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1.
Nat Commun ; 11(1): 4496, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901024

RESUMO

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.


Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inositol/metabolismo , Longevidade/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Inositol/administração & dosagem , Locomoção/fisiologia , Longevidade/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Camundongos , Mitofagia/fisiologia , Modelos Animais , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA-Seq
2.
Ecotoxicol Environ Saf ; 204: 111052, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739675

RESUMO

Transgenerational effects on sensitivity to pesticides are poorly studied. This study investigated the transgenerational influences of maternal body mass in the major pest moth Spodoptera littoralis, with a focus on sensitivity to chlorpyrifos pesticide. In 147 clutches of a laboratory strain of S. littoralis, we compared larval mortality between control larvae and larvae treated with chlorpyrifos. Because of the classic positive relationships between offspring size and maternal size and between offspring size and offspring quality, sensitivity to chlorpyrifos was predicted to be lower in larvae of larger mothers. Surprisingly, we found the opposite result, with higher pesticide toxicity in larvae of larger mothers. This result is partly explained by the lack of a relationship between larval mass and larval sensitivity to chlorpyrifos. This means that another offspring characteristic linked to maternal size should have affected larval sensitivity to chlorpyrifos. More generally, knowledge of the effects of the traits and ecological environments of mothers on offspring sensitivity to pesticides remains limited. Ecotoxicologists should pay more attention to such maternal effects on sensitivity to pesticides, both in pests and non-target species.


Assuntos
Clorpirifos/toxicidade , Epigênese Genética , Resistência a Inseticidas/genética , Inseticidas/toxicidade , Spodoptera/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Longevidade/efeitos dos fármacos , Exposição Materna , Spodoptera/genética , Spodoptera/crescimento & desenvolvimento
3.
Int J Nanomedicine ; 15: 5227-5237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801688

RESUMO

Background: Large-scale production and application of amorphous silica nanoparticles (SiNPs) have enhanced the risk of human exposure to SiNPs. However, the toxic effects and the underlying biological mechanisms of SiNPs on Caenorhabditis elegans remain largely unclear. Purpose: This study was to investigate the genome-wide transcriptional alteration of SiNPs on C. elegans. Methods and Results: In this study, a total number of 3105 differentially expressed genes were identified in C. elegans. Among them, 1398 genes were significantly upregulated and 1707 genes were notably downregulated in C. elegans. Gene ontology analysis revealed that the significant change of gene functional categories triggered by SiNPs was focused on locomotion, determination of adult lifespan, reproduction, body morphogenesis, multicellular organism development, endoplasmic reticulum unfolded protein response, oocyte development, and nematode larval development. Meanwhile, we explored the regulated effects between microRNA and genes or signaling pathways. Pathway enrichment analysis and miRNA-gene-pathway-network displayed that 23 differential expression microRNA including cel-miR-85-3p, cel-miR-793, cel-miR-241-5p, and cel-miR-5549-5p could regulate the longevity-related pathways and inflammation signaling pathways, etc. Additionally, our data confirmed that SiNPs could disrupt the locomotion behavior and reduce the longevity by activating ins-7, daf-16, ftt-2, fat-5, and rho-1 genes in C. elegans. Conclusion: Our study showed that SiNPs induced the change of the whole transcriptome in C. elegans, and triggered negative effects on longevity, development, reproduction, and body morphogenesis. These data provide abundant clues to understand the molecular mechanisms of SiNPs in C. elegans.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Nanopartículas/toxicidade , Animais , Proteínas de Caenorhabditis elegans/genética , Redes Reguladoras de Genes/efeitos dos fármacos , Genoma Helmíntico , Humanos , Longevidade/efeitos dos fármacos , MicroRNAs/genética , Testes de Mutagenicidade/métodos , Nanopartículas/química , Reprodução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Transcriptoma , Resposta a Proteínas não Dobradas/genética
4.
Ecotoxicol Environ Saf ; 204: 111108, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32798750

