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1.
BMC Pharmacol Toxicol ; 25(1): 14, 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38308341

RESUMEN

OBJECTIVE: Uranium exposure may cause serious pathological injury to the body, which is attributed to oxidative stress and inflammation. However, the pathogenesis of uranium toxicity has not been clarified. Here, we evaluated the level of oxidative stress to determine the relationship between uranium exposure, nephrotoxic oxidative stress, and endothelial inflammation. METHODS: Forty male Sprague-Dawley rats were divided into three experimental groups (U-24h, U-48h, and U-72h) and one control group. The three experimental groups were intraperitoneally injected with 2.0 mg/kg uranyl acetate, and tissue and serum samples were collected after 24, 48, and 72 h, respectively, whereas the control group was intraperitoneally injected with 1.0 ml/kg normal saline and samples were collected after 24 h. Then, we observed changes in the uranium levels and oxidative stress parameters, including the total oxidative state (TOS), total antioxidant state (TAS), and oxidative stress index (OSI) in kidney tissue and serum. We also detected the markers of kidney injury, namely urea (Ure), creatine (Cre), cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL). The endothelial inflammatory markers, namely C-reactive protein (CRP), lipoprotein phospholipase A2 (Lp-PLA2), and homocysteine (Hcy), were also quantified. Finally, we analyzed the relationship among these parameters. RESULTS: TOS (z = 3.949; P < 0.001), OSI (z = 5.576; P < 0.001), Ure (z = 3.559; P < 0.001), Cre (z = 3.476; P < 0.001), CysC (z = 4.052; P < 0.001), NGAL (z = 3.661; P < 0.001), and CRP (z = 5.286; P < 0.001) gradually increased after uranium exposure, whereas TAS (z = -3.823; P < 0.001), tissue U (z = -2.736; P = 0.001), Hcy (z = -2.794; P = 0.005), and Lp-PLA2 (z = -4.515; P < 0.001) gradually decreased. The serum U level showed a V-shape change (z = -1.655; P = 0.094). The uranium levels in the kidney tissue and serum were positively correlated with TOS (r = 0.440 and 0.424; P = 0.005 and 0.007) and OSI (r = 0.389 and 0.449; P = 0.013 and 0.004); however, serum U levels were negatively correlated with TAS (r = -0.349; P = 0.027). Partial correlation analysis revealed that NGAL was closely correlated to tissue U (rpartial = 0.455; P = 0.003), CysC was closely correlated to serum U (rpartial = 0.501; P = 0.001), and Lp-PLA2 was closely correlated to TOS (rpartial = 0.391; P = 0.014), TAS (rpartial = 0.569; P < 0.001), and OSI (rpartial = -0.494; P = 0.001). Pearson correlation analysis indicated that the Hcy levels were negatively correlated with tissue U (r = -0.344; P = 0.030) and positively correlated with TAS (r = 0.396; P = 0.011). CONCLUSION: The uranium-induced oxidative injury may be mainly reflected in enhanced endothelial inflammation, and the direct chemical toxicity of uranium plays an important role in the process of kidney injury, especially in renal tubular injury. In addition, CysC may be a sensitive marker reflecting the nephrotoxicity of uranium; however, Hcy is not suitable for evaluating short-term endothelial inflammation involving oxidative stress.


Asunto(s)
Uranio , Ratas , Masculino , Animales , Lipocalina 2/metabolismo , Uranio/toxicidad , Uranio/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Ratas Sprague-Dawley , Estrés Oxidativo , Antioxidantes/farmacología , Riñón/patología , Inflamación/metabolismo , Urea
2.
Biomolecules ; 11(6)2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-34071485

