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1.
J Agric Food Chem ; 69(2): 638-645, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33398988

RESUMO

With widespread applications of the latest neonicotinoid in agriculture, dinotefuran has gradually become a hazardous contaminant for plants through the generation of excessive reactive oxygen species. However, the potential toxic mechanisms of oxidative damages to plants induced by dinotefuran are still unknown. As a core component of the glutathione antioxidant enzyme system, glutathione peroxidases have been used as biomarkers to reflect excessive oxidative stress. In this study, the hazardous effects of dinotefuran on AtGPX6 were investigated at the molecular level. The intrinsic fluorescence intensity of AtGPX6 was quenched using the static quenching mechanism upon binding with dinotefuran. Moreover, a single binding site was predicted for AtGPX6 toward dinotefuran, and the complex formation was presumed to be driven by hydrogen bonds or van der Waals forces, which conformed with the molecular docking results. In addition, AtGPX6 exhibited moderate binding affinity with dinotefuran based on the bio-layer interferometry assay. In addition, the loosening and unfolding of the protein skeleton of AtGPX6 with the addition of dinotefuran were explored along with the increase of hydrophobicity around tryptophan residues. Lastly, the toxic effects of dinotefuran on the root growth of Arabidopsis seedlings were also examined. The exploration of the binding mechanism of dinotefuran with AtGPX6 at the molecular level would provide the toxicity assessment of dinotefuran on plants.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/enzimologia , Guanidinas/farmacologia , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Arabidopsis/química , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Sítios de Ligação , Inseticidas/química , Simulação de Acoplamento Molecular , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Plântula/química , Plântula/efeitos dos fármacos , Plântula/enzimologia , Plântula/genética
2.
Food Chem ; 339: 127985, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920305

RESUMO

There is limited research focusing on the effects of human gut microbiota on the oral bioaccessibility and intestinal absorption of pesticide residues in food. In the present study, we use a modified setup of the Simulator of the Human Intestinal Microbial Ecosystem for the determination of pesticide residue bioaccessibility in Chaenomeles speciosa, and a Caco-2 cell model of human intestinal absorption. Results showed that gut microbiota played a dual role based their effects on contaminant release and metabolism in the bioaccessibility assay, and Lactobacillus plantarum was one of key bacterial species in the gut microbiota that influenced pesticide stability significantly. The addition of L. plantarum to the system reduced the relative amounts (by 11.40-86.51%) of six pesticides. The interaction between the food matrix and human gut microbiota led to different absorption rates, and the barrier effects increased with an increase in incubation time.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Praguicidas/farmacologia , Rosaceae/química , Bactérias/metabolismo , Células CACO-2 , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Lactobacillus plantarum/efeitos dos fármacos , Lactobacillus plantarum/isolamento & purificação , Neonicotinoides/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Compostos Organotiofosforados/metabolismo , Compostos Organotiofosforados/farmacologia , Praguicidas/química , Praguicidas/metabolismo , Rosaceae/metabolismo , Tiametoxam/metabolismo , Tiametoxam/farmacologia
3.
J Agric Food Chem ; 68(52): 15403-15408, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33337883

RESUMO

The importance of glutathione S-transferases (GSTs) in imidacloprid resistance in Nilaparvata lugens, a major rice pest, and other insects was often excluded, mostly due to the slight effects of diethyl maleate (DEM) on synergizing imidacloprid in resistant populations. Here, we found that the synergistic effects of DEM were time-dependent. At 24 or 48 h, the time often selected to record mortalities in imidacloprid bioassay, DEM really did not cause an obvious increase in imidacloprid toxicity. However, significant effects were observed after 72 h. The results revealed that GSTs, as phase II detoxification enzymes to metabolize secondary products generated from phase I detoxification enzymes, were also important in imidacloprid resistance in N. lugens, but might have occurred a little later than that of P450s and CarEs as phase I enzymes. The constitutive overexpression in the imidacloprid-resistant strain G25 and expression induction by imidacloprid in the susceptible strain S25 indicated that four GST genes, NlGSTs1, NlGSTs2, NlGSTe1, and NlGSTm1, were important in imidacloprid resistance, which was confirmed by RNAi test. The higher expression levels and more expression induction by imidacloprid in the midgut and fat body compared to the whole insect supported the important roles of these four GSTs, which was also supported by the more overexpression times in the midgut and fat body versus the whole insect between G25 and S25 strains. Taking the data together, the study ascertained the roles of GSTs in imidacloprid resistance in N. lugens.


