Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 125
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Theranostics ; 9(18): 5412-5423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410224

RESUMO

It is well known that tumor necrosis factor-related apoptosis inducing ligand receptor 1 or 2 (DR4/DR5) is specifically expressed in various tumor cells, but less or no expression in most normal cells. Many first generations of TRAIL agonists including recombinant preparations of TRAIL, agonistic antibodies against DR4/DR5 have been developed in phase I/II clinical trials for cancer therapy. However, the outcomes of clinical trials by using DR4/DR5 agonist mono-therapy were disappointed even though the safety profile was well tolerance. In the present study, we report an anti-DR5 antibody-drug conjugate (ADC, named as Zapadcine-1) possesses a higher potential for the therapy of lymphocyte leukemia and solid cancers. Methods: Zapadcine-1 was made by a fully humanized DR5-specific monoclonal antibody (Zaptuzumab) coupled via a cleavable linker to a highly toxic inhibitor of tubulin, monomethyl auristatin D (MMAD), by using ThioBridge technology. Cytotoxicity of the ADC in various tumor cells was identified by luminescent cell viability assay and the efficacy in vivo was determined in cells derived xenografts (CDX) of Jurkat E6-1, BALL-1, Reh, and patient derived xenografts (PDX) of human acute leukemia. Preliminary safety evaluation was carried out in rat and monkey. Results: Zapadcine-1 possesses a similar binding ability to the death receptor DR5 as the naked monoclonal antibody Zaptuzumab, and can be rapidly endocytosed into the lysosome of cancer cells. Zapadcine-1 specifically kills human lymphocyte leukemia cells and solid tumor cells, but not normal cells tested. More importantly, Zapadcine-1 drastically eliminates the xenografts in both CDX and PDX models of human acute leukemia. The excellent and comparable therapeutic efficacy is also observed in lung cancer NCI-H1975 CDX mouse model. The maximum-tolerated dose (MTD) of single injected Zapadcine-1 in rat and cynomolgus monkey shows an acceptable safety profile. Conclusion: These data demonstrate a promising anti-cancer activity, meriting further exploration of its potential as a novel cancer therapeutic agent, especially for the acute lymphocyte leukemia.

2.
J Mol Model ; 25(8): 235, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332539

RESUMO

Menthol is an often used skin penetration enhancer because of its high efficiency and relative safety, but the mechanism how it works has not been fully understood up to date. In this study, quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. The skin is modeled as a ceramide (CER2) bilayer. Potential of mean force (PMF) calculations on quercetin in both CER2 and menthol-involved CER2 bilayers have been performed. The results show that the free energy minimum of quercetin in the presence of menthol molecules shifts toward the headgroup region of the bilayer, and the central energy barrier decreases, facilitating the penetration of quercetin. The presence of menthol molecules enhances the permeability of quercetin. This study may shed light on the mechanism of penetration enhancer, providing useful information in the design of more efficient transdermal drug delivery system. Graphical abstract Quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. Potential of mean force calculations reveal that the central energy barrier of quercetin decreases in the presence of menthol, facilitating the penetration of quercetin. Our results are helpful to understand the mechanism of penetration enhancer, aiding in the design of more efficient transdermal drug delivery system.

3.
Ecotoxicol Environ Saf ; 180: 762-769, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31154201

RESUMO

Alkyl phenanthrene (A-Phen) and Dechlorane Plus (DP) are ubiquitous environmental pollutants that widely co-exist in the environment. It has been established that both A-Phen and DP elicit neurotoxicity, but the potential interactive toxicity of these contaminants is not well-known. To determine whether a mixture of A-Phen and DP would exhibit interactive effects on neurodevelopment, we co-exposed 3-methylphenanthrene (3-MP), a representative of A-Phen, with DP. Our results illustrated that exposure to 5 or 20 µg/L 3-MP alone or in combination with 60 µg/L DP caused neurobehavioral anomalies in zebrafish. In accordance with the behavioral deficits, 3-MP alone or co-exposed with DP significantly decreased axonal growth of secondary motoneurons, altered intracellular Ca2+ homeostasis and induced cell apoptosis in the muscle of zebrafish. Additionally, 3-MP alone or co-exposed with DP significantly increased reactive oxygen species (ROS) and the mRNA levels of apoptosis-related genes. These findings indicate that 3-MP alone or co-exposed with DP induces neurobehavioral deficits through the combined effects on neuronal connectivity and muscle function. Chemical analysis revealed significant increases in 3-MP and DP bioaccumulation in zebrafish co-exposed with 3-MP and DP. Elevated bioaccumulation resulting from mixture exposure may represent a significant contribution of the synergistic effects observed in combined chemical exposure.


