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1.
Environ Mol Mutagen ; 64(3): 167-175, 2023 03.
Article in English | MEDLINE | ID: mdl-36841969

ABSTRACT

Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture- and animal-based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof-of-principle experiments with testicular cancer patients exposed to a cisplatin-based regimen validated the ability of flow cytometric blood-based micronucleated reticulocyte (MN-RET) and PIG-A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross-sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN-RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN-RET in both the cross-sectional and prospective studies. However, no evidence of PIG-A gene mutation was found in hydroxyurea-treated children, despite the fact that the two assays use the same rapidly-dividing, highly-exposed cell type. Collectively, these results reinforce the complementary nature of MN-RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA.


Subject(s)
Anemia, Sickle Cell , Testicular Neoplasms , Humans , Male , Animals , Hydroxyurea/adverse effects , Prospective Studies , Cross-Sectional Studies , Testicular Neoplasms/chemically induced , Testicular Neoplasms/drug therapy , Cisplatin/adverse effects , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/genetics , Mutagenesis , Mutagens/therapeutic use
2.
Rev Assoc Med Bras (1992) ; 68(9): 1191-1198, 2022 Sep.
Article in English | MEDLINE | ID: mdl-36228250

ABSTRACT

OBJECTIVE: Bronchiectasis is a chronic respiratory disease characterized by inflammation, irreversible dilation of the bronchi, and recurrent pulmonary infections, with a high morbidity and mortality rate, but is less studied from the point of view of its prevalence and associated factors not directly related to respiratory prognosis. As it is a disease related to the exacerbation of the inflammatory process and oxidative stress, this study searched to investigate the micronucleus frequency in patients with and without bronchiectasis treated at a specialized pulmonology service in a hospital in the extreme south of Brazil. METHODS: Patients with a confirmed tomographic diagnosis of bronchiectasis were defined as cases. Mutagenicity was evaluated by the micronucleus test in patients' oral mucosa cells. Data collection was performed through a questionnaire containing socioeconomic, demographic, lifestyle, and health condition information. RESULTS: Of the 95 patients involved in this study, 21 (22.1%) were diagnosed with bronchiectasis aged between 12 and 89 years. There was no significant difference in the frequency of micronucleus between patients with and without bronchiectasis. There was a significant positive association between age and frequency of micronucleus among patients with bronchiectasis, but this association does not occur among patients without the disease. CONCLUSION: This is the first study to investigate data on the prevalence and clinical and epidemiological aspects of this chronic disease in Brazil, especially those related to the genotoxicity outcome.


Subject(s)
Bronchiectasis , Pulmonary Medicine , Adolescent , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , Bronchiectasis/diagnosis , Bronchiectasis/epidemiology , Child , Hospitals , Humans , Middle Aged , Mutagens/therapeutic use , Young Adult
3.
Sci Data ; 9(1): 610, 2022 10 08.
Article in English | MEDLINE | ID: mdl-36209289

ABSTRACT

Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate immunity, or dysregulate survival and growth of cells. To identify chemical agents with pro- or antiviral effects we conducted arrayed high-content image-based multi-cycle infection screens of 1,280 mainly FDA-approved compounds with three human viruses, rhinovirus (RV), influenza A virus (IAV), and herpes simplex virus (HSV) differing in genome organization, composition, presence of an envelope, and tropism. Based on Z'-factors assessing screening quality and Z-scores ranking individual compounds, we identified potent inhibitors and enhancers of infection: the RNA mutagen 5-Azacytidine against RV-A16; the broad-spectrum antimycotic drug Clotrimazole inhibiting IAV-WSN; the chemotherapeutic agent Raltitrexed blocking HSV-1; and Clobetasol enhancing HSV-1. Remarkably, the topical antiseptic compound Aminacrine, which is clinically used against bacterial and fungal agents, inhibited all three viruses. Our data underscore the versatility and potency of image-based, full cycle virus propagation assays in cell-based screenings for antiviral agents.


Subject(s)
Anti-Infective Agents, Local , Herpes Simplex , Influenza A virus , Aminacrine/therapeutic use , Anti-Infective Agents, Local/therapeutic use , Antiviral Agents/pharmacology , Azacitidine/therapeutic use , Clobetasol/therapeutic use , Clotrimazole/therapeutic use , Herpes Simplex/drug therapy , Humans , Mutagens/therapeutic use , Rhinovirus
4.
Curr Pharm Biotechnol ; 23(13): 1556-1568, 2022.
Article in English | MEDLINE | ID: mdl-34951360

ABSTRACT

Cancer is the uncontrolled proliferation of cells that involves accumulation of genetic mutations by different types of mutagens including physical, chemical, and biological. Consequently, normal cell cycles get interrupted. Immunological assays, histopathological tests, polymerase chain reaction, computed tomography, magnetic resonance, and radiation therapy are some conventional techniques for cancer diagnostics. However, these techniques are not only expensive, time-consuming, tedious but also toxic to healthy cells. Therefore, these limitations are overcome by nanodevices that show high sensitivity, selectivity, rapidity, and cost-effectiveness in the detection of cancer biomarkers. Electrochemical biosensors are more efficient in the early diagnosis of cancers that help in patients' effective and timely treatment. Distinct types of nanotools viz. inorganic, organic, and polymeric nanomaterials are used in cancer therapeutics. Nano approaches have shown many advantages: they are site-specific, require meager amounts of drugs, limited toxicity, avoid drug resistance, and are more efficient, sensitive, and reliable. Therefore, future research should focus on developing highly inventive nanotools for the diagnosis and therapeutics of cancers.


Subject(s)
Biosensing Techniques , Neoplasms , Biomarkers, Tumor , Humans , Mutagens/therapeutic use , Nanotechnology , Neoplasms/diagnosis , Neoplasms/drug therapy
5.
Electron. j. biotechnol ; 53: 8-13, Sep.2021. ilus, tab, graf
Article in English | LILACS | ID: biblio-1444447

ABSTRACT

BACKGROUND Osteoarthritis (OA) is a form of arthritis due to degradation of articular cartilage. OA is asso ciated with stiffness, joint pain, and dysfunction, affecting adults worldwide. Galangin is a bioactive fla vonoid that exerts several therapeutic and biological activities. Anti-hyperglycemic, anti-inflammatory, anti-cancer, and anti-apoptotic activities of galangin have been reported in several studies. In the present study, rats were divided into normal control, OA (control), galangin 10 mg/kg (low-dose), galangin 100 mg/kg (high-dose), and celecoxib 30 mg/kg (positive control) groups. All doses were administered orally for 14 consecutive days. The urinary type II collagen (mCTX-II) level as well as reactive oxygen spe cies, tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, superoxide dismutase, catalase, lipid peroxidation, reduced glutathione, and glutathione peroxidase levels were measured. In addition, the CTX-II mRNA and protein expression levels were measured. RESULTS Galangin supplementation significantly reduced the mCTX-II level compared with controls. Galangin treatment significantly reduced reactive oxygen species, lipid peroxidation, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha levels, but increased catalase, superoxide dismutase, glu tathione peroxidase, and reduced glutathione levels. Galangin treatment significantly reduced the CTX-II mRNA and protein expression levels. The low CTX-II level in tissue indicated the inhibition of cartilage degradation. CONCLUSIONS In summary, supplementation with galangin was effective against OA. The identification of potential therapeutic agents that inhibit inflammation may be useful for the management and prevention of OA


Subject(s)
Animals , Male , Rats , Osteoarthritis/drug therapy , Flavonoids/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Celecoxib/therapeutic use , Mutagens/therapeutic use , Reactive Oxygen Species , Rats, Sprague-Dawley
6.
Sci Rep ; 9(1): 4987, 2019 03 21.
Article in English | MEDLINE | ID: mdl-30899037

ABSTRACT

One of the greatest challenges of modern medicine is to find cheaper and easier ways to produce transporters for biologically active substances, which will provide selective and efficient drug delivery to the target cells, while causing low toxicity towards healthy cells. Currently, metal-based nanoparticles are considered a successful and viable solution to this problem. In this work, we propose the use of novel synthesis method of platinum nanoparticles (PtNPs) connected with their precise biophysical characterization and assessment of their potential toxicity. To work as an efficient nanodelivery platform, nanoparticles should interact with the desired active compounds spontaneously and non-covalently. We investigated possible direct interactions of PtNPs with ICR-191, a model acridine mutagen with well-established biophysical properties and mutagenic activity, by Dynamic Light Scattering, fluorescence spectroscopy, and Isothermal Titration Calorimetry. Moreover, to determine the biological activity of ICR-191-PtNPs aggregates, we employed Ames mutagenicity test, eukaryotic cell line analysis and toxicity test against the model organism Caenorhabditis elegans. PtNPs' interesting physicochemical properties associated to the lack of toxicity in a tested range of concentrations, as well as their ability to modulate ICR-191 biological activity, suggest that these particles successfully work as potential delivery platforms for different biologically active substances.


