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[PMID]:29305864
[Au] Autor:Lian X; Gu J; Gao B; Li Y; Damodaran C; Wei W; Fu Y; Cai L
[Ad] Endereço:Department of Urology, The First Hospital of Jilin University, Changchun 130021, China; Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.
[Ti] Título:Fenofibrate inhibits mTOR-p70S6K signaling and simultaneously induces cell death in human prostate cancer cells.
[So] Source:Biochem Biophys Res Commun;496(1):70-75, 2018 01 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fenofibrate is the most widely used lipid-lowering drug, but it seems to have anti-tumor effects in several tumor cell lines. However, there are only a few reports on its effects on human prostate cancer cells. Thus, we investigated the anti-proliferative effects of fenofibrate on human prostate cancer cells and potential mechanisms. The methods used include cell viability analysis with an MTT assay, as well as apoptosis and related signaling pathway analyses with flow cytometry and Western blotting. Fenofibrate inhibited PC-3 cell growth in dose- and time-dependent manners. The fenofibrate-induced cell death is predominantly apoptotic death that is mediated by both the caspase-3 activation and apoptosis-inducing factor (AIF) signaling pathways. Fenofibrate also increased the expression of Bad and decreased the expression of Bcl-2 and Survivin. Mechanistically, fenofibrate-induced cell death was associated with decreased p-p70S6K and the mammalian target of rapamycin (mTOR) phosphorylation levels. When further exploring the upstream mediators of mTOR/p70S6K, we found that fenofibrate increased p38 MAPK and AMPK phosphorylation but did not significantly change the phosphorylation levels of PI3K, AKT, and JNK. However, the inhibition of either p38 MAPK or AMPK with their specific inhibitor did not change the effect of fenofibrate-induced cell death. These findings suggested that fenofibrate indeed significantly inhibited the proliferation of PC-3 cells via apoptotic action, which is associated with the inactivation of the mTOR/p70S6K-dependent cell survival pathway. Although the mechanisms by which fenofibrate inactivates this pathway remains unclear, this study reveals great potential for its use for the clinical treatment of prostate cancers.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Fenofibrato/administração & dosagem
Neoplasias da Próstata/tratamento farmacológico
Neoplasias da Próstata/metabolismo
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Seres Humanos
Masculino
Terapia de Alvo Molecular/métodos
Neoplasias da Próstata/patologia
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180107
[St] Status:MEDLINE


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[PMID]:28980001
[Au] Autor:Qiu F; Matlock G; Chen Q; Zhou K; Du Y; Wang X; Ma JX
[Ad] Endereço:Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
[Ti] Título:Therapeutic Effects of PPARα Agonist on Ocular Neovascularization in Models Recapitulating Neovascular Age-Related Macular Degeneration.
[So] Source:Invest Ophthalmol Vis Sci;58(12):5065-5075, 2017 Oct 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: This study was designed to evaluate effects of fenofibric acid (Feno-FA), a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, on ocular neovascularization (NV) in models recapitulating neovascular age-related macular degeneration (AMD), and to explore whether the effects are PPARα dependent. Methods: Laser-induced choroidal NV (CNV) in rats and very low-density lipoprotein receptor knockout (Vldlr-/-) mice received daily intraperitoneal injections of Feno-FA or vehicle. Vascular leakage was examined by fundus fluorescein angiography and permeability assay using Evans blue as tracer. In CNV rats, severity of CNV was evaluated by CNV areas and CNV volume. In Vldlr-/- mice, subretinal NV (SRNV) and intraretinal NV (IRNV) were quantified in choroid flat mount and retina flat mount, respectively. Inflammatory factors were measured using Western blotting and retinal leukostasis assay. Further, Pparα-/- mice and age-matched wild-type (WT) mice were used for laser-induced CNV and treated with Feno-FA to explore the underlying mechanism. Results: Feno-FA significantly reduced vascular leakage in CNV rats and Vldlr-/- mice, reduced CNV volume in laser-induced CNV rats, and suppressed SRNV and IRNV in Vldlr-/- mice. In addition, Feno-FA downregulated the expression of inflammatory factors, including VEGF, TNF-α, and intercellular cell adhesion molecule-1 (ICAM-1), in the eyecups of CNV rats and decreased adherent retinal leukocytes in Vldlr-/- mice. Furthermore, Pparα-/- mice developed more severe CNV compared with WT mice, and PPARα knockout abolished the beneficial effects of Feno-FA on CNV. Conclusions: Feno-FA has therapeutic effects on ocular NV in models recapitulating neovascular AMD through a PPARα-dependent mechanism.
[Mh] Termos MeSH primário: Neovascularização de Coroide/tratamento farmacológico
Modelos Animais de Doenças
Fenofibrato/análogos & derivados
Hipolipemiantes/uso terapêutico
PPAR alfa/agonistas
Degeneração Macular Exsudativa/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Western Blotting
Permeabilidade Capilar
Neovascularização de Coroide/metabolismo
Neovascularização de Coroide/patologia
Fenofibrato/uso terapêutico
Angiofluoresceinografia
Injeções Intraperitoneais
Molécula 1 de Adesão Intercelular/metabolismo
Leucostasia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
PPAR alfa/genética
PPAR alfa/metabolismo
Ratos
Ratos Endogâmicos BN
Receptores de LDL/genética
Receptores de LDL/metabolismo
Tomografia de Coerência Óptica
Fator de Necrose Tumoral alfa/metabolismo
Fator A de Crescimento do Endotélio Vascular/metabolismo
Degeneração Macular Exsudativa/metabolismo
Degeneração Macular Exsudativa/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypolipidemic Agents); 0 (PPAR alpha); 0 (Receptors, LDL); 0 (Tumor Necrosis Factor-alpha); 0 (VLDL receptor); 0 (Vascular Endothelial Growth Factor A); 0 (vascular endothelial growth factor A, rat); 126547-89-5 (Intercellular Adhesion Molecule-1); BGF9MN2HU1 (fenofibric acid); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22091


  3 / 2393 MEDLINE  
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[PMID]:28767589
[Au] Autor:Ju HB; Zhang FX; Wang S; Song J; Cui T; Li LF; Zhang HY
[Ad] Endereço:Department of Endocrinology, Kunming General Hospital of Chengdu Military Area Command, Kunming, China.
[Ti] Título:Effects of fenofibrate on inflammatory cytokines in diabetic retinopathy patients.
[So] Source:Medicine (Baltimore);96(31):e7671, 2017 Aug.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The role of cytokines in diabetic retinopathy (DR) and effects of fenofibrate on cytokines were explored by observing changes in serum IL-1ß, TNF-α, VEGF, and Lp-PLA2 in different stages of DR and the intervention effect of oral fenofibrate on cytokines.In total, 190 patients with type 2 DR were enrolled and divided into 3 groups: diabetic without retinopathy (NDR) group (n = 30), nonproliferative diabetic retinopathy (NPDR) group (n = 80), and proliferative diabetic retinopathy (PDR) group (n = 80). According to whether or not to accept fenofibrate treatment, NPDR and PDR groups were further divided into the NPDR control (NPDR1) group (n = 40) and the NPDR treatment (NPDR2) group (n = 40), and the proliferative diabetic retinopathy control (PDR1, n = 40) group and the proliferative diabetic retinopathy treatment (PDR2) group (n = 40). At 12 weeks after fenofibrate treatment, serum IL-1ß, TNF-α, VEGF, and Lp-PLA2 levels were detected.In PDR and NPDR patients, levels of serum cytokines such as IL-1ß (120.56 ±â€Š27.32 pg/mL vs 112.34 ±â€Š19.45 pg/mL vs 82.9 ±â€Š13.8 pg/mL), TNF-α (125.86 ±â€Š25.57 pg/mL vs 109.48 ±â€Š20.15 pg/mL vs 80.7 ±â€Š12.8 pg/mL), VEGF (166.65 ±â€Š37.74 pg/mL vs 148.54 ±â€Š36.27 pg/mL vs 88.97 ±â€Š24.86 pg/mL), and Lp-PLA2 (172.34 ±â€Š45.22 µg/L vs 154.66 ±â€Š40.98 µg/L vs 125.88 ±â€Š38.87 µg/L) were significantly higher than in diabetes patients without retinopathy. After fenofibrate treatment, serum IL-1ß, TNF-α, VEGF, and Lp-PLA2 significantly decreased in NPDR and PDR patients.Serum IL-1ß, TNF-α, VEGF, and Lp-PLA2 play an important role in occurrence and development of diabetic retinopathy. Fenofibrate can reduce cytokine levels in DR patients and improve inflammatory response.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/uso terapêutico
Citocinas/sangue
Retinopatia Diabética/tratamento farmacológico
Retinopatia Diabética/imunologia
Fenofibrato/uso terapêutico
Hipolipemiantes/uso terapêutico
[Mh] Termos MeSH secundário: Biomarcadores/sangue
Glicemia/efeitos dos fármacos
Diabetes Mellitus Tipo 2/sangue
Diabetes Mellitus Tipo 2/tratamento farmacológico
Diabetes Mellitus Tipo 2/imunologia
Retinopatia Diabética/sangue
Feminino
Seres Humanos
Masculino
Meia-Idade
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Biomarkers); 0 (Blood Glucose); 0 (Cytokines); 0 (Hypolipidemic Agents); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007671


  4 / 2393 MEDLINE  
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[PMID]:28766701
[Au] Autor:Puligheddu M; Melis M; Pillolla G; Milioli G; Parrino L; Terzano GM; Aroni S; Sagheddu C; Marrosu F; Pistis M; Muntoni AL
[Ad] Endereço:Sleep Disorder Research Center, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
[Ti] Título:Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy.
[So] Source:Epilepsia;58(10):1762-1770, 2017 Oct.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ADNFLE]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated α4 or ß2 subunits. Fenofibrate, a common lipid-regulating drug, is an agonist at peroxisome proliferator-activated receptor alpha (PPARα) that is a ligand-activated transcription factor, which negatively modulates the function of ß2-containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLE\NFLE patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype. METHODS: We first tested the efficacy of fenofibrate in transgenic mice carrying the mutation in the α4-nAChR subunit (Chrna4S252F) homologous to that found in humans. Subsequently, an add-on protocol was implemented in a clinical setting and fenofibrate was administered to pharmacoresistant NFLE patients. RESULTS: Here, we show that a chronic fenofibrate diet markedly reduced the frequency of large inhibitory postsynaptic currents (IPSCs) recorded from cortical pyramidal neurons in Chrna4S252F mice, and prevented nicotine-induced increase of IPSC frequency. Moreover, fenofibrate abolished differences between genotypes in the frequency of sleep-related movements observed under basal conditions. Patients affected by NFLE, nonresponders to traditional therapy, by means of adjunctive therapy with fenofibrate displayed a reduction of seizure frequency. Furthermore, digital video-polysomnographic recordings acquired in NFLE subjects after 6 months of adjunctive fenofibrate substantiated the significant effects on control of motor-behavioral seizures. SIGNIFICANCE: Our preclinical and clinical studies suggest PPARα as a novel disease-modifying target for antiepileptic drugs due to its ability to regulate dysfunctional nAChRs.
[Mh] Termos MeSH primário: Anticonvulsivantes/farmacologia
Epilepsia Resistente a Medicamentos/tratamento farmacológico
Epilepsia do Lobo Frontal/tratamento farmacológico
Fenofibrato/uso terapêutico
PPAR alfa/agonistas
[Mh] Termos MeSH secundário: Adulto
Animais
Benzodiazepinas/uso terapêutico
Carbamazepina/análogos & derivados
Carbamazepina/uso terapêutico
Modelos Animais de Doenças
Epilepsia Resistente a Medicamentos/genética
Quimioterapia Combinada
Eletroencefalografia
Epilepsia do Lobo Frontal/genética
Feminino
Fenofibrato/farmacologia
Seres Humanos
Masculino
Camundongos
Camundongos Transgênicos
Meia-Idade
Mutação
Piracetam/análogos & derivados
Piracetam/uso terapêutico
Polissonografia
Receptores Nicotínicos/genética
Triazinas/uso terapêutico
Ácido Valproico/uso terapêutico
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (PPAR alpha); 0 (Receptors, Nicotinic); 0 (Triazines); 0 (nicotinic acetylcholine receptor alpha4 subunit); 12794-10-4 (Benzodiazepines); 230447L0GL (etiracetam); 2MRO291B4U (clobazam); 33CM23913M (Carbamazepine); 614OI1Z5WI (Valproic Acid); U202363UOS (Fenofibrate); U3H27498KS (lamotrigine); VZI5B1W380 (oxcarbazepine); ZH516LNZ10 (Piracetam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170803
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13863


  5 / 2393 MEDLINE  
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[PMID]:28698097
[Au] Autor:Kato M; Ohtake H; Sato H; Seto Y; Onoue S
[Ad] Endereço:Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
[Ti] Título:Enzymatic reactive oxygen species assay to evaluate phototoxic risk of metabolites.
[So] Source:Toxicol Lett;278:59-65, 2017 Aug 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The present study aimed to verify the feasibility of an enzymatic reactive oxygen species (eROS) assay to evaluate the phototoxic risk of compounds after their metabolization. The eROS assay was designed based on the combined use of an in vitro drug metabolism system and a ROS assay. The incubation time of compounds with human hepatic S9 fractions was optimized with the use of fenofibrate (FF), a typical phototoxicant with metabolite-related phototoxicity, and the reproducibility and robustness of the eROS assay were examined using FF. The eROS assay was applied to 12 phototoxic compounds, including 7 phototoxicants with metabolite-related phototoxicity, to clarify the assay performance. According to the eROS data on singlet oxygen generation from FF and metabolic conversion profiles of FF and fenofibric acid, the incubation time of chemicals with human hepatic S9-mix was determined to be 4min. The singlet oxygen-based evaluation system in the eROS assay was found to be acceptable as a high-throughput assay because of its favorable intra-/inter-day reproducibility (coefficient of variation: ca. 8%) and robustness (Z'-factor: 0.23). Singlet oxygen data on phototoxicants with phototoxic metabolites tended to exceed 120% of control, suggesting the feasibility of the eROS assay to evaluate metabolite-related phototoxic potentials. However, further data accumulation is still needed to improve the assay performance because the eROS assay provided false predictions for some compounds. The present eROS assay may be applicable in part for evaluating the phototoxic risk of drug candidates after their metabolization in the early stage of drug discovery.
[Mh] Termos MeSH primário: Bioensaio
Dermatite Fototóxica/etiologia
Fenofibrato/toxicidade
Fígado/efeitos dos fármacos
Processos Fotoquímicos
Oxigênio Singlete/metabolismo
Testes de Toxicidade/métodos
[Mh] Termos MeSH secundário: Biomarcadores/metabolismo
Biotransformação
Dermatite Fototóxica/metabolismo
Relação Dose-Resposta a Droga
Estudos de Viabilidade
Fenofibrato/metabolismo
Fenofibrato/efeitos da radiação
Seres Humanos
Fígado/enzimologia
Reprodutibilidade dos Testes
Medição de Risco
Fatores de Tempo
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 17778-80-2 (Singlet Oxygen); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE


  6 / 2393 MEDLINE  
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[PMID]:28668840
[Au] Autor:Schmeel LC; Schmeel FC; Schmidt-Wolf IGH
[Ad] Endereço:Department of Radiology and Radiation Oncology, University Hospital Bonn, Bonn, Germany.
[Ti] Título: Apoptosis Induction by Fenofibrate in Lymphoma and Multiple Myeloma.
[So] Source:Anticancer Res;37(7):3513-3520, 2017 07.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Recent innovations in the treatment of multiple myeloma have enriched our therapeutic repertoire regarding the treatment of multiple myeloma during the last decades. However, despite today's therapies many multiple myeloma (MM) patients experience relapse of disease and eventually remain incurable. Wnt/ß-catenin signaling has been demonstrated in lymphoma and MM, rendering related signaling molecules promising therapeutic targets. Fenofibrate, an extensively scrutinized and widely used drug for primary hypercholesterolemia or mixed dyslipidemia, has proven anticarcinogenic properties mediated by peroxisome proliferator-activated receptor-alpha (PPARα) agonism, thereby also influencing WNT-associated signaling molecules. MATERIALS AND METHODS: The antitumor apoptotic effect of fenofibrate at doses ranging from 0.1-200 µM was investigated on a total of seven human, two murine myeloma/lymphoma cell lines and two healthy control cell lines, as determined by 3'3-Dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide (PI) staining in flow cytometry. RESULTS: Fenofibrate significantly reduced viability due to apoptosis induction in all investigated myeloma and lymphoma cell lines in a dose-dependent manner, whereas healthy control cells were less sensitive. CONCLUSION: Our results provide a rationale for future in vitro and in vivo studies with fenofibrate as a safe and well-tolerated agent in MM and lymphoma treatment.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Fenofibrato/farmacologia
Linfoma/tratamento farmacológico
Mieloma Múltiplo/tratamento farmacológico
[Mh] Termos MeSH secundário: Anticarcinógenos/farmacologia
Carbocianinas/administração & dosagem
Linhagem Celular Tumoral
Seres Humanos
Linfoma/metabolismo
Mieloma Múltiplo/metabolismo
Coloração e Rotulagem/métodos
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticarcinogenic Agents); 0 (Carbocyanines); 0 (beta Catenin); 54501-79-0 (3,3'-dihexyl-2,2'-oxacarbocyanine); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE


  7 / 2393 MEDLINE  
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[PMID]:28641720
[Au] Autor:Sporková A; Certíková Chábová V; Dolezelová S; Jíchová S; Kopkan L; Vanourková Z; Kompanowska-Jezierska E; Sadowski J; Maxová H; Cervenka L
[Ad] Endereço:Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
[Ti] Título:Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney.
[So] Source:Am J Med Sci;353(6):568-579, 2017 Jun.
[Is] ISSN:1538-2990
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: There is vast evidence that the renin-angiotensin system is not the sole determinant of blood pressure (BP) elevation in human renovascular hypertension or the relevant experimental models. This study tested the hypothesis that kidney deficiency of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent ω-hydroxylase pathway of arachidonic acid metabolism, is important in the pathophysiology of the maintenance phase of 2-kidney, 1-clip (2K1C) Goldblatt hypertension. MATERIALS AND METHODS: In 2K1C Goldblatt rats with established hypertension, angiotensin II, angiotensin 1-7, 20-HETE concentrations and gene expression of CYP4A1 enzyme (responsible for 20-HETE formation) of the nonclipped kidney were determined. We examined if 14 days׳ administration of fenofibrate, a lipid-lowering drug, would increase CYP4A1 gene expression and renal 20-HETE formation, and if increased 20-HETE concentrations in the nonclipped kidney would decrease BP (telemetric measurements). RESULTS: CYP4A1 gene expression, 20-HETE and angiotensin 1-7 concentrations were lower and angiotensin II levels were higher in the nonclipped kidney of 2K1C rats than in sham-operated rats. Fenofibrate increased CYP4A1 gene expression and 20-HETE concentration in the nonclipped kidney and significantly decreased BP in 2K1C rats but did not restore it to normotensive range. The treatment did not change BP in sham-operated rats. CONCLUSIONS: Our results suggest that alterations in the RAS and CYP-dependent ω-hydroxylase metabolites of arachidonic acid in the nonclipped kidneys are both important in the pathophysiology of the maintenance phase of 2K1C Goldblatt hypertension. Therefore, fenofibrate treatment effectively attenuated hypertension, probably via stimulation of 20-HETE formation in the nonclipped kidney.
[Mh] Termos MeSH primário: Fenofibrato/farmacologia
Fenofibrato/uso terapêutico
Ácidos Hidroxieicosatetraenoicos/deficiência
Hipertensão Renovascular/tratamento farmacológico
Rim/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Hipertensão Renovascular/fisiopatologia
Hipolipemiantes/farmacologia
Hipolipemiantes/uso terapêutico
Rim/metabolismo
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxyeicosatetraenoic Acids); 0 (Hypolipidemic Agents); 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170628
[Lr] Data última revisão:
170628
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE


  8 / 2393 MEDLINE  
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[PMID]:28627437
[Au] Autor:You WJ; Fan YF; Xu YH; Wu K; Tan XY
[Ad] Endereço:Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture of P.R.C., Fishery College, Huazhong Agricultural University, Wuhan 430070, China.
[Ti] Título:Molecular characterization and functional analysis of PPARα promoter in yellow catfish Pelteobagrus fulvidraco.
[So] Source:Gene;627:106-113, 2017 Sep 05.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that plays critical roles in the regulation of many important physiological processes. In the present study, the 1686-bp PPARα promoter for yellow catfish Pelteobagrus fulvidraco was first cloned and characterized. The transcription start site (TSS) of PPARα gene was mapped using RLM-5'RACE method. The luciferase vectors were constructed and transiently transfected into HepG cells and HEK293 cells, respectively, for functional analysis of promoters. Bioinformatics analysis revealed the putative core promoter regions including a TATA-box and a CAAT-box located at -35bp and -75bp upstream of the TSS, respectively. A cluster of putative binding sites of several transcription factors, such as AP1, C H ZFP, E-box, HNF4α, NF-κB, PPAR, Sp1 and STAT1, were identified. Deletion analysis indicated that these transcriptional factor binding sites were essential to the basal promoter activity. Subsequent mutation analysis showed that the PPARα promoter activity was down-regulated following mutation of the TFBSs including NF-κB, PPAR and HNF4α, indicating that these TFBSs were responsible for PPARα activation. Furthermore, the transcription activity of the PPARα promoter was increased and PPARα mRNA expression was up-regulated after fenofibrate treatment. Overall, the present study provided new insights into the mechanisms for transcriptional regulation of PPARα in fish.
[Mh] Termos MeSH primário: Peixes-Gato/genética
Proteínas de Peixes/genética
PPAR alfa/genética
Regiões Promotoras Genéticas
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Clonagem Molecular
Ácidos Graxos/metabolismo
Fenofibrato/farmacologia
Deleção de Genes
Expressão Gênica/efeitos dos fármacos
Células HEK293
Células Hep G2
Seres Humanos
Sítio de Iniciação de Transcrição
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Fish Proteins); 0 (PPAR alpha); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE


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[PMID]:28606915
[Au] Autor:Ong KL; O'Connell R; Januszewski AS; Jenkins AJ; Xu A; Sullivan DR; Barter PJ; Scott RS; Taskinen MR; Waldman B; Colman PG; Best JD; Simes JR; Rye KA; Keech AC; FIELD study investigators
[Ad] Endereço:Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; oklws@yahoo.com.hk.
[Ti] Título:Baseline Circulating FGF21 Concentrations and Increase after Fenofibrate Treatment Predict More Rapid Glycemic Progression in Type 2 Diabetes: Results from the FIELD Study.
[So] Source:Clin Chem;63(7):1261-1270, 2017 Jul.
[Is] ISSN:1530-8561
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. METHODS: Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A ), the homeostasis model assessment of ß-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. RESULTS: Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period ( = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only ( = 0.01). CONCLUSIONS: Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.
[Mh] Termos MeSH primário: Diabetes Mellitus Tipo 2/tratamento farmacológico
Fenofibrato/farmacologia
Fenofibrato/uso terapêutico
Fatores de Crescimento de Fibroblastos/sangue
Índice Glicêmico/efeitos dos fármacos
[Mh] Termos MeSH secundário: Idoso
Alanina Transaminase/metabolismo
Doenças Cardiovasculares/fisiopatologia
Doenças Cardiovasculares/prevenção & controle
Feminino
Estilo de Vida Saudável
Seres Humanos
Hipolipemiantes/farmacologia
Hipolipemiantes/uso terapêutico
Modelos Lineares
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypolipidemic Agents); 0 (fibroblast growth factor 21); 62031-54-3 (Fibroblast Growth Factors); EC 2.6.1.2 (Alanine Transaminase); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1373/clinchem.2016.270876


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[PMID]:28422956
[Au] Autor:Jo E; Li S; Liang Q; Zhang X; Wang H; Herbert TP; Jenkins TA; Xu A; Ye JM
[Ad] Endereço:School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia.
[Ti] Título:Chronic activation of PPARα with fenofibrate reduces autophagic proteins in the liver of mice independent of FGF21.
[So] Source:PLoS One;12(4):e0173676, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autophagy is a catabolic mechanism to degrade cellular components to maintain cellular energy levels during starvation, a condition where PPARα may be activated. Here we report a reduced autophagic capacity in the liver following chronic activation of PPARα with fenofibrate (FB) in mice. Chronic administration of the PPARα agonist FB substantially reduced the levels of multiple autophagy proteins in the liver (Atg3, Agt4B, Atg5, Atg7 and beclin 1) which were associated with a decrease in the light chain LC3II/LC3I ratio and the accumulation of p62. This was concomitant with an increase in the expression of lipogenic proteins mSREBP1c, ACC, FAS and SCD1. These effects of FB were completely abolished in PPARα-/- mice but remained intact in mice with global deletion of FGF21, a key downstream mediator for PPARα-induced effects. Further studies showed that decreased the content of autophagy proteins by FB was associated with a significant reduction in the level of FoxO1, a transcriptional regulator of autophagic proteins, which occurred independently of both mTOR and Akt. These findings suggest that chronic stimulation of PPARα may suppress the autophagy capacity in the liver as a result of reduced content of a number of autophagy-associated proteins independent of FGF21.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Fenofibrato/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Fígado/efeitos dos fármacos
PPAR alfa/agonistas
[Mh] Termos MeSH secundário: Animais
Autofagia/genética
Proteína 5 Relacionada à Autofagia/antagonistas & inibidores
Proteína 5 Relacionada à Autofagia/genética
Proteína 5 Relacionada à Autofagia/metabolismo
Proteína 7 Relacionada à Autofagia/antagonistas & inibidores
Proteína 7 Relacionada à Autofagia/genética
Proteína 7 Relacionada à Autofagia/metabolismo
Proteínas Relacionadas à Autofagia/antagonistas & inibidores
Proteínas Relacionadas à Autofagia/genética
Proteínas Relacionadas à Autofagia/metabolismo
Beclina-1/genética
Beclina-1/metabolismo
Glicemia/metabolismo
Cisteína Endopeptidases/genética
Cisteína Endopeptidases/metabolismo
Fatores de Crescimento de Fibroblastos/genética
Fatores de Crescimento de Fibroblastos/metabolismo
Proteína Forkhead Box O1/genética
Proteína Forkhead Box O1/metabolismo
Fígado/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
PPAR alfa/genética
PPAR alfa/metabolismo
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteína Sequestossoma-1/genética
Proteína Sequestossoma-1/metabolismo
Transdução de Sinais
Estearoil-CoA Dessaturase/genética
Estearoil-CoA Dessaturase/metabolismo
Proteína de Ligação a Elemento Regulador de Esterol 1/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/metabolismo
Triglicerídeos/metabolismo
Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores
Enzimas de Conjugação de Ubiquitina/genética
Enzimas de Conjugação de Ubiquitina/metabolismo
Receptor fas/genética
Receptor fas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Atg5 protein, mouse); 0 (Atg7 protein, mouse); 0 (Autophagy-Related Protein 5); 0 (Autophagy-Related Proteins); 0 (Beclin-1); 0 (Becn1 protein, mouse); 0 (Blood Glucose); 0 (Fas protein, mouse); 0 (Forkhead Box Protein O1); 0 (Foxo1 protein, mouse); 0 (MAP1LC3 protein, mouse); 0 (Microtubule-Associated Proteins); 0 (PPAR alpha); 0 (Sequestosome-1 Protein); 0 (Sqstm1 protein, mouse); 0 (Srebf1 protein, mouse); 0 (Sterol Regulatory Element Binding Protein 1); 0 (Triglycerides); 0 (fas Receptor); 0 (fibroblast growth factor 21); 62031-54-3 (Fibroblast Growth Factors); EC 1.14.19.1 (Scd1 protein, mouse); EC 1.14.19.1 (Stearoyl-CoA Desaturase); EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Atg4b protein, mouse); EC 3.4.22.- (Cysteine Endopeptidases); EC 6.2.1.45 (Autophagy-Related Protein 7); EC 6.3.2.- (Atg3 protein, mouse); U202363UOS (Fenofibrate)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173676



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