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1.
Adv Exp Med Biol ; 1269: 197-202, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33966217

RESUMEN

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. The limitations of our knowledge about the nature of BBB explain the slow progress in the therapy of brain diseases and absence of methods for drug delivery to the brain in clinical practice. Here, we show that the BBB opens for high-molecular-weight compounds after exposure to loud sound (100 dB 370 Hz) in rats. The role of stress induced by loud sound and the systemic and molecular mechanisms behind it are discussed in the framework of the BBB. This opens an informative platform for novel fundamental knowledge about the nature of BBB and for the development of a noninvasive brain drug delivery technology.


Asunto(s)
Barrera Hematoencefálica , Encéfalo , Animales , Transporte Biológico , Sistemas de Liberación de Medicamentos , Ratas , Sonido
2.
Chemistry ; 27(26): 7367-7375, 2021 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-33932059

RESUMEN

Anion receptors can be used to transport ions across lipid bilayers, which has potential for therapeutic applications. Synthetic bicarbonate transporters are of particular interest, as defects in transmembrane transport of bicarbonate are associated with various diseases. However, no convenient method exists to directly observe bicarbonate transport and study the mechanisms involved. Here, an assay is presented that allows the kinetics of bicarbonate transport into liposomes to be monitored directly and with great sensitivity. The assay utilises an encapsulated europium(III) complex, which exhibits a large increase in emission intensity upon binding bicarbonate. Mechanisms involving CO2 diffusion and the dissipation of a pH gradient are shown to be able to lead to an increase in bicarbonate concentration within liposomes, without transport of the anion occurring at all. By distinguishing these alternative mechanisms from actual bicarbonate transport, this assay will inform the future development of bicarbonate transporters.


Asunto(s)
Bicarbonatos , Membrana Dobles de Lípidos , Transporte Biológico , Concentración de Iones de Hidrógeno , Transporte Iónico , Cinética
3.
Plant Physiol Biochem ; 162: 730-736, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33799184

RESUMEN

Food crops often accumulate heavy metals above the recommended limits. Cadmium (Cd) is particularly harmful in terms of its potential dangers to human health. The effects of nutrient status and cation competition on Cd uptake and distribution in barley were investigated to analyse the main route for Cd entry into the plants. Cd uptake into whole plants was measured by radiotracer studies and elemental analysis using environmentally relevant concentrations. The nutrient status of the plants was altered by growing them hydroponically in micronutrient-deficient conditions (-Fe, -Mn, or -Zn). Fe and Zn were found to have a large effect on the uptake of Cd both via deficiencies and by the competition for uptake. However, Mn was found to have no effect on the uptake of Cd either via deficiency or by the competition for uptake. This strongly suggests that the main route for Cd uptake into the roots is via Fe and Zn transporters. The inhibition of Cd influx only by FeII (but not by FeIII) suggests that Cd uptake into the root occurs through divalent cation transporters. Since Cd is a non-essential metal in plants, the transport characteristics were compared with those of an essential micronutrient, Ni. At the same external concentration, more than twice as much Cd was absorbed as Ni in all of the different nutrient conditions. Ni translocation to the shoot was much lower than for Cd. The comparison of two metals showed some similarities in the root uptake processes but not in the shoot translocation.


Asunto(s)
Hordeum , Metales Pesados , Transporte Biológico , Cadmio , Raíces de Plantas
4.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802460

RESUMEN

The lysosomal storage disease Niemann-Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old Npc1-/- mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1-/- liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in Npc1-/- liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1-/- liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in Npc1-/- hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.


Asunto(s)
Glucosilceramidasa/metabolismo , Hígado/metabolismo , Glicoproteínas de la Membrana Asociadas a los Lisosomas/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Receptores Depuradores/metabolismo , Animales , Transporte Biológico/fisiología , Catepsina D/metabolismo , Línea Celular , Línea Celular Tumoral , Enfermedad de Gaucher/metabolismo , Glucosilceramidas/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Lisosomas/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Células RAW 264.7 , Esfingomielinas/metabolismo
5.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33802600

RESUMEN

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.


Asunto(s)
Aterosclerosis/metabolismo , Células Espumosas/metabolismo , ARN no Traducido/metabolismo , Animales , Transporte Biológico/fisiología , Colesterol/metabolismo , Citocinas/metabolismo , Humanos , Metabolismo de los Lípidos/fisiología
6.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809364

RESUMEN

The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs (VPS13A-D) are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research.


Asunto(s)
Transporte Biológico/genética , Membrana Celular/genética , Lípidos/genética , Proteínas de Saccharomyces cerevisiae/genética , Membrana Celular/metabolismo , Humanos , Membranas Mitocondriales/metabolismo , Mutación/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
7.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809376

RESUMEN

The diffusion process of water molecules within a polyetherimide (PEI) glassy matrix has been analyzed by combining the experimental analysis of water sorption kinetics performed by FTIR spectroscopy with theoretical information gathered from Molecular Dynamics simulations and with the expression of water chemical potential provided by a non-equilibrium lattice fluid model able to describe the thermodynamics of glassy polymers. This approach allowed us to construct a convincing description of the diffusion mechanism of water in PEI providing molecular details of the process related to the effects of the cross- and self-hydrogen bonding established in the system on the dynamics of water mass transport.


Asunto(s)
Transporte Biológico/genética , Polímeros/química , Termodinámica , Agua/química , Difusión , Enlace de Hidrógeno , Cinética , Simulación de Dinámica Molecular , Polímeros/metabolismo
8.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803444

RESUMEN

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.


Asunto(s)
Autofagia , Retículo Endoplásmico/metabolismo , Membranas Intracelulares/metabolismo , Gotas Lipídicas/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Animales , Transporte Biológico , Humanos
9.
Artículo en Inglés | MEDLINE | ID: mdl-33799986

RESUMEN

In recent years, alcohol abuse has dramatically grown with deleterious consequence for people's health and, in turn, for health care costs. It has been demonstrated, in humans and animals, that alcohol intoxication induces neuroinflammation and neurodegeneration thus leading to brain impairments. Furthermore, it has been shown that alcohol consumption is able to impair the blood-brain barrier (BBB), but the molecular mechanisms underlining this detrimental effect have not been fully elucidated. For this reason, in this study we investigated the effects of alcohol exposure on a rat brain endothelial (RBE4) cell line, as an in vitro-validated model of brain microvascular endothelial cells. To assess whether alcohol caused a concentration-related response, the cells were treated at different times with increasing concentrations (10-1713 mM) of ethyl alcohol (EtOH). Microscopic and molecular techniques, such as cell viability assay, immunofluorescence and Western blotting, were used to examine the mechanisms involved in alcohol-induced brain endothelial cell alterations including tight junction distribution, apoptosis, and reactive oxygen species production. Our findings clearly demonstrate that alcohol causes the formation of gaps between cells by tight junction disassembly, triggered by the endoplasmic reticulum and oxidative stress, highlighted by GRP78 chaperone upregulation and increase in reactive oxygen species production, respectively. The results from this study shed light on the mechanisms underlying alcohol-induced blood-brain barrier dysfunction and a better understanding of these processes will allow us to take advantage of developing new therapeutic strategies in order to prevent the deleterious effects of alcohol.


Asunto(s)
Barrera Hematoencefálica , Células Endoteliales , Animales , Transporte Biológico , Encéfalo , Especies Reactivas de Oxígeno/metabolismo , Uniones Estrechas/metabolismo
10.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802660

RESUMEN

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca2+ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca2+ concentration ([Ca2+]) under elevated pH and/or high [Ca2+] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca2+] measurements reveal that such alkalization not only upsurges Ca2+ influx into PT cells, but the mode of Ca2+ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca2+ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.


Asunto(s)
Acetazolamida/farmacología , Calcio/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Nefrolitiasis/metabolismo , Nefrolitiasis/patología , Animales , Transporte Biológico/efectos de los fármacos , Calcinosis/complicaciones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibrosis , Concentración de Iones de Hidrógeno , Inflamación/patología , Túbulos Renales Proximales/efectos de los fármacos , Ratones , Nefrolitiasis/orina , Estrés Oxidativo/efectos de los fármacos , Canales Catiónicos TRPC/metabolismo , Regulación hacia Arriba/efectos de los fármacos
11.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805725

RESUMEN

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.


Asunto(s)
Antineoplásicos/química , Transportadores de Ácidos Monocarboxílicos/química , Proteínas Musculares/química , Floretina/química , Pirimidinonas/química , Quercetina/química , Reserpina/análogos & derivados , Tiofenos/química , Uracilo/análogos & derivados , Animales , Antineoplásicos/metabolismo , Sitios de Unión , Transporte Biológico , Diseño de Fármacos , Glucólisis/fisiología , Humanos , Ácido Láctico/química , Ácido Láctico/metabolismo , Simulación del Acoplamiento Molecular , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Floretina/metabolismo , Filogenia , Unión Proteica , Conformación Proteica en Hélice alfa , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Pirimidinonas/metabolismo , Quercetina/metabolismo , Reserpina/química , Reserpina/metabolismo , Homología Estructural de Proteína , Especificidad por Sustrato , Tiofenos/metabolismo , Uracilo/química , Uracilo/metabolismo
12.
Biomed Khim ; 67(2): 119-129, 2021 Mar.
Artículo en Ruso | MEDLINE | ID: mdl-33860768

RESUMEN

High density lipoproteins (HDL) are a unique natural structure, protecting the body from the development of atherosclerotic vascular lesions and cardiovascular diseases due to this ability to remove cholesterol from cells. Plasma HDL level estimated by their cholesterol content, is a common lipid parameter, and its decrease is considered as an established atherosclerosis risk factor. However, a number of studies have shown the absence of positive clinical effects after drug-induced increase in HDL cholesterol. There is increasing evidence that not only HDL concentration, but also HDL properties, considered in this review are important. Many studies showed the decrease of HDL cholesterol efflux capacity in patients with coronary heart diseases and its association with disease severity. Some authors consider a decrease of this HDL capacity as a new additional risk factor of atherosclerosis. The review summarizes existing information on various protein and lipid components of HDL with a primary emphasis on the HDL. Special attention is paid to correlation between the HDL cholesterol efflux capacity and HDL phospholipids and the ratio "phospholipids/free cholesterol". The accumulated information indicates importance of evaluation in the HDL fraction not only in terms of their cholesterol, but also phospholipids. In addition to the traditionally used lipid criteria, this would provide more comprehensive information about the activity of the reverse cholesterol transport process in the body and could contribute to the targeted correction of the detected disorders.


Asunto(s)
Aterosclerosis , Preparaciones Farmacéuticas , Transporte Biológico , Colesterol , HDL-Colesterol/metabolismo , Humanos , Lipoproteínas HDL/metabolismo , Plasma/metabolismo , Factores de Riesgo
13.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803750

RESUMEN

The mode of action of 1-naphthylphthalamic acid (NPA) to induce conspicuous local stem swelling in the area of its application to the growing internode in intact Bryophyllum calycinum was studied based on the aspects of histological observation and comprehensive analyses of plant hormones. Histological analyses revealed that NPA induced an increase in cell size and numerous cell divisions in the cortex and pith, respectively, compared to untreated stem. In the area of NPA application, vascular tissues had significantly wider cambial zones consisting of 5-6 cell layers, whereas phloem and xylem seemed not to be affected. This indicates that stem swelling in the area of NPA application is caused by stimulation of cell division and cell enlargement mainly in the cambial zone, cortex, and pith. Comprehensive analyses of plant hormones revealed that NPA substantially increased endogenous levels of indole-3-acetic acid (IAA) in the swelling area. NPA also increased endogenous levels of cytokinins, jasmonic acid, and its precursor, 12-oxo-phytodienoic acid, but did not increase abscisic acid and gibberellin levels. It was shown, using radiolabeled 14C-IAA, that NPA applied to the middle of internode segments had little effect on polar auxin transport, while 2,3,5-triiodobenzoic acid substantially inhibited it. These results strongly suggest that NPA induces changes in endogenous levels of plant hormones, such as IAA, cytokinins, and jasmonic acid, and their hormonal crosstalk results in a conspicuous local stem swelling. The possible different mode of action of NPA from other polar auxin transport inhibitors in succulent plants is extensively discussed.


Asunto(s)
Kalanchoe/citología , Ftalimidas/farmacología , Reguladores del Crecimiento de las Plantas/farmacología , Tallos de la Planta/fisiología , Transporte Biológico/efectos de los fármacos , Ácidos Indolacéticos/farmacología , Kalanchoe/anatomía & histología , Tallos de la Planta/efectos de los fármacos
14.
Nat Commun ; 12(1): 2408, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33893307

RESUMEN

Lipid shuttling between neurons and glia contributes to the development, function, and stress responses of the nervous system. To understand how a neuron acquires its lipid supply from specific lipoproteins and their receptors, we perform combined genetic, transcriptome, and biochemical analyses in the developing Drosophila larval brain. Here we report, the astrocyte-derived secreted lipocalin Glial Lazarillo (GLaz), a homolog of human Apolipoprotein D (APOD), and its neuronal receptor, the brain-specific short isoforms of Drosophila lipophorin receptor 1 (LpR1-short), cooperatively mediate neuron-glia lipid shuttling and support dendrite morphogenesis. The isoform specificity of LpR1 defines its distribution, binding partners, and ability to support proper dendrite growth and synaptic connectivity. By demonstrating physical and functional interactions between GLaz/APOD and LpR1, we elucidate molecular pathways mediating lipid trafficking in the fly brain, and provide in vivo evidence indicating isoform-specific expression of lipoprotein receptors as a key mechanism for regulating cell-type specific lipid recruitment.


Asunto(s)
Apolipoproteínas/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Animales Modificados Genéticamente , Apolipoproteínas/genética , Transporte Biológico , Encéfalo/citología , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Perfilación de la Expresión Génica , Humanos , Larva/genética , Larva/metabolismo , Lipocalinas/genética , Lipocalinas/metabolismo , Unión Proteica , Receptores Citoplasmáticos y Nucleares/genética
15.
Molecules ; 26(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799468

RESUMEN

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood-brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.


Asunto(s)
Encéfalo/metabolismo , Animales , Transporte Biológico/fisiología , Barrera Hematoencefálica/metabolismo , Línea Celular , Línea Celular Tumoral , Técnicas de Cocultivo/métodos , Células Endoteliales/metabolismo , Humanos , Ratones , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/metabolismo , Permeabilidad/efectos de los fármacos , Tironinas/metabolismo
16.
Molecules ; 26(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802142

RESUMEN

The aim of this study was to profile the bioaccessibility and intestinal absorption of epicatechins and flavonols in different forms of green tea and its formulation: loose leaf tea, powdered tea, 35% catechins containing GTE, and GTE formulated with green tea-derived polysaccharide and flavonols (CATEPLUS™). The bioaccessibillity and intestinal absorption of epicatechins and flavonols was investigated by using an in vitro digestion model system with Caco-2 cells. The bioaccessibility of total epicatechins in loose leaf tea, powdered tea, GTE, and CATEPLUS™ was 1.27%, 2.30%, 22.05%, and 18.72%, respectively, showing that GTE and CATEPLUS™ had significantly higher bioaccessibility than powdered tea and loose leaf tea. None of the flavonols were detected in powdered tea and loose leaf tea, but the bioaccessibility of the total flavonols in GTE and CATEPLUS™ was 85.74% and 66.98%, respectively. The highest intestinal absorption of epicatechins was found in CATEPLUS™ (171.39 ± 5.39 ng/mg protein) followed by GTE (57.38 ± 9.31), powdered tea (3.60 ± 0.67), and loose leaf tea (2.94 ± 1.03). The results from the study suggest that formulating green tea extracts rich in catechins with second components obtained from green tea processing could enhance the bioavailability of epicatechins.


Asunto(s)
Flavonoides/farmacología , Té/metabolismo , Antioxidantes , Disponibilidad Biológica , Transporte Biológico , Células CACO-2 , Catequina/química , Catequina/metabolismo , Digestión/efectos de los fármacos , Digestión/fisiología , Flavonoides/metabolismo , Flavonoles/química , Flavonoles/metabolismo , Humanos , Intestinos/efectos de los fármacos , Intestinos/fisiología , Modelos Biológicos , Extractos Vegetales
17.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806722

RESUMEN

Auxins play an essential role in regulating plant growth and adaptation to abiotic stresses, such as nutrient stress. Our current understanding of auxins is based almost entirely on the results of research on the eudicot Arabidopsis thaliana, however, the role of the rice PIN-FORMED (PIN) auxin efflux carriers in the regulation of the ammonium-dependent response remains elusive. Here, we analyzed the expression patterns in various organs/tissues and the ammonium-dependent response of rice PIN-family genes (OsPIN genes) via qRT-PCR, and attempted to elucidate the relationship between nitrogen (N) utilization and auxin transporters. To investigate auxin distribution under ammonium-dependent response after N deficiency in rice roots, we used DR5::VENUS reporter lines that retained a highly active synthetic auxin response. Subsequently, we confirmed that ammonium supplementation reduced the DR5::VENUS signal compared with that observed in the N-deficient condition. These results are consistent with the decreased expression patterns of almost all OsPIN genes in the presence of the ammonium-dependent response to N deficiency. Furthermore, the ospin1b mutant showed an insensitive phenotype in the ammonium-dependent response to N deficiency and disturbances in the regulation of several N-assimilation genes. These molecular and physiological findings suggest that auxin is involved in the ammonium assimilation process of rice, which is a model crop plant.


Asunto(s)
Ácidos Indolacéticos/metabolismo , Oryza/fisiología , Desarrollo de la Planta , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Compuestos de Amonio/metabolismo , Transporte Biológico , Fertilizantes , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Familia de Multigenes , Mutación , Nitrógeno/metabolismo , Especificidad de Órganos , Desarrollo de la Planta/genética , Raíces de Plantas/crecimiento & desarrollo , Carácter Cuantitativo Heredable , Plantones/genética , Plantones/crecimiento & desarrollo
18.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806730

RESUMEN

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.


Asunto(s)
Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Animales , Transporte Biológico , Proliferación Celular , Supervivencia Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Ciclo del Ácido Cítrico , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Metabolismo Energético , Humanos , Redes y Vías Metabólicas , Microtúbulos/metabolismo , Neoplasias/patología , Neoplasias/terapia , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral
19.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806797

RESUMEN

Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.


Asunto(s)
Inflamasomas/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Resistencia a la Insulina , Músculo Esquelético/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Animales , Transporte Biológico , Enfermedad Crónica , Glucosa/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Interleucina-1beta/metabolismo , Metabolismo de los Lípidos , Músculo Esquelético/patología , Obesidad/tratamiento farmacológico , Obesidad/patología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal
20.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808520

RESUMEN

Endosome-derived small extracellular vesicles (EVs), often referred to as exosomes, are produced by almost all, if not all, cell types, and are critical for intercellular communication. They are composed of a lipid bilayer associated with membrane proteins and contain a payload of lipids, proteins and regulatory RNAs that depends on the parental cell physiological condition. By transferring their "cargo", exosomes can modulate the phenotype of neighboring and distant cells. Stem cells (SC) were widely studied for therapeutic applications regarding their regenerative/reparative potential as well as their immunomodulatory properties. Whether from autologous or allogeneic source, SC beneficial effects in terms of repair and regeneration are largely attributed to their paracrine signaling notably through secreted EVs. Subsequently, SC-derived EVs have been investigated for the treatment of various diseases, including inflammatory skin disorders, and are today fast-track cell-free tools for regenerative/reparative strategies. Yet, their clinical application is still facing considerable challenges, including production and isolation procedures, and optimal cell source. Within the emerging concept of "allogeneic-driven benefit" for SC-based therapies, the use of EVs from allogeneic sources becomes the pragmatic choice although a universal allogeneic cell source is still needed. As a unique temporary organ that ensures the mutual coexistence of two allogeneic organisms, mother and fetus, the human placenta offers a persuasive allogeneic stem cell source for development of therapeutic EVs. Advancing cell-free therapeutics nurtures great hope and provides new perspectives for the development of safe and effective treatment in regenerative/reparative medicine and beyond. We will outline the current state of the art in regard of EVs, summarize their therapeutic potential in the context of skin inflammatory disorders, and discuss their translational advantages and hurdles.


Asunto(s)
Vesículas Extracelulares/metabolismo , Medicina Regenerativa/métodos , Células Madre/metabolismo , Nanomedicina Teranóstica/métodos , Transporte Biológico , Enfermedad Crónica , Dermatitis/etiología , Dermatitis/terapia , Exosomas/metabolismo , Vesículas Extracelulares/inmunología , Humanos , Inmunomodulación , Cicatrización de Heridas
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