Assuntos
Hidrocarbonetos Clorados/toxicidade , Sistema Nervoso/efeitos dos fármacos , Fenantrenos/toxicidade , Compostos Policíclicos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Sinergismo Farmacológico , Sistema Nervoso/crescimento & desenvolvimento , Fenantrenos/síntese química , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/crescimento & desenvolvimento
4.
Cancer Chemother Pharmacol ; 84(1): 61-72, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31037333

RESUMO

PURPOSE: Epidermal growth factor receptor (EGFR) is highly expressed on non-small cell lung cancers (NSCLC) and a valuable therapeutic target. This study aimed at producing and characterizing monomethyl auristatin E (MMAE)-conjugated anti-EGFR antibody as a novel EGFR-targeting therapy for NSCLC. METHODS: A humanized anti-EGFR monoclonal antibody (named RC68) was purified and conjugated with MMAE using a MC-VC-PAB or PY-VC-PAB linker. The in vitro and in vivo antitumor activity of RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were characterized. RESULTS: The RC68 was generated from RC68-expressing cells and had a purity of > 99.0%. The RC68 recognized EGFR on tumor cells, particularly for higher EGFR expressing H125, A431, HCC827 and H1975 cells. The RC68 was conjugated with an average of 4 MMAE molecules to generate RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, respectively. The RC68-MC-VC-PAB-MMAE, RC68-PY-VC-PAB-MMAE and RC68 displayed similar binding affinity to EGFR on tumor cells, and RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were effectively internalized by H125 cells. The RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE inhibited the growth of H125 cells in vitro with an IC50 7.37-8.04 ng/mL and implanted H125 tumors in vivo, but did not affect body weights of mice. The antitumor effect of RC68-MC-VC-PAB-MMAE was stronger than RC68-PY-VC-PAB-MMAE, which was also stronger than docetaxel in vivo. CONCLUSIONS: These novel antibody-drug conjugates, particularly for RC68-MC-VC-PAB-MMAE, may be a potential candidate for treatment of EGFR + NSCLC.

5.
Cryobiology ; 87: 32-39, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30876909

RESUMO

Lipid rafts and associated membrane proteins (flotillin, caveolin) play important roles in cell signaling and sperm fertilization while heat shock proteins (Hsp) ensure properly protein folding to fulfill their physiological functions. The markedly reduced fertility in thawed sperm after cryopreservation could result from disrupted membrane lipid rafts and these proteins. To explore the effect of sperm cryopreservation on lipid rafts and heat shock proteins, we compared lipid raft integrity, and the expression levels of lipid raft associated proteins (Flot-1, Flot-2, Cav-1) as well as heat shock proteins (Hsp90, Hsp70) in fresh and thawed sperm cryopreserved under different scenarios in yellow catfish. We found higher lipid raft integrity, higher protein expression levels of Flot-1, Flot-2, Cav-1, Hsp90, and Hsp70 in fresh sperm samples than in thawed sperm samples, in thawed sperm samples cryopreserved with optimal cooling rate than those cryopreserved with sub-optimal cooling rate, and in thawed sperm samples cryopreserved with extenders supplemented with cholesterol than those supplemented with methyl-ß-cyclodextrin (for cholesterol removal). Our findings indicate that lipid raft integrity, and expression levels of Flot-1, Flot-2, Cav-1, Hsp90, and Hsp70 are clearly associated with sperm quality, and together they may play a cumulative role in reduced fertility associated with thawed sperm in aquatic species.

6.
Toxicology ; 418: 70-80, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30836164

RESUMO

Polybrominated diphenyl ethers (PBDEs) and lead (Pb) are common pollutants that co-exist in the environment. These chemicals may be associated with autism spectrum disorder (ASD), yet direct evidence is lacking. More importantly, how co-exposure of these chemicals might affect ASD has never been explored. For assessing the relationship between PBDE/Pb exposure and ASD, pregnant C57BL/6 J female mice were exposed to BDE209 (0.12 ng/day), Pb (1.2 ng/day), or a BDE209/Pb mixture from gestational day (GD) 9.5 to postnatal day (PND) 21 using ALZET osmotic pumps. Polyinosinic-polycytidylic acid (poly I:C) was included as a positive control, as its single dose injection (20 mg/kg.bw; i.p.) at mid-pregnancy (GD 12.5) produces ASD-like behaviors in mouse offspring. These ASD-like phenotypes include decreased preference for social novelty, increased marble burying behavior, and learning impairment. Similar to the poly I:C control, perinatal exposure to Pb or BDE209/Pb mixture elicited increased marble burying and learning impairment, but it had no effect on sociability. Consistent with these behavioral anomalies, Pb and BDE209/Pb co-exposure as well as poly I:C exposure increased the production of pro-inflammation cytokines interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α (TNFα), interferon γ (IFNγ), and interleukin 17 A (IL-17 A) in the serum, and decreased neuronal cells in the CA1 and CA3 subregions of the hippocampus. The majority of these changes in the BDE209/Pb mixture group were due to the effect of Pb rather than BDE209. However, BDE209/Pb co-exposure elicited a synergistic increase in the production of IL-4, IL-6, TNFα, IFNγ, and IL-17A in the serum. BDE209 exposure alone also significantly affected spatial learning and increased the production of IL-10, TNFα, and IL-17 A in the serum of male offspring. Our work demonstrates that perinatal exposure to a low dose of Pb or the BDE209/Pb mixture, although it did not induce typical ASD-like symptoms, elicited restricted, repetitive patterns of behavior and affected learning in male offspring. In addition, the synergistic increase in the systemic inflammatory response in the BDE209/Pb co-exposure group underscores the importance of evaluating chemical mixtures in disease onset.

7.
Toxicol Ind Health ; 35(2): 165-176, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30789094

RESUMO

Tetrabromobisphenol A (TBBPA) and cadmium chloride (CdCl2) are the typical representative pollutants of brominated flame retardants and heavy metals found in the air of e-waste recycling workshops. However, their metabolic kinetics through mixture inhalation is unknown. In the present study, 8-week old Institute of Cancer Research (ICR) male mice were whole-body exposed to TBBPA and CdCl2 mixtures by inhalation. Tissue samples were collected for TBBPA and cadmium (Cd) analysis at 2, 4, 6, and 8 weeks during exposure and at 4 and 8 weeks after the completion of the 8-week exposure period. TBBPA was mainly distributed to the lungs, liver, kidney, testis, and spleen, with a high amount accumulated in the brain, liver, and spleen. Cd was mainly distributed to the lungs, liver, and kidney, with a high amount accumulated in the liver, kidney, and testis and a low amount accumulated in brain and serum. Tissue burden of TBBPA and Cd in all organs increased in a dose- and time-dependent manner during the exposure period. However, 4 weeks after the completion of an 8-week exposure, TBBPA concentrations in the liver, testis, brain, and serum and Cd concentrations in the liver, testis, and kidney were higher than the corresponding tissue concentrations during the exposure period. The rapid accumulation of both TBBPA and Cd in the lungs after inhalation exposure indicated a high risk of the respiratory system diseases for workers in e-waste recycling workshops. In addition, the migration of both TBBPA and Cd from lungs to liver and testis may result in more complex toxic effects in vivo.


Assuntos
Cádmio/análise , Cádmio/farmacocinética , Exposição por Inalação/análise , Bifenil Polibromatos/análise , Bifenil Polibromatos/farmacocinética , Animais , Cádmio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Bifenil Polibromatos/metabolismo , Distribuição Tecidual
8.
Target Oncol ; 14(1): 93-105, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30635821

RESUMO

BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy. OBJECTIVE: To develop anti-EGFR antibody-drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer. METHODS: A humanized anti-EGFR monoclonal antibody (RC68) was generated by mouse immunization and complementary-determining region grafting technology. Two RC68-based ADCs, RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, were synthesized by conjugating monomethyl auristatin E (MMAE), a small-molecule cytotoxin, to RC68 through two distinct linkers (MC and PY). Internalization of the RC68-based ADCs was examined by flow cytometry. The in vitro and in vivo antitumor activities of RC68-based ADCs were evaluated in human pancreatic cancer cells and in a BXPC-3 xenograft nude mouse model, respectively. RESULTS: The RC68-based ADCs bound to EGFR on the surface of tumor cells and were effectively internalized, resulting in the death of EGFR-positive cancer cell lines. The RC68-based ADCs (at 5 or 10 mg/kg) were more potent than gemcitabine hydrochloride (60 mg/kg) at inhibiting the growth of BXPC-3 xenografts. Moreover, RC68-PY-VC-PAB-MMAE was found to have superior stability in human plasma compared with RC68-MC-VC-PAB-MMAE. CONCLUSION: A novel EGFR-targeting ADC, RC68-PY-VC-PAB-MMAE, shows promise as an effective, selective, and safe therapeutic agent for EGFR-positive pancreatic cancer.

