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1.
Nat Commun ; 11(1): 4848, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973166

RESUMO

Polydopamine (PDA) is a simple and versatile conformal coating material that has been proposed for a variety of uses; however in practice its performance is often hindered by poor mechanical properties and high roughness. Here, we show that blue-diode laser annealing dramatically improves mechanical performance and reduces roughness of PDA coatings. Laser-annealed PDA (LAPDA) was shown to be >100-fold more scratch resistant than pristine PDA and even better than hard inorganic substrates, which we attribute to partial graphitization and covalent coupling between PDA subunits during annealing. Moreover, laser annealing provides these benefits while preserving other attractive properties of PDA, as demonstrated by the superior biofouling resistance of antifouling polymer-grafted LAPDA compared to PDA modified with the same polymer. Our work suggests that laser annealing may allow the use of PDA in mechanically demanding applications previously considered inaccessible, without sacrificing the functional versatility that is so characteristic of PDA.


Assuntos
Indóis/química , Indóis/efeitos da radiação , Lasers , Polímeros/química , Polímeros/efeitos da radiação , Incrustação Biológica , Materiais Revestidos Biocompatíveis/química , Teste de Materiais , Propriedades de Superfície
3.
Molecules ; 25(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977525

RESUMO

The problem of treating viral infections is extremely relevant due to both the emergence of new viral diseases and to the low effectiveness of existing approaches to the treatment of known viral infections. This review focuses on the application of porphyrin, chlorin, and phthalocyanine series for combating viral infections by chemical and photochemical inactivation methods. The purpose of this review paper is to summarize the main approaches developed to date in the chemical and photodynamic inactivation of human and animal viruses using porphyrins and their analogues and to analyze and discuss the information on viral targets and antiviral activity of porphyrins, chlorins, of their conjugates with organic/inorganic compounds obtained in the last 10-15 years in order to identify the most promising areas.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fotoquimioterapia/métodos , Pneumonia Viral/tratamento farmacológico , Porfirinas/farmacologia , Antivirais/química , Humanos , Indóis/química , Indóis/farmacologia , Pandemias , Processos Fotoquímicos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Ligação Viral/efeitos dos fármacos
4.
Nat Commun ; 11(1): 3958, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769971

RESUMO

Catalytic versatility is an inherent property of many enzymes. In nature, terpene cyclases comprise the foundation of molecular biodiversity as they generate diverse hydrocarbon scaffolds found in thousands of terpenoid natural products. Here, we report that the catalytic activity of the terpene cyclases AaTPS and FgGS can be switched from cyclase to aromatic prenyltransferase at basic pH to generate prenylindoles. The crystal structures of AaTPS and FgGS provide insights into the catalytic mechanism of this cryptic function. Moreover, aromatic prenyltransferase activity discovered in other terpene cyclases indicates that this cryptic function is broadly conserved among the greater family of terpene cyclases. We suggest that this cryptic function is chemoprotective for the cell by regulating isoprenoid diphosphate concentrations so that they are maintained below toxic thresholds.


Assuntos
Dimetilaliltranstransferase/metabolismo , Liases Intramoleculares/metabolismo , Alternaria/enzimologia , Domínio Catalítico , Dimetilaliltranstransferase/química , Ensaios Enzimáticos , Escherichia coli/metabolismo , Fusarium/enzimologia , Indóis/química , Indóis/metabolismo , Liases Intramoleculares/química , Cinética , Ligantes , Modelos Moleculares , Prenilação , Terpenos/metabolismo
5.
Int J Nanomedicine ; 15: 5073-5082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764937

