RESUMEN
SCOPE: Tocomonoenols (T1) are little-known vitamin E derivatives naturally occurring in foods. Limited knowledge exists regarding the cellular uptake and metabolism of α-tocomonoenol (αT1) and none about that of γ-tocomonoenol (γT1). METHODS AND RESULTS: The study investigates the cytotoxicity, uptake, and metabolism of αT1 and γT1 in HepG2 cells compared to the α- and γ-tocopherols (T) and -tocotrienols (T3). None of the studied tocochromanols are cytotoxic up to 100 µmol L-1. The uptake of the γ-congeners is significantly higher than that of the corresponding α-forms, whereas no significant differences are observed based on the degree of saturation of the sidechain. Carboxymethylbutyl-hydroxychromans (CMBHC) are the predominant short-chain metabolites of all tocochromanols and conversion is higher for γT1 than αT1 as well as for the γ-congeners of T and T3. The rate of metabolism increases with the number of double bonds in the sidechain. The rate of metabolic conversion of the T1 is more similar to tocopherols than to that of the tocotrienols. CONCLUSION: This is the first evidence that both αT1 and γT1 follow the same sidechain degradation pathway and exert similar rates of metabolism than tocopherols. Therefore, investigation into the biological activities of tocomonoenols is warranted.
Asunto(s)
Cromanos , Vitamina E , Humanos , Células Hep G2 , Cromanos/farmacología , Vitamina E/farmacología , Vitamina E/análogos & derivados , Vitamina E/metabolismo , Vitamina E/farmacocinética , gamma-Tocoferol/metabolismo , gamma-Tocoferol/farmacología , Tocotrienoles/farmacología , Tocotrienoles/metabolismo , Tocotrienoles/farmacocinética , Supervivencia Celular/efectos de los fármacos , alfa-Tocoferol/farmacología , alfa-Tocoferol/metabolismo , alfa-Tocoferol/análogos & derivadosRESUMEN
Anti-rheumatoid arthritis (RA) effects of α-tocopherol (α-T) have been shown in human patients in a double-blind trial. However, the effects of α-T and its derivatives on fibroblast-like synoviocytes (FLS) during the pathogenesis of RA remain unclear. In the present study, we compared the expression levels of genes related to RA progression in FLS treated with α-T, succinic ester of α-T (TS), and phosphate ester of α-T (TP), as determined via RT-PCR. The mRNA levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP)-3, and MMP-13 were reduced by treatment with TP without cytotoxicity, while α-T and TS did not show such effects. Furthermore, intraperitoneal injection of TP ameliorated the edema of the foot and joint and improved the arthritis score in laminarin-induced RA model mice. Therefore, TP exerted anti-RA effects through by inhibiting RA-related gene expression.
Asunto(s)
Antirreumáticos/farmacología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , alfa-Tocoferol/análogos & derivados , Animales , Artritis Reumatoide/inducido químicamente , Citocinas/biosíntesis , Glucanos/toxicidad , Humanos , Metaloproteinasa 13 de la Matriz/biosíntesis , Metaloproteinasa 3 de la Matriz/biosíntesis , Ratones , alfa-Tocoferol/farmacologíaRESUMEN
UVA1 radiation (340-400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly enhanced cell survival (88%, Alamar Blue) compared to control, whereas α-T pre-treatment had no effect survival (70%, Alamar Blue). Pre-treatment of cells with 100 µM α-TP or 100 µM α-T before 57 J/cm2 UVA1 also significantly reduced ROS generation over 2 h (24.1% and 23.9% respectively) compared to the control and resulted in α-TP bioconversion into α-T. As α-TP displayed weak antioxidant activity in the cell-free assays thus its photoprotection was assigned to its bioconversion to α-T by cellular phosphatases. Through this mechanism α-TP prevented long-wave UVA1 induced cell death and scavenged UVA1 induced ROS in skin cells when added to the starved cell culture medium before UVA1 exposure by bioconversion into α-T.