9.
Molecules ; 23(8)2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30103465

RESUMO

FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After replacing the (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamide moiety in compound 3 with 5-(3-chlorophenyl)-1H-pyrazole-3-carboxamide, we traveled from FXIa inhibitor 3 to a scaffold that fused the privileged fragments into a pharmacophore for FXIa inhibitors. Subsequently, we synthesized and assessed the FXIa inhibitory potency of a series of 5-phenyl-1H-pyrazole-3-carboxamide derivatives with different P1, P1' and P2'moiety. Finally, the SAR of them was systematically investigated to afford the lead compound 7za (FXIa Ki = 90.37 nM, 1.5× aPTT in rabbit plasma = 43.33 µM) which exhibited good in vitro inhibitory potency against FXIa and excellent in vitro coagulation activities. Furthermore, the binding mode of 7za with FXIa was studied and the results suggest that the 2-methylcyclopropanecarboxamide group of 7za makes 2 direct hydrogen bonds with Tyr58B and Thr35 in the FXIa backbone, making 7za binds to FXIa in a highly efficient manner.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Desenho de Drogas , Fator XIa/antagonistas & inibidores , Fator XIa/química , Pirazóis/química , Pirazóis/farmacologia , Animais , Anticoagulantes/síntese química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Tempo de Tromboplastina Parcial , Ligação Proteica , Pirazóis/síntese química , Coelhos , Relação Estrutura-Atividade
10.
Int Immunopharmacol ; 62: 299-308, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30048860

RESUMO

B-cell lymphoma remains one of the most refractory tumors, and as such the development of novel treatment approaches, such as antibody-drug conjugates (ADCs), is required. To improve the stability and homogeneity of the ADCs, a humanized anti-CD19 monoclonal antibody (RC58) was developed in the present study. RC58 was based on the CD19 antigen as a potential molecular target of human B-cell lymphomas. RC58 has high CD19-binding affinity and can be internalized in CD19-positive cells through endocytosis. Furthermore, three types of RC58-based ADCs (ADC-1, ADC-2, and ADC-3) were generated using three kinds of Maleimide-PEG-based linkers with two different cytotoxins. The anti-tumor activities of the ADCs were confirmed by in vitro and in vivo experiments. The stability of the ADCs was also evaluated by incubation in human plasma for 10 days. In vitro experiments showed that the three ADCs had distinct inhibitory effects on several B-lymphoma cell lines. Meanwhile, a close correlation between efficacy and drug concentration was found in a nude mouse xenograft model of human B-cell lymphoma, after treatment with RC58-based ADCs. Our results suggest that ADC-1, with high efficiency, could be used as a potential therapeutic agent for human B-cell malignancies.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Desenho de Drogas , Imunoconjugados/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/química , Antineoplásicos Imunológicos/química , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Estabilidade de Medicamentos , Feminino , Células HEK293 , Humanos , Imunoconjugados/química , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Toxicol Ind Health ; 34(9): 631-639, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30003840

RESUMO

Brominated flame retardants (BFRs) and heavy metals (HMs) are two main types of pollutants in electronic waste recycling sites, which are also ubiquitously detectable in environmental media and human tissues. However, the adverse health effects of exposure to the mixture of these types of pollutants are unknown. In this study, we investigated the reproductive toxicity of a mixture of decabromodiphenyl ether (BDE-209), tetrabromobisphenol A, cadmium chloride, and lead acetate (PbAc) at the environmental relevant levels. Zebrafish were waterborne and exposed to chemical mixtures for one generation. The reproductive effects were evaluated for F0 adults and F1 offspring. Chemical residues were also analyzed in the exposed adults and their eggs at the end of exposure. Our findings demonstrated that exposure to the chemical mixture for 150 days had no effect on the survival rate of zebrafish, but it decreased body length and weight in females and increased body weight and condition factor in males. The mixture exposure resulted in a female-biased sex ratio in adults and decreased sperm density and motility in males and egg production in females. For the F1 offspring, decreased fertilization, delayed hatching, and increased malformation were found in all exposure groups. In conclusion, chronic co-exposure to BFRs and HMs at the environmental relevant levels not only affected growth, sex ratio, and sperm quantity/quality and egg production in adults but also reduced the reproductive success in the offspring, implying that multi-pollutants in the environmental media may pose a public health risk to other exposed organisms or human beings.