RESUMO

Objective: To prepare xanthatin (XA)-loaded polydopamine (PDA) nanoparticles (PDA-XA-NPs) and to investigate their adhesion and bioavailability. Materials and methods: PDA-XA-NPs were synthesized and characterized using transmission electron microscopy, zeta potential analysis and encapsulation efficiency analysis. Their in vitro release kinetics and inhibitory effects on gastric cancer were studied. The adhesion of PDA-XA-NPs was evaluated by in vivo imaging atlas. The pharmacokinetics of PDA-XA-NPs and XA was compared. Results: PDA-XA-NPs had a spherical shape, a particle size of about 380 nm, an encapsulation efficiency of (82.1 ± 0.02) % and a drug loading capacity of (5.5 ± 0.1)%. The release of PDA-XA-NPs in PBS was stable and slow, without being affected by pH. The adhesion capacity of PDA-XA-NPs for mucin was significantly higher than that of bulk drug. The gastric mucosal retention of PDA-XA-NPs reached 89.1% which significantly exceeded that of XA. In vivo imaging showed that PDA-XA-NPs targeting the stomach were retained for a period of time. The pharmacokinetics study showed that PDA-XA-NPs had a longer retention time and a slower drug release than those of XA. In vitro experiments confirmed that PDA-XA-NPs exerted similar inhibitory effects on gastric cancer to those of XA, which lasted for a period of time. Conclusion: High-adhesion NPs were constructed. Gastric cancer was targeted by orally administered PDA-XA-NPs, as a potentially feasible therapy. Eventually, the bioavailability of XA was increased.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Furanos/farmacocinética , Nanopartículas/química , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Furanos/química , Mucosa Gástrica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Masculino , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Nanopartículas/metabolismo , Tamanho da Partícula , Polímeros/química , Ratos Sprague-Dawley , Neoplasias Gástricas/patologia
6.
mBio ; 11(4)2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820005

RESUMO

We assessed various newly generated compounds that target the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various previously known compounds reportedly active against SARS-CoV-2, employing RNA quantitative PCR (RNA-qPCR), cytopathicity assays, and immunocytochemistry. Here, we show that two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, exerted potent activity against SARS-CoV-2 in cell-based assays performed using VeroE6 cells and TMPRSS2-overexpressing VeroE6 cells. While GRL-0820 and the nucleotide analog remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred. No significant anti-SARS-CoV-2 activity was found for several compounds reportedly active against SARS-CoV-2 such as lopinavir, nelfinavir, nitazoxanide, favipiravir, and hydroxychroloquine. In contrast, GRL-0920 exerted potent activity against SARS-CoV-2 (50% effective concentration [EC50] = 2.8 µM) and dramatically reduced the infectivity, replication, and cytopathic effect of SARS-CoV-2 without significant toxicity as examined with immunocytochemistry. Structural modeling shows that indole and chloropyridinyl of the derivatives interact with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using high-performance liquid chromatography-mass spectrometry (HPLC/MS), suggesting that the indole moiety is critical for the anti-SARS-CoV-2 activity of the derivatives. GRL-0920 might serve as a potential therapeutic for coronavirus disease 2019 (COVID-19) and might be optimized to generate more-potent anti-SARS-CoV-2 compounds.IMPORTANCE Targeting the main protease (Mpro) of SARS-CoV-2, we identified two indole-chloropyridinyl-ester derivatives, GRL-0820 and GRL-0920, active against SARS-CoV-2, employing RNA-qPCR and immunocytochemistry and show that the two compounds exerted potent activity against SARS-CoV-2. While GRL-0820 and remdesivir blocked SARS-CoV-2 infection, viral breakthrough occurred as examined with immunocytochemistry. In contrast, GRL-0920 completely blocked the infectivity and cytopathic effect of SARS-CoV-2 without significant toxicity. Structural modeling showed that indole and chloropyridinyl of the derivatives interacted with two catalytic dyad residues of Mpro, Cys145 and His41, resulting in covalent bonding, which was verified using HPLC/MS. The present data should shed light on the development of therapeutics for COVID-19, and optimization of GRL-0920 based on the present data is essential to develop more-potent anti-SARS-CoV-2 compounds for treating COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Indóis/farmacologia , Pneumonia Viral/tratamento farmacológico , Sequência de Aminoácidos , Animais , Betacoronavirus/enzimologia , Chlorocebus aethiops , Cloroquina/farmacologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Indóis/química , Indóis/uso terapêutico , Modelos Moleculares , Pandemias , Pneumonia Viral/virologia , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
7.
J Chromatogr A ; 1628: 461436, 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32822976

