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1.
J Med Chem ; 64(6): 3204-3221, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33710891

RESUMO

Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Fólico/análogos & derivados , Peptídeos/química , Peptídeos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Antineoplásicos/farmacocinética , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Receptor 1 de Folato/metabolismo , Ácido Fólico/farmacocinética , Ácido Fólico/farmacologia , Humanos , Modelos Moleculares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Peptídeos/farmacocinética , Timidilato Sintase/metabolismo
2.
Food Chem ; 340: 127960, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32916403

RESUMO

Folate is a fundamental vitamin for metabolism in plants and humans. A modelling approach has been developed to characterize the reactivity of folates in cowpea seeds during germination at 30 °C, using a water-to-seed ratio of 1:1 (w/w). For this purpose, the concentrations of folic acid, 10-formylfolic acid, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate were determined in seeds during germination times up to 96 h. Two reaction models were sequentially built and adjusted to experimental data to describe changes in concentration in cowpea seed during two germination phases: before 14 h and after 48 h. Results showed intense enzymatic interconversion of all folate vitamers into 5-methyltetrahydrofolate before 14 h of germination and high enzymatic production of 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate after 48 h of germination. This study suggests that a long germination process could be more beneficial than soaking to increase the production of bioavailable folates within the seed for human consumption.


Assuntos
Ácido Fólico/metabolismo , Germinação , Sementes/crescimento & desenvolvimento , Vigna/crescimento & desenvolvimento , Ácido Fólico/análogos & derivados , Ácido Fólico/análise , Cinética , Modelos Biológicos , Sementes/metabolismo , Temperatura , Tetra-Hidrofolatos/análise , Tetra-Hidrofolatos/metabolismo , Vigna/metabolismo
3.
Sci Rep ; 10(1): 1047, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974480

RESUMO

Non-invasive imaging of arthritis activity in rheumatoid arthritis (RA) patients using macrophage PET holds promise for early diagnosis and therapeutic response monitoring. Previously obtained results with macrophage tracer (R)-[11C]PK11195 were encouraging, but the imaging signal could be further improved by reduction of background uptake. Recently, the novel macrophage tracer [18F]fluoro-PEG-folate was developed. This tracer showed excellent targeting of the folate receptor ß on activated macrophages in synovial tissue in a preclinical arthritic rat model. We performed three substudies to investigate the biodistribution, potential for imaging arthritis and kinetic properties of [18F]fluoro-PEG-folate in RA patients. Firstly, biodistribution demonstrated fast clearance of [18F]fluoro-PEG-folate from heart and blood vessels and no dose limiting uptake in organs. Secondly, [18F]fluoro-PEG-folate showed uptake in arthritic joints with significantly lower background and hence significantly higher target-to-background ratios as compared to reference macrophage tracer (R)-[11C]PK11195. Lastly, dynamic scanning demonstrated fast tracer uptake in affected joints, reaching a plateau after 1 minute, co-existing with a rapid blood clearance. In conclusion, this first in man study demonstrates the potential of [18F]fluoro-PEG-folate to image arthritis activity in RA with favourable imaging characteristics of rapid clearance and low background uptake, that allow for detection of inflammatory activity in the whole body.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Receptor 2 de Folato/metabolismo , Ácido Fólico/análogos & derivados , Macrófagos/fisiologia , Polietilenoglicóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Diagnóstico Precoce , Feminino , Radioisótopos de Flúor/farmacocinética , Ácido Fólico/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismo
4.
Front Immunol ; 10: 2724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824505

RESUMO

Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-ß is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of 18F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-ß was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the 18F-based folate radiotracer 18F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-ß expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-ß was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of 18F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-ß positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of 18F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases.