Asunto(s)
Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Protectores contra Radiación/farmacología , Rayos Ultravioleta/efectos adversos , alfa-Tocoferol/análogos & derivados , Antioxidantes , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta en la Radiación , Humanos , Especies Reactivas de Oxígeno/metabolismo , alfa-Tocoferol/farmacologíaRESUMEN
BACKGROUND & AIMS: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. METHODS: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis. RESULTS: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH. CONCLUSION: Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.
Asunto(s)
Glucemia/metabolismo , Homeostasis/fisiología , Orina/química , Vitamina E/análogos & derivados , alfa-Tocoferol/análogos & derivados , Anciano , Índice de Masa Corporal , Cromanos/sangre , Cromanos/orina , Estudios Transversales , Femenino , Voluntarios Sanos , Humanos , Resistencia a la Insulina/fisiología , Modelos Lineales , Peroxidación de Lípido , Masculino , Persona de Mediana Edad , Países Bajos , Oxidación-Reducción , Propionatos/sangre , Propionatos/orina , Estudios ProspectivosRESUMEN
Vitamin E (alpha tocopherol, α-T) is an important skin antioxidant, but its penetration into the viable epidermis, where it acts, is very limited. This study investigated if phosphorylating α-tocopherol (α-TP) to form a provitamin, improved its interactions with skin, its passage into the tissue, and thus its ability to protect the skin from ultraviolet radiation (UVR) damage. At pH 7.4, when the α-TPO4-1 microspecies predominated in solution, dynamic light scattering measurements showed that α-TP formed nanoaggregates with a median hydrodynamic diameter of 9 nm (Critical aggregation constant, CAC, - 4.2 mM). At 9.0 when the α-TPO4-2 microspecies predominated there was no aggregation. The passage of α-TP nanoaggregates through regenerated cellulose membranes was significantly slower than the α-TP monomers (at pH 9) suggesting that aggregation slowed diffusion. However, a lotion formulation containing the nanoaggregates delivered more α-TP into the skin compared to the formulation containing the monomers. In addition, the nanosized α-TP aggregates delivered 8-fold more active into the stratum corneum (SC) (252.2 µg/cm2 vs 29.5 µg/cm2) and 4 fold more active into the epidermis (85.1 µg/cm2 vs 19 µg/cm2, respectively, p < 0.05) compared to α-T. Langmuir subphase injection studies at pH 7.4 (surface pressure 10 mN m-1) showed that the α-TP nanoaggregates more readily fused with the SC compared to the monomers and the membrane compression studies demonstrated that α-TP fluidised the SC lipids. Together the fusion with the SC and its fluidisation were proposed as the causes of the better α-TP penetration into the skin, which enhanced potential of α-TP to protect from UVR-induced skin damage compared to α-T.
Asunto(s)
Nanoestructuras , alfa-Tocoferol , Epidermis , Piel , Rayos Ultravioleta , alfa-Tocoferol/análogos & derivadosRESUMEN
Hinokiflavone (HF) is a natural biflavonoid extracted from medicinal plants such as Selaginella tamariscina and Platycladus orientalis. HF plays a crucial role in the treatment of several cancers. However, its poor solubility, instability, and low bioavailability have limited its use. In this study, soluplus/d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS)/dequalinium (DQA) was applied to improve the solubilization efficiency and stability of HF. HF hybrid micelles were prepared via thin-film hydration method. The physicochemical properties of micelles, including particle size, zeta potential, encapsulation efficiency, drug loading, CMC value, and stability were investigated. The in vitro cytotoxicity assay showed that the cytotoxicity of the HF hybrid micelles was higher than that of free HF. In addition, the HF hybrid micelles improved anticancer efficacy and induced mitochondria-mediated apoptosis, which is associated with the high levels of ROS inducing decreased mitochondrial membrane potential, promoting apoptosis of tumor cells. Furthermore, in vivo tumor suppression, smaller tumor volume and increased expression of pro-apoptotic proteins were found in nude mice treated with HF hybrid micelles, suggesting that HF hybrid micelles had stronger tumor suppressive activity compared with free HF. In summary, HF hybrid micelles developed in this study enhanced antitumor effect, which may be a potential drug delivery system for the treatment of lung adenocarcinoma.