RESUMO

In recent years, mussel-inspired polydopamine (PDA) based materials have been widely used as stationary phases for open-tubular capillary electrochromatography (OT-CEC) because of their various excellent properties. Nevertheless, the traditional synthesis routes of functionalized PDA-based capillary columns usually are time-consuming and limited in aqueous solutions. Herein, we report a facile and rapid route to prepare octadecylamine (ODA) functionalized PDA coated OT-CEC columns in organic solvents via a novel one-step in situ solvothermal-assisted coating strategy. Through this developed solvothermal-assisted approach, the growth rate of ODA/PDA coating was significantly speeded up and their hybrid coating process on the capillary inner surface could be rapidly completed in 60 min. The successful preparation of the solvothermal-assisted ODA/PDA hybrid coating were systematically characterized and confirmed by several methods. The influence of the preparation parameters on the formation of hybrid coating and the separation ability of the ODA/PDA modified columns were systematically explored. Consequently, the high-efficiency baseline separation of four kinds of neutral, acidic and basic analytes were achieved based on the ODA/PDA modified columns. The repeatability of the solvothermal-assisted ODA/PDA coated column was also studied, and the relative standard deviations for intra-day, inter-day and column-to-column were all less than 5%. Additionally, the solvothermal-assisted ODA/PDA modified column exhibited good stability and long lifetime.


Assuntos
Aminas/química , Eletrocromatografia Capilar/métodos , Indóis/química , Polímeros/química , Solventes/química , Temperatura , Acetonitrilos/química , Tampões (Química) , Eletro-Osmose , Halogenação , Concentração de Íons de Hidrogênio , Espectroscopia de Infravermelho com Transformada de Fourier , Fatores de Tempo
8.
Chem Biol Interact ; 330: 109231, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853594

RESUMO

Hetero mononuclear rhenium(I) metal complexes (I-V) using different substituted indole-pyrazoline based ligands were synthesized and characterized by spectroscopic and analytical methods. The binding of the rhenium complexes to Herring sperm DNA was monitored by UV spectroscopy, viscosity measurements, and molecular docking studies; groove binding was suggested as the most possible mode and the DNA-binding constants of the complexes were evaluated. In vivo and in vitro cytotoxicity of compounds were evaluated against the brine shrimp and S. cerevisiae cells. An antimicrobial study was carried out by estimating MIC (Minimum Inhibitory Concentration) against two Gram-positive and three Gram-negative bacteria. All synthesized complexes are biologically more active than the corresponding ligands. The anti-proliferation activity of complexes was evaluated on MCF-7, HCT116, and A549 cancer cells by MTT assay. The toxicity profile of synthesized compounds was confirmed by H2O2 production by reactive oxygen species. The increased concentration of lipid peroxidation end products increased free radicals, which enhancing the oxidative stress level in living organisms and results in cell death.


Assuntos
Complexos de Coordenação/farmacologia , Indóis/química , Pirazóis/química , Rênio/química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Artemia/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citotoxinas/toxicidade , DNA/metabolismo , Humanos , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Saccharomyces cerevisiae/efeitos dos fármacos
9.
Phys Rev Lett ; 125(3): 033604, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32745420

RESUMO

We demonstrate Bragg diffraction of the antibiotic ciprofloxacin and the dye molecule phthalocyanine at a thick optical grating. The observed patterns show a single dominant diffraction order with the expected dependence on the incidence angle as well as oscillating population transfer between the undiffracted and diffracted beams. We achieve an equal-amplitude splitting of 14ℏk (photon momenta) and maximum momentum transfer of 18ℏk. This paves the way for efficient, large-momentum beam splitters and mirrors for hot and complex molecules.