Assuntos
Glutationa Transferase/metabolismo , Hemípteros/enzimologia , Proteínas de Insetos/metabolismo , Resistência a Inseticidas , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Hemípteros/efeitos dos fármacos , Hemípteros/metabolismo , Inseticidas/química , Inseticidas/metabolismo , Neonicotinoides/química , Neonicotinoides/metabolismo , Nitrocompostos/química , Nitrocompostos/metabolismo
4.
PLoS One ; 15(9): e0238601, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881961

RESUMO

Canines are proven reservoir hosts of Leishmania infantum, the causative agent of human zoonotic visceral leishmaniasis, and therefore domestic dogs play a central role in transmitting the disease to humans. Studies on the effect of insecticide-impregnated dog collars for controlling canine visceral leishmaniasis (CanL) have been increasing; however, meta-analysis has not been conducted. This study assessed the effectiveness of insecticide-impregnated dog collars for preventing CanL. We searched (PubMed, Web of Science, Scopus, Embase, Ovid Medline(R), and Cochrane library), from inception until 2 May 2020. Two authors independently performed articles screening and data extraction. We applied the RoB 2.0 tool to evaluate the risk of bias in randomized trials, while the ROBINS-I tool was used for non-randomized trials. I-squared statistics(I2) and funnel plot and Egger's test, respectively, were used to assesses heterogeneity between studies and publication bias. Relative Risk (RR) and 95% Confidence Interval (CI) were calculated using the random-effects model in Stata 14 software. Out of 242 citations identified, 14 studies comprising 3786 collared dogs and 3428 uncollared dogs were eligible for meta-analysis. The use of deltamethrin-impregnated dog collars(DMC) showed an overall effectiveness of 54% (95%CI: 35-65%, I2 = 63.2%, P = 0.002) in decreasing incidence of CanL, while 10% imidacloprid and 4.5% flumethrin collars provided an overall effectiveness of 90% (95%CI: 80-96%, I2 = 0.0%, P = 0.376). DMC efficacy stratified by follow-up duration was estimated to be 58% (RR = 0.42, 95%CI: 0.20-0.87), 54% (RR = 0.46, 95%CI: 0.31-0.68), 53% (RR = 0.47, 95%CI: 0.29-0.82) for follow-up periods of 5 to 6 months, 1 year and 2 years, respectively. The current evidence indicates that using insecticide-impregnated dog collars can reduce the risk of CanL caused by L. infantum. Therefore, insecticide-impregnated dog collars could be a viable alternative for inclusion as a public health measure for controlling CanL.


Assuntos
Doenças do Cão/prevenção & controle , Inseticidas/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/prevenção & controle , Administração Cutânea , Animais , Doenças do Cão/parasitologia , Cães , Leishmaniose Visceral/veterinária , Neonicotinoides/farmacologia , Nitrilos/farmacologia , Nitrocompostos/farmacologia , Piretrinas/farmacologia
5.
Chemosphere ; 259: 127490, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32650166