RESUMO

Honeybees (Apis mellifera) play an important role in agriculture worldwide. Several factors including agrochemicals can affect honey bee health including habitat fragmentation, pesticide application, and pests. The growing human population and subsequent increasing crop production have led to widespread use of agrochemicals and there is growing concern that pollinators are being negatively impacted by these pesticides. The present study compares acute exposure to imidacloprid (0.2 and 0.4 mgL-1), ethion (80 and 106.7 mgL-1) or glyphosate (0.12 and 0.24 mgL-1) on aversive learning and movement, to chronic exposure at these and higher concentrations on movement, circadian rhythms, and survival in honey bee foragers. For acute learning studies, a blue/yellow shuttle box experiment was conducted; we observed honey bee choice following aversive and neutral stimuli. In learning studies, control bees spent >50% of the time on yellow which is not consistent with previous color bias literature in the subspecies or region of the study. The learning apparatus was also used to estimate mobility effects within 20 min of exposure. Chronic exposure (up to 2 weeks) with the above metrics was recorded by an automated monitoring system. In chronic exposure experiments, RoundUp®, was also tested to compare to its active ingredient, glyphosate. We found that imidacloprid and ethion have negative impacts on aversive learning and movement following a single-dose and that chronic exposure effects were dose-dependent for these two insecticides. In contrast, glyphosate had no effect on learning and less of an effect on movement; RoundUp® showed dose-dependent results on circadian rhythmicity. Overall, the results suggest that short-term exposure to imidacloprid and ethion adversely affect honey bee foragers and chronic exposure to glyphosate may affect pollination success.


Assuntos
Abelhas/fisiologia , Inseticidas/toxicidade , Animais , Glicina/análogos & derivados , Glicina/toxicidade , Aprendizagem/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Compostos Organotiofosforados/toxicidade , Polinização
5.
Adv Exp Med Biol ; 1207: 681-688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671785

RESUMO

Senescence is a progressive process of degeneration that occurs when cells and organisms mature. Many studies have shown that autophagy is closely related to senescence. Autophagy gradually decreases with the senescence activity of cells, and vice versa. Therefore, moderate autophagy can protect the body and inhibit cell senescence. The inactivation of genes encoding nematode insulin-like tyrosine kinase receptor (daf-2) inhibited the activity of type I PI3K (age-1), Akt molecules (akt1, akt2), PDK (pdk-1), and TOR, and increased the lifespan and autophagy of Caenorhabditis elegans.


Assuntos
Envelhecimento/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Humanos , Longevidade/efeitos dos fármacos
6.
Proc Natl Acad Sci U S A ; 117(29): 17142-17150, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636256

RESUMO

Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 Escherichia coli mutants and identified 44 E. coli mutants that modulated Caenorhabditis elegans longevity. Three of these mutants modulated C. elegans longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing E. coli mutants, Δhns E. coli, extended the lifespan of C. elegans through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPRmt). Interestingly, the lifespan modulation by Δhns did not require insulin/insulin-like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that Δhns E. coli activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans , Fatores de Transcrição Forkhead/metabolismo , Longevidade/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Aldeído Pirúvico , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Escherichia coli/metabolismo , Microbioma Gastrointestinal/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Modelos Biológicos , Aldeído Pirúvico/metabolismo , Aldeído Pirúvico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-32617729

RESUMO

Some species of fish have been used as bioindicators of aquatic environmental pollution all over the world. Pejerrey (Odontesthes bonariensis) was selected for the current study due to its sensitivity to pollutants and because is one of the emblematic fish species that inhabits shallow lakes of the Pampa region (Argentina). Recently, in Chascomús lake were recorded concentrations of Cd, Cr, Cu and Zn with values above the Argentine National Guidelines for the Protection of the Aquatic life. Regarding this, the aim of the present study was to investigate the effects of environmental concentrations of these metals on the sperm quality, fertilization and hatching rates, and embryo and larval survival of pejerrey. Also, the same endpoints were analyzed with concentrations ten times higher to simulate a polluted worst-case scenario. The results showed that the presence of some metals in aquatic environments reduced pejerrey sperm motility (in ~50%) and velocity (in ~30%). These results were obtained using a computer assisted sperm analyzer enforcing the application of this analysis as a tool or bioindicator of aquatic pollution. In addition, fertilization rate was diminished (in ~40%) for all treatments. Besides, the hatching rate, and embryo and larval survival were drastically affected being zero for the highest metal concentrations assessed. All together these results, showed that even lower metal concentrations can negatively affect different reproductive parameters of one of the most emblematic fish species of the Argentinean water bodies.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Fertilização/efeitos dos fármacos , Metais Pesados/efeitos adversos , Smegmamorpha/fisiologia , Espermatozoides/efeitos dos fármacos , Poluentes Químicos da Água/efeitos adversos , Animais , Desenvolvimento Embrionário/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Masculino , Análise do Sêmen/veterinária
8.
Nat Commun ; 11(1): 2099, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350248

RESUMO

Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate IL-17 signaling in neurons, and the extent it can alter organismal phenotypes. We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans neurons. We identify the paracaspase MALT-1 as a critical output of the pathway. MALT1 mediates signaling from many immune receptors in mammals, but was not previously implicated in IL-17 signaling or nervous system function. C. elegans MALT-1 forms a complex with homologs of Act1 and IRAK and appears to function both as a scaffold and a protease. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17-MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural circuit function downstream of IL-17 to remodel physiology and behavior.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/fisiologia , Imunidade , Interleucina-17/metabolismo , Longevidade , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Neurônios/metabolismo , Animais , Comportamento Animal , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Imunidade/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Longevidade/efeitos dos fármacos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/metabolismo , Transgenes
9.
PLoS One ; 15(5): e0232812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407334

RESUMO

Sulfoxaflor, the first commercially available sulfoximine insecticide, has been used for the control of sap-feeding insect pests such as plant bugs and aphids on a variety of crops. However, its sublethal effects on the mirid bug Apolygus lucorum, one of the key insect pests of Bt cotton and fruit trees in China, have not been fully examined. Here, we evaluated the demography and feeding behaviour of A. lucorum exposed to sulfoxaflor. The leaf-dipping bioassay showed that the LC10 and LC30 of sulfoxaflor against 3rd-instar nymphs of this insect were 1.23 and 8.37 mg L-1, respectively. The LC10 significantly extended the nymphal duration and decreased the oviposition period by 5.29 days and female fecundity by 56.99% in the parent generation (F0). The longer duration of egg, 5th-instar nymphs, preadult, and male adult longevity were observed in the F1 generation (F1) at LC10. At the LC30, the duration of egg and 1st-instar nymph, female adult longevity, and oviposition period of the F1 were significantly shorter, while the nymphal duration in the F0 and duration of 5th-instar nymphs, preadult survival rate, and male adult longevity in the F1 significantly increased. The net reproductive rate (R0), intrinsic rate of increase (r), and finite rate of increase (λ) in the F1 were not significantly affected by these two concentrations, whereas the mean generation time (T) was lower at the LC30. Additionally, the probe counts and cells mixture feeding time were markedly lengthened by the LC10 and LC30, respectively, when A. lucorum nymphs exposed to sulfoxaflor fed on Bt cotton plants without insecticides. These results clearly indicate that sulfoxaflor causes sublethal effects on A. lucorum and the transgenerational effects depend on the tested concentrations.


Assuntos
Heterópteros/patogenicidade , Inseticidas/farmacologia , Controle de Pragas , Piridinas/farmacologia , Compostos de Enxofre/farmacologia , Animais , Fertilidade/efeitos dos fármacos , Frutas/parasitologia , Gossypium/parasitologia , Heterópteros/efeitos dos fármacos , Humanos , Longevidade/efeitos dos fármacos , Ninfa/efeitos dos fármacos , Ninfa/patogenicidade , Oviposição/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Árvores/parasitologia
10.
Ecotoxicol Environ Saf ; 197: 110588, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289633

RESUMO

The ethoxylated isomers of nonylphenol (NPEs, NP-9) are one of the main active ingredients present in nonionic surfactants employed as herbicides, cosmetics, paints, plastics, disinfectants and detergents. These chemicals and their metabolites are commonly found in environmental matrices. The aim of this work was to evaluate the intergenerational toxicity of NP-9 in Caenorhabditis elegans. The lethality, length, width, locomotion and lifespan were investigated in the larval stage L4 of the wild strain N2. Transgenic green fluorescent protein (GFP) strains were employed to estimate changes in relative gene expression. RT-qPCR was utilized to measure mRNA expression for neurotoxicity-related genes (unc-30, unc-25, dop-3, dat-1, mgl-1, and eat-4). Data were obtained from parent worms (P0) and the first generation (F1). Lethality of the nematode was concentration-dependent, with 48 h-LC50 values of 3215 and 1983 µM in P0 and F1, respectively. Non-lethal concentrations of NP-9 reduced locomotion. Lifespan was also decreased by the xenobiotic, but the negative effect was greater in P0 than in F1. Non-monotonic concentration-response curves were observed for body length and width in both generations. The gene expression profile in P0 was different from that registered in F1, although the expression of sod-4, hsp-70, gpx-6 and mtl-2 increased with the surfactant concentration in both generations. None of the tested genes followed a classical concentration-neurotoxicity relationship. In P0, dopamine presented an inverted-U curve, while GABA and glutamate displayed a bimodal type. However, in F1, inverted U-shaped curves were revealed for these genes. In summary, NP-9 induced intergenerational responses in C. elegans through mechanisms involving ROS, and alterations of the GABA, glutamate, and dopamine pathways.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Etilenoglicóis/toxicidade , Tensoativos/toxicidade , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/genética , Expressão Gênica/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Neurotransmissores/metabolismo
11.
Ecotoxicol Environ Saf ; 197: 110625, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302863

RESUMO

Due to the potential of release and accumulation in the environment, nanoplastics have attracted an increasing attention. In this study, we investigated the effect of exposure to nanopolystyrene (30 nm) in nematode Caenorhabditis elegans after the fungal infection. After Candida albicans infection, exposure to nanopolystyrene (10 and 100 µg/L) for 24-h could cause the more severe toxicity on lifespan and locomotion behavior compared with fungal infection alone. The more severe activation of oxidative stress and suppression of SOD-3:GFP expression and mitochondrial unfolded protein response (mt UPR) were associated with this observed toxicity enhancement induced by nanopolystyrene exposure. Moreover, the more severe C. albicans colony formation and suppression of innate immune response as indicated by the alteration in expression of anti-microbial genes (abf-2, cnc-4, cnc-7, and fipr-22/23) further contributed to the formation of this toxicity enhancement induced by nanopolystyrene exposure. Our results demonstrated that short-term exposure to nanopolystyrene in the range of µg/L potentially enhances the adverse effects of fungal infection on organisms.


Assuntos
Caenorhabditis elegans , Candidíase/induzido quimicamente , Locomoção/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Poliestirenos/toxicidade , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/metabolismo , Candida albicans/crescimento & desenvolvimento , Candidíase/microbiologia , Estresse Oxidativo/efeitos dos fármacos
12.
PLoS One ; 15(4): e0231972, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320994

RESUMO

At present, a large number of studies have reported that hydrogen has antioxidant functions and prevents oxidative stress damage. However, it is not clear whether hydrogen can prolong longevity based on these effects. Therefore, we studied and explored the antiaging potential of exogenous hydrogen and its ability to extend longevity using Caenorhabditis elegans (C. elegans) as an animal model. Our results showed that the lifespans of the N2, sod-3 and sod-5 mutant strains were extended by approximately 22.7%, 9.5%, and 8.7%, respectively, after hydrogen treatment, but hydrogen had no effect on the lifespans of the daf-2 and daf-16 mutant strains. Meanwhile, the level of reactive oxygen species (ROS) in the hydrogen treatment group was significantly lower than that in the control group. At the transcript level, the expression of age-1 and let-363 was obviously decreased, while the expression of ins-18 was increased at the same time point (14 d). Compared with the control group, paraquat (PQ) could reduce the lifespan of the N2 and sod-5 mutant strains. Importantly, the longevity of these mutant strains recovered to normal levels when the animals were treated with exogenous hydrogen. According to these results, the lifespan of C. elegans is closely related to oxidative stress and can be significantly prolonged by reducing oxidative stress damage. Taken together, our data showed that hydrogen is a valuable antioxidant that can significantly reduce the body's ROS levels and extend the lifespan of C. elegans. This study also laid a foundation for the subsequent application of hydrogen in antiaging studies.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Hidrogênio/farmacologia , Longevidade/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/metabolismo , Regulação para Baixo/efeitos dos fármacos , Interações Medicamentosas , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat/farmacologia , Transdução de Sinais/efeitos dos fármacos
13.
Bull Entomol Res ; 110(4): 558-565, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32238200

