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1.
Int J Food Microbiol ; 361: 109460, 2022 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-34785387

RESUMO

A series of alkyl gallates were evaluated for the antibacterial activity against two common Gram-negative foodborne bacteria (Pseudomonas fluorescens and Vibrio parahaemolyticus) associated with seafood. The length of the alkyl chain plays a pivotal role in eliciting their antibacterial activities and octyl gallate (OG) exerted an excellent inhibitory efficacy. To extend the aqueous solubility, stability, and bactericidal properties of octyl gallate (OG), an inclusion complex between OG and ß-cyclodextrin (ßCD), OG/ßCD, was prepared and identified with various methods including X-ray diffraction (XRD), differential scanning calorimeter (DSC) and Fourier transform infrared spectroscopy (FTIR). Furthermore, the enhanced inhibitory effect and potential antibacterial mechanism of OG/ßCD against two Gram-negative and Gram-positive foodborne bacteria were comprehensively investigated. The results show that OG/ßCD could function against bacteria through effectively damaging the membrane, permeating into cells, and then disturbing the activity of the respiratory electron transport chain to cause the production of high-level intracellular hydroxyl radicals. Moreover, the reinforced OG/ßCD-incorporated polylactic acid (PLA) nanofibers were fabricated using the electrospinning technique as food packaging to extend the Chinese giant salamander fillet's shelf life at 4 °C. This research highlights the antibacterial effectiveness of OG/ßCD in aqueous media, which can be used as a safe multi-functionalized food additive combined with the benefits of electrospun nanofibers to extend the Chinese giant salamander fillets shelf life by 15 d at 4 °C.


Assuntos
Nanofibras , Pseudomonas fluorescens , Vibrio parahaemolyticus , beta-Ciclodextrinas , Animais , Antibacterianos/farmacologia , China , Ácido Gálico/análogos & derivados , Espectroscopia de Infravermelho com Transformada de Fourier , Urodelos , beta-Ciclodextrinas/farmacologia
2.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576044

RESUMO

α,ß-amyrenone (ABAME) is a triterpene derivative with many biological activities; however, its potential pharmacological use is hindered by its low solubility in water. In this context, the present work aimed to develop inclusion complexes (ICs) of ABAME with γ- and ß-cyclodextrins (CD), which were systematically characterized through molecular modeling studies as well as FTIR, XRD, DSC, TGA, and SEM analyses. In vitro analyses of lipase activity were performed to evaluate possible anti-obesity properties. Molecular modeling studies indicated that the CD:ABAME ICs prepared at a 2:1 molar ratio would be more stable to the complexation process than those prepared at a 1:1 molar ratio. The physicochemical characterization showed strong evidence that corroborates with the in silico results, and the formation of ICs with CD was capable of inducing changes in ABAME physicochemical properties. ICs was shown to be a stronger inhibitor of lipase activity than Orlistat and to potentiate the inhibitory effects of ABAME on porcine pancreatic enzymes. In conclusion, a new pharmaceutical preparation with potentially improved physicochemical characteristics and inhibitory activity toward lipases was developed in this study, which could prove to be a promising ingredient for future formulations.


Assuntos
Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Triterpenos/farmacologia , beta-Ciclodextrinas/farmacologia , Animais , Varredura Diferencial de Calorimetria , Simulação por Computador , Inibidores Enzimáticos/química , Lipase/química , Orlistate/farmacologia , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos , Triterpenos/síntese química , Triterpenos/química , Difração de Raios X , beta-Ciclodextrinas/química
3.
Cells ; 10(9)2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34571839

