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1.
Pestic Biochem Physiol ; 170: 104686, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980070

RESUMO

New insecticides are urgently needed for the control of arthropod vectors of public health diseases. As resistance to many insecticides used for the control of public health pests is ubiquitous, all available chemistries should be evaluated for their potential to effectively control both insecticide-susceptible and insecticide-resistant strains of mosquitoes. This study aimed to evaluate p-p'-difluoro-diphenyl-trichloroethane (DFDT) as a mosquito control technology and relate its activity to that of DDT. We found that topical DFDT was significantly less toxic than DDT to both pyrethroid-susceptible and pyrethroid-resistant strains of Anopheles gambiae and Aedes aegypti. Direct nervous system recording from Drosophila melanogaster CNS demonstrated that DFDT is approximately 10-times less potent than DDT at blocking nerve firing, which may explain its relatively lower toxicity. DFDT was shown to be at least 4500 times more vapor-active than DDT, with an LC50 in a vapor toxicity screening assay of 2.2 µg/cm2. Resistance to DFDT was assessed in two mosquito strains that possess target-site mutations in the voltage-gated sodium channel and upregulated metabolic activity. Resistance ratios for Akdr (An. gambiae) and Puerto Rico (Ae. aegypti) strains were 9.2 and 12.2, respectively. Overall, this study demonstrates that DFDT is unlikely to be a viable public health vector control insecticide.


Assuntos
Aedes/efeitos dos fármacos , Inseticidas/farmacologia , Inseticidas/toxicidade , Piretrinas/toxicidade , Animais , Compostos de Bifenilo , DDT/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Resistência a Inseticidas/efeitos dos fármacos , Mosquitos Vetores , Porto Rico , Tricloroetanos
2.
Nat Commun ; 11(1): 4608, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929085

RESUMO

Actinobacteria produce antibacterial and antifungal specialized metabolites. Many insects harbour actinobacteria on their bodies or in their nests and use these metabolites for protection. However, some actinobacteria produce metabolites that are toxic to insects and the evolutionary relevance of this toxicity is unknown. Here we explore chemical interactions between streptomycetes and the fruit fly Drosophila melanogaster. We find that many streptomycetes produce specialized metabolites that have potent larvicidal effects against the fly; larvae that ingest spores of these species die. The mechanism of toxicity is specific to the bacterium's chemical arsenal: cosmomycin D producing bacteria induce a cell death-like response in the larval digestive tract; avermectin producing bacteria induce paralysis. Furthermore, low concentrations of volatile terpenes like 2-methylisoborneol that are produced by streptomycetes attract fruit flies such that they preferentially deposit their eggs on contaminated food sources. The resulting larvae are killed during growth and development. The phenomenon of volatile-mediated attraction and specialized metabolite toxicity suggests that some streptomycetes pose an evolutionary risk to insects in nature.


Assuntos
Bactérias/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/microbiologia , Actinobacteria/fisiologia , Animais , Antraciclinas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Canfanos/toxicidade , Morte Celular/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/microbiologia , Metaboloma , Esporos Bacterianos/metabolismo , Esporos Bacterianos/fisiologia , Streptomyces/fisiologia , Análise de Sobrevida , Compostos Orgânicos Voláteis/farmacologia
3.
Pestic Biochem Physiol ; 169: 104674, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32828379

RESUMO

There is an on-going need to develop new insecticides that are not compromised by resistance and that have improved environmental profiles. However, the cost of developing novel compounds has increased significantly over the last two decades. This is in part due to increased regulatory requirements, including the need to screen both pest and pollinator insect species to ensure that pre-existing resistance will not hamper the efficacy of a new insecticide via cross-resistance, or adversely affect non-target insect species. To add to this problem the collection and maintenance of toxicologically relevant pest and pollinator species and strains is costly and often difficult. Here we present Fly-Tox, a panel of publicly available transgenic Drosophila melanogaster lines each containing one or more pest or pollinator P450 genes that have been previously shown to metabolise insecticides. We describe the range of ways these tools can be used, including in predictive screens to avoid pre-existing cross-resistance, to identify potential resistance-breaking inhibitors, in the initial assessment of potential insecticide toxicity to bee pollinators, and identifying harmful pesticide-pesticide interactions.


