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1.
Int J Nanomedicine ; 14: 6917-6932, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695366

RESUMO

Aim: To determine whether the use of a mixed polymeric micelle delivery system based on vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/VES-grafted-chitosan (CS) mixed micelles (VES-g-CSO/VES-g-CS MM) enhances the delivery of C-DMSA, a theranostic fluorescent probe, for Hg2+ detection and detoxification in vitro and in vivo. Methods: Mixed micelles self-assembled from two polymers, VES-g-CSO and VES-g-CS, were used to load C-DMSA and afforded C-DMSA@VES-g-CSO/VES-g-CS MM for cell and in vivo applications. Fluorescence microscopy was used to assess C-DMSA cellular uptake and Hg2+ detection in L929 cells. C-DMSA@VES-g-CSO/VES-g-CS MM was then administered intravenously. Hg2+ detection was assessed by fluorescence microscopy in terms of bio-distribution while detoxification efficacy in Hg2+-poisoned rat models was evaluated in terms of mercury contents in blood and in liver. Results: The C-DMSA loaded mixed micelles, C-DMSA@VES-g-CSO/VES-g-CS MM, significantly enhanced cellular uptake and detoxification efficacy of C-DMSA in Hg2+ pretreated human L929 cells. Evidence from the reduction of liver coefficient, mercury contents in liver and blood, alanine transaminase and aspartate transaminase activities in Hg2+ poisoned SD rats treated with the mixed micelles strongly supported that the micelles were effective for Hg2+ detoxification in vivo. Furthermore, ex vivo fluorescence imaging experiments also supported enhanced Hg2+ detection in rat liver. Conclusion: The mixed polymeric micelle delivery system could significantly enhance cell uptake and efficacy of a theranostic probe for Hg2+ detection and detoxification treatment in vitro and in vivo. Moreover, this nanoparticle drug delivery system could achieve targeted detection and detoxification in liver.


Assuntos
Quitosana/química , Fígado/metabolismo , Mercúrio/análise , Micelas , Oligossacarídeos/química , Succímero/química , alfa-Tocoferol/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Morte Celular/efeitos dos fármacos , Linhagem Celular , Quitosana/síntese química , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Inativação Metabólica/efeitos dos fármacos , Masculino , Mercúrio/sangue , Camundongos Endogâmicos BALB C , Nanopartículas/química , Oligossacarídeos/síntese química , Ratos Sprague-Dawley , Succímero/síntese química , alfa-Tocoferol/síntese química , alfa-Tocoferol/química
2.
Int J Nanomedicine ; 14: 6325-6337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496689

RESUMO

Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 µM), 13 (10 µM) and cis-14 (10 µM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fulerenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Fulerenos/química , Células HL-60 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Estresse Oxidativo/efeitos dos fármacos , Quinidina/farmacologia , Carga Tumoral/efeitos dos fármacos , alfa-Tocoferol/farmacologia
3.
Food Chem ; 301: 125297, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31394336

RESUMO

Candida antarctica lipase B-catalysed synthesis of lipophilic esters of polydatin was investigated along with their antioxidant activities. The effects of synthesis parameters such as solvent, substrate molar ratio, enzyme concentration, addition of molecular sieves, reaction temperature and time on the production of ester were studied and optimised. The highest production of esters was obtained with acetone as the reaction solvent. The antioxidant activities of the esters were compared with those of commercial butylated hydroxytoluene (BHT) and α-tocopherol. All polydatin esters inhibited the oxidative destruction of ß-carotene more effectively than did BHT and α-tocopherol. Results of thiobarbituric acid tests showed that in bulk fish oil, all esters were more effective than α-tocopherol at 2 mmol/kg concentration but were not as effective as BHT. In fish oil-emulsions, all esters were more effective than both BHT and α-tocopherol at 2 mmol/kg concentration. The synthesized polydatin esters are promising antioxidants for oil/fat-based foods.


