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1.
Int J Nanomedicine ; 15: 6211-6223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32904111

RESUMO

Introduction and Aim: Cinnarizine is indicated orally for treating vertigo associated with Ménière's syndrome and has a local anesthetic effect as well. The present study aims to develop an aural Cinnarizine mucoadhesive transfersomal gel to overcome the first-pass metabolism. Methods: Eighteen Cinnarizine transfersomes were prepared by the thin-film hydration technique using different types of phosphatidylcholine and edge activators in different ratios. Formulae were tested for their appearance, entrapment efficiency, and in-vitro drug release after eight hours. F1, F4, F7, F9, F10, and F12 were selected to be examined for particle size, polydispersity index, and zeta potential. According to the previous parameters, F1 and F10 were incorporated into gels using different polymers according to factorial design 23. The eight gels were tested for appearance, pH, mucoadhesion, spreadability, drug content, in-vitro drug release after eight hours, and rheology. The transfersomal gel F1A was subjected to FTIR analysis and in-vivo pharmacokinetic study. Results: The transfersomal dispersion colors were ranging between the white and yellow. Their EE % ranged from 64.36±1.985% to 94.09±1.74%, and their in-vitro release percentages were between 61.82±1.92% and 95.92±1.18%. Also, the vesicles PS ranged from 212.3±30.05nm to 2150±35.35nm, DI from 0.238±0.134 to 1±0.00 and zeta potential from -57.5±2.54 to +4.73±1.57 mV. The transfersomal gels showed pseudoplastic behavior, pH range of 5.5 to 8, a mucoadhesive force of 169.188±1.26 to 321.212±6.94 (dyne/cm2×102), spreadability of 40 ±7.03mm to 138 ±3.77mm, and in-vitro drug release of 81.63±1.128% to 97.78±0.102%. The IR spectra of the (drug-excipients) physical mixture revealed that there were no shifts of incompatibility. The in-vivo pharmacokinetic study illustrated that [AUC]0-24 of F1A was significantly higher than that of tablets at (P< 0.05), equivalent to 703.563±26.470 and 494.256±9.621ɲg.hr/mL respectively. Conclusion: The study revealed that Cinnarizine aural mucoadhesive targeted delivery provides an improved systemic bioavailability over the conventional oral route.


Assuntos
Cinarizina/administração & dosagem , Cinarizina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Géis/química , Vertigem/tratamento farmacológico , Administração Cutânea , Animais , Área Sob a Curva , Disponibilidade Biológica , Cinarizina/química , Cor , Liberação Controlada de Fármacos , Orelha Média , Géis/administração & dosagem , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Fosfatidilcolinas/química , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Nat Commun ; 11(1): 3532, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669539

RESUMO

Asexual proliferation of the Plasmodium parasites that cause malaria follows a developmental program that alternates non-canonical intraerythrocytic replication with dissemination to new host cells. We carried out a functional analysis of the Plasmodium falciparum homolog of Protein Phosphatase 1 (PfPP1), a universally conserved cell cycle factor in eukaryotes, to investigate regulation of parasite proliferation. PfPP1 is indeed required for efficient replication, but is absolutely essential for egress of parasites from host red blood cells. By phosphoproteomic and chemical-genetic analysis, we isolate two functional targets of PfPP1 for egress: a HECT E3 protein-ubiquitin ligase; and GCα, a fusion protein composed of a guanylyl cyclase and a phospholipid transporter domain. We hypothesize that PfPP1 regulates lipid sensing by GCα and find that phosphatidylcholine stimulates PfPP1-dependent egress. PfPP1 acts as a key regulator that integrates multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.


Assuntos
Eritrócitos/parasitologia , Plasmodium falciparum/enzimologia , Proteína Fosfatase 1/metabolismo , Proteínas de Protozoários/metabolismo , Animais , Proliferação de Células , GMP Cíclico/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Knockout , Fosfatidilcolinas/química , Domínios Proteicos , Proteoma , Ubiquitina-Proteína Ligases/metabolismo
3.
Food Chem ; 333: 127448, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663748

RESUMO

Antarctic krill oil (AKO) is an emerging dietary supplement containing metal ions that influence oil oxidation. Thus, this study focuses on the effect and mechanism of metal ions on phospholipid oxidation in AKO. Firstly, AKO containing Mg2+, Mn2+, Cu2+, Fe2+ and Fe3+ (200 µmol/kg) were prepared separately and incubated at 60 °C for 6 days. Peroxide value (POV) and malondialdehyde (MDA) content showed that Fe3+ exhibited the most effective prooxidative activity, with the prooxidative activity of Fe2(SO4)3 (water-soluble) being stronger than that of ferric oleate (FeOl, fat-soluble). In addition, phosphatidylethanolamine (PE) oxidation degree (more than 90%) was considerably greater than phosphatidylcholine (PC) oxidation degree (about 15%) in AKO. Differences in the structure of head group hindered chelation of PC with metal ions than PE due to electrostatic repulsion and steric hindrance. Therefore, PC significantly inhibited, while PE promoted, the oxidation of polyunsaturated triacylglycerol (TAG), like fish oil (p < 0.01).


Assuntos
Euphausiacea/química , Metais/química , Óleos/química , Fosfolipídeos/química , Animais , Regiões Antárticas , Cátions/química , Suplementos Nutricionais , Malondialdeído/química , Oxirredução , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Triglicerídeos/química
4.
J Oleo Sci ; 69(8): 801-807, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32641609

RESUMO

The health benefits of conjugated linoleic acid (CLA), a functional lipid with anti-cancer, anti-obesity, and hypotensive activity, have garnered increasing attention. The current study was conducted to determine the oxidative stability of CLA in the form of triacylglycerol (CLA-TAG) and phosphatidylcholine (CLA-PC) at the sn-2 position. Oxidation was performed at 30°C or 40°C in the dark. Hydroperoxides, as the primary oxidation products, were analyzed using diphenyl-1-pyrenylphosphine. Thiobarbituric acid reactive substances (TBARS) and volatile compounds were monitored as secondary oxidation products. The results suggest that CLA-PC was more stable against oxidation than CLA-TAG from the perspective of suppression of the generation of hydroperoxides and TBARS. However, CLA-PC produced more volatile compounds than CLA-TAG. We suggest that choline was released during the oxidation of CLA-PC, and acted as an antioxidant. The ensuing reaction between choline and hydroperoxide induced the generation of volatile compounds such as pentanal, hexanal, and heptanal.


Assuntos
Ácido Linoleico/química , Fosfatidilcolinas/química , Triglicerídeos/química , Aldeídos/análise , Antioxidantes , Colina/química , Estabilidade de Medicamentos , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/química , Oxirredução , Temperatura , Substâncias Reativas com Ácido Tiobarbitúrico/análise
5.
Int J Nanomedicine ; 15: 3539-3550, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547012

RESUMO

Background: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N',N'-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed. Materials and Methods: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments. Results: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100-120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX. Conclusion: These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.


Assuntos
Metotrexato/administração & dosagem , Micelas , Administração Cutânea , Animais , Cátions , Bovinos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Metotrexato/química , Camundongos , Concentração Osmolar , Tamanho da Partícula , Fosfatidilcolinas/química , Espectroscopia de Prótons por Ressonância Magnética , Soroalbumina Bovina/química , Pele/efeitos dos fármacos , Eletricidade Estática
6.
Leg Med (Tokyo) ; 46: 101724, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32516737

RESUMO

Hypochlorous acid, produced by myeloperoxidase upon neutrophil activation, can oxidize various compounds and exert antimicrobial activity in vivo. To elucidate the mechanisms underlying the reactions of the unsaturated phosphatidylcholines, which abound in cell membranes, with hypochlorous acid, we identified and examined phosphatidylcholine chlorination and oxidation products formed under various reaction conditions. We first investigated the products of unsaturated phosphatidylcholine and hypochlorous acid reaction with respect to hypochlorite concentration and reaction time. Next, we examined the lipids extracted postmortem from human abscesses. For all the analyses, we used liquid chromatography-quadrupole time-of-flight mass spectrometry. Various compounds, including phosphatidylcholine chlorohydrin and phosphatidylcholine hydroxide/epoxide, were detected. Oxidized phosphatidylcholines were mainly detectable upon reaction with low concentrations of sodium hypochlorite, whereas chlorinated phosphatidylcholines formed in the presence of higher concentrations. In human abscesses, oxidized phosphatidylcholines were detected in the cases with high procalcitonin concentration, whereas chlorinated phosphatidylcholines were undetected. The detections of oxidized phosphatidylcholines in human tissues might indicate previous exposure to hypochlorous acid in septic cases. Our results provide insight into the mechanisms underlying pathogen survival following inflammation associated with neutrophil activation and topical myeloperoxidase release and show postmortem biomarkers candidates for sepsis.


Assuntos
Abscesso/diagnóstico , Abscesso/metabolismo , Ácido Hipocloroso/metabolismo , Lipídeos/análise , Fosfatidilcolinas/metabolismo , Biomarcadores/metabolismo , Membrana Celular/metabolismo , Cromatografia Líquida , Medicina Legal/métodos , Halogenação , Humanos , Ácido Hipocloroso/química , Espectrometria de Massas , Ativação de Neutrófilo , Oxirredução , Peroxidase/metabolismo , Fosfatidilcolinas/química
7.
J Chromatogr A ; 1623: 461161, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32376015

RESUMO

Triacylglycerols (TAGs) containing less common fatty acids (FAs) were isolated from the seeds of three plants (Santalum album, Crepis foetida, and Leucas aspera). These FAs had allenic (laballenic acid, Lb) and acetylenic (crepenynic, C; ximenynic acids, Xi) bonds. TAGs were analyzed on reversed-phase and chiral columns. High-resolution tandem mass spectrometry identified TAGs by positive electrospray ionization (ESI+). Twenty-two molecular species of TAGs isolated from the seed oil of Santalum album were separated by RP-HPLC and chiral HPLC methods and identified by positive electrospray ionization tandem MS detection (ESI+-MS). Two major enantiomers, i.e., sn-OOLb and sn-LLLb (O represents oleic acid; and L represents linoleic acid), were synthesized from the appropriate phosphatidylcholines. This allowed the identification of enantiomers after separation by chiral chromatography by tandem mass spectrometry. Similarly, TAGs from the seeds of Crepis foetida, and Leucas aspera were analyzed by reversed-phase chromatography and identified by mass spectrometry. Four enantiomers (sn-OOC, sn-LLC, sn-OOXi, and sn-LLXi) were synthesized. A total of six and three enantiomers of TAGs containing crepenynic and ximenynic acids, respectively, were identified by chiral column analysis. The retention times of TAGs containing allenic and acetylenic bonds were always greater on the reversed-phase column than TAGs with the same number of carbon atoms and the same unsaturation (e.g., LLL versus LLLb). From the chiral column, the regioisomers and enantiomers were eluted in the order of symmetric-asymmetric-asymmetric (i.e., sn-OCO, sn-COO, and sn-OOC). Through tandem mass spectrometry, we were able to identify and distinguish regioisomer [DAG]+-type ions, i.e., [MNH4NH3RCOOH]+, that can be considered diagnostic. Unfortunately, enantiomers and TAGs with the same numbers of carbon atoms and the same unsaturation levels have identical mass spectra, such as LLL and LLLb.


Assuntos
Cromatografia Líquida de Alta Pressão , Ácidos Graxos/análise , Sementes/química , Espectrometria de Massas em Tandem , Triglicerídeos/química , Alquinos/análise , Alquinos/química , Cromatografia Líquida , Cromatografia de Fase Reversa , Ácidos Graxos/química , Ácido Linoleico/análise , Ácidos Oleicos/análise , Fosfatidilcolinas/química , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Triglicerídeos/análise , Triglicerídeos/isolamento & purificação
8.
Food Chem ; 328: 127127, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473492

RESUMO

Poor stability of fish hydrolyzed collagen (HC) hampers its applications, especially as food ingredients. The use of liposome as a vesicle can be a potential means to enhance bioactivities and stability of HC. HC from defatted Asian sea bass skin at different levels (0.25%-2%, w/v) were loaded into liposomes prepared from soy phosphatidylcholine (SPC) with various stabilizers (cholesterol (CHO) or glycerol (GLY)). The highest encapsulation efficiency (EE) was found in SPC-CHO-0.5%HC (P < 0.05) (85.42%), while liposome stabilized with GLY had the highest EE (74.54%) for SPC-GLY-0.25%HC (P < 0.05). After lyophilization, SPC-CHO-0.5%HC had higher EE than SPC-GLY-0.25%HC (P < 0.05). Increasing particle size and decreasing negative surface charge were found for both lyophilized samples. Lyophilized SPC-CHO-0.5%HC exhibited higher stability than lyophilized SPC-GLY-0.25%HC during storage at 25 °C for 28 days. Also, higher antioxidant activities in gastrointestinal track model system was found for SPC-CHO-0.5%HC. Thus, SPC-CHO liposome could be used as a promising carrier of HC.


Assuntos
Antioxidantes/química , Colágeno/química , Lipossomos/química , Lipossomos/farmacologia , Animais , Antioxidantes/farmacologia , Bass , Colesterol/química , Excipientes/química , Armazenamento de Alimentos , Liofilização , Trato Gastrointestinal , Glicerol , Hidrólise , Lecitinas/química , Tamanho da Partícula , Fosfatidilcolinas/química , Pele/química , Temperatura
9.
Phys Chem Chem Phys ; 22(21): 12281-12293, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32432296

RESUMO

Carotenoids are pigment molecules that protect biomembranes against degradation and may be involved in the formation of functional bacterial membrane microdomains. Little is known on whether different types of carotenoids have different effects on the membrane or if there is any concentration dependence of these effects. In this work, we present results from molecular dynamics simulations of phospholipid bilayers containing different amounts of either ß-carotene or zeaxanthin. Both ß-carotene and zeaxanthin show the ability to laterally condense the membrane lipids and reduce their inter-leaflet interactions. With increasing concentrations, both carotenoids increase the bilayer thickness and rigidity. The results reveal that carotenoids have similar effects to cholesterol on regulating the behavior of fluid-phase membranes, suggesting that they could function as sterol substitutes and confirming their potential role in the formation of functional membrane domains.


Assuntos
Bicamadas Lipídicas/metabolismo , Zeaxantinas/metabolismo , beta Caroteno/metabolismo , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Zeaxantinas/química , beta Caroteno/química
10.
Psychiatr Danub ; 32(1): 55-59, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303030

RESUMO

BACKGROUND: Anorexia nervosa (AN) is a serious mental disorder with a high mortality rate and often a chronic course. In contrast to many other common mental disorders, there is no drug therapy approved for AN. METHODS: We performed a narrative literature review to consider whether a choline-containing molecule, such as phosphatidylcholine (PC), with an omega (ω)-3 long chain polyunsaturated fatty acid (LCPUFA) could be a potential future medicinal treatment for AN. RESULTS: Choline and LCPUFAs have individually shown benefit for mental health. Case series and pilot studies suggest ω-3 LCPUFAs may be effective in eating disorders. However, pharmacodynamic and pharmacokinetic considerations suggest a greater benefit from the combination of both components. CONCLUSION: The combination of a choline-containing molecule with an ω-3 LCPUFA may be clinically effective and well tolerated. This idea is supported by the current literature on the role of inflammation, the microbiome, the gut-brain-axis, hormonal, neurotransmitter and intracellular signalling, and on the structure and fluidity of nerve cells membranes in patients with AN.


Assuntos
Anorexia Nervosa/tratamento farmacológico , Ácidos Graxos Ômega-3/química , Ácidos Graxos Ômega-3/uso terapêutico , Fosfatidilcolinas/uso terapêutico , Anorexia Nervosa/metabolismo , Anorexia Nervosa/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Fosfatidilcolinas/química
11.
Food Chem ; 321: 126717, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32259734

RESUMO

Effectiveness of liposomes elaborated with rapeseed phospholipid (RP) extracted from a residue of oil processing, stigmasterol (ST) and/or hydrogenated phosphatidylcholine (HPC) for the encapsulation lactoferrin (LF) was studied; lipid membrane of liposomes was characterized (bilayer size, chain conformational order, lateral packing, lipid phase, and morphology) and the protection offered to the encapsulated LF during in vitro digestion was determined. Liposomes composed of RP+STLC(low concentration) showed spherical and irregular vesicles without perforations. Lamellar structure was organized in a liquid-ordered phase with a potential orthorhombic packing. Stability and size of the liposomes were more affected by gastric digestion than intestinal digestion; 67-80% of the initially encapsulated LF remained intact after gastric digestion whereas the percentage was reduced to 16-35% after intestinal digestion. Our results shows that liposomes elaborated with RP, properly combined with other lipids, can be a useful oral delivery system of molecules sensitive to digestive enzymes.


Assuntos
Lactoferrina/farmacocinética , Lipossomos/química , Fosfolipídeos/química , Administração Oral , Brassica napus/química , Digestão , Suco Gástrico/metabolismo , Absorção Intestinal , Lactoferrina/química , Lipossomos/farmacocinética , Fosfatidilcolinas/química , Espalhamento a Baixo Ângulo , Difração de Raios X
12.
Gen Physiol Biophys ; 39(2): 107-122, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32329439

RESUMO

Solubilisation of model membranes of dioleoylphosphatidylcholine (DOPC) and DOPCcholesterol (CHOL) induced by surfactant N,N-dimethyl-1-dodecanamine-N-oxide (DDAO) was studied. At the maintained pH ~ 7.5, the DDAO molecules are in their neutral state with respect to the pK ~ 5. Pore formation in lipid bilayer was studied by fluorescence probe leakage method. The changes in the size of lipid aggregates upon increasing DDAO concentration were followed turbidimetrically. Effective ratio Re at different steps of the solubilisation process was determined. The molar partition coefficient of DDAO in case of the DOPC membrane is Kp = 2262 ± 379, for DOPC-CHOL membrane Kp = 2092 ± 594. Within the experimental error, the partition coefficient, as well as effective ratios Re, are not considerably influenced when one third of DOPC molecules is substituted with CHOL (DOPC:CHOL = 2:1). Constituents of buffer (50 mmol/dm3 PBS, 150 mmol/dm3 NaCl) caused aggregation of DOPC and DOPC-CHOL unilamellar liposomes at zero and low DDAO concentration, as was shown by SANS, turbidimetry and DIC microscopy. After solubilisation of bilayer structures by surfactant, mixed DOPC-DDAO and DOPC-CHOL-DDAO micelles with the shape of cylinders with elliptical cross section were detected.


Assuntos
Colesterol/química , Dimetilaminas/química , Bicamadas Lipídicas/química , Fosfatidilcolinas/química , Tensoativos/química , Lipossomos , Micelas
13.
Gen Physiol Biophys ; 39(2): 135-144, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32329441

RESUMO

The structure and dynamics of membranes depend on many external and internal factors that in turn determine their biological functions. One of the widely accepted and studied characteristics of biomembranes is their fluidity. We research a simple system with variable fluidity tweakable via its composition. The addition of cholesterol is employed to increase the order of lipid chains, thus decreasing the membrane fluidity, while melatonin is shown to elevate the chain disorder, thus also the membrane fluidity. We utilize the densitometric measurements to show a shift of studied systems closer or further from the gel-to-fluid phase transition. The structural changes represented by changes to membrane thickness are evaluated from small angle neutron scattering. Finally, we look at the ability of the two additives to control the interactions between membrane and amyloid-beta peptides. Our results suggest that fluidizing effect of melatonin can promote an insertion of peptide within the membrane interior. Intriguingly, the latter structure relates possibly to an Alzheimer's disease preventing mechanism postulated in the case of melatonin.


Assuntos
Colesterol/química , Melatonina/química , Fluidez de Membrana , Peptídeos beta-Amiloides/química , Bicamadas Lipídicas/química , Conformação Molecular , Fosfatidilcolinas/química
14.
J Nanobiotechnology ; 18(1): 67, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345323

RESUMO

BACKGROUND: Exenatide is an insulinotropic peptide drug for type 2 diabetes treatment with low risk of hypoglycemia, and is administrated by subcutaneous injection. Oral administration is the most preferred route for lifelong treatment of diabetes, but oral delivery of peptide drug remains a significant challenge due to the absorption obstacles in gastrointestinal tract. We aimed to produce exenatide-loaded nanoparticles containing absorption enhancer, protectant and stabilizer using FDA approved inactive ingredients and easy to scale-up method, and to evaluate their long-term oral therapeutic effect in type 2 diabetes db/db mice. RESULTS: Two types of nanoparticles, named COM NPs and DIS NPs, were fabricated using anti-solvent precipitation method. In COM NPs, the exenatide was complexed with cholic acid and phosphatidylcholine to increase the exenatide loading efficiency. In both nanoparticles, zein acted as the cement and the other ingredients were embedded in zein nanoparticles by hydrophobic interaction. Casein acted as the stabilizer. The nanoparticles had excellent lyophilization, storage and re-dispersion stability. Hypromellose phthalate protected the loaded exenatide from degradation in simulated gastric fluid. Cholic acid promoted the intestinal absorption of the loaded exenatide via bile acid transporters. The exenatide loading efficiencies of COM NPs and DIS NPs were 79.7% and 53.6%, respectively. The exenatide oral pharmacological availability of COM NPs was 18.6% and DIS NPs was 13.1%. COM NPs controlled the blood glucose level of the db/db mice well and the HbA1c concentration significantly decreased to 6.8% during and after 7 weeks of once daily oral administration consecutively. Both DIS NPs and COM NPs oral groups substantially increased the insulin secretion by more than 60% and promoted the ß-cell proliferation by more than 120% after the 7-week administration. CONCLUSIONS: Both COM NPs and DIS NPs are promising systems for oral delivery of exenatide, and COM NPs are better in blood glucose level control than DIS NPs. Using prolamin to produce multifunctional nanoparticles for oral delivery of peptide drug by hydrophobic interaction is a simple and effective strategy.


Assuntos
Exenatida/farmacologia , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Nanopartículas/química , Zeína/química , Administração Oral , Animais , Glicemia/análise , Ácido Cólico/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Exenatida/administração & dosagem , Exenatida/química , Trato Gastrointestinal/química , Trato Gastrointestinal/patologia , Hemoglobina A Glicada/análise , Meia-Vida , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Células Secretoras de Insulina/classificação , Células Secretoras de Insulina/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/metabolismo , Permeabilidade/efeitos dos fármacos , Fosfatidilcolinas/química
15.
RNA ; 26(6): 756-769, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32205323

RESUMO

The spontaneous emergence of long RNA molecules on the early Earth, a phenomenon central to the RNA World hypothesis, continues to remain an enigma in the field of origins of life. Few studies have looked at the nonenzymatic oligomerization of cyclic mononucleotides under neutral to alkaline conditions, albeit in fully dehydrated state. In this study, we systematically investigated the oligomerization of cyclic nucleotides under prebiotically relevant conditions, wherein starting reactants were subjected to repeated dehydration-rehydration (DH-RH) regimes. DH-RH conditions, a recurring geological theme that was prevalent on prebiotic Earth, are driven by naturally occurring processes including diurnal cycles and tidal pool activity. These conditions have been shown to facilitate uphill oligomerization reactions. The polymerization of 2'-3' and 3'-5' cyclic nucleotides of a purine (adenosine) and a pyrimidine (cytidine) was investigated. Additionally, the effect of amphiphiles was also evaluated. Furthermore, to discern the effect of "realistic" conditions on this process, the reactions were also performed using a hot spring water sample from a candidate early Earth environment. Our study showed that the oligomerization of cyclic nucleotides under DH-RH conditions resulted in intact informational oligomers. Amphiphiles increased the stability of both the starting monomers and the resultant oligomers in selected reactions. In the hot spring reactions, both the oligomerization of nucleotides and the back hydrolysis of the resultant oligomers were pronounced. Altogether, this study demonstrates how nonenzymatic oligomerization of cyclic nucleotides, under both laboratory-simulated prebiotic conditions and in a candidate early Earth environment, could have resulted in RNA oligomers of a putative RNA World.


Assuntos
AMP Cíclico/química , CMP Cíclico/química , Fontes Termais , Temperatura Alta , Fosfatidilcolinas/química , Água/química
16.
Phys Rev Lett ; 124(10): 108102, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32216409

RESUMO

Lipid rafts serve as anchoring platforms for membrane proteins. Thus far they escaped direct observation by light microscopy due to their small size. Here we used differently colored dyes as reporters for the registration of both ordered and disordered lipids from the two leaves of a freestanding bilayer. Photoswitchable lipids dissolved or reformed the domains. Measurements of domain mobility indicated the presence of 120 nm wide ordered and 40 nm wide disordered domains. These sizes are in line with the predicted roles of line tension and membrane undulation as driving forces for alignment.


Assuntos
Lipídeos de Membrana/administração & dosagem , Microdomínios da Membrana/química , Colesterol/química , Colesterol/metabolismo , Diglicerídeos/química , Diglicerídeos/metabolismo , Lipídeos de Membrana/química , Lipídeos de Membrana/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Microscopia Confocal/métodos , Modelos Químicos , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Espectrometria de Fluorescência/métodos
17.
Biochim Biophys Acta Biomembr ; 1862(7): 183261, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32151610

RESUMO

Antimicrobial peptides are widely studied as an alternative to traditional antibiotics. However, they are difficult to develop, as multiple factors influence their potency and selectivity toward bacterial cells. In this paper, we investigate three simplified model peptides that bear crown ethers, and the effects of simple structural modifications (peptide length and crown ether ring size) on their secondary structures and their permeabilizing activity on living cells and model membranes made with egg yolk phosphatidylcholine or 1-palmitoyl-2-oleoylphosphatidylglycerol. Circular dichroism studies show that the peptide length and the crown ether ring size do influence the conformation, but no trend could be determined from the results. Permeabilization studies with model membranes and with red blood cells demonstrated that from 13 residues to 16 residues, there is a gradual increase in activity as the peptides get longer. However, the shortest tested analogs, with 12 residues, also exhibited an increase in activity caused by the removal of one amino acid that was bearing a crown ether. Permeabilization assays showed that larger ring size analogs showed higher hemolytic activities. Altogether, the results reported help design new and more selective antimicrobial peptides.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Membrana Celular/química , Éteres de Coroa/química , Fosfatidilcolinas/química , Sequência de Aminoácidos/genética , Antibacterianos/efeitos adversos , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Dicroísmo Circular , Éteres de Coroa/farmacologia , Gema de Ovo/química , Humanos , Bicamadas Lipídicas/química , Fosfatidilcolinas/farmacologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
18.
Soft Matter ; 16(13): 3245-3256, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163059

RESUMO

We present the derivation of a new model to describe neutron spin echo spectroscopy and quasi-elastic neutron scattering data on liposomes. We compare the new model with existing approaches and benchmark it with experimental data. The analysis indicates the importance of including all major contributions in the modeling of the intermediate scattering function. Simultaneous analysis of the experimental data on lipids with full contrast and tail contrast matched samples reveals highly confined lipid tail motion. A comparison of their dynamics demonstrates the statistical independence of tail-motion and height-height correlation of the membrane. A more detailed analysis indicates that the lipid tail relaxation is confined to a potential with cylindrical symmetry, in addition to the undulation and diffusive motion of the liposome. Despite substantial differences in the chemistry of the fatty acid tails, the observation indicates a universal behavior. The analysis of partially deuterated systems confirms the strong contribution of the lipid tail to the intermediate scattering function. Within the time range from 5 to 100 ns, the intermediate scattering function can be described by the height-height correlation function. The existence of the fast-localized tail motion and the contribution of slow translational diffusion of liposomes determine the intermediate scattering function for t < 5 ns and t > 100 ns, respectively. Taking into account the limited time window lowers the bending moduli by a factor of 1.3 (DOPC) to 2 (DMPC) compared to the full range.


Assuntos
Bicamadas Lipídicas/química , Lipossomos/química , Fosfolipídeos/química , Simulação de Dinâmica Molecular , Movimento (Física) , Difração de Nêutrons , Fosfatidilcolinas/química , Análise Espectral
19.
Anesthesiology ; 132(4): 825-838, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32101976

RESUMO

BACKGROUND: High-density lipoproteins exert pleiotropic effects including antiinflammatory, antiapoptotic, and lipopolysaccharide-neutralizing properties. The authors assessed the effects of reconstituted high-density lipoproteins (CSL-111) intravenous injection in different models of sepsis. METHODS: Ten-week-old C57BL/6 mice were subjected to sepsis by cecal ligation and puncture or intraperitoneal injection of Escherichia coli or Pseudomonas aeruginosa pneumonia. CSL-111 or saline solution was administrated 2 h after the sepsis. Primary outcome was survival. Secondary outcomes were plasma cell-free DNA and cytokine concentrations, histology, bacterial count, and biodistribution. RESULTS: Compared with saline, CSL-111 improved survival in cecal ligation and puncture and intraperitoneal models (13 of 16 [81%] survival rate vs. 6 of 16 [38%] in the cecal ligation and puncture model; P = 0.011; 4 of 10 [40%] vs. 0 of 10 [0%] in the intraperitoneal model; P = 0.011). Cell-free DNA concentration was lower in CSL-111 relative to saline groups (68 [24 to 123] pg/ml vs. 351 [333 to 683] pg/ml; P < 0.001). Mice injected with CSL-111 presented a decreased bacterial count at 24 h after the cecal ligation and puncture model both in plasma (200 [28 to 2,302] vs. 2,500 [953 to 3,636] colony-forming unit/ml; P = 0.021) and in the liver (1,359 [360 to 1,648] vs. 1,808 [1,464 to 2,720] colony-forming unit/ml; P = 0.031). In the pneumonia model, fewer bacteria accumulated in liver and lung of the CSL-111 group. CSL-111-injected mice had also less lung inflammation versus saline mice (CD68+ to total cells ratio: saline, 0.24 [0.22 to 0.27]; CSL-111, 0.07 [0.01 to 0.09]; P < 0.01). In all models, no difference was found for cytokine concentration. Indium bacterial labeling underlined a potential hepatic bacterial clearance possibly promoted by high-density lipoprotein uptake. CONCLUSIONS: CSL-111 infusion improved survival in different experimental mouse models of sepsis. It reduced inflammation in both plasma and organs and decreased bacterial count. These results emphasized the key role for high-density lipoproteins in endothelial and organ protection, but also in lipopolysaccharide/bacteria clearance. This suggests an opportunity to explore the therapeutic potential of high-density lipoproteins in septic conditions.


Assuntos
HDL-Colesterol/administração & dosagem , Modelos Animais de Doenças , Lipoproteínas HDL/administração & dosagem , Fosfatidilcolinas/administração & dosagem , Sepse/tratamento farmacológico , Sepse/metabolismo , Animais , HDL-Colesterol/química , Feminino , Humanos , Lipoproteínas HDL/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/química , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
20.
PLoS One ; 15(2): e0228279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027677

RESUMO

Smoke exposure is known to decrease total pulmonary surfactant and alter its composition, but the role of surfactant in chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to analyze the compositional changes in the surfactant lipidome in COPD and identify specific lipids associated with pulmonary function decline. Bronchoalveolar lavage (BAL) fluid was obtained from 12 former smokers with COPD and 5 non-smoking, non-asthmatic healthy control volunteers. Lipids were extracted and analyzed by liquid chromatography and mass spectrometry. Pulmonary function data were obtained by spirometry, and correlations of lung function with lipid species were determined. Wild-type C57BL/6 mice were exposed to 6 months of second-hand smoke in a full-body chamber. Surfactant lipids were decreased by 60% in subjects with COPD. All phospholipid classes were dramatically decreased, including ether phospholipids, which have not been studied in pulmonary surfactant. Availability of phospholipid, cholesterol, and sphingomyelin in BAL strongly correlated with pulmonary function and this was attributable to specific lipid species of phosphatidylcholine with surface tension reducing properties, and of phosphatidylglycerol with antimicrobial roles, as well as to other less studied lipid species. Mice exposed to smoke for six months recapitulated surfactant lipidomic changes observed in human subjects with COPD. In summary, we show that the surfactant lipidome is substantially altered in subjects with COPD, and decreased availability of phospholipids correlated with decreased pulmonary function. Further investigation of surfactant alterations in COPD would improve our understanding of its physiopathology and reveal new potential therapeutic targets.


Assuntos
Lipídeos/análise , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Surfactantes Pulmonares/metabolismo , Idoso , Animais , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Humanos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Fumantes , Poluição por Fumaça de Tabaco
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