Assuntos
Radioisótopos de Flúor , Receptor 2 de Folato/imunologia , Ácido Fólico , Doenças Pulmonares Intersticiais , Macrófagos/imunologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Feminino , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Ácido Fólico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Camundongos , Estudo de Prova de Conceito , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia
5.
Chin J Nat Med ; 17(12): 928-934, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31882048

RESUMO

Two new folate-derived analogues, named uncarophyllofolic acids A (1) and B (2), respectively, were isolated from the Uncaria rhynchophylla hook bearing stem (Gouteng in Chinese). The distinct stereochemical structures of 1 and 2 were determined by spectroscopic data analysis in combination with acidic hydrolysis and Marfey's derivatization, along with comparison of their specific rotation and Cotton effect (CE) data with those of the biogenetically related known derivatives as well as theoretical calculations of electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway of 1 and 2, associating to folate metabolism and the previously reported orychophragines A-C from Orychophragmus violaceus, is discussed.


Assuntos
Ácido Fólico/química , Extratos Vegetais/química , Uncaria/química , China , Cromatografia Líquida de Alta Pressão , Ácido Fólico/análogos & derivados , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Caules de Planta/química
6.
Int J Nanomedicine ; 14: 6519-6538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616142

RESUMO

Background: Polycation carriers show great foreground in the developing efficient and safe gene delivery; nevertheless, they are cytotoxic and unstable in vivo because of the excess cationic charge. PEGylation improves the biocompatibility and stability of polycation, whereas PEGylation restrains the endosomal escape to some extent. Materials and methods: To address this issue and promote the transfection in vivo, a pH-sensitive conjugate folate-polyethylene glycol-carboxylated chitosan (shorten as FA-PEG-CCTS) was designed and coated on the surface of PEI/NLS/pDNA (PNDs), forming a versatile gene carrier FA-PEG-CCTS/PEI/NLS/pDNA (FPCPNDs). The novel carrier exhibited a few picturesque characteristics, including (i) neutral surface charge to restrain nonspecific interactions; (ii) folate receptors (FR)-mediated endocytosis to augment cellular uptake; (iii) dual proton sponge effect to realize endosome escape, and (iv) nuclear localization sequences (NLS) to enhance the transfection of pDNA. Results: FPCPNDs could compress and protect pDNA from degradation. FPCPNDs energetically targeted tumor cells because of their high binding affinity between FA and highly expressed FR on the tumor surface, accordingly enhancing the cellular uptake. In the acidic endosomes, FA-PEG-CCTS segment dissociated from PNDs. Then, PNDs realized endosomal escape through the proton sponge effect of PEI. Furthermore, FPCPNDs showed admirable transfection efficiency with the aid of NLS peptides. What's more, in vivo studies revealed that FPCPNDs had supreme antitumor activity among the whole preparations. Conclusion: In vitro and in vivo assays thus demonstrate that FPCPNDs is a hopeful strategy for gene delivery.


Assuntos
Endossomos/metabolismo , Neoplasias/metabolismo , Transfecção , Animais , Morte Celular , Linhagem Celular Tumoral , Quitosana/química , DNA/genética , DNA/metabolismo , Endocitose , Feminino , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Terapia Genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Sinais de Localização Nuclear , Tamanho da Partícula , Plasmídeos/metabolismo , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Eletricidade Estática
7.
Analyst ; 144(22): 6729-6735, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31612877

RESUMO

The conjugation of ligands to nanoparticles as drug delivery systems that target specific cells is a promising approach for the delivery of therapeutic agents to tumor cells. Herein, we prepared green-emission fluorescent carbon nanodots (CNDs) by a facile hydrothermal method with d-(+)-glucosamine hydrochloride and l-aspartic acid as the precursors, then covalently conjugated with folate (FA), polyethyleneimine (PEI) and hyaluronic acid (HA) to develop dual ligand-decorated nanocarriers (FA-PEI-HA-CNDs) for the targeted imaging of cancer cells. FA-PEI-HA-CNDs integrated the excellent fluorescence property of CNDs, and can be used for the real-time and noninvasive location tracking of cancer cells. The cellular uptake study demonstrated that FA-PEI-HA-CNDs markedly improved the internalization efficiency in A-549 cells via folate/CD44 receptor-mediated endocytosis in comparison with that of the A549 cells pretreated with excess FA, HA, and FA and HA. Therefore, these dual folate/CD44 receptor-targeted CNDs (FA-PEI-HA-CNDs) show promising potential for cancer detection, drug delivery, and individualized treatment as performance platforms.


