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1.
Chemosphere ; 240: 124857, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726599

RESUMO

Colorado potato beetle, Leptinotarsa decemlineata Say (coleoptera: chrysomelidae), is the important pest of potato all over the world. This insect pest is resistant to more than 50 active compounds belonging to various chemical groups. Potential of RNA interference (RNAi) was explored to knock down transcript levels of imidacloprid resistant genes in Colorado potato beetle (CPB) under laboratory conditions. Three important genes belonging to cuticular protein (CP), cytochrome P450 monoxygenases (P450) and glutathione synthetase (GSS) families encoding imidacloprid resistance were targeted. Feeding bio-assays were conducted on various stages of imidacloprid resistant CPB lab population by applying HT115 expressing dsRNA on potato leaflets. Survival rate of insects exposed to CP-dsRNA decreased to 4.23%, 15.32% and 47.35% in 2nd, 3rd and 4th instar larvae respectively. Larval weight and pre-adult duration were also affected due to dsRNAs feeding. Synergism of RNAi with imidacloprid conducted on the 2nd instar larvae, exhibited 100% mortality of larvae when subjected to reduced doses of GSS and CP dsRNAs along with imidacloprid. Utilization of three different dsRNAs against imidacloprid resistant CPB population reveal that dsRNAs targeting CP, P450 and GSS enzymes could be useful tool in management of imidacloprid resistant CPB populations.


Assuntos
Besouros/genética , Resistência a Medicamentos/genética , Genes de Insetos , Inseticidas/farmacologia , Larva/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Besouros/efeitos dos fármacos , Besouros/crescimento & desenvolvimento , Sistema Enzimático do Citocromo P-450/genética , Regulação para Baixo , Resistência a Medicamentos/efeitos dos fármacos , Glutationa Sintase/genética , Larva/efeitos dos fármacos , Larva/genética , Interferência de RNA/efeitos dos fármacos , Solanum tuberosum/crescimento & desenvolvimento
2.
Pestic Biochem Physiol ; 160: 95-101, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519262

RESUMO

Neonicotinoid insecticides are increasingly used in modern pest control and in conventional agriculture. Their residues are frequently found in our environment and in our food leading to chronic exposure of pollinating insects and humans. Indeed, evidence has become stronger that chronic exposure to neonicotinoids might have a direct impact on the immune response of invertebrates and vertebrates. Therefore, we compared the cellular immune response of human macrophages (THP-1) and Drosophila melanogaster hemocytes (Schneider 2 cells) after exposure to four different concentrations of the neonicotinoid imidacloprid. Cells were immune activated with LPS (lipopolysaccharide) of Escherichia coli to compare the phagocytic activity of immune activated and non-activated cells during pesticide exposure. Drosophila cells were more strongly affected by the insecticide than human macrophages. Even though imidacloprid showed an adverse effect on phagocytosis on both cells while immune activated, it decreased phagocytosis in Drosophila cells at shorter exposure time and without immune activation.


Assuntos
Drosophila melanogaster/metabolismo , Hemócitos/efeitos dos fármacos , Inseticidas/farmacologia , Macrófagos/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Fagocitose/efeitos dos fármacos , Animais , Linhagem Celular , Hemócitos/imunologia , Humanos , Macrófagos/imunologia
3.
Pestic Biochem Physiol ; 159: 27-33, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400781

RESUMO

Imidacloprid has been used to control one of most serious pests, Bemisia tabaci. However, B. tabaci has developed imidacloprid resistance mainly by over-expressing CYP6CM1. It was reported that imidacloprid-resistant B. tabaci showed no or low level of cross-resistance against dinotefuran. Here, we expressed CYP6CM1 variants using Sf9/baculovirus and/or Drosophila S2 cells and showed that CYP6CM1 variants metabolized imidacloprid but not dinotefuran. In addition, we demonstrated that imidacloprid and pymetrozine competed for a CYP6CM1 variant more efficiently than dinotefuran, using a luminescent substrate competition assay. These results suggest that lack of metabolic activity of CYP6CM1 variants against dinotefuran caused no or low level of cross-resistance.