RESUMO

Plant-derived compounds can be an environmentally friendly alternative to synthetic pesticide use for pest management. Essential oils (EOs) in several plant families have been found to be toxic to various pest species of insects through topical application, ingestion, and as fumigants. Previous studies revealed that, among various environmentally friendly insecticides, the EOs of Baccharis dracunculifolia and Pinus elliottii and an ethanol extract of Solanum granulosoleprosum plus Ricinus communis, were toxic to Ceratitis capitata and Anastrepha fraterculus (Diptera: Tephritidae) when applied topically to pupae or when ingested by adults. Here, we aimed to examine the potentially toxic effects of these plant-derived compounds when these two pestiferous fruit fly species were exposed to their vapors. We also examined their fumigant effect on female fecundity and fertility and compared it with water and ethanol controls. Exposure of C. capitata and A. fraterculus sexually mature adults to volatiles and vapors of both B. dracunculifolia and P. elliottii EOs resulted in lower longevity (half-life), survivorship, and female fecundity than the water vapor control. Toxicity of C. capitata was greater for P. elliottii than for B. dracunculifolia while the reverse was true for A. fraterculus. Exposure to vapors of S. granulosoleprosum + R. communis (S + R) had no effect on longevity but reduced survivorship of adults of both species. Interestingly, exposure to vapors of S + R, 50% (v/v) and pure ethanol resulted in greater fecundity of females of both frugivorous fly species than the water control. By contrast, fertility (% egg hatch) was in all cases high (>85%) and not different than the water control. Exposure to ethanol vapors appears to have similar effects on frugivorous tephritids as those reported on saprophagous and frugivorous species of Drosophila, a novel finding that may have important practical implications.


Assuntos
Fertilidade/efeitos dos fármacos , Óleos Voláteis/farmacologia , Tephritidae/efeitos dos fármacos , Animais , Baccharis/química , Ceratitis capitata/efeitos dos fármacos , Etanol/farmacologia , Fumigação , Inseticidas/farmacologia , Longevidade/efeitos dos fármacos , Pinus/química , Ricinus/química , Solanum/química
14.
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
15.
Adv Exp Med Biol ; 1260: 319-332, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304040

RESUMO

Metformin is a safe, effective and useful drug for glucose management in patients with diabetes. However in recent years, more attention has been paid to the possibility of using metformin as an anti-aging drug. It was shown to significantly increase the lifespan in some model organisms and delay the onset of age-associated declines. The current review summarizes advances in clinical research on the potential role of metformin in the field of lifespan and healthspan extension. Growing amounts of evidence from clinical trials suggest that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, chronic inflammation and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain types of cancer. Moreover, metformin induces autophagy by activation of AMPK and can thus be potentially used to promote heathspan by hormesis-like mechanisms. Although long-term intake of metformin is associated with low risk of adverse events, well-designed clinical trials are still required to uncover the potential use of this drug as a geroprotector.


Assuntos
Envelhecimento/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Metformina/farmacologia , Metformina/uso terapêutico , Idoso , Envelhecimento/patologia , Envelhecimento/fisiologia , Ensaios Clínicos como Assunto , Doença , Fragilidade/tratamento farmacológico , Humanos , Longevidade/fisiologia , Metformina/efeitos adversos
16.
PLoS Med ; 17(4): e1003077, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32243443

RESUMO

BACKGROUND: The rise of gonococcal antimicrobial resistance highlights the need for strategies that extend the clinically useful life span of antibiotics. Because there is limited evidence to support the current practice of switching empiric first-line antibiotic when resistance exceeds 5% in the population, our objective was to compare the impact of alternative strategies on the effective life spans of antibiotics and the overall burden of gonorrhea. METHODS AND FINDINGS: We developed and calibrated a mathematical model of gonorrhea transmission among men who have sex with men (MSM) in the United States. We calibrated the model to the estimated prevalence of gonorrhea, the rate of gonorrhea cases, and the proportion of cases presenting symptoms among MSM in the US. We used this model to project the effective life span of antibiotics and the number of gonorrhea cases expected under current and alternative surveillance strategies over a 50-year simulation period. We demonstrate that compared to the current practice, a strategy that uses quarterly (as opposed to yearly) surveillance estimates and incorporates both the estimated prevalence of resistance and the trend in the prevalence of resistance to determine treatment guidelines could extend the effective life span of antibiotics by 0.83 years. This is equivalent to successfully treating an additional 80.1 (95% uncertainty interval: [47.7, 111.9]) gonorrhea cases per 100,000 MSM population each year with the first-line antibiotics without worsening the burden of gonorrhea. If the annual number of isolates tested for drug susceptibility is doubled, this strategy could increase the effective life span of antibiotics by 0.94 years, which is equivalent to successfully treating an additional 91.1 (54.3, 127.3) gonorrhea cases per 100,000 MSM population each year without increasing the incidence of gonorrhea. Study limitations include that our conclusions might not be generalizable to other settings because our model describes the transmission of gonorrhea among the US MSM population, and, to better capture uncertainty in the characteristics of current and future antibiotics, we chose to model hypothetical drugs with characteristics similar to the antibiotics commonly used in gonorrhea treatment. CONCLUSIONS: Our results suggest that use of data from surveillance programs could be expanded to prolong the clinical effectiveness of antibiotics without increasing the burden of the disease. This highlights the importance of maintaining effective surveillance systems and the engagement of policy makers to turn surveillance findings into timely and effective decisions.


Assuntos
Antibacterianos/administração & dosagem , Gonorreia/tratamento farmacológico , Homossexualidade Masculina , Longevidade/efeitos dos fármacos , Modelos Teóricos , Guias de Prática Clínica como Assunto/normas , Gonorreia/epidemiologia , Gonorreia/transmissão , Humanos , Longevidade/fisiologia , Masculino , Resultado do Tratamento , Estados Unidos/epidemiologia
17.
PLoS One ; 15(3): e0230006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163465

RESUMO

The Caulobacter genus, including the widely-studied model organism Caulobacter crescentus, has been thought to be non-pathogenic and thus proposed as a bioengineering vector for various environmental remediation and medical purposes. However, Caulobacter species have been implicated as the causative agents of several hospital-acquired infections, raising the question of whether these clinical isolates represent an emerging pathogenic species or whether Caulobacters on whole possess previously-unappreciated virulence capability. Given the proposed environmental and medical applications for C. crescentus, understanding the potential pathogenicity of this bacterium is crucial. Consequently, we sequenced a clinical Caulobacter isolate to determine if it has acquired novel virulence determinants. We found that the clinical isolate represents a new species, Caulobacter mirare that, unlike C. crescentus, grows well in standard clinical culture conditions. C. mirare phylogenetically resembles both C. crescentus and the related C. segnis, which was also thought to be non-pathogenic. The similarity to other Caulobacters and lack of obvious pathogenesis markers suggested that C. mirare is not unique amongst Caulobacters and that consequently other Caulobacters may also have the potential to be virulent. We tested this hypothesis by characterizing the ability of Caulobacters to infect the model animal host Galleria mellonella. In this context, two different lab strains of C. crescentus proved to be as pathogenic as C. mirare, while lab strains of E. coli were non-pathogenic. Further characterization showed that Caulobacter pathogenesis in the Galleria model is mediated by lipopolysaccharide (LPS), and that differences in LPS chemical composition across species could explain their differential toxicity. Taken together, our findings suggest that many Caulobacter species can be virulent in specific contexts and highlight the importance of broadening our methods for identifying and characterizing potential pathogens.


Assuntos
Caulobacter/patogenicidade , Mariposas/microbiologia , Animais , Caulobacter/classificação , Caulobacter/genética , Caulobacter/isolamento & purificação , Modelos Animais de Doenças , Água Doce/microbiologia , Genoma Bacteriano , Lipopolissacarídeos/toxicidade , Longevidade/efeitos dos fármacos , Mariposas/fisiologia , Filogenia , Microbiologia do Solo , Virulência
18.
Nat Commun ; 11(1): 1168, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127537

RESUMO

Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc-/-) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc-/- livers. Treatment of G2-Terc-/- mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc-/- mice also decreases longevity, in contrast to lifespan extension in single S6K1-/- female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.


Assuntos
Envelhecimento/genética , RNA/genética , Serina-Treonina Quinases TOR/metabolismo , Telomerase/genética , Telômero/genética , Envelhecimento/efeitos dos fármacos , Animais , Dano ao DNA/efeitos dos fármacos , Feminino , Longevidade/efeitos dos fármacos , Longevidade/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/genética , Fosforilação , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Sirolimo/farmacologia , Taxa de Sobrevida , Serina-Treonina Quinases TOR/genética , Telômero/efeitos dos fármacos , Telômero/metabolismo
19.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165727, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32070771

RESUMO

Mitochondrial complex I (CI), the first multiprotein enzyme complex of the OXPHOS system, executes a major role in cellular ATP generation. Consequently, dysfunction of this complex has been linked to inherited metabolic disorders, including Leigh disease (LD), an often fatal disease in early life. Development of clinical effective treatments for LD remains challenging due to the complex pathophysiological nature. Treatment with the peroxisome proliferation-activated receptor (PPAR) agonist bezafibrate improved disease phenotype in several mitochondrial disease mouse models mediated via enhanced mitochondrial biogenesis and fatty acid ß-oxidation. However, the therapeutic potential of this mixed PPAR (α, δ/ß, γ) agonist is severely hampered by hepatotoxicity, which is possibly caused by activation of PPARγ. Here, we aimed to investigate the effects of the PPARα-specific fibrate clofibrate in mitochondrial CI-deficient (Ndufs4-/-) mice. Clofibrate increased lifespan and motor function of Ndufs4-/- mice, while only marginal hepatotoxic effects were observed. Due to the complex clinical and cellular phenotype of CI-deficiency, we also aimed to investigate the therapeutic potential of clofibrate combined with the redox modulator KH176. As described previously, single treatment with KH176 was beneficial, however, combining clofibrate with KH176 did not result in an additive effect on disease phenotype in Ndufs4-/- mice. Overall, both drugs have promising, but independent and nonadditive, properties for the pharmacological treatment of CI-deficiency-related mitochondrial diseases.


Assuntos
Cromanos/farmacologia , Clofibrato/farmacologia , Complexo I de Transporte de Elétrons/deficiência , Longevidade/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Bezafibrato/farmacologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Ácidos Graxos/metabolismo , Humanos , Doença de Leigh/tratamento farmacológico , Doença de Leigh/metabolismo , Doença de Leigh/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Atividade Motora/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética
20.
Molecules ; 25(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952185

RESUMO

Orange, with various bioactive phytochemicals, exerts various beneficial health effects, including anti-cancer, antioxidant, and anti-inflammatory properties. However, its anti-aging effects remain unclear. In this study, the Caenorhabditis elegans (C. elegans) model was used to evaluate the effects of orange extracts on lifespan and stress resistance. The results indicated that orange extracts dose-dependently increased the mean lifespan of C. elegans by 10.5%, 18.0%, and 26.2% at the concentrations of 100, 200, and 400 mg/mL, respectively. Meanwhile, orange extracts promoted the healthspan by improving motility, and decreasing the accumulation of age pigment and intracellular reactive oxygen species (ROS) levels without damaging fertility. The survival rates of orange extract-fed worms were obviously higher than those of untreated worms against thermal and ultraviolet-B (UV-B) stress. Moreover, the activities of superoxide dismutase (SOD) and catalase (CAT) were significantly enhanced while malondialdehyde (MDA) contents were diminished. Further investigation revealed that worms supplemented with orange extracts resulted in upregulated levels of genes, including daf-16, sod-3, gst-4, sek-1, and skn-1, and the downregulation of age-1 expression. These findings revealed that orange extracts have potential anti-aging effects through extending the lifespan, enhancing stress resistance, and promoting the healthspan.


Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/crescimento & desenvolvimento , Citrus sinensis/química , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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