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1.
An Acad Bras Cienc ; 93(suppl 3): e20200860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34550199

RESUMO

The use of agrochemicals in agriculture may impact aquatic ecosystems, particularly influencing the stream insect communities. Among aquatic insects, the family Chironomidae is the most abundant and species-diverse insect group found in freshwater ecosystems. However, in the southern hemisphere, studies with Chironomidae are still sparse, compared to Europe and North America. The present study evaluates the responses of Chironomidae species (Insecta: Diptera) to pyrimethanil fungicide in a mesocosm experiment. Water contamination and chironomid community were monitored over 10 months. After five months of monitoring, the pyrimethanil fungicide was completely degraded and there was a statistically significant increase in the Margalef Richness and Shannon-Wiener Index (H') in the control units when compared with the contaminated mesocosms (p = 0.003). Our results point out that the utilization of agrochemicals can be a harmful factor influencing negatively the Chironomidae populations. This finding has key implications for insect conservation strategies and ecological management environments.


Assuntos
Chironomidae , Fungicidas Industriais , Animais , Ecossistema , Fungicidas Industriais/toxicidade , Pirimidinas/toxicidade
2.
Sci Rep ; 11(1): 16856, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413359

RESUMO

P-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4-7 and 12 is required for inhibition.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pirimidinas/farmacologia , Quinolonas/farmacologia , Morte Celular/efeitos dos fármacos , Humanos , Células K562 , Simulação de Dinâmica Molecular , Transporte Proteico/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/toxicidade , Quinolonas/química , Quinolonas/toxicidade , Rodamina 123/metabolismo , Relação Estrutura-Atividade , Termodinâmica
3.
J Med Chem ; 64(16): 11857-11885, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34374541

RESUMO

Cathepsin C (Cat C) participates in inflammation and immune regulation by affecting the activation of neutrophil serine proteases (NSPs). Therefore, cathepsin C is an attractive target for treatment of NSP-related inflammatory diseases. Here, the complete discovery process of the first potent "non-peptidyl non-covalent cathepsin C inhibitor" was described with hit finding, structure optimization, and lead discovery. Starting with hit 14, structure-based optimization and structure-activity relationship study were comprehensively carried out, and lead compound 54 was discovered as a potent drug-like cathepsin C inhibitor both in vivo and in vitro. Also, compound 54 (with cathepsin C Enz IC50 = 57.4 nM) exhibited effective anti-inflammatory activity in an animal model of chronic obstructive pulmonary disease. These results confirmed that the non-peptidyl and non-covalent derivative could be used as an effective cathepsin C inhibitor and encouraged us to continue further drug discovery on the basis of this finding.


Assuntos
Anti-Inflamatórios/uso terapêutico , Catepsina C/antagonistas & inibidores , Inflamação/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinas/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/toxicidade , Catepsina C/metabolismo , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Inflamação/etiologia , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/toxicidade , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
ACS Appl Mater Interfaces ; 13(30): 35306-35314, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34288648

RESUMO

With the long-term and extensive abuse of antibiotics, bacteria can mutate into multidrug-resistant (MDR) strains, resist the existing antibiotics, and escape the danger of being killed. MDR bacteria-caused skin infections are intractable and chronic, becoming one of the most significant and global public-health issues. Thus, the development of novel antimicrobial materials is urgently needed. Non-antibiotic small molecule-modified gold nanoclusters (AuNCs) have great potential as a substitute for commercial antibiotics. Still, their narrow antibacterial spectrum hinders their wide clinical applications. Herein, we report that 4,6-diamino-2-pyrimidinethiol (DAPT)-modified AuNCs (DAPT-AuNCs) can fight against Gram-negative and Gram-positive bacterial strains as well as their MDR counterparts. By modifying DAPT-AuNCs on nanofibrous films, we develop an antibiotic film as innovative dressings for curing incised wounds, which exhibits excellent therapeutic effects on wounds infected by MDR bacteria. Compared to the narrow-spectral one, the broad-spectral antibacterial activity of the DAPT-AuNCs-modified film is more suitable for preventing and treating skin infections caused by various kinds of unknown bacteria. Moreover, the antibacterial films display excellent biocompatibility, implying the great potential for clinical applications.


