Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 65
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Mater Sci Eng C Mater Biol Appl ; 109: 110636, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32228909

RESUMO

Though curcumin has potential treatment value for most chronic diseases, it exerts little potency in the clinic because of its low aqueous solubility, high chemical instability and poor pharmacokinetics. To enhance its potency, we developed a zein-based micelle as a nanocarrier to encapsulate curcumin. Herein, superhydrophilic zwitterionic polymers, poly(sulfobetaine methacrylate) (PSBMA), were conjugated to zein to obtain an amphiphilic zein-PSBMA conjugate. These conjugates could self-assemble into micelles composed of antifouling PSBMA shells and zein cores. The results from the cytokine secretion assay showed that the micelles induced a low level of macrophage activation. Moreover, the results from the in vivo fluorescence imaging experiment confirmed their long-circulating property, exceeding 72 h in mice. In comparison with native curcumin, micelle-encapsulated curcumin had a 230-fold increase in stability in vitro, and its half-life was 22-fold longer, according to a pharmacokinetic study on mice. Overall, this work presents a zein-PSBMA micelle with a long circulation time as a useful nanocarrier for effective curcumin delivery.


Assuntos
Betaína/análogos & derivados , Curcumina , Portadores de Fármacos , Nanoestruturas , Zeína , Animais , Betaína/química , Betaína/farmacocinética , Betaína/farmacologia , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Células RAW 264.7 , Zeína/química , Zeína/farmacocinética , Zeína/farmacologia
2.
J Med Chem ; 62(16): 7543-7556, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31381331

RESUMO

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.


Assuntos
Betaína/farmacologia , Integrinas/antagonistas & inibidores , Pirrolidinas/química , Compostos de Amônio Quaternário/farmacologia , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Betaína/química , Betaína/farmacocinética , Células Cultivadas , Cristalografia por Raios X , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Integrinas/química , Integrinas/metabolismo , Metilação , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacocinética , Ratos , Estereoisomerismo
3.
J Nutr Biochem ; 59: 129-135, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29986307

RESUMO

Methionine partitioning between protein turnover and a considerable pool of transmethylation precursors is a critical process in the neonate. Transmethylation yields homocysteine, which is either oxidized to cysteine (i.e., transsulfuration), or is remethylated to methionine by folate- or betaine- (from choline) mediated remethylation pathways. The present investigation quantifies the individual and synergistic importance of folate and betaine for methionine partitioning in neonates. To minimize whole body remethylation, 4-8-d-old piglets were orally fed an otherwise complete diet without remethylation precursors folate, betaine and choline (i.e. methyl-deplete, MD-) (n=18). Dietary methionine was reduced from 0.3 to 0.2 g/(kg∙d) on day-5 to limit methionine availability, and methionine kinetics were assessed during a gastric infusion of [13C1]methionine and [2H3-methyl]methionine. Methionine kinetics were reevaluated 2 d after pigs were rescued with either dietary folate (38 µg/(kg∙d)) (MD + F) (n=6), betaine (235 mg/(kg∙d)) (MD + B) (n=6) or folate and betaine (MD + FB) (n=6). Plasma choline, betaine, dimethylglycine (DMG), folate and cysteine were all diminished or undetectable after 7 d of methyl restriction (P<.05). Post-rescue, plasma betaine and folate concentrations responded to their provision, and homocysteine and glycine concentrations were lower (P<.05). Post-rescue, remethylation and transmethylation rates were~70-80% higher (P<.05), and protein breakdown was spared by 27% (P<.05). However, rescue did not affect transsulfuration (oxidation), plasma methionine, protein synthesis or protein deposition (P>.05). There were no differences among rescue treatments; thus betaine was as effective as folate at furnishing remethylation. Supplemental betaine or folate can furnish the transmethylation requirement during acute protein restriction in the neonate.