Assuntos
Retardadores de Chama/toxicidade , Metais Pesados/toxicidade , Bifenil Polibromatos/toxicidade , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Masculino , Ovulação/efeitos dos fármacos , Razão de Masculinidade , Espermatozoides/efeitos dos fármacos , Testes de Toxicidade Crônica , Peixe-Zebra
12.
Bull Environ Contam Toxicol ; 101(1): 75-79, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29802430

RESUMO

Perfluorooctane sulfonic acid (PFOS), as a potential endocrine disrupting chemical, is widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on thyroid in aquatic organisms and the underlying mechanisms are largely unknown. The present study assessed the effect of chronic PFOS exposure on thyroid structure and function using zebrafish model. Zebrafish at 8 h post fertilization (hpf) were exposed to PFOS (250 µg/l) until 120 d post fertilization (dpf). Thyroid hormone (T3 and T4) level, thyroid morphology and thyroid function related gene expression were evaluated in zebrafish at 120 dpf. Our findings demonstrated that chronic PFOS exposure altered thyroid hormone level, thyroid follicular cell structure and thyroid hormone related gene expression, suggesting the validity of zebrafish as an alternative model for PFOS chronic toxicity screening.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Disruptores Endócrinos/toxicidade , Fluorcarbonetos/toxicidade , Glândula Tireoide/efeitos dos fármacos , Peixe-Zebra , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Glândula Tireoide/fisiologia
13.
Neurotoxicol Teratol ; 66: 8-16, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29309833

RESUMO

Autism spectrum disorder (ASD) has complex neurodevelopmental impairments and origins that are linked to both genetic and environmental factors. Hence, there is an urgency to establish animal models with ASD-like characteristics to understand the underlying mechanisms of ASD. Prenatal exposure to valproic acid (VPA) produced ASD-like symptoms in humans, rats, and recently zebrafish. The present study investigated the use of VPA exposure to generate an ASD model in zebrafish. Early life stage exposures produced ASD-like phenotypes in the developing brain development and behavioral changes in embryonic and larval zebrafish. Our findings revealed that treating zebrafish embryos with VPA starting at 8h post fertilization (hpf) resulted in significant: increase in the ASD macrocephalic phenotype; hyperactivity of embryo/larvae movement behaviors; and increases of ASD-like larval social behaviors. Further analysis showed increases in cell proliferation, the proportion of mature newborn neurons, and neural stem cell proliferation in the brain region, which may contribute to the brain overgrowth and macrocephaly observed following VPA exposure. Our study demonstrated that VPA exposure generates ASD-like phenotypes and behaviors, indicating that zebrafish is an alternative model to investigate underlying ASD mechanisms.

14.
J Sep Sci ; 41(9): 2029-2036, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29333682

RESUMO

One-monomer molecularly imprinted magnetic nanoparticles were prepared as adsorbents for selective extraction of bisphenol A from water in this study. A single bi-functional monomer was adopted for preparation of the molecularly imprinted polymer, avoiding the tedious trial-and-error optimizations as traditional strategy. Moreover, bisphenol F was used as the dummy template for bisphenol A to avoid the interference from residual template molecules. These nanoparticles showed not only large adsorption capacity and good selectivity to the bisphenol A but also outstanding magnetic response performance. Furthermore, they were successfully used as magnetic solid-phase extraction adsorbents of bisphenol A from various water samples, including tap water, river water, and seawater. The developed method was found to be much more efficient, convenient, and economical for selective extraction of bisphenol A compared with the traditional solid-phase extraction. Separation of these nanoparticles can be easily achieved with an external magnetic field, and the optimized adsorption time was only 15 min. The recoveries of bisphenol A in different water samples ranged from 85.38 to 93.75%, with relative standard deviation lower than 7.47%. These results showed that one-monomer molecularly imprinted magnetic nanoparticles had the potential to be popular adsorbents for selective extraction of pollutants from water.