RESUMEN

Platelet-activating factor (PAF), a proinflammatory lipid mediator, plays a crucial role in the formation of the atherosclerotic plaque. Therefore, the inhibition of endothelium inflammation by nutraceuticals, such as PAF inhibitors, is a promising alternative for preventing cardiovascular diseases. The aim of the present study was to evaluate the impact of a new functional yogurt enriched with PAF inhibitors of natural origin from olive oil by-products on PAF metabolism. Ninety-two apparently healthy, but mainly overweight volunteers (35-65 years) were randomly allocated into three groups by block-randomization. The activities of PAF's biosynthetic and catabolic enzymes were measured, specifically two isoforms of acetyl-CoA:lyso-PAF acetyltransferase (LPCATs), cytidine 5'-diphospho-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT) and two isoforms of platelet activating factor acetylhydrolase in leucocytes (PAF-AH) and plasma (lipoprotein associated phospholipase-A2, LpPLA2). The intake of the enriched yogurt resulted in reduced PAF-CPT and LpPLA2 activities. No difference was observed in the activities of the two isoforms of lyso PAF-AT. In conclusion, intake of yogurt enriched in PAF inhibitors could favorably modulate PAF biosynthetic and catabolic pathways.


Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa/antagonistas & inhibidores , 1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Suplementos Dietéticos , Inhibidores Enzimáticos/administración & dosificación , Olea , Factor de Activación Plaquetaria , Yogur , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factor de Activación Plaquetaria/antagonistas & inhibidores , Factor de Activación Plaquetaria/metabolismo
3.
Mol Nutr Food Res ; 65(13): e2100337, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33966345

RESUMEN

SCOPE: The authors used metabolomics to investigate the nutritional modulatory effect of fermented Maillard-reactive whey protein (F-MRP) on the activity of natural killer (NK) cells. METHODS AND RESULTS: Fifty subjects who had participated in our previous intervention study were included in the present study in the test (n = 20) and placebo groups (n = 30). Additional analyses using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) and gas chromatography (GC)-MS were conducted to identify relevant metabolic features. After 8 weeks, the activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) (p = 0.021), levels of interleukin (IL)-1ß (p = 0.001), and activity of NK cells were considerably increased in the test group compared with those in the placebo group. Based on the metabolites discovered by UPLC-MS, ten altered metabolic pathways were observed in the test group after 8 weeks of F-MRP consumption. Specific pathways with most pronounced associations with immune-enhancing effect of F-MRP included aminoacyl-tRNA biosynthesis, glycine/serine/threonine metabolism, arginine/proline metabolism, and sphingolipid metabolism. CONCLUSIONS: The present study demonstrated the effects of 8 weeks of F-MRP supplementation on the metabolic status manifested as changes in the Lp-PLA2 activity, IL-1ß level, and activity of NK cells. Intermediate metabolites of the identified metabolic pathways can be used to confirm the immune-enhancing efficacy of short-term supplementation.


Asunto(s)
Suplementos Dietéticos , Células Asesinas Naturales/efectos de los fármacos , Proteína de Suero de Leche/administración & dosificación , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Adulto , Aminoácidos/metabolismo , Ácidos Grasos/análisis , Femenino , Fermentación , Humanos , Interleucina-1beta/metabolismo , Células Asesinas Naturales/metabolismo , Reacción de Maillard , Masculino , Redes y Vías Metabólicas , Metabolómica , Persona de Mediana Edad , Proteína de Suero de Leche/farmacología
4.
Toxicol Appl Pharmacol ; 403: 115158, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32717241

RESUMEN

Cancer mortality is mainly caused by metastasis, which requires dynamic remodeling of cytoskeletal components such as microtubules. Targeting microtubules presents a promising antimetastatic strategy that could prevent cancer spreading and recurrence. It is known that arsenic trioxide (ATO) is able to inhibit the migration and invasion of solid malignant tumors, but its exact molecular mechanism remains unclear. Here, we report a novel molecular target and antimetastatic mechanism of ATO in head and neck squamous cell carcinoma (HNSCC). We found that cytoplasmic linker protein 170 (CLIP170) was overexpressed in HNSCC tissues and cells compared to normal controls. ATO at non-cytotoxic level (1 µM) inhibited the migration and invasion of HNSCC cells by displacing zinc in the zinc finger motif of CLIP170, which is a key protein that controls microtubule dynamics. The antimetastatic effects of ATO were equivalent to those of siRNA-mediated CLIP170 knockdown. Furthermore, ATO dysregulated microtubule polymerization via the CLIP170/LIS1/NDEL1/dynein signaling pathway in Cal27 cells as a functional consequence of CLIP170 zinc finger disruption. The effect was partially reversed by zinc supplementation. Taken together, these findings reveal that CLIP170 is a novel molecular target of ATO and demonstrate the capability and underlying mechanisms of ATO as a potential antimetastatic agent for HNSCC treatment.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Trióxido de Arsénico/farmacología , Proteínas Portadoras/metabolismo , Dineínas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Adulto , Proteínas Portadoras/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Dineínas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos , Persona de Mediana Edad , Proteínas de Neoplasias/genética
5.
J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27167608