Assuntos
Antibacterianos/uso terapêutico , Bandagens , Infecções por Escherichia coli/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/patologia , Feminino , Ouro/química , Ouro/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Infecções Cutâneas Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfidrila/química , Compostos de Sulfidrila/toxicidade , Cicatrização/efeitos dos fármacos
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281290

RESUMO

Plasmodium falciparum's resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.


Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Humanos , Iminas/química , Iminas/toxicidade , Plasmodium falciparum/crescimento & desenvolvimento , Pirimidinas/química , Pirimidinas/toxicidade , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/farmacologia
6.
Biochem Pharmacol ; 192: 114678, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34265279

RESUMO

Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor α (PPARα) in liver. The PPARα-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1adipoQ-cre) mice and corresponding normal control (fgfr1fl/fl) mice were fed with Lieber-DeCarli ethanol liquid diet for 3 weeks, liver triglyceride (TG) accumulation was increased in the fgfr1fl/fl mice to a greater extent than in the fgfr1adipoQ-cre mice. When PPARα agonist WY-14,643 was added in the liquid ethanol diet at 10 mg/L, the ethanol-induced liver TG accumulation was blunted in the fgfr1fl/fl mice but not in the fgfr1adipoQ-cre mice. There was no significant difference in WY-14,643-induced fatty acid oxidation, ethanol metabolism, and oxidative stress between the fgfr1fl/fl and fgfr1adipoQ-cre mice. Interestingly, adipose atrophy was induced by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. Serum free fatty acid was also decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. These results suggest that WY-14,643 inhibits alcoholic fatty liver and regulates adipose tissue mass and fat mobilization from adipose tissues to liver in an adipocyte FGFR1-dependent manner.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Etanol/toxicidade , Fígado Gorduroso Alcoólico/prevenção & controle , PPAR alfa/agonistas , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/deficiência , Tecido Adiposo/metabolismo , Animais , Atrofia/induzido quimicamente , Atrofia/metabolismo , Etanol/administração & dosagem , Fígado Gorduroso Alcoólico/metabolismo , Feminino , Camundongos , Camundongos Knockout , PPAR alfa/metabolismo , Proliferadores de Peroxissomos/uso terapêutico , Proliferadores de Peroxissomos/toxicidade , Pirimidinas/toxicidade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
7.
Toxicol Appl Pharmacol ; 423: 115578, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34004237

RESUMO

Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and ß-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients.


Assuntos
Acetilcisteína/metabolismo , Injúria Renal Aguda/metabolismo , Piperazinas/metabolismo , Piperazinas/toxicidade , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Piridinas/metabolismo , Piridinas/toxicidade , Pirimidinas/metabolismo , Pirimidinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
8.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800013

RESUMO

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.


Assuntos
Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , SARS-CoV-2/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Disponibilidade Biológica , COVID-19/tratamento farmacológico , Biologia Computacional/métodos , Bases de Dados de Compostos Químicos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Metiltransferases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Plantas Medicinais/química , Ligação Proteica , Domínios Proteicos/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , RNA Helicases/química , Relação Estrutura-Atividade , Termodinâmica , Proteínas não Estruturais Virais/química
9.
Cell Death Dis ; 12(3): 273, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723230

RESUMO

Chronic pancreatitis (CP) is characterized by a wide range of irreversible fibro-inflammatory diseases with largely ambiguous pathogenesis. Although neddylation pathway has been implicated in regulating immune responses, whether the dysregulation of neddylation is involved in the progression of CP and how neddylation regulates the inflammatory microenvironment of CP have not yet been reported. Here, we demonstrate that global inactivation of neddylation pathway by MLN4924 significantly exacerbates chronic pancreatitis. The increased M2 macrophage infiltration, mediated by the upregulated chemokine (C-C motif) ligand 5 (CCL5), is responsible for the enhanced pancreatitis-promoting activity of MLN4924. Both CCL5 blockade and macrophage depletion contribute to alleviating pancreatic fibrosis and inflammation in MLN4924-treated CP mice. Mechanistic investigation identifies that inactivation of Cullin-RING ligases (CRLs) stabilizes cellular levels of hypoxia-inducible factor 1α (HIF-1α), which increases CCL5 expression by promoting CCL5 transactivation. Clinically, UBE2M expression remarkably decreases in human CP tissues compared with normal specimens and the levels of CCL5 and M2 marker CD163 are negatively correlated with UBE2M intensity, suggesting that neddylation is involved in the pathogenesis of pancreatitis. Hence, our studies reveal a neddylation-associated immunopathogenesis of chronic pancreatitis and provide new ideas for the disease treatment.


Assuntos
Quimiocina CCL5/metabolismo , Quimiotaxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/metabolismo , Pâncreas/metabolismo , Pancreatite Crônica/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismo , Animais , Linhagem Celular , Quimiocina CCL5/genética , Quimiotaxia/efeitos dos fármacos , Ciclopentanos/toxicidade , Modelos Animais de Doenças , Inibidores Enzimáticos/toxicidade , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/genética , Pancreatite Crônica/patologia , Fenótipo , Pirimidinas/toxicidade , Transdução de Sinais , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Ubiquitinação
10.
Aquat Toxicol ; 233: 105783, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33662881

RESUMO

Pesticides occur in the environment as mixtures, yet the joint toxicity of pesticide mixtures remains largely under-explored and is usually overlooked in ecological risk assessment. In the current study, joint toxicity of a neonicotinoid insecticide (imidacloprid, IMI) and a strobilurin fungicide (azoxystrobin, AZO) was investigated with Chironomus dilutus over a wide range of concentrations and at different effect levels (organism, cell, and gene levels). The two pesticides, both individually and in combination, were found to induce oxidative stress and cause lethality in C. dilutus. Median lethal concentrations for IMI and AZO were 3.98 ± 1.17 and 52.9 ± 1.1 µg/L, respectively. Mixtures of the two pesticides presented synergetic effects at environmentally relevant concentrations whilst antagonistic effects at high concentrations, showing concentration-dependent joint toxicity. Investigation on the expressions of 12 genes (cyt b, coi, cox1, cyp4, cyp12m1, cyp9au1, cyp6fv1, cyp315, gst, Zn/Cu-sod, Mn-sod, and cat) revealed that the two pesticides impaired mitochondrial respiration, detoxification, and antioxidant system of C. dilutus, and the joint effects of the two pesticides were likely due to an interplay between their respective influences on these physiological processes. Collectively, the synergistic effects of the two pesticides at environmentally relevant concentrations highlight the importance to incorporate combined toxicity studies into ecological risk assessment of pesticides.


Assuntos
Chironomidae/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Praguicidas/toxicidade , Pirimidinas/toxicidade , Estrobilurinas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Chironomidae/citologia , Chironomidae/genética , Sinergismo Farmacológico , Peróxido de Hidrogênio/metabolismo , Dose Letal Mediana , Malondialdeído/metabolismo , Modelos Teóricos
11.
Ecotoxicol Environ Saf ; 211: 111920, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33497861

RESUMO

Azoxystrobin is a broad-spectrum strobilurin fungicide for use on a wide range of crops available to end-users as formulated products. Due to its extensive application, it has been detected in aquatic ecosystems, raising concerns about its environmental impact, which is still poorly explored. The objective of this work was to study the effects of a commercial formulation of azoxystrobin in the zebrafish embryo model. Sublethal and lethal effects were monitored during the exposure period from 2 h post fertilisation (hpf) to 96 hpf after exposure to azoxystrobin concentrations (1, 10 and 100 µg L-1). The responses of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR)) as well as detoxifying enzymes (glutathione-s-transferase (GST) and carboxylesterase (CarE)) were evaluated at 96 hpf. Similarly, glutathione levels (reduced (GSH) and oxidised (GSSG) glutathione), neurotransmission (acetylcholinesterase (AChE)) and anaerobic respiration (lactate dehydrogenase (LDH)) -related enzymes were assayed. At 120 hpf, larvae from each group were used for behaviour analysis. Results from this study showed concentration-dependent teratogenic effects, particularly by increasing the number of malformations (yolk and eye), with a higher prevalence at the highest concentration. However, it was found that the lowest concentration induced a high generation of reactive oxygen species (ROS) and increased activity of SOD, GST, and CarE. In addition, GR and GSSG levels were decreased by the lowest concentration, suggesting an adaptive response to oxidative stress, which is also supported by the increased AChE activity and absence of behavioural changes. These findings advance the knowledge of the azoxystrobin developmental and environmental impacts, which may impose ecotoxicological risks to non-target species.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Pirimidinas/toxicidade , Estrobilurinas/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Ecossistema , Embrião não Mamífero/fisiologia , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Estrobilurinas/farmacologia , Superóxido Dismutase/metabolismo , Peixe-Zebra/metabolismo
12.
Environ Sci Pollut Res Int ; 28(5): 5566-5574, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32974827