Assuntos
Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacologia , Animais , Animais Geneticamente Modificados , Abelhas , Sistema Enzimático do Citocromo P-450 , Drosophila melanogaster/efeitos dos fármacos
4.
J Oleo Sci ; 69(8): 941-950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32759552

RESUMO

This study reports the biological activity of essential oils from fertility tree and horseradish tree leaves, and the mechanisms by which these oils promote insecticidal activity using Drosophila melanogaster as a model organism. Adult D. melanogaster were exposed to these essential oils at a final concentration of 10 µL/g for 24 hours. The exposure of flies to the essential oil resulted in significant decrease in their survival and fecundity. In addition, the essential oils produced significant reduction in acetylcholinesterase activity and induced oxidative stress in the flies as evidenced by an increase in reactive oxygen species, thiol and thiobarbituric reactive substance levels, as well as catalase activity. The essential oils were also characterized by gas chromatography coupled with mass spectrometry. Constituents such as terpenoids, Bis (2-ethylhexyl) phthalate, benzeneacetaldehyde, phytol, octadecane, 9,12-octadecadienoic acid (Z,Z)- methyl ester, heneicosane, eicosane and others were characterized. Therefore, our results point out to the potential application of fertility tree and horseradish tree leaf essential oils as natural alternatives to synthetic insecticides in agricultural and pest control practices, especially against dipterans.


Assuntos
Acetilcolinesterase/metabolismo , Bignoniaceae/química , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Inseticidas , Moringa oleifera/química , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Animais , Relação Dose-Resposta a Droga , Óleos Voláteis/química , Ácidos Ftálicos/análise , Espécies Reativas de Oxigênio/metabolismo , Terpenos/análise , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de Tempo
5.
PLoS One ; 15(8): e0237986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841282

RESUMO

Insects experience a diversity of subtoxic and/or toxic xenobiotics through exposure to pesticides and, in the case of herbivorous insects, through plant defensive compounds in their diets. Many insects are also concurrently exposed to antioxidants in their diets. The impact of dietary antioxidants on the toxicity of xenobiotics in insects is not well understood, in part due to the challenge of developing appropriate systems in which doses and exposure times (of both the antioxidants and the xenobiotics) can be controlled and outcomes can be easily measured. However, in Drosophila melanogaster, a well-established insect model system, both dietary factors and pesticide exposure can be easily controlled. Additionally, the mode of action and xenobiotic metabolism of dichlorodiphenyltrichloroethane (DDT), a highly persistent neurotoxic organochlorine insecticide that is detected widely in the environment, have been well studied in DDT-susceptible and -resistant strains. Using a glass-vial bioassay system with blue diet as the food source, seven compounds with known antioxidant effects (ascorbic acid, ß-carotene, glutathione, α-lipoic acid, melatonin, minocycline, and serotonin) were orally tested for their impact on DDT toxicity across three strains of D. melanogaster: one highly susceptible to DDT (Canton-S), one mildly susceptible (91-C), and one highly resistant (91-R). Three of the antioxidants (serotonin, ascorbic acid, and ß-carotene) significantly impacted the toxicity of DDT in one or more strains. Fly strain and gender, antioxidant type, and antioxidant dose all affected the relative toxicity of DDT. Our work demonstrates that dietary antioxidants can potentially alter the toxicity of a xenobiotic in an insect population.


Assuntos
Antioxidantes/farmacologia , DDT/toxicidade , Dieta , Drosophila melanogaster/efeitos dos fármacos , Resistência a Inseticidas/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Genótipo , Masculino , Serotonina/farmacologia , Caracteres Sexuais
6.
PLoS One ; 15(7): e0236318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726319

RESUMO

Lately, Drosophila has been favored as a model in sleep and circadian rhythm research due to its conserved mechanism and easily manageable operation. These studies have revealed the sophisticated parameters in whole-day sleep profiles of Drosophila, drawing connections between Drosophila sleep and human sleep. In this study, we tested several sleep deprivation protocols (mechanical shakes and light interruptions) on Drosophila and delineated their influences on Drosophila sleep. We applied a daytime light-deprivation protocol (DD) mimicking jet-lag to screen drugs that alleviate sleep deprivation. Characteristically, classical sleep-aid compounds exhibited different forms of influence: phenobarbital and pentobarbital modified total sleep time, while melatonin only shortened the latency to sleep. Such results construct the basis for further research on sleep benefits in other treatments in Drosophila. We screened seven herb extracts, and found very diverse results regarding their effect on sleep regulation. For instance, Panax notoginseng and Withania somnifera extracts displayed potent influence on total sleep time, while Melissa officinalis increased the number of sleep episodes. By comparing these treatments, we were able to rank drug potency in different aspects of sleep regulation. Notably, we also confirmed the presence of sleep difficulties in a Drosophila Alzheimer's disease (AD) model with an overexpression of human Abeta, and recognized clear differences between the portfolios of drug screening effects in AD flies and in the control group. Overall, potential drug candidates and receipts for sleep problems can be identified separately for normal and AD Drosophila populations, outlining Drosophila's potential in drug screening tests in other populations if combined with the use of other genetic disease tools.


