The common pathobiology between coronary artery disease and calcific aortic stenosis: Evidence and clinical implications.

Calcific aortic valve stenosis (CAS), the most prevalent valvular disease worldwide, has been demonstrated to frequently occur in conjunction with coronary artery disease (CAD), the third leading cause of death worldwide. Atherosclerosis has been proven to be the main mechanism involved in CAS and CAD. Evidence also exists that obesity, diabetes, and metabolic syndrome (among others), along with specific genes involved in lipid metabolism, are important risk factors for CAS and CAD, leading to common pathological processes of atherosclerosis in both diseases. Therefore, it has been suggested that CAS could also be used as a marker of CAD. An understanding of the commonalities between the two conditions may improve therapeutic strategies for treating both CAD and CAS. This review explores the common pathogenesis and disparities between CAS and CAD, alongside their etiology. It also discusses clinical implications and provides evidence-based recommendations for the clinical management of both diseases.

Evaluation of application protocol of the 4% hydrogen peroxide for at-home bleaching: A randomized clinical trial.

OBJECTIVE: Few studies evaluated low concentrations of hydrogen peroxide protocols. The aim of this paper was evaluated two application protocols using 4% hydrogen peroxide in at-home bleaching. MATERIALS AND METHODS: Eighty-six patients with upper canines' shade A2 or darker were randomly allocated under two experimental conditions: two daily applications of 1 h each or a 2-h single application. Color change was evaluated using Vita Classical, Vita Bleachedguide, and digital spectrophotometer weekly and 1 month after the bleaching procedure through one-way ANOVA. The risk and intensity of tooth sensitivity (TS) was assessed through visual and numeric rating scale and measured by Fisher's exact test, Mann-Whitney test and one-way ANOVA respectively. RESULTS: After 3 weeks, the mean difference for the ΔSGU Vita Classical (1.0; 95% CI -0.1 to 2.0), ΔEab (0.7; 95% CI -1.4 to 2.8), ΔE00 (0.1; 95% CI -1.4 to 1.6) and Wi (1.8; 95% CI -1.9 to 5.5) presented no difference (p > 0.08). The relative risk for TS was 0.91 (0.72 to 1.14) without significant difference neither in the risk (p = 0.6) nor in the TS intensity for both pain scales (p > 0.65). CONCLUSIONS: The application protocols evaluated (two daily applications of 1 h each or a 2-h single application) for at-home bleaching with 4% hydrogen peroxide did not showed differences in color change and tooth sensitivity. CLINICAL RELEVANCE: Higher amount of active hydrogen peroxide in two daily applications for at-home bleaching neither accelerate bleaching nor increase the risk or intensity of tooth sensibility.

Lipid Lowering Therapy: An Era Beyond Statins.

Dyslipidemia, specifically elevated low-density lipoprotein (LDL) cholesterol levels, causes atherosclerotic cardiovascular disease (ASCVD) and increases the risk of myocardial infarction and stroke. Statins, a class of drugs that exert their effects by inhibiting HMG-CoA reductase, a key enzyme in the synthesis of cholesterol, have been the mainstay of therapy for the primary prevention of cardiovascular disease and lipids reduction. Statins are associated with side effects, most commonly myopathy and myalgias, despite their proven efficacy. This review explores non-statin lipid-lowering therapies and examines recent advances and emerging research. Over the previous decades, several lipid-lowering therapies, both as monotherapy and adjuncts to statin therapy and lipid-targeting gene therapy, have emerged, thus redefining how we treat dyslipidemia. These drugs include Bile acids sequestrants, Fibrates, Nicotinic acid, Ezetimibe, Bempedoic acid, Volanesoren, Evinacumab, and the PCSK 9 Inhibitors Evolocumab and Alirocumab. Emerging gene-based therapy includes Small interfering RNAs, Antisense oligonucleotides, Adeno-associated virus vectors, CRISPR/Cas9 based therapeutics, and Non-coding RNA therapy. Of all these therapies, Bempedoic acid works most like statins by working through a similar pathway to decrease cholesterol levels. However, it is not associated with myopathy. Overall, although statins continue to be the gold standard, non-statin therapies are set to play an increasingly important role in managing dyslipidemia.