RESUMO

The aim of this study was to fabricate a reactive oxygen species (ROS)-sensitive and folate-receptor-targeted nanophotosensitizer for the efficient photodynamic therapy (PDT) of cervical carcinoma cells. Chlorin e6 (Ce6) as a model photosensitizer was conjugated with succinyl ß-cyclodextrin via selenocystamine linkages. Folic acid (FA)-poly(ethylene glycol) (PEG) (FA-PEG) conjugates were attached to these conjugates and then FA-PEG-succinyl ß-cyclodextrin-selenocystamine-Ce6 (FAPEGbCDseseCe6) conjugates were synthesized. Nanophotosensitizers of FaPEGbCDseseCe6 conjugates were fabricated using dialysis membrane. Nanophotosensitizers showed spherical shapes with small particle sizes. They were disintegrated in the presence of hydrogen peroxide (H2O2) and particle size distribution changed from monomodal distribution pattern to multimodal pattern. The fluorescence intensity and Ce6 release rate also increased due to the increase in H2O2 concentration, indicating that the nanophotosensitizers displayed ROS sensitivity. The Ce6 uptake ratio, ROS generation and cell cytotoxicity of the nanophotosensitizers were significantly higher than those of the Ce6 itself against HeLa cells in vitro. Furthermore, the nanophotosensitizers showed folate-receptor-specific delivery capacity and phototoxicity. The intracellular delivery of nanophotosensitizers was inhibited by folate receptor blocking, indicating that they have folate-receptor specificity in vitro and in vivo. Nanophotosensitizers showed higher efficiency in inhibition of tumor growth of HeLa cells in vivo compared to Ce6 alone. These results show that nanophotosensitizers of FaPEGbCDseseCe6 conjugates are promising candidates as PDT of cervical cancer.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Nanopartículas/administração & dosagem , Oxirredução/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , beta-Ciclodextrinas/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Ácido Fólico/metabolismo , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Fotoquimioterapia/métodos , Neoplasias do Colo do Útero/metabolismo
4.
J Virol ; 95(20): e0119521, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34379506

RESUMO

Zika virus (ZIKV) is a flavivirus that is well known for the epidemic in the Americas in 2015 and 2016 in which microcephaly in newborns and other neurological complications were connected to ZIKV infection. Many aspects of the ZIKV viral life cycle, including binding and entry into the host cell, are still enigmatic. Based on the observation that CHO cells lack expression of the epidermal growth factor receptor (EGFR) and are not permissive for various ZIKV strains, the relevance of EGFR for the viral life cycle was analyzed. Infection of A549 cells by ZIKV leads to a rapid internalization of EGFR that colocalizes with the endosomal marker EEA1. Moreover, infection by different ZIKV strains is associated with an activation of EGFR and the subsequent activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade. However, treatment of the cells with methyl-ß-cyclodextrin (MßCD), which on the one hand leads to an activation of EGFR but on the other hand prevents EGFR internalization, impairs ZIKV infection. Specific inhibition of EGFR or of the Ras-Raf-MEK-ERK signal transduction cascade hinders ZIKV infection by inhibition of ZIKV entry. In accordance with this, knockout of EGFR expression impedes ZIKV entry. In the case of an already established infection, inhibition of EGFR or of downstream signaling does not affect viral replication. Taken together, these data demonstrate the relevance of EGFR in the early stages of ZIKV infection and identify EGFR as a target for antiviral strategies. IMPORTANCE These data deepen the knowledge about the ZIKV infection process and demonstrate the relevance of EGFR for ZIKV entry. In light of the fact that a variety of specific and efficient inhibitors of EGFR and of EGFR-dependent signaling have been developed and licensed, repurposing of these substances could be a helpful tool to prevent the spreading of ZIKV infection in an epidemic outbreak.


Assuntos
Internalização do Vírus/efeitos dos fármacos , Zika virus/metabolismo , Células A549 , Animais , Células CHO , Linhagem Celular , Chlorocebus aethiops , Cricetulus , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Estágios do Ciclo de Vida , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/genética , Replicação Viral/fisiologia , Zika virus/patogenicidade , Infecção por Zika virus/virologia , beta-Ciclodextrinas/farmacologia
5.
Methods Appl Fluoresc ; 9(3)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33973872

