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1.
J Food Biochem ; 43(5): e12828, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31353521

RESUMEN

1-O-alkylglycerols (AKG) are a class of natural ether lipids derived from 1-O-alkyl-2,3-diacyl-sn-glycerols by deacylation. In this study, 1-O-alkylglycerol (AKG) composition was investigated in the hepatopancreas lipids of the crab Paralithodes camtschaticus and the liver lipids of the squid Berryteuthis magister and the skate  Bathyraja parmifera. One of the principal AKG in marine organisms was 1-O-hexadecyl-sn-glycerol (AKG 16:0). To assess AKG influence on melanoma, we evaluated the cytotoxicity and antiproliferative actions of natural AKG 16:0 and synthetic 1-O-octyl-sn-glycerol (AKG 8:0) on three human melanoma cell lines SK-Mel-5, SK-Mel-28, and RPMI-7951. Natural AKG 16:0 in concentration up to 20 µM was not toxic to all cell lines. AKG 8:0 showed no toxicity to cells SK-Mel-5 and SK-Mel-28 in concentrations up to 20 µM but had moderate cytotoxicity to RPMI-7951 cells with an IC50 of 13 µM. Both investigated substances inhibited the proliferation, formation, and growth of cell colonies of RPMI-7951. PRACTICAL APPLICATIONS: AKG exhibit a variety of biological activities, including anticancer effects. In this study, the liver lipids of the skate B. parmifera and the hepatopancreas lipids of crab P. camtschaticus were shown to be sources of AKG. Our data showed that AKG can be used to prevent the formation of new colonies of malignant cells in combination therapy against melanoma. The results will be useful for future studies involving marine ether lipids and the examination of their anticancer properties against malignant cells.


Asunto(s)
Anomuros/química , Decapodiformes/química , Éteres de Glicerilo/farmacología , Melanoma/tratamiento farmacológico , Rajidae , Animales , Éteres de Glicerilo/aislamiento & purificación , Hepatopáncreas/química , Humanos , Inmunoglobulina G/aislamiento & purificación , Inmunoglobulina G/farmacología , Hígado/química , Melfalán/aislamiento & purificación , Melfalán/farmacología
2.
Int J Mol Med ; 43(5): 2153-2163, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30896810

RESUMEN

Neuropathic pain is a condition characterized by unpleasant sensory and emotional experiences associated with a number of diseases or injuries affecting the sensory system through various mechanisms. In this study, we focused on the impact of chronic neuropathic pain on the microglial state and hippocampal neurogenesis in aged mice. In addition, we examined the effects of alkyl glycerol ethers (AGE) treatment on behavioral parameters, hippocampal neuronal and microglial plasticity in aged C57BL/6 mice with neuropathic pain. For the induction of neuropathic pain, we used the model of chronic constriction injury (CCI) of the sciatic nerve. We observed painful behavior in animals subjected to CCI, expressed as a decrease in locomotor activity and the development of cold allodynia. A violation of working and long­term memory was also observed. AGE administration reduced the severity of cold allodynia and prevented memory impairment. In addition to behavioral changes, neuropathic pain was accompanied by microglial activation, changes in the hippocampal production of pro­ and anti­inflammatory cytokines, as well as a decrease in neurogenesis. The administration of AGE prevented the neuropathic pain­derived effects, including M1 microglial activation and neurogenesis disruption. However, in vitro experiments demonstrated the pro­inflammatory activation of microglial cells, emphasizing the complexity of the mechanisms underlying the pharmacological effects of AGE. On the whole, the findings of this study demonstrate that AGE treatment prevented behavioral effects of neuropathic pain in mice, and AGE may thus have potential for use in the prevention or treatment of neuropathic pain cognitive and emotional effects. However, as the mechanisms underlying this type of pain are complex, further studies are required to determine the detailed pharmacological effects of AGE.