Assuntos
Betaína/farmacologia , Ácido Fólico/farmacologia , Metionina/metabolismo , Animais , Animais Recém-Nascidos , Betaína/farmacocinética , Sangue/efeitos dos fármacos , Sangue/metabolismo , Colina/farmacologia , Feminino , Ácido Fólico/farmacocinética , Masculino , Metionina/farmacologia , Metilação/efeitos dos fármacos , Suínos , Vitamina U/farmacocinética , Vitamina U/farmacologia
4.
Acta Biomater ; 64: 290-300, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29030301

RESUMO

A fully biodegradable zwitterionic polymer and the corresponding conjugate with paclitaxel (PTX) were synthesized as promising biomaterials. Allyl-functionalized polylactide (PLA) was employed as the precursor of polymer backbones. UV-induced thiol-ene reaction was conducted to conjugate thiol-functionalized sulfobetaine (SB) with the PLA-based backbone. The resulting zwitterionic polymer did not exhibit considerable cytotoxicity. A polymer-drug conjugate was also obtained by thiol-ene reaction of both thiol-functionalized SB and PTX with allyl-functionalized PLA. The conjugate could readily form narrowly-dispersed nanoparticles in aqueous solutions with a volume-average hydrodynamic diameter (Dh,V) of 19.3 ±â€¯0.2 nm. Such a polymer-drug conjugate-based drug delivery system showed full degradability, well-suppressed non-specific interaction with biomolecules, and sustained drug release. In vitro assessments also confirmed the significant anti-cancer efficacy of the conjugate. After 72 h incubation with PLA-SB/PTX containing 10 µg/mL of PTX, the cell viabilities of A549, MCF7, and PaCa-2 cells were as low as 20.0 ±â€¯2.5%, 1.7 ±â€¯1.7%, and 14.8 ±â€¯0.9%, respectively. Both flow cytometry and confocal microscopy suggested that the conjugates could be easily uptaken by A549 cells before the major release of PTX moieties. Overall, this work elucidates promising potentials of biodegradable zwitterionic polymer-based materials in biomedical applications. STATEMENT OF SIGNIFICANCE: The applicability of FDA-approved biodegradable aliphatic polyesters has been significantly restricted because they are hydrophobic and lack functionalities. Recently zwitterionic polymers have emerged as promising hydrophilic biomaterials, but most of the reported zwitterionic polymers are non-biodegradable. This study reports a novel aliphatic polyester-based zwitterionic polymer and the corresponding polymer-drug conjugate. Their aliphatic polyester and zwitterionic components provide them with high enzymatic degradability and low nonspecific interactions with biomolecules, respectively. While the zwitterionic polymer did not show noticeable cytotoxicity, the corresponding polymer-anticancer drug conjugate exhibited acid-sensitive sustained drug release, remarkable effectiveness in killing cancer cells, as well as the ready cellular internalization. This work lays a foundation for the further development of synthetic biodegradable zwitterionic polymer-based materials which potentially may have broad and significant biomedical applications.


Assuntos
Betaína/análogos & derivados , Plásticos Biodegradáveis , Neoplasias/tratamento farmacológico , Paclitaxel , Células A549 , Betaína/química , Betaína/farmacocinética , Betaína/farmacologia , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Plásticos Biodegradáveis/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia
5.
Adv Healthc Mater ; 6(11)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28337855

RESUMO

Polymer-protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer-protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non-site specific way, or a more complex site-specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB-insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB-insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB-insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB-insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one-step coupling reaction without complex site-specific linkage technique. The synthesized PCB-insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms.


Assuntos
Betaína , Diabetes Mellitus Experimental/tratamento farmacológico , Proteínas Imobilizadas , Insulina , Polímeros , Animais , Betaína/química , Betaína/farmacocinética , Betaína/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Diabetes Mellitus Experimental/sangue , Proteínas Imobilizadas/química , Proteínas Imobilizadas/farmacocinética , Proteínas Imobilizadas/farmacologia , Insulina/química , Insulina/farmacocinética , Insulina/farmacologia , Camundongos , Polímeros/química , Polímeros/farmacocinética , Polímeros/farmacologia
6.
Mol Nutr Food Res ; 61(7)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27958675

RESUMO

Rye is one of the main cereals produced and consumed in the hemiboreal climate region. Due to its use primarily as wholegrain products, rye provides a rich source of dietary fibre as well as several classes of phytochemicals, bioactive compounds with potentially positive health implications. Here, we review the current knowledge of the metabolic pathways of phytochemical classes abundant in rye, starting from the microbial transformations occurring during the sourdough process and colonic fermentation and continuing with the endogenous metabolism. Additionally, we discuss the detection of specific metabolites by MS in different phases of their journey from the cereal to the target organs and excretion.


