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1.
Molecules ; 29(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474655

RESUMO

In this research, we explore the synthesis of and characterize α-aminophosphonates derived from anthraquinone and benzanthrone, focusing on their fluorescence properties and potential applications in confocal laser scanning microscopy (CLSM). The synthesized compounds exhibit notable solvatochromic behavior, emitting fluorescence from green to red across various solvents. Spectroscopic analysis, including 1H-, 13C-, and 31P-NMR, FTIR, and mass spectrometry, confirms the chemical structures. The compounds' toxicity is evaluated using etiolated wheat sprouts, revealing varying degrees of impact on growth and oxidative damage. Furthermore, the study introduces these α-aminophosphonates for CLSM imaging of the parasitic flatworm Opisthorchis felineus, demonstrating their potential in visualizing biological specimens. Additionally, an X-ray crystallographic study of an anthraquinone α-aminophosphonate provides valuable structural insights.


Assuntos
Benzo(a)Antracenos , Opisthorchis , Organofosfonatos , Animais , Cristalografia por Raios X , Organofosfonatos/química , Espectroscopia de Ressonância Magnética , Microscopia Confocal/métodos , Antraquinonas
2.
Molecules ; 28(13)2023 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-37446832

RESUMO

In the present study, new fluorophores based on disubstituted benzanthrone derivatives were designed starting from 9-nitro-3-bromobenzanthrone with nucleophilic substitution of the bromine atom with some secondary cyclic amines. It has been found that this reaction is positively affected by the presence of a nitro group in comparison with 3-bromobenzanthrone. The new compounds exhibit intense absorption and pronounced luminescent properties in various organic solvents. In this regard, their photophysical properties were evaluated with an experimental study of the solvatochromic behavior of the obtained compounds in various solvents. It has recently been found that the addition of an electron-withdrawing nitro group to the benzanthrone core increases its first- and second-order hyperpolarizability. Such dyes can be used in the fabrication of optical limiter devices. Therefore, the developed fluorescent molecules have a potential prospect for extensive application in optoelectronics.


Assuntos
Benzo(a)Antracenos , Corantes Fluorescentes , Solventes
3.
Environ Pollut ; 328: 121624, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37059172

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are major environmental pollutants in a number of point source contaminated sites, where they are found embedded in complex mixtures containing different polyaromatic compounds. The application of bioremediation technologies is often constrained by unpredictable end-point concentrations enriched in recalcitrant high molecular weight (HMW)-PAHs. The aim of this study was to elucidate the microbial populations and potential interactions involved in the biodegradation of benz(a)anthracene (BaA) in PAH-contaminated soils. The combination of DNA stable isotope probing (DNA-SIP) and shotgun metagenomics of 13C-labeled DNA identified a member of the recently described genus Immundisolibacter as the key BaA-degrading population. Analysis of the corresponding metagenome assembled genome (MAG) revealed a highly conserved and unique genetic organization in this genus, including novel aromatic ring-hydroxylating dioxygenases (RHD). The influence of other HMW-PAHs on BaA degradation was ascertained in soil microcosms spiked with BaA and fluoranthene (FT), pyrene (PY) or chrysene (CHY) in binary mixtures. The co-occurrence of PAHs resulted in a significant delay in the removal of PAHs that were more resistant to biodegradation, and this delay was associated with relevant microbial interactions. Members of Immundisolibacter, associated with the biodegradation of BaA and CHY, were outcompeted by Sphingobium and Mycobacterium, triggered by the presence of FT and PY, respectively. Our findings highlight that interacting microbial populations modulate the fate of PAHs during the biodegradation of contaminant mixtures in soils.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Sphingomonadaceae , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Peso Molecular , Biodegradação Ambiental , Sphingomonadaceae/genética , Sphingomonadaceae/metabolismo , Benzo(a)Antracenos/metabolismo , Solo , Poluentes do Solo/metabolismo , Microbiologia do Solo
4.
Mar Drugs ; 22(1)2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38248647