RESUMO

With the use of engineered nano-materials (ENM) becoming more prevalent, it is essential to determine potential human health impacts. Specifically, the effects on biological lipid membranes will be important for determining molecular events that may contribute to both toxicity and suitable biomedical applications. To better understand the mechanisms of ENM-induced hemolysis and membrane permeability, fluorescence lifetime imaging microscopy (FLIM) was performed on human red blood cells (RBC) exposed to titanium dioxide ENM, zinc oxide ENM, or micron-sized crystalline silica. In the FLIM images, changes in the intensity-weighted fluorescence lifetime of the lipophilic fluorescence probe Di-4-ANEPPDHQ were used to identify localized changes to membrane. Time-resolved fluorescence anisotropy and FLIM of RBC treated with methyl-ß-cyclodextrin was performed to aid in interpreting how changes to membrane order influence changes in the fluorescence lifetime of the probe. Treatment of RBC with methyl-ß-cyclodextrin caused an increase in the wobble-in-a-cone angle and shorter fluorescence lifetimes of di-4-ANEPPDHQ. Treatment of RBC with titanium dioxide caused a significant increase in fluorescence lifetime compared to non-treated samples, indicating increased membrane order. Crystalline silica also increased the fluorescence lifetime compared to control levels. In contrast, zinc oxide decreased the fluorescence lifetime, representing decreased membrane order. However, treatment with soluble zinc sulfate resulted in no significant change in fluorescence lifetime, indicating that the decrease in order of the RBC membranes caused by zinc oxide ENM was not due to zinc ions formed during potential dissolution of the nanoparticles. These results give insight into mechanisms for how these three materials might disrupt RBC membranes and membranes of other cells. The results also provide evidence for a direct correlation between the size, interaction-available surface area of the nano-material and cell membrane disruption.


Assuntos
Membrana Eritrocítica/efeitos dos fármacos , Nanoestruturas/toxicidade , Polarização de Fluorescência/métodos , Corantes Fluorescentes/química , Hemólise/efeitos dos fármacos , Humanos , Microscopia de Fluorescência/métodos , Nanoestruturas/química , Tamanho da Partícula , Compostos de Piridínio/química , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Titânio/química , Titânio/toxicidade , Óxido de Zinco/química , Óxido de Zinco/toxicidade , beta-Ciclodextrinas/farmacologia
6.
Food Funct ; 12(11): 5018-5026, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-33954318

RESUMO

Human milk is widely acknowledged as the best food for infants, and that is not just because of nutritional features. Human milk also contains a plethora of bioactive molecules, including a large set of human milk oligosaccharides (hMOs). Especially fucosylated hMOs have received attention for their anti-adhesive effects on pathogens, preventing attachment to the intestine and infection. Because hMOs are generally challenging to produce in sufficient quantities to study and ultimately apply in (medical) infant formula, novel compounds that are inspired by hMO structures (so-called "mimics") are interesting compounds to produce and evaluate for their biological effects. Here we present our thorough study into the digestion, fermentation and anti-adhesive capacity of the novel compound di-fucosyl-ß-cyclodextrin (DFßCD), which was inspired by the molecular structures of hMOs. We establish that DFßCD is not digested by α-amylase and also resistant to fermentation by microbial enzymes from a 9 month-old infant inoculum. In addition, we reveal that DFßCD blocks adhesion of enterotoxigenic E. coli (ETEC) to Caco-2 cells, especially when DFßCD is pre-incubated with ETEC prior to addition to the Caco-2 cells. This suggests that DFßCD functions through a decoy effect. We expect that our results inspire the generation and biological evaluation of other fucosylated hMOs and mimics, to obtain a comprehensive overview of the anti-adhesive power of fucosylated glycans.


Assuntos
Digestão , Fermentação , Leite Humano/química , Oligossacarídeos/química , beta-Ciclodextrinas/farmacologia , Células CACO-2 , Escherichia coli , Glicosilação , Humanos , Lactente , Fórmulas Infantis/química , Intestinos
7.
Food Chem ; 361: 130117, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058659

RESUMO

To overcome the poor water solubility of curcumin, a curcumin-ß-cyclodextrin (Cur-ß-CD) complex was prepared as a novel photosensitizer. Fourier-transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to verify the formation of Cur-ß-CD. Furthermore, the ROS generation capacity and photodynamic bactericidal effect were measured to confirm this Cur-ß-CD complex kept photodynamic activity of curcumin. The result showed Cur-ß-CD could effectively generate ROS upon blue-light irradiation. The plate count assay demonstrated Cur-ß-CD complex possess desirable photodynamic antibacterial effect against food-borne pathogens including Staphylococcus aureus, Listeria monocytogenes and Escherichia coli. The cell morphology determined by scanning electron microscope (SEM) and transmission electron microscope (TEM) showed Cur-ß-CD could cause cell deformation, surface collapse and cell structure damage of the bacteria, resulting in the leakage of cytoplasmic; while agarose gel electrophoresis and SDS-PAGE further illustrated the inactivation mechanisms by Cur-ß-CD involve bacterial DNA damage and protein degradation.