RESUMEN

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
6.
Mol Nutr Food Res ; 59(9): 1771-9, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26018800

RESUMEN

SCOPE: ω3-polyunsaturated fatty acids (ω3-PUFAs) have beneficial effects on cardiovascular function, and lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is associated with the risk of cardiovascular disease. Here, we investigated the effects of ω3-PUFAs on Lp-PLA2 expression in vitro and in vivo and explored the mechanisms involved. METHODS AND RESULTS: Human monocyticcells (THP-1) were induced into macrophages in an in vitro model. ω3-PUFAs suppressed Lp-PLA2 expression; the suppression induced by docosahexaenoic acid (DHA) was related to reduced inflammation. Tumor necrosis factor-α (TNF-α) was employed to stimulate the phosphorylation of p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB) p65 and Lp-PLA2 expression in macrophages. The stimulation was inhibited by DHA and the anti-inflammatory drug sodium salicylate. Moreover, the stimulation of Lp-PLA2 expression by TNF-α could be suppressed by NF-κB and MAPK pathway inhibitors. Then, chronic inflammation was induced in an in vivo mouse model, resulting in an increase in Lp-PLA2 expression in peripheral blood mononuclear cells (PBMCs) and arteries. This increase was suppressed by ω3-PUFAs. Inhibition of Lp-PLA2 transcription in PBMCs was also observed in ω3-PUFA-enriched swine. CONCLUSION: Our results demonstrate that the protective effects of ω3-PUFAs against cardiovascular events may be related to the suppression of Lp-PLA2 levels.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Ácidos Grasos Omega-3/farmacología , Regulación de la Expresión Génica , Macrófagos/efectos de los fármacos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Animales , Antiinflamatorios/farmacología , Enfermedades Cardiovasculares/prevención & control , Línea Celular , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/farmacología , Regulación hacia Abajo , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
7.
Food Funct ; 6(6): 2008-16, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26018873

RESUMEN

Disorders of blood lipid metabolism are the primary risk factors for many diseases. Recently, the effect of Pu-erh tea on blood lipid metabolism has received increasing attention. However, the mechanism underlying its ability to regulate blood lipid metabolism is unclear. We set out to study this through assessing the effects of Pu-erh tea aqueous extract (PTAE) on the central enzymes of blood lipid metabolism, including lipoprotein-associated phospholipase A2 (Lp-PLA2), lecithin: cholesterol acyltransferase (LCAT), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and pancreatic lipase (PL). We find that the Lp-PLA2, HMRG and PL activities are inhibited by PTAE in a dose-dependent manner and that the LCAT activity tends to increase with increasing PTAE concentrations. Lineweaver-Burk plot analyses reveal that PTAE acts as a competitive inhibitor for HMGR and PL and as a noncompetitive inhibitor for Lp-PLA2. Moreover, we determine that its active ingredients include catechins, gallic acid, caffeine, free amino acids, and soluble sugar. However, the effect of each ingredient and whether any of them have synergistic effects are still unknown. The results suggest that Pu-erh tea has a potent ability to regulate blood lipid metabolism and knowledge of the mechanisms provides insights into its potential therapeutic application as an alternative hypolipidemic drug.


Asunto(s)
Camellia sinensis/química , Inhibidores Enzimáticos/análisis , Alimentos Funcionales/análisis , Hipolipemiantes/análisis , Fitoquímicos/análisis , Hojas de la Planta/química , Té/química , 1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , 1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Animales , Camellia sinensis/microbiología , China , Inhibidores Enzimáticos/farmacología , Etnofarmacología , Fermentación , Manipulación de Alimentos , Alimentos Funcionales/microbiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/análisis , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipolipemiantes/farmacología , Cinética , Lipasa/antagonistas & inhibidores , Lipasa/metabolismo , Masculino , Medicina Tradicional China , Fosfatidilcolina-Esterol O-Aciltransferasa/antagonistas & inhibidores , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/microbiología , Conejos , Ratas , Té/microbiología
8.
ACS Chem Biol ; 10(4): 925-32, 2015 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-25602368

RESUMEN

Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300,000+ compound library. The most potent of these agents, P11, exhibited IC50 values of ∼40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos/métodos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Polarización de Fluorescencia/métodos , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Proteómica/métodos , Piridinas/química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad
9.
Lipids Health Dis ; 10: 213, 2011 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-22087726

RESUMEN

BACKGROUND: Platelet activating factor (PAF) has been proposed as a key factor and initial trigger in atherosclerosis. Recently, a modulation of PAF metabolism by bioactive food constituents has been suggested. In this study we investigated the effect of fish polar lipid consumption on PAF metabolism. RESULTS: The specific activities of four PAF metabolic enzymes; in leukocytes, platelets and plasma, and PAF concentration; either in blood cells or plasma were determined. Samples were acquired at the beginning and at the end of a previously conducted study in male New Zealand white rabbits that were fed for 45 days with atherogenic diet supplemented (group-B, n = 6) or not (group-A, n = 6) with gilthead sea bream (Sparus aurata) polar lipids.The specific activity of PAF-Acetylhydrolase (PAF-AH); a catabolic enzyme of PAF, was decreased in rabbits' platelets of both A and B groups and in rabbits' leukocytes of group A (p < 0.05). On the other hand the specific activity of Lipoprotein-associated Phospholipase A2 (Lp-PLA2); the catabolic enzyme of PAF in plasma was increased in both A and B groups in both leukocytes and platelets (p < 0.05). PAF-cholinephosphotransferase (PAF-CPT); a biosynthetic enzyme of PAF showed increased specific activity only in rabbits' leukocytes of group A (p < 0.05). Neither of the two groups showed any change in Lyso-PAF-acetyltransferase (Lyso-PAF-AT) specific activity (p > 0.05). Free and bound PAF levels increased in group A while decreased in group B (p < 0.05). CONCLUSIONS: Gilthead sea bream (Sparus aurata) polar lipids modulate PAF metabolism upon atherosclerotic conditions in rabbits leading to lower PAF levels and activity in blood of rabbits with reduced early atherosclerotic lesions compared to control group.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Activadores de Enzimas/uso terapéutico , Aceites de Pescado/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Factor de Activación Plaquetaria/biosíntesis , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Animales , Aterosclerosis/enzimología , Aterosclerosis/prevención & control , Plaquetas/enzimología , Diacilglicerol Colinafosfotransferasa/genética , Diacilglicerol Colinafosfotransferasa/metabolismo , Dieta Mediterránea , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Ácidos Grasos/química , Aceites de Pescado/química , Aceites de Pescado/farmacología , Expresión Génica , Leucocitos/enzimología , Masculino , Factor de Activación Plaquetaria/metabolismo , Conejos , Dorada
10.
Prev Cardiol ; 13(3): 130-4, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20626668

RESUMEN

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil, extended-release niacin, colesevelam hydrochloride, and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin. The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/efectos de los fármacos , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/efectos de los fármacos , Quimioterapia Combinada , Dislipidemias/tratamiento farmacológico , Estilo de Vida , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Alilamina/análogos & derivados , Alilamina/uso terapéutico , Azetidinas/uso terapéutico , Biomarcadores , LDL-Colesterol/metabolismo , Clorhidrato de Colesevelam , Ezetimiba , Ácidos Grasos Omega-3/uso terapéutico , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Niacina/uso terapéutico , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Simvastatina/uso terapéutico , Estadística como Asunto , Complejo Vitamínico B/uso terapéutico
11.
Lipids Health Dis ; 8: 55, 2009 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-20015371

RESUMEN

BACKGROUND: Atherosclerosis is a chronic disorder of the arterial wall that starts by formation of fatty streaks and gradually evolves into atherosclerotic plaques. High-density lipoproteins (HDL) blood levels are inversely correlated with atherosclerosis. This beneficial effect of HDL has been partly attributed to its antioxidant properties mediated by paraoxonase1 (PON1) or platelet-activating factor acetylhydrolase (PAF-AH). The present study was aimed to study HDL associated enzymes i.e. PON1 and PAF-AH under experimental hypercholesterolemia and their possible modulation on selenium (Se; an antioxidant) supplementation. Male Sprague Dawley rats were divided into three groups and fed on the control diet, high fat diet (HFD) and HFD + Se respectively for the period of 4 months. RESULTS: Cholesterol, triglycerides, HDL and LDL levels were significantly increased by HFD feeding. Selenium supplementation lowered the triglyceride level, whereas the other lipid values remained unchanged. Serum selenium levels were reduced by 31% and ROS levels in the liver were 2-fold increased by HFD. Se supplementation, however, diminished the HFD-induced ROS levels by 29%. Furthermore, Se also improved the HFD-mediated reduction of serum PON1 enzyme activity by 34% and PON1 protein levels by 21%. However, no significant effect of Se was detected on the reduced PAF-AH proteins levels in HFD fed rats. mRNA expression of PON1 and PAF-AH in the liver was not affected in the Se treated groups. CONCLUSION: Se supplementation appears to be protective in hypercholesterolemia by restoring the antioxidant properties of the HDL associated enzyme i.e. PON1 whereas biological system aims towards maintaining the same PAF-AH levels even on selenium supplementation indicating its probable role in both anti and pro-atherogenic activities. Therefore, Se supplementation might be a valuable approach to limit the adverse effects of hypercholesterolemia and may need further investigations.


Asunto(s)
Suplementos Dietéticos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/enzimología , Lipoproteínas HDL/sangre , Selenio/uso terapéutico , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Animales , Arildialquilfosfatasa/genética , Arildialquilfosfatasa/metabolismo , Ensayo de Inmunoadsorción Enzimática , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipercolesterolemia/sangre , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Selenio/administración & dosificación , Selenio/sangre , Selenio/farmacología
12.
Subcell Biochem ; 49: 241-68, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18751914

RESUMEN

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.


Asunto(s)
Encefalopatías/metabolismo , Lesiones Encefálicas/metabolismo , Enfermedades del Sistema Nervioso Central/metabolismo , Metabolismo de los Lípidos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/complicaciones , Aterosclerosis/metabolismo , Trastorno Bipolar/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Humanos , Inflamación/fisiopatología , Peroxidación de Lípido , Lípidos de la Membrana/metabolismo , Enfermedades de Niemann-Pick/metabolismo , Estrés Oxidativo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Esquizofrenia/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/metabolismo
13.
Nutr Metab Cardiovasc Dis ; 16(3): 174-85, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16580585

RESUMEN

BACKGROUND AND AIM: The consumption of olive oil has been associated with lower incidence of cardiovascular disease in the Mediterranean countries. This may be due in part to the action of platelet-activating factor (PAF) antagonists which we have previously demonstrated to be present in olive oil. In order to assess the in vivo effects of olive oil lipids and PAF in the development of atherosclerosis, the effects of diet supplementation with olive oil (OO), olive oil polar lipid extract (OOPLE) and olive oil neutral lipid extract (OONLE) were studied in rabbits fed a cholesterol-enriched diet. METHODS AND RESULTS: Rabbits were fed for 45 days with atherogenic diet (Group A) supplemented with OO (Group B), OOPLE (Group C) or OONLE (Group D). Lipoprotein profiles, plasma in vitro oxidation, blood PAF levels, PAF-induced platelet aggregation and PAF-acetylhydrolase (PAF-AH) activity, were measured on day 0 and 45. Atherosclerotic lesions formed in the aortic wall and wall elasticity were assessed on day 45. Changes in lipid profile were in accordance with previous studies. Blood PAF levels were higher in group A and decreased in group D on day 45. In rabbits fed an atherogenic diet (Group A) blood PAF and PAF-AH increased, atherosclerotic lesions formed and the elasticity of vessel walls declined. In animals fed olive oil (Group B) or OOPLE (Group C) blood PAF-AH increased, platelet aggregation was attenuated, less oxidation occurred in plasma, lesion thickness was reduced and vessel walls retained elasticity. Most of these beneficial changes were not seen in animals fed OONLE (Group D) although blood PAF and plasma oxidation were lower. CONCLUSIONS: The antiatherogenic effects of OO result from OOPLE. The beneficial effect of these factors is linked to PAF metabolism and proaggregant activity.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Aterosclerosis/prevención & control , Lipoproteínas/sangre , Aceites de Plantas/farmacología , Factor de Activación Plaquetaria , Agregación Plaquetaria/efectos de los fármacos , Animales , Aorta/patología , Aorta/ultraestructura , Aterosclerosis/patología , Dieta Aterogénica , Modelos Animales de Enfermedad , Hiperlipidemias/complicaciones , Hiperlipidemias/dietoterapia , Hiperlipidemias/metabolismo , Masculino , Aceite de Oliva , Oxidación-Reducción , Aceites de Plantas/química , Factor de Activación Plaquetaria/antagonistas & inhibidores , Factor de Activación Plaquetaria/efectos de los fármacos , Factor de Activación Plaquetaria/metabolismo , Conejos
14.
J Biol Chem ; 281(8): 4616-23, 2006 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-16371369

RESUMEN

F2-isoprostanes are produced in vivo by nonenzymatic peroxidation of arachidonic acid esterified in phospholipids. Increased urinary and plasma F2-isoprostane levels are associated with a number of human diseases. These metabolites are regarded as excellent markers of oxidant stress in vivo. Isoprostanes are initially generated in situ, i.e. when the arachidonate precursor is esterified in phospholipids, and they are subsequently released in free form. Although the mechanism(s) responsible for the release of free isoprostanes after in situ generation in membrane phospholipids is, for the most part, unknown, this process is likely mediated by phospholipase A2 activity(ies). Here we reported that human plasma contains an enzymatic activity that catalyzes this reaction. The activity associates with high density and low density lipoprotein and comigrates with platelet-activating factor (PAF) acetylhydrolase on KBr density gradients. Plasma samples from subjects deficient in PAF acetylhydrolase do not release F2-isoprostanes from esterified precursors. The intracellular PAF acetylhydrolase II, which shares homology to the plasma enzyme, also catalyzes this reaction. We found that both the intracellular and plasma PAF acetylhydrolases have high affinity for esterified F2-isoprostanes. However, the rate of esterified F2-isoprostane hydrolysis is much slower compared with the rate of hydrolysis of other substrates utilized by these enzymes. Studies using PAF acetylhydrolase transgenic mice indicated that these animals have a higher capacity to release F2-isoprostanes compared with nontransgenic littermates. Our results suggested that PAF acetylhydrolases play key roles in the hydrolysis of F2-isoprostanes esterified on phospholipids in vivo.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , F2-Isoprostanos/química , Fosfolípidos/química , 1-Alquil-2-acetilglicerofosfocolina Esterasa/química , Acetatos/química , Aldehídos/química , Animales , Bromuros/química , Catálisis , ADN Complementario/metabolismo , Humanos , Hidrólisis , Isoprostanos/química , Cinética , Lipoproteínas/química , Ratones , Ratones Transgénicos , Ovalbúmina/metabolismo , Oxidantes/química , Estrés Oxidativo , Fosfatidilcolinas/química , Fosfolipasas A2 , Éteres Fosfolípidos/química , Compuestos de Potasio/química , Proteínas Recombinantes/química , Tráquea/metabolismo
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