Asunto(s)
Envejecimiento/patología , Éteres de Glicerilo/uso terapéutico , Hipocampo/patología , Inflamación/patología , Neuralgia/tratamiento farmacológico , Neurogénesis , Animales , Conducta Animal , Biomarcadores/metabolismo , Enfermedad Crónica , Constricción Patológica , Citocinas/metabolismo , Éteres de Glicerilo/farmacología , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Neuralgia/patología , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratas Wistar
3.
Langmuir ; 35(9): 3568-3575, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30720282

RESUMEN

Monoglycerides are esterified adducts of fatty acid and glycerol molecules that disrupt phospholipid membranes, leading to a wide range of biological functions such as antimicrobial activity. Among monoglycerides, glycerol monolaurate (GML) exhibits particularly high antimicrobial activity, although enzymatic hydrolysis of its ester group can diminish potency. Consequently, there have been efforts to identify more chemically stable versions of GML, most notably its alkylglycerol ether equivalent called dodecylglycerol (DDG). However, despite high structural similarity, biological studies indicate that DDG and GML are not functionally equivalent and it has been speculated that the two compounds might have different interaction profiles with phospholipid membranes. To address this outstanding question, herein, we employed supported lipid bilayer (SLB) platforms to experimentally characterize the interactions of DDG with phospholipid membranes. Quartz crystal microbalance-dissipation experiments identified that DDG causes concentration-dependent membrane morphological changes in SLBs and the overall extent of membrane remodeling events was greater than that caused by GML. In addition, time-lapsed fluorescence microscopy imaging experiments revealed that DDG causes extensive membrane tubulation that is distinct from how GML induces membrane budding. We discuss how differences in the head group properties of DDG and GML contribute to distinct membrane interaction profiles, offering insight into how the molecular design of DDG not only improves chemical stability but also enhances membrane-disruptive activity.


Asunto(s)
Membrana Celular/efectos de los fármacos , Éteres de Glicerilo/farmacología , Lauratos/farmacología , Membrana Dobles de Lípidos/química , Monoglicéridos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Éteres de Glicerilo/química , Éteres de Glicerilo/toxicidad , Humanos , Lauratos/química , Lauratos/toxicidad , Microscopía Fluorescente , Monoglicéridos/química , Monoglicéridos/toxicidad , Fosfatidilcolinas/química , Tecnicas de Microbalanza del Cristal de Cuarzo
4.
Brain Pathol ; 29(5): 622-639, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30667116

RESUMEN

Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue.


Asunto(s)
Éteres de Glicerilo/farmacología , Oligodendroglía/metabolismo , Plasmalógenos/metabolismo , Animales , Axones/metabolismo , Sistema Nervioso Central/metabolismo , Condrodisplasia Punctata Rizomélica/metabolismo , Enfermedades Desmielinizantes , Modelos Animales de Enfermedad , Leucodistrofia Metacromática/fisiopatología , Ratones , Ratones Noqueados , Vaina de Mielina/metabolismo , Vaina de Mielina/fisiología , Oligodendroglía/fisiología , Peroxisomas , Médula Espinal/metabolismo
5.
J Oleo Sci ; 67(4): 455-462, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29526871

RESUMEN

Alkyl glyceryl ethers (AKGs) are widely used as emulsion stabilizers, and their anti-inflammatory effects are well known. Daily exposure to environmental stresses, such as chemicals, low humidity and ultraviolet light (UV), can initiate and promote the development of various skin problems. Among those stresses, it has been established that UV induces skin pigmentation and accelerates premature skin aging due to the inflammation that results. Here, we investigated whether chimyl alcohol (CA), which is an AKG, suppresses the inflammatory process. The suppression of cell damage and the reduction of intracellular levels of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEKs) after UVB exposure was evaluated using the Neutral red (NR) and the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assays, respectively. Moreover, the expression levels of mRNAs and proteins related to inflammation were evaluated by Real-time RT-PCR and ELISA assays, respectively. CA suppressed prostaglandin E2 (PGE2) production in UVB-exposed NHEKs according to the down-regulated expression level of cyclooxygenase-2 (COX-2) mRNA. Furthermore, CA up-regulated the mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ, nuclear factor E2-related factor 2 (Nrf2) and γ-glutamyl cysteine synthase (γ-GCS) in NHEKs. Finally, we examined the effects of CA on siPPAR-γ transfected NHEKs. siPPAR-γ transfection of NHEKs abolished the mRNA expression levels of Nrf2 and UVB-stimulated PGE2 secretion that were regulated by CA. Hence, CA suppresses the UVB-induced COX-2 mRNA expression and PGE2 production through PPAR-γ as an agonist. We conclude that CA provides useful protection and/or alleviation against UV damage.


Asunto(s)
Dinoprostona/biosíntesis , Células Epidérmicas , Éteres de Glicerilo/farmacología , Queratinocitos/metabolismo , PPAR gamma/metabolismo , Células Cultivadas , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Depresión Química , Expresión Génica/efectos de los fármacos , Glutamato-Cisteína Ligasa/genética , Humanos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , PPAR gamma/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rayos Ultravioleta/efectos adversos
6.
Macromol Biosci ; 18(1)2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28834620

RESUMEN

Treatment of retinal diseases currently demands frequent intravitreal injections due to rapid clearance of the therapeutics. The use of high molecular weight polymers can extend the residence time in the vitreous and prolong the injection intervals. This study reports a water soluble graft copolymer as a potential vehicle for sustained intravitreal drug delivery. The copolymer features a high molecular weight hyaluronic acid (HA) backbone and poly(glyceryl glycerol) (PGG) side chains attached via hydrolysable ester linkers. PGG, a polyether with 1,2-diol groups in every repeating unit available for conjugation, serves as a detachable carrier. The influence of synthesis conditions and incubation in physiological media on the molecular weight of HA is studied. The cleavage of the PGG grafts from the HA backbone is quantified and polymer-from-polymer release kinetics are determined. The biocompatibility of the materials is tested in different cell cultures.


Asunto(s)
Portadores de Fármacos/química , Ácido Hialurónico/farmacología , Polímeros/química , Enfermedades de la Retina/tratamiento farmacológico , Portadores de Fármacos/farmacología , Glicerol/química , Glicerol/farmacología , Éteres de Glicerilo/química , Éteres de Glicerilo/farmacología , Humanos , Ácido Hialurónico/química , Inyecciones Intravítreas , Cinética , Peso Molecular , Polímeros/farmacología , Enfermedades de la Retina/patología , Cuerpo Vítreo/efectos de los fármacos , Agua/química
7.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(3): 219-234, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29217479

RESUMEN

Cardiac myocyte membranes contain lipids which remodel dramatically in response to heart growth and remodeling. Lipid species have both structural and functional roles. Physiological and pathological cardiac remodeling have very distinct phenotypes, and the identification of molecular differences represent avenues for therapeutic interventions. Whether the abundance of specific lipid classes is different in physiological and pathological models was largely unknown. The aim of this study was to determine whether distinct lipids are regulated in settings of physiological and pathological remodeling, and if so, whether modulation of differentially regulated lipids could modulate heart size and function. Lipidomic profiling was performed on cardiac-specific transgenic mice with 1) physiological cardiac hypertrophy due to increased Insulin-like Growth Factor 1 (IGF1) receptor or Phosphoinositide 3-Kinase (PI3K) signaling, 2) small hearts due to depressed PI3K signaling (dnPI3K), and 3) failing hearts due to dilated cardiomyopathy (DCM). In hearts of dnPI3K and DCM mice, several phospholipids (plasmalogens) were decreased and sphingolipids increased compared to mice with physiological hypertrophy. To assess whether restoration of plasmalogens could restore heart size or cardiac function, dnPI3K and DCM mice were administered batyl alcohol (BA; precursor to plasmalogen biosynthesis) in the diet for 16weeks. BA supplementation increased a major plasmalogen species (p18:0) in the heart but had no effect on heart size or function. This may be due to the concurrent reduction in other plasmalogen species (p16:0 and p18:1) with BA. Here we show that lipid species are differentially regulated in settings of physiological and pathological remodeling. Restoration of lipid species in the failing heart warrants further examination.


Asunto(s)
Cardiomegalia/metabolismo , Éteres de Glicerilo/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Miocardio/metabolismo , Plasmalógenos/metabolismo , Remodelación Ventricular/efectos de los fármacos , Animales , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/genética , Cardiomegalia/patología , Ratones , Ratones Transgénicos , Miocardio/patología , Plasmalógenos/genética , Remodelación Ventricular/genética
8.
Acta Histochem ; 119(8): 812-821, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29107326

RESUMEN

Neuropathic pain manifested by a number of sensory symptoms is often accompanied by disorders of higher nervous activity, such as memory impairment, depression, anxiety, anhedonia, etc. This emphasizes the involvement of supraspinal structures including the hippocampus in neuropathic pain pathogenesis. In the present study, we focused on the impact of chronic neuropathic pain on hippocampal neurogenesis and microglial state. In addition, we test the effect of alkyl glycerol ethers on hippocampal neuronal and microglial plasticity as well as behavioral parameters. Neuropathic pain was induced using the model of sciatic nerve chronic constriction injury. We found an impairment of working memory and locomotor activity in animals with neuropathic pain, which was prevented by alkyl glycerol ethers treatment. Sciatic nerve ligation in mice contributed to the decrease in hippocampal neurogenesis intensity. Alkyl glycerol ethers administration significantly reduced this effect. Neuropathic pain-associated neurogenesis reduction was accompanied by an increased percentage of Iba1-labeled area in the CA1 hippocampal region on the 14th and 28th days after surgery. In addition, we observed a decrease in hippocampal pro-inflammatory microglia marker CD86 immunostaining on day 28 after surgery in alkyl glycerol ethers-treated mice with sciatic nerve ligation. These results are consistent with data on pro- and anti-inflammatory cytokines expression in the hippocampus. Alkyl glycerol ethers administration increased IL-10 and decreased IL-1ß hippocampal expression in animals with neuropathic pain. Taken together, these data suggest that neuropathic pain-behavior in rodents is accompanied by changes in microglia polarization, thereby contributing to neurogenesis impairment and cognitive disturbances. Alkyl glycerol ethers prevented M1 microglial activation, contributing to the maintenance of normal neurogenesis levels within the hippocampus and normalizing working memory.


Asunto(s)
Éteres de Glicerilo/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Neuralgia , Neurogénesis/efectos de los fármacos , Animales , Éteres de Glicerilo/uso terapéutico , Masculino , Ratones , Neuralgia/tratamiento farmacológico
9.
Molecules ; 22(1)2017 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-28117757

RESUMEN

The absorption modulating activity of two alkylglycerol derivatives (batyl and chimyl alcohol) on skin barrier properties was evaluated. Biophysical tests such as transepidermal water loss (TEWL) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, as well as in vitro skin permeation studies, were performed in order to determine the effect of these compounds as chemical absorption modulators. Four drugs were used as models: three NSAIDS (diclofenac, naproxen, and piroxicam) and glycyrrhizic acid. The results showed that treatment of the skin with alkylglycerols caused (i) a reduction on the amount of drug permeated; (ii) a reduction in TEWL; and (iii) changes in the ATR-FTIR peaks of stratum corneum lipids, indicative of a more ordered structure. All of these findings confirm that alkyl glycerols have an absorption retarding effect on the drugs tested. Such effects are expected to give rise to important applications in the pharmaceutical and cosmetic sectors, in cases where it is desirable for the drug to remain in the superficial layers of the skin to achieve a local effect.


Asunto(s)
Portadores de Fármacos/farmacología , Éteres de Glicerilo/farmacología , Permeabilidad/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Piel/metabolismo , Administración Cutánea , Animales , Diclofenaco/administración & dosificación , Diclofenaco/metabolismo , Ácido Glicirrínico/administración & dosificación , Ácido Glicirrínico/metabolismo , Naproxeno/administración & dosificación , Naproxeno/metabolismo , Piroxicam/administración & dosificación , Piroxicam/metabolismo , Piel/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Porcinos
10.
J Asian Nat Prod Res ; 19(7): 691-696, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27756152

RESUMEN

Chemical investigation on CH2Cl2 extract of the marine sponge Leucandra sp. afforded two new compounds named leucanone A (1) and naamine J (2), together with eight known compounds (3-10). Their structures were elucidated on the basis of NMR spectroscopic analyses, and comparing with the literature. The cytotoxic activities of the compounds were evaluated against four cancer cell lines, and compound 2 showed mild cytotoxic activities against MCF-7, A549, HeLa, and PC9 cancer cell lines with IC50 values in the range of 20.1-45.3 µM.


Asunto(s)
Alcaloides/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Imidazoles/aislamiento & purificación , Lípidos/aislamiento & purificación , Poríferos/química , Alcaloides/química , Alcaloides/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Éteres de Glicerilo/química , Éteres de Glicerilo/aislamiento & purificación , Éteres de Glicerilo/farmacología , Células HeLa , Humanos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Lípidos/química , Lípidos/farmacología , Células MCF-7 , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular
11.
PLoS One ; 11(10): e0165228, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27783695

RESUMEN

Preservatives are added to cosmetics to protect the consumers from infections and prevent product spoilage. The concentration of preservatives should be kept as low as possible and this can be achieved by adding potentiating agents. The aim of the study was to investigate the mechanisms behind potentiation of the bactericidal effect of a commonly used preservative, 2-phenoxyethanol (PE), by the potentiating agent ethylhexylglycerin (EHG). Sub-lethal concentrations of EHG (0.075%) and PE (0.675%) in combination led to rapid killing of E. coli (> 5 log reduction of cfu after 30 min), leakage of cellular constituents, disruption of the energy metabolism, morphological deformities of cells and condensation of DNA. Used alone, EHG disrupted the membrane integrity even at low concentrations. In conclusion, sub-lethal concentrations of EHG potentiate the effect of PE through damage of the cell membrane integrity. Thus, adding EHG to PE in a 1:9 ratio has a similar effect on membrane damage and bacterial viability as doubling the concentration of PE. This study provides insight about the mechanism of action of a strong potentiating agent, EHG, which is commonly used in cosmetics together with PE.


Asunto(s)
Escherichia coli/efectos de los fármacos , Glicoles de Etileno/farmacología , Éteres de Glicerilo/farmacología , Conservadores Farmacéuticos/farmacología , Antibacterianos/farmacología , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Cosméticos/química , Sinergismo Farmacológico , Metabolismo Energético , Microscopía Electrónica de Transmisión
12.
Oncotarget ; 7(51): 84326-84337, 2016 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-27741517

RESUMEN

Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.


Asunto(s)
Apoptosis , Puntos de Control de la Fase M del Ciclo Celular , Neurofibromina 1/metabolismo , Proteína Quinasa C/metabolismo , Proteínas de Unión al GTP ral/metabolismo , Transporte Activo de Núcleo Celular , Animales , Línea Celular , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Éteres de Glicerilo/farmacología , Humanos , Ratones Endogámicos BALB C , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismo , Neurofibromina 1/genética , Fosforilación , Proteína Quinasa C/antagonistas & inhibidores , Interferencia de ARN , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión al GTP ral/genética
13.
Chem Phys Lipids ; 194: 2-11, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26187854

RESUMEN

We have assessed the effect of two ether glycerol lipids, 77-6 ((2S, 3R)-4-(Tetradecyloxy)-2-amino-1,3-butanediol) and 56-5 ((S)-2-Amino-3-O-hexadecyl-1-propanol), which are substrates for sphingosine kinases, on inflammatory responses. Treatment of differentiated U937 macrophage-like cells with 77-6 but not 56-5 enhanced IL-1ß release; either alone or in the presence of LPS. The stimulatory effect of sphingosine or 77-6 on LPS-stimulated IL-1ß release was reduced by pretreatment of cells with the caspase-1 inhibitor, Ac-YVAD-CHO, thereby indicating a role for the inflammasome. The enhancement of LPS-stimulated IL-1ß release in response to sphingosine, but not 77-6, was reduced by pretreatment of cells with the cathepsin B inhibitor, CA074Me, indicating a role for lysosomal destabilization in the effect of sphingosine. Administration of 56-5 to mice increased disease progression in an experimental autoimmune encephalomyelitis model and this was associated with a considerable increase in the infiltration of CD4(+) T-cells, CD11b(+) monocytes and F4/80(+) macrophages in the spinal cord. 56-5 and 77-6 were without effect on the degradation of myc-tagged sphingosine 1-phosphate 1 receptor in CCL39 cells. Therefore, the effect of 56-5 on EAE disease progression is likely to be independent of the inflammasome or the sphingosine 1-phosphate 1 receptor. However, 56-5 is chemically similar to platelet activating factor and the exacerbation of EAE disease progression might be linked to platelet activating factor receptor signaling.


Asunto(s)
Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Éteres de Glicerilo/farmacología , Interleucina-1beta/metabolismo , Lípidos/farmacología , Animales , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/metabolismo , Éteres de Glicerilo/química , Células HEK293 , Humanos , Lípidos/química , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Esfingosina/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Células U937
14.
Drug Deliv ; 23(7): 2497-2512, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25777339

RESUMEN

Archaeosomes as liposomes made with one or more ether lipids that are unique to the domain of Archaeobacteria, found in Archaea constitute a novel family of liposome. Achaean-type lipids consist of archaeol (diether) and/or caldarchaeol (tetraether) core structures. Archaeosomes can be produced using standard procedures (hydrated film submitted to sonication, extrusion and detergent dialysis) at any temperature in the physiological range or lower, therefore making it possible to encapsulate thermally stable compounds. Various physiological as well as environmental factors affect its stability. Archaeosomes are widely used as drug delivery systems for cancer vaccines, Chagas disease, proteins and peptides, gene delivery, antigen delivery and delivery of natural antioxidant compounds. In this review article, our major aim was to explore the applications of this new carrier system in pharmaceutical field.


Asunto(s)
Adyuvantes Inmunológicos/química , Archaea/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Éteres de Glicerilo/administración & dosificación , Liposomas/química , Péptidos/administración & dosificación , Péptidos/metabolismo , Estabilidad de Medicamentos , Técnicas de Transferencia de Gen , Éteres de Glicerilo/química , Éteres de Glicerilo/metabolismo , Éteres de Glicerilo/farmacología , Humanos , Péptidos/química
15.
Atherosclerosis ; 243(2): 598-608, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26545014

RESUMEN

BACKGROUND AND AIM: We previously reported a negative association of circulating plasmalogens (phospholipids with proposed atheroprotective properties) with coronary artery disease. Plasmalogen modulation was previously demonstrated in animals but its effect on atherosclerosis was unknown. We assessed the effect of plasmalogen enrichment on atherosclerosis of murine models with differing levels of oxidative stress. METHODS AND RESULTS: Six-week old ApoE- and ApoE/glutathione peroxidase-1 (GPx1)-deficient mice were fed a high-fat diet with/without 2% batyl alcohol (precursor to plasmalogen synthesis) for 12 weeks. Mass spectrometry analysis of lipids showed that batyl alcohol supplementation to ApoE- and ApoE/GPx1-deficient mice increased the total plasmalogen levels in both plasma and heart. Oxidation of plasmalogen in the treated mice was evident from increased level of plasmalogen oxidative by-product, sn-2 lysophospholipids. Atherosclerotic plaque in the aorta was reduced by 70% (P = 5.69E-07) and 69% (P = 2.00E-04) in treated ApoE- and ApoE/GPx1-deficient mice, respectively. A 40% reduction in plaque (P = 7.74E-03) was also seen in the aortic sinus of only the treated ApoE/GPx1-deficient mice. Only the treated ApoE/GPx1-deficient mice showed a decrease in VCAM-1 staining (-28%, P = 2.43E-02) in the aortic sinus and nitrotyrosine staining (-78%, P = 5.11E-06) in the aorta. CONCLUSION: Plasmalogen enrichment via batyl alcohol supplementation attenuated atherosclerosis in ApoE- and ApoE/GPx1-deficient mice, with a greater effect in the latter group. Plasmalogen enrichment may represent a viable therapeutic strategy to prevent atherosclerosis and reduce cardiovascular disease risk, particularly under conditions of elevated oxidative stress and inflammation.


Asunto(s)
Enfermedades de la Aorta/prevención & control , Apolipoproteínas E/deficiencia , Aterosclerosis/prevención & control , Glutatión Peroxidasa/deficiencia , Éteres de Glicerilo/farmacología , Plasmalógenos/sangre , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/patología , Colesterol/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Glutatión Peroxidasa/genética , Éteres de Glicerilo/metabolismo , Mediadores de Inflamación/metabolismo , Lisofosfolípidos/sangre , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/enzimología , Oxidación-Reducción , Estrés Oxidativo , Placa Aterosclerótica , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/metabolismo
16.
J Biomed Mater Res B Appl Biomater ; 103(8): 1663-9, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25611332

RESUMEN

The use of bioactive materials instead of inert materials to fill the root canal space could be an effective approach to achieve a hermetic seal and stimulate the healing of periapical tissues. The purpose of this study was to develop and characterize an endodontic sealer based on a glycerol salicylate resin and α-tricalcium phosphate (αTCP) at physical and chemical properties. Different sealers were formulated using 70% of a glycerol salicylate resin and 30% of a mixture of calcium hydroxide and αTCP (0, 5, 10, or 15%, in weight). Sealers formulated were characterized based on setting time, in vitro degradation over time, pH, cytotoxicity, and mineral deposition. Sealers presented setting time ranging from 240 to 405 min, and basic pH over 8.21 after 28 days. Higher αTCP concentration leads to sealers with low solubility. Cell viability after 48 h in direct contact with sealers was similar to a commercial sealer used as reference. The 10% and 15% αTCP sealers exhibited a calcium-phosphate layer on the surface after immersion in water and SBF for 7 days. Glycerol salicylate sealers with 10% and 15% α-tricalcium phosphate showed reliable physical-chemical properties and apatite-forming ability.


Asunto(s)
Fosfatos de Calcio/farmacología , Fibroblastos/metabolismo , Éteres de Glicerilo/farmacología , Ensayo de Materiales , Materiales de Obturación del Conducto Radicular/farmacología , Salicilatos/farmacología , Animales , Fosfatos de Calcio/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fibroblastos/citología , Éteres de Glicerilo/química , Ratones , Materiales de Obturación del Conducto Radicular/química , Salicilatos/química
17.
J Biol Chem ; 290(7): 4225-37, 2015 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-25519911

RESUMEN

Exosomes are vesicles released by cells after fusion of multivesicular bodies with the plasma membrane. In this study, we have investigated whether ether lipids affect the release of exosomes in PC-3 cells. To increase the cellular levels of ether lipids, the ether lipid precursor hexadecylglycerol was added to cells. Lipidomic analysis showed that this compound was in fact able to double the cellular levels of ether lipids in these cells. Furthermore, increased levels of ether lipids were also found in exosomes released by cells containing high levels of these lipids. Interestingly, as measured by nanoparticle tracking analysis, cells containing high levels of ether lipids released more exosomes than control cells, and these exosomes were similar in size to control exosomes. Moreover, silver staining and Western blot analyses showed that the protein composition of exosomes released in the presence of hexadecylglycerol was changed; the levels of some proteins were increased, and the levels of others were reduced. In conclusion, this study clearly shows that an increase in cellular ether lipids is associated with changes in the release and composition of exosomes.


Asunto(s)
Exosomas/química , Exosomas/metabolismo , Éteres de Glicerilo/farmacología , Lípidos/análisis , Cuerpos Multivesiculares/metabolismo , Neoplasias de la Próstata/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/patología , Células Tumorales Cultivadas
18.
PLoS One ; 9(9): e107991, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25268119

RESUMEN

Androgen ablation therapy causes a temporary reduction in tumor burden in patients with advanced prostate cancer. Unfortunately the malignancy will return to form lethal castration-recurrent prostate cancer (CRPC). The androgen receptor (AR) remains transcriptionally active in CRPC in spite of castrate levels of androgens in the blood. AR transcriptional activity resides in its N-terminal domain (NTD). Possible mechanisms of continued AR transcriptional activity may include, at least in part, expression of constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD). Current therapies that target the AR LBD, would not be effective against these AR variants. Currently no drugs are clinically available that target the AR NTD which should be effective against these AR variants as well as full-length AR. Niphatenones were originally isolated and identified in active extracts from Niphates digitalis marine sponge. Here we begin to characterize the mechanism of niphatenones in blocking AR transcriptional activity. Both enantiomers had similar IC50 values of 6 µM for inhibiting the full-length AR in a functional transcriptional assay. However, (S)-niphatenone had significantly better activity against the AR NTD compared to (R)-niphatenone. Consistent with niphatenones binding to and inhibiting transactivation of AR NTD, niphatenones inhibited AR splice variant. Niphatenone did not affect the transcriptional activity of the related progesterone receptor, but slightly decreased glucocorticoid receptor (GR) activity and covalently bound to GR activation function-1 (AF-1) region. Niphatenone blocked N/C interactions of AR without altering either AR protein levels or its intracellular localization in response to androgen. Alkylation with glutathione suggests that niphatenones are not a feasible scaffold for further drug development.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos Hormonales/farmacología , Éteres de Glicerilo/farmacología , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Masculino , Metribolona/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Estructura Terciaria de Proteína , Receptores Androgénicos/química , Receptores Androgénicos/fisiología , Estereoisomerismo , Activación Transcripcional/efectos de los fármacos
19.
Int J Nanomedicine ; 9: 3335-45, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25045264