Assuntos
Antioxidantes/química , Emulsões/química , Óleos de Peixe/química , Glucosídeos/química , Estilbenos/química , Antioxidantes/farmacologia , Hidroxitolueno Butilado/farmacologia , Esterificação , Ésteres/química , Ácidos Graxos/química , Ácidos Graxos Ômega-3/química , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Lipase/química , Lipase/metabolismo , Oxirredução , Solventes/química , Temperatura Ambiente , alfa-Tocoferol/farmacologia
4.
J Nutr Sci Vitaminol (Tokyo) ; 65(3): 272-277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257268

RESUMO

The reoccurrence of androgen-dependent prostate cancer after anti-androgen therapy mainly depends on prostate cancer stem-like cells. To reduce the risk, it is important to delete the cancer stem-like cells. Furthermore, to induce differentiation of cancer stem-like cells is critical to abrogate stemness of the cells. Therefore, we tried to investigate a possibility on the establishment of a new effective therapy to eradicate the cancer stem-like cells via the induction of differentiation in this study. Prostate cancer stem-like cells from an androgen-dependent prostate cancer cell line (LNCaP cell) had severe resistance against an anti-androgen therapeutic agent. We selected Bowman-Birk inhibitor (BBI) from soybeans reported as a chemopreventive agent in prostate cancer to differentiate the caner stem-like cells and α-tocopheryl succinate (TOS) known as a mitocan to induce effectively cytotoxic effect against the cancer stem-like cells. In fact, only TOS treatment had cytotoxic effect against the cancer stem-like cells, but the addition of BBI treatment to the cells treated with TOS reinforced TOS-mediated cytotoxicity in the cancer stem-like cells. This reinforcement coincided with the combination-enhanced apoptosis in the stem-like cells. Also, we confirmed caspase9-caspase3 cascade mainly contributed to the enhancement of the cytotoxicity in the stem-like cells caused by the combination, indicating that the reinforcement of BBI on TOS-mediated apoptosis via mitochondria related to the enhancing cytotoxic effect of the combination on the prostate cancer stem-like cells. Overall, it seems that the combination is an effective new approach to reduce the reoccurrence of prostate cancer targeting prostate cancer stem cells.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Inibidor da Tripsina de Soja de Bowman-Birk/farmacologia , alfa-Tocoferol/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino
5.
Int J Med Sci ; 16(4): 494-500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171899

RESUMO

Aim: Sulfasalazine (SSZ) displayed anti-cancer activities. Vitamin E succinate (VES) could inhibit cell growth in various cancer cells. However, chemical therapies were often not useful for triple-negative breast cancer cells (TNBCs) treatment. Here, this study investigated the anti-cancer effects and the mechanisms on TNBCs under combination treatment with SSZ and VES. Methods: Cell viability was analyzed by using the MTT assay. The H2O2 levels were determined by using lucigenin-amplified chemiluminescence method. In addition, caspase and MAPs signals were studied by using western blotting. Results: Low-dose VES antagonized the SSZ-induced cytotoxicity effects while high-dose VES promoted the SSZ-induced cytotoxicity effects on TNBCs. In addition, SSZ alone treatment activated both caspase-3 and ERK signals, however, VES alone treatment only activated JNK signals. On the other hand, activation of caspase-3, JNK, and ERK were found in SSZ plus VES-treated cells. Conclusion: Combined SSZ and VES has synergistic or antagonistic cytotoxic effects depending on VES concentration. In addition, different cytotoxic signals are induced on SSZ-treated, VES-treated and SSZ plus VES-treated cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sulfassalazina/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , alfa-Tocoferol/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peróxido de Hidrogênio/isolamento & purificação , MAP Quinase Quinase 4/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
J Endod ; 45(8): 1053-1059, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155299