Assuntos
Colo/microbiologia , Microbiologia de Alimentos , Compostos Fitoquímicos/farmacocinética , Secale/química , Betaína/metabolismo , Betaína/farmacocinética , Colo/metabolismo , Manipulação de Alimentos , Humanos , Compostos Fitoquímicos/metabolismo
7.
Basic Clin Pharmacol Toxicol ; 120(5): 450-456, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27983775

RESUMO

Meldonium (3-(2,2,2-trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 (OCTN2). Inhibition of OCTN2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization-related cardioprotective effects. The recent inclusion of meldonium in the World Anti-Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of the treatment was tested with and without administration of carnitine, γ-butyrobetaine (GBB) and furosemide to evaluate the importance of competition for OCTN2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB. In conclusion, the competition of meldonium, carnitine and GBB for OCTN2-mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long-term treatment, OCTN2-mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium.


Assuntos
Betaína/análogos & derivados , Carnitina/administração & dosagem , Metilidrazinas/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Betaína/administração & dosagem , Betaína/farmacocinética , Betaína/farmacologia , Transporte Biológico/efeitos dos fármacos , Carnitina/farmacocinética , Carnitina/farmacologia , Furosemida/administração & dosagem , Furosemida/farmacologia , Masculino , Metilidrazinas/farmacologia , Camundongos , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Membro 5 da Família 22 de Carreadores de Soluto , Distribuição Tecidual
8.
Acta Biomater ; 40: 235-242, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27134016

RESUMO

UNLABELLED: Vascular endothelial growth factor (VEGF) is the growth factor responsible for the triggering of angiogenesis, the process of blood vessel formation supporting the long-term viability of any repaired or regenerated tissue. As the growth factor is effective only when concentration gradients are generated, new shuttles need to be developed that ensure both the control of gradients at the site of tissue repair and the release of VEGF at physiological levels. Magnetic hyperthermia is the production of heat induced by magnetic materials through their exposure to an external oscillating magnetic field. In this paper, magnetic nanoparticles capable of generating controllable hyperthermia were functionalised with hyperbranched poly(epsilon-lysine) peptides integrating in their core parallel thermoresponsive elastin-like peptide sequences and presenting an uppermost branching generation tethered by the zwitterionic amino acid carboxybetaine. The results show that these functionalised magnetic nanoparticles avidly bind VEGF and release it only upon generation of mild-hyperthermic pulses generated by oscillating magnetic filed. The VEGF release occurred in a temperature range at which the elastin-like peptides collapse. It is proposed that, through the application of an external magnetic field, these magnetic carriers could generated gradients of VEGF in vivo and allow its tuned delivery in a number of clinical applications. STATEMENT OF SIGNIFICANCE: The present paper for the first time reveals the possibility to control the delivery of VEGF through mild hyperthermia stimuli generated by a oscillating magnetic field. To this purpose, magnetic nanoparticles of high size homogeneity and coated with a thin coating of poly(acrylic acid) were functionalised with a novel class of poly(epsilon lysine) dendrimers integrating in their structure a thermoresponsive amino acid sequence mimicking elastin and exposing at high density a zwitterionic modified amino acid, the carboxybetaine, known to be able to bind macromolecules. Physicochemical and biochemical characterisation elegantly show the link between the thermal properties of the nanoparticles and of the dendrimer change of conformation and how this enable the release of VEGF at temperature values compatible with the growth factor stability.


Assuntos
Antracenos/química , Sistemas de Liberação de Medicamentos/métodos , Hipertermia Induzida/métodos , Campos Magnéticos , Nanopartículas de Magnetita/química , Polilisina/química , Fator A de Crescimento do Endotélio Vascular , Antracenos/síntese química , Antracenos/farmacocinética , Betaína/síntese química , Betaína/química , Betaína/farmacocinética , Humanos , Polilisina/síntese química , Polilisina/farmacocinética , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/farmacocinética
9.
Acta Biomater ; 40: 263-272, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26607767