RESUMO

The one strain many compounds (OSMAC) strategy is an effective method for activating silent gene clusters by cultivating microorganisms under various conditions. The whole genome sequence of the marine-derived strain Streptomyces globisporus SCSIO LCY30 revealed that it contains 30 biosynthetic gene clusters (BGCs). By using the OSMAC strategy, three types of secondary metabolites were activated and identified, including three angucyclines, mayamycin A (1), mayamycin B (2), and rabolemycin (3); two streptophenazines (streptophenazin O (4) and M (5)); and a macrolide dimeric dinactin (6), respectively. The biosynthetic pathways of the secondary metabolites in these three families were proposed based on the gene function prediction and structural information. The bioactivity assays showed that angucycline compounds 1-3 exhibited potent antitumor activities against 11 human cancer cell lines and antibacterial activities against a series of Gram-positive bacteria. Mayamycin (1) selectively exhibited potent cytotoxicity activity against triple-negative breast cancer (TNBC) cell lines such as MDA-MB-231, MDA-MB-468, and Bt-549, with IC50 values of 0.60-2.22 µM.


Assuntos
Família Multigênica , Streptomyces , Humanos , Benzo(a)Antracenos , Streptomyces/genética , Antibacterianos/farmacologia
5.
Sci Total Environ ; 851(Pt 1): 158121, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-35988620

RESUMO

Riparian zone, an important land-water interface, plays an essential role in maintaining the ecological health of rivers, whereas the effects of Polycyclic aromatic hydrocarbons (PAHs) on the health of biological communities in riparian groundwater remain undetermined. To understand the responses of multiple communities to environmental variables, the distribution and ecosystem risk of 16 PAHs have been investigated in the Beiluo River, China. The distribution of multiple communities in riparian groundwater was investigated by environmental DNA metabarcoding, including 16S rRNA, 18S rRNA, and COI gene sequencing for bacteria, microbial eukaryotes (including algae, fungi, and protozoa), and metazoan, respectively, followed by correlation analysis between multiple communities and PAH contamination levels. The concentration of PAHs in the Beiluo River ranged largely from 35.32 to 728.59 ng/L. Here, the Shannon's diversity index of bacteria (Firmicutes) decreased possibly due to the occurrence of Pyrene, which mainly derives from coal and biomass combustion. Furthermore, the reduced richness of fungi (Ascomycota, Basidiomycota) and algae (Chlorophyta, Chrysophyceae) can be attributed to the presence of medium molecular weight (MMW) PAHs (Pyrene, Benz(a)anthracene, Chrysene), and low molecular weight (LMW) PAHs (Naphthalene, Fluorene, Phenanthrene). The richness and Shannon's diversity index of metazoan (Arthropoda) were promoted owing to MMW PAHs (Chrysene, Fluoranthene) generated from coal and biomass combustion and traffic emission. The ecological risk of PAHs in the groundwater environment of the Beiluo River was characterized as low to medium, where LMW and MMW PAHs posed higher risk than the high molecular weight (HMW) compounds. Overall, this study provides insights into the structures of riparian multi-biological communities altered by PAHs.


Assuntos
Fenantrenos , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Animais , Benzo(a)Antracenos/análise , Biodiversidade , Biota , Crisenos/análise , Carvão Mineral/análise , Ecossistema , Monitoramento Ambiental , Fluorenos/análise , Sedimentos Geológicos/química , Naftalenos/análise , Fenantrenos/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Pirenos/análise , RNA Ribossômico 16S , RNA Ribossômico 18S , Medição de Risco , Rios/química , Água/análise , Poluentes Químicos da Água/análise
6.
Cell Biol Toxicol ; 38(5): 865-887, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34036453