RESUMO

Insect resistance to chemical insecticide is a global problem that presents an ongoing threat to sustainable agriculture. Although the increased production of detoxification enzymes has been frequently implicated in resistance development, the mechanisms employed by insecticide-resistant insects for overexpression of these genes remain elusive. Here we report that neuropeptide adipokinetic hormone (AKH) negatively regulates the expression of CYP6ER1 and CYP6AY1, two important cytochrome P450 monooxygenases (P450s) that confer resistance to neonicotinoid imidacloprid in the brown planthopper (BPH). Imidacloprid exposure suppresses AKH synthesis in the susceptible BPH, and AKH is inhibited in the imidacloprid-resistant strain. RNA interference (RNAi) and AKH peptide injection revealed that imidacloprid exposure inhibits the AKH signaling cascade and then provokes reactive oxygen species (ROS) burst. These in turn activate the transcription factors cap 'n' collar isoform-C (CncC) and muscle aponeurosis fibromatosis (MafK). RNAi and ROS scavenger assays showed that ROS induces CYP6ER1 expression by activating CncC and MafK, while ROS mediates induction of CYP6AY1 through another unidentified pathway in the resistant BPH. Collectively, these results provide new insights into the regulation of insecticide resistance and implicate both the neuropeptide AKH-mediated ROS burst and transcription factors are involved in the overexpression of P450 detoxification genes in insecticide-resistant insects.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Hemípteros/química , Hormônios de Inseto/fisiologia , Resistência a Inseticidas/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Oligopeptídeos/fisiologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Animais , Família 6 do Citocromo P450/metabolismo , Hemípteros/fisiologia , Imidazóis/metabolismo , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/fisiologia
6.
Proc Natl Acad Sci U S A ; 117(19): 10246-10253, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32327610

RESUMO

The evolution of insect resistance to pesticides poses a continuing threat to agriculture and human health. While much is known about the proximate molecular and biochemical mechanisms that confer resistance, far less is known about the regulation of the specific genes/gene families involved, particularly by trans-acting factors such as signal-regulated transcription factors. Here we resolve in fine detail the trans-regulation of CYP6CM1, a cytochrome P450 that confers resistance to neonicotinoid insecticides in the whitefly Bemisia tabaci, by the mitogen-activated protein kinase (MAPK)-directed activation of the transcription factor cAMP-response element binding protein (CREB). Reporter gene assays were used to identify the putative promoter of CYP6CM1, but no consistent polymorphisms were observed in the promoter of a resistant strain of B. tabaci (imidacloprid-resistant, IMR), which overexpresses this gene, compared to a susceptible strain (imidacloprid-susceptible, IMS). Investigation of potential trans-acting factors using in vitro and in vivo assays demonstrated that the bZIP transcription factor CREB directly regulates CYP6CM1 expression by binding to a cAMP-response element (CRE)-like site in the promoter of this gene. CREB is overexpressed in the IMR strain, and inhibitor, luciferase, and RNA interference assays revealed that a signaling pathway of MAPKs mediates the activation of CREB, and thus the increased expression of CYP6CM1, by phosphorylation-mediated signal transduction. Collectively, these results provide mechanistic insights into the regulation of xenobiotic responses in insects and implicate both the MAPK-signaling pathway and a transcription factor in the development of pesticide resistance.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Medicamentos/genética , Regulação da Expressão Gênica , Hemípteros/crescimento & desenvolvimento , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Sistema Enzimático do Citocromo P-450/genética , Hemípteros/efeitos dos fármacos , Hemípteros/genética , Hemípteros/metabolismo , Inseticidas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Fosforilação , Regiões Promotoras Genéticas
7.
Sci Rep ; 10(1): 5713, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235887

RESUMO

Imidacloprid (IMI) is one of the most frequently used neonicotinoid insecticides, but recent studies have shown adverse effects on mammals. IMI was found to be neurotoxic and hepatotoxic. In the present study, the effects of repeated oral administration of two doses of IMI (5 and 20 mg/kg/day) for 28 days on hippocampus and liver of female KM mice were studied. The histopathological and biochemical experiments indicated obvious damages to the hippocampus and liver of mice in the high-dose group (20 mg/kg/day). Using a high-throughput metabolomics platform based on ultrahigh performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS), we studied effects of IMI on metabolic profiles in the hippocampus and liver of mice. Significant differences among the control group, the low-dose group and the high-dose group were clearly presented using multivariate analysis. The changed metabolic profile in the low-dose group (5 mg/kg/day) revealed that the metabolic disturbance in the hippocampus and liver of mice had been induced by low-dose of IMI, although no significant histopathological changes were observed in the low-dose group. Six differential metabolites in the hippocampus and 10 differential metabolites in the liver were identified as the possible biomarkers to distinguish IMI exposure from the control group using the variable importance in projection (VIP) value and receiver operating characteristic (ROC) analysis. The metabolism disturbances of important biochemical pathways in the hippocampus and liver of mice in the exposed groups were elucidated, mostly concentrated in lipid metabolism, amino acid metabolism, nucleotide metabolism, carbohydrate metabolism, and energy metabolism (p < 0.05). Such investigations give out a global view of IMI-induced damages in the hippocampus and liver of mice and imply a health risk associated with early metabolic damage in mice.


