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1.
Cell Physiol Biochem ; 48(6): 2231-2246, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30114701

RESUMEN

BACKGROUND/AIMS: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. METHODS: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan's National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. RESULTS: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. CONCLUSION: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.


Asunto(s)
Angelica sinensis/química , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Angelica sinensis/metabolismo , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Anhídridos Ftálicos/química , Anhídridos Ftálicos/farmacología , Anhídridos Ftálicos/uso terapéutico , Modelos de Riesgos Proporcionales , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Factores de Transcripción/agonistas , Transcriptoma/efectos de los fármacos
2.
Biochem Biophys Res Commun ; 486(2): 378-384, 2017 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-28315325

RESUMEN

Muscle loss is a typical process of aging. Green tea consumption is known to slow down the progress of aging. Their underlying mechanisms, however, remain largely unknown. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic compound of green tea, on myogenic differentiation and found that EGCG significantly increases myogenic differentiation. After EGCG treatment, the expression of myogenic marker genes, such as myosin heavy chain, are increased through activation of TAZ, a transcriptional coactivator with a PDZ-binding motif. TAZ-knockdown does not stimulate EGCG-induced myogenic differentiation. EGCG facilitates the interaction between TAZ and MyoD, which stimulates MyoD-mediated gene transcription. EGCG induces nuclear localization of TAZ through the dephosphorylation of TAZ at its Ser89 residue, which relieves 14-3-3 binding in the cytosol. Interestingly, inactivation of Lats kinase is observed after EGCG treatment, which is responsible for the production of dephosphorylated TAZ. Together, these results suggest that EGCG induces myogenic differentiation through TAZ, suggesting that TAZ plays an important role in EGCG induced muscle regeneration.


Asunto(s)
Catequina/análogos & derivados , Diferenciación Celular/efectos de los fármacos , Mioblastos/efectos de los fármacos , Células Satélite del Músculo Esquelético/efectos de los fármacos , Factores de Transcripción/agonistas , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Aciltransferasas , Animales , Catequina/farmacología , Línea Celular , Regulación de la Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Proteína MioD/genética , Proteína MioD/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Miogenina/genética , Miogenina/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Células Satélite del Músculo Esquelético/citología , Células Satélite del Músculo Esquelético/metabolismo , Transducción de Señal , Té/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Biosci Biotechnol Biochem ; 80(7): 1425-32, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26940726

RESUMEN

Bone homeostasis is maintained by balancing bone formation and bone resorption, but an imbalance between them is associated with various bone-related diseases such as osteoporosis and rheumatoid arthritis. We found that 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK), which were isolated as promising compounds from Alpinia zerumbet rhizomes, promote differentiation of osteoblastic MC3T3-E1 cells. DK and DDK increased the alkaline phosphatase activity and matrix mineralization of MC3T3-E1 cells. DK exerts larger effects than DDK. The gene expression of runt-related transcription factor 2 and osterix, which are essential transcription factors in the early period of osteoblast differentiation, was significantly increased by DK treatment. The mRNA level of distal-less homeobox 5 was also enhanced by DK treatment, and DK activated the p38 mitogen-activated protein kinase pathway. Therefore, DK may have clinical potential for preventing osteoporosis, and could be considered as a potential anabolic therapeutic agent.


Asunto(s)
Alpinia/química , Diferenciación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Pironas/farmacología , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/agonistas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Regulación de la Expresión Génica , Proteínas de Homeodominio/agonistas , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis/genética , Extractos Vegetales/química , Pironas/aislamiento & purificación , ARN Mensajero/agonistas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rizoma/química , Factor de Transcripción Sp7 , Factores de Transcripción/agonistas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Int J Toxicol ; 34(3): 274-83, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25972379

RESUMEN

In the present study, the neuroprotective effect of 5-hydroxy-6,7,4'-trimethoxyflavone (flavone 1), a natural flavone, was investigated in comparison with another flavone, 5,7,4'-trihydroxyflavone (flavone 2) on the hippocampus of amyloid beta (Aß)-injected rats. Rats were treated with the 2 flavones (1 mg/kg/d) for 1 week before Aß injection. Seven days after Aß administration, memory function of rats was assessed in a passive avoidance test (PAT). Changes in the levels of mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), phospho-adenosine monophosphate (AMP)-activated protein kinase (pAMPK), AMPK, phospho-cAMP-responsive element-binding protein (CREB), CREB, and nuclear respiratory factor 1 (NRF-1) proteins were determined by Western blot analysis. Our results showed an improvement in memory in rats pretreated with flavonoids. At the molecular level, phosphorylation of CREB, known as the master modulator of memory processes, increased. On the other hand, the level of mitochondrial biogenesis factors, PGC-1α and its downstream molecules NRF-1 and TFAM significantly increased by dietary administration of 2 flavones. In addition, flavone 1 and flavone 2 prevented mitochondrial swelling and mitochondrial membrane potential reduction. Our results provided evidence that flavone 1 is more effective than flavone 2 presumably due to its O-methylated groups. In conclusion, it seems that in addition to classical antioxidant effect, flavones exert part of their protective effects through mitochondrial biogenesis.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Suplementos Dietéticos , Modelos Animales de Enfermedad , Flavonas/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Nootrópicos/uso terapéutico , Factores de Transcripción/agonistas , Enfermedad de Alzheimer/metabolismo , Animales , Reacción de Prevención , Conducta Animal , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/agonistas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo/metabolismo , Masculino , Memoria , Dinámicas Mitocondriales , Proteínas Mitocondriales/agonistas , Proteínas Mitocondriales/metabolismo , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fosforilación , Procesamiento Proteico-Postraduccional , Ratas Wistar , Factores de Transcripción/metabolismo
5.
Free Radic Biol Med ; 71: 339-350, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24675225

RESUMEN

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 and dentatorubropallidoluysian atrophy, as well as Huntington disease, are a group of neurodegenerative disorders caused by a CAG triplet-repeat expansion encoding a long polyglutamine (polyQ) tract in the respective mutant proteins. The cytoplasmic and nuclear aggregate formation, a pathological hallmark of polyQ diseases, is probably the initial process triggering the subsequent pathological events. Compromised oxidative stress defense capacity and mitochondrial dysfunction have emerged as contributing factors to the pathogenesis of polyQ diseases. The roots of licorice (Glycyrrhiza species) have long been used as an herbal medicine. In this study, we demonstrate the aggregate-inhibitory effect of Glycyrrhiza inflata herb extract and its constituents licochalcone A and ammonium glycyrrhizinate (AMGZ) in both 293 and SH-SY5Y ATXN3/Q75 cells, SCA3 cell models. The reporter assay showed that G. inflata herb extract, licochalcone A, and AMGZ could enhance the promoter activity of peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A), a known regulator of mitochondrial biogenesis and antioxidative response genes. G. inflata extract, licochalcone A, and AMGZ upregulated PPARGC1A expression and its downstream target genes, SOD2 and CYCS, in the 293 ATXN3/Q75 cell model. The expression of nuclear factor erythroid 2-related factor 2 (NFE2L2), the principal transcription factor that binds to antioxidant-responsive elements (AREs) to promote ARE-dependent gene expression when the cells respond to oxidative stress, and its downstream genes, HMOX1, NQO1, GCLC, and GSTP1, was also increased by G. inflata herb extract, licochalcone A, and AMGZ. Knockdown of PPARGC1A increased aggregates in ATXN3/Q75 cells and also attenuated the aggregate-inhibiting effect of the tested compounds. G. inflata extract and its constituents significantly elevated GSH/GSSG ratio and reduced reactive oxidative species in ATXN3/Q75 cells. The study results suggest that the tested agents activate PPARGC1A activity and NFE2L2-ARE signaling to increase mitochondrial biogenesis, decrease oxidative stress, and reduce aggregate formation in SCA3 cellular models.


