Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 624
Filtrar
Mais filtros










Filtros aplicados

Base de dados
Intervalo de ano de publicação
1.
Chemosphere ; 255: 126955, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32416390

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) can induce skin toxicity. Although some investigations have been conducted to assess the skin toxicity of different PAHs, few comparisons using a series of PAHs with different ring numbers and arrangements have been done. We aimed to explore the skin absorption of 6 PAH compounds and their effect on cutaneous inflammation. In vitro skin permeation was rated by Franz cell with pig skin. Molecular docking was employed to compute the PAH interaction with stratum corneum (SC) lipids. Cultured keratinocytes were exposed to PAHs for analyzing cytotoxicity, cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), chemokines, and differentiation proteins. The in vivo topical PAH exposure in mice was characterized by skin absorption, transepidermal water loss (TEWL), PGE2 level, and histology. The skin deposition from the aqueous vehicle increased following the increase of PAH lipophilicity and molecular size, with benzo[a]pyrene (5-ring PAH) showing the greatest absorption. Pyrene was the compound showing the highest penetration across the skin (flux). Although the PAHs fluoranthene, pyrene, chrysene, and 1,2-benzanthracene all had 4 rings, the skin permeation was quite different. 1,2-Benzanthracene showed the greatest absorption among the 4-ring compounds. The PAHs with higher absorption exhibited stronger interaction with SC lipids according to the in silico modeling. Chrysene and 1,2-benzanthracene generally showed the highest COX-2 and PGE2 expression, followed by benzo[a]pyrene. The lowest COX-2 and PGE2 upregulation was observed for naphthalene (2-ring PAH). A contrary tendency was detected for the upregulation of chemokines. Filaggrin and integrin ß1 in keratinocytes were suppressed at a comparable level by all PAHs. The skin's absorption of PAHs showed strong in vivo-in vitro correlation. 1,2-Benzanthracene and benzo[a]pyrene highly disrupted the skin barrier and elevated the inflammation in vivo. The tendency toward in vivo inflammation caused by various PAHs could be well predicted by the combined estimation using in vitro skin absorption and a keratinocyte bioassay. This study also established the structure-permeation relationship (SPR) of PAHs.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Absorção Cutânea , Pele/metabolismo , Animais , Benzo(a)Antracenos , Benzo(a)pireno/toxicidade , Crisenos , Inflamação/metabolismo , Queratinócitos , Camundongos , Simulação de Acoplamento Molecular , Naftalenos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Pirenos , Suínos
2.
Ecotoxicol Environ Saf ; 200: 110780, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470683

RESUMO

A green synthesis method for nanoscale silver using ß-cyclodextrin as both reducing agent and stabilizer was developed. ß-cyclodextrin was used not only as a reducing agent but also a stabilizing agent for nano-silver, and is also an excellent detection substrate due to its special structure (inner hydrophobic and outer hydrophilic ring structure). Then, the green synthesized silver nanoparticles were used as Surface-enhanced Raman spectroscopy (SERS) enhanced substrates to detect polycyclic aromatic hydrocarbons, such as: anthracene, pyrene, chrysene and triphenylene. The SERS substrate can be used for both quantitative detection of the four polycyclic aromatic hydrocarbons and qualitative identification of mixtures of these hydrocarbons. This synthesis method is simple and convenient, having great potential in simultaneous and rapid detection of environmental organic pollutants.


Assuntos
Química Verde/métodos , Nanopartículas Metálicas/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Prata/química , Análise Espectral Raman/métodos , beta-Ciclodextrinas/química , Antracenos/análise , Crisenos/análise , Interações Hidrofóbicas e Hidrofílicas , Pirenos/análise
3.
PLoS One ; 15(1): e0227508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935242