Assuntos
Ciprofloxacino/química , Indóis/química , Modelos Químicos , Antibacterianos/química , Interferometria/métodos , Modelos Moleculares , Pigmentos Biológicos/química , Espalhamento de Radiação
10.
Nat Commun ; 11(1): 3841, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737323

RESUMO

Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Ácidos Hidroxâmicos/química , Indóis/química , Proteínas Repressoras/química , Vorinostat/química , Regulação Alostérica , Sítio Alostérico , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Ativação Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Indóis/metabolismo , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Especificidade por Substrato , Termodinâmica , Vorinostat/metabolismo
11.
Int J Nanomedicine ; 15: 4483-4500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606690

RESUMO

Purpose: Tumor metastasis and drug resistance have always been vital aspects to cancer mortality and prognosis. To compromise metastasis and drug resistance, a nanoparticle IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) has been engineered to accomplish efficient targeted epigenotherapy forced by PHF2-induced MET (mesenchymal to epithelial transition). Materials and Methods: IPPD-PHF2 nanoparticle was synthesized and characterized by several analytical techniques. The transfection efficiency of IPP-PHF2 (IR780/PLGA-PEI-PHF2) was compared with PP-PHF2 (PLGA-PEI-PHF2) in vitro by WB and in vivo by IHC, and the cytotoxicity of IPP was compared with Lipo2000 in vitro by CCK8 assay. The inhibition of cancer cell migration caused by PHF2-upregulation was tested by wound healing assay, and the enhanced chemotherapeutic sensitivity was detected by flow cytometry. Tumor-targeting property of IPPD-PHF2 was proved by fluorescent imaging in vivo with MDA-MB-231 tumor-bearing nude mice. Except for fluorescent imaging ability, considerable photoacoustic signals of IPPD-PHF2 at tumor sites were verified. The anti-tumor activity of IPPD-PHF2 was investigated using in vivo human breast cancer MDA-MB-231 cell models. Results: Tumor-targeting nanoparticle IPPD-PHF2 had an average size of about 319.2 nm, a stable zeta potential at about 38 mV. The encapsulation efficiency of doxorubicin was around 39.28%, and the adsorption capacity of plasmids was about 64.804 µg/mg. Significant up-regulation of PHF2 induced MET and caused reduced migration as well as enhanced chemotherapeutic sensitivity. Either IPPD (IR780/PLGA-PEI(Dox)) or IPP-PHF2 (IR780/PLGA-PEI-PHF2) presented minor therapeutic effects, whereas IPPD-PHF2 specifically accumulated within tumors, showed extraordinary transfection efficiency specifically in tumor sites, acted as inhibitors of metastasis and proliferation, and presented good multimodality imaging potentials in vivo. Conclusion: IPPD-PHF2 NPs is a promising tool to bring epigenotherapy into a more practical era, and the potential application of harm-free multimodality imaging guidance is of great value.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transfecção , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Indóis/química , Camundongos Nus , Nanopartículas/ultraestrutura , Metástase Neoplásica , Técnicas Fotoacústicas , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
12.
Chemosphere ; 260: 127579, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32679375

RESUMO

As important emerging contaminants, nonsteroidal anti-inflammatory drugs (NSAIDs) are the most intensively prescribed pharmaceuticals introduced to drinking water due to their incomplete removal in wastewater treatment. While concentrations of NSAIDs in drinking water are generally low, they have been attracting increasing concern as a result of their disinfection byproducts (DBPs) generated in drinking water disinfection. In this work, detection methods were set up for four representative indole-derivative NSAIDs (indomethacin, acemetacin, sulindac, and etodolac) using ultra performance liquid chromatography/electrospray ionization-triple quadruple mass spectrometry (UPLC/ESI-tqMS). ESI+ was better for detection of indomethacin and sulindac, whereas ESI- was suitable to detection of acemetacin and etodolac. With optimized MS parameters, the instrument detection and quantitation limits of the four indole derivatives were achieved to be 1.1-24.6 ng/L and 3.7-41.0 ng/L, respectively. During chlorination, indomethacin and acemetacin could undergo five major reaction types (chlorine substitution, hydrolysis, decarboxylation, C-C coupling, and C-N cleavage) to form a series of DBPs, among which 19 were proposed/identified with structures. Based on the revealed structures of DBPs, transformation pathways of indomethacin and acemetacin in chlorination were partially elucidated. Notably, individual and mixture toxicity of indomethacin and acemetacin before/after chlorination were evaluated using a well-established acute toxicity assessment and a Hep G2 cell cytotoxicity assay, respectively. Results showed that the predicted acute toxicity of a few chlorination DBPs were higher than their precursors; chlorination substantially enhanced the mixture cytotoxicity of indomethacin by over 10 times and slightly increased the mixture cytotoxicity of acemetacin.


Assuntos
Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/toxicidade , Desinfecção/métodos , Poluentes Químicos da Água/análise , Anti-Inflamatórios não Esteroides/química , Cloro/química , Cromatografia Líquida , Desinfetantes/química , Água Potável/química , Halogenação , Células Hep G2 , Humanos , Indóis/análise , Indóis/química , Indóis/toxicidade , Indometacina/análogos & derivados , Indometacina/análise , Indometacina/química , Indometacina/toxicidade , Espectrometria de Massas por Ionização por Electrospray/métodos , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Purificação da Água/métodos
13.
PLoS One ; 15(7): e0227395, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628681

RESUMO

The FluidFM enables the immobilization of single cells on a hollow cantilever using relative underpressure. In this study, we systematically optimize versatile measurement parameters (setpoint, z-speed, z-length, pause time, and relative underpressure) to improve the quality of force-distance curves recorded with a FluidFM. Using single bacterial cells (here the gram negative seawater bacterium Paracoccus seriniphilus and the gram positive bacterium Lactococcus lactis), we show that Single Cell Force Spectroscopy experiments with the FluidFM lead to comparable results to a conventional Single Cell Force Spectroscopy approach using polydopamine for chemical fixation of a bacterial cell on a tipless cantilever. Even for the bacterium Lactococcus lactis, which is difficult to immobilze chemically (like seen in an earlier study), immobilization and the measurement of force-distance curves are possible by using the FluidFM technology.


Assuntos
Aderência Bacteriana , Lactococcus lactis/fisiologia , Microscopia de Força Atômica/métodos , Paracoccus/fisiologia , Células Imobilizadas/fisiologia , Vidro/química , Indóis/química , Polímeros/química , Água do Mar/microbiologia , Análise de Célula Única , Propriedades de Superfície , Titânio/química
14.
J Chromatogr A ; 1625: 461269, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709321

RESUMO

Fluorous affinity means remarkably specific interaction between highly organic fluorides. This work aims to explore the potential of fluoro-functionalized stationary phase for the separation of organic fluorides by means of fluorous-fluorous interaction. Here, by using the Michael addition strategy between 1H,1H,2H,2H-perfluorodecanethiol (PFDT) and polydopamine (PD), a novel fluoro-functionalized stationary phase was synthesized for open-tubular capillary electrochromatography (OT-CEC). The PFDT@PD was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray Photoelectron Spectrometer (XPS). The PFDT@PD@capillary exhibited outstanding separation performance towards neutral compounds (such as alkylbenzenes and chlorobenzenes) and organic fluorides (such as fluorobenzenes and perfluoroalkyl methacrylates etc.) with high resolution and high separation efficiency by hydrophobic interaction and fluorous-fluorous interaction. In addition, the column shows good stability and reproducibility. The relative standard deviations (RSDs) of the retention time for intra-day (n = 5) and inter-day (n = 3) runs and between columns (n = 3) are less than 0.39%, 1.22% and 3.87%, respectively. This novel type of fluoro-functionalized stationary phase represents a great application potential in organic fluorides separation field.


Assuntos
Eletrocromatografia Capilar/métodos , Fluoretos/isolamento & purificação , Flúor/química , Compostos Orgânicos/isolamento & purificação , Eletro-Osmose , Indóis/química , Parabenos/análise , Parabenos/química , Polímeros/química , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Life Sci ; 256: 117892, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502538

RESUMO

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.


Assuntos
Acetilcolinesterase/metabolismo , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Indóis/farmacologia , Malation/toxicidade , Receptor trkB/metabolismo , Transdução de Sinais , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Indóis/administração & dosagem , Indóis/química , Indóis/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
16.
Int J Nanomedicine ; 15: 3605-3620, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547017

RESUMO

Purpose: Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that eventually develops into a joint collapse and results in joint dysfunction. Early intervention and treatment are essential for preserving the joints and avoiding hip replacement. In this study, a system of human umbilical mesenchymal stem cells-supermagnetic iron oxide nanoparticles (NPs) @polydopamine (SCIOPs) was constructed. The magnetic targeting system gathers in the lesion area, inhibits the apoptosis of bone cells, enhances osteogenic effect, and effectively treats ONFH under external magnetic field. Materials and Methods: The supermagnetic iron oxide NPs @polydopamine (SPION@PDA NPs) were characterized by transmission electron microscopy and zeta potential, respectively. The effects of SPION@PDA NPs on the viability, proliferation, and differentiation of stem cells were detected by the CCK8 method, flow cytometry, and staining, respectively. The serum inflammatory indicators were detected by Luminex method. The bone mass of the femoral head was analyzed by micro computed tomography. The expression of apoptosis and osteoblast-related cytokines was detected by Western blotting. The osteogenesis of the femoral head was detected by histological and immunohistochemical sections. Results: The SCIOPs decreased the pro-inflammatory factors, and the micro CT showed that the bone repair of the femoral head was enhanced after treatment. The hematoxylin and eosin sections also showed an increase in the osteogenesis in the femoral head. Western blotting results showed and increased expression of anti-apoptotic proteins Akt and Bcl-2, decreased expression of apoptotic proteins caspase-3 and Bad, and increased expression of osteogenic proteins Runx-2 and Osterix in the femoral head. Conclusion: Under the effect of magnetic field and homing ability of stem cells, SCIOPs inhibited the apoptosis of osteoblasts, improved the proliferation ability of osteoblasts, and promoted bone repair in the femoral head through the Akt/Bcl-2/Bad/caspase-3 signaling pathway, thereby optimizing the tissue repair ability.


Assuntos
Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/terapia , Glucocorticoides/efeitos adversos , Fenômenos Magnéticos , Nanopartículas de Magnetita/química , Células-Tronco Mesenquimais/citologia , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Hemólise/efeitos dos fármacos , Humanos , Indóis/química , Nanopartículas de Magnetita/toxicidade , Nanopartículas de Magnetita/ultraestrutura , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese/efeitos dos fármacos , Polímeros/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Microtomografia por Raio-X , Proteína de Morte Celular Associada a bcl/metabolismo
17.
Virus Res ; 286: 198068, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32565126

RESUMO

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.


Assuntos
Antivirais/química , Betacoronavirus/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Indóis/química , Perileno/análogos & derivados , Glicoproteína da Espícula de Coronavírus/química , Sulfonamidas/química , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Expressão Gênica , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Indóis/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Perileno/química , Perileno/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Sulfonamidas/farmacologia , Termodinâmica , Interface Usuário-Computador , Internalização do Vírus/efeitos dos fármacos
18.
Eur J Med Chem ; 200: 112359, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32531682

RESUMO

Cancer chemotherapy is frequently hampered by drug resistance, so the resistance to anticancer agents represents one of the major obstacles for the effective cancer treatment. Indole derivatives have the potential to act on diverse targets in cancer cells and exhibit promising activity against drug-resistant cancers. Moreover, some indole-containing compounds such as Semaxanib, Sunitinib, Vinorelbine, and Vinblastine have already been applied in clinics for various kinds of cancer even drug-resistant cancer therapy. Thus, indole derivatives are one of significant resources for the development of novel anti-drug-resistant cancer agents. This review focuses on the recent development of indole derivatives with potential therapeutic application for drug-resistant cancers, and the mechanisms of action, the critical aspects of design as well as structure-activity relationships, covering articles published from 2010 to 2020.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/química , Antineoplásicos/química , Desenho de Fármacos , Humanos , Indóis/farmacologia , Relação Estrutura-Atividade
19.
Adv Exp Med Biol ; 1195: 189-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468477

RESUMO

In the present work, new indole derivatives, i.e., 5-[N,N-di alkyl amino alkoxy] azaindole 2,3- di-one derivatives, are synthesized and characterized. These compounds were subjected to acute toxicity and then screened for antiepileptic activity on maximal electroshock seizure (MES) model in albino Wistar rats. In that study 5-[2-dimethyl amino ethoxy] Azaindole-3-hydrazone,2-one and 5-[2- dimethyl amino ethoxy] Azaindole 2-one,3-thiothiosemicarbazone(IIIa) showed good antiepileptic activity and less neurotoxicity compared to phenytoin. The purpose of the present study is to investigate the effect of 5-[2-dimethyl amino ethoxy] Indole 2,3- di one and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone(IIIa) derivatives on biogenic amines concentrations in rat brain after induction of seizures by MES method. The aim of study was relationship between seizure activities and altered the monoamines such as Noradrenaline (NA), Dopamine (DA), Serotonin (5-HT) in forebrain of rats in MES seizure models. In MES model, study of 5-[2-dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one(Va) and 5-[2-dimethyl amino ethoxy]Azaindole 2-one,3-thiosemicarbazone(IIIa) (100 mg/kg) showed significant restoration of the decreased levels of brain monoamines such as noradrenaline, dopamine, and 5-hydroxytryptamine. Thus, this study suggests that 5-[2-Dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one (V) and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone (IIIa) increased the monoamines on rat brain, which may decrease the susceptibility to MES-induced seizure in rats.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Indóis/síntese química , Indóis/uso terapêutico , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/uso terapêutico , Álcoois/síntese química , Álcoois/química , Álcoois/farmacologia , Álcoois/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Indóis/química , Indóis/farmacologia , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
20.
Soft Matter ; 16(21): 5044-5053, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452496

RESUMO

Conventional approaches to mitigate fouling of membrane surfaces impart hydrophilicity to the membrane surface, which increases the water of hydration and fluidity near the surface. By contrast, we demonstrate here that tuning the membrane surface energy close to that of the dispersive component of water surface tension (21.8 mN m-1) can also improve the antifouling properties of the membrane. Specifically, ultrafiltration (UF) membranes were first modified using polydopamine (PDA) followed by grafting of amine-terminated polysiloxane (PSi-NH2). For example, with 2 g L-1 PSi-NH2 coating solution, the obtained coating layer contains 53% by mass fraction PSi-NH2 and exhibits a total surface energy of 21 mN m-1, decreasing the adsorption of bovine serum albumin by 44% compared to the unmodified membrane. When challenged with 1 g L-1 sodium alginate in a constant-flux crossflow system, the PSi-NH2-grafted membrane exhibits a 70% lower fouling rate than the pristine membrane at a water flux of 110 L (m2 h)-1 and good stability when cleaned with NaOH solutions.


Assuntos
Incrustação Biológica/prevenção & controle , Membranas Artificiais , Siloxanas/química , Absorção Fisico-Química , Alginatos/química , Indóis/química , Polímeros/química , Soroalbumina Bovina/química , Ultrafiltração/métodos , Purificação da Água/métodos
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