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2.
Microbiology ; 165(2): 197-207, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30566075

RESUMO

The human pathogen Staphylococcus aureus produces saturated fatty acids, but can incorporate both exogenous saturated and unsaturated fatty acids into its lipid membrane. S. aureus encounters unsaturated fatty acids in the host skin where they serve as an innate immune defence due to their toxicity. Previously, we identified a fatty acid kinase in S. aureus that is necessary for the utilization of exogenous fatty acids. The goal of this study was to determine the effects of fatty acids on mutants deficient in the exogenous fatty acid utilization machinery. We have demonstrated that mutants lacking a functional fatty acid kinase (fakA) or both fatty acid carrier proteins (fakB1 fakB2) are more resistant to unsaturated fatty acids. Previous studies suggested a role for ammonia-producing enzymes in resistance to unsaturated fatty acids, but these enzymes do not contribute to the resistance of the fakA mutant, despite increased urease transcription and protein activity in the mutant. Additionally, while pigment is altered in mutants unable to use exogenous fatty acids, staphyloxanthin does not contribute to fatty acid resistance of an fakA mutant. Because exposure to unsaturated fatty acids probably initiates a stress response, we investigated the role of the alternative sigma factor σB and determined if it is necessary for the fatty acid resistance observed in the fakA mutant. Collectively, this study demonstrates that the inability to incorporate unsaturated fatty acids leads to increased resistance to those fatty acids, and that resistance requires a σB stress response.


Assuntos
Vias Biossintéticas/genética , Ácidos Graxos Insaturados/toxicidade , Ácidos Graxos/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Proteínas de Bactérias/genética , Ácidos Graxos Insaturados/metabolismo , Mutação , Fosfotransferases/genética , Fator sigma/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-28974407

RESUMO

In recent years, the interest in the use of vitellogenin (VTG) as a biomarker of endocrine disruption in fish has led to VTG being considered as a potential tool in invertebrates. Among aquatic invertebrate models in ecotoxicology, the copepods are considered as reference species in marine, estuarine and freshwater ecosystems. In this context, we identified a VTG cDNA in Eurytemora affinis. The Ea-VTG2 cDNA is 5416bp in length with an open reading frame (ORF) of 5310bp that encodes a putative protein of 1769 amino acids residues. Phylogenetic analysis confirmed the hypothesis of a VTG duplication event before the emergence of the copepod species. The analysis of the Ea-VTG2 expression by qPCR in males and females according to their reproductive stages allowed transcript basal levels to be determined. The expression pattern revealed a gradual increase of transcript levels during maturation in females. Important inter-sex differences were observed with a VTG level in males ranging from about 1900- to 6800-fold lower than in females depending on their stage. Moreover, the protein was only detected in ovigerous females. The inducibility of Ea-VTG2 by chemicals was studied in males exposed to either a model of endocrine disruptor in vertebrates i.e. 4-nonylphenol (4-NP) or a crustacean hormone i.e. Methyl Farnesoate (MF), and in males sampled from a multi-contaminated estuary. No induction was highlighted. The VTG should not be considered as an appropriate biomarker in E. affinis as previously suggested for other crustaceans.


Assuntos
Copépodes/metabolismo , Disruptores Endócrinos/toxicidade , Vitelogeninas/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Biomarcadores , Clonagem Molecular , DNA Complementar , Ácidos Graxos Insaturados/toxicidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Poluentes Químicos da Água/toxicidade
5.
Chemosphere ; 174: 289-296, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28183054

RESUMO

BACKGROUND: Seafood is a good source of Omega-3 polyunsaturated fatty acids (ω3-PUFA) but also contains the toxic contaminant methylmercury (MeHg). National estimates of exposure to both compounds through seafood intake in Mexico are not known. The objective of the current study was to describe national seafood consumption habits and to estimate seafood-based exposure to ω3-PUFAs and MeHg. METHODS: We analyzed data from a 24-h dietary recall extracted from the 2012 National Health and Nutrition Survey of Mexico (n = 10,096 subjects aged 1y and older). National per capita seafood intake as well as information on age, sex, socioeconomic status, and geographic region was obtained. The contribution of each seafood item to the total MeHg exposure was estimated, as was the balance between estimated exposures to ω3-PUFAs and MeHg. RESULTS: A mean daily seafood intake of 10 g/day was estimated. The top species consumed in decreasing order were: canned tuna, sunfish, shrimp, mullet, carp and schoolshark (constituted 60% of seafood intake). Canned tuna and schoolshark contributed 75% of the population's estimated exposure to MeHg. The best balance of population-level exposures to ω3-PUFAs and MeHg was found in salmon, sardine, trout and anchovies. CONCLUSION: Environmental dietary exposure to MeHg is a public health concern and thus a good understanding of seafood consumption is needed to create national consumption guidelines. The current study provides nationally-representative data in Mexico from which decisions can be made (e.g., UN Minamata Convention) and future studies conducted.