Assuntos
Antibacterianos/química , Curcumina/química , Fármacos Fotossensibilizantes/química , beta-Ciclodextrinas/química , Antibacterianos/farmacologia , Varredura Diferencial de Calorimetria , Curcumina/farmacologia , Escherichia coli/efeitos dos fármacos , Luz , Listeria monocytogenes/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Difração de Raios X , beta-Ciclodextrinas/farmacologia
8.
Microb Pathog ; 156: 104928, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957243

RESUMO

The present study aimed to investigate the antibacterial and modulatory activities of (+)-ß-citronellol (ßCT), ß-cyclodextrin (ß-CD), and their complex ßCT/ß-CD and characterize them using infrared spectroscopy. Infrared spectra were recorded in the 750-4000 cm-1 region. The antibacterial effects of these compounds and their modulatory-antibiotic activities were determined using the minimum inhibitory concentration (MIC) test. Signatures of these pure compounds were detected in the infrared spectrum of the ßCT/ß-CD complex. The MIC of the ßCT/ß-CD complex against the tested strains was found to be 1024 µg/mL. The antagonistic and synergistic effects of these compounds were also observed using the modulation tests. ßCT or ß-CD alone did not exhibit any direct antibacterial activity. However, the ßCT/ß-CD complex in combination with gentamicin showed a synergistic effect against E. coli.


Assuntos
Escherichia coli , beta-Ciclodextrinas , Monoterpenos Acíclicos , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus , beta-Ciclodextrinas/farmacologia
9.
Molecules ; 26(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919170

RESUMO

Understanding the host-guest chemistry of α-/ß-/γ- cyclodextrins (CDs) and a wide range of organic species are fundamentally attractive, and are finding broad contemporary applications toward developing efficient drug delivery systems. With the widely used ß-CD as the host, we herein demonstrate that its inclusion behaviors toward an array of six simple and bio-conjugatable adamantane derivatives, namely, 1-adamantanol (adm-1-OH), 2-adamantanol (adm-2-OH), adamantan-1-amine (adm-1-NH2), 1-adamantanecarboxylic acid (adm-1-COOH), 1,3-adamantanedicarboxylic acid (adm-1,3-diCOOH), and 2-[3-(carboxymethyl)-1-adamantyl]acetic acid (adm-1,3-diCH2COOH), offer inclusion adducts with diverse adamantane-to-CD ratios and spatial guest locations. In all six cases, ß-CD crystallizes as a pair supported by face-to-face hydrogen bonding between hydroxyl groups on C2 and C3 and their adjacent equivalents, giving rise to a truncated-cone-shaped cavity to accommodate one, two, or three adamantane derivatives. These inclusion complexes can be terminated as (adm-1-OH)2⊂CD2 (1, 2:2), (adm-2-OH)3⊂CD2 (2, 3:2), (adm-1-NH2)3⊂CD2 (3, 3:2), (adm-1-COOH)2⊂CD2 (4, 2:2), (adm-1,3-diCOOH)⊂CD2 (5, 1:2), and (adm-1,3-diCH2COOH)⊂CD2 (6, 1:2). This work may shed light on the design of nanomedicine with hierarchical structures, mediated by delicate cyclodextrin-based hosts and adamantane-appended drugs as the guests.