RESUMO

It has been reported that bond strength can be reversed to prebleached levels with the application of 10% alpha-tocopherol in a 2-hour time frame or by delaying bonding for 2 weeks. This study evaluated the effectiveness of a 5-minute application of 20% alpha-tocopherol to reverse the deleterious effects of nonvital bleaching on consequent bond strength. Thirty third molars were assigned to the following 3 groups: unbleached, bleached, and bleached followed by treatment with alpha-tocopherol. The bleached groups were exposed to sodium perborate (2 g/mL) for 7 days. The postbleach treatment group was subsequently treated with 20% alpha-tocopherol for 5 minutes, and then all groups were restored with composite resin. After 24 hours of storage at 37°C and 100% humidity, restored tooth specimens were sectioned into 1-mm2 dentin-composite beams. Six beams from each tooth were subjected to microtensile bond strength testing. Representative beams were further evaluated with Raman microspectroscopy and scanning electron microscopy. The mean bond strength values (MPa) for each group were as follows: unbleached control group = 26.2, bleached control group = 20.3, and post-bleach treatment group = 18.5. A 1-factor analysis of variance and Tukey post hoc test (α = 0.05) indicated that bleaching had a detrimental effect on bond strength and that short-term alpha-tocopherol treatments did not improve postbleach bond strength. Raman microspectroscopy and scanning electron microscopy revealed no noted improvement for the post-bleach treatment group.The application of 20% alpha-tocopherol in a clinically relevant time frame was not effective in counteracting the deleterious effect of bleaching on bond strength. Bonding procedures should be delayed after tooth bleaching.


Assuntos
Antioxidantes , Colagem Dentária , Dentina , Clareamento Dental , alfa-Tocoferol , Antioxidantes/farmacologia , Boratos , Resinas Compostas , Dentina/efeitos dos fármacos , Cimentos de Resina , Resistência à Tração , alfa-Tocoferol/farmacologia
7.
Free Radic Res ; 53(5): 535-561, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31039616

RESUMO

Mitochondrial dysfunction and oxidative stress are involved in neurodegenerative diseases associated with an enhancement of lipid peroxidation products such as 7ß-hydroxycholesterol (7ß-OHC). It is, therefore, important to study the ability of 7ß-OHC to trigger mitochondrial defects, oxidative stress, metabolic dysfunctions and cell death, which are hallmarks of neurodegeneration, and to identify cytoprotective molecules. The effects of biotin were evaluated on 158N murine oligodendrocytes, which are myelin synthesizing cells, exposed to 7ß-OHC (50 µM) with or without biotin (10 and 100 nM) or α-tocopherol (positive control of cytoprotection). The effects of biotin on 7ß-OHC activities were determined using different criteria: cell adhesion; plasma membrane integrity; redox status. The impact on mitochondria was characterized by the measurement of transmembrane mitochondrial potential (ΔΨm), reactive oxygen species (ROS) overproduction, mitochondrial mass, quantification of cardiolipins and organic acids. Sterols and fatty acids were also quantified. Cell death (apoptosis, autophagy) was characterized by the enumeration of apoptotic cells, caspase-3 activation, identification of autophagic vesicles, and activation of LC3-I into LC3-II. Biotin attenuates 7ß-OHC-induced cytotoxicity: loss of cell adhesion was reduced; antioxidant activities were normalized. ROS overproduction, protein and lipid oxidation products were decreased. Biotin partially restores mitochondrial functions: attenuation of the loss of ΔΨm; reduced levels of mitochondrial O2•- overproduction; normalization of cardiolipins and organic acid levels. Biotin also normalizes cholesterol and fatty acid synthesis, and prevents apoptosis and autophagy (oxiapoptophagy). Our data support that biotin, which prevents oligodendrocytes damages, could be useful in the treatment of neurodegeneration and demyelination.


Assuntos
Antioxidantes/farmacologia , Biotina/farmacologia , Hidroxicolesteróis/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , alfa-Tocoferol/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Catalase/genética , Catalase/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Ácidos Graxos/biossíntese , Regulação da Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Hidroxicolesteróis/farmacologia , Metabolismo dos Lipídeos/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
8.
Acta Biochim Pol ; 66(2): 223-228, 2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-30980652

RESUMO

A chicken embryo develops in ovo without access to a constant circulating maternal nutrient supply, and therefore all necessary nutrients are initially stored in the yolk, and with progressive development are transferred to the liver, where they are taken up in response to various needs. Fluctuations in hepatic trace elements correlate with their mobilization from egg stores. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) intoxication causes liver damage by production of free radicals, while α-tocopherol is a well-known antioxidant and may play a protective role. In the experiment presented here, a solution containing only TCDD, TCDD and α-tocopherol, as well as α-tocopherol exclusively, was administrated into the yolk sac. The iron, zinc, copper and magnesium distribution was evaluated using histological and chemical methods. It has been found that α-tocopherol has no influence on magnesium and zinc content in the liver. The observed increase in iron content may be caused by antagonistic action of iron and α-tocopherol. On the other hand, synergistic action of α-tocopherol and TCDD has been noted with respect to the copper content.


Assuntos
Fígado/embriologia , Fígado/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Substâncias Protetoras/farmacologia , Teratogênios/toxicidade , Oligoelementos/metabolismo , alfa-Tocoferol/farmacologia , Animais , Embrião de Galinha , Galinhas , Cobre/metabolismo , Feminino , Hepatócitos/patologia , Ferro/metabolismo , Fígado/patologia , Magnésio/metabolismo , Dibenzodioxinas Policloradas/administração & dosagem , Substâncias Protetoras/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Zinco/metabolismo , alfa-Tocoferol/administração & dosagem
9.
Lipids ; 54(5): 289-299, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30990908

RESUMO

Of the antioxidant vitamin E isoforms, α-tocopherol (αT) and γ-tocopherol (γT) are the most abundant in the human diet, and αT is consumed from both natural and synthetic sources. αT and γT may differentially impact inflammation and influence cardiovascular outcomes, in part by modulating gene expression. The goal of this study was to compare the effects of natural αT, synthetic αT, and γT on gene expression in two human cell lines. Human aortic smooth muscle cells (HASMC) and endothelial cells (HAEC) were either: (1) treated with 25 µM tocopherols alone, or (2) pretreated with tocopherols prior to a pro-inflammatory cytokine (tumor necrosis factor-alpha, TNF-α) stimulation. The expression of atherosclerosis-related genes was measured using RT2 Profiler PCR arrays. Tocopherol treatments alone did not significantly modulate the expression of genes in unstimulated HASMC or HAEC. TNF-α stimulation significantly upregulated genes involved with apoptosis and stress response in both cell lines. Pretreating cells with tocopherols did not normalize the gene expression changes induced by TNF-α. However, αT pretreatments, but not γT pretreatments, attenuated TNF expression in both HASMC and HAEC. These findings suggest that under stimulated conditions, αT modestly modulates the expression of selective genes and that αT may be more anti-inflammatory than γT.


Assuntos
Antioxidantes/farmacologia , Aorta/citologia , Aorta/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , alfa-Tocoferol/farmacologia , gama-Tocoferol/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/química , Aterosclerose/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/química , gama-Tocoferol/química
10.
J Biochem Mol Toxicol ; 33(8): e22347, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31022331

RESUMO

Brain damage is a major complication of fulminant hepatic failure. d-Galactosamine (d-GalN)-induced liver toxicity causes damage to brain. The effects of vitamins and selenium mixture against d-GalN stimulated brain injury were investigated in this study. Sprague-Dawley female rats aged 2.0-2.5 months were used for the study. The rats were divided into four categories. A 0.9% NaCl solution was intraperitoneally given to the experimental rats in the first group. Using gavage technique, the second group of animals were subjected to a formulation consisting of 100 mg·kg-1 ·day-1 vitamin C, 15 mg·kg-1 ·day-1 of ß-carotene, 100 mg·kg-1 ·day-1 of α-tocopherol in addition to 0.2 mg·kg-1 ·day-1 of sodium selenate for 3 days. The third group was given a single dose of d-GalN hydrochloride at the concentration of 500 mg·kg-1 through a saline injection. The final group was given similar concentrations of both the antioxidant combination and d-GalN. Tissue samples were collected under ether anesthesia. The rats treated with d-GalN showed brain damage; increased myeloperoxidase, catalase, glutathione peroxidase, glutathione-S-transferase, lactate dehydrogenase, and superoxide dismutase activities; and decreased glutathione levels. Treatment with vitamins and selenium combination resulted in alleviation of these alterations in the rats. These findings suggest that administration of the vitamins and selenium combination suppresses oxidative stress and protects brain cells from injury induced by d-GalN.