Assuntos
Hipocampo/efeitos dos fármacos , Inseticidas/farmacologia , Fígado/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Metabolismo dos Carboidratos/efeitos dos fármacos , Cromatografia Líquida , Metabolismo Energético/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Espectrometria de Massas , Metabolômica , Camundongos
8.
Pharmacol Rep ; 72(1): 225-237, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016856

RESUMO

BACKGROUND: Hyperactivation of blood platelets is an essential factor in the pathomechanism of diabetes-evoked angiopathies. The aim of this work was to investigate whether blood platelets hyperactivation resulting from type 2 diabetic hyperglycaemia-increased pyruvate dehydrogenase complex activity and excessive acetyl-CoA accumulation may be brought to the normal range by the enzyme inhibitors. METHODS: Platelets were isolated from the blood of 9 type 2 diabetic patients and 10 healthy donors. Effects of 3-bromopyruvate and 3-nitropropionate on pyruvate dehydrogenase complex (PDHC) and succinate dehydrogenase activities, as well as levels of acetyl-CoA, ATP, thiobarbituric acid reactive species and aggregation were assessed in non-activated and thrombin-activated platelets. RESULTS: In type 2 diabetic patients fasting plasma glucose and fructosamine levels were 61 and 64% higher, respectively, than in the healthy group (p < 0.001). In non-activated diabetic platelets PDHC activity, PDHC-E2, acetyl-CoA and ATP levels were 66, 70, 68 and 60%, higher, respectively, than in platelets from healthy controls (p < 0.01). 3-bromopyruvate (0.1 mM) decreased pyruvate dehydrogenase activity in healthy and diabetic platelets by 42% and 59%, respectively. Similar inhibitory effects were observed for acetyl-CoA and ATP levels, aggregation and TBARS accumulation rates. Succinate dehydrogenase activity was inhibited by 3-nitropropionate (10 mM) to 38 and 41% of control values in healthy and diabetic platelets, respectively, but affected neither function nor acetyl-CoA metabolism in platelets of both groups. CONCLUSIONS: These data indicate that inhibition of pyruvate dehydrogenase excessive activity in diabetic platelets by 3-bromopyruvate may normalise their functional parameters through adjustment of acetyl-CoA/ATP levels to control values. Platelets from blood of diabetic patients display higher activities of pyruvate dehydrogenase complex (PDHC), higher levels of dihydrolipoate transacetylase (DLAT, E2 subunit of PDHC) as well as higher levels of acetyl-CoA yielding greater ATP/ADP accumulation than in platelets of normoglycemic subjects. Therefore, in diabetic platelets, thrombin caused higher release of ATP/ADP triggering excessive production of reactive oxygen species (ROS) and stronger aggregation compared to control platelets. In diabetic platelets, relative excess of DLAT in PDHC made them highly susceptible to 3-bromopyruvate (3BrP) inhibition. Resulting limitation of acetyl-CoA provision by 3-BrP normalised activity of diabetic platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Complexo Piruvato Desidrogenase/antagonistas & inibidores , Piruvatos/farmacologia , Acetilcoenzima A/metabolismo , Trifosfato de Adenosina/metabolismo , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/fisiopatologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrocompostos/farmacologia , Propionatos/farmacologia , Succinato Desidrogenase/metabolismo
9.
Int J Mol Sci ; 21(2)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963875

RESUMO

The existence of a temperature effect of insecticides frustrated the control of the green plant bug Apolygus lucorum (Meyer-Dür). Previous studies mostly focused on the application of insecticides, but the underlying mechanism remains incompletely understood. Here, we report a transcriptome profiling of A. lucorum treated by three kinds of temperature coefficient insecticides (TCIs) (positive TCI: imidacloprid, negative TCI: b-cypermethrin and non-effect TCI: phoxim) at 15 °C, 25 °C and 35 °C by using next- and third-generation RNA-Seq methods. A total of 34,739 transcripts were annotated from 277.74 Gb of clean data. There were more up-regulated transcripts than down-regulated transcripts in all three kinds of TCI treatments. Further Venn diagrams indicate the regulatory transcripts and regulatory modes were different at the three temperatures. The responses to imidacloprid involved more detox and stress response transcripts such as cytochrome P450 (CYP450), carboxylesterase (CarE) and catalase (CAT) at 35 °C, which was the case for beta-cypermethrin at 15 °C. UDP-glucuronyltransferase (UGT) and heat shock protein (HSP) transcripts were heavily involved, and thus deserve particular note in the temperature effect of insecticides. This high-confidence transcriptome atlas provides improved gene information for further study on the insecticide temperature effect related physiological and biochemical processes of A. lucorum.


Assuntos
Perfilação da Expressão Gênica/métodos , Heterópteros/crescimento & desenvolvimento , Proteínas de Insetos/genética , Inseticidas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Heterópteros/efeitos dos fármacos , Heterópteros/genética , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência Molecular , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Compostos Organotiofosforados/farmacologia , Piretrinas/farmacologia , Análise de Sequência de RNA , Temperatura
10.
Chemistry ; 26(32): 7219-7225, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31984562

RESUMO

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids-a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure-activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug-target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.


Assuntos
Antibacterianos/síntese química , Asparagina/análogos & derivados , Bactérias Gram-Negativas/efeitos dos fármacos , Nitrocompostos/química , Antibacterianos/química , Antibacterianos/farmacologia , Asparagina/química , Asparagina/farmacologia , Bactérias Gram-Negativas/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Nitrocompostos/farmacologia , Relação Estrutura-Atividade
11.
Sci Rep ; 10(1): 226, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937822

RESUMO

The mirid bug, Apolygus lucorum, has become a major pest of many crops and fruit trees since the widespread adoption of Bt cotton in northern China. Neonicotinoid insecticides, such as dinotefuran, applied to control this pest may show sublethal effects, but evidence for such effects is lacking. Here, we investigated the sublethal and transgenerational effects of dinotefuran on biological parameters and feeding behavioural traits of A. lucorum using the age-stage, two-sex life table and electrical penetration graphs (EPGs), respectively. The LC10 and LC30 of dinotefuran against 3rd-instar nymphs of A. lucorum were 14.72 and 62.95 mg L-1, respectively. These two concentrations significantly extended the development duration from 3rd-instar nymph to adult in parent generation (F0). LC30 also increased the oviposition period and male adult longevity and reduced nymphal survival rate in the F0. For offspring generation (F1), the egg duration, preadult duration, and total preoviposition period were significantly lower at LC10 than in the control, and the egg duration, duration of 4th-instar nymphs, preadult duration, oviposition period, and fecundity were also decreased at LC30. However, the four demographic parameters of F1 generation, namely, net reproductive rate (R0), intrinsic rate of increase (r), finite rate of increase (λ), and mean generation time (T), were not affected by dinotefuran. The significant differences in the number of probes and duration of each of four feeding waveforms failed to be detected when A. lucorum nymphs treated by dinotefuran feed on Bt cotton plants without insecticide exposure. Overall, the dinotefuran concentrations tested here have sublethal, but no transgenerational impacts on A. lucorum.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Guanidinas/farmacologia , Heterópteros/fisiologia , Longevidade , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Oviposição/efeitos dos fármacos , Reprodução , Animais , Heterópteros/efeitos dos fármacos , Inseticidas/farmacologia , Ninfa/efeitos dos fármacos , Ninfa/fisiologia
12.
BMC Ophthalmol ; 20(1): 28, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941474