RESUMO

Herein, the concentrations of food toxicants, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs), in salmon fillets smoke flavored with different smoking wood chips (oak, apple, bourbon soaked oak, cherry and hickory) and barbecuing were determined. Benzo[a]anthracene (up to 0.24 ng/g) and chrysene (0.22 ng/g) were determined in the raw salmon fillets. While ∑PAH8 (benzo[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenzo[a,h]anthracene, benzo[g,h,i]perylene, indeno[1,2,3-cd]pyrene) in the raw samples ranged between 0.44 and 0.46 ng/g, smoke flavoring increased the amount of ∑PAH8 and the amount varied between 0.47 and 0.73 ng/g. Salmon smoked flavored with bourbon soaked oak, cherry and hickory wood chips and barbecued showed significantly (P <0.05) lower contents of ∑PAH4 (benzo[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[a]pyrene) and ∑PAH8 compared to non-smoke flavored barbecued samples. Additionally, smoke flavoring with apple, bourbon soaked oak, and cherry wood chips significantly (P <0.05) reduced the total HAA contents in barbecued salmon. A remarkable result was that the bourbon-soaked oak and cherry wood chips had inhibitory effects on both PAH and HAA contents. In sum, barbecued non-smoke flavored and smoke flavored salmon with different wood chips could be considered safe from the perspective of the detected amounts of PAHs and HAAs in salmon fillets.


Assuntos
Aminas/análise , Aromatizantes/análise , Compostos Heterocíclicos/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Alimentos Marinhos/análise , Animais , Benzo(a)pireno/análise , Cromatografia Líquida de Alta Pressão , Crisenos/análise , Fluorenos/análise , Limite de Detecção , Salmão , Fumaça , Madeira/química
4.
Chemosphere ; 242: 125150, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31671302

RESUMO

The paper presents the results of a study of the content of 12 polyaromatic hydrocarbons (PAHs) in the snow cover of the city of Ivanovo (Russian Federation). It is shown that their average content exceeds the background level by 6.6 times, which made it possible to identify for which compounds the admission channels are associated with transboundary transport (naphthalene, pyrene, benz [b]fluorantin, benzo [a]pyrene and dibenz [a,h]anthracene), and for which with local emission sources (anthracene, phenanthrene, fluoranthene, chrysene, benz [k]fluorantin, and benzo [g,h,i]perylene). According to the known indicator ratios of the concentrations of PAHs, the main sources of release (pyrogenic and mixed) PAHs into the environment were estimated. The combination of experimental data in combination with factor analysis allowed identifying priority PAHs (naphthalene, fluoren, fluoranthene, benzo [a]pyrene and benzo [g,h,i]perylene), which should be included in the environmental monitoring programs of the region. Environmental risk assessments are given, which showed that the level of pollutant does not always adequately reflect the environmental impact for the territories. Thus, the contribution to the total PAH concentration of benz [b]fluorantin is only 9%, and to the amount of environmental risk - 51%. This must be taken into account in order to prioritize the control of individual components of PAHs in environmental objects.


Assuntos
Monitoramento Ambiental , Poluentes Ambientais/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Neve/química , Benzo(a)pireno/análise , Crisenos , Fluorenos , Medição de Risco , Federação Russa
5.
Food Chem ; 303: 125398, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470272

RESUMO

Roasting is an important process in cocoa production which may lead to formation of non-desirable compounds such as polycyclic aromatic hydrocarbons (PAHs). Therefore, PAH4 (sum of four different polycyclic aromatic hydrocarbons; benz[a]anthracene, chrysene, benzo[b]fluoranthene, and benzo[a]pyrene) in roasted cocoa beans was determined using a modified method (combination of QuEChERS and DLLME), and quantified by HPLC-FLD. The modified method was validated and met the performance criteria required by the EU Regulation (No. 836/2011). Results show a significant (p < 0.05) increase of PAH4 (0.19-7.73 ng/g) with an increase in temperatures (110-190 °C) and duration (10-50 min). The PAHs content in whole cocoa bean roasting was detected even at the lowest temperature (110 °C) compared to nib roasting detected at 150 °C which indicates that PAHs was transferred from dried shells to roasted cocoa beans during the roasting process. The data obtained may help to control and minimize PAH4 formation during cocoa processing.