Assuntos
Adamantano/química , Adamantano/farmacologia , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , Adamantano/análogos & derivados , Calorimetria , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade
10.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799511

RESUMO

In uremic patients, high-density lipoprotein (HDL) loses its anti-inflammatory features and can even become pro-inflammatory due to an altered protein composition. In chronic kidney disease (CKD), impaired functions of polymorphonuclear leukocytes (PMNLs) contribute to inflammation and an increased risk of cardiovascular disease. This study investigated the effect of HDL from CKD and hemodialysis (HD) patients on the CD14 expression on PMNLs. HDL was isolated using a one-step density gradient centrifugation. Isolation of PMNLs was carried out by discontinuous Ficoll-Hypaque density gradient centrifugation. CD14 surface expression was quantified by flow cytometry. The activity of the small GTPase Rac1 was determined by means of an activation pull-down assay. HDL increased the CD14 surface expression on PMNLs. This effect was more pronounced for HDL isolated from uremic patients. The acute phase protein serum amyloid A (SAA) caused higher CD14 expression, while SAA as part of an HDL particle did not. Lipid raft disruption with methyl-ß-cyclodextrin led to a reduced CD14 expression in the absence and presence of HDL. HDL from healthy subjects but not from HD patients decreased the activity of Rac1. Considering the known anti-inflammatory effects of HDL, the finding that even HDL from healthy subjects increased the CD14 expression was unexpected. The pathophysiological relevance of this result needs further investigation.


Assuntos
Receptores de Lipopolissacarídeos/genética , Lipoproteínas HDL/farmacologia , Neutrófilos/efeitos dos fármacos , Insuficiência Renal Crônica/genética , Uremia/genética , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Lipoproteínas HDL/isolamento & purificação , Masculino , Microdomínios da Membrana/química , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Cultura Primária de Células , Diálise Renal , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/metabolismo , Uremia/metabolismo , Uremia/fisiopatologia , Uremia/terapia , beta-Ciclodextrinas/farmacologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
11.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803405

RESUMO

Cyclodextrins (CDs) have been widely used as pharmaceutical excipients for formulation purposes for different delivery systems. Recent studies have shown that CDs are able to form complexes with a variety of biomolecules, such as cholesterol. This has subsequently paved the way for the possibility of using CDs as drugs in certain retinal diseases, such as Stargardt disease and retinal artery occlusion, where CDs could absorb cholesterol lumps. However, studies on the retinal toxicity of CDs are limited. The purpose of this study was to examine the retinal toxicity of different beta-(ß)CD derivatives and their localization within retinal tissues. To this end, we performed cytotoxicity studies with two different CDs-2-hydroxypropyl-ßCD (HPßCD) and randomly methylated ß-cyclodextrin (RMßCD)-using wild-type mouse retinal explants, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and fluorescence microscopy. RMßCD was found to be more toxic to retinal explants when compared to HPßCD, which the retina can safely tolerate at levels as high as 10 mM. Additionally, studies conducted with fluorescent forms of the same CDs showed that both CDs can penetrate deep into the inner nuclear layer of the retina, with some uptake by Müller cells. These results suggest that HPßCD is a safer option than RMßCD for retinal drug delivery and may advance the use of CDs in the development of drugs designed for intravitreal administration.


Assuntos
Ciclodextrinas/farmacologia , Ciclodextrinas/toxicidade , Retina/efeitos dos fármacos , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina/toxicidade , Animais , Ciclodextrinas/metabolismo , Testes Imunológicos de Citotoxicidade/métodos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Excipientes , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Retina/metabolismo , Solubilidade , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/toxicidade
12.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808780

RESUMO

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.


Assuntos
Celulose , Ciclodextrinas , Doxorrubicina , Portadores de Fármacos , Neoplasias/tratamento farmacológico , Células A549 , Celulose/química , Celulose/farmacocinética , Celulose/farmacologia , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Ciclodextrinas/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinética , beta-Ciclodextrinas/farmacologia , gama-Ciclodextrinas/química , gama-Ciclodextrinas/farmacocinética , gama-Ciclodextrinas/farmacologia
13.
Eur J Pharmacol ; 901: 174060, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33819466