Assuntos
Dieta/estatística & dados numéricos , Ingestão de Alimentos , Exposição Ambiental/análise , Ácidos Graxos Insaturados/análise , Compostos de Metilmercúrio/análise , Alimentos Marinhos/análise , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Ácidos Graxos Insaturados/toxicidade , Feminino , Peixes , Humanos , Lactente , Masculino , Compostos de Metilmercúrio/toxicidade , México , Adulto Jovem
6.
J Appl Toxicol ; 37(3): 374-381, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27553699

RESUMO

The freshwater zooplankton Daphnia magna has been extensively employed in chemical toxicity tests such as OECD Test Guidelines 202 and 211. Previously, it has been demonstrated that the treatment of juvenile hormones (JHs) or their analogues to female daphnids can induce male offspring production. Based on this finding, a rapid screening method for detection of chemicals with JH-activity was recently developed using adult D. magna. This screening system determines whether a chemical has JH-activity by investigating the male offspring inducibility. Although this is an efficient high-throughput short-term screening system, much remains to be discovered about JH-responsive pathways in the ovary, and whether different JH-activators act via the same mechanism. JH-responsive genes in the ovary including developing oocytes are still largely undescribed. Here, we conducted comparative microarray analyses using ovaries from Daphnia magna treated with fenoxycarb (Fx; artificial JH agonist) or methyl farnesoate (MF; a putative innate JH in daphnids) to elucidate responses to JH agonists in the ovary, including developing oocytes, at a JH-sensitive period for male sex determination. We demonstrate that induction of hemoglobin genes is a well-conserved response to JH even in the ovary, and a potential adverse effect of JH agonist is suppression of vitellogenin gene expression, that might cause reduction of offspring number. This is the first report demonstrating different transcriptomics profiles from MF and an artificial JH agonist in D. magna ovary, improving understanding the tissue-specific mode-of-action of JH. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Daphnia/efeitos dos fármacos , Hormônios Juvenis/genética , Ovário/efeitos dos fármacos , Testes de Toxicidade/métodos , Transcriptoma/efeitos dos fármacos , Animais , Daphnia/genética , Ácidos Graxos Insaturados/toxicidade , Feminino , Hormônios Juvenis/agonistas , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ovário/metabolismo , Fenilcarbamatos/toxicidade
7.
Aquat Toxicol ; 179: 125-33, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27606904

RESUMO

Diatoms have been shown to produce and release a wide range of secondary metabolites that mediate interactions between individuals of different species. Among these compounds, different types of fatty acid derived long-chained polyunsaturated aldehydes (PUAs) have been related to multiple functions such as intra- or interspecific signals and adverse effect on the reproduction of marine organisms. Several studies have reported changes on growth, cell membrane permeability, flow cytometric properties and cell morphology in phytoplankton organisms exposed to PUAs, but little information is available on the effect of these compounds on benthic microalgae. Ostreopsis cf. ovata is a toxic benthic dinoflagellate which causes massive blooms along the Mediterranean coasts typically during the late summer period. In this study the effects of three toxic PUAs known to be produced by several algae (2E,4E-decadienal, 2E,4E-octadienal and 2E,4E-heptadienal) on the growth, cytological features and cell morphology of O. cf. ovata were investigated. Our results show a clear decrease of O. cf. ovata growth with longer-chain molecules than with shorter-chain ones, confirmed also by EC50 values calculated at 48h for 2E,4E-decadienal and 2E,4E-octadienal (6.6±1.5, 17.9±2.6µmolL(-1) respectively) and at 72h for 2E,4E-heptadienal (18.4±0.7µmolL(-1)). Moreover, morphological analysis highlighted up to 79% of abnormal forms of O. cf. ovata at the highest concentrations of 2E,4E-decadienal tested (9, 18 and 36µmolL(-1)), a gradual DNA degradation and an increase of lipid droplets with all tested PUAs. Further studies are needed to better clarify the interactions between diatoms and O. cf. ovata, especially on bloom-forming dynamics.


Assuntos
Aldeídos/toxicidade , Dinoflagelados/efeitos dos fármacos , Ácidos Graxos Insaturados/toxicidade , Poluentes da Água/toxicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Dinoflagelados/crescimento & desenvolvimento , Dinoflagelados/metabolismo , Ácidos Graxos Insaturados/química , Proliferação Nociva de Algas , Microalgas/metabolismo , Microscopia de Fluorescência , Reprodução/efeitos dos fármacos , Poluentes da Água/química
9.
FEMS Yeast Res ; 16(2): fow007, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26833421

RESUMO

Polyunsaturated fatty acids (PUFA) such as linoleic acid (LA, n-6, C18:2) and γ-linolenic acid (GLA, n-6, C18:3) are essential and must be obtained from the diet. There has been a growing interest in establishing a bio-sustainable production of PUFA in several microorganisms, e.g. in yeast Saccharomyces cerevisiae. However, PUFAs can also be toxic to cells because of their susceptibility to peroxidation. Here we investigated the negative effects of LA and GLA production on S. cerevisiae by characterizing a strain expressing active Δ6 and Δ12 desaturases from the fungus Mucor rouxii. Previously, we showed that the PUFA-producing strain has low viability, down-regulated genes for oxidative stress response, and decreased proteasome activity. Here we show that the PUFA strain accumulates high levels of reactive oxygen species (ROS) and lipid peroxides, and accumulates damaged proteins. The PUFA strain also showed great increase in metacaspase Yca1p activity, suggesting cells could die by caspase-mediated cell death. When treated with antioxidant vitamin C, ROS, lipid peroxidation and protein carbonylation were greatly reduced, and the activity of the metacaspase was significantly decreased too, ultimately doubling the lifespan of the PUFA strain. When deleting YCA1, the caspase-like activity and the oxidative stress decreased and although the lifespan was slightly prolonged, the phenotype could not be fully reversed, pointing that Yca1p was not the main executor of cell death.


Assuntos
Caspases/metabolismo , Morte Celular , Ácidos Graxos Insaturados/toxicidade , Redes Reguladoras de Genes , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/fisiologia , Ácido Ascórbico , Citosol/química , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/análise , Viabilidade Microbiana/efeitos dos fármacos , Mucorales/enzimologia , Mucorales/genética , Estresse Oxidativo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética
10.
Vet Parasitol ; 217: 89-94, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26827867

RESUMO

The present study was conducted aiming to evaluate the in vitro and in vivo anti-parasitic efficacy of an isolated compound against the ciliate Cryptocaryon irritans. The compound was previously isolated from fermentation products of Streptomyces sp. CJK17 and designated as SFrD. Toxicity of the compound SFrD against the fish hosts (Larimichthys crocea) was also tested and its chemical structure was elucidated. The obtained results showed that the compound has potent anti-parasitic efficacy with the 10 min-, 1 h-, 2 h-, 3 h- and 4 h-LC50 (95% Confidence Intervals) of 6.8 (6.5-7.1), 3.9 (2.8-5.0), 3.3 (2.6-4.0), 2.7 (2.3-3.1) and 2.5 (2.2-2.8) mg L(-1) against theronts of C. irritans and the 6h-LC50 (95% CI) of 3.0 (2.8-3.2) mg L(-1) against the tomonts, respectively. Exposure of the compound SFrD remarkably reduced the mortality of fish infected with C. Irritans, from 100% in the control group to 61.7% and 38.3% in groups of 3.1 mg L(-1) and 6.3 mg L(-1), respectively. In the test of exposing fish to 40 mg L(-1) compound SFrD for 24h, no visible effects were observed affecting the normal behavior or any macroscopic changes. By spectrum analysis (EI-MS, (1)H NMR and (13)C NMR), the compound SFrD was identified as Leptomycin B. This study firstly demonstrated that Leptomycin B has potent anti-parasitic efficacy against ciliates in cultured marine fish.


Assuntos
Infecções por Cilióforos/veterinária , Doenças dos Peixes/tratamento farmacológico , Hymenostomatida/efeitos dos fármacos , Streptomyces/química , Animais , Comportamento Animal/efeitos dos fármacos , Infecções por Cilióforos/tratamento farmacológico , Cristalização , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Ácidos Graxos Insaturados/uso terapêutico , Ácidos Graxos Insaturados/toxicidade , Espectroscopia de Ressonância Magnética , Perciformes/parasitologia , Espectrometria de Massas por Ionização por Electrospray , Análise de Sobrevida
11.
FASEB J ; 30(5): 2027-39, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26887439

RESUMO

The degree of fatty acid unsaturation in membrane phospholipids affects many membrane-associated functions and can be influenced by dietary consumption of fatty acids such as saturated fatty acids and polyunsaturated fatty acids (PUFAs). Cells must adapt to changes in composition of membrane fatty acids by regulating lipid-metabolizing enzymes. In this study, we investigated how cells respond to loading with excess PUFAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. A lipidomics analysis revealed that dipalmitoylphosphatidylcholine (DPPC) was increased after the production of PUFA-containing phospholipids in cells loaded with PUFAs. An RNA interference screen of lipid-metabolizing enzymes revealed that lysophosphatidylcholine acyltransferase 1 (LPCAT1) was involved in the DPPC production. Moreover, LPCAT1 knockdown markedly enhanced the cytotoxicity induced by excess PUFAs. PUFA-induced cytotoxicity was dependent on caspase and unfolded protein response (UPR) sensor proteins inositol requiring 1α and protein kinase R-like endoplasmic reticulum kinase, suggesting that excess PUFAs trigger UPR-mediated apoptosis. In murine retina, in which PUFAs are highly enriched, DPPC was produced along with increase of PUFA-containing phospholipids. In LPCAT1 knockout mice, DPPC level was reduced and UPR was activated in the retina. Our results provide insight into understanding of the retinal degeneration seen in rd11 mice that lack LPCAT1.-Akagi, S., Kono, N., Ariyama, H., Shindou, H., Shimizu, T., Arai, H. Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids.


Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Ácidos Graxos Insaturados/toxicidade , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/genética , Animais , Linhagem Celular , Sobrevivência Celular , Ácido Eicosapentaenoico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Knockout , Retina/metabolismo , Degeneração Retiniana/metabolismo
12.
Arch Toxicol ; 90(4): 927-36, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25975990

RESUMO

Unsaturated compounds are known to cause false-positive reactions in the local lymph node assay (LLNA) but not in the guinea pig maximization test. We have tested a panel of substances (succinic acid, undecylenic acid, 1-octyn-3-ol, fumaric acid, maleic acid, linoleic acid, oleic acid, alpha-linolenic acid, squalene, and arachidonic acid) in the loose-fit coculture-based sensitization assay (LCSA) to evaluate whether unspecific activation of dendritic cells is a confounder for sensitization testing in vitro. Eight out of 10 tested substances caused significant up-regulation of CD86 on dendritic cells cocultured with keratinocytes and would have been classified as sensitizers; only succinic acid was tested negative, and squalene had to be excluded from data analysis due to poor solubility in cell culture medium. Based on human data, only undecylenic acid can be considered a true sensitizer. The true sensitizing potential of 1-octyn-3-ol is uncertain. Fumaric acid and its isomer maleic acid are not known as sensitizers, but their esters are contact allergens. A group of 18- to 20-carbon chain unsaturated fatty acids (linoleic acid, oleic acid, alpha-linolenic acid, and arachidonic acid) elicited the strongest reaction in vitro. This is possibly due to the formation of pro-inflammatory lipid mediators in the cell culture causing nonspecific activation of dendritic cells. In conclusion, both the LLNA and the LCSA seem to provide false-positive results for unsaturated fatty acids. The inclusion of T cells in dendritic cell-based in vitro sensitization assays may help to eliminate false-positive results due to nonspecific dendritic cell activation. This would lead to more accurate prediction of sensitizers, which is paramount for consumer health protection and occupational safety.


Assuntos
Antígeno B7-2/metabolismo , Ácidos Graxos Insaturados/imunologia , Testes Cutâneos/métodos , Animais , Técnicas de Cocultura/métodos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Reações Falso-Positivas , Ácidos Graxos Insaturados/toxicidade , Cobaias , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Ensaio Local de Linfonodo , Ácido Succínico/imunologia , Ácido Succínico/toxicidade , Regulação para Cima/efeitos dos fármacos
13.
Environ Pollut ; 208(Pt B): 868-74, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26600417

RESUMO

Agricultural chemical inputs have been considered as a risk factor for the global declines in amphibian populations, yet the application of agricultural fungicides has increased dramatically in recent years. Currently little is known about the potential toxicity of fungicides on the embryos of amphibians. We studied the effects of ten commonly used fungicides (four strobilurins, two SDHIs, two triazoles, fludioxonil and folpet) on Xenopus tropicalis embryos. Lethal and teratogenic effects were respectively examined after 48 h exposure. The median lethal concentrations (LC50s) and the median teratogenic concentrations (TC50s) were determined in line with actual exposure concentrations. These fungicides except two triazoles showed obvious lethal effects on embryos; however LC50s of four strobilurins were the lowest and in the range of 6.81-196.59 µg/L. Strobilurins, SDHIs and fludioxonil induced severe malformations in embryos. Among the ten fungicides, the lowest TC50s were observed for four strobilurins in the range of 0.61-84.13 µg/L. The teratogenicity shared similar dose-effect relationship and consistent phenotypes mainly including microcephaly, hypopigmentation, somite segmentation and narrow fins. The findings indicate that the developmental toxicity of currently-used fungicides involved with ecologic risks on amphibians. Especially strobilurins are highly toxic to amphibian embryos at µg/L level, which is close to environmentally relevant concentrations.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Teratogênios/toxicidade , Xenopus/embriologia , Animais , Ácidos Graxos Insaturados/toxicidade , Dose Letal Mediana , Metacrilatos/toxicidade , Estrobilurinas , Testes de Toxicidade , Triazóis/toxicidade
14.
Ecotoxicol Environ Saf ; 120: 418-27, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26122735

RESUMO

The ecotoxicological effects of pyraoxystrobin, a novel strobilurin fungicide, were studied using outdoor freshwater microcosms and the species sensitivity distribution approach. The microcosms were treated with pyraoxystrobin at concentrations of 0, 1.0, 3.0, 10, 30 and 100µg/L. Species sensitivity distribution (SSD) curves were constructed by means of acute toxicity data using the BurrliOZ model for fourteen representatives of sensitive invertebrates, algae and fish and eleven taxa of invertebrates and algae, respectively. The responses of zooplankton, phytoplankton and physical and chemical endpoints in microcosms were studied. Zooplankton, especially Sinodiaptomus sarsi was the most sensitive to pyraoxystrobin exposure in the microcosms. Short-term toxic effects (<8 weeks) on zooplankton occurred in 1µg/L treatment group. The duration of toxic effects on S. sarsi could not be evaluated within the initial 56 days. Significant long-term toxic effects were observed at 10, 30 and 100µg/L (>281 days) for S. sarsi and the zooplankton community. Based on the results obtained from the organisms in the microcosm system, 1µg/L was recommended as the NOEAEC (no observed ecologically adverse effect concentration). Also, 0.33µg/L was derived as the Regulatory Acceptable Concentration based on the ecological recovery option (ERO-RAC) of pyraoxystrobin. For all fourteen tested species, the median HC5 (hazardous concentration affecting 5% of species) was 0.86µg/L, and the lower limit HC5 (LL-HC5) was 0.39µg/L. For the eleven taxa of invertebrates and algae tested, the median HC5 was 1.1µg/L, and the LL-HC5 was 0.26µg/L. The present study positively contributes to the suggestion of adequately using acute L(E)C50-based HC5/ LL-HC5 for deriving protective concentrations for strobilurin fungicides, and it should be valuable for full comprehension of the potential toxicity of pyraoxystrobin in aquatic ecosystems.


Assuntos
Antifúngicos/toxicidade , Copépodes/efeitos dos fármacos , Acrilatos/análise , Acrilatos/toxicidade , Animais , Fenômenos Químicos , Copépodes/metabolismo , Cyprinidae/metabolismo , Daphnia/efeitos dos fármacos , Daphnia/metabolismo , Ácidos Graxos Insaturados/análise , Ácidos Graxos Insaturados/toxicidade , Água Doce/química , Sedimentos Geológicos/química , Dose Letal Mediana , Metacrilatos/análise , Metacrilatos/toxicidade , Penaeidae/efeitos dos fármacos , Penaeidae/metabolismo , Fitoplâncton/efeitos dos fármacos , Fitoplâncton/metabolismo , Pirazóis/análise , Pirazóis/toxicidade , Medição de Risco , Especificidade da Espécie , Estrobilurinas , Testes de Toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Zooplâncton/efeitos dos fármacos , Zooplâncton/metabolismo
15.
Methods Enzymol ; 555: 3-18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25747472

RESUMO

4-HNE (4-hydroxy-2-nonenal) is a highly reactive α,ß-unsaturated aldehyde generated from oxidation of polyunsaturated fatty acids and has been suggested to play a role in the pathogenesis of several diseases. 4-HNE can bind to amino acids, proteins, polynucleotides, and lipids and exert cytotoxicity. 4-HNE forms adducts (Michael adducts) with cysteine, lysine, as well as histidine on proteins with the thiol function as the most reactive nucleophilic moiety. Thus, detoxification strategies by 4-HNE scavenging compounds might be of interest. Recently, hydrogen sulfide (H2S) has been identified as an endogenous vascular gasotransmitter and neuromodulator. Assuming that the low-molecular thiol H2S may react with 4-HNE, methods to monitor the ability of H2S to counteract the protein-modifying and cytotoxic activity of 4-HNE are described in this chapter.


Assuntos
Aldeídos/toxicidade , Ácidos Graxos Insaturados/toxicidade , Sulfeto de Hidrogênio/farmacologia , Hidroxiácidos/toxicidade , Albumina Sérica/química , Compostos de Sulfidrila/química , Aldeídos/química , Aldeídos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/metabolismo , Humanos , Sulfeto de Hidrogênio/química , Concentração de Íons de Hidrogênio , Hidroxiácidos/química , Hidroxiácidos/metabolismo , Immunoblotting , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Oxirredução , Sulfetos/química
16.
Bioorg Med Chem Lett ; 25(6): 1192-5, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25690788

RESUMO

Herbarin A and B were isolated from the fungal strains of Cladosporium herbarum found in marine sponges Aplysina aerophoba and Callyspongia aerizusa. Total synthesis of Herbarin A and B was achieved by carrying out a multi-step synthesis approach, and the antioxidant properties were evaluated using FRAP assay. Toxicity of these compounds was determined using a zebrafish embryo model.


Assuntos
Antioxidantes/síntese química , Ácidos Graxos Insaturados/síntese química , Pironas/síntese química , Animais , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Cladosporium/química , Cladosporium/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/toxicidade , Modelos Animais , Pironas/química , Pironas/toxicidade , Peixe-Zebra/crescimento & desenvolvimento
17.
Pharm Biol ; 53(4): 477-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25471519

RESUMO

CONTEXT: There is a need for the discovery of novel natural and semi-synthetic sunscreen that is safe and effective. Piperine has a UV absorption band of 230-400 nm with high molar absorptivity. This compound has a high potential to be developed to sunscreen. OBJECTIVE: This study develops new UV protection compounds from piperine by using chemical synthesis. MATERIALS AND METHODS: Piperine was isolated from Piper nigrum L. (Piperaceae) fruits, converted to piperic acid by alkaline hydrolysis, and prepared as ester derivatives by chemical synthesis. The piperate derivatives were prepared as 5% o/w emulsion, and the SPF values were evaluated. The best compound was submitted to cytotoxicity test using MTT assay. RESULTS: Piperic acid was prepared in 86.96% yield. Next, piperic acid was reacted with alcohols using Steglich reaction to obtain methyl piperate, ethyl piperate, propyl piperate, isopropyl piperate, and isobutyl piperate in 62.39-92.79% yield. All compounds were prepared as 5% oil in water emulsion and measured its SPF and UVA/UVB values using an SPF-290S analyzer. The SPF values (n = 6) of the piperate derivatives were 2.68 ± 0.17, 8.89 ± 0.46, 6.86 ± 0.91, 16.37 ± 1.8, and 9.68 ± 1.71. The UVA/UVB ratios of all compounds ranged from 0.860 to 0.967. Cytotoxicity of isopropyl piperate was evaluated using human skin fibroblast cells and the IC50 was equal to 120.2 µM. DISCUSSION AND CONCLUSION: From the results, isopropyl piperate is an outstanding compound that can be developed into a UV protection agent.


Assuntos
Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/farmacologia , Piper nigrum/química , Pele/efeitos dos fármacos , Protetores Solares/isolamento & purificação , Protetores Solares/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional , Ácidos Graxos Insaturados/toxicidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Humanos , Ligações de Hidrogênio , Modelos Moleculares , Pele/citologia , Pele/efeitos da radiação , Espectrofotometria Ultravioleta , Protetores Solares/toxicidade
18.
Bioorg Med Chem Lett ; 24(24): 5635-5638, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25466189

RESUMO

A one-pot environmentally friendly transamidation of ω-3 fatty acid ethyl esters to amides and mono- or diacylglycerols was investigated via the use of a polymer-supported lipase. The method was used to synthesize a library of fatty acid monoglyceryl esters and amides. These new derivatives were found to have potent growth inhibition effects against A549 lung cancer cells.


Assuntos
Amidas/química , Ácidos Graxos Insaturados/química , Amidas/síntese química , Amidas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Ésteres , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/toxicidade , Humanos , Lipase/química , Lipase/metabolismo , Relação Estrutura-Atividade
19.
J Med Chem ; 57(12): 5370-80, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24801499

RESUMO

(2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.


Assuntos
Anticarcinógenos/química , Ácidos Graxos Insaturados/química , Hiperlipidemias/induzido quimicamente , Naftalenos/química , Receptor X Retinoide alfa/agonistas , Animais , Anticarcinógenos/farmacologia , Anticarcinógenos/toxicidade , Apoptose/efeitos dos fármacos , Bexaroteno , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Cristalografia por Raios X , Ácidos Graxos Insaturados/farmacologia , Ácidos Graxos Insaturados/toxicidade , Feminino , Humanos , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/prevenção & controle , Modelos Moleculares , Estrutura Molecular , Naftalenos/farmacologia , Naftalenos/toxicidade , Ratos , Receptor X Retinoide alfa/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/toxicidade , Ativação Transcricional
20.
Bioorg Med Chem Lett ; 24(9): 2173-6, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24717155

RESUMO

Twenty-one novel benzothiophene-substituted oxime ether strobilurins, which employed a benzothiophene group to stabilise the E-styryl group in Enoxastrobin (an unsaturated oxime strobilurin fungicide developed by Shenyang Research Institute of Chemical Industry, China) were designed and synthesised. The biological assay indicated that most compounds exhibited good or excellent fungicidal activities, especially against Colletotrichum lagenarium and Puccinia sorghi Schw. In addition, methyl 3-methoxypropenoate oxime ethers and N-methoxy-carbamic acid methyl esters exhibited good in vivo fungicidal activities against Erysiphe graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. under the tested concentrations. Notably, (E,E)-methyl 3-methoxy-2-(2-((((6-chloro-1-(1H-benzo[b]thien-2-yl)ethylidene)amino)oxy)methyl)phenyl)propenoate (5E) exhibited more potent in vivo fungicidal activities against nearly all of the tested fungi at a concentration of 0.39 mg/L compared to Enoxastrobin.


Assuntos
Fungos/efeitos dos fármacos , Fungicidas Industriais/química , Fungicidas Industriais/toxicidade , Tiofenos/química , Tiofenos/toxicidade , Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/toxicidade , Fungicidas Industriais/síntese química , Metacrilatos/síntese química , Metacrilatos/química , Metacrilatos/toxicidade , Oximas/síntese química , Oximas/química , Oximas/toxicidade , Estrobilurinas , Tiofenos/síntese química
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