One-year follow-up evaluation of reservoirs in bleaching trays for at-home bleaching.

OBJECTIVE: To evaluate the color change stability and patient satisfaction after one-year of at-home bleaching with 10% carbamide peroxide (CP) in trays with or without reservoirs. MATERIALS AND METHODS: Forty-six patients were subjected to bleaching with CP (3 h/daily; 21 days) with a bleaching tray with or without reservoirs. The color was measured one-month and one-year after the completion of bleaching using the spectrophotometer (ΔEab, Δ00 and ΔWi), and shade guide units (ΔSGU). Patients' satisfaction were assessed using a 5-point Likert Scale questionnaire. Data were submitted to paired t-test (α = 0.05). RESULTS: No significant difference between color change after one-month and one-year was observed (VITA Classical shade guide unit and the ΔWi; p > 0.53). Significant differences were observed for the VITA Bleachedguide 3D-MASTER shade guide, ΔEab and ΔE00 (p < 0.03). The level of patient satisfaction was similar between groups (p = 1.00). CONCLUSIONS: Bleaching tray design did not have any influence on the bleaching stability for the 10% CP (Opalescence PF, Ultradent). Patients were very satisfied with the bleaching outcomes regardless of the bleaching tray design. CLINICAL RELEVANCE: Placement of reservoirs in bleaching trays does not increase longevity of dental bleaching. No clinically important color rebound was observed 1 year after bleaching with 10% CP.

Evaluation of Metals in Soil and Tissues of Economic-Interest Plants Grown in Sites Affected by the Fundão Dam Failure in Mariana, Brazil.

The objective of this study was to evaluate the concentration of potentially toxic elements in Brachiaria decumbens, Stylosanthes guianensis, and Saccharum officinarum plants and soil samples in affected and unaffected areas by rupture of the Fundão dam, Brazil. Samples were collected in areas affected by residues from the Fundão dam (RAA1, RAA2, RAA3) and in an unaffected area (control). The material was analyzed for the composition of micronutrients and trace elements in soil and plants, as well as contamination factor (CF), accumulation factor, and translocation factor (TF). Overall, the results showed that soil and plant tissues had increased Fe, Mn, Cu, and Cr content and decreased Zn content in the affected areas, compared to the control. Leaves and roots of B. decumbens showed an increase in Fe content in affected areas, compared to the control, reaching a mean maximum value of 42 958 µg/g of roots of RAA2-collected plants. As a result, CF for Fe of B. decumbens was classified as very high and they presented low TF values. Furthermore, B. decumbens collected in affected areas showed an increase of Fe, Mn, Cu, and Cr in leaves, stems, and roots, whereas in Stylosanthes guianensis, there was an increase of Fe concentration in all tissues and Cr in leaves. Also, Saccharum officinarum showed the accumulation of Mn in the stem and Cu in leaves and stem. On the other hand, there was no contamination of plants by hazardous elements such as Pb, Cd, and As in the samples analyzed. In conclusion, increases in the content of Fe, Mn, Cu, and Cr were found in soil and several plant tissues of residue-affected areas, which could compromise plant growth and represent potential hazards arising from the biomagnification process in the food chain. Integr Environ Assess Manag 2020;16:596-607. © 2020 SETAC.