Assuntos
Extratos Vegetais/farmacologia , Privação do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Melatonina/farmacologia , Mutação , Panax notoginseng/química , Fenobarbital/farmacologia , Extratos Vegetais/química , Sono/efeitos dos fármacos , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Withania/química
7.
Pestic Biochem Physiol ; 168: 104631, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32711765

RESUMO

Herbivorous insects encounter a variety of toxic environmental substances ranging from ingested plant defensive compounds to human-introduced insecticidal agents. Dietary antioxidants are known to reduce the negative physiological impacts of toxins in mammalian systems through amelioration of reactive oxygen-related cellular damage. The analogous impacts to insects caused by multigenerational exposure to pesticides and the effects on adaptive responses within insect populations, however, are currently unknown. To address these research gaps, we used Drosophila as a model system to explore adaptive phenotypic responses to acute dichlorodiphenyltrichloroethane (DDT) exposure in the presence of the dietary antioxidant vitamin C and to examine the structural genomic consequences of this exposure. DDT resistance increased significantly among four replicates exposed to a low concentration of DDT for 10 generations. In contrast, dietary intake of vitamin C significantly reduced DDT resistance after mutigenerational exposure to the same concentration of DDT. As to the genomic consequences, no significant differences were predicted in overall nucleotide substitution rates across the genome between any of the treatments. Despite this, replicates exposed to a low concentration of DDT without vitamin C showed the highest number of synonymous and non-synonymous variants (3196 in total), followed by the DDT plus vitamin C (1174 in total), and vitamin C alone (728 in total) treatments. This study demonstrates the potential role of diet (specifically, antioxidant intake) on adaptive genome responses, and thus on the evolution of pesticide resistance within insect populations.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Inseticidas/farmacologia , Animais , Antioxidantes , Ácido Ascórbico , DDT , Dieta , Humanos , Resistência a Inseticidas/efeitos dos fármacos
8.
Ecotoxicol Environ Saf ; 201: 110811, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544744

RESUMO

Xenobiotic mediated renal toxicity is one of the major health concerns to the organisms, including humans. New chemicals with nephrotoxic potential are continuously being added to the list of existing nephrotoxicants. To predict the nephrotoxicity of these new chemicals, reliable and cost-effective alternative animal models are required. It is a prerequisite for the identification and assessment of these compounds as potential nephrotoxicants to prevent renal toxicity in the exposed population. Drosophila melanogaster, a genetically tractable invertebrate animal model, has a renal system functionally analogous to humans. The Malpighian tubules (MTs) of D. melanogaster are similar to the tubular part of nephron of the human kidney. Besides, it recapitulates the renal toxicity hallmark with mammals when exposed to known nephrotoxicants. In this study, first instar larvae of D. melanogaster (Oregon R) were exposed to different concentrations of two well-known nephrotoxicants, cadmium (Cd) and mercury (Hg). Akin to higher organisms, Cd and Hg exposure to D. melanogaster produce similar phenotypes. MTs of exposed D. melanogaster larvae exhibited increased oxidative stress, activated cellular antioxidant defense mechanism, GSH depletion, increased cleaved caspase-3 expression, increased DEVDase activity and increased cell death. The functional status of MTs was assessed by fluid secretion rate (FSR), efflux activity of transporter protein, mitochondrial membrane potential (MMP), ATP level and expression of junctional protein (Dlg). All the phenotypes observed in MTs of D. melanogaster larvae recapitulate the phenotypes observed in higher organisms. Increased uric acid level, the hallmark of renal dysfunction, was also observed in exposed larvae. Taken together, the study suggests that MTs of D. melanogaster may be used as a functional model to evaluate xenobiotic mediated nephrotoxicity.


