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1.
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
2.
Artículo en Inglés | MEDLINE | ID: mdl-32031980

RESUMEN

Background Type 2 diabetes mellitus (T2DM) is a major risk factor of atherosclerosis. Hyperglycemia in T2DM causes advanced formation of glycation end products (AGE) which leads to oxidative stress and chronic inflammation. Oxidative stress occurs due to increased levels of reactive oxygen species (ROS) such as H2O2. On the other hand, lipoprotein-associated phospholipase (Lp-PLA2) has pro-inflammatory effects, which cause instability of atherosclerosis plaques. This condition causes hypoxemic cells to stimulate HIFα induced vasa vasorum angiogenesis. This study aims to understand the potential of PSP as an anti-angiogenic agent through decreased levels of H2O2 and Lp-PLA2 leading to the decline of vasa vasorum angiogenesis in diabetic rat model. In addition, this study also measured the lipid profile of diabetic rat model in relation to vasa vasorum angiogenesis. Methods True laboratory experiment with randomized post-test control of group design using 25 wistar rats (Rattus norvegicus) were divided into five groups; one normal group and four group with High Fat Diet (HFD) and low dose streptozotocin (30 mg/kgBW) injection sc, treated with placebo and three various doses of PSP 50, 150, 300 mg/kgBW. Results ANOVA test (p < 0.05) shows that there is a significant influence of polysaccharide peptide (PSP) feeding on the decreased amount of vasa vasorum angiogenesis (p = 0.00), lipid profile (cholesterol total and triglyceride; p = 0.01, p = 0.001), and amount of H202 (p = 0.003). The amount of Lp-PLA2 declined to (p = 0.184). This result indicates that PSP prevents inflammation in atherosclerosis. Conclusions PSP of Ganoderma lucidum is an anti-angiogenic agent in T2DM.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Aterosclerosis/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Peróxido de Hidrógeno/antagonistas & inhibidores , Neovascularización Patológica/tratamiento farmacológico , Extractos Vegetales/farmacología , Reishi/química , Vasa Vasorum/efectos de los fármacos , Animales , Aterosclerosis/etiología , Aterosclerosis/patología , Neovascularización Patológica/etiología , Neovascularización Patológica/patología , Ratas , Ratas Wistar , Vasa Vasorum/patología
3.
J Med Chem ; 60(24): 10231-10244, 2017 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-29193967

RESUMEN

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Estabilidad de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Hepatocitos/efectos de los fármacos , Humanos , Masculino , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética
4.
Molecules ; 22(1)2017 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-28098805

RESUMEN

Anti-inflammatory compounds were investigated from the ethanol extract of the roots and rhizomes of Asarum heterotropoides var. mandshuricum, a traditional Chinese medicine called Xixin and used for pain and inflammatory. Nine new compounds were isolated, including six new lignans, neoasarinin A-C (1-3), neoasarininoside A and B (4 and 5), and asarinin B (7), and one new monoterpene, asarincin A (8), two new amides, asaramid II and III (10 and 11), and one new natural monoterpene, asaricin B (9), along with 37 known compounds (6, 12-47). Their structures and absolute configurations were elucidated on the basis of spectroscopic methods and chemical analyses. This is the first report of the absolute configuration of asarinin A (6). The 8-O-4' neolignans (1-5) were reported in the genus Asarum for the first time. The 15 compounds 17, 19, 22-25, 28, 31, 36, 40, 42, 43, 45-47 were isolated from the genus Asarum, and compounds 16, 32, 33, 37 and 39 were isolated from A. heterotropoides var. mandshuricum for the first time. Thirty-seven of the isolates were evaluated for anti-inflammatory activity against the release of ß-glucuronidase in polymorphonuclear leukocytes (PMNs) induced by the platelet-activating factor (PAF), and compounds 1, 4, 7, 8, 14, 17-19, 22, 24, 25, 29, 30, 32, 33, 40-43, 45, and 46 showed potent anti-inflammatory activities in vitro, with 27.9%-72.6% inhibitions at 10-5 mol/L. The results of anti-inflammatory assay suggested that lignans obtained from the CHCl3 extract might be the main active components of Xixin.


Asunto(s)
Amidas/química , Antiinflamatorios/química , Asarum/química , Medicamentos Herbarios Chinos/química , Lignanos/química , Monoterpenos/química , 1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , 1-Alquil-2-acetilglicerofosfocolina Esterasa/farmacología , Amidas/aislamiento & purificación , Amidas/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Cloroformo , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Etanol , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/metabolismo , Humanos , Lignanos/aislamiento & purificación , Lignanos/farmacología , Estructura Molecular , Monoterpenos/aislamiento & purificación , Monoterpenos/farmacología , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Extractos Vegetales/química , Raíces de Plantas/química , Cultivo Primario de Células , Ratas , Rizoma/química , Solventes/química , Relación Estructura-Actividad
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.
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
7.
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
8.
Expert Opin Investig Drugs ; 18(10): 1425-30, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19691442

RESUMEN

Phase II results of the trials of two phospholipase A2 inhibitors which may be of value in the treatment of atherosclerosis and cardiovascular disease have been reported in the past year. Darapladib (GlaxoSmithKline) is an inhibitor of lipoprotein-associated phospholipase A2 and varespladib (Anthera) inhibits several forms of the secreted phospholipase A2s. Despite the apparent similarity of mechanism, which is also built into the compounds' names, the role of the two types of phospholipase in atherogenesis is very different. Evidence for this comes from a range of preclinical studies and from epidemiological data which are summarised here. These data provide a basis for the Phase II studies and support decisions to move into Phase III, a decision which in the case of darapladib has been made and studies commenced (STABILITY trial). For varespladib the FRANCIS-ACS trial in acute coronary syndrome patients is in progress.


Asunto(s)
Aterosclerosis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Inhibidores de Fosfolipasa A2 , 1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Acetatos/farmacología , Acetatos/uso terapéutico , Animales , Aterosclerosis/fisiopatología , Benzaldehídos/farmacología , Benzaldehídos/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Cetoácidos , Oximas/farmacología , Oximas/uso terapéutico
9.
Expert Opin Ther Targets ; 6(3): 309-14, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12223071

RESUMEN

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is so named because it is found in human plasma largely associated with low-density lipoprotein (LDL). It is secreted by macrophages and able to hydrolyse oxidised fatty acids from oxidised phospholipids in LDL thereby releasing pro-atherogenic lysophosphatidylcholine and fatty acids. Inhibition of this enzyme activity was proposed to be antiatherogenic and this hypothesis has been confirmed both in vitro and in animal studies using specific inhibitors. In addition, the enzyme has been shown to be present in human atherosclerotic plaques and to be a potential risk factor for coronary heart disease in epidemiological studies. However, Lp-PLA(2) is identical to platelet-activating factor acetylhydrolase (PAF-AH), whose activity is regarded as antiatherogenic. The role of this enzyme in humans, represented as Lp-PLA(2) or PAF-AH, remains to be clarified. Specific and potent inhibitors of Lp-PLA(2) have been described and help address this question. This is a novel approach directed specifically towards processes in atherogenesis which take place in the artery wall. Innovative strategies for clinical development are required to progress novel molecular strategies such as this.


Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Aterosclerosis/tratamiento farmacológico , Diseño de Fármacos , Fosfolipasas A/antagonistas & inhibidores , 1-Alquil-2-acetilglicerofosfocolina Esterasa/fisiología , Animales , Aterosclerosis/sangre , Aterosclerosis/enzimología , Aterosclerosis/etiología , Estudios de Casos y Controles , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Lipoproteínas LDL/sangre , Macrófagos/metabolismo , Persona de Mediana Edad , Fosfolipasas A/fisiología , Fosfolipasas A2 , Conejos , Enfermedades Vasculares/sangre , Enfermedades Vasculares/enzimología
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