RESUMO

BACKGROUND: Corneal infections with antibiotic-resistant microorganisms are an increasingly difficult management challenge and chemically or photochemically cross-linking the cornea for therapy presents a unique approach to managing such infections since both direct microbial pathogens killing and matrix stabilization can occur simultaneously. The present study was undertaken in order to compare the anti-microbial efficacy, in vitro, of 5 candidate cross-linking solutions against 5 different microbial pathogens with relevance to infectious keratitis. METHODS: In vitro bactericidal efficacy studies were carried out using 5 different FARs [diazolidinyl urea (DAU), 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDM), sodium hydroxymethylglycinate (SMG), 2-(hydroxymethyl)-2-nitro-1,3-propanediol (NT = nitrotriol), 2-nitro-1-propanol (NP)] against 5 different microbial pathogens including two antibiotic-resistant species [methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Pseudomonas aeruginosa (PA), and Candida albicans (CA)]. Standard in vitro antimicrobial testing methods were used. RESULTS: The results for MSSA were similar to those for MRSA. DAU, DMDM, and SMG all showed effectiveness with greater effects generally observed with longer incubation times and higher concentrations. Against MRSA, 40 mM SMG at 120 min showed a > 95% kill rate, p < 0.02. Against VRE, 40 mM DAU for 120 min showed a > 94% kill rate, p < 0.001. All FARs showed bactericidal effect against Pseudomonas aeruginosa, making PA the most susceptible of the strains tested. Candida showed relative resistance to these compounds, requiring high concentrations (100 mM) to achieve kill rates greater than 50%. CONCLUSION: Our results show that each FAR compound has different effects against different cultures. Our antimicrobial armamentarium could potentially be broadened by DAU, DMDM, SMG and other FARs for antibiotic-resistant keratitis. Further testing in live animal models are indicated.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Formaldeído/metabolismo , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Resistência a Medicamentos , Farmacorresistência Bacteriana , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Testes de Sensibilidade Microbiana , Nitrocompostos/farmacologia , Propanóis/farmacologia , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Trometamina/análogos & derivados , Trometamina/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
13.
Eur J Med Chem ; 186: 111829, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757526

RESUMO

The implication of DNA methylation in cancer is today clearly established. Despite that nucleoside analogues are currently used for leukaemia treatment, their low stability in physiological conditions and their lack of selectivity arise the need for the identification of non-nucleoside DNA methyltransferase inhibitors. Here, we describe the synthesis and pharmacological characterisation of a novel class of DNA methyltransferase inhibitors: the 3-halo-3-nitroflavanones. We showed that 3-bromo-3-nitroflavanones 3b and 4a have a micromolar DNMT inhibition and an increased potency in a cell reporter model. Interestingly they are significantly more stable than the reference compounds and induce a low cytotoxicity, supporting them as new candidates for the development of non-cytotoxic cell-reprogramming epi-drugs for anticancer treatment.


Assuntos
Antineoplásicos/farmacologia , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Flavanonas/farmacologia , Nitrocompostos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavanonas/química , Células HCT116 , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade
14.
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
15.
Arch Insect Biochem Physiol ; 103(3): e21630, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31621115

RESUMO

The Colorado potato beetle (Leptinotarsa decemlineata) is a major agricultural pest of solanaceous crops. An effective management strategy employed by agricultural producers to control this pest species is the use of systemic insecticides. Recent emphasis has been placed on the use of neonicotinoid insecticides. Despite efforts to curb resistance development through integrated pest management approaches, resistance to neonicotinoids in L. decemlineata populations continues to increase. One contributing factor may be alterations in insect fatty acids, which have multiple metabolic functions and are associated with the synthesis of xenobiotic-metabolizing enzymes to mitigate the effects of insecticide exposure. In this study, we analyzed the fatty acid composition of L. decemlineata populations collected from an organic production field and from a commercially managed field to determine if fatty acid composition varied between the two populations. We demonstrate that a population of L. decemlineata that has a history of systemic neonicotinoid exposure (commercially managed) has a different lipid composition and differential expression of known metabolic detoxification mechanisms relative to a population that has not been exposed to neonicotinoids (organically managed). The fatty acid data indicated an upregulation of Δ6 desaturase in the commercially managed L. decemlineata population and suggest a role for eicosanoids and associated metabolic enzymes as potential modulators of insecticide resistance. We further observed a pattern of delayed emergence within the commercially managed population compared with the organically managed population. Variations in emergence timing together with specific fatty acid regulation may significantly influence the capacity of L. decemlineata to develop insecticide resistance.


Assuntos
Besouros/efeitos dos fármacos , Ácidos Graxos/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Resistência a Inseticidas/genética , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Besouros/enzimologia , Ácidos Graxos/metabolismo , Inseticidas/farmacologia
16.
Acta Trop ; 202: 105256, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31682815

RESUMO

In recent years, attractive toxic sugar bait has been used in the mosquito control in nature, and achieved good control effects. However, the current researches about toxic sugar bait did not focus on whether the wild mosquito population used for control is resistant or not. The purpose of this study was to evaluate the effectiveness of the toxic sugar bait against mosquito resistant populations to test the effects of bait on the control of mosquitoes with different levels of resistance. Boric acid, dinotefuran and deltamethrin were separately formulated into toxic sugar bait to test their anti-mosquito activity against Culex quinquefasciatus. Using the sugar baits formulated with boric acid and dinotefuran, the mortality of Cx. quinquefasciatus resistant populations was significantly higher than that of sensitive populations at the same concentration. Conversely, with the use of sugar baits formulated with deltamethrin, the mortality of Cx. quinquefasciatus resistant populations was significantly lower than that of sensitive populations at the same concentration. The results suggested that toxic sugar baits might have a good application prospect in high resistant mosquito management.


Assuntos
Culex/efeitos dos fármacos , Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacologia , Açúcares , Animais , Ácidos Bóricos/administração & dosagem , Ácidos Bóricos/farmacologia , Feminino , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Inseticidas/administração & dosagem , Controle de Mosquitos/métodos , Neonicotinoides/administração & dosagem , Neonicotinoides/farmacologia , Nitrilos/administração & dosagem , Nitrilos/farmacologia , Nitrocompostos/administração & dosagem , Nitrocompostos/farmacologia , Piretrinas/administração & dosagem , Piretrinas/farmacologia
17.
Folia Microbiol (Praha) ; 65(2): 393-405, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31401762

RESUMO

Nosocomial infections are an important cause of morbi-mortality worldwide. The increase in the rate of resistance to conventional drugs in these microorganisms has stimulated the search for new therapeutic options. The nitro moiety (NO2) is an important pharmacophore of molecules with high anti-infective activity. We aimed to synthesize new nitro-derivates and to evaluate their antibacterial and anti-Candida potential in vitro. Five compounds [3-nitro-2-phenylchroman-4-ol (3); 3-nitro-2-phenyl-2H-chromene (4a); 3-nitro-2-(4-chlorophenyl)-2H-chromene (4b); 3-nitro-2-(4-fluorophenyl)-2H-chromene (4c), and 3-Nitro-2-(2,3-dichlorophenyl)-2H-chromene (4d)] were efficiently synthesized by Michael-aldol reaction of 2-hydroxybenzaldehyde with nitrostyrene, resulting in one ß-nitro-alcohol (3) and four nitro-olefins (4a-4d). The antibacterial and anti-Candida potentials were evaluated by assaying minimal inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and minimum bactericidal concentration (MBC). Mono-halogenated nitro-compounds (4b and 4c) showed anti-staphylococcal activity with MIC values of 15.6-62.5 µg/mL and MBC of 62.5 µg/mL. However, the activity against Gram-negative strains was showed to be considerably lower and our data suggests that this effect was associated with the outer membrane. Furthermore, nitro-compounds 4c and 4d presented activity against Candida spp. with MIC values ranging from 7.8-31.25 µg/mL and MFC of 15.6-500 µg/mL. In addition, these compounds were able to induce damage in fungal cells increasing the release of intracellular material, which was associated with actions on the cell wall independent of quantitative changes in chitin and ß-glucan. Together, these findings show that nitro-compounds can be exploited as anti-staphylococcal and anti-Candida prototypes.