Assuntos
Alternativas aos Testes com Animais , Cádmio/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Rim/efeitos dos fármacos , Túbulos de Malpighi/efeitos dos fármacos , Mercúrio/toxicidade , Animais , Antioxidantes/metabolismo , Transporte Biológico , Cádmio/metabolismo , Humanos , Rim/metabolismo , Larva/efeitos dos fármacos , Túbulos de Malpighi/metabolismo , Mercúrio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Xenobióticos/metabolismo , Xenobióticos/toxicidade
9.
J Environ Sci Health B ; 55(8): 732-748, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32567974

RESUMO

In present study, we constructed the direct protein-protein interaction network of insecticide resistance based on subcellular localization analysis. Totally 177 of 528 resistance proteins were identified and they were located in 11 subcellular localizations. We further analyzed topological properties of the network and the biological characteristics of resistance proteins, such as k-core, neighborhood connectivity, instability index and aliphatic index. They can be used to predict the key proteins and potential mechanisms from macro-perspective. The problem of resistance has not been solved fundamentally, because the development of new insecticides can't keep pace with the development speed of resistance, and the lack of understanding of molecular mechanism of resistance. As the further analysis to reduce data noise, we constructed the direct protein-protein interaction network of insecticide resistance based on subcellular localization analysis. The interaction between proteins located at the same subcellular location belongs to direct interactions, thus eliminating indirect interaction. Totally 177 of 528 resistance proteins were identified and they were located in 11 subcellular localizations. We further analyzed topological properties of the network and the biological characteristics of resistance proteins, such as k-core, neighborhood connectivity, instability index and aliphatic index. They can be used to predict the hub proteins and potential mechanisms from macro-perspective. This is the first study to explore the insecticide resistance molecular mechanism of Drosophila melanogaster based on subcellular localization analysis. It can provide the bioinformatics foundation for further understanding the mechanisms of insecticide resistance. It also provides a reference for the study of molecular mechanism of insecticide resistance of other insects.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/efeitos dos fármacos , Resistência a Inseticidas/fisiologia , Mapas de Interação de Proteínas , Animais , Resistência a Inseticidas/efeitos dos fármacos
10.
J Vis Exp ; (158)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32364549

RESUMO

Drosophila melanogaster provides an excellent model to study the genetic underpinnings of alcohol sensitivity. In contrast to studies in human populations, the Drosophila model allows strict control over genetic background, and virtually unlimited numbers of individuals of the same genotype can be reared rapidly under well-controlled environmental conditions without regulatory restrictions and at relatively low cost. Flies exposed to ethanol undergo physiological and behavioral changes that resemble human alcohol intoxication, including loss of postural control, sedation, and development of tolerance. Here, we describe a simple, low-cost, high-throughput assay for assessing alcohol sedation sensitivity in large numbers of single flies. The assay is based on video recording of single flies introduced without anesthesia in 24-well cell culture plates in a set-up that enables synchronous initiation of alcohol exposure. The system enables a single person to collect individual ethanol sedation data on as many as 2,000 flies within an 8 h work period. The assay can, in principle, be extended to assess the effects of exposure to any volatile substance and applied to measure effects of acute toxicity of volatiles on other insects, including other fly species.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Etanol/toxicidade , Animais , Tolerância a Medicamentos/genética , Genótipo , Fatores de Tempo
11.
Nat Commun ; 11(1): 2106, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355156

RESUMO

Here, we describe a drug-inducible genetic system for insect sex-separation that demonstrates proof-of-principle for positive sex selection in D. melanogaster. The system exploits the toxicity of commonly used broad-spectrum antibiotics geneticin and puromycin to kill the non-rescued sex. Sex-specific rescue is achieved by inserting sex-specific introns into the coding sequences of antibiotic-resistance genes. When raised on geneticin-supplemented food, the sex-sorter line establishes 100% positive selection for female progeny, while the food supplemented with puromycin positively selects 100% male progeny. Since the described system exploits conserved sex-specific splicing mechanisms and reagents, it has the potential to be adaptable to other insect species of medical and agricultural importance.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Engenharia Genética/métodos , Gentamicinas/farmacologia , Puromicina/farmacologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Resistência a Medicamentos , Éxons , Feminino , Genética Populacional , Homozigoto , Íntrons , Masculino , Controle de Pragas , Processamento de RNA , Análise para Determinação do Sexo
12.
PLoS One ; 15(4): e0230970, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287318

RESUMO

The ability to predict when an individual will die can be extremely useful for many research problems in aging. A technique for predicting death in the model organism, Drosophila melanogaster, has been proposed which relies on an increase in the permeability of the fly intestinal system, allowing dyes from the diet to permeate the body of the fly shortly before death. In this study we sought to verify this claim in a large cohort study using different populations of D. melanogaster and different dyes. We found that only about 50% of the individuals showed a visible distribution of dye before death. This number did not vary substantially with the dye used. Most flies that did turn a blue color before death did so within 24 hours of death. There was also a measurable effect of the dye on the fly mean longevity. These results would tend to limit the utility of this method depending on the application the method was intended for.


Assuntos
Drosophila melanogaster/fisiologia , Intestinos/fisiologia , Longevidade/fisiologia , Envelhecimento/fisiologia , Animais , Corantes/administração & dosagem , Corantes/farmacocinética , Corantes/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Feminino , Longevidade/efeitos dos fármacos , Masculino , Modelos Biológicos , Permeabilidade
13.
Chemosphere ; 253: 126629, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32283422

RESUMO

Recent reports demonstrate that octopamine receptor (OR) agonists such as formamidine pesticides cause reproductive and developmental toxicity through endocrine disrupting effects in both humans and animals. Herein, we studied the effects of different sublethal concentrations of OR agonists, Amitraz and Chlordimeform, on growth, development, and reproduction of D. melanogaster from a genotype perspective view. As a result, the sublethal concentrations for both OR agonists delayed the developmental time including pupation and eclosion. It significantly reduced the lifespan, eclosion rate, and production of eggs. The mRNA expression of genes relevant for development and metabolism was significantly changed after exposure to sublethal concentrations of both OR agonists. Octopamine receptor in mushroom bodies (Oamb), trehalase enzyme (Treh), hemocyte proliferation (RyR), and immune response (IM4) genes were upregulated whereas, trehalose sugar (Tret1-1), mixed function oxidase enzyme (Cyp9f2), lifespan (Atg7), male mating behavior (Ple), female fertility (Ddc), and lipid metabolism (Sxe2) genes were downregulated. These results support the conclusion that OR agonists activate the octopamine receptor in D. melanogaster leading to an increase of trehalase enzyme activity and degradation of trehalose sugar into free glucose which results in rapid energy exhaustion, hyperexcitation, and disturbing of the octopaminergic system in D. melanogaster.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Octopamina/toxicidade , Amidinas , Animais , Proteína 7 Relacionada à Autofagia , Comportamento Animal , Drosophila melanogaster/efeitos dos fármacos , Feminino , Masculino , Metabolismo/genética , Receptores de Amina Biogênica , Toluidinas
14.
Bull Environ Contam Toxicol ; 104(5): 588-594, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32193571

RESUMO

Female vinegar flies (Drosophila melanogaster) preferentially oviposit eggs on oviposition substrates that decrease larval foraging costs. We tested whether female D. melanogaster would avoid oviposition substrates containing lead (Pb2+), which could potentially decrease offspring fitness. Wild type D. melanogaster were reared on control or Pb-treated medium from egg stage to adulthood and tested for differences in oviposition substrate preference, fecundity (number of eggs laid) and Pb accumulation. Control females laid a significantly lower proportion of eggs on Pb-treated substrates than Pb-treated females. Pb-treated females laid significantly more eggs than control females. Pb-treated adults accumulated significantly more Pb than control-treated adults. These results indicate that Pb exposure disrupts normal oviposition avoidance behaviors, which could increase larval foraging costs for larval offspring. These factors could induce population declines and have cascading implications for the ecosystem.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Larva/efeitos dos fármacos , Chumbo/toxicidade , Oviposição/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/fisiologia , Ecossistema , Feminino , Fertilidade/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Modelos Teóricos
15.
Biochem J ; 477(4): 833-852, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32108870

RESUMO

Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.


Assuntos
Modelos Animais de Doenças , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Mitocôndrias/genética , Neurônios/metabolismo , Doenças Priônicas/patologia , Príons/toxicidade , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/crescimento & desenvolvimento , Ciclo Celular , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neurônios/patologia , Fenótipo , Doenças Priônicas/induzido quimicamente , Doenças Priônicas/genética , Biossíntese de Proteínas , Transcriptoma
16.
Insect Biochem Mol Biol ; 119: 103335, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32061770

RESUMO

Life history trade-offs lead to various strategies that maximize fitness, but the developmental mechanisms underlying these alternative strategies continue to be poorly understood. In insects, trade-offs exist between size and developmental time. Recent studies in the fruit fly Drosophila melanogaster have suggested that the steroidogenic prothoracic glands play a key role in determining the timing of metamorphosis. In this study, the nutrient-dependent growth and transcriptional activation of prothoracic glands were studied in D. melanogaster and the tobacco hornworm Manduca sexta. In both species, minimum viable weight (MVW) was associated with activation of ecdysteroid biosynthesis genes and growth of prothoracic gland cells. However, the timing of MVW attainment in M. sexta is delayed by the presence of the sesquiterpenoid hormone, juvenile hormone (JH), whereas in D. melanogaster it is not. Moreover, in D. melanogaster, the transcriptional regulation of ecdysteroidogenesis becomes nutrient-independent at the MVW/critical weight (CW) checkpoint. In contrast, in M. sexta, starvation consistently reduced transcriptional activation of ecdysteroid biosynthesis genes even after CW attainment, indicating that the nature of CW differs fundamentally between the two species. In D. melanogaster, the prothoracic glands dictate the timing of metamorphosis even in the absence of nutritional inputs, whereas in M. sexta, prothoracic gland activity is tightly coupled to the nutritional status of the body, thereby delaying the onset of metamorphosis before CW attainment. We propose that selection for survival under unpredictable nutritional availability leads to the evolution of increased modularity in both morphological and endocrine traits.


Assuntos
Drosophila melanogaster/fisiologia , Ecdisteroides/metabolismo , Hormônios Juvenis/metabolismo , Traços de História de Vida , Manduca/fisiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Peso Corporal , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Glândulas Endócrinas/fisiologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/fisiologia , Manduca/efeitos dos fármacos , Manduca/crescimento & desenvolvimento , Metamorfose Biológica
17.
Ecotoxicol Environ Saf ; 192: 110328, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078840

RESUMO

In this study pillar[5]arene (P5) and a quinoline-functionalized pillar[5]arene (P5-6Q) which is used for detecting radioactive element, gas adsorption and toxic ions were synthesized. These materials were characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared (FTIR), elemental analysis, melting point, Mass Spectroscopy, Scanning Electron Microscopy (SEM) and Zeta Potential. The cytotoxic and genotoxic potential of P5 and P5-6Q at distinct concentrations of 12.5, 25, 50, and 100 µg/mL were also investigated by Allium ana-telophase and comet assays on Allium cepa roots and Drosophila melanogaster haemocytes. P5 and P5-6Q showed dose dependent cytotoxic effect by decreasing mitotic index (MI) and genotoxic effect by increasing chromosomal aberrations (CAs such as disturbed anaphase-telophase, polyploidy, stickiness, chromosome laggards and bridges) and DNA damage at the exposed concentrations. These changes in P5-6Q were lower than P5. Further research is necessary to clarify the cytotoxic and genotoxic action mechanisms of P5 and P5-6Q at molecular levels.


Assuntos
Calixarenos/toxicidade , Dano ao DNA , Drosophila melanogaster/efeitos dos fármacos , Cebolas/efeitos dos fármacos , Anáfase/efeitos dos fármacos , Animais , Calixarenos/química , Aberrações Cromossômicas , Ensaio Cometa , Citotoxinas/química , Citotoxinas/toxicidade , Drosophila melanogaster/genética , Hemócitos/efeitos dos fármacos , Índice Mitótico , Cebolas/genética , Raízes de Plantas/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Telófase/efeitos dos fármacos
18.
J Agric Food Chem ; 68(10): 3061-3070, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32059103