Assuntos
Cacau/química , Cromatografia Líquida de Alta Pressão/métodos , Microextração em Fase Líquida/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Antracenos/análise , Antracenos/isolamento & purificação , Benzo(a)pireno/análise , Benzo(a)pireno/isolamento & purificação , Crisenos/análise , Crisenos/isolamento & purificação , Fluorenos/análise , Fluorenos/isolamento & purificação , Sementes/química
6.
Ecotoxicology ; 28(8): 964-972, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414340

RESUMO

Polyaromatic hydrocarbons are a group of chemical pollutants which cause a significant threat to the living organisms in estuaries and marine ecosystems. We report the effect of chrysene, a major PAH pollutant found in Cochin Estuary along the southwest coast of India, on the neuroendocrine and immune gene expression of the post larvae (PL-25) of Penaeus monodon. The PL- 25 of P. monodon were administered with feed coated with increasing concentrations of chrysene (1, 2 and 3 µg/g) for 10 days and the gene expression was studied on 7th, 11th and 15th day. The PL exposed to chrysene showed moulting stress and changes in the levels of moult-inhibiting hormone I (MIH I) indicated by irregular moulting in the experimental tanks. At the molecular level, the higher concentration of chrysene induced two-fold upregulation of neuroendocrine (MIH I) and downregulation of immune (ProPO and crustin) gene on the 7th day of exposure. The expression of MIH I gene reduced on withdrawing the experimental feed (on 11th day), while continued downregulation of ProPO and crustin were observed on the 11th day. The results of the present study indicate that the microgram levels of PAH can impinge the neuroendocrine and immune system of the P. monodon, which may induce morbidity and mortality to the larvae in polluted coastal ecosystems. Therefore, more attention may be given to avoid PAH pollution in the estuaries to maintain a healthy ecosystem and to protect the animals from extinction.


Assuntos
Crisenos/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Imunotoxinas/efeitos adversos , Neurotoxinas/efeitos adversos , Penaeidae/efeitos dos fármacos , Poluentes Químicos da Água/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Sistema Imunitário/efeitos dos fármacos , Índia , Sistemas Neurossecretores/efeitos dos fármacos , Penaeidae/crescimento & desenvolvimento , Penaeidae/imunologia , Penaeidae/fisiologia
7.
Food Chem ; 297: 124977, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31253260

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are primarily produced during the incomplete combustion of organic matter. PAHs are suspected endocrine disruptors and possible carcinogenic materials. The major sources of human exposure to PAHs are inhaled fumes and food. The aim of this study was to provide an alternative drying method to mitigate PAH formation in dried red peppers. We prepared dried red pepper samples using air-drying and heat pump-assisted drying methods, and measured the concentrations of four PAHs (PAH4), benzo[a] anthracene (B[a]A), chrysene (CHR), benzo[b]fluoranthene (B[b]F), and benzo[a]pyrene (B[a]P), in the resulting pepper samples. The PAH concentrations ranged from 3.61 to 18.0 µg/kg and from 2.22 to 8.35 µg/kg in the air-dried and heat pump-dried pepper samples, respectively. Overall, the results have shown that dried peppers contain PAH4, that the drying conditions for these contaminants should be optimized for mitigating the PAH formation in dried red peppers.


Assuntos
Capsicum/química , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Antracenos/análise , Antracenos/metabolismo , Benzo(a)pireno/análise , Benzo(a)pireno/metabolismo , Carcinógenos/análise , Carcinógenos/metabolismo , Crisenos/análise , Crisenos/metabolismo , Dessecação , Fluorenos/análise , Fluorenos/metabolismo , Temperatura Alta , Hidrocarbonetos Policíclicos Aromáticos/análise
8.
Environ Sci Pollut Res Int ; 26(22): 22772-22782, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175571