Subject(s)
Aminacrine/analogs & derivatives , Drug Delivery Systems/adverse effects , Metal Nanoparticles/chemistry , Nitrogen Mustard Compounds/chemistry , Platinum/chemistry , Aminacrine/chemical synthesis , Aminacrine/chemistry , Aminacrine/therapeutic use , Biophysical Phenomena , Humans , Metal Nanoparticles/therapeutic use , Mutagens/chemistry , Mutagens/therapeutic use , Mutagens/toxicity , Nitrogen Mustard Compounds/chemical synthesis , Nitrogen Mustard Compounds/therapeutic use
7.
Int J Mol Med ; 43(2): 701-708, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30483736

ABSTRACT

Tumor necrosis factor (TNF)­related apoptosis­inducing ligand (TRAIL) is a member of the TNF superfamily and is an antitumor drug that induces apoptosis in tumor cells with minimal or no effects on normal cells. Here, it is demonstrated that 6­shogaol (6­sho), a bioactive component of ginger, exerted anti­inflammatory and anticancer properties, attenuated tumor cell propagation and induced TRAIL­mediated cell death in liver cancer cells. The current study identified a potential pathway by revealing that TRAIL and 6­sho or chloroquine acted together to trigger reactive oxygen species (ROS) production, to upregulate tumor­suppressor protein 53 (p53) expression and to change the mitochondrial transmembrane potential (MTP). Treatment with N­acetyl­L­cysteine reversed these effects, restoring the MTP and attenuated ROS production and p53 expression. Interestingly, treatment with 6­sho increased p62 and microtubule­associated proteins 1A/1B light chain 3B­II levels, indicating an inhibited autophagy flux. In conclusion, attenuation of 6­sho­induced autophagy flux sensitized cells to TRAIL­induced apoptosis via p53 and ROS, suggesting that the administration of TRAIL in combination with 6­sho may be a suitable therapeutic method for the treatment of TRAIL­resistant Huh7 liver cells.


Subject(s)
Autophagy/drug effects , Catechols/pharmacology , Liver Neoplasms/metabolism , Reactive Oxygen Species/metabolism , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Suppressor Protein p53/biosynthesis , Acetylcysteine/pharmacology , Apoptosis/drug effects , Caspases, Initiator/metabolism , Catechols/therapeutic use , Cell Line, Tumor , Chloroquine/metabolism , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Synergism , Drug Therapy, Combination , Zingiber officinale/chemistry , Humans , Membrane Potential, Mitochondrial/drug effects , Mutagens/pharmacology , Mutagens/therapeutic use , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , TNF-Related Apoptosis-Inducing Ligand/therapeutic use
8.
Environ Mol Mutagen ; 60(3): 302-304, 2019 04.
Article in English | MEDLINE | ID: mdl-30525240

ABSTRACT

Sickle cell anemia (SCA) is a hereditary hematological disease that is characterized by a point mutation in the beta globin S gene and has no specific treatment; hydroxyurea (HU) is the only therapeutic agent used in clinical practice. In the present study, we evaluated the deoxyribonucleic acid (DNA) damage index (DI) and chromosomal damage in leukocytes of adult patients with SCA with and without HU. The DI was assessed by the comet assay and chromosomal damage by the leukocyte micronucleus test of adult patients treated with HU (SCA-HU) and without the use of HU (SCA-NoHU). This is a cross-sectional study with 77 patients with SCA who attended a referral hospital in Fortaleza, Brazil. The control group (CG) consisted of 58 reportedly healthy individuals. The comparisons of means were performed by analysis of variance and Tukey's post-test. Values of P < 0.05 were considered statistically significant. SCA-NoHU patients had statistically higher DI values and a statistically significantly higher frequency of micronuclei compared to the CG. In addition, HU treatment accentuated DNA lesions by significantly increasing both parameters in treated patients (SCA-HU). HU potentiates DNA damage and the occurrence of chromosomal damage, which may promote genomic instability, mutation occurrence, and carcinogenesis. Studies are needed to evaluate the involved pathways, repair mechanisms, and the clinical impact that such damage can cause. Environ. Mol. Mutagen. 60:302-304, 2019. © 2018 Wiley Periodicals, Inc.