RESUMO

Farnesol (FAR) is a sesquiterpene alcohol with a range of reported biological effects including cardioprotective, antioxidant and antiarrhythmic properties. However, due to its volatility, the use of drug incorporation systems, such as cyclodextrins, have been proposed to improve its pharmacological properties. Thus, the aim of this study was to evaluate and characterize the cardiovascular effects of FAR alone, and to investigate the antihypertensive effects of FAR complexed with ß-cyclodextrin (ßCD) in rats. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after intravenous administration of FAR (0,5; 2,5; 5 and 7,5 mg/kg) in normotensive rats, and after oral acute administration (200 mg/kg) of FAR and FAR/ßCD complex in NG-nitro-L-arginine-methyl-ester (L-NAME) hypertensive rats. In normotensive animals, FAR induced dose-dependent hypotension associated with bradycardia. These effects were not affected by pre-treatment with L-NAME or indomethacin (INDO), but were partially attenuated by atropine. Pre-treatment with hexamethonium (HEXA) only affected hypotension. In the hypertensive rats, FAR/ßCD potentialized the antihypertensive effect when compared to FAR alone. Molecular docking experiments demonstrated for the first time that FAR has affinity to bind to the M3 and M2 muscarinic, and nicotinic receptors through hydrogen bonds in the same residues as known ligands. In conclusion, our results demonstrated that FAR induced hypotension associated with bradycardia, possibly through the muscarinic and nicotinic receptors. The inclusion complex with ßCD improved the antihypertensive effects of FAR, which can be relevant to improve current cardiovascular therapy using volatile natural components.


Assuntos
Fármacos Cardiovasculares/farmacologia , Farneseno Álcool/farmacologia , Hipertensão/tratamento farmacológico , beta-Ciclodextrinas/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/tratamento farmacológico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar
14.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668543

RESUMO

Chrysin (CHR) is a natural flavonoid with a wide range of pharmacological activities, including hepatoprotection, but poor water solubility. By including water-soluble hydroxypropyl (HPBCD) and randomly methylated (RAMEB) ß-cyclodextrin, we aimed to increase its biodisponibility and the effectiveness of the antifibrotic effects of chrysin at oral administration. Liver fibrosis in mice was induced in 7 weeks by CCl4 i.p. administration, and afterwards treated with 50 mg/kg of CHR-HPBCD, CHR-RAMEB, and free chrysin. CCl4 administration increased hepatic inflammation (which was augmented by the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6) and induced fibrosis, as determined using histopathology and electron microscopy. These results were also confirmed by the upregulation of Collagen I (Col I) and matrix metalloproteinase (MMP) expression, which led to extracellular fibrotic matrix proliferation. Moreover, the immunopositivity of alpha-smooth muscle actin (a-SMA) in the CCl4 group was evidence of hepatic stellate cell (HSC) activation. The main profibrotic pathway was activated, as confirmed by an increase in the transforming growth factor- ß1 (TGF-ß1) and Smad 2/3 expression, while Smad 7 expression was decreased. Treatment with CHR-HPBCD and CHR-RAMEB considerably reduced liver injury, attenuated inflammation, and decreased extracellular liver collagen deposits. CHR-RAMEB was determined to be the most active antifibrotic complex. We conclude that both nanocomplexes exert anti-inflammatory effects and antifibrotic effects in a considerably stronger manner than for free chrysin administration.


Assuntos
Flavonoides/farmacologia , Cirrose Hepática , MicroRNAs/biossíntese , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , beta-Ciclodextrinas/farmacologia , Animais , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , MicroRNAs/genética , NF-kappa B/genética , Transdução de Sinais/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
15.
Mol Pharm ; 18(3): 1080-1092, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33554596

RESUMO

Extracellular vesicles (EVs) secreted from probiotics, defined as live microorganisms with beneficial effects on the host, are expected to be new nanomaterials for EV-based therapy. To clarify the usability of probiotic-derived EVs in terms of EV-based therapy, we systematically evaluated their characteristics, including the yield, physicochemical properties, the cellular uptake mechanism, and biological functions, using three different types of probiotics: Bifidobacterium longum, Clostridium butyricum, and Lactobacillus plantarum WCFS1. C. butyricum secreted the largest amounts of EVs, whereas all the EVs showed comparable particle sizes and zeta potentials, ranging from 100 to 150 nm and -8 to -10 mV, respectively. The silkworm larvae plasma assay indicated that these EVs contain peptidoglycan that activates the host's immune response. Moreover, a cellular uptake study of probiotic-derived EVs in RAW264.7 cells (mouse macrophage-like cells) and DC2.4 cells (mouse dendritic cells) in the presence of inhibitors (cytochalasin B, chlorpromazine, and methyl-ß-cyclodextrin) revealed that probiotic-derived EVs were mainly taken up by these immune cells via clathrin-mediated endocytosis and macropinocytosis. Furthermore, all the probiotic-derived EVs stimulated the innate immune system through the production of inflammatory cytokines (TNF-α and IL-6) from these immune cells, clarifying their utility as a novel adjuvant formulation. These findings on probiotic-derived EVs are valuable for understanding the biological significance of probiotic-derived EVs and the development of EV-based immunotherapy.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vesículas Extracelulares/metabolismo , Probióticos/metabolismo , Animais , Células Cultivadas , Clorpromazina/farmacologia , Citocalasina B/farmacologia , Citocinas/imunologia , Endocitose/efeitos dos fármacos , Endocitose/imunologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Camundongos , Células RAW 264.7 , beta-Ciclodextrinas/farmacologia
16.
Nature ; 590(7846): 509-514, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568813