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Biflavonoides/administración & dosificación , Portadores de Fármacos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Micelas , Mitocondrias/efectos de los fármacos , Células A549 , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Biflavonoides/farmacocinética , Biflavonoides/farmacología , Decualinio/administración & dosificación , Decualinio/química , Decualinio/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Tamaño de la Partícula , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polivinilos/administración & dosificación , Polivinilos/química , Polivinilos/farmacocinética , Solubilidad , Ensayos Antitumor por Modelo de Xenoinjerto , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/química , alfa-Tocoferol/farmacocinéticaRESUMEN
In this study, pH-triggered polymeric micelle comprising α-tocopherol (TOC) and heparin (HEP) was developed and loaded with docetaxel (DTX). The amphiphilic copolymer was synthesized by grafting TOC onto HEP backbone by a pH-cleavable bond. DTX-loaded micelles were characterized in terms of critical micelle concentration (CMC), particle size, zeta potential, entrapment efficiency (EE), pH-responsive behavior, and drug release. In vitro cytotoxicity of the micelles against breast cancer cells was investigated by MTT assay. The cellular uptake of coumarin-loaded micelles was also evaluated. Furthermore, the pharmacokinetics of DTX-loaded micelles was evaluated and compared with that of Taxotere®.HEP-CA-TOC copolymers showed low CMC values and high EE. At pH 7.4, the micelles remained stable in size and shape, whereas considerable changes in particle size and morphology were observed at pH 5.5. DTX-loaded micelles showed pH-dependent drug release profiles. Coumarin-loaded micelles showed higher cellular uptake than free coumarin. Therefore, the DTX-loaded micelles showed more toxicity against breast cancer cells than free DTX. A significant increase in T1/2 ß, AUC0-∞ and MRT was observed in DTX-loaded micelle treated group as compared to the group treated with Taxotere®.The results suggest that the pH-sensitive HEP-modified micelles could be promising for enhanced intracellular drug delivery of DTX for cancer treatment.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Docetaxel/administración & dosificación , Heparina/análogos & derivados , alfa-Tocoferol/análogos & derivados , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Docetaxel/farmacocinética , Docetaxel/farmacología , Liberación de Fármacos , Femenino , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , MicelasRESUMEN
Distal metastases of tumors result from the interaction between "seeds" (circulating tumor cells, CTCs) and "soil" (premetastatic niche, PMN). Various strategies focus on CTC inhibition, but only a few strategies inhibit PMN formation. The main predisposition of PMN formation in melanoma lies in the pulmonary recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11b+Ly6G+ cells) induced by tumors, which increase vascular permeability by secreting matrix metalloproteinase-9 (MMP-9) and result in immunosuppression by secreting interleukin-10 (IL-10) in premetastatic lungs. Here, a micellar hypotoxic low molecular weight heparin-tocopherol succinate nanoparticle (LMWH-TOS nanoparticle, LT NP) was established and investigated for its influence on PMN formation in this study. We first demonstrated that the hydrophilic segment LMWH in LT NPs can inhibit early pulmonary recruitment of G-MDSCs through interrupting their extravasation by inhibiting P-selectin/PSGL-1-mediated adhesion between vascular endothelial cells and G-MDSCs. In addition, the hydrophobic segment (TOS) in LT NPs significantly inhibited the expression of MMP-9 in G-MDSCs. As a result, the drug-free nanoparticles could maintain the normal microenvironment of lungs, thus effectively inhibiting implantation and colonization of CTCs. Further, phenylboronic acid (PBA)-modified and doxorubicin/immunopotentiator α-galactosylceramide (αGC)-coloaded nanoparticles (PLT/DOX/αGC NPs) were exploited. PBA modification achieved targeted chemotherapy by binding to overexpressed sialic acid residues on the tumor cell surface. This nanosystem effectively inhibited the postoperative metastasis and tumor recurrence simultaneously. Our work provides a proof of concept that the prevention of PMN formation through interfering G-MDSCs with self-delivery nanosystems is a safe and effective antimetastasis strategy.
Asunto(s)
Células Endoteliales/efectos de los fármacos , Neoplasias Pulmonares/prevención & control , Melanoma Experimental/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Nanopartículas/uso terapéutico , Células Neoplásicas Circulantes/efectos de los fármacos , Animales , Células Endoteliales/patología , Heparina de Bajo-Peso-Molecular/uso terapéutico , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Ratones , Micelas , Células Supresoras de Origen Mieloide/patología , Nanomedicina , Células Neoplásicas Circulantes/patología , Microambiente Tumoral/efectos de los fármacos , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/uso terapéuticoRESUMEN
When α-tocopherol (α-Toc) exerts its antioxidative effect, a portion of α-Toc is converted to certain oxidation products. Although accumulation of such oxidation products is considered to cause a deterioration in the quality of foods, their distribution and generation in food samples have been still unknown. In this study, we tried to analyze α-Toc hydroperoxide (Toc-OOH) stereoisomers and tocopherylquinone (TQ) in extra virgin olive oil (EVOO) using liquid chromatography-tandem mass spectrometry. Photo-irradiation (5000â¯lx) to EVOO increased Toc-OOH stereoisomers but not TQ. In contrast, thermal oxidation (150⯰C) of EVOO increased TQ but not Toc-OOH. We considered that the generation of Toc-OOH and TQ were due to the [4+2]-cycloaddition reaction and proton donation from the phenolic hydrogen, respectively. Our data and method would be helpful for understanding of α-Toc oxidation mechanisms in edible oil samples or the estimation of food quality.
Asunto(s)
Aceite de Oliva/química , Vitamina E/análogos & derivados , alfa-Tocoferol/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Oxidación-Reducción , Espectrometría de Masas en Tándem , Vitamina E/análisis , Vitamina E/química , alfa-Tocoferol/análisis , alfa-Tocoferol/químicaAsunto(s)
Acné Vulgar/complicaciones , Cicatriz/tratamiento farmacológico , Cosmecéuticos/administración & dosificación , Eritema/tratamiento farmacológico , Hiperpigmentación/tratamiento farmacológico , Acné Vulgar/tratamiento farmacológico , Adulto , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/efectos adversos , Ácido Ascórbico/análogos & derivados , Cicatriz/etiología , Cosmecéuticos/efectos adversos , Combinación de Medicamentos , Eritema/etiología , Femenino , Éteres de Glicerilo/administración & dosificación , Éteres de Glicerilo/efectos adversos , Humanos , Hiperpigmentación/etiología , Masculino , Crema para la Piel/administración & dosificación , Crema para la Piel/efectos adversos , Resultado del Tratamiento , Adulto Joven , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/efectos adversos , alfa-Tocoferol/análogos & derivadosRESUMEN
The phosphorylation of (+) alpha tocopherol produces adhesive nanostructures that interact with oral biofilms to restrict their growth. The aim of this work was to understand if these adhesive (+) alpha tocopheryl phosphate (α-TP) nanostructures could also control macrophage responses to the presence of oral bacteria. The (+) α-TP planar bilayer fragments (175â¯nm⯱â¯21â¯nm) formed in a Trizma®/ethanol vehicle swelled when exposed to the cell lines (maximum stabilized sizeâ¯=â¯29⯵m). The swelled (+) α-TP aggregates showed selective toxicity towards THP-1 macrophages (LD50â¯=â¯304⯵M) compared to human gingival fibroblasts (HGF-1 cells; LD50â¯>â¯5â¯mM), and they inhibited heat killed bacteria stimulated MCP-1 production in both macrophages (control 57.3⯱â¯18.1â¯pg/mL vs (+) α-TP 6.5⯱â¯3.2â¯pg/mL) and HGF-1 cells (control 673.5⯱â¯133â¯pg/mL vs (+) α-TP - 463.9⯱â¯68.9â¯pg/mL).
Asunto(s)
Macrófagos/efectos de los fármacos , Boca/efectos de los fármacos , Nanoestructuras/administración & dosificación , alfa-Tocoferol/análogos & derivados , Biopelículas/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular , Quimiocina CCL2/genética , Encía/efectos de los fármacos , Encía/crecimiento & desarrollo , Encía/microbiología , Encía/patología , Factor de Crecimiento de Hepatocito/genética , Humanos , Macrófagos/metabolismo , Macrófagos/microbiología , Monocitos/efectos de los fármacos , Monocitos/microbiología , Boca/crecimiento & desarrollo , Boca/microbiología , Boca/patología , Nanoestructuras/química , Fosforilación/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , alfa-Tocoferol/química , alfa-Tocoferol/farmacologíaRESUMEN
Currently, there are limited treatment options for multi-drug resistant breast cancer. Lipid-modified cationic peptides have the potential to reach the mitochondria, which are attractive targets for the treatment of multi-drug resistant (MDR) breast cancer; yet, little is known about their mitochondrial targeting and anti-cancer activity. Interestingly, lipid-modified cationic peptides, typically used as gene transfection agents, exhibit similar structural features to mitochondrial targeted peptides. Using octahistidine-octaarginine (H8R8) as a model cationic peptide for cell penetration and endosomal escape, we explored the anti-cancer potential of lipid-modified cationic peptides as a function of amphiphilicity, biodegradability and lipid structure. We found that cationic peptides modified with a lipid that is at least 12 carbons in length exhibit potent anti-cancer activity in the low micromolar range in both EMT6/P and EMT6/AR-1 breast cancer cells. Comparing degradable and non-degradable linkers, as well as L- and D-amino acid sequences, we found that the anti-cancer activity is mostly independent of the biodegradation of the lipid-modified cationic peptides. Two candidates, stearyl-H8R8 (Str-H8R8) and vitamin E succinate-H8R8 (VES-H8R8) were cytotoxic to cancer cells by mitochondria depolarization. We observed increased reactive oxygen species (ROS) production, reduced cell bioenergetics and drug efflux, triggering apoptosis and G1 cell cycle arrest. Compared to Str-H8R8, VES-H8R8 showed enhanced cancer cell selectivity and drug efflux inhibition, thereby serving as a potential novel therapeutic agent. This study deepens our understanding of lipid-modified cationic peptides and uncovers their potential in multi-drug resistant breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Lípidos/farmacología , Mitocondrias/efectos de los fármacos , Oligopéptidos/farmacología , Tensoactivos/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Lípidos/química , Mitocondrias/patología , Oligopéptidos/química , Tensoactivos/química , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/farmacologíaRESUMEN
Polyoxyethanyl-α-tocopheryl sebacate (PTS) is an amphiphilic compound with self-emulsifying properties known to form micelles. In this work, we report the production of PTS micelles for the encapsulation and delivery of a hydrophobic derivative of methotrexate, MTX di-ethylated (MTX-OEt). We optimized the micelles production by testing two different techniques: auxiliary solvent and sonication. Small and homogeneous micelles (≈40â¯nm) were obtained through the auxiliary solvent method performed at 30⯰C and using 15â¯mg/mL of PTS. The produced micelles with the most promising physicochemical properties did not induce cytotoxicity when tested in normal human cells (BJ5ta cells), being considered for the encapsulation of MTX-OEt. This prodrug was achieved by Fisher esterification using ethanol, being isolated in good yield (ηâ¯=â¯68%). MTX-OEt was efficiently encapsulated onto the produced micelles which preserved their physicochemical properties. The PTS micelles loaded with MTX-OEt, free MTX-OEt and free unmodified MTX revealed similar biological effect against cancer cells (Caco-2 cells). These results demonstrated that the biological activity of MTX is not altered after modification. The developed PTS micelles revealed a promising intracellular delivery performance with potentiality for cancer therapy.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Metotrexato/administración & dosificación , Micelas , alfa-Tocoferol/análogos & derivados , Línea Celular , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Metotrexato/química , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/químicaRESUMEN