Assuntos
Guanidinas/metabolismo , Guanidinas/farmacologia , Hemípteros/efeitos dos fármacos , Hemípteros/metabolismo , Inseticidas/metabolismo , Inseticidas/farmacologia , Neonicotinoides/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Animais , Hemípteros/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Resistência a Inseticidas/genética , Triazinas/metabolismo , Triazinas/farmacologia
4.
Pestic Biochem Physiol ; 159: 98-106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400791

RESUMO

The cotton aphid, Aphis gossypii Glover, is a destructive global crop pest. Control of A. gossypii has relied heavily on the application of chemical insecticides. The cotton aphid has developed resistance to numerous insecticides, including imidacloprid, which has been widely used to control cotton pests in China since the 1990s. Our objective was to investigate the potential role of UDP-glycosyltransferases (UGTs) in imidacloprid resistance based on transcriptomic and proteomic analyses of field-originated imidacloprid-resistant (IMI_R) and -susceptible (IMI_S) A. gossypii clones. The transcriptomic and proteomic analyses revealed that 12 out of 512 differentially expressed genes and three out of 510 differentially expressed proteins were predicted as UDP-glycosyltransferase (UGT). Based on quantitative real-time PCR analysis, nine UGT genes, UGT343A4, UGT344A15, UGT344A16, UGT344B4, UGT344C7, UGT344C9, UGT344N4, UGT 24541, and UGT7630, were up-regulated in the IMI_R clone compared to the IMI_S clone. Meanwhile, UGT344A16, UGT344B4, UGT344C7, and UGT344N4 were overexpressed at the protein level based on western blot analysis. Furthermore, knockdown of UGT344B4 or UGT344C7 using RNA interference (RNAi) significantly increased sensitivity to imidacloprid in the IMI_R clone. In conclusion, UGTs potentially contributed to imidacloprid resistance in A. gossypii originating from cotton-growing regions of China. These results provide insights into the way we study insecticide resistance in cotton aphids.


Assuntos
Afídeos/efeitos dos fármacos , Glucosiltransferases/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Afídeos/genética , Afídeos/metabolismo , Glucosiltransferases/genética , Resistência a Inseticidas/genética , Proteômica , Transcriptoma/genética
5.
Infect Dis Poverty ; 8(1): 64, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307509

RESUMO

BACKGROUND: The wetlands used for some agricultural activities constitute productive breeding sites for many mosquito species. Thus, the agricultural use of insecticide targeting other pests may select for insecticide resistance in malaria mosquitoes. The purpose of this study is to clarify some knowledge gaps on the role of agrochemicals in the development of insecticide resistance in malaria vectors is of utmost importance for vector control. METHODS: Using the CDC bottle test and the log-probit analysis, we investigated for the first time the resistance levels of Anopheles coluzzii mosquitoes to neonicotinoids, insecticides used exclusively for crop protection in Côte d'Ivoire. The study was conducted in two agricultural regions (Tiassale and Gagnoa) and one non-agricultural region (Vitre) between June and August 2017 using clothianidin, acetamiprid and imidacloprid. RESULTS: Mosquito populations from Tiassale and Gagnoa (agricultural settings) were determined to be resistant to acetamiprid with mortality rates being < 85% at 24 h post-exposure. In Vitre (non-agricultural area) however, the mosquito population was susceptible to acetamiprid. In all three localities, mosquito populations were resistant to imidacloprid (mortality rates were 60% in Vitre, 37% in Tiassale, and 13% in Gagnoa) and completely susceptible to clothianidin (100% mortality). An. coluzzii represented 100% of mosquito collected in Gagnoa, 86% in Tiassale and 96% in Vitre. CONCLUSIONS: This study provides strong evidence that agricultural use of insecticides can cause insecticide resistance in malaria vector populations. Insecticide resistance driven by agrochemical usage should be considered when vector control strategies are developed.


Assuntos
Anopheles/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Mosquitos Vetores/efeitos dos fármacos , Seleção Genética/efeitos dos fármacos , Animais , Anopheles/fisiologia , Costa do Marfim , Guanidinas/farmacologia , Mosquitos Vetores/fisiologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Tiazóis/farmacologia
6.
J Agric Food Chem ; 67(26): 7232-7242, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184888

RESUMO

In the present study, the effect of imidacloprid uptake from contaminated soils on the growth of leaf vegetable Shanghaiqing was investigated. The result showed that during 35-day exposure, the concentration of imidacloprid (IMI) was in the order of vegetable shoots > vegetable roots > soil, indicating that IMI was more readily concentrated in vegetable shoots than in roots. Moreover, the biomass of IMI-treated vegetable shoots was comparable to that of the controls with early exposure, but was higher than that of the controls after 7-day exposure, showing that the test concentration of IMI could stimulate vegetable growth. The plant metabolic analysis of vegetable shoots using LC-QTOF/MS revealed that IMI may cause oxidative stress to the plant shoots with early exposure; however, the stressful situation of IMI seems to be relieved with the increase of some substances (such as spermidine and phenylalanine) with late exposure. Moreover, the upregulation of N-rich amino acids (glutamine, aspartate, and arginine) suggested that the process of fixing inorganic nitrogen in the plant should be enhanced, possibly contributing to enhanced growth rates. Additionally, four IMI's metabolites were identified by using MS-FINDER software, and the distribution of three metabolites in vegetable tissues was compared.


Assuntos
Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Poluentes do Solo/farmacologia , Verduras/efeitos dos fármacos , Aminoácidos/metabolismo , Transporte Biológico/efeitos dos fármacos , Inseticidas/análise , Espectrometria de Massas , Neonicotinoides/análise , Nitrocompostos/análise , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Brotos de Planta/química , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/metabolismo , Solo/química , Poluentes do Solo/análise , Verduras/química , Verduras/crescimento & desenvolvimento , Verduras/metabolismo
7.
Pestic Biochem Physiol ; 157: 204-210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153470

RESUMO

Sulfoxaflor is the first commercially available sulfoximine insecticide, which exhibits highly efficacy against many sap-feeding insect pests and has been applied as an alternative insecticide against cotton aphid in China. This study was conducted to investigate the risk of resistance development, the cross-resistance pattern and the potential resistance mechanisms of sulfoxaflor in Aphis gossypii. A colony (SulR strain) of A. gossypii with 245-fold resistance, originated from Xinjiang field population, was established by continuous selection using sulfoxaflor. The SulR strain has developed cross-resistance to imidacloprid (80.8-fold), acetamiprid (19.3-fold), thiamethoxam (10.0-fold), and flupyradifurone (107.5-fold), while no cross-resistance was detected to malathion, omethoate, bifenthrin, methomyl, and carbosulfan. Piperonyl butoxide and S, S, S-tributyl phosphorotrithioate could significantly increase the toxicity of sulfoxaflor to the SulR strain by 5.99- and 4.18-fold, respectively, whereas no synergistic effect with diethyl maleate was observed. The activities of P450s and carboxylesterase were significantly higher in the SulR strain than that in the SS strain. Further gene expression determination demonstrated that nine P450 genes were significantly increased in SulR strain and suppression the expression of CYP6CY13 and CYP6CY19 by RNAi significantly increased the susceptibility of SulR adult aphids to sulfoxaflor. These results demonstrated that the enhancing detoxification by cytochrome P450 monooxygenase may be involved in A.gossypii resistance to sulfoxaflor.


Assuntos
Afídeos/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Piridinas/farmacologia , Compostos de Enxofre/farmacologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Afídeos/genética , Afídeos/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Piretrinas/farmacologia
8.
Pestic Biochem Physiol ; 157: 26-32, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153474

RESUMO

Nitenpyram is very effective in controlling Nilaparvata lugens (brown planthopper, BPH), and its resistance has been reported in field populations; however, the resistance mechanism remains unclear. In the present study, cross-resistance and resistance mechanisms in nitenpyram-resistant BPH were investigated. A resistant strain (NR) with a high resistance level (164.18-fold) to nitenpyram was evolved through successive selection for 42 generations from a laboratory susceptible strain (NS). The bioassay results showed that the NR exhibited cross-resistance to imidacloprid (37.46-fold), thiamethoxam (71.66-fold), clothianidin (149.17-fold), dinotefuran (98.13-fold), sulfoxaflor (47.24-fold), cycloxaprid (9.33-fold), etofenprox (10.51-fold) and isoprocarb (9.97-fold) but not to triflumezopyrim, chlorpyrifos and buprofezin. The NR showed a 3.21-fold increase in cytochrome P450 monooxygenase (P450) activity compared to that in the NS, while resistance was also synergized (4.03-fold) with the inhibitor piperonyl butoxide (PBO), suggesting a role of P450. Furthermore, the mRNA expression levels of cytochrome P450 (CYP) genes by quantitative real-time PCR results indicated that twelve P450 genes were significantly overexpressed in the NR strain, especially CYP6ER1 (203.22-fold). RNA interference (RNAi) suppression of CYP6ER1 through injection of dsCYP6ER1 led to significant susceptibility in the NR strain. The current study expands our understanding of the nitenpyram resistance mechanism in N. lugens, provides an important reference for integrated pest management (IPM), and enriches the theoretical system of insect toxicology.


Assuntos
Hemípteros/efeitos dos fármacos , Neonicotinoides/farmacologia , Animais , Carbamatos/farmacologia , Guanidinas/farmacologia , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Resistência a Inseticidas , Nitrocompostos/farmacologia , Piretrinas/farmacologia , Piridinas/farmacologia , Pirimidinonas/farmacologia , Interferência de RNA , Tiazóis/farmacologia
9.
J Cancer Res Clin Oncol ; 145(8): 2045-2050, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31250159

RESUMO

BACKGROUND: RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells. DESIGN: The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis. RESULTS: RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity. CONCLUSION: Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.


Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Citoproteção/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Neoplasias/patologia , Nitrocompostos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Apoptose/efeitos dos fármacos , Células CACO-2 , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
10.
Curr Top Med Chem ; 19(13): 1075-1091, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223089

RESUMO

BACKGROUND: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Nitrocompostos/farmacologia , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Adulto , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais Cultivadas
11.
Chemosphere ; 229: 392-400, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082706

RESUMO

Hippodamia variegata is one of the most abundant ladybird species in Greece, preying on several aphid species and other arthropods, of which many are pests of cultivated plants. Imidacloprid, a neonicotinoid insecticide, is commonly used for controlling sucking insects; at the same time, however, it can cause various sub-lethal effects on non-target organisms. The development of IPM programs against pests requires an evaluation of the side effects of insecticides on natural enemies. We evaluated the sub-lethal effects of imidacloprid on H. variegata. Our results demonstrate that imidacloprid at a LC10 (3.92 mg (a.i.) L-1 and LC30 (8.69 mg (a.i.) L-1) decreased adult longevity and survival rate. In addition, demographic parameters, such as the intrinsic rate of increase (r), finite rate of increase (λ) and net reproductive rate (R0), were reduced when exposed to sub-lethal concentrations of imidacloprid. These results demonstrate a negative influence of imidacloprid at sub-lethal concentrations on H. variegata which could reduce biological control services provided by this predator.


Assuntos
Besouros/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Controle Biológico de Vetores , Animais , Afídeos , Besouros/fisiologia , Grécia , Inseticidas/farmacologia , Inseticidas/toxicidade , Longevidade/efeitos dos fármacos , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Reprodução/efeitos dos fármacos
12.
Molecules ; 24(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109107

RESUMO

Nitric oxide-releasing aspirins (NO-aspirins) are aspirin derivatives that are safer than the parent drug in the gastrointestinal context and have shown superior cytotoxic effects in several cancer models. Despite the rationale for their design, the influence of nitric oxide (NO•) on the effects of NO-aspirins has been queried. Moreover, different isomers exhibit varying antitumor activity, apparently related to their ability to release NO•. Here, we investigated the effects and mode of action of NO-aspirins in non-small-cell lung cancer (NSCLC) cells, comparing two isomers, NCX4016 and NCX4040 (-meta and -para isomers, respectively). NCX4040 was more potent in decreasing NSCLC cell viability and migration and exhibited significant synergistic effects in combination with erlotinib (an epidermal growth factor receptor inhibitor) in erlotinib-resistant cells. We also studied the relationship among the effects of NO-aspirins, NO• release, and PGE2 levels. NCX4040 released more NO• and significantly decreased PGE2 synthesis relative to NCX4016; however, NO• scavenger treatment reversed the antiproliferative effects of NCX4016, but not those of NCX4040. By contrast, misoprostol (a PGE2 receptor agonist) significantly reversed the antiproliferative effect of NCX4040, but not those of NCX4016. Furthermore, misoprostol reversed the antimigratory effects of NCX4040. Overall, these results indicate that PGE2 inhibition is important in the mode of action of NO-aspirins.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Óxido Nítrico/metabolismo , Anti-Inflamatórios não Esteroides/química , Aspirina/análogos & derivados , Aspirina/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/química , Dinoprostona/biossíntese , Sinergismo Farmacológico , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Estrutura Molecular , Nitrocompostos/farmacologia
13.
Molecules ; 24(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959739

RESUMO

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman's spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood⁻brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer's disease.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Alcaloides/química , Butirilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Alcaloides/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Berberina/análogos & derivados , Berberina/química , Berberina/farmacologia , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/química , Inibidores da Colinesterase/química , Simulação por Computador , Corydalis/química , Dissacarídeos/química , Dissacarídeos/farmacologia , Humanos , Modelos Moleculares , Nitrocompostos/química , Nitrocompostos/farmacologia , Ligação Proteica/efeitos dos fármacos
14.
Pestic Biochem Physiol ; 156: 36-43, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31027579

RESUMO

Declines in honey bee populations represent a worldwide concern. The widespread use of neonicotinoid insecticides has been one of the factors linked to these declines. Sublethal doses of a neonicotinoid insecticide, imidacloprid, has been reported to cause olfactory learning deficits in honey bees via impairment of the target organ, the brain. In the present study, olfactory learning of honey bees was compared between controls and imidacloprid-treated bees. The brains of imidacloprid-treated and control bees were used for comparative transcriptome analysis by RNA-Seq to elucidate the effects of imidacloprid on honey bee learning capacity. The results showed that the learning performance of imidacloprid-treated bees was significantly impaired in comparison with control bees after chronic oral exposure to imidacloprid (0.02 ng/µl) for 11 days. Gene expression profiles between imidacloprid treatment and the control revealed that 131 genes were differentially expressed, of which 130 were downregulated in imidacloprid-treated bees. Validation of the RNA-Seq data using qRT-PCR showed that the results of qRT-PCR and RNA-Seq exhibited a high level of agreement. Gene ontology annotation indicated that the oxidation-reduction imbalance might exist in the brain of honey bees due to oxidative stress induced by imidacloprid exposure. KEGG and ingenuity pathway analysis revealed that transient receptor potential and Arrestin 2 in the phototransduction pathway were significantly downregulated in imidacloprid-treated bees, and that five downregulated genes have causal effects on behavioral response inhibition in imidacloprid-treated bees. Our results suggest that downregulation of brain genes involved in immune, detoxification and chemosensory responses may result in decreased olfactory learning capabilities in imidacloprid-treated bees.


Assuntos
Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Abelhas , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Oxirredução/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
15.
Chemosphere ; 226: 651-658, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30965243

RESUMO

Competition is a key structuring component of biological communities, which is affected by both biotic and abiotic environmental stressors. Among the latter, anthropic stressors and particularly pesticides are noteworthy due to their intrinsic toxicity and large use in agroecosystems. However this issue has been scarcely documented so far. In this context, we carried out experiments under laboratory conditions to evaluate stress imposed by the neonicotinoid insecticide imidacloprid on intra and interspecific competition among two major wheat pest aphids. The bird cherry-oat aphid Rhopalosiphum padi L. and the English grain aphid Sitobion avenae F. were subjected to competition on wheat seedlings under varying density combinations of both species and subjected or not to imidacloprid exposure. Intraspecific competition does take place without insecticide exposure, but so does interspecific competition between both aphid species with R. padi prevailing over S. avenae. Imidacloprid interfered with both intra and interspecific competition suppressing the former and even the latter for up to 14 days, but not afterwards when a shift in dominance takes place favoring S. avenae over R. padi, in contrast with the interspecific competition without imidacloprid exposure. These findings hinted that insecticides are indeed able to mediate species interaction and competition influencing community structure and raising management concerns for favoring potential secondary pest outbreaks.


Assuntos
Afídeos/classificação , Afídeos/crescimento & desenvolvimento , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Comportamento Competitivo/efeitos dos fármacos , Ecologia , Triticum/parasitologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-30889439

RESUMO

In order to elucidate the question whether resistance to nitro drugs in G. lamblia is due to common resistance markers, trophozoites of three resistant G. lamblia strains, namely C4, 1062ID10, and 713M3 were grown in the presence of the two nitro drugs metronidazole and nitazoxanide and compared to their corresponding wild-types WBC6, 106, and 713 by mass spectometry shotgun analysis of their proteomes. Depending on the strain and the nitro drug, more than 200 to 500 differentially expressed proteins were identified, but there were no common patterns across strains and drugs. All resistant strains underwent antigenic variation with distinct surface antigens like variant surface proteins or cysteine rich proteins depending on strain and nitro compound. A closer look on enzymes involved in nitroreduction and detoxification of nitro radicals, NO or O2 suggested the existence of distinct strategies for each drug and each strain. Therefore, we conclude that resistance to nitro drugs in G. lamblia is not correlated with a specific pattern of differentially expressed proteins and therefore seems not to be the result of a directed process.


Assuntos
Antiprotozoários/farmacologia , Resistência a Múltiplos Medicamentos , Giardia lamblia/efeitos dos fármacos , Nitrocompostos/farmacologia , Proteômica , Variação Antigênica , Marcadores Genéticos , Testes de Sensibilidade Parasitária
17.
J Pharmacol Exp Ther ; 369(3): 503-510, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894457

RESUMO

Underlying pathogenic mechanisms in chronic kidney disease (CKD) include chronic inflammation, oxidant stress, and matrix remodeling associated with dysregulated nuclear factor-κ B, nuclear factor-κ B, and SMAD signaling pathways, respectively. Important cytoprotective mechanisms activated by oxidative inflammatory conditions are mediated by nitrated fatty acids that covalently modify proteins to limit inflammation and oxidant stress. In the present study, we evaluated the effects of chronic treatment with CXA-10 (10-nitro-9(E)-octadec-9-enoic acid) in the uninephrectomized deoxycorticosterone acetate-high-salt mouse model of CKD. After 4 weeks of treatment, CXA-10 [2.5 millligrams per kilogram (mpk), p.o.] significantly attenuated increases in plasma cholesterol, heart weight, and kidney weight observed in the model without impacting systemic arterial blood pressure. CXA-10 also reduced albuminuria, nephrinuria, glomerular hypertrophy, and glomerulosclerosis in the model. Inflammatory MCP-1 and fibrosis (collagen, fibronectin, plasminogen activator inhibitor-1, and osteopontin) renal biomarkers were significantly reduced in the CXA-10 (2.5 mpk) group. The anti-inflammatory and antifibrotic effects, as well as glomerular protection, were not observed in the enalapril-treated group. Also, CXA-10 appears to exhibit hormesis as all protective effects observed in the low-dose group were absent in the high-dose group (12.5 mpk). Taken together, these findings demonstrate that, at the appropriate dose, the nitrated fatty acid CXA-10 exhibits anti-inflammatory and antifibrotic effects in the kidney and limits renal injury in a model of CKD.


Assuntos
Citoproteção/efeitos dos fármacos , Acetato de Desoxicorticosterona/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Rim/efeitos dos fármacos , Rim/patologia , Nitrocompostos/farmacologia , Ácidos Oleicos/farmacologia , Sais/efeitos adversos , Animais , Acetato de Desoxicorticosterona/farmacocinética , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Nitrocompostos/farmacocinética , Ácidos Oleicos/farmacocinética , Estresse Oxidativo/efeitos dos fármacos , Distribuição Tecidual
18.
Oncol Rep ; 41(5): 3127-3136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896840

RESUMO

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Nitrocompostos/farmacologia , Estirenos/farmacologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Nitrocompostos/química , Nitrocompostos/uso terapêutico , Cultura Primária de Células , Prognóstico , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade , Estirenos/química , Estirenos/uso terapêutico
19.
Ecotoxicol Environ Saf ; 175: 155-163, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30897414

RESUMO

A well-known strategy for managing pest resistance is application of mixture of pesticides. Conventionally formulated pesticides have several environmental incompatibilities. The use of biocompatible and biodegradable nanocarriers in formulating pesticides could improve environmental protection. In this study, a mixture of imidacloprid and lambda-cyhalothrin was co-encapsulated for the first time using liposomes as nanocarrier to simultaneously deliver these insecticides. Ethanol injection was used to produce self-assembled liposomes. The formed nanoliposomes were coated with different concentrations of chitosan. Nanoparticles were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM) and FT-IR spectroscopy. The encapsulation efficiencies of lambda-cyhalothrin and imidacloprid were about 93% and 51%, respectively. The insecticide carrying liposomes had a size and surface charge of 57 nm and +0.6 mV, respectively. The size and surface charge of the particles produced were increased to 69 nm and +31 mV after being coated with chitosan (0.1%, W/V). In this study, residual activity of technical grade imidacloprid, lambda-cyhalothrin and their mixture and the effect of adjuvants used in commercial and nano formulations of these insecticides on Myzus persicae Sulzer was investigated. The insecticidal effects and duration of residual activity of nano-formulations was correlated with concentration of chitosan in final formulation. In accordance with the life cycle of M. persicae, using the mixture of imidacloprid and lambda-cyhalothrin improves the residual effect over their use alone. The use of lipid nanocarriers makes the improvement even further and can be a better alternative to conventional combination of these insecticides due to their more environmental friendliness.


Assuntos
Afídeos/efeitos dos fármacos , Nanopartículas , Neonicotinoides/administração & dosagem , Nitrilos/administração & dosagem , Nitrocompostos/administração & dosagem , Piretrinas/administração & dosagem , Animais , Cápsulas , Imidazóis/administração & dosagem , Inseticidas/administração & dosagem , Lipossomos , Neonicotinoides/farmacologia , Nitrilos/farmacologia , Nitrocompostos/farmacologia , Praguicidas , Piretrinas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Reprod Fertil Dev ; 31(5): 1017-1032, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30836053

RESUMO

3-nitropropionic acid (3-NPA) is known to be a mitochondrial toxin produced by plants and fungi, which may produce DNA damage in cells. However, studies of its reproductive toxicology are lacking. We know that poly(ADP-ribose) polymerase (PARP) plays an important role in a large variety of physiological processes and is involved in DNA repair pathways. The present study was therefore aimed at exploring the involvement of PARP-1 activation and cleavage after 3-NPA stimulation in female mice. We observed an increased number of atretic follicles and multi-oocyte follicles (MOFs) after treatment with 3-NPA and serum concentrations of 17ß-oestradiol and progesterone were significantly reduced. Our results provide evidence that PARP-1 cleavage and activational signals are involved in pathological ovarian processes stimulated by 3-NPA. In addition, total superoxide dismutase, glutathione peroxidase and catalase activities were significantly increased, whereas succinate dehydrogenase was decreased in a dose-dependent manner. Results from our in vitro study similarly indicated that 3-NPA inhibited the proliferation of mouse granulosa cells and increased apoptosis in a dose-dependent manner. In summary, 3-NPA induces granulosa cell apoptosis, follicle atresia and MOFs in the ovaries of female mice and causes oxidative stress so as to disrupt endogenous hormonal systems, possibly acting through PARP-1 signalling.


Assuntos
Células da Granulosa/efeitos dos fármacos , Nitrocompostos/farmacologia , Oócitos/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Propionatos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Glutationa Peroxidase/metabolismo , Células da Granulosa/metabolismo , Camundongos , Oócitos/metabolismo , Folículo Ovariano/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Progesterona/sangue , Superóxido Dismutase/metabolismo
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