RESUMO

Exposure to environmental and occupational contaminants leads to lung cancer. 3-Nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one, 3-NBA) is a potential carcinogen in ambient air or diesel particulate matter. Studies have revealed that short-term exposure to 3-NBA induces cell death, reactive oxygen species activation, and DNA adduct formation and damage. However, details of the mechanism by which chronic exposure to 3-NBA influences lung carcinogenesis remain largely unknown. In this study, human lung epithelial BEAS-2B cells were continuously exposed to 0-10-µM 3-NBA for 6 months. NanoString analysis was conducted to evaluate gene expression in the cells, revealing that 3-NBA-mediated transformation results in a distinct gene expression signature including carbon cancer metabolism, metastasis, and angiogenesis. Alterations in tumor-promoting genes such as EREG (epiregulin), SOX9, E-cadherin, TWIST, and IL-6 were involved in epithelial cell aggressiveness. Kaplan-Meier plotter analyses indicated that increased EREG and IL-6 expressions in early-stage lung cancer cells are correlated with poor survival. In vivo xenografts on 3-NBA-transformed cells exhibited prominent tumor formation and metastasis. EREG knockout cells exposed to 3-NBA for a short period exhibited high apoptosis and low colony formation. By contrast, overexpression of EREG in 3-NBA-transformed cells markedly activated the PI3K/AKT and MEK/ERK signaling pathways, resulting in tumorigenicity. Furthermore, elevated IL-6 and EREG expressions synergistically led to STAT3 signaling activation, resulting in clonogenic cell survival and migration. Taken together, chronic exposure of human lung epithelial cells to 3-NBA leads to malignant transformation, in which the EREG signaling pathway plays a pivotal mediating role. • Short-term exposure of lung epithelial cells to 3-NBA can lead to ROS production and cell apoptosis. • Long-term chronic exposure to 3-NBA upregulates the levels of tumor-promoting genes such as EREG and IL-6. • Increased EREG expression in 3-NBA-transformed cells markedly contributes to tumorigenesis through PI3K/AKT and MEK/ERK activation and synergistically enhances the IL-6/STAT3 signaling pathway, which promotes tumorigenicity.


Assuntos
Adutos de DNA , Neoplasias Pulmonares , Benzo(a)Antracenos , Caderinas/metabolismo , Carbono/metabolismo , Carbono/farmacologia , Carcinogênese/metabolismo , Carcinógenos , Transformação Celular Neoplásica/metabolismo , Adutos de DNA/metabolismo , Adutos de DNA/farmacologia , Epirregulina/genética , Epirregulina/metabolismo , Epirregulina/farmacologia , Células Epiteliais/metabolismo , Humanos , Interleucina-6/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/farmacologia , Material Particulado/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
7.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299187

RESUMO

By culturing microorganisms under standard laboratory conditions, most biosynthetic gene clusters (BGCs) are not expressed, and thus, the products are not produced. To explore this biosynthetic potential, we developed a novel "semi-targeted" approach focusing on activating "silent" BGCs by concurrently introducing a group of regulator genes into streptomycetes of the Tübingen strain collection. We constructed integrative plasmids containing two classes of regulatory genes under the control of the constitutive promoter ermE*p (cluster situated regulators (CSR) and Streptomyces antibiotic regulatory proteins (SARPs)). These plasmids were introduced into Streptomyces sp. TÜ17, Streptomyces sp. TÜ10 and Streptomyces sp. TÜ102. Introduction of the CSRs-plasmid into strain S. sp. TÜ17 activated the production of mayamycin A. By using the individual regulator genes, we proved that Aur1P, was responsible for the activation. In strain S. sp. TÜ102, the introduction of the SARP-plasmid triggered the production of a chartreusin-like compound. Insertion of the CSRs-plasmid into strain S. sp. TÜ10 resulted in activating the warkmycin-BGC. In both recombinants, activation of the BGCs was only possible through the simultaneous expression of aur1PR3 and griR in S. sp. TÜ102 and aur1P and pntR in of S. sp. TÜ10.


Assuntos
Proteínas de Bactérias/genética , Benzo(a)Antracenos/metabolismo , Família Multigênica , Proteínas Recombinantes/genética , Streptomyces/genética , Proteínas de Bactérias/metabolismo , Benzopiranos , Regulação Bacteriana da Expressão Gênica , Glicosídeos/biossíntese , Regiões Promotoras Genéticas , Proteínas Recombinantes/metabolismo , Streptomyces/crescimento & desenvolvimento , Streptomyces/metabolismo , Fatores de Transcrição/metabolismo , Trissacarídeos/biossíntese
8.
Biomolecules ; 11(4)2021 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919651

RESUMO

Luminescent derivatives of benzanthrone are becoming more useful based on their light-absorbing and fluorescent-emitting properties. Our previous studies showed that luminescent staining properties of the same benzanthrone dye differ for variable parasite samples. Therefore, two types of benzanthrone dyes were prepared. One has a strongly basic amidine group and a halogen atom, and the other has an amide moiety and a tertiary amine group. Trematoda Parafasciolopsis fasciolaemorpha is a liver fluke of a moose (Alces alces) and has a significant influence on the health and abundance of the moose population. Staining protocols for parasite P. fasciolaemorpha specific organ or organ systems imaging are mostly time-consuming and labor-intensive. The study aimed to compare the fixation technique and the staining protocol by synthesized benzanthrone luminescent dyes to determine detailed morphology, anatomical arrangement of the organ systems and gross organization of the muscle layers of P. fasciolaemorpha using confocal laser scanning microscopy. Luminophores were tested for samples fixed in different fixatives. Developed dyes and staining protocol resulting in imaging of all parts of trematode without additional sample preparation procedures, which usually are required for parasite examination. Obtained results confirmed that the most qualitative results could be reached using 3-N-(2-piperidinylacetamido)benzanthrone dye which has amide moiety and a tertiary amine group. Based on obtained results, 3-N-(2-piperidinylacetamido)benzanthrone gave more qualitative parasite visualization than 2-bromo-3-N-(N',N'-dimethylformamidino)benzanthrone.


Assuntos
Benzo(a)Antracenos/química , Corantes Fluorescentes/síntese química , Coloração e Rotulagem/métodos , Trematódeos/citologia , Animais , Corantes Fluorescentes/normas , Microscopia Confocal/métodos , Músculos/citologia , Músculos/metabolismo , Sensibilidade e Especificidade , Fixação de Tecidos/métodos
9.
J Appl Toxicol ; 41(10): 1568-1583, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33559210

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are generated by the incomplete combustion of carbon. Exposures correlate with systemic immune dysfunction and overall immune suppression. Real-world exposures to PAHs are almost always encountered as mixtures; however, research overwhelmingly centers on isolated exposures to a single PAH, benzo[a]pyrene (B[a]P). Here, a human monocyte line (U937) was exposed to B[a]P, benz[a]anthracene (B[a]A), or a mixture of six PAHs (6-MIX) to assess the differential toxicity on monocytes. Further, monocytes were exposed to PAHs with and without CYP1A1 inhibitors during macrophage differentiation to delineate PAH exposure and PAH metabolism-driven alterations to the immune response. U937 monocytes exposed to B[a]P, B[a]A, or 6-MIX had higher levels of cellular health and growth not observed following equimolar exposures to other individual PAHs. PAH exposures during differentiation did not alter monocyte-derived macrophage (MDM) numbers; however, B[a]A and 6-MIX exposures significantly altered M1/M2 polarization in a CYP1A1-dependent manner. U937-MDM adherence was differentially suppressed by all three PAH treatments with 6-MIX exposed U937-MDM having significantly more adhesion than U937-MDM exposed to either individual PAH. Finally, 6-MIX exposures during differentiation reduced U937-MDM endocytic function significantly less than B[a]A exposed cells. Exposure to a unique PAH mixture during U937-MDM differentiation resulted in mixture-specific alterations of pro-inflammatory markers compared to individual PAH exposures. While subtle, these differences highlight the probability that using a model PAH, B[a]P, may not accurately reflect the effects of PAH mixture exposures. Therefore, future studies should include various PAH mixtures that encompass probable real-world PAH exposures for the endpoints under investigation.


Assuntos
Benzo(a)Antracenos/toxicidade , Benzopirenos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Diferenciação Celular/imunologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Humanos
10.
Artigo em Inglês | MEDLINE | ID: mdl-33124510

RESUMO

In this study, DNA-functionalize-magnetic beads were investigated as sorbent materials for effective removing 1,2-benzanthracene (BaA) from water. In order to reveal the removal mechanism, the interaction mode between BaA and DNA was evaluated by using various characterization tools such as UV-visible and circular dichroism spectroscopy, fluorescence and resonance scattering spectroscopy, and agarose gel electrophoresis. In the presence of BaA, the melting temperature of DNA increased from 76.2 °C to 82.3 °C, which closely related to the intercalating of BaA. It was found that a part of the ethidium bromide (EB) binding sites to DNA were occupied by BaA in EB competing study. The results indicated that a new complex appeared between hsDNA and BaA, and the number of the binding sites (n) and the binding constants (KA) at different temperatures were obtained. DNA binding saturation value (≈0.80) was obtained by resonance scattering spectra study. BaA could be enriched and removed by DNA-functionalize-magnetic beads via the intercalation, and the removal efficiency was 97.73% when the initial concentration was 2.45 x10-6 mol·L-1 (559.31 µg/L).


Assuntos
Benzo(a)Antracenos/química , Benzo(a)Antracenos/isolamento & purificação , DNA/química , Substâncias Intercalantes/química , Substâncias Intercalantes/isolamento & purificação , Imãs/química , Microesferas , Desnaturação de Ácido Nucleico , Temperatura
11.
Nat Commun ; 11(1): 5863, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203852

RESUMO

Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance.


Assuntos
Adutos de DNA/genética , DNA Primase/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Recombinação Homóloga/fisiologia , Enzimas Multifuncionais/metabolismo , 4-Nitroquinolina-1-Óxido/toxicidade , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , Benzo(a)Antracenos/administração & dosagem , Benzo(a)Antracenos/toxicidade , Linhagem Celular , Adutos de DNA/metabolismo , DNA Primase/genética , DNA de Cadeia Simples , DNA Polimerase Dirigida por DNA/genética , Humanos , Enzimas Multifuncionais/genética , Quinolonas/toxicidade , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Imagem Individual de Molécula , Troca de Cromátide Irmã
12.
Arch Toxicol ; 94(10): 3541-3552, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32623606

RESUMO

Molds of the genus Alternaria produce several mycotoxins, some of which may pose a threat for health due to their genotoxicity. Due to the lack of adequate toxicological and occurrence data, they are currently not regulated. Interactions between mycotoxins, gut microbiota and food constituents might occur after food ingestion, modifying the bioavailability and, therefore, overall toxicity of mycotoxins. The present work aimed to investigate the impact of in vitro short-term fecal incubation on the in vitro DNA-damaging effects exerted by 5 µg/mL of an Alternaria alternata extract, containing, among others, 15 nM alternariol, 12 nM alternariol monomethyl ether, 241 nM altertoxin II and 301 nM stemphyltoxin III, all of which are known as genotoxic. The involvement of microorganisms, undigested food constituents and soluble substances of human fecal samples in modifying the composition and the genotoxicity of the extract was investigated through the application of LC-MS/MS analysis and comet assays in HT-29 cells. Results showed that the potential of the mycotoxins to induce DNA strand breaks was almost completely quenched, even before anaerobic incubation, by contact with the different fractions of the fecal samples, while the potency to induce formamidopyrimidine DNA glycosylase (FPG)-sensitive sites was only slightly reduced. These effects were in line with a reduction of mycotoxin concentrations found in samples analyzed by LC-MS/MS. Although a direct correlation between the metabolic activity of the gut microbiota and modifications in mycotoxin contents was not clearly observed, adsorptive phenomena to bacterial cells and to undigested food constituents might explain the observed modifications.


Assuntos
Dano ao DNA , Fezes/microbiologia , Conteúdo Gastrointestinal , Microbioma Gastrointestinal , Micotoxinas/toxicidade , Adulto , Alternaria/química , Benzo(a)Antracenos/toxicidade , Cromatografia Líquida , Ensaio Cometa , Fezes/química , Feminino , Alimentos , Contaminação de Alimentos/análise , Células HT29 , Humanos , Lactonas/toxicidade , Masculino , Mutagênicos/toxicidade , Perileno/análogos & derivados , Perileno/toxicidade , Espectrometria de Massas em Tandem
13.
Ecotoxicol Environ Saf ; 202: 110864, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32610224

RESUMO

An increasing amount of Fluoranthene (Fla) and Benz(a)anthracene (BaA) is being produced and used, eventually entering the soil sediments. The accumulation of Fla and BaA will cause poisoning to typical enzymes (α-Amylase) and organisms (Eisenia fetida) in soil. However, the studies about exploring and comparing the different effects of Fla, BaA and their joint effect at different levels are rarely reported. In this paper, the different effects of Fla, BaA and their mixed pollutant on α-Amylase were evaluated and compared at the molecular level, and the effect of Fla-BaA to the antioxidant system of earthworm (Eisenia fetida) was investigated from the aspects of concentration and exposure time at the animal level. The results showed that Fla-BaA had the greatest influence on the skeleton structure and the microenvironment of amino acid residue of α-Amylase compared to Fla and BaA, and in the mixed pollutant system, the joint effect mode was additive mode. The inhibitory effect of Fla-BaA on the activity of α-Amylase was also stronger than that of the system alone. The assays at the animal level showed that low concentrations (below 5 mg/kg) of Fla-BaA increased the activity of GSH-Px and SOD while high concentrations inhibited their activity. The POD that was activated throughout the experiment period suggested its key role in the earthworm antioxidant system. Changes in T-AOC and MDA showed that long-term and high-dose of Fla-BaA exposure inhibited the antioxidant capacity of Eisenia fetida, causing lipid peroxidation and damage to cells.


Assuntos
Benzo(a)Antracenos/toxicidade , Fluorenos/toxicidade , Poluentes do Solo/toxicidade , Animais , Antracenos , Antioxidantes/metabolismo , Poluentes Ambientais/metabolismo , Poluição Ambiental , Peroxidação de Lipídeos/efeitos dos fármacos , Oligoquetos/efeitos dos fármacos , Solo/química , Testes de Toxicidade
14.
Biomolecules ; 10(7)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659980

RESUMO

Alternaria molds simultaneously produce a large variety of mycotoxins, of which several were previously reported to induce enzymes of phase I metabolism through aryl hydrocarbon receptor activation. Thus, we investigated the potential of naturally occurring Alternaria toxin mixtures to induce Cytochrome P450 (CYP) 1A1/1A2/1B1 activity. Two variants of an extract from cultured Alternaria alternata, as well as the toxins alternariol (AOH), alternariol monomethyl ether (AME), altertoxin I (ATX-I), and altertoxin II (ATX-II), were tested singularly and in binary mixtures applying the 7-ethoxy-resorufin-O-deethylase (EROD) assay in MCF-7 breast cancer cells. Sub-cytotoxic concentrations of the two toxin mixtures, as well as ATX-I, ATX-II and AOH, exhibited dose-dependent enhancements of CYP 1 activity. ATX-I and ATX-II interacted synergistically in this respect, demonstrating the two perylene quinones as major contributors to the extract's potential. Binary mixtures between AOH and the two altertoxins respectively exhibited concentration-dependent antagonistic as well as synergistic combinatory effects. Notably, AME showed no efficacy towards EROD enzyme activity or impact on other toxins' efficacy. Hence, this study provides insights into synergistic and other combinatory effects of Alternaria toxins in natural co-occurrence scenarios in the context of AhR signalling pathway activation in breast cancer cells.


Assuntos
Alternaria/metabolismo , Hidrocarboneto de Aril Hidroxilases/metabolismo , Neoplasias da Mama/metabolismo , Micotoxinas/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzo(a)Antracenos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactonas/farmacologia , Células MCF-7 , Perileno/análogos & derivados , Perileno/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-32522345

RESUMO

The aryl hydrocarbon receptor (AhR) transcription factor is activated by polycyclic aromatic hydrocarbons (PAH) and other ligands. Activated AhR binds to dioxin responsive elements (DRE) and initiates transcription of target genes, including the gene encoding prostaglandin endoperoxide synthase 2 (PTGS-2), which is also activated by the transcription factor NF-ĸB. PTGS-2 catalyzes the conversion of arachidonic acid (AA) into prostaglandins, thromboxanes or isoprostanes. 15-F2t-Isoprostane (IsoP), regarded as a universal marker of lipid peroxidation, is also induced by PAH exposure. We investigated the processes associated with lipid peroxidation in human alveolar basal epithelial cells (A549) exposed for 4 h or 24 h to model PAH (benzo[a]pyrene, BaP; 3-nitrobenzanthrone, 3-NBA) and organic extracts from ambient air particulate matter (EOM), collected in two seasons in a polluted locality. Both EOM induced the expression of CYP1A1 and CYP1B1; 24 h treatment significantly reduced PTGS-2 expression. IsoP levels decreased after both exposure periods, while the concentration of AA was not affected. The effects induced by BaP were similar to EOM except for increased IsoP levels after 4 h exposure and elevated AA concentration after 24 h treatment. In contrast, 3-NBA treatment did not induce CYP expression, had a weak effect on PTGS-2 expression, and, similar to BaP, induced IsoP levels after 4 h exposure and AA levels after 24 h treatment. All tested compounds induced the activity of NF-ĸB after the longer exposure period. In summary, our data suggest that EOM, and partly BaP, reduce lipid peroxidation by a mechanism that involves AhR-dependent inhibition of PTGS-2 expression. The effect of 3-NBA on IsoP levels is probably mediated by a different mechanism independent of AhR activation.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Mutagênicos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Células A549 , Benzo(a)Antracenos/toxicidade , Benzo(a)pireno/toxicidade , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Humanos , NF-kappa B/metabolismo , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade
16.
J Appl Toxicol ; 40(9): 1239-1247, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32368826

RESUMO

We previously demonstrated that particulate matter ≤2.5 µm (PM2.5) suppresses the immune response in the spleen in vivo. Although PM2.5 includes the polycyclic aromatic hydrocarbon (PAH) such as dibenzo[a,h]anthracene (DBA), it is unclear whether PAH has a direct effect on the responses of splenocytes. In our study, the concentration of DBA used was approximately 0.8 µm, which is much lower than concentrations used in other toxicological studies of DBA. Although exposure to high concentrations of DBA is implicated in carcinogenesis, the effects of low doses of DBA on immune cells in vivo remain unclear. Here, we investigated the effects of low DBA doses on mouse splenocytes in vivo. Mice were administered dimethyl sulfoxide or DBA (0.4 or 0.8 µm) intratracheally. Twenty-four hours after treatment, the mice were killed and their splenocytes were collected. DBA treatment enhanced mitogen-induced cell proliferation and cytokine production in the mouse splenocytes. Furthermore, DBA enhanced splenic CD4+ and CD8+ cell proliferation and cytokine production. The nuclear factor of activated T cells (NFAT) was activated in CD4+ cells. DBA also activated nuclear factor-kappa B and CCAAT enhancer-binding protein pathways in CD11b+ cells. DBA-enhanced splenocyte activation was Toll-like receptor 2-, 4-, 9- and MyD88-independent. These results suggest that NFAT represents a promising marker for evaluation of the effects of DBA on T cells and T-cell-dependent antibody responses.


Assuntos
Benzo(a)Antracenos/toxicidade , Biomarcadores/sangue , Proliferação de Células/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Dimetil Sulfóxido/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Material Particulado/toxicidade , Baço/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Animais
17.
J Membr Biol ; 253(3): 247-256, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393995

RESUMO

The increasing resistance of many pathogens to most of the common antimicrobials requires the development of new substances with more effective antimicrobial properties. In the present work, we investigated the mechanism of the antimicrobial activity of novel water soluble ammonium quaternary benzanthrone (Compound B) on model membranes, composed of dipalmitoylphosphatidylcholine, 1-palmitoyl-2-oleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, and dipalmitoylphosphatidylethanolamine (DPPE). The lipids were chosen to represent a model of a bacterial membrane. The changes in surface pressure of the model membranes, before and after the addition of Compound B, were studied by the Langmuir's monolayer method, and the compressional modulus for each monolayer was determined. In addition, the surface morphology of the lipid monolayers before and after injection of Compound B was monitored by Brewster Angle Microscopy. The results showed that Compound B penetrated all the monolayers studied. The most noticeable effects were found with the negatively charged phosphatidylglycerols and with DPPE leading to the conclusion that the electrostatic interactions between the compound and the lipid head groups and the possible formation of hydrogen bonds between the amino group of the ethanolamine and the keto groups in the structure of Compound B are of great importance. In addition, the penetration ability of the benzoquinone with all phospholipids studied was stable even at higher values of the surface pressure, i.e. thicker monolayers, due to the hydrophobic interaction, which plays also an important role for the antimicrobial activity of Compound B.


Assuntos
Compostos de Amônio , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Benzo(a)Antracenos/química , Benzo(a)Antracenos/farmacologia , Compostos de Amônio/química , Benzo(a)Antracenos/síntese química , Membranas Artificiais , Estrutura Molecular , Fosfatidilgliceróis/química , Fosfolipídeos/química , Solubilidade , Propriedades de Superfície , Água/química
18.
Toxicol Lett ; 331: 75-81, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32434050

RESUMO

Fungi of the genus Alternaria infest many agricultural crops and produce numerous mycotoxins, of which altertoxin II (ATX II) is one of the most mutagenic metabolites. ATX II carries an epoxide group but the formation of DNA adducts has not been demonstrated to date. We report now that ATX II gives rise to two covalent adducts with guanine when incubated with DNA under cell-free conditions. These adducts were demonstrated by LC-high resolution MS after enzymatic degradation of the incubated DNA to deoxynucleosides. The major adduct results from the covalent binding of ATX II, presumably through the epoxide group, to guanine, whereas the minor guanine adduct is derived from the major one by the elimination of two equivalents of water. In addition, a third adduct was detected, formed through covalent binding of ATX II to cytosine followed by the loss of two equivalents of water. The direct DNA reactivity of ATX II may explain its high mutagenicity.


Assuntos
Benzo(a)Antracenos/toxicidade , Adutos de DNA/análise , DNA/química , Guanina/química , Mutagênicos/toxicidade , Alternaria/química , Animais , Benzo(a)Antracenos/isolamento & purificação , Cromatografia Líquida , DNA/isolamento & purificação , Masculino , Espectrometria de Massas , Salmão , Testículo
19.
Chemosphere ; 255: 126955, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32416390

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) can induce skin toxicity. Although some investigations have been conducted to assess the skin toxicity of different PAHs, few comparisons using a series of PAHs with different ring numbers and arrangements have been done. We aimed to explore the skin absorption of 6 PAH compounds and their effect on cutaneous inflammation. In vitro skin permeation was rated by Franz cell with pig skin. Molecular docking was employed to compute the PAH interaction with stratum corneum (SC) lipids. Cultured keratinocytes were exposed to PAHs for analyzing cytotoxicity, cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), chemokines, and differentiation proteins. The in vivo topical PAH exposure in mice was characterized by skin absorption, transepidermal water loss (TEWL), PGE2 level, and histology. The skin deposition from the aqueous vehicle increased following the increase of PAH lipophilicity and molecular size, with benzo[a]pyrene (5-ring PAH) showing the greatest absorption. Pyrene was the compound showing the highest penetration across the skin (flux). Although the PAHs fluoranthene, pyrene, chrysene, and 1,2-benzanthracene all had 4 rings, the skin permeation was quite different. 1,2-Benzanthracene showed the greatest absorption among the 4-ring compounds. The PAHs with higher absorption exhibited stronger interaction with SC lipids according to the in silico modeling. Chrysene and 1,2-benzanthracene generally showed the highest COX-2 and PGE2 expression, followed by benzo[a]pyrene. The lowest COX-2 and PGE2 upregulation was observed for naphthalene (2-ring PAH). A contrary tendency was detected for the upregulation of chemokines. Filaggrin and integrin ß1 in keratinocytes were suppressed at a comparable level by all PAHs. The skin's absorption of PAHs showed strong in vivo-in vitro correlation. 1,2-Benzanthracene and benzo[a]pyrene highly disrupted the skin barrier and elevated the inflammation in vivo. The tendency toward in vivo inflammation caused by various PAHs could be well predicted by the combined estimation using in vitro skin absorption and a keratinocyte bioassay. This study also established the structure-permeation relationship (SPR) of PAHs.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Absorção Cutânea , Pele/metabolismo , Animais , Benzo(a)Antracenos , Benzo(a)pireno/toxicidade , Crisenos , Inflamação/metabolismo , Queratinócitos , Camundongos , Simulação de Acoplamento Molecular , Naftalenos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Pirenos , Suínos
20.
Microb Pathog ; 144: 104127, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32169485

RESUMO

Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S. aureus virulence. Herein, we report the inhibitory profile of 27 tetrangomycin derivatives over staphyloxanthin production. The experimental result showed that naphthoquinone dehydro-α-lapachone (25 - EC50 = 57.29 ± 1.15 µM) and 2-Isopropylnaphtho[2,3-b]furan-4,9-dione (26 EC50 = 82.10 ± 1.09 µM) are the most potent compounds and suggest that hydrogen acceptor groups and lipophilic moieties decorating the naphthoquinone ring are crucial for STXBI. In addition, we present an in situ analysis, through RAMAN spectroscopy, that is inexpensive and might be employed to probe the mechanism of action of staphyloxanthin biosynthesis inhibitors. Therefore, our molecular simplification strategies afforded promising lead compounds for the development of drugs that modulate S. aureus staphyloxanthin biosynthesis.


Assuntos
Antibacterianos/farmacologia , Naftoquinonas/farmacologia , Staphylococcus aureus/metabolismo , Xantofilas/metabolismo , Benzo(a)Antracenos/química , Benzo(a)Antracenos/farmacologia , Farmacorresistência Bacteriana Múltipla , Naftalenos/química , Naftalenos/farmacologia , Naftoquinonas/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Virulência/antagonistas & inibidores , Fatores de Virulência/biossíntese
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