15.
Oncotarget ; 8(23): 37186-37199, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28415603

RESUMO

Factor Xa (FXa) plays a significant role in the blood coagulation cascade and is a promising target for anticoagulation drugs. Three oral FXa inhibitors have been approved by FDA for treating thrombotic diseases. In this study, 43 novel compounds were synthesized anthranilamide-based FXa inhibitors aiming to ameliorate the toxicity of traditional FXa inhibitors in clinic. The data indicated that the compounds 6a, 6a-b, 6a-e, 6k, 6k-a and 6k-b showed remarkable FXa inhibitory activity and excellent selectivity over thrombin in vitro. Selected compounds also exhibited anticoagulant activities in vitro consequently and were potent novel anti-coagulators in further.


Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa/uso terapêutico , Fator Xa/metabolismo , Trombose/tratamento farmacológico , ortoaminobenzoatos/síntese química , Adulto , Anticoagulantes/metabolismo , Coagulação Sanguínea , Biologia Computacional , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/metabolismo , Humanos , Masculino , Modelos Moleculares , Terapia de Alvo Molecular , Plasma/metabolismo , Rivaroxabana/uso terapêutico , Trombina/metabolismo , ortoaminobenzoatos/metabolismo
16.
Environ Pollut ; 224: 7-15, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28288352

RESUMO

Developmental neurobehavioral toxicity of Dechlorane Plus (DP) was investigated using the embryo-larval stages of zebrafish (Danio rerio). Normal fertilized embryos were waterborne exposed to DP at 15, 30, 60 µg/L beginning from 6 h post-fertilization (hpf). Larval teratology, motor activity, motoneuron axonal growth and muscle morphology were assessed at different developmental stages. Results showed that DP exposure significantly altered embryonic spontaneous movement, reduced touch-induced movement and free-swimming speed and decreased swimming speed of larvae in response to dark stimulation. These changes occurred at DP doses that resulted no significant teratogenesis in zebrafish. Interestingly, in accord with these behavioral anomalies, DP exposure significantly inhibited axonal growth of primary motoneuron and induced apoptotic cell death and lesions in the muscle fibers of zebrafish. Furthermore, DP exposure at 30 µg/L and 60 µg/L significantly increased reactive oxygen species (ROS) and malondialdehyde (MDA) formation, as well as the mRNA transcript levels of apoptosis-related genes bax and caspase-3. Together, our data indicate that DP induced neurobehavioral deficits may result from combined effects of altered neuronal connectivity and muscle injuries.


Assuntos
Axônios/efeitos dos fármacos , Hidrocarbonetos Clorados/toxicidade , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Compostos Policíclicos/toxicidade , Peixe-Zebra , Animais , Caspase 3/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Malondialdeído/metabolismo , Natação
17.
Oncotarget ; 8(70): 115254-115269, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29383157

RESUMO

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs is responsible for tumor initiation, progression, recurrence and chemo-resistance. Celecoxib is one of the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs), which have chemo-preventive activity against cancers, including breast cancer and colorectal cancer. However, the mechanisms by which NSAIDs exert its cancer prevention effects have yet been completely understood. In the present study, we investigated for the first time the effect of celecoxib on breast CSCs inhibition and its potential molecular mechanisms. Our results demonstrated that celecoxib suppresses CSC self-renewal, sensitizes chemo-resistance, inhibits epithelial to mesenchymal transition (EMT), and attenuates metastasis and tumorigenesis. Further exploring the underlying mechanism revealed that celecoxib targets breast CSCs by inhibiting the synthesis of prostaglandin E2 and down-regulating the Wnt pathway activity. Our findings suggest that celecoxib, by targeting CSCs, may be used as an adjuvant chemotherapy drug to improve breast cancer treatment outcomes.

18.
Chemosphere ; 169: 262-270, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27880925

RESUMO

The developmental and reproductive toxicity of bisphenol A (BPA) has been demonstrated in a variety of model systems. Zebrafish (Danio rerio) were waterborne-exposed to BPA during three different developmental stages: embryonic period:6 h post fertilization (hpf) to 5 months post fertilization (mpf); larval period: 6 days post fertilization (dpf) to 5 mpf; and sexually mature period: 3 mpf to 5 mpf. Evaluations included F0 adult growth, reproduction parameters, and F1 offspring development. BPA exposure did not affect zebrafish growth in any of exposure groups. Testis weight was decreased only following the 6 hpf to 5 mpf 0.001 µM BPA exposure. The lowest effect level indicated by a reduction in sperm volume, density, motility, and velocity across a range of exposure durations was 0.001 µM, with all but sperm density significant for the longest exposure duration, which was also the only significant endpoint for the lowest exposure concentration in the 3-5 mpf exposure group. Nonmonotonic concentration-response curves were noted for all F0 reproductive endpoints for at least one of the two longest exposure durations. For the F1 offspring of fish exposed from 6 hpf to 5 mpf, malformations and mortality were increased following 0.001 µM BPA exposure, while egg production and fertilization were reduced in higher concentration treatment groups. Overall, BPA exposure during three different developmental periods impaired zebrafish reproductive development, with most significance changes found in the lowest concentration treatment groups. Genetic impacts on gamete development may underlie the secondary effects of reduced fertilization rate, embryonic mortality, and malformations.


Assuntos
Compostos Benzidrílicos/toxicidade , Fertilização/fisiologia , Depuradores de Radicais Livres/toxicidade , Fenóis/toxicidade , Reprodução/fisiologia , Espermatozoides/fisiologia , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Relação Dose-Resposta a Droga , Fertilização/efeitos dos fármacos , Masculino , Reprodução/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
19.
Sci Rep ; 6: 38466, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27929129

RESUMO

Perfluorooctanesulfonate (PFOS) has been widely detected in the environment, wildlife and humans, but few studies have ever examined its mutagenic effect in vivo. In the present study, we use a transgenic fish model, the λ transgenic medaka, to evaluate the potential mutagenicity of PFOS in vivo following a subchronic exposure of 30 days. The mutant frequency of cII target gene was 3.46 × 10-5 in liver tissue from control fish, which increased by 1.4-fold to 4.86 × 10-5 in fish exposed to 6.7 µg/L PFOS, 1.55-fold to 5.36 × 10-5 in fish exposed to 27.6 µg/L PFOS, and 2.02-fold to 6.99 × 10-5 in fish exposed to 87.6 µg/L PFOS. This dose-dependent increase of mutant frequency was also accompanied with mutational spectrum changes associated with PFOS exposure. In particular, PFOS-induced mutation was characterized by +1 frameshift mutations, which increased from 0% in control fish to 13.2% in fish exposed to 27.6 µg/L PFOS and 14.6% in fish exposed to 87.6 µg/L PFOS. Our findings provide the first evidence of PFOS's mutagenicity in an aquatic model system. Given the fact that most conventional mutagenic assays were negative for PFOS, we propose that PFOS-induced mutation in liver tissue of λ transgenic medaka may be mediated through compromised liver function.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Carcinógenos/toxicidade , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , Mutação/efeitos dos fármacos , Animais , Animais Geneticamente Modificados/genética , Fígado/patologia , Testes de Mutagenicidade , Mutação/genética , Oryzias/genética
20.
Aging (Albany NY) ; 8(11): 2754-2776, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27852980

RESUMO

Breast cancer incidence increases during aging, yet the mechanism of age-associated mammary tumorigenesis is unclear. Mammary stem cells are believed to play an important role in breast tumorigenesis, but how their function changes with age is unknown. We compared mammary epithelial cells isolated from young and old mammary glands of different cohorts of C57BL6/J and BALB/c mice, and our findings revealed that old mammary glands were characterized by increased basal cell pool comprised of mostly CD49fhi cells, altered luminal-to-basal cell ratio, and irregular ductal morphology. More interestingly, basal stem cells in old mice were increased in frequency, but showed a functional decline of differentiation and increased neoplastic transformation potential. Gene signature enrichment analysis revealed a significant enrichment of a luminal cell gene expression signature in the basal stem cell-enriched population from old mice, suggesting some luminal cells were expressing basal markers. Immunofluorescence staining confirmed the presence of luminal cells with high CD49f expression in hyperplastic lesions implicating these cells as undergoing luminal to basal phenotypic changes during aging. Whole transcriptome analysis showed elevated immune and inflammatory responses in old basal stem cells and stromal cells, which may be the underlying cause for increased CD49fhi basal-like cells in aged glands.


Assuntos
Envelhecimento/patologia , Transformação Celular Neoplásica/patologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/patologia , Células-Tronco/patologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Feminino , Perfilação da Expressão Gênica , Inflamação/metabolismo , Inflamação/patologia , Integrina alfa6/metabolismo , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA