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[PMID]:29175453
[Au] Autor:Zhang Y; Lickteig AJ; Csanaky IL; Klaassen CD
[Ad] Endereço:School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: youcai.zhang@tju.edu.cn.
[Ti] Título:Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.
[So] Source:Toxicol Appl Pharmacol;338:112-123, 2018 01 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Bile/metabolismo
Fígado/metabolismo
PPAR alfa/fisiologia
[Mh] Termos MeSH secundário: Animais
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Clofibrato/farmacologia
Feminino
Íleo/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (PPAR alpha); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180311
[Lr] Data última revisão:
180311
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


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[PMID]:28714084
[Au] Autor:Ji Z; LeBaron MJ
[Ad] Endereço:Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan, 48674.
[Ti] Título:Applying the erythrocyte Pig-a assay concept to rat epididymal sperm for germ cell mutagenicity evaluation.
[So] Source:Environ Mol Mutagen;58(7):485-493, 2017 Aug.
[Is] ISSN:1098-2280
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Pig-a assay, a recently developed in vivo somatic gene mutation assay, is based on the identification of mutant erythrocytes that have an altered repertoire of glycosylphosphatidylinositol (GPI)-anchored cell surface markers. We hypothesized that the erythrocyte Pig-a assay concept could be applied to rat cauda epididymal spermatozoa (sperm) for germ cell mutagenicity evaluation. We used GPI-anchored CD59 as the Pig-a mutation marker and examined the frequency of CD59-negative sperm using flow cytometry. A reconstruction experiment that spiked un-labeled sperm (mutant-mimic) into labeled sperm at specific ratios yielded good agreement between the detected and expected frequencies of mutant-mimic sperm, demonstrating the analytical ability for CD59-negative sperm detection. Furthermore, this methodology was assessed in F344/DuCrl rats administered N-ethyl-N-nitrosourea (ENU), a prototypical mutagen, or clofibrate, a lipid-lowering drug. Rats treated with 1, 10, or 20 mg/kg body weight/day (mkd) ENU via daily oral garage for five consecutive days showed a dose-dependent increase in the frequency of CD59-negative sperm on study day 63 (i.e., 58 days after the last ENU dose). This ENU dosing regimen also increased the frequency of CD59-negative erythrocytes. In rats treated with 300 mkd clofibrate via daily oral garage for consecutive 28 days, no treatment-related changes were detected in the frequency of CD59-negative sperm on study day 85 (i.e., 57 days after the last dose) or in the frequency of CD59-negative erythrocytes on study day 29. In conclusion, these data suggest that the epidiymal sperm Pig-a assay in rats is a promising method for evaluating germ cell mutagenicity. Environ. Mol. Mutagen. 58:485-493, 2017. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Epididimo
Proteínas de Membrana/genética
Testes de Mutagenicidade/métodos
Mutagênicos/toxicidade
Espermatozoides/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Antígenos CD59/genética
Clofibrato/toxicidade
Eritrócitos/efeitos dos fármacos
Eritrócitos/metabolismo
Eritrócitos/patologia
Etilnitrosoureia/toxicidade
Citometria de Fluxo
Glicosilfosfatidilinositóis/biossíntese
Masculino
Ratos Endogâmicos F344
Espermatozoides/metabolismo
Espermatozoides/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD59 Antigens); 0 (Glycosylphosphatidylinositols); 0 (Membrane Proteins); 0 (Mutagens); 0 (phosphatidylinositol glycan-class A protein); HPN91K7FU3 (Clofibrate); P8M1T4190R (Ethylnitrosourea)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1002/em.22109


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[PMID]:28389698
[Au] Autor:Venkatachalam AB; Parmar MB; Wright JM
[Ad] Endereço:Department of Biology, Dalhousie University, 1355 Oxford Street, PO BOX 15000, Halifax, NS, B3H 4R2, Canada.
[Ti] Título:Evolution of the duplicated intracellular lipid-binding protein genes of teleost fishes.
[So] Source:Mol Genet Genomics;292(4):699-727, 2017 Aug.
[Is] ISSN:1617-4623
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Increasing organismal complexity during the evolution of life has been attributed to the duplication of genes and entire genomes. More recently, theoretical models have been proposed that postulate the fate of duplicated genes, among them the duplication-degeneration-complementation (DDC) model. In the DDC model, the common fate of a duplicated gene is lost from the genome owing to nonfunctionalization. Duplicated genes are retained in the genome either by subfunctionalization, where the functions of the ancestral gene are sub-divided between the sister duplicate genes, or by neofunctionalization, where one of the duplicate genes acquires a new function. Both processes occur either by loss or gain of regulatory elements in the promoters of duplicated genes. Here, we review the genomic organization, evolution, and transcriptional regulation of the multigene family of intracellular lipid-binding protein (iLBP) genes from teleost fishes. Teleost fishes possess many copies of iLBP genes owing to a whole genome duplication (WGD) early in the teleost fish radiation. Moreover, the retention of duplicated iLBP genes is substantially higher than the retention of all other genes duplicated in the teleost genome. The fatty acid-binding protein genes, a subfamily of the iLBP multigene family in zebrafish, are differentially regulated by peroxisome proliferator-activated receptor (PPAR) isoforms, which may account for the retention of iLBP genes in the zebrafish genome by the process of subfunctionalization of cis-acting regulatory elements in iLBP gene promoters.
[Mh] Termos MeSH primário: Proteínas de Ligação a Ácido Graxo/genética
Oryzias/genética
PPAR alfa/genética
PPAR gama/genética
Proteínas de Ligação ao Retinol/genética
Smegmamorpha/genética
Tetraodontiformes/genética
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Animais
Evolução Biológica
Clofibrato/farmacologia
Evolução Molecular
Duplicação Gênica/genética
Regulação da Expressão Gênica/genética
Genes Duplicados/genética
Família Multigênica/genética
PPAR alfa/agonistas
PPAR gama/agonistas
Regiões Promotoras Genéticas/genética
Ativação Transcricional/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Fatty Acid-Binding Proteins); 0 (PPAR alpha); 0 (PPAR gamma); 0 (Retinol-Binding Proteins); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE
[do] DOI:10.1007/s00438-017-1313-5


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[PMID]:28248971
[Au] Autor:Kochem M; Breslin PA
[Ad] Endereço:Rutgers University Department of Nutritional Sciences, New Brunswick, NJ, United States of America.
[Ti] Título:Clofibrate inhibits the umami-savory taste of glutamate.
[So] Source:PLoS One;12(3):e0172534, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In humans, umami taste can increase the palatability of foods rich in the amino acids glutamate and aspartate and the 5'-ribonucleotides IMP and GMP. Umami taste is transduced, in part, by T1R1-T1R3, a heteromeric G-protein coupled receptor. Umami perception is inhibited by sodium lactisole, which binds to the T1R3 subunit in vitro. Lactisole is structurally similar to the fibrate drugs. Clofibric acid, a lipid lowering drug, also binds the T1R3 subunit in vitro. The purpose of this study was to determine whether clofibric acid inhibits the umami taste of glutamate in human subjects. Ten participants rated the umami taste intensity elicited by 20 mM monosodium glutamate (MSG) mixed with varying concentrations of clofibric acid (0 to 16 mM). In addition, fourteen participants rated the effect of 1.4 mM clofibric acid on umami enhancement by 5' ribonucleotides. Participants were instructed to rate perceived intensity using a general Labeled Magnitude Scale (gLMS). Each participant was tested in triplicate. Clofibric acid inhibited umami taste intensity from 20 mM MSG in a dose dependent manner. Whereas MSG neat elicited "moderate" umami taste intensity, the addition of 16 mM clofibric acid elicited only "weak" umami intensity on average, and in some subjects no umami taste was elicited. We further show that 1.4 mM clofibric acid suppressed umami enhancement from GMP, but not from IMP. This study provides in vivo evidence that clofibric acid inhibits glutamate taste perception, presumably via T1R1-T1R3 inhibition, and lends further evidence that the T1R1-T1R3 receptor is the principal umami receptor in humans. T1R receptors are expressed extra-orally throughout the alimentary tract and in regulatory organs and are known to influence glucose and lipid metabolism. Whether clofibric acid as a lipid-lowering drug affects human metabolism, in part, through T1R inhibition warrants further examination.
[Mh] Termos MeSH primário: Clofibrato/administração & dosagem
Ácido Glutâmico/administração & dosagem
Percepção Gustatória/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adulto
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Masculino
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/metabolismo
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (taste receptors, type 1); 3KX376GY7L (Glutamic Acid); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170302
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172534


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[PMID]:27742692
[Au] Autor:Kochem M; Breslin PA
[Ad] Endereço:Department of Nutritional Sciences, Rutgers University, 65 Dudley Road, New Brunswick, NJ 08901, USA and.
[Ti] Título:Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste.
[So] Source:Chem Senses;42(1):79-83, 2017 Jan.
[Is] ISSN:1464-3553
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition.
[Mh] Termos MeSH primário: Clofibrato/farmacologia
Edulcorantes/farmacologia
Paladar/efeitos dos fármacos
Paladar/fisiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Feminino
Seres Humanos
Masculino
Receptores Acoplados a Proteínas-G/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); 0 (Sweetening Agents); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161016
[St] Status:MEDLINE


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[PMID]:27193034
[Au] Autor:More VR; Campos CR; Evans RA; Oliver KD; Chan GN; Miller DS; Cannon RE
[Ad] Endereço:Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
[Ti] Título:PPAR-α, a lipid-sensing transcription factor, regulates blood-brain barrier efflux transporter expression.
[So] Source:J Cereb Blood Flow Metab;37(4):1199-1212, 2017 Apr.
[Is] ISSN:1559-7016
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood-brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood-brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/genética
Barreira Hematoencefálica/metabolismo
Regulação da Expressão Gênica
PPAR alfa/fisiologia
[Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética
Ácidos Alcanossulfônicos/farmacologia
Animais
Transporte Biológico
Barreira Hematoencefálica/efeitos dos fármacos
Encéfalo/irrigação sanguínea
Capilares/efeitos dos fármacos
Capilares/metabolismo
Clofibrato/farmacologia
Jejum/metabolismo
Fluorcarbonetos/farmacologia
Ácido Linoleico/farmacologia
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Oxazóis/farmacologia
PPAR alfa/agonistas
PPAR alfa/antagonistas & inibidores
PPAR alfa/genética
Ratos Sprague-Dawley
Tirosina/análogos & derivados
Tirosina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Alkanesulfonic Acids); 0 (Fluorocarbons); 0 (GW 6471); 0 (Multidrug Resistance-Associated Proteins); 0 (Oxazoles); 0 (PPAR alpha); 42HK56048U (Tyrosine); 4AF605U6JN (multidrug resistance-associated protein 2); 9H2MAI21CL (perfluorooctane sulfonic acid); 9KJL21T0QJ (Linoleic Acid); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160520
[St] Status:MEDLINE
[do] DOI:10.1177/0271678X16650216


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[PMID]:27354598
[Au] Autor:Schmeel LC; Schmeel FC; Schmidt-Wolf IG
[Ad] Endereço:Department of Radiology and Radiation Oncology, University Hospital Bonn, Bonn, Germany Center for Integrated Oncology (CIO), Medical Clinic and Polyclinic III, University Hospital Bonn, Bonn, Germany.
[Ti] Título:Clofibrate Demonstrates Efficacy in In Vitro Treatment of Lymphoma and Multiple Myeloma.
[So] Source:Anticancer Res;36(7):3395-400, 2016 Jul.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Multiple myeloma (MM), a hematological malignancy of monoclonal B-lymphocytes, remains largely incurable and novel treatments are urgently required. Aberrant activation of wingless-related integration site (WNT)/ß-catenin signaling has been demonstrated in both lymphoma and MM, rendering its signaling molecules attractive for the development of new targeted-therapies. Clofibrate has proven anticarcinogenic effects attributed to peroxisome proliferator-activated receptor alpha (PPARα) agonism, also affecting WNT-associated signaling molecules. MATERIALS AND METHODS: The antitumor apoptotic effect of clofibrate at doses ranging from 0.1-600 µM was investigated on four human and one murine myeloma cell lines, as well as in two human lymphoma cell lines, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay. RESULTS: Clofibrate significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were hardly affected. CONCLUSION: Given the known safety profile and induction of apoptosis at low effective doses, our data warrant further investigation of clofibrate as a novel therapy agent in MM.
[Mh] Termos MeSH primário: Clofibrato/farmacologia
Linfoma/tratamento farmacológico
Mieloma Múltiplo/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170107
[Lr] Data última revisão:
170107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160630
[St] Status:MEDLINE


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[PMID]:27110876
[Au] Autor:Ibarra-Lara L; Del Valle-Mondragón L; Soria-Castro E; Torres-Narváez JC; Pérez-Severiano F; Sánchez-Aguilar M; Ramírez-Ortega M; Cervantes-Pérez LG; Pastelín-Hernández GS; Oidor-Chan VH; Zarco-Olvera G; Sánchez-Mendoza A
[Ad] Endereço:Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
[Ti] Título:Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle.
[So] Source:Pharmacol Rep;68(4):692-702, 2016 Aug.
[Is] ISSN:1734-1140
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Arterial high blood pressure is a risk factor for target organ damage; the most susceptible organs are the arteries, brain, kidneys, and heart. The damage mechanisms include oxidative stress and renin-angiotensin system (RAS) overactivity. Therefore, our aim was to study whether clofibrate-induced peroxisome proliferator-activated receptor-alpha (PPAR-α) stimulation is able to prevent alterations in cardiac functioning derived from RAS overstimulation in the left ventricle of rats with hypertension secondary to aortic coarctation and to improve antioxidant defenses. METHODS: Male Wistar rats were assigned to Control (Sham)- or aortic coarctation-surgery and further divided to receive (1 or 21 days) vehicle, clofibrate (100mg/kg), captopril (20mg/kg), or clofibrate+captopril. The left ventricle was obtained to measure: angiotensin II and -(1-7), AT1 and AT2 receptors, angiotensin converting enzyme (ACE)-1 and -2, and MAS receptor; the activity and expression of superoxide dismutase, catalase, endothelial nitric oxide synthase, the production of reactive oxygen species (ROS) and peroxidated lipids; as well as ex vivo cardiac functioning. RESULTS: Clofibrate decreased angiotensin II, AT1 receptor and ACE expression, and raised angiotensin-(1-7), AT2 receptor, ACE-2 expression, superoxide dismutase and endothelial nitric oxide synthase participation. These effects promoted lower coronary vascular resistance and improved mechanical work compared to aortic coarctated vehicle-treated rats. CONCLUSIONS: Clofibrate-induced PPAR-α stimulation changes the angiotensin II receptor profile, favors the ACE2/angiotensin-(1-7)/AT2 receptor axis decreasing the vasoconstrictor environment, activates the antioxidant defense, and facilitates endothelial nitric oxide synthase activity favoring vasodilation. This may represent a protection for the stressed heart.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Clofibrato/farmacologia
Ventrículos do Coração/fisiopatologia
Hipertensão/fisiopatologia
PPAR alfa/agonistas
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Angiotensina I/metabolismo
Angiotensina II/metabolismo
Animais
Coartação Aórtica/complicações
Coartação Aórtica/fisiopatologia
Captopril/farmacologia
Catalase/metabolismo
Sinergismo Farmacológico
Peroxidação de Lipídeos/efeitos dos fármacos
Masculino
Óxido Nítrico Sintase Tipo III/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Fragmentos de Peptídeos/metabolismo
Peptidil Dipeptidase A/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
Ratos
Espécies Reativas de Oxigênio/metabolismo
Receptor Tipo 1 de Angiotensina/metabolismo
Receptor Tipo 2 de Angiotensina/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Sistema Renina-Angiotensina/efeitos dos fármacos
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (PPAR alpha); 0 (Peptide Fragments); 0 (Proto-Oncogene Proteins); 0 (Reactive Oxygen Species); 0 (Receptor, Angiotensin, Type 1); 0 (Receptor, Angiotensin, Type 2); 0 (Receptors, G-Protein-Coupled); 0 (proto-oncogene proteins c-mas-1); 11128-99-7 (Angiotensin II); 9041-90-1 (Angiotensin I); 9G64RSX1XD (Captopril); EC 1.11.1.6 (Catalase); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.15.1.1 (Superoxide Dismutase); EC 3.4.15.1 (Peptidyl-Dipeptidase A); EC 3.4.17.- (angiotensin converting enzyme 2); HPN91K7FU3 (Clofibrate); IJ3FUK8MOF (angiotensin I (1-7))
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160426
[St] Status:MEDLINE


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[PMID]:27050838
[Au] Autor:Ibarra-Lara Mde L; Sánchez-Aguilar M; Soria E; Torres-Narváez JC; Del Valle-Mondragón L; Cervantes-Pérez LG; Pérez-Severiano F; Ramírez-Ortega Mdel C; Pastelín-Hernández G; Oidor-Chan VH; Sánchez-Mendoza A
[Ad] Endereço:a Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Juan Badiano No. 1, Col. Sección XVI, Tlalpan, 14080 Mexico City, México.
[Ti] Título:Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction.
[So] Source:Can J Physiol Pharmacol;94(6):634-42, 2016 Jun.
[Is] ISSN:1205-7541
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1ß, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Regulação para Baixo/fisiologia
Mediadores da Inflamação/metabolismo
Infarto do Miocárdio/metabolismo
PPAR alfa/biossíntese
[Mh] Termos MeSH secundário: Animais
Clofibrato/farmacologia
Clofibrato/uso terapêutico
Regulação da Expressão Gênica
Masculino
Infarto do Miocárdio/tratamento farmacológico
PPAR alfa/genética
Distribuição Aleatória
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammation Mediators); 0 (PPAR alpha); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160407
[St] Status:MEDLINE
[do] DOI:10.1139/cjpp-2015-0356


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[PMID]:27020044
[Au] Autor:Bodié K; Buck WR; Pieh J; Liguori MJ; Popp A
[Ad] Endereço:Abbvie Deutschland GmbH & Co. KG, Preclinical Safety, D-67061 Ludwigshafen, Germany. Electronic address: karen.bodie@abbvie.com.
[Ti] Título:Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.
[So] Source:Exp Toxicol Pathol;68(5):289-99, 2016 May.
[Is] ISSN:1618-1433
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study.
[Mh] Termos MeSH primário: Clofibrato/toxicidade
Hipolipemiantes/toxicidade
Músculo Esquelético/efeitos dos fármacos
[Mh] Termos MeSH secundário: Alanina Transaminase/sangue
Alanina Transaminase/urina
Animais
Aspartato Aminotransferases/sangue
Aspartato Aminotransferases/urina
Biomarcadores/sangue
Biomarcadores/urina
Creatina Quinase/sangue
Creatina Quinase/urina
Proteína 3 Ligante de Ácido Graxo
Proteínas de Ligação a Ácido Graxo/sangue
Proteínas de Ligação a Ácido Graxo/urina
Perfilação da Expressão Gênica
Coração/efeitos dos fármacos
Masculino
Músculo Esquelético/patologia
Miocárdio/patologia
Mioglobina/sangue
Cadeias Leves de Miosina/sangue
Cadeias Leves de Miosina/urina
Parvalbuminas/sangue
Parvalbuminas/urina
Ratos
Ratos Sprague-Dawley
Troponina C/sangue
Troponina C/urina
Troponina I/sangue
Troponina I/urina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (FABP3 protein, rat); 0 (Fatty Acid Binding Protein 3); 0 (Fatty Acid-Binding Proteins); 0 (Hypolipidemic Agents); 0 (Myoglobin); 0 (Myosin Light Chains); 0 (Parvalbumins); 0 (Troponin C); 0 (Troponin I); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.2 (Alanine Transaminase); EC 2.7.3.2 (Creatine Kinase); HPN91K7FU3 (Clofibrate)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160330
[St] Status:MEDLINE



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