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1.
Environ Pollut ; 256: 113406, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662251

RESUMO

Toluene is a highly volatile organic solvent present in gasoline. Exposure mainly occurs by absorption via the pulmonary tract and easily reaches the central nervous system, which causes toxic effects. Toluene toxicity has been described but not well established. The present work aimed to evaluate the effects of airborne exposure to toluene, the in vivo model Caenorhabditis elegans was assessed to determine whether nematode could be used to evaluate the effects of exposure to toluene and the possible mechanisms of toxicity of the solvent. Worms at the first or fourth larval stages were exposed to toluene for 48 or 24 h, respectively, in a laboratory-developed vapor chamber at concentrations of 450, 850, 1250 and 1800 ppm. We observed increases in worm mortality and significant developmental delays that occurred in a concentration-dependent manner. An increased incidence of apoptotic events in treated germline cells was shown, which was consistent with observed reductions in reproductive capacity. In addition, toluene promoted significant behavioural changes affecting swimming movements and radial locomotion, which were associated with changes in the fluorescence intensity and morphology of GABAergic and cholinergic neurons. We conclude that toluene exposure was toxic to C. elegans, with effects produced by the induction of apoptosis and neuronal damage.


Assuntos
Poluentes Atmosféricos/toxicidade , Caenorhabditis elegans/fisiologia , Tolueno/toxicidade , Poluentes Atmosféricos/análise , Animais , Apoptose/fisiologia , Caenorhabditis elegans/efeitos dos fármacos , Células Germinativas , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Tolueno/análise
2.
Environ Pollut ; 256: 113382, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31662252

RESUMO

The widespread use of zinc oxide nanoparticles (ZnO-NPs) has led to their release into the environment, and they thus represent a potential risk for both humans and ecosystems. However, the negative impact of ZnO-NPs on the immune system, especially in relation to host defense against pathogenic infection and its underlying regulatory mechanisms, remains largely unexplored. This study investigated the effects of early-life long-term ZnO-NPs exposure (from L1 larvae to adults) on innate immunity and its underlying mechanisms using a host-pathogen Caenorhabditis elegans model, and this was compared with the effect of ionic Zn. The results showed that the ZnO-NPs taken up by C. elegans primarily accumulated in the intestine and that early-life long-term ZnO-NPs exposure at environmentally relevant concentrations (50 and 500 µg/L) decreased the survival of wild-type C. elegans when faced with pathogenic Pseudomonas aeruginosa PA14 infection. Early-life long-term ZnO-NPs (500 µg/L) exposure significantly increased (by about 3-fold) the accumulation of live P. aeruginosa PA14 colonies in the intestine of C. elegans. In addition, ZnO-NPs (500 µg/L) inhibited the intestinal nuclear translocation of SKN-1 and also downregulated gcs-1 gene expression, which is an SKN-1 target gene. Further evidence revealed that early-life long-term exposure to ZnO-NPs (500 µg/L) did not increase susceptibility to mutation among the genes (pmk-1, sek-1, and nsy-1) encoding the p38 mitogen-activated protein kinase (MAPK) cascade in response to P. aeruginosa PA14 infection, though ZnO-NPs significantly decreased the mRNA levels of pmk-1, sek-1, and nsy-1. This study provides regulatory insight based on evidence that ZnO-NPs suppress the innate immunity of C. elegans and highlights the potential health risks of certain environmental nanomaterials, including ZnO-NPs, in terms of their immunotoxicity at environmentally relevant concentrations.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Imunidade Inata/efeitos dos fármacos , Nanopartículas/toxicidade , Fatores de Transcrição/metabolismo , Óxido de Zinco/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Ecossistema , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento
3.
Chemosphere ; 242: 125078, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31704520