To increase the efficacy of small molecule chemotherapeutic drug (SMCD) and reduce its toxic and side effects, we selected two model drugs doxorubicin (DOX) and chloroquine (CQ). DOX is a SMCD and CQis a chemosensitizer with autophagy inhibition. Poly(lactic-co-glycolic acid) (PLGA) and alpha-tocopherol polyethylene glycol 1000 succinate were chosen as delivery carriers to design and prepare a novel type of drug co-delivery single-nanoparticles by emulsification-solvent volatilisation, named NPDOX+CQ. The physicochemical properties of NPDOX+CQ were characterised. Then A549 cells and A549/Taxol cells were used for the in vitro anti-cancer effect study. At the same time, cellular uptake, intracellular migration and anti-cancer mechanism of nanoparticles were studied. The NPs showed a uniform spherical shape with good dispersibility, and both drugs had good encapsulation efficiency and loading capacity. In all formulations, NPDOX+CQ showed the highest in vitro cytotoxicity. The results showed that NPs could protect drugs from being recognised and excluded by P-glycoprotein (P-gp). Moreover, the results of the mechanistic study demonstrated that NPs were transported by autophagy process after being taken up by the cells. Therefore, during the migration of NPDOX+CQ, CQ could exert its efficacy and block autophagy so that DOX would not be hit by autophagy. Western Blot results showed that NPDOX+CQ had the best inhibition effect of autophagy. It can be concluded that the system can prevent the drug from being recognised and excluded by P-gp, and CQ blocks the process of autophagy so that the DOX is protected and more distributed to the nucleus of multidrug resistance (MDR) cell. The NPDOX+CQ constructed in this study provides a feasible strategy for reversing MDR in tumour cells.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Cloroquina/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Cloroquina/farmacocinética , Cloroquina/farmacología , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Nanopartículas/química , Neoplasias/metabolismo , Polietilenglicoles/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , alfa-Tocoferol/análogos & derivadosRESUMEN
BACKGROUND AND PURPOSE: Atherosclerosis is characterized by chronic low-grade inflammation with concomitant lipid accumulation in the arterial wall. Anti-inflammatory and anti-atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated-unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid-associated antioxidant α-tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α-tocopherol, we designed and synthesized a novel nitroalkene-α-tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites. EXPERIMENTAL APPROACH: We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro-inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model. KEY RESULTS: NATOH exhibited similar antioxidant capacity to α-tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down-regulated NF-κB-dependent expression of pro-inflammatory markers (including IL-1ß and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice. CONCLUSIONS AND IMPLICATIONS: In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non-conventional anti-inflammatory compound (NATOH) with significant potential for clinical application.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Aterosclerosis/tratamiento farmacológico , Ciclopentanos/farmacología , Inflamación/tratamiento farmacológico , Nitrocompuestos/farmacología , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antioxidantes/síntesis química , Antioxidantes/química , Aterosclerosis/metabolismo , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Femenino , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Estructura Molecular , Células RAW 264.7RESUMEN
The extracellular polymer substances (EPS) generated by biofilms confers resistance to antimicrobial agents through electrostatic and steric interactions that hinder molecular diffusion. This resistance mechanism is particularly evident for antibacterial nanomaterials, which inherently diffuse more slowly compared to small organic antibacterial agents. The aim of this study was to determine if a biofilm's resistance to antibacterial nanomaterial diffusion could be diminished using electrolytes to screen the EPS's electrostatic interactions. Anionic (+) alpha-tocopherol phosphate (α-TP) liposomes were used as the antimicrobial nanomaterials in the study. They self-assembled into 700 nm sized structures with a zeta potential of -20 mV that were capable of killing oral bacteria (S. oralis growth inhibition time of 3.34 ± 0.52 h). In a phosphate (-ve) buffer the -ve α-TP liposomes did not penetrate multispecies oral biofilms, but in a Tris (hydroxymethyl)aminomethane (+ve) buffer they did (depth - 12.4 ± 3.6 µm). The Tris did not modify the surface charge of the α-TP nanomaterials, rather it facilitated the α-TP-biofilm interactions through electrolyte screening (Langmuir modelled surface pressure increase of 2.7 ± 1.8 mN/ m). This data indicated that EPS resistance was mediated through charge repulsion and that this effect could be diminished through the co-administration of cationic electrolytes.