RESUMO

Pyrethroids are one of the most commonly used classes of insecticides, and their acid and alcohol components are esterase degradation products, usually considered to be biologically inactive. In this study, it was found that several pyrethroid acids had a spatial repellent activity that was greater than DEET, often more active than the parent pyrethroids, and showed little cross resistance in a pyrethroid-resistant Puerto Rico strain of Aedes aegypti mosquitoes. Further investigation revealed that the acids can synergize not only contact repellent standards but also other pyrethroid components as well as the parent pyrethroids themselves. Synergism by the pyrethroid acids is expressed as both increased spatial repellency and vapor toxicity as well as human bite protection. Electrophysiological studies confirmed that pyrethroid acids (100 µM) had no effect on neuronal discharge in larval Drosophila melanogaster CNS and were detected by electroantennography, and there was little resistance to olfactory sensing of these acids in antennae from Puerto Rico strain mosquitoes carrying kdr mutations. Thus, the data suggest that the pyrethroid acids have a different mode of action than the parent pyrethroids, unrelated to the voltage-sensitive sodium channel. The results highlight the potential of pyrethroid acids to be useful in future repellent formulations.


Assuntos
Aedes/efeitos dos fármacos , Repelentes de Insetos/toxicidade , Piretrinas/química , Piretrinas/toxicidade , Ácidos/química , Ácidos/toxicidade , Aedes/genética , Álcoois/química , Álcoois/toxicidade , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Sinergismo Farmacológico , Repelentes de Insetos/química , Resistência a Inseticidas , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Estrutura Molecular , Controle de Mosquitos , Porto Rico
19.
Food Chem Toxicol ; 137: 111128, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31952986

RESUMO

The pathogenesis of Parkinson's disease has not been fully clarified yet but its cause is known to be multifactorial. One of these factors is oxidative stress induced by exposure to environmental toxifiers. We studied the effect of Bisphenol A (BPA) at concentrations of 0.5 mM and 1 mM, the concentration of 1 mM corresponding to Lowest Observed Adverse Effect Level (LOAEL) for humans in adult Drosophila melanogaster. The BPA induced oxidative stress was established by increased levels of malondialdehyde, reactive species, and decreased activity of the antioxidant enzymes superoxide dismutase and catalase, and detoxificant enzyme glutathione-S-transferase. Associated with oxidative stress, there was a reduction of acetylcholinesterase activity and a reduction of dopamine levels, which are related to the decreased locomotion activity as observed in negative geotaxis, open field and equilibrium behaviors in group exposed to 1 mM of BPA. Oxidative stress also impaired mitochondrial and cellular metabolic activity in the head causing an increase in the mortality of flies exposed to both BPA concentrations. Therefore, BPA induced Parkinsonian-like changes in flies and it is possible that the oxidative stress is closely related to this effect, providing new insights for future studies.


Assuntos
Compostos Benzidrílicos/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/crescimento & desenvolvimento , Doença de Parkinson/etiologia , Fenóis/toxicidade , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Glutationa Transferase/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nível de Efeito Adverso não Observado , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
20.
Proc Natl Acad Sci U S A ; 117(4): 2004-2013, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932432

RESUMO

Environmental cues such as nutrients alter cellular behaviors by acting on a wide array of molecular sensors inside cells. Of emerging interest is the link observed between effects of dietary sugars on cancer proliferation. Here, we identify the requirements of hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) for Drosophila homeodomain-interacting protein kinase (Hipk)-induced growth abnormalities in response to a high sugar diet. On a normal diet, OGT is both necessary and sufficient for inducing Hipk-mediated tumor-like growth. We further show that OGT maintains Hipk protein stability by blocking its proteasomal degradation and that Hipk is O-GlcNAcylated by OGT. In mammalian cells, human HIPK2 proteins accumulate posttranscriptionally upon OGT overexpression. Mass spectrometry analyses reveal that HIPK2 is at least O-GlcNAc modified at S852, T1009, and S1147 residues. Mutations of these residues reduce HIPK2 O-GlcNAcylation and stability. Together, our data demonstrate a conserved role of OGT in positively regulating the protein stability of HIPKs (fly Hipk and human HIPK2), which likely permits the nutritional responsiveness of HIPKs.


Assuntos
Carcinogênese/patologia , Proteínas de Transporte/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Glucose/farmacologia , N-Acetilglucosaminiltransferases/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Acetilglucosamina/metabolismo , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Proteínas de Transporte/genética , Proliferação de Células , Células Cultivadas , Proteínas de Drosophila/genética , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Células HEK293 , Humanos , Células MCF-7 , Camundongos , N-Acetilglucosaminiltransferases/genética , Fosforilação , Proteínas Quinases/genética , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/genética , Edulcorantes/farmacologia
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