RESUMO

Azoxystrobin (AZ) is an aryloxy pyrimidine fungicide extensively applied in the agriculture field all over the world. There is a little information about the ecotoxicity of AZ fungicide on the freshwater snail Lymnaea luteola (L. luteola). The present study investigated the toxic effect of AZ fungicide on L. luteola by using various measures. We determined the mean LC50 value-96 h of AZ fungicide (0.79 mg/L) for L. luteola, in a static system. Based on this value, three sublethal concentrations, viz., I (0.079 mg/L), II (~ 0.40 mg/L), and III (~ 0.53 mg/L), were determined. The snails were exposed to these three concentrations of AZ fungicide for 96 h, and hemolymph and digestive glands were collected after 24 and 96 h for assessment of oxidative stress, apoptosis, and histological and genotoxic changes. The induction of intracellular reactive oxygen species (ROS) and apoptosis in hemocyte cells was increased in a dose- and time-dependent manner. It was observed that lipid peroxide (LPO) and glutathione S transferase (GST) were increased, and glutathione and superoxide dismutase decreased in digestive glands. A similar trend was observed for the DNA damage as measured in terms of the percentage of tail DNA and olive tail moment in digestive gland cells. This study showed the collective use of oxidative stress, histological, and genotoxicity parameters in in vivo laboratory studies using snails that are useful for screening the toxic potential of environmental contaminants such as AZ fungicide.Graphical abstract.


Assuntos
Fungicidas Industriais , Lymnaea , Animais , Dano ao DNA , Características da Família , Água Doce , Fungicidas Industriais/toxicidade , Estresse Oxidativo , Pirimidinas/toxicidade , Espécies Reativas de Oxigênio , Caramujos , Estrobilurinas
13.
Eur J Pharmacol ; 892: 173744, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33220270

RESUMO

Benzodiazepines (BDZs) and non-BDZ sedative-hypnotics are effective for the management of chronic insomnia; however, they are associated with adverse effects such as headache, dizziness, and palpitations. Furthermore, long-term use of these medications is associated with decreased blood pressure (BP) or depressed baroreflex function. Therefore, here, we assessed whether BDZs and non-BDZs cause vasorelaxation directly. Vasorelaxation in response to 22 BDZs, 2 non-BDZs, and tandospirone was determined by myograph methods using isolated Wistar rat thoracic aortas. All the drugs relaxed phenylephrine-contracted rat aortas in a concentration-dependent manner. Zolpidem and tandospirone caused over 80% relaxation at a concentration of 10 µM; diazepam, estazolam, etizolam, and tofisopam caused 60-70% relaxation; whereas 18 other BDZs (alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, ethyl loflazepate, flunitrazepam, flurazepam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, temazepam, and triazolam) and zaleplon caused less than 50% relaxation. The relaxation was partially but significantly inhibited to the same extent by a nitric oxide (NO) synthase antagonist and after endothelium removal. Binding assay of gamma-aminobutyric acid type A receptors was performed using [3H]flunitrazepam. No correlation was observed between vasorelaxation at a concentration of 10 µM and the binding affinities for 23 drugs. The study demonstrated that zaleplon, zolpidem, tandospirone, and many BDZs cause vasorelaxation to different extents via endothelial NO-dependent and endothelium-independent pathways. In conclusion, the direct vasodilatory effects of these drugs may be involved in the mechanisms underlying their adverse effects. Additionally, the decreased BP observed in persons who take BDZs or non-BDZs may be partly due to direct vasodilation.


Assuntos
Aorta Torácica/efeitos dos fármacos , Benzodiazepinas/toxicidade , Hipnóticos e Sedativos/toxicidade , Hipotensão Ortostática/induzido quimicamente , Isoindóis/toxicidade , Artérias Mesentéricas/efeitos dos fármacos , Piperazinas/toxicidade , Pirimidinas/toxicidade , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/fisiopatologia , Relação Dose-Resposta a Droga , Hipotensão Ortostática/fisiopatologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/fisiopatologia , Ratos Wistar
14.
Bioorg Chem ; 106: 104385, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33272709

RESUMO

Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family and plays a key role in the modulation of the B-cell receptor (BCR)-mediated signaling pathway. Inhibition of BTK has been proven to be an effective therapeutic approach for various hematological malignancies, such as chronic lymphocytic leukemia (CLL), mantle cell leukemia (MCL), diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Here, a new series of imidazole group-substituted arylaminopyrimidines (IAAPs) were designed and synthesized as potent inhibitors of the enzymatic activity of BTK with a half maximal inhibitory concentration (IC50) ranging from 13.10 to 42.40 nM. In particular, 11a and 11b exhibited stronger antiproliferative activity against AML and B lymphomas cell lines compared with BTK inhibitor ibrutinib and showed low cytotoxicity against normal peripheral blood mononuclear cells (PBMCs). In addition, analysis of the mechanism of action of these compounds revealed that 11a and 11b induced significant apoptosis in AML and B lymphoma cells by arresting the cell cycle at the G1/G0 or G2/M stage and blocked BTK autophosphorylation as well as the ensuing abrogation of pro-survival AKT and ERK signaling. Taken together, these results suggest that 11a and 11b might serve as valuable preclinical candidates for the treatment of AML and B-cell lymphoma.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Imidazóis/toxicidade , Leucemia Mieloide Aguda/enzimologia , Leucócitos Mononucleares/efeitos dos fármacos , Linfoma de Células B/enzimologia , Masculino , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Transdução de Sinais/efeitos dos fármacos
15.
Environ Pollut ; 270: 116087, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33234374

RESUMO

Azoxystrobin (AZ) and pyraclostrobin (PY) are strobilurin fungicides that inhibit fungal mitochondrial respiration. In this study, a representative model, zebrafish (Danio rerio), was used as a test species for acute and developmental toxicity. Survival and malformation rates were observed only PY-treated embryos, with an LC50 value of 77.75 ppb accompanied by a dramatic decrease in hatching rate, while AZ did not show great mortality. Morphological changes were observed in PY-treated embryos with the occurrence of pericadial edema at 25 ppb. A delay in growth was observed after treatment with pyraclostrobin at 50 ppb. Use of genetically engineered Tg(cmlc:EGFP) allowed fluorescence observation during heart development. PY interfered with normal heart development via upregulation of the nppa gene responsible for the expression of natriuretic peptides. Heart function was dramatically reduced as indicated by reduced heart rates. Increased expression of the nppa gene was also seen in AZ-treated embryos. The expression level of cyp24a1 was also up-regulated, while ugt1a1 and sult1st6 were down-regulated after treatment of zebrafish embryos with AZ or PY. Overall, strobilurin fungicides might inhibit normal heart formation and function within the range of concentrations tested.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Embrião não Mamífero , Pirimidinas/toxicidade , Estrobilurinas/toxicidade
16.
Environ Toxicol ; 36(4): 562-571, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33226166

RESUMO

Azoxystrobin (AZO) and Iprodione (IPR) fungicides are extensively used worldwide, and therefore, contaminate all environmental compartments. The toxicity and the mechanisms by which they affected immune cells are complex and remain unknown. This study investigated the impact of AZO and IPR on the in vitro function of mice peritoneal macrophages including lysosomal enzyme activity and tumor necrosis factor (TNF)α and nitric oxide (NO) production in response to lipopolysaccharide (LPS) stimulation, the proliferation of mice splenocytes stimulated by concanavalin (Con)A and LPS, and the production of the Th1cytokine interferon-gamma (IFNγ) and the Th2 cytokine interleukin (IL)-4 and IL-10 by ConA-activated splenocytes. This is the first report indicating that AZO and IPR fungicides dose-dependently inhibited mice macrophage lysosomal enzyme activity and LPS-stimulated production of TNFα and NO. Mitogen-induced proliferation of mice splenocytes was also suppressed by AZO and IPR in a dose-dependent manner. More pronounced impact was observed on ConA-induced response. The production of IFNγ by ConA-stimulated splenocytes was dose-dependently inhibited; however, the production of IL-4 and IL-10 increased in the same conditions. These results suggested that AZO and IPR polarized Th1/Th2 cytokine balance towards Th2 response. Overall, marked immunosuppressive effects were observed for AZO. The immunomodulatory effects caused by AZO and IPR were partially reversed by the pharmacological antioxidant N-acetylcysteine (NAC), suggesting that both fungicides exerted their actions through, at least in part, oxidative stress-dependent mechanism. Collectively, our data showed that AZO and IPR fungicides exerted potent immunomodulatory effects in vitro with eventually strong consequences on immune response and immunologically based diseases.


Assuntos
Acetilcisteína/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Poluentes Ambientais/toxicidade , Fungicidas Industriais/toxicidade , Hidantoínas/toxicidade , Macrófagos Peritoneais , Pirimidinas/toxicidade , Estrobilurinas/toxicidade , Aminoimidazol Carboxamida/toxicidade , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Baço/efeitos dos fármacos , Baço/imunologia
17.
Toxicol Appl Pharmacol ; 410: 115339, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33221319

RESUMO

Udenafil is a long-acting oral phosphodiesterase type 5 inhibitor used to treat erectile dysfunction which may also have beneficial effects on cardiovascular diseases. Udenafil is mainly biotransformed to the active metabolite N-dealkylated udenafil via cytochrome P450 3A. The aim of this study was to investigate the gender differences and dose proportionality of the toxicokinetics of udenafil and its metabolite N-dealkylated udenafil in rodents. Udenafil was administered orally by gavage to male and female B6C3F1/N mice (100, 240, 350, and 500 mg/kg) and F344 rats (60, 120, and 240 mg/kg). Plasma concentrations of udenafil and N-dealkylated udenafil were simultaneous measured via liquid chromatography-tandem mass spectrometry. Female mice showed higher systemic exposure to udenafil than male mice, whereas female rats showed lower systemic exposure to udenafil than male rats after repeated administration at high dose. Systemic exposure to the metabolite, N-dealkylated udenafil, was lower in female than male mice and rats. A dose proportionality assessment by power model revealed a lack of dose proportionality in systemic exposure (Cmax, AUC24h and AUCinf) after administration of 100-500 mg/kg of udenafil in mice and 60-240 mg/kg in rats. This study thus demonstrates gender and species differences with regard to the toxicokinetic profiles of udenafil and its active metabolite N-dealkylated udenafil after oral administration of udenafil to mice and rats of both sexes. Our findings suggest the possibility of gender differences in the toxicokinetics of udenafil in humans and suggests that further study is needed in this cohort.


Assuntos
Inibidores da Fosfodiesterase 5/metabolismo , Inibidores da Fosfodiesterase 5/toxicidade , Pirimidinas/metabolismo , Pirimidinas/toxicidade , Caracteres Sexuais , Sulfonamidas/metabolismo , Sulfonamidas/toxicidade , Administração Oral , Animais , Feminino , Masculino , Camundongos , Ratos , Ratos Endogâmicos F344 , Roedores , Toxicocinética
18.
Exp Anim ; 70(2): 169-176, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33239495

RESUMO

Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various degrees of hepatotoxicity. Our study aimed to investigate the effect of taxifolin on pazopanib-induced liver toxicity. A total of 18 rats were divided into three groups: the pazopanib (PP), pazopanib plus taxifolin (TPP), and control (C) group. Taxifolin was administered to the TPP (n=6) group with a dose of 50 mg/kg. Distilled water was orally admnistered to the C (n=6) and PP (n=6) groups as a solvent. Subsequently, pazopanib 200 mg/kg was administered to the TPP and PP groups via the stomach. This procedure was repeated once a day for four weeks. Then, all rats were sacrificed, and their livers were removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), and total antioxidant status (TAS) levels were evaluated. MDA and TOS levels were higher in the PP group compared with the levels of the other parameters (P<0.001). tGSH and TAS levels were lower in the PP group than in the TPP and C groups (P<0.001), and the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were higher. Furthermore, liver tissue damage, including hemorrhage, hydropic degeneration, and necrosis was observed in the PP group. Administration of taxifolin before pazopanib significantly improved degenerative changes. Our study demonstrated that the administration of taxifolin is significantly effective in preventing pazopanib-induced hepatotoxicity in rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Indazóis/toxicidade , Substâncias Protetoras/farmacologia , Pirimidinas/toxicidade , Quercetina/análogos & derivados , Sulfonamidas/toxicidade , Animais , Fígado/efeitos dos fármacos , Masculino , Quercetina/farmacologia , Ratos , Ratos Wistar
19.
Food Chem ; 335: 127658, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32731124

RESUMO

Raphanus sativus var. longipinnatus, was exposed under experimental conditions to herbicides: rimsulfuron (RIM), administrated as (1) pure substance, (2) in commercially available formulation (RIMEL), (3) its degradation product: 4,6-dimethoxypyrimidin-2-amine (2ADP), (4) mesotrione (MES), (5) sulcotrione (SUL). Profiling and fingerprinting strategies, conducted by LC-MS/MS-FL, were employed to find markers of plant exposure to herbicide stress. The presence ofRIM metabolite in the tissues of plant exposed to this herbicide proved that it is necessary to determine both parent compound and its by-products to obtain reliable information on plant exposure to agrochemicals. A higher content of normetanephrine (NMN) (18-175%) and lower content of tyramine (TYR) (49-75%) and epinephrine (E) (75-83%) was observed in plant tissues exposed to RIM and 2ADP in comparison to blank sample. Therefore, NMN, TRY and E may be considered as markers of plant response to RIM. Non-target analysis enables to recognize the type of herbicide used during cultivation.


Assuntos
Herbicidas/toxicidade , Resíduos de Praguicidas/análise , Piridinas/toxicidade , Raphanus/química , Raphanus/efeitos dos fármacos , Sulfonamidas/toxicidade , Cromatografia Líquida , Cicloexanonas/farmacocinética , Cicloexanonas/toxicidade , Biomarcadores Ambientais , Epinefrina/análise , Mesilatos/farmacocinética , Mesilatos/toxicidade , Metaboloma , Normetanefrina/análise , Plantas Comestíveis/química , Plantas Comestíveis/efeitos dos fármacos , Piridinas/farmacocinética , Pirimidinas/toxicidade , Raphanus/metabolismo , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem , Tiramina/análise
20.
Xenobiotica ; 51(1): 72-81, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32660295

RESUMO

Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats. In vitro binding of FNL to rat and human plasma proteins was ∼90%, suggesting that FNL is a highly protein bound fungicide. The predicted in vivo hepatic clearance of FNL in rats and humans was estimated to be 36.71 and 14.39 mL/min/kg, respectively, indicating it to be an intermediate clearance compound. Reaction phenotyping assay showed that CYP3A4 mainly contributed to the overall metabolism of FNL. The oral toxicokinetic study of FNL in rats at no observed adverse effect level dose (1 mg/kg) showed maximum plasma concentration (C max) of 33.97 ± 4.45 ng/mL at 1 h (T max). The AUC0-∞ obtained was 180.18 ± 17.76 h*ng/mL, whereas, the t 1/2 was ∼4.74 h. Following intravenous administration, FNL displayed a clearance of 42.48 mL/min/kg which was close to the predicted in vivo hepatic clearance. The absolute oral bioavailability of FNL at 1 mg/kg dose in rats was 45.25%. FNL at 10 mg/kg oral dose exhibited non-linear toxicokinetics with greater than dose-proportional increase in the systemic exposure (AUC0-∞ 8270.53 ± 1798.59 h*ng/mL).


Assuntos
Fungicidas Industriais/metabolismo , Pirimidinas/metabolismo , Administração Intravenosa , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Disruptores Endócrinos , Fungicidas Industriais/toxicidade , Infusões Intravenosas , Ligação Proteica , Pirimidinas/toxicidade , Ratos , Toxicocinética
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