Assuntos
Corantes Fluorescentes/química , Pontos Quânticos/química , Células A549 , Carbono/química , Carbono/toxicidade , Endocitose/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/análogos & derivados , Ácido Fólico/síntese química , Ácido Fólico/toxicidade , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/análogos & derivados , Ácido Hialurônico/síntese química , Ácido Hialurônico/toxicidade , Ligantes , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Polietilenoimina/análogos & derivados , Polietilenoimina/síntese química , Polietilenoimina/toxicidade , Pontos Quânticos/toxicidade
8.
Arch Biochem Biophys ; 674: 108106, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31520592

RESUMO

In view of previous crystallographic studies, N4-hydroxy-dCMP, a slow-binding thymidylate synthase inhibitor apparently caused "uncoupling" of the two thymidylate synthase-catalyzed reactions, including the N5,10-methylenetetrahydrofolate one-carbon group transfer and reduction, suggesting the enzyme's capacity to use tetrahydrofolate as a cofactor reducing the pyrimidine ring C(5) in the absence of the 5-methylene group. Testing the latter interpretation, a possibility was examined of a TS-catalyzed covalent self-modification/self-inactivation with certain pyrimidine deoxynucleotides, including 5-fluoro-dUMP and N4-hydroxy-dCMP, that would be promoted by tetrahydrofolate and accompanied with its parallel oxidation to dihydrofolate. Electrophoretic analysis showed mouse recombinant TS protein to form, in the presence of tetrahydrofolate, a covalently bound, electrophoretically separable 5-fluoro-dUMP-thymidylate synthase complex, similar to that produced in the presence of N5,10-methylenetetrahydrofolate. Further studies of the mouse enzyme binding with 5-fluoro-dUMP/N4-hydroxy-dCMP by TCA precipitation of the complex on filter paper showed it to be tetrahydrofolate-promoted, as well as to depend on both time in the range of minutes and the enzyme molecular activity, indicating thymidylate synthase-catalyzed reaction to be responsible for it. Furthermore, the tetrahydrofolate- and time-dependent, covalent binding by thymidylate synthase of each 5-fluoro-dUMP and N4-hydroxy-dCMP was shown to be accompanied by the enzyme inactivation, as well as spectrophotometrically confirmed dihydrofolate production, the latter demonstrated to depend on the reaction time, thymidylate synthase activity and temperature of the incubation mixture, further documenting its catalytic character.


Assuntos
Fluordesoxiuridilato/metabolismo , Tetra-Hidrofolatos/metabolismo , Timidilato Sintase/metabolismo , Animais , Desoxicitidina Monofosfato/análogos & derivados , Desoxicitidina Monofosfato/metabolismo , Inibidores Enzimáticos/metabolismo , Ácido Fólico/análogos & derivados , Ácido Fólico/metabolismo , Camundongos , Ligação Proteica , Espectrofotometria Ultravioleta
9.
Stem Cells ; 37(11): 1441-1454, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31381815

RESUMO

In a previous study, we showed that folate receptor-α (FRα) translocates to the nucleus where it acts as a transcription factor and upregulates Hes1, Oct4, Sox2, and Klf4 genes responsible for pluripotency. Here, we show that acetylation and phosphorylation of FRα favor its nuclear translocation in the presence of folate and can cause a phenotypic switch from differentiated glial cells to dedifferentiated cells. shRNA-FRα mediated knockdown of FRα was used to confirm the role of FRα in dedifferentiation. Ocimum sanctum hydrophilic fraction-1 treatment not only blocks the folate mediated dedifferentiation of glial cells but also promotes redifferentiation of dedifferentiated glial cells, possibly by reducing the nuclear translocation of ~38 kDa FRα and subsequent interaction with chromatin assembly factor-1. Stem Cells 2019;37:1441-1454.