O objetivo deste estudo foi avaliar a concentração de elementos potencialmente tóxicos em plantas de Brachiaria decumbens, Stylosanthes guianensis e Saccharum officinarum e amostras de solos em áreas afetadas e não afetadas pelo rompimento da barragem de Fundão. As amostras foram coletadas em áreas afetadas por resíduos da barragem de Fundão (RAA1, RAA2, RAA3) e em uma área não afetada (controle). O material foi analisado quanto à composição de micronutrientes e elementos-traço no solo e plantas, além de fatores de contaminação (CF), bioacumulação e translocação (TF). No geral, os resultados mostraram que o solo e as plantas apresentaram maiores teores de Fe, Mn, Cu e Cr e menores teores de Zn nas áreas afetadas em comparação ao controle. Folhas e raízes de B. decumbens apresentaram aumento no teor de Fe nas áreas afetadas em relação ao controle, atingindo o valor máximo médio de 42.958 µg/g nas raízes de plantas coletadas em RAA2. Como resultado, CF para Fe de B. decumbens foi classificado como muito alto, mas com baixos valores de TF. Além disso, B. decumbens coletadas nas áreas afetadas apresentaram aumento de Fe, Mn, Cu e Cr nas folhas, caules e raízes, enquanto que em Stylosanthes guianensis houve aumento da concentração de Fe em todos as partes das plantas e Cr nas folhas. Saccharum officinarum também apresentou acúmulo de Mn no caule e Cu nas folhas e caule. Por outro lado, não há contaminação das plantas por elementos perigosos como Pb, Cd e As nas amostras analisadas. Concluindo, foram encontrados aumentos nos teores de Fe, Mn, Cu e Cr no solo e em vários tecidos vegetais, o que pode comprometer o crescimento das plantas e representar riscos potenciais decorrentes do processo de biomagnificação na cadeia alimentar. Integr Environ Assess Manag 2020;16:596-607.

Is arsenite more toxic than arsenate in plants?

In order to evaluate the differential absorption and toxicity of arsenate (AsV) and arsenite (AsIII), Lemna valdiviana plants were grown in a nutrient solution and subjected to 0.0 (control); 0.5; 1.0; 1.5; 2.0; 3.0; 4.0; 5.0 and 7.5 mg L-1 of AsIII or AsV for three days. Exposure to both chemical forms resulted in As bioaccumulation, although AsIII-grown plants showed higher As content in tissues. In AsV-grown plants, the relative growth rate (RGR) decreased to 50%, at a concentration of 4.0 mg L-1, while for treatments with AsIII, the same decrease was observed at 1.0 mg L-1. The tolerance index decreased with increasing concentrations, with lower values for AsIII. Plants treated with AsIII showed increased superoxide anion levels, whilst higher levels of hydrogen peroxide were present in AsV-treated plants. Moreover, malondialdehyde (MDA) levels were higher for plants subjected to AsIII when compared to AsV at lower concentrations. Concentrations of 1 mg L-1 of AsIII and 4 mg L-1 of AsV showed equivalent MDA levels. Superoxide dismutase and catalase activities were increased at low concentrations and were inhibited at higher concentrations of AsIII and AsV, whereas peroxidase activity was positively modulated by increased AsIII or AsV concentrations. In conclusion, L. valdiviana plants took up and accumulated arsenic as AsIII or AsV, demonstrating the potential for phytoremediation of this metalloid. Furthermore, AsIII-exposed plants showed enhanced toxicity when compared to AsV, at the same applied concentration, although toxicity was more related to internal As concentrations, regardless of the chemical form applied.

Occupational exposure of workers to pesticides: Toxicogenetics and susceptibility gene polymorphisms.

Farm workers are often exposed to pesticides, which are products belonging to a specific chemical group that affects the health of agricultural workers and is mostly recognized as genotoxic and carcinogenic. The exposure of workers from Piauí, Brazil, to these hazardous chemicals was assessed and cytogenetic alterations were evaluated using the buccal micronucleus assay, hematological and lipid parameters, butyrylcholinesterase (BChE) activity and genetic polymorphisms of enzymes involved in the metabolism of pesticides, such as PON1, as well as of the DNA repair system (OGG1, XRCC1 and XRCC4). Two groups of farm workers exposed to different types of pesticides were evaluated and compared to matched non-exposed control groups. A significant increase was observed in the frequencies of micronuclei, kariorrhexis, karyolysis and binucleated cells in the exposed groups (n = 100) compared to controls (n = 100). No differences were detected regarding the hematological parameters, lipid profile and BChE activity. No significant difference was observed either regarding DNA damage or nuclear fragmentation when specific metabolizing and DNA repair genotypes were investigated in the exposed groups.

