductase Gene ◽  
Parasite Populations

ABSTRACT In vitro sulfadoxine and pyrimethamine resistance has been associated with point mutations in the dihydropteroate synthase and dihydrofolate reductase domains, respectively, but the in vivo relevance of these point mutations has not been well established. To analyze the correlation between genotype and phenotype, 10 Cameroonian adult patients were treated with sulfadoxine-pyrimethamine and followed up for 28 days. After losses to follow-up (n = 1) or elimination of DNA samples due to mixed parasite populations with pyrimethamine-sensitive and pyrimethamine-resistant profiles (n = 3), parasite genomic DNA from day 0 blood samples of six patients were analyzed by DNA sequencing. Three patients who were cured had isolates characterized by a wild-type or mutant dihydrofolate reductase gene (with one or two mutations) and a wild-type dihydropteroate synthase gene. Three other patients who failed to respond to sulfadoxine-pyrimethamine treatment carried isolates with triple dihydrofolate reductase gene mutations and either a wild-type or a mutant dihydropteroate synthase gene. Three dihydrofolate reductase gene codons (51, 59, and 108) may be reliable genetic markers that can accurately predict the clinical outcome of sulfadoxine-pyrimethamine treatment in Africa.

scholarly journals Transcription of alpha-specific genes in Saccharomyces cerevisiae: DNA sequence requirements for activity of the coregulator alpha 1.

1993 ◽  
Vol 13 (11) ◽  
pp. 6866-6875 ◽  
Author(s):  
D C Hagen ◽  
L Bruhn ◽  
C A Westby ◽  
G F Sprague
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Binding Site ◽  
Dna Sequences ◽  
Point Mutations ◽  
Transcription Activation ◽  
Specific Gene ◽  
Binding Assays ◽  
Weak Binding

Transcription activation of alpha-specific genes in Saccharomyces cerevisiae is regulated by two proteins, MCM1 and alpha 1, which bind to DNA sequences, called P'Q elements, found upstream of alpha-specific genes. Neither MCM1 nor alpha 1 alone binds efficiently to P'Q elements. Together, however, they bind cooperatively in a manner that requires both the P' sequence, which is a weak binding site for MCM1, and the Q sequence, which has been postulated to be the binding site for alpha 1. We analyzed a collection of point mutations in the P'Q element of the STE3 gene to determine the importance of individual base pairs for alpha-specific gene transcription. Within the 10-bp conserved Q sequence, mutations at only three positions strongly affected transcription activation in vivo. These same mutations did not affect the weak binding to P'Q displayed by MCM1 alone. In vitro DNA binding assays showed a direct correlation between the ability of the mutant sequences to form ternary P'Q-MCM1-alpha 1 complexes and the degree to which transcription was activated in vivo. Thus, the ability of alpha 1 and MCM1 to bind cooperatively to P'Q elements is critical for activation of alpha-specific genes. In all natural alpha-specific genes the Q sequence is adjacent to the degenerate side of P'. To test the significance of this geometry, we created several novel juxtapositions of P, P', and Q sequences. When the Q sequence was opposite the degenerate side, the composite QP' element was inactive as a promoter element in vivo and unable to form stable ternary QP'-MCM1-alpha 1 complexes in vitro. We also found that addition of a Q sequence to a strong MCM1 binding site allows the addition of alpha 1 to the complex. This finding, together with the observation that Q-element point mutations affected ternary complex formation but not the weak binding of MCM1 alone, supports the idea that the Q sequence serves as a binding site for alpha 1.

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