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1.
Toxicol Lett ; 322: 87-97, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935479

RESUMO

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.


Assuntos
Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Dicloretos de Etileno/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Cerebelo/metabolismo , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Locomoção/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Medição de Risco , Transdução de Sinais
2.
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
3.
Food Chem Toxicol ; 135: 110926, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676350

RESUMO

In the present study, we investigated the detrimental effects of ethoxyquin (EQ) on zebrafish embryonic development using different endpoints including lethality, malformations, locomotion and gene expression. EQ is primarily used as a preservative in animal feed and it has been shown to have negative impacts on different laboratory animals. However, studies on the adverse effects of EQ in aquatic animals are still limited. In this study, zebrafish eggs were exposed to different concentrations of EQ ranging from 1 to 100 µM for six days. In the 100 µM treated groups 95 and 100% mortality was observed at 24 and 48 h, respectively. Delayed development, decreased pigmentation and pericardial edema were observed in larvae. Behavioral analysis of larvae demonstrated a distinct locomotive pattern in response to EQ both in light and dark indicating a possible developmental neurotoxicity and deficits in locomotion. The expression levels of genes involved in several physiological pathways including stress response, cell cycle and DNA damage were altered by EQ. Our results demonstrate that EQ could cause developmental and physiological toxicity to aquatic organisms. Hence, its toxic effect should be further analyzed and its use and levels in the environment must be monitored carefully.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Etoxiquina/toxicidade , Conservantes de Alimentos/toxicidade , Transcriptoma/efeitos dos fármacos , Peixe-Zebra/embriologia , Animais , Locomoção/efeitos dos fármacos
4.
Sci Total Environ ; 703: 135623, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31761353

RESUMO

Caenorhabditis elegans is a useful animal model for assessing adverse effects of environmental toxicants or stresses. C. elegans was used as an assay system to investigate the effects of exposure to nanopolystyrene (30 nm) on wild-type and sod-3 mutant animals under microgravity stress condition. Using brood size and locomotion behaviors as endpoints, we found that nanopolystyrene exposure enhanced the toxicity of microgravity stress on nematodes, and this toxicity enhancement could be further strengthened by mutation of sod-3 encoding a Mn-SOD protein. Induction of reactive oxygen species (ROS) production and activation of mitochondrial unfolded protein response (mt UPR) were associated with this toxicity enhancement. In sod-3 mutant nematodes, the enhancement in toxicity of microgravity stress by exposure to nanopolystyrene (10 µg/L) was detected. Our data will be helpful for understanding the potential effects of nanopolystyrene exposure on nematodes under the microgravity stress condition.


Assuntos
Caenorhabditis elegans/fisiologia , Poluentes Ambientais/toxicidade , Poliestirenos/toxicidade , Animais , Locomoção/efeitos dos fármacos , Estresse Oxidativo
5.
Food Chem Toxicol ; 135: 110865, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31618664

RESUMO

Development is especially sensitive to Chlorpyrifos (CPF) toxicity, associated with several neurodegenerative and neurodevelopmental disorders where motor function dysfunction is a core symptom. Amongst the alternative molecular targets to cholinesterases inhibition, developmental CPF alters different components in the most important neurotransmitter systems, although this depends on the exposure period. Exposure during the late postnatal preweaning stage is the least studied by far. This period includes essential neurodevelopmental processes and has an important translational meaning. The present study analyzed the influence of low doses of CPF on this developmental window on locomotor activity and the state of the different neurotransmitter systems by pharmacological challenges. Brain gene expression and microbiome modulation following CPF were also analyzed. CPF exposure long-term increased spontaneous vertical activity, female's activity following acute stress, hyposensitized the cholinergic system and hypersensitized the GABAergic system, up-regulated both muscarinic 2 receptor and GABA-A-α2 receptor subunit in the dorsal striatum and the frontal cortex, respectively and induced gut microbiota dysbiosis at both genus and species levels. The present study supports alternative molecular targets than the ChEs following late postnatal, preweaning exposure to low doses of CPF, focusing on both cholinergic and GABAergic systems and the gut microbiome as an important factor.