Assuntos
Ácido Ascórbico/farmacologia , Encéfalo/efeitos dos fármacos , Galactosamina/administração & dosagem , Selênio/farmacologia , alfa-Tocoferol/farmacologia , beta Caroteno/farmacologia , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Lesões Encefálicas/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Ratos , Ratos Sprague-Dawley
11.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018515

RESUMO

At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the ß-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the ß-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 µM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Curcumina/análogos & derivados , Magnésio/química , Manganês/química , Zinco/química , Animais , Antineoplásicos Fitogênicos/síntese química , Antioxidantes/síntese química , Hidroxitolueno Butilado/farmacologia , Cátions Bivalentes , Linhagem Celular Tumoral , Cisplatino/farmacologia , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Curcumina/química , Células Epiteliais , Humanos , Concentração Inibidora 50 , Ligantes , Peroxidação de Lipídeos/efeitos dos fármacos , Células MCF-7 , Masculino , Camundongos , Modelos Moleculares , Testes de Toxicidade Aguda , alfa-Tocoferol/farmacologia
12.
Mater Sci Eng C Mater Biol Appl ; 101: 438-447, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029339

RESUMO

With an increase in the demand for skin regeneration products, there is a noticeable increase in developing materials that encourage, wound healing and skin regeneration. It has been reported that antioxidants play an important role in anti-inflammatory reactions, cellular proliferation and remodeling phase of wound healing. While consideration all these factors, a novel α-tocopherol acetate (vitamin E) (VE) loaded bi-layered electrospun membrane, based on lower polycaprolactone (PCL) layer and upper polylactic acid (PLA) layer, was fabricated through electrospinning. Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), in-vitro degradation studies, swelling studies and VE release studies were performed to evaluate structural, physical and in-vitro behavior of membranes. Biological properties of membranes were evaluated through cell proliferation assay, cell adhesion studies, live/dead cell assay and CAM assay. SEM images showed that the average diameter of nanofibers ranged from 1 to 6 µm, while addition of VE changed the diameter and morphology of fibers. Bi-layered membranes showed significant swelling behavior through water uptake, membranes loaded with 30% VE showed 8.7% and 6.8% degradation in lysozyme and H2O2 respectively. 20% and 30% VE loaded membranes followed Korsmeyer-Peppas and first order drug release kinetics followed by non-fickian drug release kinetics. Membranes showed non-toxic behavior and supported cell proliferation via alamar blue assay, cell adhesion via SEM, cell viability via live/dead assay and wound healing by scratch assay. CAM assay showed that membranes having VE supported angiogenesis and showed significant formation of blood vessels making it suitable for skin regeneration and wound healing. Results showed that large surface area of nanofibers, porous structure and biocompatible nature are suitable for targeted clinical applications.


Assuntos
Pele/citologia , alfa-Tocoferol/química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Microscopia Eletrônica de Varredura , Poliésteres/química , Espectroscopia de Infravermelho com Transformada de Fourier , Engenharia Tecidual/métodos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos , alfa-Tocoferol/farmacologia
13.
Recent Pat Biotechnol ; 13(2): 137-148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973107

RESUMO

BACKGROUND: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. OBJECTIVE: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. METHOD: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. RESULTS: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. CONCLUSION: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.