Assuntos
Receptor 1 de Folato/metabolismo , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Receptor 1 de Folato/genética , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacologia , Humanos , Técnicas de Transferência Nuclear , Ocimum sanctum/química , Fator 3 de Transcrição de Octâmero/metabolismo , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Acta Crystallogr D Struct Biol ; 75(Pt 7): 682-693, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31282477

RESUMO

Tuberculosis is a disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single infectious pathogen, with a high prevalence in developing countries in Africa and Asia. There still is a need for the development or repurposing of novel therapies to combat this disease owing to the long-term nature of current therapies and because of the number of reported resistant strains. Here, structures of dihydrofolate reductase from M. tuberculosis (MtDHFR), which is a key target of the folate pathway, are reported in complex with four antifolates, pyrimethamine, cycloguanil, diaverdine and pemetrexed, and its substrate dihydrofolate in order to understand their binding modes. The structures of all of these complexes were obtained in the closed-conformation state of the enzyme and a fine structural analysis indicated motion in key regions of the substrate-binding site and different binding modes of the ligands. In addition, the affinities, through Kd measurement, of diaverdine and methotrexate have been determined; MtDHFR has a lower affinity (highest Kd) for diaverdine than pyrimethamine and trimethoprim, and a very high affinity for methotrexate, as expected. The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates.


Assuntos
Antagonistas do Ácido Fólico/química , Ácido Fólico/análogos & derivados , Mycobacterium tuberculosis/enzimologia , Tetra-Hidrofolato Desidrogenase/química , Sítios de Ligação , Cristalização/métodos , Cristalografia por Raios X/métodos , Escherichia coli/genética , Ácido Fólico/química , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Tuberculose/microbiologia
11.
Nanomedicine (Lond) ; 14(15): 2011-2025, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31355696

RESUMO

Aim: Constructing a new drug-delivery system using carboxylated graphene quantum dots (cGQDs) for tumor chemotherapy in vivo. Materials & methods: A drug-delivery system was synthesized through a crosslink reaction of cGQDs, NH2-poly(ethylene glycol)-NH2 and folic acid. Results: A drug delivery system of folic acid-poly(ethylene glycol)-cGQDs was successfully constructed with ideal entrapment efficiency (97.5%) and drug-loading capacity (40.1%). Cell image indicated that the nanosystem entered into human cervical cancer cells mainly through macropinocytosis-dependent pathway. In vivo experiments showed the outstanding antitumor ability and low systemic toxicity of this nanodrug-delivery system. Conclusion: The newly developed drug-delivery system provides an important alternative for tumor therapy without causing systemic adverse effects.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Grafite/química , Mitoxantrona/administração & dosagem , Pontos Quânticos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Ácido Fólico/análogos & derivados , Células HeLa , Humanos , Camundongos Nus , Mitoxantrona/farmacocinética , Mitoxantrona/uso terapêutico , Neoplasias do Colo do Útero/patologia
12.
Int J Nanomedicine ; 14: 4309-4317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354262

RESUMO

Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded. Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker. Methods: JF1 was then loaded into the folate-PEG modified CaCO3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging. Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled "turn-on" property enables precise and fast indication of tumor in vitro and in vivo. Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment.


Assuntos
Carbonato de Cálcio/química , Catepsina B/metabolismo , Diagnóstico por Imagem , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Animais , Corantes Fluorescentes/química , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/patologia , Especificidade de Órgãos , Polietilenoglicóis/química
13.
Mol Pharm ; 16(9): 3985-3995, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31356752

RESUMO

Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection. Data show that EC2220 produces a far greater IHC signal in FRα-positive tissues over that produced with EC17, a folate-fluorescein SMRC that is released from the formaldehyde-denatured FRα protein. Furthermore, the extent of the EC2220 IHC signal was proportional to the level of FRα expression. This EC2220-based assay was qualified both in vitro and in vivo using normal tissue, cancer tissue, and polycystic kidneys. Overall, EC2220 is a sensitive and effective reagent for evaluating functional and accessible receptor expression in vitro and in vivo.


Assuntos
Receptor 1 de Folato/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Doenças Renais Policísticas/tratamento farmacológico , Células A549 , Animais , Doxiciclina/farmacologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/metabolismo , Receptor 1 de Folato/análise , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Ácido Fólico/metabolismo , Células HeLa , Humanos , Lisina/análogos & derivados , Lisina/química , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Neoplasias/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Doenças Renais Policísticas/induzido quimicamente , Doenças Renais Policísticas/metabolismo , Proteína Quinase C/genética , Distribuição Tecidual , Compostos de Tritil/química , Compostos de Tritil/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Artigo em Inglês | MEDLINE | ID: mdl-31103944

RESUMO

Folates are important micronutrients in lentils (Lens culinaris Medik.). In this work, the folate extraction workflow in ascorbate-containing buffer was optimized and validated, and the concentrations of eight folate monoglutamates in cultivated and six wild lentil species, grown under field or greenhouse conditions, were quantified by ultra-performance liquid chromatography and mass spectrometry (UPLC-MS). In general wild lentil species had higher folate concentrations than cultivated genotypes. Lens tomentosus had the highest folate concentration with median values of 439.7 and 360.9 µg/100 g in the field and greenhouse, followed by Lens orientalis with 416.6 and 327.6 µg/100 g, respectively. A significant effect (P < 0.05) of growing conditions was observed in four out of six wild lentil species, with seeds from the field having higher folate concentration (6% to 45%) compared with the greenhouse. MeFox, an oxidation product of 5-methyltetrahydrofolate, was present in all lentil species at concentrations 2.2 to 5.6 times higher than the total folates.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ácido Fólico/análogos & derivados , Ácido Fólico/análise , Glutamatos/isolamento & purificação , Lens (Planta)/química , Espectrometria de Massas/métodos , Ácido Fólico/química , Ácido Fólico/isolamento & purificação , Glutamatos/química , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Sementes/química
15.
Muscle Nerve ; 60(2): 124-136, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31074875

RESUMO

Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut-immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture, and mindfulness-based practices in the treatment of neuropathic pain is encouraging. This article reviews the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain. Muscle Nerve 60: 124-136, 2019.


Assuntos
Dietoterapia , Suplementos Nutricionais , Terapia por Exercício , Estilo de Vida , Neuralgia/terapia , Doenças do Sistema Nervoso Periférico/terapia , Complexo Vitamínico B/uso terapêutico , Acetilcarnitina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Dieta , Disbiose/metabolismo , Exercício Físico , Ácidos Graxos Ômega-3/uso terapêutico , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Microbioma Gastrointestinal , Humanos , Medicina Integrativa , Síndrome Metabólica/metabolismo , Neuralgia/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Fosfato de Piridoxal/uso terapêutico , Ácido Tióctico/uso terapêutico , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/metabolismo , Deficiência de Vitaminas do Complexo B , Vitamina D/uso terapêutico
16.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052315

RESUMO

(1) Background: The folate receptor (FR) is a target for cancer treatment and detection. Expression of the FR is restricted in normal cells but overexpressed in many types of tumors. Folate was conjugated with peptides for enhancing binding affinity to the FR. (2) Materials and Methods: For conjugation, folate was coupled with propargyl or dibenzocyclooctyne, and 4-azidophenylalanine was introduced in peptides for "click" reactions. We measured binding kinetics including the rate constants of association (ka) and dissociation (kd) of folate-peptide conjugates with purified FR by biolayer interferometry. After optimization of the conditions for the click reaction, we successfully conjugated folate with designed peptides. (3) Results: The binding affinity, indicated by the equilibrium dissociation constant (KD), of folate toward the FR was enhanced by peptide conjugation. The enhanced FR binding affinity by peptide conjugation is a result of an increase in the number of interaction sites. (4) Conclusion: Such peptide-ligand conjugates will be important in the design of ligands with higher affinity. These high affinity ligands can be useful for targeted drug delivery system.


Assuntos
Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/análogos & derivados , Alcinos/química , Azidas/química , Química Click/métodos , Ciclo-Octanos/química , Receptores de Folato com Âncoras de GPI/química , Ácido Fólico/metabolismo , Simulação de Acoplamento Molecular , Peptídeos/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Propanóis/química , Ligação Proteica
17.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052347

RESUMO

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO's therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers.


Assuntos
Antineoplásicos/toxicidade , Trióxido de Arsênio/toxicidade , Ácido Fólico/análogos & derivados , Lipossomos/química , Neoplasias do Colo do Útero/metabolismo , Apoptose/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Papillomaviridae , Polietilenoglicóis/química , Neoplasias do Colo do Útero/virologia
18.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052503

RESUMO

Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration.


Assuntos
Materiais Biocompatíveis/uso terapêutico , Fenda Labial/terapia , Fissura Palatina/terapia , Medicina Regenerativa/métodos , Animais , Fenda Labial/epidemiologia , Fenda Labial/patologia , Fenda Labial/fisiopatologia , Fissura Palatina/epidemiologia , Fissura Palatina/patologia , Fissura Palatina/fisiopatologia , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Osteogênese/efeitos dos fármacos , Transplante de Células-Tronco/métodos , Engenharia Tecidual/métodos
19.
Org Biomol Chem ; 17(27): 6585-6594, 2019 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-31032834

RESUMO

Despite the advantages of photodynamic therapy (PDT) over chemotherapy or radiotherapy such as low side effects, lack of treatment resistance and spatial selectivity inherent to light activation of the drug, several limitations especially related to the photosensitiser (PS) prevent PDT from becoming widespread in oncology. Herein, new folic acid- and biotin-conjugated PSs for tumour-targeting PDT are reported, with promising properties related to PDT such as intense absorption following one-photon excitation in the red or two-photon excitation in the near-infrared, and also high singlet oxygen quantum yield (close to 70% in DMSO). Cellular studies demonstrated that both targeted PSs induced phototoxicity, the folate-targeted PS being the most effective one with 80% of cell death following 30 min of irradiation and a phototoxicity four times higher than that of the non-targeted PS. This result is in accordance with the uptake of the folate-targeted PS in HeLa cells, mediated by the folate receptors. Moreover, this folate-targeted PS was also phototoxic following two-photon excitation at 920 nm, opening new perspectives for highly selective PDT treatment of small and deep tumours.


Assuntos
Biotina/análogos & derivados , Ácido Fólico/análogos & derivados , Neoplasias/tratamento farmacológico , Porfirinas/química , Morte Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ácido Fólico/farmacologia , Células HeLa , Humanos , Fotoquimioterapia , Fótons , Fármacos Fotossensibilizantes , Porfirinas/farmacologia
20.
Mater Sci Eng C Mater Biol Appl ; 101: 464-471, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029341

RESUMO

Curcumin shows a potential anticancer activity, as it is involved in signaling pathway suppressing ß-catenin response transcription. In this study, the effects of curcumin released from the biocompatible and biodegradable polyaspartamide based micelles on colon cancer treatment via the Wnt/ß-catenin signaling pathway are investigated. Hydrophobic octadecylamine (C18) and hydrophilic O-(2-aminoethyl) polyethylene glycol (PEG) were grafted on a polysuccinimide (PSI) backbone for micelle formation. Folic acid (FA) was employed to facilitate the targeting activity to colon cancer cells and curcumin was conjugated via acid cleavable linkage, hydrazone (Hyd) to provide the pH sensitive drug release. Two types of micellar structures, Folate-PEG/Hyd-Curcumin/C18-g-PSI (FA-Cur) and PEG/Hyd-Curcumin/C18-g-PSI (NFA-Cur), were synthesized and their chemical structure was identified by 1H NMR spectroscopy. The cytotoxicity carried out by MTT assay informed that the cell viability of FA-Cur treated SW480 was much lower than that of NFA-Cur treated one at the concentration > 0.25 µg mL-1. Western blot assay showed that FA-Cur inhibited the target genes, cyclin D1 and c-myc, more strongly than NFA-Cur at the concentration > 0.5 µg mL-1. From these results, FA-Cur micelles are expected to be a promising candidate for colon anti-cancer via inhibiting Wnt/ß-catenin pathway.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias do Colo/metabolismo , Curcumina/química , Curcumina/farmacologia , Ácido Fólico/análogos & derivados , Micelas , Polietilenoglicóis/química , Via de Sinalização Wnt/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácido Fólico/química , Humanos
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