Asunto(s)
Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Electrólitos/química , Nanoestructuras/química , Streptococcus oralis/efectos de los fármacos , alfa-Tocoferol/análogos & derivados , Antibacterianos/química , Biopelículas/crecimiento & desarrollo , Tampones (Química) , Farmacorresistencia Bacteriana/efectos de los fármacos , Matriz Extracelular de Sustancias Poliméricas/química , Liposomas/química , Tamaño de la Partícula , Permeabilidad , Electricidad Estática , Streptococcus oralis/química , Streptococcus oralis/crecimiento & desarrollo , alfa-Tocoferol/química , alfa-Tocoferol/farmacologíaRESUMEN
BACKGROUND: The economic burden of cosmetics, such as moisturizers, has been increasing. Despite the high price of some market moisturizers, there have been no studies evaluating the allergenicity of these products. OBJECTIVE: The aim of this study was to evaluate the potential allergens within moisturizers based on economic value, by analyzing the substances found in moisturizers available online at the largest drugstore chain-CVS Health (CVS Health, Woonsocket, RI). METHODS: In this cross-sectional study, ingredients found in 50 expensive and 50 inexpensive moisturizers were matched with sensitizers within the Core Allergen Series published by the American Contact Dermatitis Society and the North American Contact Dermatitis Group. Student t test was used to compare the mean number of allergens present in each group. A χ test or Fisher exact test, where necessary, was used to compare the rates of specific allergen groups between the expensive and inexpensive products. RESULTS: Twenty-six allergenic substances were present overall in the 100 total products surveyed. The expensive moisturizers averaged significantly more allergens per product (8.28 vs 5.60, P = 0.003) than the inexpensive products. CONCLUSIONS: The sensitizing potential of expensive moisturizers may be higher than that of inexpensive moisturizers. Physicians may counsel cosmetic-induced allergic contact dermatitis (ACD) patients that monetary value is not a suitable proxy for evaluating the risk of ACD.
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Alérgenos/análisis , Crema para la Piel/química , Crema para la Piel/economía , Acrilatos/análisis , Alérgenos/efectos adversos , Comercio , Estudios Transversales , Dermatitis Alérgica por Contacto/etiología , Emolientes/análisis , Emulsionantes/análisis , Humanos , Perfumes/análisis , Farmacias , Extractos Vegetales/análisis , Conservadores Farmacéuticos/análisis , Crema para la Piel/efectos adversos , alfa-Tocoferol/análogos & derivados , alfa-Tocoferol/análisisRESUMEN
Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.
Asunto(s)
Apoptosis/efectos de los fármacos , Araquidonato 15-Lipooxigenasa/metabolismo , Hierro/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Vitaminas/farmacología , alfa-Tocoferol/análogos & derivados , Animales , Línea Celular , Citoprotección/efectos de los fármacos , Ratones , alfa-Tocoferol/farmacologíaRESUMEN
A polymer of Galactosamine-hyaluronic acid-Vitamin E succinate (Gal-HA-VES) was designed to prepare multifunctional self-assembled micelles for delivery of Norcantharidin (NCTD) to Hepatic carcinoma. NCTD/Gal-HA-VES showed higher cytotoxicity toward CD44-overexpressing MCF-7 cells, MCF-7/Adr cells and ASGP-R overexpressing HepG2 cells, consistent with the enhanced cellular uptake in the selected cell models, indicating Gal-HA-VES micelles were taken up in MCF-7 and HepG2 cells by CD44 and ASGPR receptor mediated endocytosis, respectively. Moreover, the accumulation of Rhodamine 123 demonstrated that Gal-HA-VES has the same action of TPGS as a P-glycoprotein inhibitor blocked drug efflux-related MDR mechanism in resistant MCF-7/Adr cells. The Cell apoptosis assays indicated that NCTD/Gal-HA-VES were more effective in triggering apoptosis, compared with free NCTD or NCTD/HA-VES groups. In vivo study demonstrated that NCTD/Gal-HA-VES group exhibited enhanced tumor targeting and antitumor activity with lower systemic toxicity. Hence NCTD/Gal-HA-VES micelles system can achieve significant tumor targeting and effective treatment of hepatic carcinoma.