Assuntos
Anti-Infecciosos/farmacologia , Nitrocompostos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Candida/efeitos dos fármacos , Candida/crescimento & desenvolvimento , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Nitrocompostos/síntese química , Nitrocompostos/química
18.
Insect Mol Biol ; 29(1): 92-103, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31456272

RESUMO

Ninety-four putative G protein-coupled receptors (GPCRs) were identified in the Musca domestica genome. They were annotated and compared with their homologues in Drosophila melanogaster. Phylogenetic analyses of the GPCRs from both species revealed that several family members shared a closer relationship based on the domain architecture. The expression profiles of these genes were examined by quantitative real-time PCR amongst three strains of the house fly, a near-isogenic line strain with imidacloprid resistance (N-IRS), the corresponding susceptible strain (CSS) and another strain derived from field populations with imidacloprid resistance (IRS). We found that five GPCR genes were upregulated in the N-IRS and eight GPCR genes were upregulated in the IRS strains compared to the CSS strain. The transgenic lines of D. melanogaster with the GPCR genes (LOC101899380 in the N-IRS strain and LOC101895664 in the IRS strain) exhibited significantly increased tolerance to imidacloprid, and higher expression of cytochrome P450 genes. Bioinformatic analysis of LOC101899380 was carried out based on its full-length nucleic acid sequence and putative amino acid sequence, and it was named Methuselah-like10 (Mthl10) owing to its homology with D. melanogaster Mthl10. A cell-base cell counting kit-8 toxicity assay demonstrated that the expression of the GPCR gene LOC101899380 in Spodoptera frugiperda (Sf9) cells using a baculovirus-mediated expression system can elevate the cell tolerance to imidacloprid, indirectly supporting the hypothesis that the GPCR gene LOC101899380 plays some role in imidacloprid resistance. These results should be useful for furthering understanding of the regulatory pathway by which house flies develop resistance.


Assuntos
Moscas Domésticas/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Receptores de Superfície Celular/genética , Animais , Animais Geneticamente Modificados , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Drosophila melanogaster/genética , Moscas Domésticas/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Células Sf9
19.
Molecules ; 24(24)2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31847419

RESUMO

Carbohydrates are abundant renewable resources and are a feedstock for green chemistry and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass, mannitol was selected in the present project as a valuable platform, directly available from the chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic Michael addition of dimethyl malonate, ß-keto esters, and other nucleophiles on the nitro alkene afforded high stereoselectivity and densely functionalized chiral molecules, which were further synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation of enantiomerically pure organic molecules from the chiral pool.


Assuntos
Manitol/química , Nitrocompostos/química , Catálise , Técnicas de Química Sintética , Teoria da Densidade Funcional , Ésteres , Espectroscopia de Ressonância Magnética , Manitol/análogos & derivados , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/farmacologia , Estereoisomerismo
20.
Genes (Basel) ; 10(12)2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31757092

RESUMO

Aphids cause serious losses to the production of wheat. The grain aphid, Sitobion avenae, which is the dominant species of aphid in all wheat regions of China, is resistant to a variety of insecticides, including imidacloprid and chlorpyrifos. However, the resistance and mechanism of insecticide tolerance of S. avenae are still unclear. Therefore, this study employed transcriptome analysis to compare the expression patterns of stress response genes under imidacloprid and chlorpyrifos treatment for 15 min, 3 h, and 36 h of exposure. S. avenae adult transcriptome was assembled and characterized first, after which samples treated with insecticides for different lengths of time were compared with control samples, which revealed 602267 differentially expressed unigenes (DEUs). Among these DEUs, 31-790 unigenes were classified into 66-786 categories of gene ontology (GO) functional groups, and 24-760 DEUs could be mapped into 54-268 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, 11 insecticide-tolerance-related unigenes were chosen to confirm the relative expression by quantitative real-time polymerase chain reaction (qRT-PCR) in each treatment. Most of the results between qRT-PCR and RNA sequencing (RNA-Seq) are well-established. The results presented herein will facilitate molecular research investigating insecticide resistance in S. avenae, as well as in other wheat aphids.


Assuntos
Afídeos/genética , Resistência a Inseticidas/genética , Animais , Afídeos/efeitos dos fármacos , Clorpirifos/farmacologia , Perfilação da Expressão Gênica , Genes de Insetos , Inseticidas/farmacologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Transcriptoma/efeitos dos fármacos
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