Subject(s)
Anemia, Sickle Cell/drug therapy , Antisickling Agents/adverse effects , Antisickling Agents/therapeutic use , DNA Damage/drug effects , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Adolescent , Adult , Brazil , Cross-Sectional Studies , DNA Damage/genetics , Female , Humans , Leukocytes/cytology , Male , Micronucleus Tests , Middle Aged , Mutagens/adverse effects , Mutagens/therapeutic use , Young Adult
9.
Anticancer Res ; 38(1): 481-489, 2018 01.
Article in English | MEDLINE | ID: mdl-29277813

ABSTRACT

AIM: We previously found that low-dose X-ray treatment after systemic administration of acridine orange (AO), which is known to have a low toxicity in animals, inhibited tumor growth in experimental studies using mouse osteosarcoma. In this pilot study, we planned to verify the toxicity of intravenous injection of low-dose AO in humans and investigate the anticancer effect of radiation after systemic AO administration (iAOR) for human cancer. PATIENTS AND METHODS: Eight patients with terminal cancer were treated with iAOR. RESULTS: None of the patients exhibited an adverse effect from AO injection. Three out of the five patients who received a full course of iAOR exhibited clinical or image-based responses, whereas two patients did not. CONCLUSION: The systemic administration of AO was confirmed not to be toxic in humans, and iAOR was suggested to be potentially effective against radioresistant cancer.


Subject(s)
Acridine Orange/toxicity , Acridine Orange/therapeutic use , Mutagens/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Humans , Mutagens/toxicity , Pilot Projects , Treatment Outcome
10.
Mutagenesis ; 32(5): 517-524, 2017 10 17.
Article in English | MEDLINE | ID: mdl-29040706

ABSTRACT

Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin (OXP), which causes DNA double-strand breaks, and vinflunine (VFN), which disrupts the mitotic spindle, are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response. Endpoints examined included micronucleus (MN) induction using the cytokinesis-blocked micronucleus (CBMN) assay and pancentromeric fluorescence in situ hybridisation. Also, survivin expression was monitored since it regulates the mitotic spindle checkpoint and inhibits apoptosis. OXP produced cytogenetic damage (micronuclei in binucleated cells) via its clastogenic but also previously unknown aneugenic action, possibly through interfering with topoisomerase II, whilst VFN produced micronuclei in mononucleated cells because of incomplete karyokinesis. Survivin expression was found to be significantly reduced in a concentration-dependent manner by not only OXP but surprisingly also VFN. This resulted in large numbers of multinucleated cells found with the CBMN assay. As survivin is upregulated in cancers, eliminating apoptosis inhibition might provide a more targeted chemotherapy approach; particularly, when considering VFN, which only affects cycling cells by inhibiting their mitotic spindle, and alongside possibly other pro-apoptotic compounds. Hence, these newly found properties of VFN -the inhibition of survivin expression-might demonstrate a promising chemotherapeutic approach as VFN induces less DNA damage in normal somatic cells compared to other chemotherapeutic compounds.


Subject(s)
Colonic Neoplasms/drug therapy , Inhibitor of Apoptosis Proteins/drug effects , Lymphocytes/drug effects , Micronuclei, Chromosome-Defective/chemically induced , Organoplatinum Compounds/adverse effects , Vinblastine/analogs & derivatives , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gene Expression Regulation , Humans , In Situ Hybridization, Fluorescence , Inhibitor of Apoptosis Proteins/genetics , Lymphocytes/metabolism , Male , Micronucleus Tests , Mutagens/adverse effects , Mutagens/therapeutic use , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Survivin , Vinblastine/adverse effects , Vinblastine/therapeutic use
11.
Genes Dev ; 31(4): 353-369, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28279982

ABSTRACT

Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that antiviral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumors. Classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells can initiate type I IFN signaling. Here, we demonstrate that DNA-damaging modalities used during cancer therapy lead to the release of ssDNA fragments from the cell nucleus into the cytosol, engaging this innate immune response. We found that the factors that control DNA end resection during double-strand break repair, including the Bloom syndrome (BLM) helicase and exonuclease 1 (EXO1), play a major role in generating these DNA fragments and that the cytoplasmic 3'-5' exonuclease Trex1 is required for their degradation. Analysis of mRNA expression profiles in breast tumors demonstrates that those with lower Trex1 and higher BLM and EXO1 expression levels are associated with poor prognosis. Targeting BLM and EXO1 could therefore represent a novel approach for circumventing the IRDS produced in response to cancer therapeutics.


Subject(s)
DNA Damage , Exodeoxyribonucleases/metabolism , Immunity, Innate/genetics , Interferons/metabolism , Phosphoproteins/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Cell Line, Tumor , Cytoplasm/enzymology , Cytoplasm/immunology , Cytoplasm/metabolism , DNA Damage/drug effects , DNA, Single-Stranded/immunology , DNA, Single-Stranded/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mice , Mutagens/therapeutic use , Mutagens/toxicity , Radiation Tolerance/immunology , Radiation, Ionizing , Reactive Oxygen Species , Signal Transduction
12.
Viruses ; 8(10)2016 10 13.
Article in English | MEDLINE | ID: mdl-27754363

ABSTRACT

Hepatitis E virus (HEV), an important agent of viral hepatitis worldwide, can cause severe courses of infection in pregnant women and immunosuppressed patients. To date, HEV infections can only be treated with ribavirin (RBV). Major drawbacks of this therapy are that RBV is not approved for administration to pregnant women and that the virus can acquire mutations, which render the intra-host population less sensitive or even resistant to RBV. One of the proposed modes of action of RBV is a direct mutagenic effect on viral genomes, inducing mismatches and subsequent nucleotide substitutions. These transition events can drive the already error-prone viral replication beyond an error threshold, causing viral population extinction. In contrast, the expanded heterogeneous viral population can facilitate selection of mutant viruses with enhanced replication fitness. Emergence of these mutant viruses can lead to therapeutic failure. Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis.


Subject(s)
Antiviral Agents/pharmacology , Hepatitis E virus/drug effects , Hepatitis E virus/genetics , Mutagens/pharmacology , Mutation , Ribavirin/pharmacology , Selection, Genetic , Antiviral Agents/therapeutic use , Coronaviridae , Drug Resistance, Viral , Hepatitis E/drug therapy , Hepatitis E/virology , Humans , Mutagens/therapeutic use , Ribavirin/therapeutic use , Treatment Outcome , Virulence , Viruses
13.
Genet Mol Res ; 12(4): 6040-51, 2013 Dec 02.
Article in English | MEDLINE | ID: mdl-24338398

ABSTRACT

Cisplatin is an effective antineoplastic drug. However, it provokes considerable collateral effects, including genotoxic and clastogenic activity. It has been reported that a diet rich in glutamine can help inhibit such collateral effects. We evaluated this activity in 40 Swiss mice, distributed into eight experimental groups: G1 - Control group (PBS 0.1 mL/10 g body weight); G2 - cisplatin group (cisplatin 6 mg/kg intraperitoneally); G3, G4, G5 - glutamine groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally); G6, G7, G8 - Pre-treatment groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally and cisplatin 6 mg/kg intraperitonially). For the micronucleus assay, samples of blood were collected (before the first use of the drugs at T0, then 24 (T1) and 48 (T2) hours after the first administration). For the comet assay, blood samples were collected only at T2. The damage reduction percentages for the micronucleus assay were 90.0, 47.3, and 37.3% at T1 and 46.0, 38.6, and 34.7% at T2, for G6, G7, and G8 groups, respectively. For the comet assay, the damage reduction percentages were 113.0, 117.4, and 115.0% for G6, G7, and G8, respectively. We conclude that glutamine is able to prevent genotoxic and clastogenic damages caused by cisplatin.


Subject(s)
Antimutagenic Agents/pharmacology , Antineoplastic Agents/toxicity , Cisplatin/toxicity , DNA Damage , Glutamine/pharmacology , Animals , Antimutagenic Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Glutamine/therapeutic use , Leukocytes, Mononuclear/drug effects , Male , Mice , Micronucleus Tests , Mutagens/therapeutic use , Mutagens/toxicity
14.
Mutat Res ; 747(2): 240-5, 2012 Sep 18.
Article in English | MEDLINE | ID: mdl-22698567

ABSTRACT

1,3-Butadiene (BD) is a carcinogenic air pollutant. Its bioactivation produces four major metabolites, i.e., 3,4-epoxy-1-butene (EB), 3,4-epoxy-1,2-butanediol (EBD), 1,2,3,4-diepoxybutane (DEB), and 3-butene-1,2-diol (BDD). Studies have been mostly focused on DEB due to its strong mutagenicity/carcinogenicity. In contrast, studies of genotoxicity of EB, EBD, and BDD have been limited. In particular, genotoxicity of EBD and BDD using strand breaks as the endpoint has not been investigated. To obtain a more complete understanding of BD toxicity, in the present study, we used comet assay to investigate DNA damage induced by EB, EBD, and BDD in human hepatocyte L02 cells, with the aim to determine their relative potencies, the types of DNA damage, and the possible pathway to form strand breaks. Using alkaline comet assay (pH>13), it was observed that EB and EBD caused similar concentration-dependent increases in DNA migration from 50 to 1000µM. However, BDD induced a statistically significant increase only at 1000µM, and the increase itself was very small. EBD was as potent as EB at lower concentrations (≤200µM), and was slightly less potent than EB at higher concentrations. The results indicated that these metabolites could generate strand breaks in cells with the rank order of the potencies being EB>≈EBD≫BDD. All three compounds failed to cause statistically significant increases in DNA migration in pre-lysed cells, suggesting that they did not produce strand breaks through chemical pathways under our experimental conditions. By using comet assays at pH 11.9 and pH 9, it was demonstrated that EB and EBD generated both single-strand breaks (SSB) and alkali-labile sites, but BDD produced only SSB. To our knowledge, this is the first report to investigate EBD- and BDD-induced strand breaks in cells. The results implied that EBD could play an important role in toxicity of BD.


Subject(s)
Butadienes/metabolism , Butylene Glycols/toxicity , Carcinogens/toxicity , DNA Damage , Epoxy Compounds/toxicity , Hepatocytes/drug effects , Mutagens/toxicity , Mutagens/therapeutic use , Cell Line, Transformed , Comet Assay , DNA Breaks, Single-Stranded , Humans
15.
Ann Nucl Med ; 26(1): 41-6, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21996780

ABSTRACT

OBJECTIVE: To investigate the genotoxic effects of (90)Y and (186)Re in patients with hemophilia who were undergoing radionuclide synovectomy (RS) procedure in the last 3 years. METHODS: Nineteen patients were enrolled in the study. Most of the patients (n = 17) were hemophilia-A (mean age 20.6 ± 10.5 years) and 18 patients (mean age 22.6 ± 10.6 years) with hemophilia who were not exposed to RS procedure were included in the study as control group. Most cases in the control group (n = 13) were hemophilia-A. (90)Y for knee joints and (186)Re for elbow or ankle joints were used to perform RS in hemophilic patients. We studied the micronucleus (MN) test on peripheral blood lymphocytes as an indicator of radiation-induced cytogenetic damage and calculated nuclear division index. RESULTS: There was no significant difference between the patients with and without RS with respect to MN values. However, both values obtained in RS-exposed patients and control group were much elevated than values reported in literature from healthy controls. The mean MN values of patients below 20 years old were much lower but not significant than those above 20 years old. MN frequencies between (186)Re and (90)Y groups were also analyzed, and no significant difference was observed. Hemophilia patients who were treated with (186)Re showed higher levels of MN compared to patients treated with (90)Y although the difference was not significant. CONCLUSIONS: Radioisotope synovectomy (RS) seems to be a safe procedure not causing a significant genotoxic effect on hemophilic patients, however, further studies including larger series of patients are needed to better understand the effects of RS on patients' health.


Subject(s)
Chromosome Breakage/radiation effects , Hemophilia A/genetics , Hemophilia A/surgery , Rhenium/adverse effects , Synovectomy , Adolescent , Adult , Child , Humans , Male , Micronucleus Tests , Middle Aged , Mutagens/adverse effects , Mutagens/therapeutic use , Retrospective Studies , Rhenium/therapeutic use , Young Adult , Yttrium Radioisotopes/adverse effects , Yttrium Radioisotopes/therapeutic use
16.
Behav Brain Res ; 223(2): 329-35, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21596067

ABSTRACT

Depression is a common mental disorder; however, its molecular mechanism has not been fully elucidated. In this study, we investigated the role of maternal deprivation (MD) and chronic mild stress (CMS) in the pathogenesis of depression in rat models. The mRNA levels of prostate apoptosis response-4 (Par-4) and dopamine receptor D2 (DRD2) genes in the striatum were measured by real-time PCR. Methylation level in the promoter of Par-4 gene was detected by bisulfite sequencing. Correlation between gene expression and depression-like behaviors were analyzed. Our results demonstrated that MD and CMS alone or their combination (dual stresses: DS) caused depression-like behaviors in rats. The mRNA levels of Par-4 and DRD2 genes in the striatum were significantly lower in MD-, CMS-, and DS-treated rats than in control rats. Importantly, Par-4 and DRD2 mRNA levels significantly correlated with depression-like behaviors. However, no significant differences in total methylation levels in the promoter of Par-4 gene were found between four groups. Our study suggested that either maternal deprivation or chronic mild stress plays a crucial role in the development of depression-like behaviors in rats. This process is associated with down-regulated Par-4 and DRD2 gene expression in the striatum through a non-methylation mechanism.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Corpus Striatum/metabolism , Depression/genetics , Depression/psychology , Receptors, Dopamine D2/genetics , Stress, Psychological/genetics , Stress, Psychological/psychology , Animals , Apoptosis Regulatory Proteins/biosynthesis , Blotting, Western , Defecation/genetics , Defecation/physiology , Depression/etiology , Female , Male , Methylation , Motor Activity/physiology , Mutagens/therapeutic use , Pregnancy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Stress, Psychological/complications , Sucrose , Sulfites , Swimming/psychology
17.
World J Gastroenterol ; 16(27): 3377-84, 2010 Jul 21.
Article in English | MEDLINE | ID: mdl-20632439

ABSTRACT

AIM: To investigate the mechanism by which galangin, a polyphenolic compound derived from medicinal herbs, induces apoptosis of hepatocellular carcinoma (HCC) cells. METHODS: The 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to measure cell viability. Apoptosis was evaluated by in situ uptake of propidium iodide and Hoechst 33258 and was then detected by fluorescence microscopy. Protein expressions were detected by Western blotting. To confirm the apoptotic pathway mediated by galangin, cells were transfected by bcl-2 gene to overexpress Bcl-2 or siRNA to down-regulate Bcl-2 expression. RESULTS: Galangin (46.25-370.0 micromol/L) exerted an anti-proliferative effect, induced apoptosis, and decreased mitochondrial membrane potential in a dose and time-dependent manner. Treatment with galangin induced apoptosis by translocating the pro-apoptotic protein Bax to the mitochondria, which released apoptosis-inducing factor and cytochrome c into the cytosol. Overexpression of Bcl-2 attenuated galangin-induced HepG2 cell apoptosis, while decreasing Bcl-2 expression enhanced galangin-induced cell apoptosis. CONCLUSION: Our data suggests that galangin mediates apoptosis through a mitochondrial pathway, and may be a potential chemotherapeutic drug for the treatment of HCC.


Subject(s)
Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor/drug effects , Flavonoids/pharmacology , Liver Neoplasms/pathology , Mitochondria/drug effects , Mutagens/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor/metabolism , Cell Line, Tumor/pathology , Dose-Response Relationship, Drug , Flavonoids/therapeutic use , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Mutagens/therapeutic use , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology
18.
Biosci Biotechnol Biochem ; 74(5): 923-7, 2010.
Article in English | MEDLINE | ID: mdl-20460693

ABSTRACT

Butea superba is a traditional tuberous Thai plant enriched with flavonoids that is used for treating erectile dysfunction. We investigated the mutagenic and antimutagenic potentials of a B. superba extract by using the pre-incubation method of the Ames test. Salmonella typhimurium strains TA 98 and TA 100 were applied as the tester strains in the presence and absence of an S9 mixture. Prior to the mutagenic and antimutagenic tests, the survival of the tester strains was measured by treating with the B. superba extract. The results show that the B. superba extract exhibited dose-dependent cytotoxic effects. Data from the Ames test revealed that the B. superba extract to be non-mutagenic in the presence and absence of the S9 mixture. In contrast, the B. superba extract showed antimutagenic potential towards either or both of the tested mutagens: 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide (AF-2) and benzo(a)pyrene (B(a)P) in the respective presence and absence of the S9 mixture, respectively. The plant antimutagenic activity was confirmed by a rec assay. A further study by micronucleus test demonstrated that the B. superba extract at the maximum loading volume could induce acute micronucleus formation in the tested animals. The in vitro mutagenic and antimutagenic assays confirmed the safe consumption of B. superba products at low dose (not more than 781.25 microg/ml of the plant extract), but the in vivo genotoxic assay demonstrated the unsafe consumption at a high dose (300 mg/kg of the BW plant extract or 16 g/kg of the BW plant powder).


Subject(s)
Butea/chemistry , Erectile Dysfunction/drug therapy , Medicine, Traditional , Plant Extracts/pharmacology , Plant Extracts/toxicity , Animals , Antimutagenic Agents/pharmacology , Antimutagenic Agents/therapeutic use , Antimutagenic Agents/toxicity , Bone Marrow/drug effects , Bone Marrow/metabolism , Dose-Response Relationship, Drug , Male , Micronucleus Tests , Mutagenicity Tests , Mutagens/pharmacology , Mutagens/therapeutic use , Mutagens/toxicity , Plant Extracts/therapeutic use , Rats , Rats, Wistar , Salmonella typhimurium/drug effects
19.
Gastroenterology ; 132(3): 921-30, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17383421

ABSTRACT

BACKGROUND AND AIMS: Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial. METHODS: The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control. RESULTS: Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable. CONCLUSIONS: Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Mutagens/pharmacology , Mutation/drug effects , Ribavirin/pharmacology , Viral Nonstructural Proteins/genetics , Adult , Antiviral Agents/blood , Antiviral Agents/therapeutic use , Cell Line, Tumor , DNA Mutational Analysis , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/therapeutic use , Male , Middle Aged , Monosaccharides/pharmacology , Mutagens/therapeutic use , RNA, Viral/blood , Replicon/drug effects , Retrospective Studies , Ribavirin/blood , Ribavirin/therapeutic use , Time Factors , Triazoles/pharmacology
20.
Urology ; 66(6): 1327-31, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16360478

ABSTRACT

OBJECTIVES: To test the capability of the flavonoid galangin to protect pig urinary bladder from damage due to a period of repetitive field stimulation as well as a period of anoxia/glucopenia and reperfusion. METHODS: Smooth muscle strips of the pig bladder were mounted for tension recording in small organ baths and the strips underwent either 1.5 hours of repetitive field stimulation at 32 Hz for 15 seconds every 5 minutes or under anoxia/glucopenia and reperfusion conditions. Galangin, at different concentrations, was added to the reperfusion Krebs solution to check the effect of this flavonoid compared with untreated strips under the same conditions. A group of experiments was performed to examine its possible underlying mechanisms. RESULTS: Repetitive field stimulation for 1.5 hours caused a progressive decrease in the maximal contractile response to electrical field stimulation (34% decrease). Galangin (10(-7) M) partially prevented the progressive decrease in the contractile response. This effect was significantly reduced when verapamil was added to the solution. Galangin significantly improved the response of strips to electrical field stimulation under anoxia/glucopenia and reperfusion conditions compared with untreated tissues. CONCLUSIONS: Galangin has a protective effect on bladder contractility by an action that at least, in part, depends on l-type calcium channels. Furthermore, galangin protects detrusor nerves against the anoxia/glucopenic and reperfusion damage.


Subject(s)
Flavonoids/therapeutic use , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/innervation , Mutagens/therapeutic use , Urinary Bladder Diseases/prevention & control , Urinary Bladder/drug effects , Urinary Bladder/innervation , Animals , Electric Stimulation , Flavonoids/pharmacology , Glucose/deficiency , Hypoxia/prevention & control , In Vitro Techniques , Mutagens/pharmacology , Swine , Urinary Bladder Diseases/etiology
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