RESUMO

The widespread use of tetrabromobisphenol A (TBBPA) in industries has resulted in its frequent detection in environmental matrices, and the mechanisms of its associated hazards need further investigation. In this study, the nematode Caenorhabditis elegans (C. elegans) was exposed to environmentally relevant concentrations of TBBPA (0, 0.1, 1, 10, 100, 200 µg/L) to determine its effects. At TBBPA concentrations above 1 µg/L, the number of head thrashes, as the most sensitive physiological indicator, decreased significantly. Using the Illumina HiSeq™ 2000 sequencer, differentially expressed genes (DEGs) were determined, and 52 were down regulated and 105 were up regulated in the 200 µg/L TBBPA treatment group versus the control group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database analysis demonstrated that dorso-ventral axis formation is related to neurotoxicity; metabolism of xenobiotics by Cytochrome P450 (CYP450) and glutathione-S-transferase (GST) was found to be the vital metabolic mechanisms and were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). GST was ascribed to the augmentation because mutations in cyp-13A7 were constrained under TBBPA exposure. Additionally, oxidative stress indicators accumulated in a dose-dependent relationship. These results will help understand the molecular basis for TBBPA-induced toxicity in C. elegans and open novel avenues for facilitating the exploration of more efficient strategies against TBBPA toxicity.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Bifenil Polibromatos/toxicidade , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Perfilação da Expressão Gênica , Glutationa Transferase/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo Real
4.
Environ Pollut ; 256: 113439, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672355

RESUMO

Nanoplastics can be used in various fields, such as personal care products. Nevertheless, the effect of nanoplastic exposure on metabolism and its association with stress response remain largely unclear. Using Caenorhabditis elegans as an animal model, we determined the effect of nanopolystyrene exposure on lipid metabolism and its association with the response to nanopolystyrene. Exposure (from L1-larave to adult day-3) to 100 nm nanopolystyrene (≥1 µg/L) induced severe lipid accumulation and increase in expressions of mdt-15 and sbp-1 encoding two lipid metabolic sensors. Meanwhile, we found that SBP-1 acted downstream of intestinal MDT-15 during the control of response to nanopolystyrene. Intestinal transcriptional factor SBP-1 activated two downstream targets, fatty acyl CoA desaturase FAT-6 and heat-shock protein HSP-4 (a marker of endoplasmic reticulum unfolded protein response (ER UPR)) to regulate nanopolystyrene toxicity. Both MDT-15 and SBP-1 were involved in the activation of ER-UPR in nanopolystyrene exposed nematodes. Moreover, SBP-1 regulated the innate immune response by activating FAT-6 in nanopolystyrene exposed nematodes. In the intestine, function of MDT-15 and SBP-1 in regulating nanopolystyrene toxicity was under the control of upstream signaling cascade (PMK-1-SKN-1) in p38 MAPK signaling pathway. Therefore, our data raised an important molecular basis for potential protective function of lipid metabolic response in nanopolystyrene exposed nematodes.


Assuntos
Caenorhabditis elegans/fisiologia , Poluentes Ambientais/toxicidade , Poliestirenos/toxicidade , Animais , Caenorhabditis elegans/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Lipídeos , Sistema de Sinalização das MAP Quinases , Transdução de Sinais , Resposta a Proteínas não Dobradas
5.
Phytomedicine ; 66: 153132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790899

RESUMO

BACKGROUND: Chlorogenic acid (CGA) is a polyphenol widely distributed in plants and plant-derived food with antioxidant and protective activities against cell stress. Caenorhabditis elegans is a model organism particularly useful for understanding the molecular and biochemical mechanisms associated with aging and stress in mammals. In C. elegans, CGA was shown to improve resistance to thermal, while the underlying mechanisms that lead to this effect require further understanding. PURPOSE: The present study was conducted to investigate the underlying molecular mechanisms behind CGA response conferring thermotolerance to C. elegans. METHODS AND RESULTS: Signaling pathways that could be involved in the CGA-induced thermotolerance were evaluated in C. elegans strains with loss-of-function mutation. CGA-induced thermotolerance required hypoxia-inducible factor HIF-1 but no insulin pathway. CGA exposition (1.4 µM CGA for 18 h) before thermal stress treatment increased HIF-1 levels and activity. HIF-1 activation could be partly attributed to an increase in radical oxygen species and a decrease in superoxide dismutase activity. In addition, CGA exposition before thermal stress also increased autophagy just as hormetic heat condition (HHC), worms incubated at 36 °C for 1 h. RNAi experiments evidenced that autophagy was increased by CGA via HIF-1, heat-shock transcription factor HSF-1 and heat-shock protein HSP-16 and HSP-70. In contrast, autophagy induced by HHC only required HSF-1 and HSP-70. Moreover, suppression of autophagy induction showed the significance of this process for adapting C. elegans to cope with thermal stress. CONCLUSION: This study demonstrates that CGA-induced thermotolerance in C. elegans is mediated by HIF-1 and downstream, by HSF-1, HSPs and autophagy resembling HHC.