RESUMO

Mechanosensitive channels sense mechanical forces in cell membranes and underlie many biological sensing processes1-3. However, how exactly they sense mechanical force remains under investigation4. The bacterial mechanosensitive channel of small conductance, MscS, is one of the most extensively studied mechanosensitive channels4-8, but how it is regulated by membrane tension remains unclear, even though the structures are known for its open and closed states9-11. Here we used cryo-electron microscopy to determine the structure of MscS in different membrane environments, including one that mimics a membrane under tension. We present the structures of MscS in the subconducting and desensitized states, and demonstrate that the conformation of MscS in a lipid bilayer in the open state is dynamic. Several associated lipids have distinct roles in MscS mechanosensation. Pore lipids are necessary to prevent ion conduction in the closed state. Gatekeeper lipids stabilize the closed conformation and dissociate with membrane tension, allowing the channel to open. Pocket lipids in a solvent-exposed pocket between subunits are pulled out under sustained tension, allowing the channel to transition to the subconducting state and then to the desensitized state. Our results provide a mechanistic underpinning and expand on the 'force-from-lipids' model for MscS mechanosensation4,11.


Assuntos
Microscopia Crioeletrônica , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/ultraestrutura , Escherichia coli/química , Canais Iônicos/metabolismo , Canais Iônicos/ultraestrutura , Membranas Artificiais , Fosfatidilcolinas/metabolismo , Detergentes/farmacologia , Escherichia coli/ultraestrutura , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Interações Hidrofóbicas e Hidrofílicas , Canais Iônicos/química , Canais Iônicos/genética , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Mecanotransdução Celular/efeitos dos fármacos , Modelos Moleculares , Mutação , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacologia , Conformação Proteica/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia
17.
J Enzyme Inhib Med Chem ; 36(1): 605-617, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33557644

RESUMO

The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with ß-cyclodextrin (ß-CD). First, the phase solubility diagram of MA in ß-CD was drawn from 0 to 21 × 10-3 M of ß-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:ß-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:ß-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the ß-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:ß-CD complex.


Assuntos
Ácido Mefenâmico/química , beta-Ciclodextrinas/química , Animais , Bovinos , Eritrócitos/efeitos dos fármacos , Humanos , Ácido Mefenâmico/farmacologia , Modelos Moleculares , Estrutura Molecular , Desnaturação Proteica/efeitos dos fármacos , Soroalbumina Bovina/química , Solubilidade , beta-Ciclodextrinas/farmacologia
18.
Adv Mater ; 33(7): e2007293, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33448050

RESUMO

Using nanotechnology for improving the immunotherapy efficiency represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements in the complicated immune activation processes. Herein, a supramolecular assembled programmable immune activation nanomedicine (PIAN) for sequentially finishing multiple steps after intravenous injection and eliciting robust antitumor immunity in situ is reported. The programmable nanomedicine is constructed by supramolecular assembly via host-guest interactions between poly-[(N-2-hydroxyethyl)-aspartamide]-Pt(IV)/ß-cyclodextrin (PPCD), CpG/polyamidoamine-thioketal-adamantane (CpG/PAMAM-TK-Ad), and methoxy poly(ethylene glycol)-thioketal-adamantane (mPEG-TK-Ad). After intravenous injection and accumulation at the tumor site, the high level of reactive oxygen species in the tumor microenvironment promotes PIAN dissociation and the release of PPCD (mediating tumor cell killing and antigen release) and CpG/PAMAM (mediating antigen capturing and transferring to the tumor-draining lymph nodes). This results in antigen-presenting cell activation, antigen presentation, and robust antitumor immune responses. In combination with anti-PD-L1 antibody, the PIAN cures 40% of mice in a colorectal cancer model. This PIAN provides a new framework for designing programmable nanomedicine as in situ cancer vaccine for cancer immunotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Vacinas Anticâncer/química , Neoplasias Colorretais/imunologia , Dendrímeros/química , Animais , Células Apresentadoras de Antígenos , Antineoplásicos/farmacologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Interleucina-6/metabolismo , Camundongos , Neoplasias Experimentais , Polietilenoglicóis/química , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismo , beta-Ciclodextrinas/farmacologia
19.
Drug Deliv ; 28(1): 306-318, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33509000

RESUMO

Chronic rhinosinusitis (CRS) is a rather prevalent condition with a chronic inflammatory process, which is hard to cure. Herein, a new antibacterial drug, nitric oxide (NO), was used for the attempt on CRS therapy. To achieve this, a star copolymer (ß-CD-PAMAM) consisting of the ß-cyclodextrin (ß-CD) core and seven PAMAM-G3 arms, which was designed as a low-cytotoxicity and high NO loading carrier, were synthesized and characterizied. The obtained ß-CD-PAMAM/NONOate showed the effect in inhibiting and dispersing the biofilm of S. aureus, as well as the effective antibacterial performance, implying the promising application in CRS treatment. The in vivo assay confirmed that ß-CD-PAMAM/NONOate displayed excellent therapy effect on CRS and significantly improved the symptoms of the experimental rats, which was no significant different in therapy effect with the clinical Rhinocort. Incorporated with its little toxicity in vitro and in vivo, the ß-CD-PAMAM/NONOate was suggested a promising application in CRS therapy.


Assuntos
Doença Crônica/tratamento farmacológico , Dendrímeros/farmacologia , Óxido Nítrico/farmacologia , Poliaminas/farmacologia , Sinusite/tratamento farmacológico , beta-Ciclodextrinas/farmacologia , Animais , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sinusite/microbiologia , Staphylococcus aureus/efeitos dos fármacos
20.
Reprod Domest Anim ; 56(3): 519-530, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33405303

RESUMO

Many experiments show that vitrification significantly reduces the fertilization capacity of mammalian oocytes, restricting the application of vitrified oocytes. It has been proven that the JUNO protein plays a vital role in mammalian oocytes fertilization. However, little information is available about the effects of vitrification on the JUNO protein and the procedure to protect it in bovine oocytes. Here, the present study was designed to investigate the effect of vitrification on the JUNO protein level in bovine oocytes. In this study, MII oocytes were treated with cholesterol-loaded methyl-ß-cyclodextrin (CLC; 0, 10, 15, 20 mM) for 45 min before vitrification and methyl-ß-cyclodextrin (MßCD; 0, 2.25, 4.25, 6.25 mM) for 45 min after thawing (38-39°C). Then, the expression level and function of JUNO protein, cholesterol level in the membrane, the externalization of phosphatidylserine, sperm binding capacity and the developmental ability of vitrified bovine oocytes were examined. Our results showed that vitrification significantly decreased the JUNO protein level, cholesterol level, sperm binding capacity, development ability, and increased the promoter methylation level of the JUNO gene and apoptosis level of bovine oocytes. Furthermore, 15 mM CLC + 4.25 mM MßCD treatment significantly improved the cholesterol level and increased sperm binding and development ability of vitrified bovine oocytes. In conclusion, the combination treatment of cholesterol-loaded methyl-ß-cyclodextrin and methyl-ß-cyclodextrin significantly improves the fertilization capacity of vitrified bovine oocytes by protecting fertilization protein JUNO.


Assuntos
Colesterol/farmacologia , Fertilização/efeitos dos fármacos , Oócitos/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , Animais , Bovinos , Colesterol/metabolismo , Criopreservação/veterinária , Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Fertilização In Vitro/veterinária , Masculino , Oócitos/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Vitrificação
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