RESUMO

This investigation focused on the potential sources of polycyclic aromatic hydrocarbons (PAHs) in different matrices and their temporal variations surrounding a coal-fired thermal power plant in India. Samples were collected in different seasons for 1 year. Gas chromatography-mass spectroscopy (GC-MS) was used to perform the measurement of 16 priority PAHs. Average PAH concentrations were ranged from 0.71 to 2.99 ng/m3 in air and 1.59-22.7 ng/g in soil respectively. High levels of PAHs were found in soil compared to air, which indicated deposition in soil. This could be because of the fallout of high-molecular-weight compounds. During the monsoons, PAH concentrations in the air were the lowest compared to the other seasons because of the dilution effect. Phenanthrene, fluoranthene, and pyrenes were dominant in the air, contributing up to 32.5%, 22.7%, and 19.2% of total PAHs, respectively. On the other hand, soils contained fluoranthene (12.3%), pyrene (10.7%), benzo[b]fluoranthene (10%), chrysene (9.82%), and indeno[123-c,d]pyrene (9.64%) compounds. The occurrence of indeno[1,2,3-cd]pyrene (9.14 ng/g) indicated that the soil is contaminated from fly ash and diesel emissions from the thermal power plant and vehicular emission. The diagnostic ratios, thematic maps, and principal component analysis revealed that the fly ash, diesel emissions from the thermal power plant, vehicles, and biomass burning were the probable sources of PAHs in the study area. The human health risk assessment studies reveal that the soil samples are more prone to carcinogenicity than air samples. As per our knowledge, this is the first report on the impact of PAHs on air and soil in this region.


Assuntos
Monitoramento Ambiental , Poluentes Ambientais/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Centrais Elétricas , Crisenos , Carvão Mineral/análise , Fluorenos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Índia , Fenantrenos , Pirenos , Medição de Risco , Solo , Poluentes do Solo/análise , Emissões de Veículos/análise
9.
Environ Toxicol ; 34(9): 992-1000, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31087746

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) comprise a large family of toxic compounds that come from natural and anthropogenic sources. Chrysene is a PAH with multiple effects, but the toxic potentials of mono-methylchrysenes are less characterized. A comparison of chrysene and six mono-methylchrysenes was performed using assays for cytotoxicity, human aryl hydrocarbon receptor (AhR) reporter gene signaling, and AhR-regulated target gene and protein expression. Sulforhodamine B and trypan blue dye binding assays revealed these chrysenes to be similar in their cytotoxic effects on HepG2 cells. A yeast-based reporter assay detecting human AhR-mediated gene expression identified 4-methylchrysene as being six times more potent and 5-methylchrysene about one-third as potent as chrysene. Other methylchrysenes were more similar to chrysene in the ability to act as AhR ligands. The mono-methylchrysenes all strongly induced CYP1A1 mRNA and protein and moderately induced CYP1B1 expression in HepG2 cells. Levels of CYP1A2 mRNA were induced at higher concentrations of the chrysenes, but protein expression was not significantly altered. The PCR-based gene expression and immunoblotting analyses indicated induced expression differences across the chrysene members were similar to each other. Overall, the effects of methylated chrysenes were comparable to unsubstituted chrysene, suggesting members of this group may be considered approximately equivalent in their effects. © 2019 Wiley Periodicals, Inc.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Crisenos/toxicidade , Expressão Gênica/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1/genética , Genes Reporter/efeitos dos fármacos , Células Hep G2 , Humanos , Receptores de Hidrocarboneto Arílico/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Transdução de Sinais/efeitos dos fármacos
10.
Environ Sci Pollut Res Int ; 26(13): 13510-13521, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30911966