Assuntos
Analgésicos Opioides/farmacologia , Antioxidantes/farmacologia , Tolerância a Medicamentos/genética , Genes fos , Morfina/farmacologia , Dor/tratamento farmacológico , alfa-Tocoferol/farmacologia , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Dor/genética , Dor/metabolismo , Dor/fisiopatologia , Patentes como Assunto , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
14.
Clinics (Sao Paulo) ; 74: e688, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30864639

RESUMO

OBJECTIVES: This study aims to compare the differential gene expression resulting from tocotrienol-rich fraction and α-tocopherol supplementation in healthy older adults. METHODS: A total of 71 eligible subjects aged 50 to 55 years from Gombak and Kuala Lumpur, Malaysia, were divided into three groups and supplemented with placebo (n=23), α-tocopherol (n=24) or tocotrienol-rich fraction (n=24). Blood samples were collected at baseline and at 3 and 6 months of supplementation for microarray analysis. RESULTS: The number of genes altered by α-tocopherol was higher after 6 months (1,410) than after 3 months (273) of supplementation. α-Tocopherol altered the expression of more genes in males (952) than in females (731). Similarly, tocotrienol-rich fraction modulated the expression of more genes after 6 months (1,084) than after 3 months (596) and affected more genes in males (899) than in females (781). α-Tocopherol supplementation modulated pathways involving the response to stress and stimuli, the immune response, the response to hypoxia and bacteria, the metabolism of toxins and xenobiotics, mitosis, and synaptic transmission as well as activated the mitogen-activated protein kinase and complement pathways after 6 months. However, tocotrienol-rich fraction supplementation affected pathways such as the signal transduction, apoptosis, nuclear factor kappa B kinase, cascade extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2, immune response, response to drug, cell adhesion, multicellular organismal development and G protein signaling pathways. CONCLUSION: Supplementation with either α-tocopherol or tocotrienol-rich fraction affected the immune and drug response and the cell adhesion and signal transduction pathways but modulated other pathways differently after 6 months of supplementation, with sex-specific responses.


Assuntos
Antioxidantes/farmacologia , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Tocotrienóis/farmacologia , alfa-Tocoferol/farmacologia , Adesão Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Método Simples-Cego , Fatores de Tempo
15.
Ulus Travma Acil Cerrahi Derg ; 25(1): 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30742296

RESUMO

BACKGROUND: Acute pancreatitis is a disease with high morbidity and mortality, despite all the advances in technology. The overall mortality rate of acute pancreatitis is 10%, whereas the mortality rate in infected necrotizing pancreatitis is approximately 35%. In this study, we aimed to establish acute pancreatitis in rats in order to try out the alpha-tocopherol treatment protocol and to reveal the results biochemically and histopathologically. METHODS: Twenty-four male male Sprague-Dawley rats weighing between 300 and 350 g were used in the study. In Group 1, 80 µg/kg of normal saline was subcutaneously injected into eight rats; in Group 2, 80 µg/kg of cerulein was subcutaneously injected into eight rats; and in Group 3, 80 µg/kg of cerulein was subcutaneously injected into eight rats. In addition, 30 mg/kg of alpha-tocopherol was intraperitoneally injected into eight rats. RESULTS: The mean Schoenberg score, serum amylase, and lipase and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels were statistically significantly higher in Group 2 than in Group 1. The mean Schoenberg score and serum amylase and lipase levels were statistically significantly lower in Group 3 than in Group 2. CONCLUSION: In this experimental study rat model of cerulein-induced acute pancreatitis, 30 mg/kg of alpha-tocopherol was injected intraperitoneally to examine its effect on pancreatitis. The improvement was observed in the histopathological examination of pancreatic tissues. We think that alpha-tocopherol may have a therapeutic effect on pancreatic tissue.


Assuntos
Pâncreas/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Substâncias Protetoras , alfa-Tocoferol , Doença Aguda , Animais , Modelos Animais de Doenças , Masculino , Pâncreas/patologia , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos Sprague-Dawley , alfa-Tocoferol/farmacologia , alfa-Tocoferol/uso terapêutico
16.
Molecules ; 24(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781435

RESUMO

This study investigated the effects of α-tocopherol (α-TOH) on the physicochemical properties of sturgeon surimi during 16-week storage at -18 °C. An aliquot of 0.1% (w/w) of α-TOH was added into the surimi and subjected to frozen storage, and 8% of a conventional cryoprotectant (4% sorbitol and 4% sucrose, w/w) was used as a positive control. Based on total viable count, pH and whiteness, α-TOH exhibited a better protection for frozen sturgeon surimi than cryoprotectant during frozen storage. According to soluble protein content, carbonyl content, total sulfhydryl content, and surface hydrophobicity, α-TOH and cryoprotectant showed the same effects on retarding changes of proteins. The results of breaking force, deformation, gel strength, water-holding capacity and microstructure of sturgeon surimi indicated that the gel properties of frozen sturgeon surimi were retained by α-TOH. Our results suggest that α-TOH is an attractive candidate to maintain the quality of sturgeon surimi during frozen storage.


Assuntos
Crioprotetores/farmacologia , Peixes/metabolismo , Congelamento , alfa-Tocoferol/farmacologia , Animais , Produtos Pesqueiros/análise , Produtos Pesqueiros/microbiologia , Conservação de Alimentos/métodos , Armazenamento de Alimentos/métodos , Compostos de Sulfidrila/metabolismo
17.
Biomed Res Int ; 2019: 6146972, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30766885

RESUMO

The combination of doxorubicin and cyclophosphamide commonly used to treat breast cancer can cause premature ovarian failure and infertility. α-Tocopherol is a potent antioxidant whereas γ-tocopherol causes apoptosis in a variety of cancer models in vitro including breast cancer. We hypothesised that the combination of doxorubicin (Dox) and 4-hydroperoxycyclophosphamide (4-Cyc) would be more cytotoxic in vitro than each agent alone, and that α-tocopherol would reduce and γ-tocopherol would augment the cytotoxicity of the combined chemotherapeutics. Human MCF-7 breast cancer and KGN ovarian cells were exposed to Dox, 4-Cyc, combined Dox and 4-Cyc, α-tocopherol, γ-tocopherol, or a combination of Dox and 4-Cyc with α-tocopherol or γ-tocopherol. Cell viability was assessed using a crystal violet assay according to four schedules: 24h exposure, 24h exposure + 24h culture in medium, 24h exposure + 48h culture in medium, or 72h continuous exposure. Supernatants from each separate KGN culture experiment (n=3) were examined using an estradiol ELISA. Dox was cytotoxic to both MCF-7 and KGN cells, but 4-Cyc only killed MCF-7 cells. γ-Tocopherol significantly decreased MCF-7 but not KGN cell viability. The combined chemotherapeutics and γ-tocopherol were more cytotoxic to MCF-7 than KGN cells, and α-tocopherol reduced the cytotoxicity of the combined chemotherapeutics towards KGN ovarian cells, but not MCF-7 cells. The addition of both γ-tocopherol and α-tocopherol to the chemotherapeutic combination of Dox and cyclophosphamide has the potential to increase in vitro chemotherapeutic efficacy against breast cancer cells whilst decreasing cytotoxicity towards ovarian granulosa cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , alfa-Tocoferol/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7
18.
Neurobiol Dis ; 125: 123-134, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30710675

RESUMO

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-ß (Aß) using a cell-based BBB model. Results from HTS identified etodolac and α-tocopherol as promising drugs for further investigation. Both drugs were tested separately and in combination for the purpose of targeting multiple pathways including neuroinflammation and oxidative stress. In vitro studies assessed the effects of etodolac and α-tocopherol individually and collectively for BBB integrity and Aß transport, synaptic markers and Aß production in APP-transfected neuronal cells, as well as effects on inflammation and oxidative stress in astrocytes. Transgenic 5XFAD mice were used to translate in vitro results of etodolac and α-tocopherol independently and with concurrent administration. Compared to either drug alone, the combination significantly enhanced the BBB function, decreased total Aß load correlated with increased expression of major transport proteins, promoted APP processing towards the neuroprotective and non-amyloidogenic pathway, induced synaptic markers expression, and significantly reduced neuroinflammation and oxidative stress both in vitro and in vivo. Collective findings demonstrated the combination produced mixed interaction showing additive, less than additive or synergistic effects on the evaluated markers. In conclusion, this study highlights the significance of combination therapy to simultaneously target multiple disease pathways, and suggest the repurposing and combination of etodolac and α-tocopherol as a novel therapeutic strategy against AD.


Assuntos
Doença de Alzheimer/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Etodolac/farmacologia , alfa-Tocoferol/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos
19.
Int J Pharm ; 560: 334-346, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30797074

RESUMO

Astaxanthin and alpha-tocopherol have various biological potential with induction of intracellular ROS production in cytosol, endoplasmic reticulum and mitochondrial site. The present study was performed to prepare nanoemulsion (NEs) formulation of astaxanthin and alpha-tocopherol with sodium caseinate (AS-AT/SC NEs) using spontaneous emulsification and ultrasonication for analyzing intracellular ROS production in apoptosis. NEs was characterized with standard analysis, which revealed a high stability of normal pH with a small size and unique zeta potential of spherical structure droplets with no toxicity and faster cell migration. It induced ROS production and confirmed using fluorescent stains due to their unique physicochemical and functional properties. Therefore, it played a significant role in the induction of oxidative stress inside the cell as dose-dependent cytotoxicity at different concentrations. AS-AT/SC NEs with protective effect in maintaining intracellular ROS, oxidative stress and mitochondrial membrane potential to reduced apoptosis morphology in cancer cells through mitochondria-mediated apoptosis that inhibits cell death, thus cell survival was initiated at greater extent. Thereby exhibiting a significant remarkable therapeutic effect in cancer field. To best of our knowledge, this is first study concluded that induction of apoptosis potential by AS-AT/SC NEs emerged as a potential way to eradicate cancer cells.


Assuntos
Caseínas/química , Nanopartículas , alfa-Tocoferol/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Relação Dose-Resposta a Droga , Emulsões , Humanos , Concentração de Íons de Hidrogênio , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Xantofilas/administração & dosagem , Xantofilas/farmacologia , alfa-Tocoferol/farmacologia
20.
Adv Clin Exp Med ; 28(7): 973-980, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30684314

RESUMO

BACKGROUND: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause adverse effects in many organs. Toxic effects are caused due to the formation of a TCDD complex with the cytoplasmatic aryl hydrocarbon receptor (AhR), whose mechanism of action is similar to that of the estrogen receptor (ER). Some substances, including α-tocopherol (E) and acetylsalicylic acid (ASA), can reduce the toxic effects of TCDD in offspring. OBJECTIVES: The objective of this study was to evaluate the co-expression of AhR and ER in the incisors of rat offspring whose mothers were exposed to TCDD, using immunohistochemical and histological techniques. Moreover, the possible protective role of E and ASA was investigated. MATERIAL AND METHODS: Four groups of 2-day-old rat offspring, whose mothers were intoxicated by TCDD before mating, were established: control group (C), TCDD group, TCDD+E group and TCDD+ASA group. RESULTS: In the TCDD group, there was an increase in ER expression and a decrease in AhR expression in comparison with the C group. In the TCDD+E and TCDD+ASA groups, there was a weak or negative ER expression and slightly stronger expression of AhR than in the TCDD group. CONCLUSIONS: The co-expression of AhR and ER during tooth development suggests the role of AhR and ER in the control of this process. Both receptors are also involved in the process of detoxification of TCDD. The increase in AhR in TCDD+E and TCDD+ASA groups indicate a preventive action of antioxidant and antiinflammatory pharmaceutics, which may limit negative effects of TCDD.


Assuntos
Aspirina/farmacologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Estrogênicos/metabolismo , Tocoferóis/farmacologia , Anormalidades Dentárias/induzido quimicamente , Dente/crescimento & desenvolvimento , alfa-Tocoferol/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Poluentes Ambientais , Feminino , Humanos , Imuno-Histoquímica , Mães , Ratos
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