Assuntos
Autofagia/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Ácido Clorogênico/farmacologia , Proteínas de Choque Térmico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Ácido Clorogênico/química , Proteínas de Choque Térmico/genética , Resposta ao Choque Térmico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Termotolerância/efeitos dos fármacos , Fatores de Transcrição/genética
6.
Food Chem ; 307: 125537, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31644978

RESUMO

Cafestol, a coffee diterpene, is a known agonist of farnesoid X receptors (FXR), which are involved in cholesterol homeostasis. FXR plays critical roles in other lipid metabolic pathways, including fat oxidation; however, little is known about cafestol's effects on fatty acid metabolism. Thus, the goal was to investigate cafestol's effects on fatty acid metabolism using Caenorhabditis elegans. Cafestol at 60 µM reduced fat accumulation and increased locomotor activity (an indicator of energy expenditure) by 20% and 38%, respectively, compared to the control. Cafestol's effects were dependent on daf-12 (a functional homolog of the human FXR) with upregulation of ech-1.1 (a homolog of enoyl-CoA hydratase involved in fatty acid ß-oxidation) and tub-1 (an ortholog of the human TUBBY involved in the neurological regulation of energy expenditure) without any effects on lipogenesis, lipolysis or lipid uptake and transport. Therefore, cafestol increased fat oxidation and energy expenditure via DAF-12-dependent pathway in C. elegans.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Diterpenos/farmacologia , Metabolismo Energético , Metabolismo dos Lipídeos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Animais , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/metabolismo , Enoil-CoA Hidratase/metabolismo , Humanos
7.
J Agric Food Chem ; 68(2): 461-470, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31868356

RESUMO

Contamination of the environment by toxic pesticides has become of great concern in agricultural countries. Chlorpyrifos (CP) is among the pesticides most commonly detected in the environment owing to its wide agricultural applications. The aim of this study was to compare potential changes in the toxicity of CP after irradiation. To this end, photolysis of CP was conducted under simulated sunlight, and neurotoxicity assessment was carried out at CP of 20 and 50 µg L-1 and its corresponding irradiated mixture solutions which contain a mixture of identified intermediates using the nematode, Caenorhabditis elegans as a model organism. Photodegradation of 20 µg L-1 CP for 1 h produced no obvious reduction of physiological damage, and more serious effects on animal movement were detected after exposure of the animals to a solution of 50 µg L-1 for 1 h irradiation compared with unirradiated solution. GABAergic and cholinergic neurons were selectively vulnerable to CP exposure, and maximal neuropathological alterations were observed after 1 h irradiation of the CP solutions in coherence with the behavioral impairment. The generation of photoproducts was considered to be responsible for the enhanced disturbance on those biological processes. This work provided useful information on the toxicological assessments of chemicals that were produced during the environmental transformation of pesticides.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Clorpirifos/toxicidade , Neurônios/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Clorpirifos/química , Clorpirifos/efeitos da radiação , Feminino , Masculino , Estrutura Molecular , Praguicidas/química , Praguicidas/efeitos da radiação , Fotólise , Luz Solar
8.
Ecotoxicol Environ Saf ; 187: 109709, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654870