RESUMEN

In this work, the in vitro anti-Leishmania activity of photodynamic liposomes made of soybean phosphatidylcholine, sodium cholate, total polar archaeolipids (TPAs) extracted from the hyperhalophile archaea Halorubrum tebenquichense and the photosensitizer zinc phthalocyanine (ZnPcAL) was compared to that of ultradeformable photodynamic liposomes lacking TPAs (ZnPcUDLs). We found that while ZnPcUDLs and ZnPcALs (130 nm mean diameter and -35 mV zeta potential) were innocuous against promastigotes, a low concentration (0.01 µM ZnPc and 7.6 µM phospholipids) of ZnPcALs irradiated at a very low-energy density (0.2 J/cm(2)) eliminated L. braziliensis amastigotes from J774 macrophages, without reducing the viability of the host cells. In such conditions, ZnPcALs were harmless for J774 macrophages, HaCaT keratinocytes, and bone marrow-derived dendritic cells. Therefore, topical photodynamic treatment would not likely affect skin-associated lymphoid tissue. ZnPcALs were extensively captured by macrophages, but ZnPcUDLs were not, leading to 2.5-fold increased intracellular delivery of ZnPc than with ZnPcUDLs. Despite mediating low levels of reactive oxygen species, the higher delivery of ZnPc and the multiple (caveolin- and clathrin-dependent plus phagocytic) intracellular pathway followed by ZnPc would have been the reason for the higher antiamastigote activity of ZnPcALs. The leishmanicidal activity of photodynamic liposomal ZnPc was improved by TPA-containing liposomes.


Asunto(s)
Antiprotozoarios/farmacología , Éteres de Glicerilo/farmacología , Indoles/farmacología , Leishmania/efectos de los fármacos , Leishmania/efectos de la radiación , Liposomas/farmacología , Compuestos Organometálicos/farmacología , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacocinética , Antiprotozoarios/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Éteres de Glicerilo/química , Éteres de Glicerilo/farmacocinética , Éteres de Glicerilo/toxicidad , Humanos , Indoles/química , Indoles/farmacocinética , Indoles/toxicidad , Liposomas/química , Liposomas/farmacocinética , Liposomas/toxicidad , Macrófagos/metabolismo , Ratones , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/toxicidad , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo
20.
Archaea ; 2012: 513231, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23055819

RESUMEN

The relation between archaeal lipid structures and their activity as adjuvants may be defined and explored by synthesizing novel head groups covalently linked to archaeol (2,3-diphytanyl-sn-glycerol). Saturated archaeol, that is suitably stable as a precursor for chemical synthesis, was obtained in high yield from Halobacterium salinarum. Archaeosomes consisting of the various combinations of synthesized lipids, with antigen entrapped, were used to immunize mice and subsequently determine CD8(+) and CD4(+)-T cell immune responses. Addition of 45 mol% of the glycolipids gentiotriosylarchaeol, mannotriosylarchaeol or maltotriosylarchaeol to an archaetidylglycerophosphate-O-methyl archaeosome, significantly enhanced the CD8(+) T cell response to antigen, but diminished the antibody titres in peripheral blood. Archaeosomes consisting of all three triglycosyl archaeols combined with archaetidylglycerophosphate-O-methyl (15/15/15/55 mol%) resulted in approximately additive CD8(+) T cell responses and also an antibody response not significantly different from the archaetidylglycerophosphate-O-methyl alone. Synthetic archaetidylserine played a role to further enhance the CD8(+) T cell response where the optimum content was 20-30 mol%. Vaccines giving best protection against solid tumor growth corresponded to the archaeosome adjuvant composition that gave highest immune activity in immunized mice.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Vacunas contra el Cáncer/inmunología , Éteres de Glicerilo/farmacología , Halobacterium salinarum/química , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/aislamiento & purificación , Animales , Anticuerpos/sangre , Antígenos de Neoplasias/administración & dosificación , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Éteres de Glicerilo/administración & dosificación , Éteres de Glicerilo/aislamiento & purificación , Glucolípidos/administración & dosificación , Glucolípidos/aislamiento & purificación , Glucolípidos/farmacología , Ratones , Ratones Endogámicos C57BL , Neoplasias/patología , Neoplasias/prevención & control
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