Agents of earthy-musty taste and odor in water: evaluation of cytotoxicity, genotoxicity and toxicogenomics.

Considering the limited number of studies on the biological effects on human health of cyanobacterial compounds that cause taste and odor, the present study assessed the cytotoxic and genotoxic potentials of 2-methylisoborneol (2-MIB) and geosmin (GEO) using the MTT assay and the in vitro comet and cytokinesis-block micronucleus (CBMN-Cyt) assays in human HepG2 cells. The toxicogenomics of genes responsive to DNA damage and metabolization by the exposure of cells to 2-MIB and GEO were also investigated. The results showed that concentrations of 2-MIB and GEO above 100 and 75 µg/mL, respectively, were cytotoxic to HepG2 cells. Doses of 2-MIB (12.5, 25, 50, 75 and 100 µg/mL) and GEO (12.5, 25, 50, and 75 µg/mL) were unable to induce neither DNA damage nor events associated with chromosomal instability. Similarly, no concentration of each compound induced increments in the expression of CDKN1A, GADD45α, MDM2 and TP53 DNA damage responsive genes as well as in CYP1A1 and CYP1A2 metabolizing genes. Although cytotoxicity was observed, concentrations that caused it are much higher than those expected to occur in aquatic environments. Thus, environmentally relevant concentrations of both compounds are not expected to exhibit cytotoxicity or genotoxicity to humans.

Effects of artichoke (Cynara scolymus) leaf and bloom head extracts on chemically induced DNA lesions in Drosophila melanogaster.

The genotoxicity of bloom head (BHE) and leaf (LE) extracts from artichoke (Cynara scolymus L.), and their ability to modulate the mutagenicity and recombinogenicity of two alkylating agents (ethyl methanesulfonate - EMS and mitomycin C - MMC) and the intercalating agent bleomycin (BLM), were examined using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Neither the mutagenicity nor the recombinogenicity of BLM or MMC was modified by co- or post-treatment with BHE or LE. In contrast, co-treatment with BHE significantly enhanced the EMS-induced genotoxicity involving mutagenic and/or recombinant events. Co-treatment with LE did not alter the genotoxicity of EMS whereas post-treatment with the highest dose of LE significantly increased this genotoxicity. This enhancement included a synergistic increase restricted to somatic recombination. These results show that artichoke extracts promote homologous recombination in proliferative cells of D. melanogaster.

In vivo and in vitro genotoxicity assessment of 2-methylisoborneol, causal agent of earthy-musty taste and odor in water.

The water eutrophication process by phosphorus and nitrogen allows cyanobacteria blooms which promote, among other effects, the generation and release of the metabolite 2-methylisoborneol (2-MIB) in the environment. This substance has been shown to be recalcitrant to conventional water treatment, degrading water quality. Considering the limited number of studies on the biological effects of 2-MIB in eukaryotic organisms, the present study assessed the genotoxicity of 2-MIB using the in vitro comet assay and cytokinesis block-micronucleus (CBMN-Cytome) assay on Chinese Hamster Ovary (CHO) cells and the in vivo Drosophila melanogaster Somatic Mutation and Recombination Test (SMART). The results showed that 2-MIB (125, 250 and 500 µg/mL) was unable to induce gene and chromosome mutations or events associated with mitotic recombination in the SMART. Similarly, four different concentrations (7.5, 15, 30 and 60 µg/mL) of 2-MIB did not induce increments in frequencies of micronuclei, nuclear buds, and nucleoplasmatic bridges in the CBMN-Cytome assay. In the comet assay, the positive results were restricted to the highest dose, 60 µg/mL of 2-MIB. The results obtained may help evaluate the genotoxic profile of extracellular algal products.

Evaluation of antioxidant and mutagenic activities of honey-sweetened cashew apple nectar.

In vitro chemical properties and antioxidant potential and in vivo mutagenic activity of honey-sweetened cashew apple nectar (HSCAN), a beverage produced from the cashew pseudo-fruit (Anacardium occidentale L.) and of its constituents were assessed. Analytical procedures were carried out to investigate the honey used in the HSCAN preparation, and the results observed are in accordance with Brazilian legal regulations, except for diastase number. HSCAN and pulp were investigated for ascorbic acid, carotenoid, anthocyanin and total phenolic contents, and both showed high acid ascorbic concentrations. Antioxidant capacity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and/or ß-carotene/linoleic acid systems were applied and demonstrated a weak antioxidant capacity of honey and HSCAN, but cashew apple pulp demonstrated high antioxidant capacity. A weakly positive mutagenic effect of cashew pulp 20% was observed using the somatic mutation and recombination test (SMART) in Drosophila melanogaster only in the high-bioactivation (HB) cross. On the contrary, HSCAN was not mutagenic in both standard and high bioactivation crosses. HSCAN exhibited slight antioxidant activity, which could be associated with the high amount of ascorbic acid found in the samples evaluated. The beverage prepared did not induce DNA damage in somatic cells of D. melanogaster, which means that it is neither mutagenic nor recombinagenic in this test system.

Antimutagenic and antirecombinagenic activities of noni fruit juice in somatic cells of Drosophila melanogaster.

Noni, a Hawaiian name for the fruit of Morinda citrifolia L., is a traditional medicinal plant from Polynesia widely used for the treatment of many diseases including arthritis, diabetes, asthma, hypertension and cancer. Here, a commercial noni juice (TNJ) was evaluated for its protective activities against the lesions induced by mitomycin C (MMC) and doxorrubicin (DXR) using the Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. Three-day-old larvae, trans-heterozygous for two genetic markers (mwh and flr3 ), were co-treated with TNJ plus MMC or DXR. We have observed a reduction in genotoxic effects of MMC and DXR caused by the juice. TNJ provoked a marked decrease in all kinds of MMC- and DXR-induced mutant spots, mainly due to its antirecombinagenic activity. The TNJ protective effects were concentration-dependent, indicating a dose-response correlation, that can be attributed to a powerful antioxidant and/or free radical scavenger ability of TNJ.

Protective activity of Cynara scolymus L. leaf extract against chemically induced complex genomic alterations in CHO cells.

Cynara scolymus L., popularly known as artichoke, has been widely used in traditional medicine as an herbal medicament for therapeutic purposes. The study aimed at assessing the protective activity of Cynara scolymus leaf extract (LE) against DNA lesions induced by the alkylating agent ethylmethnesulphonate (EMS) in Chinese hamster ovary cells (CHO). The ability of C. scolymus L. LE to modulate the mutagenicity of EMS was examined using the cytokinesis block micronucleus (CBMN) cytome assay in three antigenotoxic protocols, pre- post- and simultaneous treatments. In the pre-treatment, C. scolymus L. LE reduced the frequencies of MNi and NBUDs induced by EMS in the lower concentration. In contrast, at the highest concentration (5 mg/ml) artichoke enhanced the frequency of MNi, potentiating EMS genotoxicity. In the simultaneous treatment only the induction of MNi was repressed by the exposure of cells to C. scolymus L. LE. No modification in genotoxicity was observed in LE post-treatment. The results obtained in this study suggest that lower concentrations of artichoke prevent chemically induced genomic damage in mammalian cells. In this context, the protective activity of C. scolymus L. could be associated to its constitutive antioxidants compounds.

Artichoke induces genetic toxicity in the cytokinesis-block micronucleus (CBMN) cytome assay.

Artichoke leaves are used in traditional medicine as an herbal medicament for the treatment of hepatic related diseases, as well as choleretic and diuretic. The aim of the present study was to evaluate the capacity of Cynara scolymus L. leaves extract (LE) to cause chromosomal instability and cytotoxicity in Chinese hamster ovary cells (CHO) employing the cytokinesis-block micronucleus (CBMN) cytome assay. Cells were treated with four concentrations of C. scolymus for two exposure times: 1h and 24h. Our findings showed that LE did not increase the frequencies of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, all concentrations of the extract produced increments in micronuclei frequencies (MNi) in both exposure times, when compared to the negative control. No significant differences were observed in the nuclear division cytotoxicity index (NDCI), reflecting the absence of cytotoxic effects associated to LE. The results demonstrated the ability of C. scolymus LE to promote chromosomal mutations which are, probably, a result of the pro-oxidant activity of LE constituents such as flavonoids and chlorogenic acids. The data obtained in this study suggests that high concentrations of artichoke can pose a risk associated to its consumption.

In vivo genotoxicity evaluation of an artichoke (Cynara scolymus L.) aqueous extract.

UNLABELLED: The Cynara scolymus (artichoke) is widely consumed as tea or food and shows important therapeutic properties. However, few studies have assessed the possible toxic effects of artichoke extracts. This study evaluates genotoxic and mutagenic activities of artichoke leaf aqueous extract in mice using the comet assay and the micronucleus test. Leaf extracts were given by gavage (500 mg/kg, 1000 mg/kg, and 2000 mg/kg) for 3 consecutive days. Extract composition was investigated using phytochemical screening and high-performance liquid chromatography (HPLC). In addition, antioxidant capacity was analyzed through the diphenyl-picrylhydrazyl (DPPH) and xanthine oxidase assay. Phytochemical screening detected the presence of phenolic compounds, flavonoids, and saponins. HPLC analyses indicated the presence of chlorogenic acid, caffeic acid, isoquercetrin, and rutin. Extracts showed a dose-dependent free radical scavenging effect of DPPH and an inhibitory effect of xanthine oxidase. The genotoxic results showed that leaf extracts did not increase micronuclei in peripheral blood cells. Compared to the control group, a significant increase in comet assay values was observed only in bone marrow of group treated with 2000 mg/kg, the highest dose tested, indicating that artichoke tea should be consumed with moderation. PRACTICAL APPLICATION: This is the first report of in vivo mutagenic and genotoxic evaluation with C. scolymus. The present study revealed leaf aqueous extract from artichoke shows lack of mutagenicity in vivo, and low genotoxicity and antioxidant activity; indicating that artichoke tea should be consumed with moderation.

Artichoke induces genetic toxicity and decreases ethyl methanesulfonate-related DNA damage in Chinese hamster ovary cells.

Cynara scolymus L. (Asteraceae), popularly known as artichoke, has been widely used in herbal medicine for the treatment of hepatic diseases. The genotoxicity of C. scolymus L. leaf extract (LE) and the ability to modulate the genetic toxicity of the alkylating agent ethyl methanesulfonate (EMS) were assessed using the comet assay on Chinese hamster ovary cells. Genotoxicity was evaluated after 1- and 24-h treatments using four different LE concentrations: 0.62, 1.25, 2.5, and 5.0 mg/mL. Antigenotoxicity was assessed for pretreatment, simultaneous treatment, and post-treatment. All doses used led to a significant increase in the frequency of DNA damage, after exposure for 1 and 24 h. In the antigenotoxicity experiments, LE reduced the frequency of DNA damage induced by EMS in the simultaneous treatment only. However, the lowest dose was more protective than higher concentrations. Flavonoids and phenolic compounds are, probably, the C. scolymus constituents responsible for its genotoxic and antigenotoxic effects.

Genotoxicity testing of combined treatment with cisplatin, bleomycin, and 5-fluorouracil in somatic cells of Drosophila melanogaster.

The simultaneous treatment with the cross-linking agent cisplatin, the radiomimetic antitumoral drug bleomycin, and the anti-metabolite drug 5-fluorouracil has been used as a regimen to treat patients with squamous cell carcinoma of the head and neck. Considering that these drugs interact directly with DNA, one of the important late-occurring complications from treatment of primary malignancies is the therapy-related secondary cancers as a result of the genotoxic activity of the drugs on normal cells. In this sense, the genotoxicity of this combination was evaluated using the wing somatic mutation and recombination test in Drosophila melanogaster. The mutant spots observed in marker-heterozygous and balancer-heterozygous flies were compared in order to quantitatively and qualitatively estimate the genotoxic effect of these drugs. Cisplatin (0.003 and 0.006mM), bleomycin (0.005 and 0.01mM), and both combinations preferentially induced recombinational events, while mutation is the major event regarding the genetic toxicity of 5-fluorouracil (0.025 and 0.05mM). The combination of these drugs produced synergistic and antagonistic genotoxic effects, depending on the concentrations used, which could impose a higher risk of secondary effects associated with their genotoxic effects, emphasizing the importance of long-term monitoring in patients being treated with these drugs.

Recombinagenic and mutagenic activities of fluoroquinolones in Drosophila melanogaster.

Fluoroquinolones are widely used in human and in veterinary medicine due to their broad-spectrum antibacterial activity. They act by inhibiting type II DNA topoisomerases (gyrase and topoisomerase IV). Because of the sequence homology between prokaryotic and eukaryotic topoisomerases II, fluoroquinolones can pose a hazard to eukaryotic cells. However, published information concerning the genotoxic profiles of these drugs in vivo is sparse and inconsistent. We have assessed the activities of three fluoroquinolones, ciprofloxacin, enrofloxacin and norfloxacin, in the Drosophila melanogaster Somatic Mutation and Recombination Test (SMART) and measured their mutagenic and recombinagenic potentials. Norfloxacin was non-genotoxic. Ciprofloxacin and enrofloxacin induced significant increases in spot frequencies in trans-heterozygous flies. To test the roles of somatic recombination and mutation in the observed genotoxicity, balancer-heterozygous flies were also analyzed. Ciprofloxacin and enrofloxacin were preferential inducers of homologous recombination in proliferative cells, an event linked to loss of heterozygosity.

Evaluation of the genotoxicity of cisplatin, paclitaxel and 5-fluorouracil combined treatment in the Drosophila wing-spot test.

The somatic mutation and recombination test in Drosophila melanogaster was applied to analyze the mutagenic and recombinagenic activity of the chemotherapeutic drugs cisplatin, paclitaxel, and 5-fluorouracil, comparing the effects observed in combinatory treatments with those observed in single administrations. The results obtained in two different genotypes allowed to quantitatively and qualitatively estimate the contribution of genotoxic effects. The results obtained with the individual drug treatments showed that cisplatin and 5-fluorouracil were genotoxic, being able to increase the frequency of total spots on both genotypes. While cisplatin preferentially induced DNA damage of recombinational origin, all the damages induced by 5-fluorouracil were caused by gene and/or chromosome mutations, and the aneuploidogenic compound paclitaxel was not genotoxic. The combination of these drugs does not exert a synergist genotoxic effect in both genotypes compared to the single-agent administration. Instead, it was observed a modification in the proportion of mutation and recombination to the final genotoxicity observed. The antiproliferative activity of PAC could be responsible for the non-synergic genotoxic effect observed. Based on our results it is possible to suggest that cisplatin/paclitaxel/5-fluorouracil treatment regimen cannot impose a higher risk of the development of genotoxicity-associated secondary tumors in comparison to their individual applications.

The genetic toxicity effects of lamivudine and stavudine antiretroviral agents.

IMPORTANCE OF THE FIELD: The nucleoside reverse transcriptase inhibitors (NRTIs) are used in antiretroviral therapy worldwide for the treatment of HIV infections. These drugs act by blocking reverse transcriptase enzyme activity, causing pro-viral DNA chain termination. As a consequence, NRTIs could cause genomic instability and loss of heterozygosity. AREAS COVERED IN THIS REVIEW: This review highlights the toxic and genotoxic effects of NRTIs, particularly lamivudine (3TC) and stavudine (d4T) analogues. In addition, a battery of short-term in vitro and in vivo systems are described to explain the potential genotoxic effects of these NRTIs as a single drug or a complexity of highly active antiretroviral therapy. WHAT THE READER WILL GAIN: The readers will gain an understanding of a secondary effect that could be induced by 3TC and d4T treatments. TAKE HOME MESSAGE: Considering that AIDS has become a chronic disease, more comprehensive toxic genetic studies are needed, with particular attention to the genetic alterations induced by NRTIs. These alterations play a primary role in carcinogenesis and are also involved in secondary and subsequent steps of carcinogenesis.