Assuntos
Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inseticidas/toxicidade , Locomoção/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar , Receptor Muscarínico M2/metabolismo , Desmame , Ácido gama-Aminobutírico/metabolismo
6.
J Photochem Photobiol B ; 202: 111700, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810039

RESUMO

Zinc oxide (ZnO), an inorganic metal oxide established in the form of nanoparticles, has considerable biological properties. The current research uses Selaginella convolute (S. convolute) leaf extract to establish ZnO NPs and to assess their use in pain management. S. Convolute leaf extract mediated ZnO NPs were characterized by modern techniques and instruments such as Fourier transforms infrared spectroscopy (FTIR), electron microscopy, X-ray diffraction (XRD), and Ultraviolet-vis-spectroscopy (UV-vis), energy dispersive X-ray spectroscopy (EDX), indicating the emergence of spherical NPs of which is around 40 nm. The FTIR spectrum also signified that S. convolute plant extract polyphenols acted as a capping ligand for the fabricated ZnO NPs. Possessed ZnO NPs have shown important characteristics of muscle relaxing and antinociceptive. A concentration dependent acetic acid induced writhing effect was noted for both S. convolute extract and ZnO NPs. S. convolute plant extract and ZnO NPs are found to exhibit highest muscle relaxation effect in both traction and chimney tests and no sedative effect was shown by both ZnO NPs and plant extract. The present results showed that the S. convolute leaves extract is a very effective green reducing agent for the preparation of ZnO NPs and the prepared NPs can be used in pain management in emerging nursing care in future.


Assuntos
Nanopartículas Metálicas/química , Selaginellaceae/química , Óxido de Zinco/química , Ácido Acético/toxicidade , Animais , Química Verde , Locomoção/efeitos dos fármacos , Nanopartículas Metálicas/uso terapêutico , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Relaxamento Muscular/efeitos dos fármacos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Manejo da Dor , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Selaginellaceae/metabolismo
7.
Aquat Toxicol ; 218: 105357, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31812648

RESUMO

Aquatic media are ultimate recipients of various contaminants including pesticides pervasively applied in agrosystems. Characterizing the ecotoxicity of pesticides and their mixtures to aquatic wildlife at field-realistic levels is thus crucial for environmental risk assessment. This study aims at assessing the effects of two current-use insecticides, imidacloprid and chlorpyrifos, on Gammarus fossarum using multi-level biomarkers. In microcosms, gammarids were exposed for 72 h to insecticides tested individually or in mixture at 0.01, 0.1 and 1 µg/L of each chemical. Multi-metric responses were assessed at the individual level (behavioural traits: locomotion, respiration and amplexus formation) and the cellular level (enzymes involved in growth, moulting, digestion and cell stress). The results showed insecticide-elicited behavioural and biochemical responses from the lowest concentration of 0.01 µg/L. Overall, single exposures stimulated behavioural traits and inhibited enzymatic activities, highlighting subtle impacts at different organizational levels but these were not dose related. For binary mixtures, antagonistic effects (i.e. less-than-additive) on biomarkers were mainly observed when compared with single exposures. Multi-variable analyses indicated the complementarity of behavioural and biochemical biomarkers in identifying sublethal biological alterations and dose-dependent multiple action sites of insecticides. Besides, the mortality observed only for the mixture at 1 µg/L demonstrated a high lethal potential of insecticides in a simple binary combination. To conclude, this study demonstrates disturbances in individual performances and cellular impairments occurring at environmentally realistic exposure levels in a non-target wild species. Since the sublethal effects, such as those identified with this multi-biomarker approach, could lead to long-term alterations in population dynamics of agricultural areas, they constitute promising early endpoints for risk assessment of insecticides.


Assuntos
Anfípodes/efeitos dos fármacos , Clorpirifos/toxicidade , Biomarcadores Ambientais/efeitos dos fármacos , Inseticidas/toxicidade , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Poluentes Químicos da Água/toxicidade , Anfípodes/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Locomoção/efeitos dos fármacos
8.
Ecotoxicol Environ Saf ; 188: 109870, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31683046

RESUMO

BPF, a substitute of BPA, has been widely detected in environment and human bodies. Although the genotoxicity, endocrine disrupting effects, reproductive toxicity of BPF has been well documented, its neurodevelopmental toxicity still remains nebulous. In our study, zebrafish embryos were exposed to BPF treatment (0, 7, 70 and 700 µg/L) for 3 or 6 days. Our results showed that BPF exposure markedly decreased zebrafish locomotor behavior, increased oxidative stress, promoted apoptosis and altered brain structure in zebrafish. In addition, the expressions of neurodevelopment related genes were also downregulated upon BPF treatment. In conclusion, our results systematically demonstrated the developmental neurotoxicity of BPF in zebrafish.


Assuntos
Compostos Benzidrílicos/toxicidade , Encéfalo/efeitos dos fármacos , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Exposição Ambiental , Feminino , Locomoção/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento
9.
Aquat Toxicol ; 219: 105384, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31869577

RESUMO

Tritium (3H), a radioactive isotope of hydrogen, is ubiquitously present in the environment. In a previous study, we highlighted a mis-regulation of genes involved in muscle contraction, eye transparency and response to DNA damages after exposure of zebrafish embryo-larvae from 3 hpf to 96 hpf at 0.4 and 4 mGy/h of tritiated water (HTO). The present study aimed to link this gene mis-regulation to responses observed at higher biological levels. Analyses on spontaneous tail movement, locomotor activity and heart rate were performed. Histological sections of eyes were made to evaluate the impact of HTO on eye transparency and whole embryo immunostainings were realized to assess DNA double strand breaks repair using gamma-H2AX foci. We found a decrease of basal velocity as well as a decrease of response in 96 hpf larvae exposed at 0.4 mGy/h after a tactile stimulus as compared to controls. Histological sections of larvae eyes performed after the exposure to 4 mGy/h did not show obvious differences in lens transparency or retinal development between contaminated and control organisms. Gamma-H2AX foci detection revealed no differences in the number of foci between contaminated organisms and controls, for both dose rates. Overall, results highlighted more detrimental effects of HTO exposure on locomotor behavior in 96 hpf larvae exposed at the lowest dose rate. Those results could be linked to mis-regulation of genes involved in muscle contraction found in a previous study at the same dose rate. It appears that not all effects found at the molecular scale were confirmed using higher biological scales. These results could be due to a delay between gene expression modulation and the onset of physiological disruption or homeostatic mechanisms to deal with tritium effects. However, crossing data from different scales highlighted new pathways to explore, i.e. neurotoxic pathways, for better understanding HTO effects on organisms.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Trítio/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Dano ao DNA , Olho/efeitos dos fármacos , Olho/crescimento & desenvolvimento , Olho/patologia , Larva/genética , Peixe-Zebra/genética
10.
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
11.
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
12.
PLoS Negl Trop Dis ; 13(11): e0007826, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730614

RESUMO

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines given the anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970's but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ's anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000×) affinity for the human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.


Assuntos
Anti-Helmínticos/farmacologia , Benzodiazepinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Locomoção/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia
13.
Ecotoxicol Environ Saf ; 186: 109760, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31606642

RESUMO

Graphene nanocomposites are emerging carbon-based materials with interesting electrical, mechanical, optical and magnetic properties, relevant for applications in different fields. Despite this increased use, the impact of graphene nanocomposites residues in the environment has not been properly studied. Thus, the goal of this work was to assess the toxicity of two nickel/graphene nanocomposites (G/Ni1 and G/Ni2) differing in size and shape to Danio rerio embryos. Their toxicity was evaluated using apical (mortality, development and hatching), biochemical [cholinesterase (ChE), glutathione-S-transferase (GST), and catalase (CAT) activities] and behavioral (locomotor activity) endpoints. At the tested concentrations, neither of the nanocomposites presented lethal or developmental effects. Nevertheless, both nanocomposites induced behavioral effects, reducing swimming distances. This effect was, however detected at lower concentrations in the G/Ni1 nanocomposite. At biochemical level, only G/Ni1 nanocomposite showed to interfere with the measured parameters, increasing the activities of ChE, CAT and GST. Differences in the effects induced by the two nanocomposites seem to be related not only with their size, but also with the shape and the ability to continuously release nickel ions to aqueous medium. This work highlights the importance of studying graphene nanocomposites effects to aquatic organisms even when acute toxicity is not expected. The relevance of the effects found in this work need to be further analyzed in light of the consequences to the long-term fitness of the organisms and in light of the environmental concentrations expected for this type of compounds.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Grafite/toxicidade , Locomoção/efeitos dos fármacos , Nanocompostos/toxicidade , Níquel/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Embrião não Mamífero/metabolismo , Fenômenos Magnéticos , Tamanho da Partícula , Natação
14.
Nat Commun ; 10(1): 4682, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615993

RESUMO

A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8+ T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia.


Assuntos
Caquexia , Carcinoma Ductal Pancreático/metabolismo , Imidazóis/farmacologia , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ingestão de Alimentos/efeitos dos fármacos , Expressão Gênica , Humanos , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Knockout , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Análise de Sequência de RNA , Taxa de Sobrevida , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/agonistas , Carga Tumoral , Microambiente Tumoral/imunologia
15.
Pak J Pharm Sci ; 32(4): 1643-1648, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608885

RESUMO

Murraya koenigii (L.) spreng (curry leaves) have traditionally been used for its various medicinal properties. The current study was conducted to assess the comparative effect of Murraya koenigii (L.) spreng (curry leaves) and market available beta blocker drug Atenolol on cardiac enzyme (CK-MB) level in male albino rats. Out of total 26 locally bred male Albino Wistar rats (180 to 200gm weight) two rats were treated with only voltral for dose adjustment. Remaining 24 rats were randomly categorized into following 1 control (C) group and 3 experimental groups Model (M), Test 1 (T1) and Test 2 (T2) containing 6 rats in each group. Rats in C group were orally fed by 0.9% saline solution while rats of M and both test groups T1 and T2 were orally treated with voltral tablet (30mg /kg body weight) for three weeks to increase the level of CK-MB heart enzyme. After voltral treatment rats in test group T1 were treated orally with Atenolol (30 mg/kg body weight) and T2 with Murraya koenigii (L.) spreng (curry leaves) extract (180 mg/kg body weight) for last three weeks. Results show that rats treated with Atenolol showed a decrease in level of heart enzyme as compare to M group, while Murraya koenigii (L.) spreng treated rats group T2 showed more significant decrease of heart enzyme (CK-MB) level as compared to M and T1 groups with significantly improved behavioral activity including increased locomotor activity, short-term memory and reduction in depression. These results demonstrate that natural herbal treatment by curry leaves extract play an effective role in lowering the cardiac enzyme (CK-MB) level to its normal range which helps reducing the risk of CVD and CHD.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Creatina Quinase Forma MB/sangue , Murraya/química , Preparações de Plantas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Miocárdio/enzimologia , Folhas de Planta/química , Ratos Wistar
16.
Pak J Pharm Sci ; 32(3 Special): 1349-1353, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31551214

RESUMO

Qingnaopian has been used in traditional Chinese medicine for treating central nervous system (CNS) injury and inflammatory diseases. The aim of this study was to investigate the effects of Qingnaopian in concussion mice. C57BL/6 mice were used to establish the mild Traumatic Brain Injury (mTBI)/ concussion using the weight-drop techniques. Animal behavioral experiments righting reflex response and locomotor activity were assessed. The expression of pro inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 and Glial fibrillary acidic protein (GFAP) were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot method, respectively. SPSS 19.0 software was used for statistical analysis. The results showed that righting reflex time and locomotor activity were higher in model group compared with those in control group. Qingnaopian treated mice had lower pro inflammatory cytokines, such as IL-1, IL-6 and TNF-α with alleviated GFAP. In short, Qingnaopian treatment improved GFAP induced by blow to head and inflammatory cytokines in concussion mice.


Assuntos
Concussão Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Encefalite/tratamento farmacológico , Proteína Glial Fibrilar Ácida/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Concussão Encefálica/complicações , Ácidos Cumáricos/análise , Citocinas/líquido cefalorraquidiano , Medicamentos de Ervas Chinesas/química , Encefalite/líquido cefalorraquidiano , Encefalite/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Reflexo de Endireitamento/efeitos dos fármacos
17.
Appl Microbiol Biotechnol ; 103(20): 8571-8584, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31501937

RESUMO

Specific recognition and bacterial adhesion to host cells by uropathogenic Escherichia coli (UPEC) are the first steps towards infection of epithelial tissue of the human urogenital system. Therefore, targeting of UPEC virulence factors, relevant for adhesion, is a promising approach for prevention of recurrent urinary tract infections (UTI). A fully characterized plant-derived aqueous extract from the leaves of Orthosiphon stamineus (OWE), a plant traditionally used in clinical practice in Europe and Asia for UTI, has been shown to exert strong antiadhesive effects under in vitro and in vivo conditions. For improved understanding of the underlying mechanisms, transcriptome analysis of OWE-treated UPEC strain UTI89 by Illumina sequencing and cross-validation of these data by qPCR indicated significant downregulation of bacterial adhesins (curli, type 1-, F1C-, and P fimbriae) and of the chaperone-mediated protein folding/unfolding and pilus assembly process; in contrast, flagellar and motility-related genes were upregulated. We conclude that OWE transforms the sessile lifestyle of bacteria into a motile one and therefore disables bacterial attachment to the host cell. Additionally, the extract inhibited gene expression of multiple iron-acquisition systems (ent, fep, feo, fhu, chu, sit, ybt). The present study explains the antiadhesive and anti-infective effect of the plant extract by pinpointing specific biochemical and molecular targets.


Assuntos
Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Chaperonas Moleculares/antagonistas & inibidores , Orthosiphon/química , Extratos Vegetais/farmacologia , Escherichia coli Uropatogênica/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Células Epiteliais/microbiologia , Perfilação da Expressão Gênica , Locomoção/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Escherichia coli Uropatogênica/fisiologia
18.
Chemosphere ; 235: 1022-1029, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561291

RESUMO

Chemical exposure during the early life stages of development may have long lasting effects on organisms that are rarely studied. The present work intended to evaluate the effect of embryonic exposure to the pesticide carbaryl on adult fish behavior. Zebrafish (Danio rerio) embryos were exposed, for 4 days, to sublethal concentrations of carbaryl (0.01, 0.1 and 1.0 mg/L) plus a control and then kept in standard cultivation conditions until adulthood. A battery of behavioral tests was then performed to assess anxiety-like behavior (locomotor activity, thigmotaxis and novel tank diving test), social behavior, and feeding. Developmental exposure of zebrafish to sublethal concentrations of carbaryl produced important behavioral alterations in the adulthood. Main effects included decreased locomotion/hypoactivity (increase in slow movements and decrease of medium and rapid movements), especially in the light periods. Moreover, spatial pattern also changed: while during dark periods control fish increased activity in the outer zone of the tank, this was not observed in exposed fish. Overall, this demonstrated the importance of life stage exposure, clearly demonstrating long lasting effects of a (chemical) stress event at embryonic stages. This data supports the need of considering this scenario in environmental risk evaluations. Further work should focus on the mechanistic effects of developmental disruption responsible for the effects observed.


Assuntos
Comportamento Animal/efeitos dos fármacos , Carbaril/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Inseticidas/toxicidade , Peixe-Zebra/embriologia , Animais , Locomoção/efeitos dos fármacos
19.
Ecotoxicol Environ Saf ; 185: 109677, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31563747

RESUMO

The aim of this study was to develop a new method, using a vibration sensor, to address the drawbacks of preexisting methods for monitoring soil ecological toxicity. A novel method was designed by inspiration from seismometers, which record signals originating from the ground motion caused by earthquake events. Similarly, the newly developed method using a vibration sensor detects the signals generated by earthworm activity, which reflects the soil ecological toxicity. To establish the new method, a stepwise approach was adopted: (1) the effects of operational conditions on the overall performance of the system were evaluated, and (2) the feasibility of the method was tested by an application study. A number of crucial factors influencing the overall performance of the method were evaluated. These were categorized based on three features: soil, tested organism, and instrumentation. The soil properties evaluated included soil type (artificial and natural), moisture content, and bulk density. In terms of the organism, the effect of the number of earthworms was investigated. Finally, with regard to instrumentation, appropriate soil chamber specifications and monitoring duration were identified. The most effective conditions for each factor were determined based on a comparative evaluation of changes in the activity levels and body weights of the earthworms. After the first step of the study, an application study was carried out to demonstrate the feasibility of the proposed method. Zinc (Zn)-contaminated soils were tested under the most efficient operational conditions identified in the preceding study. The results of the study confirm that the method is applicable to natural soils, and the best performance was achieved under soil conditions of 50-60% maximum water holding capacity and 0.95 g/cm3 bulk density. Furthermore, the optimal number of earthworms was found to be five, which corresponds 19.84 g soil per earthworm. With respect to the instrumental conditions, the most efficient specification was a cylindrical soil chamber with a diameter of 94 mm and height of 54 mm. Additionally, the most relevant monitoring duration was found to be 7 days. The results indicate that the method can shorten the testing period, reduce the soil amount and earthworm number required, and facilitate the real-time monitoring of mortality. Based on the results of the application study, we validated the proposed vibration sensor-based method for characterizing earthworm behavior in terms of its feasibility for monitoring the ecological toxicity of soil. The results indicate that dermal contact and feeding activity of earthworms decreased significantly with increasing Zn concentrations in the soil. The EC50 value of Zn calculated based on the earthworm behavior was 340.97 mg/kg. Based on the results, it is concluded that the proposed method cannot only overcome the shortcomings of traditional test methods using earthworms, but also enable real-time ecotoxicity in soil environments.


Assuntos
Monitoramento Ambiental , Locomoção/efeitos dos fármacos , Oligoquetos/efeitos dos fármacos , Poluentes do Solo/toxicidade , Solo/química , Animais , Monitoramento Ambiental/instrumentação , Monitoramento Ambiental/métodos , Poluentes do Solo/análise , Fatores de Tempo , Vibração , Zinco/análise , Zinco/toxicidade
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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