RESUMO

Among the most used chemicals in the world are nonionic surfactants. One of these environmental pollutants is nonylphenol ethoxylate (NP-9), also known as Tergitol, and its degradation product, nonylphenol (NP). The objective of this work was to determine the toxicity of NP and NP-9 in Caenorhabditis elegans. Wild-type L4 larvae were exposed to different concentrations of the surfactants to measure functional endpoints. Mutant strains were employed to promote the activation of toxicity signaling pathways related to mtl-2, gst-1, gpx-4, gpx-6, sod-4, hsp-70 and hsp-4. Additionally, stress response was also assessed using a daf-16::GFP transgenic strain. The lethality was concentration dependent, with 24-h LC50 of 122 µM and 3215 µM for NP and NP-9, respectively. Both compounds inhibited nematode growth, although NP was more potent; and at non-lethal concentrations, nematode locomotion was reduced. The increase in the expression of tested genes was significant at 10 µM for NP-9 and 0.001 µM for NP, implying a likely role for the activation of oxidative and cellular stress, as well as metabolism pathways. With the exception of glutathione peroxidase, which has a bimodal concentration-response curve for NP, typical of endocrine disruption, the other curves for this xenobiotic in the strains evaluated were almost flat for most concentrations, until reaching 50-100 µM, where the effect peaked. NP and NP-9 induced the activation and nuclear translocation of DAF-16, suggesting that transcription of stress-response genes may be mediated by the insulin/IGF-1 signaling pathway. In contrast, NP-9 induced a concentration-dependent response for the sod-4 and hsp-4 mutants, with greater fluorescence induction than NP at similar levels. In short, NP and NP-9 affect the physiology of C. elegans and modulate gene expression related to ROS production, cellular stress and metabolism of xenobiotics.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Etilenoglicóis/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Expressão Gênica/efeitos dos fármacos , Larva/metabolismo , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Estresse Oxidativo/genética
9.
Ecotoxicol Environ Saf ; 187: 109848, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670182

RESUMO

Dimethyl terephthalate (DMT) is a primary ingredient widely used in the manufacture of polyesters and industrial plastics; its environmental fate is of concern due to its global use. Microorganisms play key roles in the dissipation of DMT from the environment; however, the enzymes responsible for the initial transformation of DMT and the possible altered toxicity due to this biotransformation have not been extensively studied. To reduce DMT toxicity, we identified the esterase gene dmtH involved in the initial transformation of DMT from the AOPP herbicide-transforming strain Sphingobium sp. C3. DmtH shows 24-41% identity with α/ß-hydrolases and belongs to subfamily V of bacterial esterases. The purified recombinant DmtH was capable of transforming DMT to mono-methyl terephthalate (MMT) and potentially transforming other p-phthalic acid esters, including diallyl terephthalate (DAT) and diethyl terephthalate (DET). Using C. elegans as an assay model, we observed the severe toxicity of DMT in inducing reactive oxygen species (ROS) production, decreasing locomotion behavior, reducing lifespan, altering molecular basis for oxidative stress, and inducing mitochondrial stress. In contrast, exposure to MMT did not cause obvious toxicity, induce oxidative stress, and activate mitochondrial stress in nematodes. Our study highlights the usefulness of Sphingobium sp. C3 and its esterase DmtH in transforming p-phthalic acid esters and reducing the toxicity of DMT to organisms.


Assuntos
Poluentes Ambientais/toxicidade , Esterases/genética , Genes Bacterianos , Ácidos Ftálicos/toxicidade , Sphingomonadaceae/metabolismo , Animais , Biodegradação Ambiental , Biotransformação , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Poluentes Ambientais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/metabolismo , Plásticos/química , Sphingomonadaceae/enzimologia , Sphingomonadaceae/genética
10.
Ecotoxicol Environ Saf ; 187: 109777, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31670241

RESUMO

Microbial community of an organism plays an important role on its fitness, including stress responses. In this study, we investigated the effect of the culturable subset of soil microbial community (SMB) on the stress response of the soil nematode Caenorhabditis elegans, upon exposure to one of the major soil contaminants, cadmium (Cd). Life history traits and the stress responses to Cd exposure were compared between SMB- and Escherichia coli strain OP50-fed worms. SMB-fed worms showed higher reproduction rates and longer lifespans. Also, the SMB-fed worms showed more tolerant response to Cd exposure. Gene expression profiling suggested that the chemical stress and immune response of worms were boosted upon SMB feeding. Finally, we investigated C. elegans gut microbial communities in the presence and absence of Cd in OP50- and SMB-fed C. elegans. In the OP50-fed worms, changes in microbial community by Cd exposure was severe, whereas in the SMB-fed worms, it was comparatively weak. Our results suggest that the SMB affects the response of C. elegans to Cd exposure and highlight the importance of the gut microbiome in host stress response.


Assuntos
Cádmio/toxicidade , Caenorhabditis elegans/efeitos dos fármacos , Escherichia coli , Microbioma Gastrointestinal/efeitos dos fármacos , Microbiologia do Solo , Poluentes do Solo/toxicidade , Ração Animal , Animais , Caenorhabditis elegans/microbiologia , Escherichia coli/crescimento & desenvolvimento , Trato Gastrointestinal/microbiologia , Longevidade , Estresse Oxidativo/efeitos dos fármacos , Solo/química
11.
Life Sci ; 243: 117237, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887302

RESUMO

AIMS: Dauricine has been found that has significant neuroprotective effect on Alzheimer's disease (AD), but the mechanism is unclear, so we further investigated the possible mechanism of dauricine on AD. MAIN METHODS: Cell counting kit-8 (CCK8) was applied to measure the cytotoxicity of dauricine on SH-SY5Y cells that overexpress the Swedish mutant form of human ß-amyloid precursor protein (APPsw) and control cells (Neo). We used the Cu2+ to induce oxidative damage on APPsw cells, then tested the effect of dauricine on the damage and relative factors including reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) activity. The secretion level of amyloid beta 1-42(Aß1-42), protein expression of apoptosis-related factors and the components of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were determined by western blotting. Aß1-42-transgenic Caenorhabditis elegans GMC101, a model of AD, was applied to evaluate the neuroprotective effect of dauricine through the behavioral experiment and relative anti-oxidative tests. KEY FINDINGS: In vitro, dauricine decreased the secretion level of Aß1-42, significantly reduced the level of Cu2+-induced ROS, and restored MMP and SOD activity in APPsw cells. Meanwhile, dauricine could suppress the activation of caspase-3 and to upregulate the expression of Bcl-2. Dauricine also regulated the proteins levels of Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) that is necessary for the activation of Nrf2 in APPsw cell. As oxidative stress induced by Aß or paraquat (PQ), dauricine showed protective effects in the survival experiment of GMC101 worms. SIGNIFICANCE: Those data revealed that dauricine has the pharmacological activity of anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Tetra-Hidroisoquinolinas/uso terapêutico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Geneticamente Modificados , Antioxidantes/farmacologia , Benzilisoquinolinas/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Linhagem Celular , Cobre/farmacologia , Modelos Animais de Doenças , Humanos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidroisoquinolinas/farmacologia
12.
J Photochem Photobiol B ; 201: 111637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706086

RESUMO

Plants are considered to be a leading source for possible human therapeutic agents. This holistic study has investigated the anti-quorum sensing (anti-QS), anti-infection, antioxidant and anti-photoaging properties of neglected plant Diplocyclos palmatus. The results showed that D. palmatus methanolic leaf extract (DPME) effectively inhibited the quorum sensing (QS) regulated virulence factor production as well as biofilm formation in Serratia marcescens. The transcriptomic analysis revealed that DPME significantly downed the expression of QS-regulated genes such as fimA, fimC, flhC, bsmB, pigP and shlA in S. marcescens, which supports the outcome of in vitro bioassays. Further, the docking study revealed that the presence of active compounds, namely tocopherols and phytol, DPME exhibited its anti-QS activity against S. marcescens. In addition, DPME treatment extended the lifespan of S. marcescens infected C. elegans by the action of dropping the internal accumulation. Further, qPCR analysis clearly revealed that DPME treatment significantly up-regulated the expression of the lifespan-related gene (daf-16) and immune-related genes (clec-60, clec-87, lys-7 and bec-1) in S. marcescens infected C.elegans. On the other hand, DPME extensively reduced the UV-A induced ROS stress, thereby, extended the lifespan in UV-A photoaged C. elegans. Further, the qPCR analysis also confirmed the up-regulation of daf-16, clec-60, clec-87 and col-19 genes which advocated the improvement of the lifespan, healthspan and collagen production in UV-A photoaged C. elegans. Further bioassays evidenced that that the lifespan extension of photoaged C. elegans was accomplished by the actions of antioxidants such as tocopherols and phytol in DPME.


Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos da radiação , Cucurbitaceae/química , Extratos Vegetais/farmacologia , Percepção de Quorum/efeitos dos fármacos , Serratia marcescens/fisiologia , Raios Ultravioleta , Envelhecimento/efeitos da radiação , Animais , Antioxidantes/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Colágeno/metabolismo , Cucurbitaceae/metabolismo , Longevidade/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismo , Infecções por Serratia/patologia , Infecções por Serratia/veterinária , Regulação para Cima/efeitos dos fármacos
13.
PLoS Negl Trop Dis ; 13(11): e0007895, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31765374

RESUMO

The anthelmintic treatment of nematode infections remains the pillar of worm control in both human and veterinary medicine. Since control is threatened by the appearance of drug resistant nematodes, there is a need to develop novel compounds, among which phytochemicals constitute potential anthelmintic agents. Caenorhabditis elegans has been pivotal in anthelmintic drug discovery and in revealing mechanisms of drug action and resistance. By using C. elegans, we here revealed the anthelmintic actions of three plant terpenoids -thymol, carvacrol and eugenol- at the behavioral level. Terpenoids produce a rapid paralysis of worms with a potency rank order carvacrol > thymol > eugenol. In addition to their paralyzing activity, they also inhibit egg hatching, which would, in turn, lead to a broader anthelmintic spectrum of activity. To identify drug targets, we performed an in vivo screening of selected strains carrying mutations in receptors involved in worm locomotion for determining resistance to the paralyzing effect of terpenoids. The assays revealed that two Cys-loop receptors with key roles in worm locomotion -Levamisole sensitive nicotinic receptor (L-AChR) and GABA(A) (UNC-49) receptor- are involved in the paralyzing effects of terpenoids. To decipher the mechanism by which terpenoids affect these receptors, we performed electrophysiological studies using a primary culture of C. elegans L1 muscle cells. Whole cell recordings from L1 cells demonstrated that terpenoids decrease macroscopic responses of L-AChR and UNC-49 receptor to their endogenous agonists, thus acting as inhibitors. Single-channel recordings from L-AChR revealed that terpenoids decrease the frequency of opening events, probably by acting as negative allosteric modulators. The fact that terpenoids act at different receptors may have important advantages regarding efficacy and development of resistance. Thus, our findings give support to the use of terpenoids as either an alternative or a complementary anthelmintic strategy to overcome the ever-increasing resistance of parasites to classical anthelmintic drugs.


Assuntos
Anti-Helmínticos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/enzimologia , Receptores de Canais Iônicos de Abertura Ativada por Ligante com Alça de Cisteína/antagonistas & inibidores , Terpenos/farmacologia , Animais , Células Cultivadas , Locomoção/efeitos dos fármacos , Células Musculares/efeitos dos fármacos
14.
BMC Complement Altern Med ; 19(1): 313, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730453

RESUMO

BACKGROUND: Jianpi-yangwei (JPYW), a traditional Chinese medicine (TCM), helps to nourish the stomach and spleen and is primarily used to treat functional declines related to aging. This study aimed to explore the antiaging effects and mechanism of JPYW by employing a Caenorhabditis elegans model. METHODS: Wild-type C. elegans N2 worms were cultured in growth medium with or without JPYW, and lifespan analysis, oxidative and heat stress resistance assays, and other aging-related assays were performed. The effects of JPYW on the levels of superoxide dismutase (SOD) and the expression of specific genes were examined to explore the underlying mechanism of JPYW. RESULTS: Compared to control worms, JPYW-treated wild-type worms showed increased survival times under both normal and stress conditions (P < 0.05). JPYW-treated worms also exhibited enhanced reproduction, movement and growth and decreased intestinal lipofuscin accumulation compared to controls (P < 0.05). Furthermore, increased activity of SOD, downregulated expression levels of the proaging gene clk-2 and upregulated expression levels of the antiaging genes daf-16, skn-1, and sir-2.1 were observed in the JPYW group compared to the control group. CONCLUSION: Our findings suggest that JPYW extends the lifespan of C. elegans and exerts antiaging effects by increasing the activity of an antioxidant enzyme (SOD) and by regulating the expression of aging-related genes. This study not only indicates that this Chinese compound exerts antiaging effects by activating and repressing target genes but also provides a proven methodology for studying the biological mechanisms of TCMs.


Assuntos
Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Humanos , Longevidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
15.
Environ Sci Pollut Res Int ; 26(36): 36820-36831, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31745774

RESUMO

The adverse effects of heavy metals, such as cadmium, zinc, and copper, occur due to the generation of reactive oxygen species (ROS). The use of Caenorhabditis elegans for the purposes of conservation and biomonitoring is of great interest. In the present study, ROS, malondialdehyde (MDA), and citric acid levels and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in a model organism were tested to study toxicity. C. elegans was exposed to three different concentrations of cadmium (CdCl2, 5, 10, 50 µM), zinc (ZnSO4, 10, 100, 500 µM), and copper (CuSO4, 10, 100, 500 µM) for 3 days. ROS levels increased by 1.3- to 2.1-fold with increasing metal concentrations. The MDA content increased by approximately 7-, 5-, 2-fold after exposure to high concentrations of cadmium, zinc, and copper, respectively. Furthermore, the citric acid content increased by approximately 3-fold in the cadmium (Cd, 5 µM), zinc (Zn, 10 µM), and copper (Cu, 100 µM) treatment groups compared to that in untreated C. elegans. Therefore, citric acid may play an important role in heavy metal detoxification. Excess citric acid also slightly increased the LC50 by 1.3- to 2.0-fold, basic movements by 1.0- to 1.5-fold, decreased the ROS content by 2.4- to 2.1-fold, the MDA content by 4- to 2-fold, the SOD activity by 9- to 3-fold, the GPx activity by 4.0- to 3.0-fold, and the mRNA expression levels of GPxs by 3.2- to 1.8-fold after metals treatment. And it is most significantly in the alleviation of citric acid to cadmium. This study not only provides information to further understand the effects of heavy metal exposure on ROS, MDA, GPx, SOD, and citric acid in worms but also indicates that supplemental citric acid can protect animals from heavy metal stress and has broad application prospects in decreasing oxidative damage caused by heavy metals.


Assuntos
Antioxidantes/metabolismo , Caenorhabditis elegans/fisiologia , Ácido Cítrico/metabolismo , Metais Pesados/toxicidade , Animais , Cádmio/toxicidade , Caenorhabditis elegans/efeitos dos fármacos , Cobre/toxicidade , Malondialdeído/metabolismo , Oxirredução , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Zinco/toxicidade
16.
PLoS Genet ; 15(10): e1008341, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658255

RESUMO

In order to respond to changing environments and fluctuations in internal states, animals adjust their behavior through diverse neuromodulatory mechanisms. In this study we show that electrical synapses between the ASH primary quinine-detecting sensory neurons and the neighboring ASK neurons are required for modulating the aversive response to the bitter tastant quinine in C. elegans. Mutant worms that lack the electrical synapse proteins INX-18 and INX-19 become hypersensitive to dilute quinine. Cell-specific rescue experiments indicate that inx-18 operates in ASK while inx-19 is required in both ASK and ASH for proper quinine sensitivity. Imaging analyses find that INX-19 in ASK and ASH localizes to the same regions in the nerve ring, suggesting that both sides of ASK-ASH electrical synapses contain INX-19. While inx-18 and inx-19 mutant animals have a similar behavioral phenotype, several lines of evidence suggest the proteins encoded by these genes play different roles in modulating the aversive quinine response. First, INX-18 and INX-19 localize to different regions of the nerve ring, indicating that they are not present in the same synapses. Second, removing inx-18 disrupts the distribution of INX-19, while removing inx-19 does not alter INX-18 localization. Finally, by using a fluorescent cGMP reporter, we find that INX-18 and INX-19 have distinct roles in establishing cGMP levels in ASK and ASH. Together, these results demonstrate that electrical synapses containing INX-18 and INX-19 facilitate modulation of ASH nociceptive signaling. Our findings support the idea that a network of electrical synapses mediates cGMP exchange between neurons, enabling modulation of sensory responses and behavior.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Conexinas/genética , Sinapses Elétricas/genética , Nociceptores/metabolismo , Quinina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , GMP Cíclico/genética , Sinapses Elétricas/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/genética , Nociceptores/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Elife ; 82019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610847

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aß)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aß peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aß-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aß expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aß-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aß-induced pathology and a promising target for intervention.


Assuntos
Peptídeos beta-Amiloides/genética , Caenorhabditis elegans/metabolismo , Ciclo do Ácido Cítrico/genética , Mitocôndrias/metabolismo , Neurônios/metabolismo , Estresse Fisiológico/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Ciclo do Ácido Cítrico/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hipoglicemiantes/farmacologia , Complexo Cetoglutarato Desidrogenase/genética , Complexo Cetoglutarato Desidrogenase/metabolismo , Análise do Fluxo Metabólico , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Neurônios/efeitos dos fármacos , Neurônios/patologia , Agregados Proteicos/efeitos dos fármacos , Carbonilação Proteica , Estresse Fisiológico/efeitos dos fármacos
18.
Nat Commun ; 10(1): 4905, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659167

RESUMO

Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine's prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.


Assuntos
Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hidralazina/administração & dosagem , Sirtuína 1/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Feminino , Humanos , Longevidade/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Sirtuína 1/genética
19.
Environ Pollut ; 255(Pt 1): 113185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522005

RESUMO

Modeling for the toxicity of ionic liquids (ILs) is necessary to fill data gaps for untested chemicals and to understand the relevant mechanisms at the molecular level. In order for many researchers to easily predict toxicity and/or develop some prediction model, simple method(s) based on a single parameter should be proposed. Therefore, previously our group developed a comprehensive toxicity prediction model with unified linear free-energy relationship descriptors to address the single parameter for predicting the toxicities, as follows (Cho et al., 2016b). Log 1/toxicity in the unit of mM= (2.254 Ec - 2.545 Sc + 0.646 Ac - 1.471 Bc + 1.650 Vc + 2.917 J+ - 0.201 Ea + 0.418 Va + 0.131 J-) - 0.709. It is considered that the model can calculate the general toxicological effect of ILs in parenthesis, as it was developed on the basis of numerous toxic effects i.e., 58 toxicity testing methods and about 1600 data points. In order to check the hypothesis, the values calculated by the model were correlated with four different datasets from insect cell line (Spodoptera frugiperda 9), earthworm (Eisenia fetida), nematode (Caenorhabditis elegans), and fish (Danio rerio). The results clearly showed that the calculated values are in good agreement with each dataset. In the case of S. frugiperda 9 cells, the calculated parameters were correlated with log1/LC50 values, measured after 24 h and 48 h incubation, in R2 of 0.67 and 0.88, respectively. The R2 values for the earthworm, nematode, and fish were 0.88, 0.96, and 0.94-0.95, respectively. This study confirmed that the comprehensive model can be simply and accurately used to predict toxicity of ILs.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Líquidos Iônicos/toxicidade , Oligoquetos/efeitos dos fármacos , Spodoptera/efeitos dos fármacos , Peixe-Zebra , Animais , Conjuntos de Dados como Assunto , Dose Letal Mediana , Modelos Químicos , Relação Quantitativa Estrutura-Atividade
20.
Environ Pollut ; 255(Pt 1): 113137, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541829

RESUMO

The potential adverse effects of nanoplastics, such as nanopolystyrene, have received the great attention recently. However, the molecular response of organisms to nanoplastics is still largely unknown. In this study, we employed Caenorhabditis elegans as an animal model to investigate the long non-coding RNAs (lncRNAs) in response to long-term exposure to low-dose nanopolystyrene (100 nm). Based on Hiseq 2000 sequencing and qRT-PCR confirmation, we identified 36 lncRNAs (21 down-regulated lncRNAs and 15 up-regulated lncRNAs) in response to nanopolystyrene (1 µg/L). Using intestinal reactive oxygen species (ROS) production and locomotion behavior as endpoints, we found that RNAi knockdown of linc-2, linc-9, or linc-61 induced a susceptibility to nanopolystyrene toxicity, and RNAi knockdown of linc-18 or linc-50 induced a resistance to nanopolystyrene toxicity. Meanwhile, nanopolystyrene (1 µg/L) increased expressions of linc-2, linc-9, linc-18, and linc-61 and decreased linc-50 expression, suggesting that these 5 lncRNAs mediated two different responses to nanopolystyrene exposure. Bioinformatical analysis implied that these 5 lncRNAs were associated with multiple biological processes and signaling pathways. Our results demonstrated the crucial roles of lncRNAs in response to long-term exposure to low-dose nanopolystyrene in organisms.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Poliestirenos/toxicidade , RNA Longo não Codificante/genética , Animais , Regulação para Baixo , Intestinos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Regulação para Cima
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