RESUMO

Biofuel is a renewable energy source for transportation. Given the toxicity associated with particulate polycyclic aromatic hydrocarbons (PAHs) is not fully understood, investigating the difference of adverse health risks posed between vapor and particulate PAH emissions from biodiesel-fueled engine combustion was the objective of this study. Three different fuel types, including typical diesel, emulsified diesel with a water fraction from 10 to 19% (v/v), and emulsified biodiesel with water (10%) and biofuel fractions from 10 to 40% (v/v), were studied. The fugacity model and risk assessment were conducted to predict the health risks when different fuels were used. In the results, the addition of water and biofuel elevated and reduced the total PAH emissions in the exhausts, respectively. After the emission, chrysene and benzo(a)anthracene were two dominant carcinogenic species in the environment. The excess cancer risk of the PAH emission significantly decreased (e.g., up to two orders of magnitude) while the emulsified biodiesel was applied, with limiting the formation of benzo(a)pyrene being the explanation. The PAH emissions with molecular weights ranging from 166 to 255 g/mol were significantly different between the vapor and particulate phases during the emulsified biodiesel combustion (p < 0.01). From the viewpoint of cancer risk, the contribution posed by the particulate PAHs was significantly greater than those by the vapor PAHs (e.g., from 54% (benzo(a)pyrene) to 76% (benzo(b)fluoranthene)). Benzo(a)pyrene and chrysene represent the species with the highest and lowest risks, respectively. The multi-ringed PAHs with four or five rings were more indicative of potential cancer risk posed by the PAHs associated with particulate matters during combustion of the emulsified biodiesel.


Assuntos
Biocombustíveis/análise , Fluorenos/análise , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Emissões de Veículos/análise , Carcinógenos , Crisenos , Poeira , Emulsões , Fluorenos/química , Gases , Humanos , Material Particulado/química , Hidrocarbonetos Policíclicos Aromáticos/química , Água
11.
Bioprocess Biosyst Eng ; 42(6): 963-969, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888502

RESUMO

Polycyclic aromatics hydrocarbons (PAHs) are ubiquitous and toxic pollutants that are dangerous to humans and living organism in aquatic environment. Normally, PAHs has lower molecular weight such as phenanthrene and naphthalene that are easy and efficient to degrade, but high-molecular-weight PAHs such as chrysene and pyrene are difficult to be biodegraded by common microorganism. This study investigated the isolation and characterization of a potential halophilic bacterium capable of utilizing two high-molecular-weight PAHs. At the end of the experiment (25-30 days of incubation), bacterial counts have reached a maximum level (over 40 × 1016 CFU/mL). The highest biodegradation rate of 77% of chrysene in 20 days and 92% of pyrene in 25 days was obtained at pH 7, temperature 25 °C, agitation of 150 rpm and Tween 80 surfactant showing to be the most impressive parameters for HMWPAHs biodegradation in this research. The metabolism of initial compounds revealed that Hortaea sp. B15 utilized pyrene to form phthalic acid while chrysene was metabolized to form 1-hydroxy-2-naphthoic acid. The result showed that Hortaea sp. B15 can be promoted for the study of in situ biodegradation of high molecular weight PAH.


Assuntos
Bactérias/crescimento & desenvolvimento , Crisenos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Pirenos/metabolismo
12.
Molecules ; 24(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884744

RESUMO

The formation of polycyclic aromatic hydrocarbons (PAHs) is a strong global concern due to their harmful effects. To help the reduction of their emissions, a crucial understanding of their formation and a deep exploration of their growth mechanism is required. In the present work, the formation of benzo(a)pyrene was investigated computationally employing chrysene and benz(a)anthracene as starting materials. It was assumed a type of methyl addition/cyclization (MAC) was the valid growth mechanism in this case. Consequently, the reactions implied addition reactions, ring closures, hydrogen abstractions and intramolecular hydrogen shifts. These steps of the mechanism were computed to explore benzo(a)pyene formation. The corresponding energies of the chemical species were determined via hybrid density funcional theory (DFT), B3LYP/6-31+G(d,p) and M06-2X/6-311++G(d,p). Results showed that the two reaction routes had very similar trends energetically, the difference between the energy levels of the corresponding molecules was just 6.13 kJ/mol on average. The most stable structure was obtained in the benzo(a)anthracene pathway.


Assuntos
Benzo(a)Antracenos/química , Benzo(a)pireno/química , Carcinógenos/química , Hidrocarbonetos Policíclicos Aromáticos/química , Benzo(a)Antracenos/toxicidade , Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Crisenos/química , Humanos , Hidrogênio/química , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/toxicidade
13.
Eur J Med Chem ; 162: 32-50, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30408747

RESUMO

Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease.


Assuntos
Antivirais/química , Crisenos/química , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Crisenos/farmacologia , Crisenos/toxicidade , Lisossomos/metabolismo , Camundongos , Tensoativos , Internalização do Vírus/efeitos dos fármacos , Peixe-Zebra
14.
Carcinogenesis ; 39(11): 1380-1388, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30184109

RESUMO

Melanoma has a high propensity to metastasize and exhibits a poor response to classical therapies. Dysregulation of the chemokine receptor gene CXCR4 is associated with melanoma progression, and although n-3 polyunsaturated fatty acids (PUFAs) are known to be beneficial for melanoma prevention, the underlying mechanism of this effect is unclear. Here, we used the n-3 fatty acid desaturase (Fat-1) transgenic mouse model of endogenous n-3 PUFA synthesis to investigate the influence of elevated n-3 PUFA levels in a mouse model of metastatic melanoma. We found that relative to wild-type (WT) mice, Fat-1 mice exhibited fewer pulmonary metastatic colonies and improved inflammatory indices, including reduced serum tumor necrosis factor alpha (TNF-α) levels and pulmonary myeloperoxidase activity. Differential PUFA metabolites in serum were considered a key factor to alter cancer cell travelling to lung, and we found that n-6 PUFAs such as arachidonic acid induced CXCR4 protein expression although n-3 PUFAs such as eicosapentaenoic acid (EPA) decreased CXCR4 levels. In addition, serum levels of the bioactive EPA metabolite, 18-HEPE, were elevated in Fat-1 mice relative to WT mice, and 18-HEPE suppressed CXCR4 expression in B16-F0 cells. Moreover, relative to controls, numbers of pulmonary metastatic colonies were reduced in WT mice receiving intravenous injections either of 18-HEPE or 18-HEPE-pretreated melanoma cells. Our results indicate that 18-HEPE is a potential anticancer metabolite that mediates, at least in part, the preventive effect of n-3 PUFA on melanoma metastasis.


Assuntos
Caderinas/genética , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Hidroxieicosatetraenoicos/farmacologia , Melanoma Experimental/patologia , Receptores CXCR4/metabolismo , Animais , Ácido Araquidônico/metabolismo , Linhagem Celular Tumoral , Crisenos , Modelos Animais de Doenças , Ácido Eicosapentaenoico/sangue , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Ômega-3/biossíntese , Ácidos Graxos Ômega-3/genética , Feminino , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica/prevenção & controle , Peroxidase/metabolismo , Receptores CXCR4/genética , Fator de Necrose Tumoral alfa/sangue
15.
J Med Chem ; 61(16): 7289-7313, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30067361

RESUMO

GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Crisenos/química , Morfolinas/química , Relação Estrutura-Atividade , Triterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Ácido Benzoico/química , Disponibilidade Biológica , Técnicas de Química Sintética , Crisenos/farmacologia , Cães , Desenho de Fármacos , Estabilidade de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Morfolinas/farmacologia , Polimorfismo Genético , Ratos Sprague-Dawley , Triterpenos/farmacologia
16.
Environ Pollut ; 242(Pt A): 519-527, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30005264

RESUMO

This study provides contamination levels, distributions and source apportionment of PAHs in surface sediments in the mid-Adriatic and along the Croatian coast. Median summed concentrations of parent and alkyl-PAHs are circa 10 times lower in the off-shore transect stations of the mid-Adriatic (22.3 and 18.2 µg.kg-1 d.w.) than the ranges determined at the coastal stations, including those of Kastela bay (227-331 and 11.7-197 µg.kg-1 d.w., respectively). The highest levels, circa 20 times higher, were found in Sibenik bay (median 6603 and 3051 µg.kg-1). The overall range of PAH concentrations spans more than 2000 times between the lowest and the highest contamination level. The geographical distributions reflect the presence of strong gradients at local and regional scales. A major factor influencing sedimentary PAH distributions at local scale appears to be the distance from their known continental and coastal upstream emission sites (urban, industrial, harbour …), whereas at regional scale, this distribution depends more on the routes of entry of PAHs into the study area. Two combustion and one petroleum model source profiles of PAHs were determined by alternative least square analysis. Benzo[b+j]fluoranthenes and fluoranthene/pyrene are compounds characterizing two pyrogenic sources respectively, while signatures of alkyl-substituted homologues (phenanthrenes/anthracenes, fluranthenes/pyrenes, chrysenes and dibenzothiophenes) delineate a petrogenic source profile. The quantitative apportionment of source contributions shows significant geographical differences, with a dominant petrogenic source found along the mid-Adriatic transect (approximately 74%) and in Kastela bay (61%). In the coastal sediments about a fifty-fifty contamination mix is assigned to a petrogenic/pyrogenic source of PAHs (47% and 53% respectively), whereas in Sibenik bay a strong predominance is apportioned to the combustion compounds (81%).


Assuntos
Monitoramento Ambiental , Sedimentos Geológicos/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes Químicos da Água/análise , Antracenos/análise , Crisenos , Croácia , Fluorenos , Sedimentos Geológicos/análise , Petróleo/análise , Fenantrenos/análise , Pirenos
17.
Pharmacol Res Perspect ; 6(4): e00408, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29930812

RESUMO

This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose-escalation studies in healthy subjects which assessed single oral doses (5-250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug-related AEs. GSK2838232 tested fasted was quickly absorbed with a tmax of 2-3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and Cmax. Overall, following single doses GSK2838232 AUC and Cmax generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20-200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and Cmax by 10- and 3-fold, respectively. Half-life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat-dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once-daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.


Assuntos
Fármacos Anti-HIV/farmacocinética , Butiratos/farmacocinética , Crisenos/farmacocinética , Adulto , Fármacos Anti-HIV/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Butiratos/efeitos adversos , Crisenos/efeitos adversos , Método Duplo-Cego , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/farmacologia , Adulto Jovem
18.
Environ Sci Pollut Res Int ; 25(19): 18947-18959, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29717431

RESUMO

To identify status, source of polycyclic aromatic hydrocarbons (PAHs) in urban soils and to assess soil environmental quality in Xi'an City, China, total 45 soil samples were collected from surface layer (0-10 cm) in different functional areas. Total concentrations of 16 US EPA priority PAHs ranged from 149.9 to 5770 µg kg-1, with a mean of 1246 µg kg-1. High molecular weight (HMW) PAHs accounted for the majority (42.4-72.2%) of the total PAHs in the urban soils, and phenanthrene (Phe), fluorene (Flo), pyrene (Pyr), benzo(b)fluoranthene (BbF), and chrysene (Chr) were the major compounds. Concentrations of PAHs varied among different functional areas. High level of PAHs was particularly apparent in industrial zones and city road overpass, while low level was recorded in scenic spots and campus. The integration of isomer ratios, principal component analysis (PCA), and positive matrix factor (PMF) indicated that the sources of PAHs in Xi'an urban soils were mainly derived from vehicle emissions and coal combustion. Based on incremental lifetime cancer risks (ILCR) model, the urban soils from the three functional areas (industrial zone, urban road, and city road overpass) posed potential cancer risk, and the cancer risks of direct ingestion for children were apparently higher than that for adolescence and for adult, respectively. Therefore, attention should be paid to the health risk for children exposed to PAHs in the urban soils.


Assuntos
Monitoramento Ambiental , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes do Solo/análise , Adolescente , Adulto , Criança , China , Crisenos/análise , Cidades , Carvão Mineral , Fluorenos/análise , Humanos , Indústrias , Neoplasias/epidemiologia , Fenantrenos/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Pirenos/análise , Medição de Risco , Solo/química , Poluentes do Solo/toxicidade , Emissões de Veículos/análise
19.
Arch Environ Contam Toxicol ; 75(2): 295-305, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29550936

RESUMO

Determining the biotransformation potential of commercial chemicals is critical for estimating their persistence in the aquatic environment. In vitro systems are becoming increasingly important as screening methods for assessing the potential for chemical metabolism. Depletion rate constants (kd) for several organic chemicals with high octanol-water partition coefficient (Kow) values (9-methylanthracene, benzo(a)pyrene, chrysene, and PCB-153) in rainbow trout hepatocytes were determined to estimate biotransformation rate constants (kMET) that were used in fish bioconcentration factor (BCF) models. Benzo[a]pyrene was rapidly biotransformed when incubated singly; however, its depletion rate constant (kd) declined 79% in a mixture of all four chemicals. Chrysene also exhibited significant biotransformation and its depletion rate constant declined by 50% in the mixture incubation. These data indicate that biotransformation rates determined using single chemicals may overestimate metabolism in environments containing chemical mixtures. Incubations with varying cell concentrations were used to determine whether cell concentration affected kd estimates. No statistically significant change in depletion rate constants were seen, possibly due to an increase in nonspecific binding of hydrophobic chemicals as cell density increased, decreasing overall biotransformation. A new model was used to estimate BCFs from kMET values calculated from empirically derived kd values. The inclusion of kMET in models resulted in significantly lower BCF values (compared kMET = 0). Modelled BCF values were consistent with empirically derived BCF values from the literature.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Oncorhynchus mykiss , Compostos Orgânicos/química , Compostos Orgânicos/farmacocinética , Animais , Antracenos , Benzo(a)pireno/farmacocinética , Biotransformação , Crisenos/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Masculino , Bifenilos Policlorados/farmacocinética , Poluentes Químicos da Água/química , Poluentes Químicos da Água/farmacocinética
20.
BMC Cancer ; 18(1): 236, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29490609

RESUMO

BACKGROUND: Consumption of very hot (> 65 °C) beverages is probably associated with increased risk of oesophageal cancer. First associations were reported for yerba mate and it was initially believed that high content of polycyclic aromatic hydrocarbons (PAH) might explain the risk. Later research on other beverage groups such as tea and coffee, which are also consumed very hot, found associations with increased risk of oesophageal cancer as well. The risk may therefore not be inherent in any compound contained in mate, but due to temperature. The aim of this study was to quantitatively assess the risk of PAH in comparison with the risk of the temperature effect using the margin of exposure (MOE) methodology. METHODS: The human dietary benzo[a]pyrene (BaP) and PAH4 (sum of benzo[a]pyrene, benzo[a]anthracene, chrysene, and benzo[b]fluoranthene) exposure through consumption of coffee, mate, and tea was estimated. The oesophageal cancer risk assessment for both PAH and temperature was conducted using the MOE approach. RESULTS: Considering differences in the transfer of the PAH from the leaves of mate and tea or from the ground coffee to the infusion, and considering the different preparation methods, exposures may vary considerably. The average individual exposure in µg/kg bw/day arising from consumption of 1 cup (0.2 L) of infusion was highest for mate (2.85E-04 BaP and 7.22E-04 PAH4). The average per capita exposure in µg/kg bw/day was as follows: coffee (4.21E-04 BaP, 4.15E-03 PAH4), mate (4.26E-03 BaP, 2.45E-02 PAH4), and tea (8.03E-04 BaP, 4.98E-03 PAH4). For all individual and population-based exposure scenarios, the average MOE for BaP and PAH4 was > 100,000 independent of beverage type. MOE values in this magnitude are considered as a very low risk. On the contrary, the MOE for the temperature effect was estimated as < 1 for very hot drinking temperatures, corroborating epidemiological observations about a probable oesophageal cancer risk caused by this behaviour. CONCLUSIONS: The temperature effect but not PAH exposure may pose an oesophageal cancer risk. Consumer education on risks associated with consumption of 'very hot' beverages and policy measures to threshold serving temperatures should be discussed.


Assuntos
Café/efeitos adversos , Neoplasias Esofágicas/etiologia , Temperatura Alta , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Chá/efeitos adversos , Animais , Benzo(a)Antracenos/efeitos adversos , Benzo(a)pireno/efeitos adversos , Crisenos/efeitos adversos , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/epidemiologia , Fluorenos/efeitos adversos , Humanos , Camundongos , Ratos , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA