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1.
Ecotoxicol Environ Saf ; 188: 109908, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31706243

RESUMO

Pesticides have been extensively produced and used to help the agricultural production which leads to the contamination of the environment, soil, groundwater sources, and even foodstuffs. Fungicides carbendazim (CBZ) and chlorothalonil (Chl) are widely applied in agriculture and other aspects. CBZ or Chl have been reported to disrupt spermatogenesis and decrease semen quality. However, it is not understood the effects of pubertal exposure to low doses of CBZ and Chl together, and the underlying mechanisms. Therefore, the aim of current investigation was to explore the negative impacts of pubertal exposure to low doses of CBZ and Chl together on spermatogenesis and the role of epigenetic modifications in the process. We demonstrated that CBZ and Chl together synergize to decrease sperm motility in vitro (CBZ 1.0 + Chl 0.1, CBZ 10.0 + CHl 1.0, CBZ 100.0 + Chl 10 µM in incubation medium for 24 h) and sperm concentration and motility in vivo with ICR mice (CBZ 0.1 + Chl 0.1, CBZ 1.0 + CHl 1.0, CBZ 10.0 + Chl 10 mg/kg body weight; oral gavage for five weeks). CBZ + Chl significantly increase reactive oxygen species (ROS) and apoptosis by the increase in the protein level of caspase 8 in vitro. Moreover, CBZ + Chl synergized to disrupt mouse spermatogenesis with the disturbance in sperm production proteins and sperm proteins (VASA, A-Myb, STK31, AR, Acrosin). CBZ + Chl synergized to decrease the protein level of estrogen receptor alpha and the protein level of DNA methylation marker 5 mC in Leydig cells, and to increase the protein levels of histone methylation marker H3K9 and the methylation enzyme G9a in germ cells. Therefore, greater attention should be paid to the use of CBZ and Chl as pesticides to minimise their adverse impacts on spermatogenesis.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Epigênese Genética/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Nitrilos/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Receptor alfa de Estrogênio/metabolismo , Masculino , Metilação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/efeitos dos fármacos
2.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487790

RESUMO

Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential mutagenic activities of novel benzimidazole derivatives 1-4 using the Ames test and to study their structure-activity relationship (SAR). An Ames test was carried out on two strains of Salmonella typhimurium (TA98 and TA100) in the absence and presence of metabolic activation. Genetic analysis was performed prior to the Ames test to determine the genotypes of the bacterial tester strains. Both bacterial strains showed dependency on histidine with the presence of rfa mutation, uvrB deletion, and plasmid pKM101. Further, all derivatives tested showed no mutagenic activity in the absence of metabolic activation in both tester strains. However, in the presence of metabolic activation, compound 1 appeared to induce mutation at 2.5 µg/plate when tested against the TA98 strain. These results suggest that the absence of the -OH group at the ortho-position over the phenyl ring might be the cause of increased mutagenic activity in compound 1. Additionally, the presence of mutagenic activity in compound 1 when it was metabolically activated indicates that this compound is a promutagen.


Assuntos
Benzimidazóis/química , Resistência Microbiana a Medicamentos/genética , Mutagênicos/química , Ativação Metabólica , Benzimidazóis/metabolismo , Benzimidazóis/toxicidade , Genótipo , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Relação Estrutura-Atividade
3.
Environ Sci Pollut Res Int ; 26(30): 31133-31141, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31463752

RESUMO

To improve crop yielding, a large amount of fungicides is continuously applied during the agricultural management, while the effects of fungicides residues on microbial processing of N in soil need further study. In the present study, two broad spectrum fungicides, chlorothalonil and carbendazim, were applied at the rates of 5, 10, and 50 mg of active ingredient (A.I.) per kg of dry soil combined with urea with 200 mg of N per kg of dry soil under laboratory conditions. The results showed that chlorothalonil obviously retarded the hydrolysis of urea, whereas carbendazim accelerated it in 4 days after the treatments (P < 0.05). Chlorothalonil reduced denitrification, nitrification, and N2O production (P < 0.05), but not for carbendazim. Further analysis on N-associated microbial communities showed chlorothalonil reduced nitrosomonas populations at the rates of 10 and 50 mg of A.I. per kg and autotrophic nitrifying bacterial populations at three application rates (P < 0.05), but Carbendazim decreased nitrosomonas populations only at the rate of 50 mg of A.I. per kg and also autotrophic nitrifying bacterial populations at three rates and heterotrophic nitrifying bacterial populations at the rates of 10 and 50 mg of A.I. per kg. The reasons for this difference were ascribed to arrest urea hydrolysis and impediment of denitrification and nitrification processes by chlorothalonil. In conclusion, to improve crop yielding, chlorothalonil might be more beneficial to conserve soil N by improving soil N fertility, compared with carbendazim.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Nitrilos/toxicidade , Nitrogênio/metabolismo , Microbiologia do Solo , Ureia/metabolismo , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Desnitrificação/efeitos dos fármacos , Fertilizantes , Fungicidas Industriais/toxicidade , Hidrólise , Nitrificação/efeitos dos fármacos , Nitrogênio/química , Solo/química , Ureia/química
4.
Environ Pollut ; 252(Pt A): 51-61, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146238

RESUMO

Melatonin (Mel) serves as an important signalling molecule in various aspects of stress tolerance in plants. However, the function of Mel in pesticide metabolism remains unknown. Here, selecting the widely used fungicide carbendazim (MBC) as the model, we found that exogenous Mel had the ability to alleviate pesticide phytotoxicity and residues in tomato as well as in some other vegetables. Additionally, overexpression of the Mel biosynthetic gene caffeic acid O-methyltransferase 1 (COMT1) significantly enhanced the capacity of the tomato to reduce MBC phytotoxicity and residue. This outcome was mainly because of the Mel-induced antioxidant capability, as well as the key detoxification process. Indeed, levels of reactive oxygen species (ROS) and lipid peroxides significantly decreased after applying exogenous Mel or overexpressing COMT1, which resulted from direct ROS scavenging, and increased Mel levels significantly enhanced antioxidant enzymatic activity. More importantly, Mel activated the ascorbate-glutathione cycle to participate in glutathione S-transferase-mediated pesticide detoxification. A grafting experiment showed that rootstocks from COMT1 transgenic plants increased the Mel accumulation of wild-type scions, resulting in MBC metabolism in the scions. To our knowledge, this is the first report providing evidence of Mel-induced pesticide metabolism, which provides a novel approach for minimizing pesticide residues in crops by exploiting plant self-detoxification mechanisms.


Assuntos
Benzimidazóis/metabolismo , Carbamatos/metabolismo , Fungicidas Industriais/metabolismo , Inativação Metabólica/fisiologia , Lycopersicon esculentum/metabolismo , Melatonina/metabolismo , Metiltransferases/metabolismo , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Fungicidas Industriais/toxicidade , Glutationa Transferase/metabolismo , Peróxidos Lipídicos/metabolismo , Melatonina/biossíntese , Metiltransferases/biossíntese , Plantas Geneticamente Modificadas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
J Agric Food Chem ; 67(24): 6683-6690, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31140797

RESUMO

Fungicides are frequently detected in natural water and have gained increasing attention as a result of their potential toxicity to non-target aquatic organisms. Carbendazim (CAR), a commonly used fungicide, was selected to explore its toxicity and biodegradation in a typical freshwater diatom Navicula sp. Results showed that the growth of Navicula sp. was inhibited by CAR, with a 24 h EC50 value of 2.18 mg L-1. Although the algal growth rate was recovered after 72 h of exposure, the chlorophyll a content remained significantly decreased when the concentration of CAR was above 0.5 mg L-1. Moreover, Navicula sp. had a negative effect on the removal of CAR, and the acute toxicity by CAR was likely due to its rapid accumulation in algal cells. Mass spectrometric data revealed the transformation products of CAR from hydroxylation, methylation, decarboxylation, demethylation, and deamination in algal cultures. These results provide a better understanding of the environmental risks of CAR in water and point to the need for additional studies on the potential adverse biological effects of its intermediates.


Assuntos
Benzimidazóis/metabolismo , Carbamatos/metabolismo , Diatomáceas/metabolismo , Fungicidas Industriais/metabolismo , Poluentes Químicos da Água/metabolismo , Benzimidazóis/química , Benzimidazóis/toxicidade , Carbamatos/química , Carbamatos/toxicidade , Diatomáceas/química , Diatomáceas/efeitos dos fármacos , Diatomáceas/crescimento & desenvolvimento , Água Doce/análise , Fungicidas Industriais/química , Fungicidas Industriais/toxicidade , Espectrometria de Massas , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade
6.
Environ Sci Pollut Res Int ; 26(16): 16289-16302, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30980366

RESUMO

Aquatic organisms might be exposed episodically or continuously to chemicals for long-term periods throughout their life span. Pesticides are one example of widely used chemicals and thus represent a potential hazard to aquatic organisms. In addition, these chemicals may be present simultaneously in the environment or as pulses, being difficult to predict accurately how their joint effects will take place. Therefore, the aim of the present study was to investigate how Daphnia magna (clone k6) exposed throughout generations to a model pesticide (the fungicide carbendazim) would react upon an exposure to another chemical compound (triclosan) and to a mixture of both chemicals (carbendazim and triclosan). Responses of daphnids continuously exposed to carbendazim and kept in clean medium will be compared using immobilization tests and the comet assay (DNA integrity). The results showed that triclosan presented similar toxicity to daphnids exposed for 12 generations (F12) to carbendazim (similar 48-h-LC50 values for immobilization data), when compared with daphnids kept in clean medium. However, at subcellular level, daphnids previously exposed to carbendazim for 12 generations (F12) showed different responses than those from clean medium, presenting a higher toxicity; a general higher percentage of DNA damage was observed, after exposure to a range of concentrations of triclosan and to the binary combination of triclosan + carbendazim. The patterns of toxicity observed for the binary mixture triclosan + carbendazim were generally similar for daphnids in clean medium and daphnids exposed to carbendazim, with a dose level deviation with antagonism observed at low doses of the chemical mixture for the immobilization data and a dose ratio deviation with synergism mainly caused by triclosan for DNA damage. With this study, we contributed to the knowledge on long-term induced effects of carbendazim exposure, while looking at the organismal sensitivity to another chemical (triclosan) and to a mixture of carbendazim and triclosan using lethality as an endpoint at the individual level and DNA damage as a subcellular endpoint.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Daphnia/efeitos dos fármacos , Triclosan/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Daphnia/fisiologia , Ecotoxicologia/métodos , Fungicidas Industriais/toxicidade , Praguicidas/toxicidade , Testes de Toxicidade Crônica
7.
Ecotoxicol Environ Saf ; 176: 242-249, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30939404

RESUMO

Pesticides, fungicides are reportedly involved in a decline in spermatozoa quality, especially motility, and a consequent increase in the rate of infertility. Fungicide carbendazim (CBZ) is widely used in agriculture and other aspects. Although CBZ is known to disrupt spermatogenesis, causing a decrease in spermatozoa concentration and motility, the mechanisms are not fully understood. We aimed to further explore the underlying mechanisms of CBZ disruption of spermatogenesis. Pubertal mice were exposed to low doses (0.1, 1 and 10 mg/kg body weight) of CBZ for 5 weeks, then many factors related to spermatogenesis have been explored. It was found that 0.1-10 mg/kg body weight of CBZ exposure decreased mouse sperm motility and concentration, diminished the important protein factors (VASA, PGK2, B-Amy and CREM) for spermatogenesis, reduced sperm protein acrosin level, disrupted very vital epigenetic factors H3K27, 5 mC and 5 hmC. Furthermore, CBZ exposure damaged estrogen receptor alpha (ERα) pathway by decreased the protein levels of ERα and its targets PI3K and AKT. In summary low doses of CBZ exposure disrupted mouse spermatogenesis through estrogen receptor signaling; and that histone methylation and DNA methylation might play vital roles in CBZ disturbance of spermatogenesis through intertwining with estrogen signaling pathways. CBZ from the contamination in environment or food chain poses a serious threat to the normal development of spermatozoa. Therefore we strongly recommend to minimise the use of CBZ since it causes the severe issues on spermatogenesis.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Metilação de DNA/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Histonas/metabolismo , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estrogênios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/genética , Espermatozoides/metabolismo
8.
Toxicol In Vitro ; 58: 78-85, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30851412

RESUMO

The fungicide Carbendazim is widely used in agriculture and preservation of films and fibers. In mammals, it can promote germ cell mutagenicity, carcinogenicity, and reproductive toxicity. However, few data about the effects of this toxicant upon the respiratory system are available. In this work, we evaluated Carbendazim toxicity upon A549 alveolar cells both in monolayer and upon air-liquid interface cell system. Monolayer cell exposed to non-cytotoxic concentrations of this fungicide showed cell arrest at G2/M phase, and did not show additional alterations. On the other hand, alveolar 3D reconstructed epithelial model (air-liquid interface cell system) was characterized and exposed to IC25 of Carbendazim using the Vitrocell® Cloud 12 chamber. Expression of Active Caspase-3, α-tubulin and ROS was significantly increased after such exposure. Mitochondrial activity was also reduced after exposed to Carbendazim. The obtained results indicate that besides the environmental and reproductive toxicity concerns regarding Carbendazim exposure, pulmonary toxicity must be considered for this fungicide. In addition, we observed that the way of exposure impacts considerably on the cell response for in vitro assessment of chemicals inhalation toxicity profile.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Técnicas de Cultura de Células/métodos , Fungicidas Industriais/toxicidade , Células A549 , Células Epiteliais Alveolares/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-30822534

RESUMO

The well-known and effective anthelmintic oxibendazole was recently shown to have a broad spectrum of biological abilities, such as anti-cancer and anti-inflammation activities. In contrast, the mechanism of oxibendazole's anti-proliferative effect via cell signaling pathways and its role in pre-implantation has not been studied. Therefore, in this study we demonstrated the effects of oxibendazole on the proliferation of porcine trophectoderm (pTr) cells and porcine luminal epithelial (pLE) cells, a well-known in vitro model system of the fetal-maternal interface. Cell proliferation decreased in both pTr and pLE cells in response to oxibendazole, and we determined that this was modulated through intracellular cell signal transduction. Phosphorylation of ERK1/2, P90RSK, and S6 were downregulated by exposure to a 200 nM dose of oxibendazole in both types of cells, while the expression of phosphorylated JNK, AKT, and P70S6K was upregulated. Pre-treatment with a PI3K/AKT inhibitor (Wortmannin), ERK1/2 inhibitor (U0126), and JNK inhibitor (SP600125) induced the signaling interactions of these molecules, and oxibendazole co-treatment with each inhibitor resulted in even greater decreases in cell proliferation. Furthermore, intracellular and mitochondrial calcium ion accumulation was observed, which would mean that calcium ion homeostasis was disrupted, causing damage to the mitochondrial membrane potential. These deteriorated conditions ultimately led to apoptotic cell death. Taken together, the results of the present study identified that the apoptotic effect of oxibendazole on pTr and pLE cells is regulated by cell signaling pathways, and thus oxibendazole could influence the connection between the conceptus and the maternal uterus.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Útero/citologia , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos
10.
Pestic Biochem Physiol ; 153: 95-105, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30744902

RESUMO

Target leaf spot caused by Corynespora cassiicola is an economically important foliar disease on cucumber. In recent years, this disease has caused a serious problem on greenhouse-cultivated cucumber in China. In this study, to explore the characteristics and possible causes of heavy occurrence of the disease, we monitored the resistance of C. cassiicola strains from different provinces of China to benzimidazole and quinone outside inhibitor (QoI) fungicides. The results from sequence comparison of target genes ß-tubulin and Cytb of 619C. cassiicola strains indicate that resistance frequency to benzimidazoles and QoIs is up to 100%. Furtherly, molecular resistance mechanism of C. cassiicola to benzimidazoles and QoIs was analysed. One single mutation E198A and three double mutations E198A&M163I, E198A&F167Y and E198A&F200S were observed in target gene ß-tubulin, which confers resistance to benzimidazoles. To our knowledge, this is the first report that double mutations of ß-tubulin confer resistance to benzimidazoles in filamentous fungi. Compared with single mutation E198A, three double mutations significantly decreased sensitivity to benzimidazoles. Moreover, significant difference of sensitivity to benzimidazoles was observed among three double mutations. These mutation genotypes of ß-tubulin have different geographical distribution and the mutation E198A&M163I is prevalent, occupying for 63.94%. In addition, strong cross resistance patterns between carbendazim, benomyl and thiabendazole were observed in C. cassiicola strains conferring different ß-tubulin mutations. For QoI resistance, the only mutation G143A of Cytb was detected in tested 619C. cassiicola strains. Strong positive cross resistance was observed when comparing the EC50 values of sensitive and resistant strains of C. cassiicola for six intrinsically different QoIs such as azoxystrobin, fluoxastrobin, pyraclostrobin, fenaminstrobin, picoxystrobin and coumoxystrobin. Taken together, all the results not only provide novel insights into understanding resistance mechanism to benzimidazoles and QoIs in filamentous fungi, but also provide some important references for resistance management of target leaf spot on cucumber.


Assuntos
Ascomicetos/efeitos dos fármacos , Benzimidazóis/toxicidade , Cucumis sativus/microbiologia , Farmacorresistência Fúngica/genética , Fungicidas Industriais/toxicidade , Estrobilurinas/toxicidade , Agricultura , Ascomicetos/genética , China , Citocromos b/genética , Proteínas Fúngicas/genética , Mutação , Tubulina (Proteína)/genética
11.
Int J Toxicol ; 38(2): 96-109, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30791754

RESUMO

BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.


Assuntos
Benzimidazóis/farmacocinética , Benzimidazóis/toxicidade , Proteínas de Membrana/antagonistas & inibidores , Piperazinas/farmacocinética , Piperazinas/toxicidade , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Ratos Wistar , Testes de Toxicidade
12.
Drug Dev Res ; 80(4): 490-503, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30793347

RESUMO

Antimicrobial drug resistance is one of the most critical problems that plagued the human race in modern times. Discovery of novel antibiotics is important to counter this threat. Accordingly, herein we have reported the discovery of substituted benzimidazole class of molecules with antimicrobial property (specifically against Staphylococcus aureus). They were initially identified through a random screening and a novel catalytic synthetic strategy was utilized to access them. in vitro screening and phenotypic profiling revealed the antimicrobial nature. De novo transcriptome and gene analyses predicted the putative targets. This work provides a solid foundation for developing the benzimidazoles as a target specific antimicrobial preclinical candidate.


Assuntos
Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Descoberta de Drogas , Perfilação da Expressão Gênica , Staphylococcus aureus/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/toxicidade , Benzimidazóis/química , Benzimidazóis/toxicidade , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Valor Preditivo dos Testes , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento
13.
Analyst ; 144(5): 1546-1554, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30643917

RESUMO

We report a novel fluorescent probe HBN-TCF for the detection of SO2 derivatives. This probe exhibited near-infrared fluorescence emission with an excitation wavelength of 620 nm. After reacting with SO32-, the emission channel at 664 nm decreased, while the new strong emission channel at 482 nm increased (λex = 400 nm), with a large emission distance (Δλ = 182 nm) observed. This probe exhibited the rapid and selective detection of SO2 derivatives compared with other sulfur-containing species and featured a low detection limit (82 nM). This colorimetric and ratiometric fluorescent probe showed high selectivity and sensitivity for detecting SO2 derivatives. The probe was also successfully exploited for the fluorescence imaging of intracellular and exogenous SO2 derivatives in BEL-7402 cells.


Assuntos
Benzimidazóis/química , Compostos de Benzilideno/química , Corantes Fluorescentes/química , Sulfitos/análise , Dióxido de Enxofre/análise , Benzimidazóis/síntese química , Benzimidazóis/efeitos da radiação , Benzimidazóis/toxicidade , Compostos de Benzilideno/síntese química , Compostos de Benzilideno/efeitos da radiação , Compostos de Benzilideno/toxicidade , Linhagem Celular Tumoral , Colorimetria/métodos , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Luz , Limite de Detecção , Microscopia de Fluorescência/métodos
14.
Environ Toxicol Chem ; 38(2): 412-422, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30508263

RESUMO

Anthropogenic activities such as the use of pesticides may affect aquatic biota populations, due to potential agricultural runoffs or disposals. Carbendazim is one example of a widely used fungicide with a high potential to end up in aquatic ecosystems through runoff. Deleterious effects observed at the individual level are possibly explained by changes in homeostasis at the cellular level, and both factors can then be used to predict effects at the population level. In the present study, an isoclonal population of Daphnia magna (clone K6) was exposed to a concentration that mimics relevant levels of carbendazim in the environment over 12 generations. The effects of carbendazim were assessed in some generations using the following endpoints: biochemical biomarkers (cholinesterase, catalase, and glutathione-S-transferase), lipid peroxidation and energy-related parameters (carbohydrates, lipids, and proteins along with available energy and energy consumption), parental longevity, and population growth (r). Long-term exposure to carbendazim had no effect on the intrinsic rate of natural increase (r) of adult D. magna, but longevity was decreased at the F12 generation compared to that of control. Differences between the exposed and nonexposed populations were found for cholinesterase, glutathione-S-transferase, and lipid peroxidation. However, for catalase and energy-related parameters, no differences were observed between these 2 populations. Natural variability was seen throughout the test period, under control conditions, within the 12 generations. Overall, carbendazim induced some effects at the subcellular level that translated into changes in longevity but these later vanished in terms of population effects. Environ Toxicol Chem 2019;38:412-422. © 2018 SETAC.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Daphnia/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Daphnia/enzimologia , Daphnia/crescimento & desenvolvimento , Ecossistema , Peroxidação de Lipídeos/efeitos dos fármacos , Longevidade , Reprodução/efeitos dos fármacos
15.
Environ Sci Pollut Res Int ; 26(5): 4324-4336, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29740769

RESUMO

This study aimed at investigating the degradation of fungicide carbendazim (CBZ) via photo-Fenton reactions in artificially and solar irradiated photoreactors at laboratory scale and in a semi-pilot scale Raceway Pond Reactor (RPR), respectively. Acute toxicity was monitored by assessing the sensibility of bioluminescent bacteria (Aliivibrio fischeri) to samples taken during reactions. In addition, by-products formed during solar photo-Fenton were identified by liquid chromatography coupled to mass spectrometry (UFLC-MS). For tests performed in lab-scale, two artificial irradiation sources were compared (UVλ > 254nm and UV-Visλ > 320nm). A complete design of experiments was performed in the semi-pilot scale RPR in order to optimize reaction conditions (Fe2+ and H2O2 concentrations, and water depth). Efficient degradation of carbendazim (> 96%) and toxicity removal were achieved via artificially irradiated photo-Fenton under both irradiation sources. Control experiments (UV photolysis and UV-Vis peroxidation) were also efficient but led to increased acute toxicity. In addition, H2O2/UVλ > 254nm required longer reaction time (60 minutes) when compared to the photo-Fenton process (less than 1 min). While Fenton's reagent achieved high CBZ and acute toxicity removal, its efficiency demands higher concentration of reagents in comparison to irradiated processes. Solar photo-Fenton removed carbendazim within 15 min of reaction (96%, 0.75 kJ L-1), and monocarbomethoxyguanidine, benzimidazole isocyanate, and 2-aminobenzimidazole were identified as transformation products. Results suggest that both solar photo-Fenton and artificially irradiated systems are promising routes for carbendazim degradation.


Assuntos
Benzimidazóis/análise , Carbamatos/análise , Peróxido de Hidrogênio/química , Ferro/química , Raios Ultravioleta , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Aliivibrio fischeri/efeitos dos fármacos , Benzimidazóis/efeitos da radiação , Benzimidazóis/toxicidade , Carbamatos/efeitos da radiação , Carbamatos/toxicidade , Desenho de Equipamento , Modelos Teóricos , Fotólise , Testes de Toxicidade Aguda , Poluentes Químicos da Água/efeitos da radiação , Poluentes Químicos da Água/toxicidade
16.
ACS Infect Dis ; 5(3): 418-429, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30580519

RESUMO

We have previously reported on the antischistosomal activity of pyrido[1,2- a]benzimidazole (PBI) derivatives. As a follow-up, we designed and prosecuted further structure-activity relationship (SAR) studies that incorporate N-aryl substitutions on the PBI scaffold. Investigations into the in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms revealed several leads with promising potency. Active compounds with a good cytotoxicity profile were tested in vivo whereby 6 and 44 induced noteworthy reduction (62-69%) in the worm load in the Schistosoma mansoni mouse model. Pharmacokinetic analysis on 44 pointed to slow absorption, low volume of distribution, and low plasma clearance indicating the potential of these compounds to achieve a long duration of action. Overall, our work demonstrates that PBI chemotype is a promising scaffold in the discovery of new antischistosomal leads.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacocinética , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/química , Esquistossomicidas/farmacocinética , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/toxicidade , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/parasitologia , Esquistossomicidas/administração & dosagem , Esquistossomicidas/toxicidade , Relação Estrutura-Atividade
17.
Toxicol Sci ; 166(2): 382-393, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496565

RESUMO

Carbendazim (CBZ), a systemic, broad-spectrum benzimidazole fungicide, is widely used to control fungal diseases and has been regarded as an endocrine disruptor that causes mammalian toxicity in different target organs. Here, we discovered that chronic administrations of CBZ at 0.2, 1, and 5 mg/kg body weight for 14 weeks not only changed the composition of gut microbiota but also induced significant increases in body, liver, and epididymal fat weight in mice. At the biochemical level, the serum triglyceride (TG) and glucose levels also increased after CBZ exposure. Moreover, the level of serum lipoprotein lipase (LPL), which plays an important role in fatty acid release from TG, was decreased significantly. For gut microbiota, 16S rRNA gene sequencing and real-time qPCR revealed that CBZ exposure significantly perturbed the mice gut microbiome, and gas chromatography found that the production of short-chain fatty acids were altered. Moreover, CBZ exposure increased the absorption of exogenous TG in the mice intestine and inhibited the TG consumption, eventually leading the serum triglyceride to maintain higher levels. The increase of lipid absorption in the intestine direct caused hyperlipidemia and the multi-tissue inflammatory response. In response to the rise of lipid in blood, the body maintains the balance of lipid metabolism in mice by reducing lipid synthesis in the liver and increasing lipid storage in the fat. Chronic CBZ exposure induced the gut microbiota dysbiosis and disturbed lipid metabolism, which promoted the intestinal absorption of excess triglyceride and caused multiple tissue inflammatory responses in mice.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Disbiose/induzido quimicamente , Disbiose/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Transtornos do Metabolismo dos Lipídeos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Fungicidas Industriais/toxicidade , Microbioma Gastrointestinal/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/microbiologia , Insulina/sangue , Absorção Intestinal/efeitos dos fármacos , Transtornos do Metabolismo dos Lipídeos/microbiologia , Lipase Lipoproteica/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Bacteriano/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/metabolismo
18.
Inorg Chem ; 57(22): 14427-14434, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30406647

RESUMO

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Complexos de Coordenação/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citocromos c/química , DNA/química , Estabilidade de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Estrutura Molecular , Osmio/química , Rutênio/química , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Ubiquitina/química
19.
ACS Chem Biol ; 13(10): 2868-2879, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30184433

RESUMO

The poly(ADP-ribose) polymerase (PARP) family of enzymes plays a crucial role in cellular and molecular processes including DNA damage detection and repair and transcription; indeed, PARP inhibitors are under clinical evaluation as chemotherapeutic adjuncts given their capacity to impede genomic DNA repair in tumor cells. Conversely, overactivation of PARP can lead to NAD+ depletion, mitochondrial energy failure, and cell death. Since PARP activation facilitates genomic but impedes mitochondrial DNA repair, nonselective PARP inhibitors are likely to have opposing effects in these cellular compartments. Herein, we describe the synthesis and evaluation of the mitochondria-targeting PARP inhibitor, XJB-veliparib. Attachment of the hemigramicidin S pentapeptide isostere for mitochondrial targeting using a flexible linker at the primary amide site of veliparib did not disrupt PARP affinity or inhibition. XJB-veliparib was effective at low nanomolar concentrations (10-100 nM) and more potent than veliparib in protection from oxygen-glucose deprivation (OGD) in primary cortical neurons. Both XJB-veliparib and veliparib (10 nM) preserved mitochondrial NAD+ after OGD; however, only XJB-veliparib prevented release of NAD+ into cytosol. XJB-veliparib (10 nM) appeared to inhibit poly(ADP-ribose) polymer formation in mitochondria and preserve mitochondrial cytoarchitecture after OGD in primary cortical neurons. After 10 nM exposure, XJB-veliparib was detected by LC-MS in mitochondria but not nuclear-enriched fractions in neurons and was observed in mitoplasts stripped of the outer mitochondrial membrane obtained from HT22 cells. XJB-veliparib was also effective at preventing glutamate-induced HT22 cell death at micromolar concentrations. Importantly, in HT22 cells exposed to H2O2 to produce DNA damage, XJB-veliparib (10 µM) had no effect on nuclear DNA repair, in contrast to veliparib (10 µM) where DNA repair was retarded. XJB-veliparib and analogous mitochondria-targeting PARP inhibitors warrant further evaluation in vitro and in vivo, particularly in conditions where PARP overactivation leads to mitochondrial energy failure and maintenance of genomic DNA integrity is desirable, e.g., ischemia, oxidative stress, and radiation exposure.


Assuntos
Benzimidazóis/farmacologia , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular , Reparo do DNA/efeitos dos fármacos , Camundongos , NAD/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Oligopeptídeos/síntese química , Oligopeptídeos/toxicidade , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/toxicidade , Ratos Sprague-Dawley
20.
Environ Pollut ; 242(Pt B): 1427-1435, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30142558

RESUMO

The increased use of pesticides during recent years necessitates a reevaluation of the effect of those compounds by extending the range of nontarget species commonly used in risk assessment. In the present work, we thus determined the impact of the pesticides glyphosate, carbendazim, and malathion on the parasite Chordodes nobilii in both natural and reconstituted freshwater as the assay medium and tested the sensitivity of three of this species's ecologically relevant parameters-e. g., embryo nonviablity and the infective capability of larvae exposed for 48 or 96 h either in ovo or after hatching via the infection index mean abundance-to compare those parameters to data from previous trials with reconstituted freshwater. In natural-freshwater assays, at environmentally relevant concentrations, all three pesticides inhibited the preparasitic-stage endpoints; with carbendazim being the most toxic pesticide and the subsequent infectivity of larvae exposed in ovo the most sensitive endpoint. In general, the 50%-inhibitory concentrations assayed in reconstituted freshwater were higher than those obtained in natural freshwater, indicating a certain protective effect; whereas the maximal toxicity of the three pesticides in both aqueous environments was essentially similar. The sensitivity of C. nobilii to these agents demonstrated that this species is one of the most susceptible to toxicity by all three pesticides. These findings with the assay methodology provide relevant information for a future assessment of the risk of toxicity to aquatic ecosystems and furthermore underscore the need to include parasitic organisms among the nontarget species canvassed. We also recommend that in the bioassays in which the risk assessment is carried out, water from a nontarget species's natural environment be used in parallel in order to obtain more conclusive results.


Assuntos
Benzimidazóis/toxicidade , Carbamatos/toxicidade , Glicina/análogos & derivados , Helmintos/efeitos dos fármacos , Malation/toxicidade , Praguicidas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bioensaio , Embrião não Mamífero/efeitos dos fármacos , Feminino , Água Doce , Glicina/toxicidade , Larva/efeitos dos fármacos , Masculino
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