RESUMO

UNLABELLED: Nanomedicines have emerged as indispensable platforms for cancer theranostics, however, the therapeutic outcomes were often compromised not only by the multiple biological barriers during the itinerary from the initial injection site to the intracellular action site but also the insufficient drug release at the pathological site. Herein, novel bioreducible double head agent, combining reversible addition-fragmentation chain transfer agent and ring opening polymerization initiator through disulfide linkage, was firstly prepared. Well-defined cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone block copolymers (termed as cRGD-PCSSL) were facilely synthesized using this initiator. Subsequently, shell sheddable and drug-encapsulated zwitterionic nanoparticles were constructed by one-step self-assembly with doxorubicin (DOX) (termed as cRGD-PCSSL/DOX NPs). The reduction-responsive shedding of PCB shells resulted in the rapid loss of cRGD-PCSSL/DOX NPs stability in the presence of glutathione, facilitating the rapid DOX release. Results of flow cytometry and fluorescence microscopy demonstrated that cRGD-PCSSL/DOX NPs could be internalized by HepG2 cells via receptor-mediated endocytosis with fast intracellular drug release, leading to considerable cytotoxicity in comparison with free DOX. Importantly, the low protein adsorption and excellent serum stability properties of cRGD-PCSSL/DOX NPs translated into prolonged systemic circulation and enhanced tumor accumulation. Furthermore, intravenous injection of cRGD-PCSSL/DOX NPs in tumor-bearing mice exhibited significantly higher antitumor efficiency and lower systemic toxicity compared to free DOX. Consequently, the novel zwitterionic NPs, which facilely overcome the dilemma between multifunctionality and complexity by programmatically circumventing the multiple biological barriers, would represent a promising platform for enhanced anticancer drug delivery. STATEMENT OF SIGNIFICANCE: Herein, novel bioreducible RAFT and ROP double-head agent was first reported for the synthesis of cRGDfK-polycarboxybetaine methacrylate-SS-polycaprolactone zwitterionic block copolymers (cRGD-PCB-SS-PCL, termed as cRGD-PCSSL) through controllable polymerization methods. Firstly, this synthetic route surmounted the major disadvantage of most current used methods, which required thiol exchange reaction between active disulfide bond and free thiol groups at the chain ends. Secondly, the prepared cRGD-PCSSL/DOX NPs reasonably integrated cRGD for active tumor targeting and receptor-mediated endocytosis, zwitterionic PCB with nonfouling property for prolonged systemic circulation, disulfide linkage for reduction-responsive drug release, biodegradable PCL for hydrophobic anticancer drug loading. Finally, the systematic evaluation fully verified that the in vitro optimized cRGD-PCSSL/DOX NPs translated into significantly better therapeutic efficiency with reduced side effects in vivo.


Assuntos
Doxorrubicina , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas , Neoplasias , Animais , Betaína/química , Betaína/farmacocinética , Betaína/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Ácidos Polimetacrílicos/farmacologia , Ratos , Ratos Wistar , Nanomedicina Teranóstica/métodos
10.
Br J Nutr ; 113(3): 445-53, 2015 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-25585164

RESUMO

The bran and particularly the aleurone fraction of wheat are high in betaine and other physiological methyl donors, which may exert beneficial physiological effects. We conducted two randomised, controlled, cross-over postprandial studies to assess and compare plasma betaine and other methyl donor-related responses following the consumption of minimally processed bran and aleurone fractions (study A) and aleurone bread (study B). For both studies, standard pharmacokinetic parameters were derived for betaine, choline, folate, dimethylglycine (DMG), total homocysteine and methionine from plasma samples taken at 0, 0·5, 1, 2 and 3 h. In study A (n 14), plasma betaine concentrations were significantly and substantially elevated from 0·5 to 3 h following the consumption of both bran and aleurone compared with the control; however, aleurone gave significantly higher responses than bran. Small, but significant, increases were also observed in DMG measures; however, no significant responses were observed in other analytes. In study B (n 13), plasma betaine concentrations were significantly and substantially higher following consumption of the aleurone bread compared with the control bread; small, but significant, increases were also observed in DMG and folate measures in response to consumption of the aleurone bread; however, no significant responses were observed in other analytes. Peak plasma betaine concentrations, which were 1·7-1·8 times the baseline levels, were attained earlier following the consumption of minimally processed aleurone compared with the aleurone bread (time taken to reach peak concentration 1·2 v. 2·1 h). These results showed that the consumption of minimally processed wheat bran, and particularly the aleurone fraction, yielded substantial postprandial increases in plasma betaine concentrations. Furthermore, these effects appear to be maintained when aleurone was incorporated into bread.


Assuntos
Betaína/sangue , Pão , Fibras na Dieta/administração & dosagem , Período Pós-Prandial , Sementes , Triticum , Adulto , Betaína/análise , Betaína/farmacocinética , Colina/análise , Colina/sangue , Estudos Cross-Over , Feminino , Ácido Fólico/análise , Ácido Fólico/sangue , Manipulação de Alimentos , Humanos , Masculino , Sarcosina/análogos & derivados , Sarcosina/sangue , Sementes/química , Triticum/química
11.
Curr Eye Res ; 40(3): 267-73, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24833321

RESUMO

PURPOSE: To develop a contact lens system that will control the release of an osmoprotectant and a moisturizing agent with the aim to reduce symptoms of ocular dryness. MATERIALS AND METHODS: Profiles of the release of osmoprotectant betaine and moisturizing agent dexpanthenol from senofilcon A and narafilcon B contact lenses were determined in vitro under sink conditions. Both types of lenses were also infused with vitamin E to increase the duration of drug release due to the formation of the vitamin E diffusion barriers in the lenses. The release profiles from vitamin E-infused lenses were compared with those from the control lenses. RESULTS: Both dexpanthenol and betaine are released from commercial silicone hydrogel lenses for only about 10 min. Vitamin E loadings into contact lenses at about 20-23% can increase the release times to about 10 h, which is about 60 times larger compared to the control unmodified lenses. CONCLUSIONS: Vitamin E-loaded silicone hydrogel contact lenses released betaine and dexpanthenol in a controlled fashion.


Assuntos
Betaína/farmacocinética , Lentes de Contato Hidrofílicas , Lipotrópicos/farmacocinética , Ácido Pantotênico/análogos & derivados , Vitamina E/metabolismo , Transporte Biológico Ativo , Sistemas de Liberação de Medicamentos , Síndromes do Olho Seco/tratamento farmacológico , Hidrogéis , Osmorregulação , Ácido Pantotênico/farmacocinética , Silicones , Complexo Vitamínico B/farmacocinética
12.
Biotechnol Bioeng ; 112(2): 405-15, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25182778

RESUMO

Efficient intracellular delivery of molecules is needed to modulate cellular behavior for laboratory and medical applications, but is often limited by trade-offs between achieving high intracellular delivery and maintaining high cell viability. Here, we studied photoacoustic delivery of molecules into cells by exposing DU145 human prostate carcinoma cells to nanosecond laser pulses in the presence of carbon black nanoparticles. Under strong laser exposure conditions, less than 30% of cells were viable and exhibited uptake. Addition of poloxamer surfactant at those laser exposure conditions increased cell viability to almost 90%, with intracellular uptake in >80% of cells. This remarkable increase in efficiency of intracellular delivery and cell viability may be attributed to enhanced cell membrane resealing by poloxamer surfactant after photoacoustic delivery. While F-68 poloxamer was effective, the larger, more-hydrophobic F-127 poloxamer provided the best results. There was no significant protective effect from addition of Ca(2+) , BAPTA-AM, ATP, fetal bovine serum or glycine betaine, which were expected to promote active cell membrane repair mechanisms and other active intracellular protective processes. We conclude that poloxamer surfactant preserves cell viability during photoacoustic delivery of molecules into cells, thereby enabling highly efficient intracellular delivery.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Técnicas Fotoacústicas/métodos , Poloxâmero/farmacologia , Tensoativos/farmacologia , Betaína/química , Betaína/farmacocinética , Betaína/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/farmacologia , Humanos , Espaço Intracelular/química , Nanopartículas/química , Poloxâmero/química , Fuligem/química , Fuligem/farmacologia , Tensoativos/química
13.
Br J Nutr ; 112(9): 1459-68, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25216241

RESUMO

To elucidate the effects of maternal dietary betaine supplementation on hepatic expression of cholesterol metabolic genes in newborn piglets and the involved epigenetic mechanisms, we fed gestational sows with control or betaine-supplemented diets (3 g/kg) throughout pregnancy. Neonatal piglets born to betaine-supplemented sows had higher serum methionine concentration and hepatic content of betaine, which was associated with significantly up-regulated hepatic expression of glycine N-methyltransferase. Prenatal betaine exposure increased hepatic cholesterol content and modified the hepatic expression of cholesterol metabolic genes in neonatal piglets. Sterol regulatory element-binding protein 2 was down-regulated at both mRNA and protein levels, while 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) was down-regulated at the mRNA level, but up-regulated at the protein level, in betaine-exposed piglets. The transcriptional repression of HMGCR was associated with CpG island hypermethylation and higher repressive histone mark H3K27me3 (histone H3 lysine 27 trimethylation) on the promoter, whereas increased HMGCR protein content was associated with significantly decreased expression of miR-497. Furthermore, LDL receptor was significantly down-regulated at both mRNA and protein levels in the liver of betaine-exposed piglets, which was associated with promoter CpG hypermethylation. In addition, the expression of cholesterol-27α-hydroxylase (CYP27α1) was up-regulated at both mRNA and protein levels, while the expression of cholesterol-7α-hydroxylase (CYP7α1) was increased at the mRNA level, but unchanged at the protein level associated with increased expression of miR-181. These results indicate that maternal betaine supplementation increases hepatic cholesterol content in neonatal piglets through epigenetic regulations of cholesterol metabolic genes, which involve alterations in DNA and histone methylation and in the expression of microRNA targeting these genes.


Assuntos
Animais Recém-Nascidos , Betaína/administração & dosagem , Colesterol/genética , Epigênese Genética/efeitos dos fármacos , Fígado/metabolismo , Sus scrofa , Animais , Betaína/farmacocinética , Ácidos e Sais Biliares/sangue , Colesterol/análise , Colesterol/sangue , Colesterol 7-alfa-Hidroxilase/genética , Metilação de DNA , Dieta/veterinária , Suplementos Nutricionais , Feminino , Expressão Gênica/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/genética , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Metionina/sangue , Metionina/metabolismo , MicroRNAs/genética , Gravidez , RNA Mensageiro/análise , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
14.
Amino Acids ; 46(8): 1785-93, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24760587

RESUMO

Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects.


Assuntos
Desempenho Atlético , Betaína/farmacologia , Composição Corporal/efeitos dos fármacos , Exercício Físico/fisiologia , Resistência Física/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Betaína/metabolismo , Betaína/farmacocinética , Disponibilidade Biológica , Creatina/biossíntese , Suplementos Nutricionais , Hormônio do Crescimento/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Músculo Esquelético/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Receptor de Insulina/metabolismo
15.
Biol Reprod ; 90(4): 81, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24599290

RESUMO

Betaine (N,N,N-trimethylglycine) has previously been shown to function in cell volume homeostasis in early mouse embryos and also to be a key donor to the methyl pool in the blastocyst. A betaine transporter (SLC6A20A or SIT1) has been shown to be activated after fertilization, but there is no saturable betaine uptake in mouse oocytes or eggs. Unexpectedly, the same high level of betaine is present in mature metaphase II (MII) eggs as is found in one-cell embryos despite the lack of transport in oocytes or eggs. Significant saturable betaine transport is, however, present in intact cumulus-oocyte complexes (COCs). This transport system has an affinity for betaine of ∼227 µM. The inhibition profile indicates that betaine transport by COCs could be completely blocked by methionine, proline, leucine, lysine, and arginine, and transport is dependent on Na(+) but not Cl(-). This is consistent with transport by a y+L-type amino acid transport system. Both transcripts and protein of one y+L isoform, SLC7A6 (y+LAT2), are present in COCs, with little or no expression in isolated germinal vesicle (GV)-stage oocytes, MII eggs, or one-cell embryos. Betaine accumulated by COCs is transferred into the enclosed GV oocyte, which requires functional gap junctions. Thus, at least a portion of the endogenous betaine in MII eggs could be derived from transport into cumulus cells and subsequent transfer into the enclosed oocyte before gap junction closure during meiotic maturation. The oocyte-derived betaine then could be regulated and supplemented by the SIT1 transporter that arises in the embryo after fertilization.