Asunto(s)
Elementos de Respuesta Antioxidante , Glycyrrhiza/química , Factor 2 Relacionado con NF-E2/agonistas , Péptidos/antagonistas & inhibidores , Extractos Vegetales/farmacología , Factores de Transcripción/agonistas , Línea Celular Tumoral , Chalconas/farmacología , Regulación de la Expresión Génica , Gutatión-S-Transferasa pi/genética , Gutatión-S-Transferasa pi/metabolismo , Ácido Glicirrínico/farmacología , Células HEK293 , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/patología , Modelos Biológicos , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas , Estrés Oxidativo , Péptidos/química , Péptidos/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química , Agregado de Proteínas , Transducción de Señal , Superóxido Dismutasa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Agua
6.
Eur J Nutr ; 53(3): 929-37, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24146099

RESUMEN

BACKGROUND AND AIM: Apoptosis is a major cause of myocyte death, and taurine is anti-apoptotic. Heat shock protein 70 (HSP70) (which is regulated by heat shock factor-HSF-1) is also anti-apoptotic, and caspase 3 stimulates the apoptotic pathway. This study investigated whether taurine affects atherogenic diet-induced myocardial apoptosis, and whether HSP70, HSF-1 and caspase 3 are involved. METHODS: New Zealand white rabbits were divided into 3 groups for 4 weeks according to their diet. Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol. Group 3 received MC diet + 2.5% taurine (MCT). RESULTS: The atherogenic diet did not affect myocardial HSP70 or HSF-1 protein, but increased myocardial apoptotic nuclei to 40% (p < 0.01) versus 7% in con and 12% in MCT (p < 0.01). However, in MCT, myocardial HSP70 expression increased by 42.7% versus con and MC (p = 0.016), HSF-1 by 12% versus con and MC (p < 0.05), and total nuclei count increased by 37% versus MC (p < 0.05). Caspase 3 subunits remained unchanged in all groups, and HSP70 was increased approximately twofold in endothelial layer of arterioles (p = 0.01). CONCLUSION: This study shows that taurine could reduce myocardial apoptotic nuclei and thus confer myocardial cytoprotection via stimulating myocardial HSP70 via HSF-1 and caspase 3-independent mechanisms.


Asunto(s)
Apoptosis , Aterosclerosis/prevención & control , Proteínas de Unión al ADN/agonistas , Suplementos Dietéticos , Proteínas HSP70 de Choque Térmico/agonistas , Miocardio/metabolismo , Taurina/uso terapéutico , Factores de Transcripción/agonistas , Animales , Antioxidantes/uso terapéutico , Arteriolas/enzimología , Arteriolas/metabolismo , Arteriolas/patología , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Cardiotónicos/uso terapéutico , Caspasa 3/metabolismo , Vasos Coronarios/enzimología , Vasos Coronarios/metabolismo , Vasos Coronarios/patología , Proteínas de Unión al ADN/metabolismo , Dieta Aterogénica/efectos adversos , Endotelio Vascular/enzimología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Proteínas HSP70 de Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico , Inmunohistoquímica , Masculino , Miocardio/enzimología , Miocardio/patología , Estrés Oxidativo , Conejos , Distribución Aleatoria , Factores de Transcripción/metabolismo
7.
Rejuvenation Res ; 13(2-3): 148-51, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20370498

RESUMEN

The age-related decay of mitochondrial function is a major contributor to the aging process. We tested the effects of 2-month-daily acetyl-L-carnitine (ALCAR) supplementation on mitochondrial biogenesis in the soleus muscle of aged rats. This muscle is heavily dependent on oxidative metabolism. Mitochondrial (mt) DNA content, citrate synthase activity, transcript levels of some nuclear- and mitochondrial-coded genes (cytochrome c oxidase subunit IV [COX-IV], 16S rRNA, COX-I) and of some factors involved in the mitochondrial biogenesis signaling pathway (peroxisome proliferator-activated receptor gamma [PPARgamma] coactivator-1alpha [PGC-1alpha], mitochondrial transcription factor A mitochondrial [TFAM], mitochondrial transcription factor 2B [TFB2]), as well as the protein content of PGC-1alpha were determined. The results suggest that the ALCAR treatment in old rats activates PGC-1alpha-dependent mitochondrial biogenesis, thus partially reverting the age-related mitochondrial decay.


Asunto(s)
Acetilcarnitina/farmacología , Envejecimiento/efectos de los fármacos , Suplementos Dietéticos , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Proteínas de Unión al ARN/fisiología , Factores de Transcripción/fisiología , Acetilcarnitina/administración & dosificación , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/genética , Citrato (si)-Sintasa/metabolismo , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Genes Mitocondriales/efectos de los fármacos , Masculino , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/fisiología , Músculo Esquelético/citología , Músculo Esquelético/ultraestructura , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN/agonistas , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Endogámicas F344 , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismo
8.
Biochem Biophys Res Commun ; 394(3): 439-42, 2010 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-20226165

RESUMEN

Celastrol, a quinone methide triterpene, is a pharmacologically active compound present in Thunder God Vine root extracts used as a remedy of inflammatory and autoimmune diseases, e.g. rheumatoid arthritis. Celastrol is one of the most promising medicinal molecules isolated from the plant extracts of traditional medicines. Molecular studies have identified several molecular targets which are mostly centered on the inhibition of IKK-NF-kappaB signaling. Celastrol (i) inhibits directly the IKKalpha and beta kinases, (ii) inactivates the Cdc37 and p23 proteins which are co-chaperones of HSP90, (iii) inhibits the function of proteasomes, and (iv) activates the HSF1 and subsequently triggers the heat shock response. It seems that the quinone methide structure present in celastrol can react with the thiol groups of cysteine residues, forming covalent protein adducts. In laboratory experiments, celastrol has proved to be a potent inhibitor of inflammatory responses and cancer formation as well as alleviating diseases of proteostasis deficiency. Celastrol needs still to pass several hurdles, e.g. ADMET assays, before it can enter the armoury of western drugs.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Tripterygium/química , Triterpenos/farmacología , Antiinflamatorios no Esteroideos/química , Autoinmunidad/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Chaperoninas/antagonistas & inhibidores , Cisteína/química , Proteínas de Unión al ADN/agonistas , Proteínas HSP70 de Choque Térmico/metabolismo , Factores de Transcripción del Choque Térmico , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Triterpenos Pentacíclicos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Prostaglandina-E Sintasas , Factores de Transcripción/agonistas , Triterpenos/química
9.
Clin Rev Allergy Immunol ; 36(1): 52-61, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18751930

RESUMEN

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects. Ursodeoxycholic acid (UDCA) has consistently been shown to improve serum liver tests and might lower the risk of colon carcinoma and cholangiocarcinoma by yet unknown mechanisms. Whether "high dose" UDCA improves the long-term prognosis in PSC as suggested by small pilot trials remains to be demonstrated. The present overview discusses potential therapeutic options aside of targeted immunological therapies and UDCA. The C23 bile acid norUDCA has been shown to markedly improve biochemical and histological features in a mouse model of sclerosing cholangitis without any toxic effects. Studies in humans are eagerly being awaited. Nuclear receptors like the farnesoid-X receptor (FXR), pregnane-X receptor (PXR), vitamin D receptor (VDR), and peroxisome-proliferator-activator receptors (PPARs) have been shown to induce expression of diverse carriers and biotransformation enzymes of the intestinal and hepatic detoxification machinery and/or to modulate fibrogenesis. Pros and cons of respective receptor agonists for the future treatment of PSC are discussed in detail. In our view, the novel bile acid norUDCA and agonists of PPARs, VDR, and PXR appear particularly attractive for further studies in PSC.


Asunto(s)
Colangitis Esclerosante/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéutico , Animales , Colangitis Esclerosante/inmunología , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/metabolismo , Humanos , Ligandos , Ratones , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptor X de Pregnano , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/agonistas , Receptores de Esteroides/metabolismo , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Ácido Ursodesoxicólico/análogos & derivados
10.
J Nat Prod ; 72(1): 24-8, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19102680

RESUMEN

Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (1)-activated rate of human pancreatic IB phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.


Asunto(s)
Anticolesterolemiantes/farmacología , Ácidos y Sales Biliares/metabolismo , Colesterol/metabolismo , Diterpenos/farmacología , Inhibidores de Fosfolipasa A2 , Pregnenodionas/farmacología , Animales , Commiphora , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/antagonistas & inhibidores , Humanos , Modelos Moleculares , Estructura Molecular , Páncreas/enzimología , Fosfolipasas A2/efectos de los fármacos , Extractos Vegetales/farmacología , Gomas de Plantas/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Porcinos , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidores
11.
Bioorg Med Chem Lett ; 18(20): 5497-502, 2008 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-18815030

RESUMEN

The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor (FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of pyrazolidine-3,5-dione derivatives (1a-u and 7) was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activities against FXR. Most of them showed agonistic potencies and 10 of them (1a, 1b, 1d-f, 1j, 1n, 1t, 5b, and 7) exhibited lower EC(50) values than the reference drug CDCA. Molecular modeling studies for the representative compounds 1a, 1d, 1f, 1j, 1n, 1u, 5b, and 7 were also presented. The novel structural scaffold has provided a new direction for finding potent and selective FXR partial and full agonists (referred to as 'selective bile acid receptor modulators', SBARMs).


Asunto(s)
Proteínas de Unión al ADN/agonistas , Evaluación Preclínica de Medicamentos/métodos , Pirazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Ácidos y Sales Biliares/química , Química Farmacéutica/métodos , Proteínas de Unión al ADN/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Ligandos , Luciferasas/química , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Pirazoles/farmacología , Receptores Citoplasmáticos y Nucleares/química , Factores de Transcripción/química , Activación Transcripcional
12.
J Ethnopharmacol ; 119(2): 291-8, 2008 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-18691646

RESUMEN

AIM OF THE STUDY: The study aimed at evaluating the hypolipidemic effects of Purified Salvia miltiorrhiza extract (PSME) and investigating the potential molecular mechanisms by which PSME modulated lipid profiles in hyperlipidemic rats. MATERIALS AND METHODS: Sprague-Dawley male rats on a high-fat/high-cholesterol diet were treated orally with PSME, GW3965 (a selective liver X receptor agonist) or vehicle alone. Gene expression analysis and transactivation assays were used to clarify the molecular mechanisms of action of PSME. RESULTS: The concentrations of plasma total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides in rats treated with PSME at 150 mg kg day(-1) were significantly decreased (P < 0.01), accompanied with significantly decreased concentrations of liver total cholesterol and triglycerides (P < 0.01). In both drug-treated rats, the concentration of high-density lipoprotein cholesterol (HDL-cholesterol) was significantly elevated (P < 0.01). Intriguingly, short heterodimer partner (SHP) mRNA level was significantly higher in PSME-treated rats (P < 0.01), accompanied with the significantly decreased mRNA level of sterol regulatory element binding protein 1c (SREBP1c) (P < 0.01), which contributed to the decreases of liver and plasma triglycerides through a farnesoid X receptor-SHP-SREBP1c pathway. ATP-binding Cassette Transporter B11 (ABCB11) and murine Mdr2 P-glycoprotein (also known as ABCB4) were significantly induced by PSME, which were responsible for biliary cholesterol solubility by proper biliary secretion of bile salts and phospholipids. The transactivation assays were used to identify PSME as a farnesoid X receptor/liver X receptor alpha coagonist. CONCLUSION: These results indicated that PSME as a farnesoid X receptor/liver X receptor alpha coagonist largely improved the lipid profiles in the hyperlipidemic rats.


Asunto(s)
Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Extractos Vegetales/farmacología , Salvia miltiorrhiza/química , Animales , Colesterol/sangre , Colesterol/metabolismo , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Proteínas de Unión al ADN/agonistas , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Hipolipemiantes/aislamiento & purificación , Receptores X del Hígado , Masculino , Receptores Nucleares Huérfanos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/agonistas , Activación Transcripcional/efectos de los fármacos , Triglicéridos/sangre , Triglicéridos/metabolismo
13.
Biochem Biophys Res Commun ; 372(3): 395-9, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18457666

RESUMEN

In the course of an effort to identify novel agonists of the farnesoid X receptor (FXR), coumestrol was determined to be one such ligand. Reporter and in vitro coactivator interaction assays revealed that coumestrol bound and activated FXR. Treatment of Hep G2 cells with coumestrol stimulated the expression of FXR target genes, thereby regulating the expression of target genes of the liver X receptor and hepatocyte nuclear factor-4alpha. Through these actions, coumestrol is expected to exert beneficial effects on lipid and glucose metabolism.


Asunto(s)
Cumestrol/farmacología , Proteínas de Unión al ADN/agonistas , Glucosa/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Fitoestrógenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Transcripción Genética/efectos de los fármacos , Apolipoproteínas B/metabolismo , Línea Celular , Proteínas de Unión al ADN/metabolismo , Humanos , Ligandos , Metabolismo de los Lípidos/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo
14.
Mol Endocrinol ; 21(7): 1603-16, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17456796

RESUMEN

Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many of which are regulated by the nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR). Further studies demonstrate that cafestol is an agonist ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, sterol 12alpha-hydroxylase, and Na(+)-taurocholate cotransporting polypeptide in the liver of wild-type but not FXR null mice. Cafestol did not affect genes known to be up-regulated by FXR in the liver of wild-type mice, but did increase expression of the positive FXR-target genes intestinal bile acid-binding protein and fibroblast growth factor 15 (FGF15) in the intestine. Because FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on liver gene expression. PXR-dependent gene regulation of cytochrome P450 3A11 and other targets by cafestol was also only seen in the intestine. Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR, and this may contribute to its impact on cholesterol homeostasis.


Asunto(s)
Proteínas de Unión al ADN/agonistas , Diterpenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores de Esteroides/agonistas , Factores de Transcripción/agonistas , Animales , Apolipoproteína E3/genética , Colesterol 7-alfa-Hidroxilasa/genética , Café/química , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Diterpenos/efectos adversos , Diterpenos/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/genética , Humanos , Hipercolesterolemia/inducido químicamente , Técnicas In Vitro , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Modelos Biológicos , Receptor X de Pregnano , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/deficiencia , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional/efectos de los fármacos
15.
Phytomedicine ; 13(6): 401-11, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16716909

RESUMEN

Nuclear receptors represent a very good family of protein targets for the prevention and treatment of diverse diseases. In this study, we screened natural compounds and their derivatives, and discovered ligands for the retinoic acid receptors (RARs) and the farnesoid X receptor (FXR). In the reporter assay systems of nuclear receptors presented here, two fluorescent proteins, enhanced yellow fluorescent protein (EYFP) and enhanced cyan fluorescent protein (ECFP), were used for detection of a ligand-based induction and as an internal control, respectively. By optimizing the conditions (e.g., of hormone response elements and promoter genes for reporter plasmids), we established a battery of assay systems for ligands of RARs, retinoid X receptor (RXR) and FXR. The screening using the reporter assay system can be carried out without the addition of co-factors or substrates. As a result of screening of more than 140 compounds, several compounds were detected which activate RARs and/or FXR. Caffeic acid phenylethyl ester (CAPE), known as a component of propolis from honeybee hives, and other derivatives of caffeic acid up-regulated the expression of reporter gene for RARs. Grifolin and ginkgolic acids, which are non-steroidal skeleton compounds purified from mushroom or ginkgo leaves, up-regulated the expression of the reporter gene for FXR.


Asunto(s)
Ácidos Cafeicos/farmacología , Proteínas de Unión al ADN/agonistas , Colorantes Fluorescentes/química , Genes Reporteros/genética , Receptores de Ácido Retinoico/agonistas , Factores de Transcripción/agonistas , Animales , Proteínas Bacterianas/química , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/efectos de los fármacos , Ginkgo biloba , Proteínas Fluorescentes Verdes/química , Hepatophyta , Humanos , Ligandos , Proteínas Luminiscentes/química , Ratones , Fitoterapia , Plantas Medicinales , Regiones Promotoras Genéticas/genética , Própolis , Receptores Citoplasmáticos y Nucleares , Receptores de Ácido Retinoico/química , Receptores de Ácido Retinoico/genética , Factores de Transcripción/química , Factores de Transcripción/genética
16.
J Lipid Res ; 47(2): 384-92, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16269825

RESUMEN

Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal -230 to -96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.


Asunto(s)
Arildialquilfosfatasa/genética , Ácidos y Sales Biliares/farmacología , Proteínas de Unión al ADN/fisiología , Factores de Crecimiento de Fibroblastos/fisiología , Expresión Génica/efectos de los fármacos , Factores de Transcripción/fisiología , Administración Oral , Animales , Antracenos/farmacología , Arildialquilfosfatasa/sangre , Arildialquilfosfatasa/metabolismo , Línea Celular Tumoral , Ácido Quenodesoxicólico/farmacología , Colesterol 7-alfa-Hidroxilasa/genética , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/farmacología , Ácido Cólico/farmacología , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/genética , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Factores de Crecimiento de Fibroblastos/genética , Humanos , Isoxazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Proteínas de Transferencia de Fosfolípidos/genética , Regiones Promotoras Genéticas/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Factores de Transcripción/agonistas , Factores de Transcripción/genética
17.
Am J Physiol Gastrointest Liver Physiol ; 289(2): G267-73, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15817812

RESUMEN

Previous studies have demonstrated a dramatic induction of inflammatory gene expression in livers from mice fed a high-fat, high-cholesterol diet containing cholate after 3-5 wk. To determine the contribution of cholate in mediating these inductions, C57BL/6 mice were fed a chow diet supplemented with increasing concentrations of cholic acid (CA) for 5 days. A dose-dependent induction in the hepatic levels of TNF-alpha, VCAM-1, ICAM-1, and SAA-2 mRNA were observed. As positive controls, a dose-dependent repression of cholesterol 7alpha-hydroxylase and a dose-dependent induction of small heterodimer partner (SHP) expression were also observed, suggesting that farnesoid X receptor (FXR) was activated. In addition, ICAM-1 and SHP mRNA levels were also induced in primary human hepatocytes when treated with chenodeoxycholic acid or GW4064, a FXR-selective agonist. The involvement of FXR in CA-induced inflammatory gene expression was further investigated in the human hepatic cell line HepG2. Both ICAM-1 and SHP expression were induced in a dose- and time-dependent manner by treatment with the FXR-selective agonist GW4064. Moreover, the induction of ICAM-1 by GW4064 was inhibited by the FXR antagonist guggulsterone or with transfection of FXR siRNA. Finally, the activity of FXR was mapped to a retinoic acid response element (RARE) site containing an imbedded farnesoid X response element (FXRE) on the human ICAM-1 promoter and FXR and retinoid X receptor were demonstrated to bind to this site. Finally, FXR-mediated activation of ICAM-1 could be further enhanced by TNF-alpha cotreatment in hepatocytes, suggesting a potential cooperation between cytokine and bile acid-signaling pathways during hepatic inflammatory events.


Asunto(s)
Ácidos Cólicos/farmacología , Proteínas de Unión al ADN/metabolismo , Hepatocitos/fisiología , Molécula 1 de Adhesión Intercelular/genética , Transducción de Señal/inmunología , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/genética , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Hepatocitos/citología , Humanos , Isoxazoles/farmacología , Hígado/citología , Hígado/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Receptores Citoplasmáticos y Nucleares , Elementos de Respuesta/genética , Transducción de Señal/genética , Factores de Transcripción/agonistas , Factores de Transcripción/genética , Factor de Necrosis Tumoral alfa/farmacología
18.
Hypertension ; 43(5): 993-1002, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15007034

RESUMEN

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Bencimidazoles/farmacología , Benzoatos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Adipocitos/efectos de los fármacos , Animales , Bencimidazoles/química , Benzoatos/química , Compuestos de Bifenilo/farmacología , Glucemia/análisis , Diferenciación Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Insulina/sangre , Irbesartán , Losartán/farmacología , Masculino , Ratones , Modelos Moleculares , Mioblastos/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Rosiglitazona , Relación Estructura-Actividad , Telmisartán , Tetrazoles/farmacología , Tiazoles/farmacología , Tiazolidinedionas/farmacología , Tiazolidinas , Factores de Transcripción/química , Factores de Transcripción/genética , Triglicéridos/sangre , Valina/análogos & derivados , Valina/farmacología , Valsartán , Aumento de Peso/efectos de los fármacos
19.
J Lipid Res ; 45(3): 592-601, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14999041

RESUMEN

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the transcription of a variety of genes involved in lipid metabolism and is the target receptor for the hypolipidemic drug class of fibrates. In the present study, the molecular and physiological effects of seven different PPAR-activating drugs have been examined in a rodent model of dyslipidemia. The drugs examined were selected to display varying potencies and efficacies toward PPAR-alpha. To help elucidate the link between the gene regulation elicited by PPAR-alpha ligands and the concomitant physiological changes, we have used cDNA microarray analysis to identify smaller gene sets that are predictive of the function of these ligands. A number of genes showed strong correlations to the relative PPAR-alpha efficacy of the drugs. Furthermore, using multivariate analysis, a strong relationship between the drug-induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Perfilación de la Expresión Génica , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismo , Animales , Apolipoproteínas C/sangre , Biomarcadores , Línea Celular , Colesterol en la Dieta/farmacología , Modelos Animales de Enfermedad , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/inducido químicamente , Hiperlipidemias/genética , Ligandos , Masculino , Estructura Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Valor Predictivo de las Pruebas , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Triglicéridos/sangre
20.
J Pharmacol Sci ; 93(3): 347-55, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14646253

RESUMEN

The nuclear receptor PPAR (peroxisome proliferator-activated receptor) has three subtypes named alpha, delta(beta), and gamma that may act as receptors for a range of compounds including antihyperglycaemic drugs, insulin sensitizers, and non-steroidal anti-inflammatory drugs (NSAIDs). Although profiling of the subtype selectivity of the compounds for PPAR is indispensable to elucidate their pharmacological action, the absence of an appropriate transactivation assay for PPAR delta led us to develop a sensitive and reproducible method. We found that co-expression of PPAR delta, retinoid X receptor (RXR) alpha, and coactivators such as CBP and SRC-1 enhanced basal and agonist-dependent activation of PPAR responsive element (PPRE)-driven transcription by PPAR delta, rendering a PPRE-driven reporter assay reliable and sensitive. Utilizing this assay for PPAR delta, we re-evaluated the subtype selectivity of a variety of anti-inflammatory drugs for human PPAR. The PPAR agonists tested included two leukotriene (LT) D(4) antagonist, seven NSAIDs, and two anti-rheumatoid drugs. We found that a novel LTD(4) antagonist, FK011 ([2-(((2-(4-tert-butyl-1,3-thiazol-2-yl)-1-benzofuran-5-yl)oxy)methyl)phenyl]acetic acid), showed marked agonistic activity for PPAR gamma. NSAIDs were classified into the following three groups: those showing no activity for all subtypes, those that were selective for PPAR gamma such as indomethacin and diclofenac, and those showing agonistic activity for the delta and gamma subtypes such as ibuprofen. These results will be important to studies on the molecular mechanisms of pharmacological actions of LTD(4) antagonists and NSAIDs.


Asunto(s)
Antiinflamatorios/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/agonistas , Factores de Transcripción/fisiología , Animales , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Subunidades de Proteína/agonistas , Subunidades de Proteína/clasificación , Subunidades de Proteína/fisiología , Receptores Citoplasmáticos y Nucleares/clasificación , Factores de Transcripción/clasificación
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