Assuntos
Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Betaína/metabolismo , Blastocisto/metabolismo , Células do Cúmulo/metabolismo , Oócitos/metabolismo , Aminoácidos/metabolismo , Animais , Betaína/farmacocinética , Transporte Biológico/fisiologia , Blastocisto/citologia , Proteínas de Transporte/metabolismo , Células do Cúmulo/citologia , Feminino , Fertilização/fisiologia , Proteínas da Membrana Plasmática de Transporte de GABA , Junções Comunicantes/metabolismo , Íons/metabolismo , Camundongos , Camundongos Endogâmicos , Oócitos/citologia , Gravidez , Trítio
16.
J Control Release ; 172(3): 641-52, 2013 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-24056145

RESUMO

Although the careful selection of shell-forming polymers for the construction of nanoparticles is an obvious parameter to consider for shielding of core materials and their payloads, providing for prolonged circulation in vivo by limiting uptake by the immune organs, and thus, allowing accumulation at the target sites, the immunotoxicities that such shielding layers elicit is often overlooked. For instance, we have previously performed rigorous in vitro and in vivo comparisons between two sets of nanoparticles coated with either non-ionic poly(ethylene glycol) (PEG) or zwitterionic poly(carboxybetaine) (PCB), but only now report the immunotoxicity and anti-biofouling properties of both polymers, as homopolymers or nanoparticle-decorating shell, in comparison to the uncoated nanoparticles, and Cremophor-EL, a well-known low molecular weight surfactant used for formulation of several drugs. It was found that both PEG and PCB polymers could induce the expression of cytokines in vitro and in vivo, with PCB being more immunotoxic than PEG, which corroborates the in vivo pharmacokinetics and biodistribution profiles of the two sets of nanoparticles. This is the first study to report on the ability of PEG, the most commonly utilized polymer to coat nanomaterials, and PCB, an emerging zwitterionic anti-biofouling polymer, to induce the secretion of cytokines and be of potential immunotoxicity. Furthermore, we report here on the possible use of immunotoxicity assays to partially predict in vivo pharmacokinetics and biodistribution of nanomaterials.


Assuntos
Betaína/análogos & derivados , Betaína/imunologia , Nanopartículas/toxicidade , Polietilenoglicóis/química , Animais , Betaína/farmacocinética , Betaína/toxicidade , Linhagem Celular , Citocinas/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/toxicidade
17.
ACS Nano ; 6(10): 8970-82, 2012 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-23043240

RESUMO

Nanoparticles with tunable pharmacokinetics are desirable for various biomedical applications. Poly(ethylene glycol) (PEG) is well-known to create "stealth" effects to stabilize and extend the blood circulation of nanoparticles. In this work, poly(carboxybetaine) (PCB), a new nonfouling polymer material, was incorporated as surface-grafted coatings, conjugated onto degradable shell cross-linked knedel-like nanoparticles (dSCKs) composed of poly(acrylic acid)-based shells and poly(lactic acid) cores, to compare the in vivo pharmacokinetics to their PEG-functionalized analogues. A series of five dSCKs was prepared from amphiphilic block copolymers, having different numbers and lengths of either PEG or PCB grafts, by supramolecular assembly in water followed by shell cross-linking, and then studied by a lactate assay to confirm their core hydrolytic degradabilities. Each dSCK was also conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocyclic chelators and tyramine moieties to provide for (64)Cu and/or radiohalogen labeling. The high specific activity of (64)Cu radiolabeling ensured nanogram administration of dSCKs for in vivo evaluation of their pharmacokinetics. Biodistribution studies demonstrated comparable in vivo pharmacokinetic profiles of PCB-grafted dSCKs to their PEG-conjugated counterparts. These results indicated that PCB-functionalized dSCKs have great potential as a theranostic platform for translational research.


Assuntos
Implantes Absorvíveis , Betaína/farmacocinética , Materiais Revestidos Biocompatíveis/farmacocinética , Nanopartículas/química , Polietilenoglicóis/farmacocinética , Ácidos Polimetacrílicos/farmacocinética , Animais , Betaína/síntese química , Materiais Revestidos Biocompatíveis/síntese química , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Polietilenoglicóis/síntese química , Ácidos Polimetacrílicos/síntese química , Distribuição Tecidual
19.
Exp Dermatol ; 17(12): 1031-6, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18557924

RESUMO

Compatible organic osmolytes, such as betaine, myo-inositol and taurine, are involved in cell protection. Human dermal fibroblasts accumulate these osmolytes and express mRNA specific for their transporting systems betaine-/gamma-amino-n-butyric acid (GABA) transporter (BGT-1), sodium-dependent myo-inositol transporter (SMIT) and taurine transporter (TAUT). Taurine uptake was about sixfold higher than that of betaine and myo-inositol. Compared with normoosmotic (305 mOsm/l) control, hyperosmotic exposure (405 mOsm/l) led to a twofold induction of osmolyte uptake. Ultraviolet A (UVA) upregulated osmolyte transporter mRNA levels and increased osmolyte uptake. Taurine inhibited UVA-induced interleukin-6 (Il-6) mRNA expression by 40%. Furthermore, Il-6 accumulation in the supernatants of UVA-irradiated dermal fibroblasts was much slower when cells were preincubated with taurine. These data indicate that taurine accumulation seems to be part of the fibroblast response to UVA radiation and may protect against UVA-induced Il-6 overexpression.


Assuntos
Fibroblastos/metabolismo , Compostos Orgânicos/metabolismo , Raios Ultravioleta , Betaína/farmacocinética , Betaína/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/efeitos da radiação , Proteínas de Transporte/genética , Células Cultivadas , Derme/efeitos dos fármacos , Derme/metabolismo , Derme/efeitos da radiação , Eletrólitos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Proteínas da Membrana Plasmática de Transporte de GABA , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Proteínas de Choque Térmico/genética , Humanos , Inositol/farmacocinética , Inositol/farmacologia , Interleucina-6/genética , Interleucina-6/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Concentração Osmolar , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Solução Salina Hipertônica/farmacologia , Simportadores/genética , Taurina/farmacocinética , Taurina/farmacologia
20.
Am J Clin Nutr ; 87(3): 577-85, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18326594

RESUMO

BACKGROUND: Betaine comes from the diet and from choline, and it is associated with vascular disease in some patient groups. Betaine supplementation lowers plasma total homocysteine. OBJECTIVE: We compared the acute effects of dietary and supplementary betaine and choline on plasma betaine and homocysteine under standard conditions and after a methionine load. DESIGN: In a randomized crossover study, 8 healthy men (19-40 y) consumed a betaine supplement (approximately 500 mg), high-betaine meal (approximately 517 mg), choline supplement (500 mg), high-choline meal (approximately 564 mg), high-betaine and -choline meal (approximately 517 mg betaine, approximately 622 mg choline), or a low-betaine and -choline control meal under standard conditions or postmethionine load. Plasma betaine, dimethylglycine, and homocysteine concentrations were measured hourly for 8 h and at 24 h after treatment. RESULTS: Dietary and supplementary betaine raised plasma betaine concentrations relative to control (P < 0.001) under standard conditions. This was not associated with raised plasma dimethylglycine concentration, and no significant betaine appeared in the urine. A small increase in dimethylglycine excretion was observed when either betaine or choline was supplied (P = 0.011 and < 0.001). Small decreases in plasma homocysteine 6 h after ingestion under standard conditions (P < or = 0.05) were detected after a high-betaine meal and after a high-betaine and high-choline meal. Dietary betaine and choline and betaine supplementation attenuated the increase in plasma homocysteine at both 4 and 6 h after a methionine load (P < or = 0.001). CONCLUSIONS: Dietary betaine and supplementary betaine acutely increase plasma betaine, and they and choline attenuate the postmethionine load rise in homocysteine concentrations.


Assuntos
Betaína/farmacocinética , Dieta , Suplementos Nutricionais , Homocisteína/sangue , Metionina/farmacologia , Administração Oral , Adulto , Análise de Variância , Área Sob a Curva , Betaína/sangue , Betaína/urina , Colina/metabolismo , Colina/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Sarcosina/análogos & derivados , Sarcosina/sangue , Sarcosina/urina , Estatísticas não Paramétricas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA