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1.
Environ Toxicol ; 35(2): 242-253, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31710167

RESUMO

Fluoride is an environmental contaminant that is ubiquitously present in air, water, and soil. It is commonly added in minute quantity to drinking water, toothpaste, and mouth rinses to prevent tooth decay. Epidemiological findings have demonstrated that exposure to fluoride induced neurodevelopmental toxicity, developmental neurotoxicity, and motor disorders. The neuroprotective effect of clofibrate, a peroxisome proliferator-activated receptor alpha agonist, was investigated in the present study. Forty male Wistar rats were used for this study and randomly grouped into 10 rats per group as control, sodium fluoride (NaF) alone (300 ppm), NaF plus clofibrate (250 mg/kg), and NaF plus lisinopril (10 mg/kg), respectively, for 7 days. NaF was administered in drinking water while clofibrate and lisinopril were administered by oral gavage. Markers of neuronal inflammation and oxidative stress, acetylcholinesterase activity, and neurobehavioral (hanging wire and open field) tests were performed. Immunohistochemistry was performed on brain tissues, and they were probed with glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and cerebellar Ca2+ -binding protein calbindin-D28k. The results showed that NaF significantly increased of oxidative stress and neuroinflammation and inhibited AChE activity. Immunostaining showed reactive astrocytes, microgliosis, loss of dendritic spines, and arborization in Purkinje cells in rats administered only NaF. Neurobehavioral results showed that cotreatment of NaF with clofibrate improved muscular strength and locomotion, reduced anxiety, and significantly reduced astrocytic count. Overall, cotreatment of NaF with either clofibrate or lisinopril showed neuroprotective effects by mitigating neuronal inflammation and oxidative and motor incoordination. Hence, clofibrate could be seen as a novel drug candidate against neurodegeneration and motor disorders.


Assuntos
Ataxia/prevenção & controle , Calbindinas/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/metabolismo , Clofibrato/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/agonistas , Fluoreto de Sódio/toxicidade , Animais , Ataxia/imunologia , Biomarcadores/metabolismo , Fluoretos/farmacologia , Inflamação , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
3.
Molecules ; 24(2)2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30642049

RESUMO

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.


Assuntos
Clofibrato/farmacologia , Hipolipemiantes/farmacologia , Inflamação/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/metabolismo , PPAR alfa/metabolismo , Roedores
4.
Environ Mol Mutagen ; 60(1): 42-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30338550

RESUMO

The Pig-a assay is an emerging and promising in vivo method to determine mutagenic potential of chemicals. Since its development in 2008, remarkable progress has been made in harmonizing and characterizing the test procedures, primarily using known mutagenic chemicals. The purpose of the present study was to evaluate specificity of the Pig-a assay using two nongenotoxic and well-characterized rodent liver carcinogens, phenobarbital and clofibrate, in male F344/DuCrl rats. Daily oral administration of phenobarbital or clofibrate at established hepatotoxic doses for 28 days resulted in substantial hepatic alterations, however, did not increase the frequency of Pig-a mutation markers (RETCD59- and RBCCD59- ) compared to vehicle control or pre-exposure (Day -5) mutant frequencies. These results are consistent with the existing literature on the nonmutagenic mode of action (MoA) of phenobarbital and clofibrate liver tumors. The present study contributes to the limited, but expanding evidence on the specificity of the Pig-a assay and further for the investigations of carcinogenic MoAs, i.e., mutagenic or nonmutagenic potential of chemicals. Environ. Mol. Mutagen. 60:42-46, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Carcinógenos/toxicidade , Clofibrato/toxicidade , Glicosilfosfatidilinositóis/genética , Neoplasias Hepáticas/induzido quimicamente , Testes de Mutagenicidade/métodos , Fenobarbital/toxicidade , Animais , Bioensaio , Fígado/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Masculino , Mutação/efeitos dos fármacos , Projetos Piloto , Ratos , Ratos Endogâmicos F344 , Sensibilidade e Especificidade
5.
Invest Ophthalmol Vis Sci ; 59(15): 5803-5815, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30521668

RESUMO

Purpose: To determine if drug-induced peroxisome proliferator-activated receptor α (PPARα) signal pathway modulation affects refractive development and myopia in guinea pigs. Methods: Pigmented guinea pigs were randomly divided into normal vision (unoccluded) and form deprivation myopia (FDM) groups. Each group received daily peribulbar injections of either a vehicle or (1) PPARα agonist, GW7647, clofibrate, or bezafibrate or (2) PPARα antagonist, GW6471, for 4 weeks. Baseline and posttreatment refraction and ocular biometric parameters were measured. Immunofluorescent staining of PPARα and two of its downstream readouts, cytosolic malic enzyme 1 (ME1) and apolipoproteinA II (apoA-II), was undertaken in selected scleral sections. Western blot analysis determined collagen type I expression levels. Results: GW6471 induced a myopic shift in unoccluded eyes, but had no effect on form-deprived eyes. Conversely, GW7647 inhibited FDM progression without altering unoccluded eyes. Bezafibrate and clofibrate had effects on refraction similar to those of GW7647 in unoccluded and form-deprived eyes. GW6471 downregulated collagen type I expression in unoccluded eyes whereas bezafibrate inhibited collagen type I decreases in form-deprived eyes. GW6471 also reduced the density of ME1- and apoA-II-stained cells in unoccluded eyes whereas bezafibrate increased apoA-II-positive cell numbers in form-deprived eyes. Conclusions: As GW7647 and GW6471 had opposing effects on myopia development, PPARα signaling modulation may be involved in this condition in guinea pigs. Fibrates are potential candidates for treating myopia since they reduced both FDM and the associated axial elongation. Bezafibrate also inhibited form deprivation-induced decreases in scleral collagen type I expression and the density of apoA-II expressing cells.


Assuntos
Modelos Animais de Doenças , Miopia/metabolismo , PPAR alfa/fisiologia , Refração Ocular/fisiologia , Privação Sensorial , Animais , Apolipoproteína A-II/metabolismo , Bezafibrato/farmacologia , Biometria , Western Blotting , Butiratos/farmacologia , Clofibrato/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Eletrorretinografia , Técnica Indireta de Fluorescência para Anticorpo , Cobaias , Pressão Intraocular , Malato Desidrogenase/metabolismo , Miopia/etiologia , Miopia/prevenção & controle , Oxazóis/farmacologia , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Tirosina/análogos & derivados , Tirosina/farmacologia
6.
Bioorg Med Chem Lett ; 28(18): 3119-3122, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119959

RESUMO

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p < 0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.


Assuntos
Antioxidantes/farmacologia , Clofibrato/farmacologia , Hepatócitos/efeitos dos fármacos , Hipolipemiantes/farmacologia , Álcool Feniletílico/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Peso Corporal/efeitos dos fármacos , Clofibrato/administração & dosagem , Clofibrato/química , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Tamanho do Órgão/efeitos dos fármacos , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Polietilenoglicóis/farmacologia , Relação Estrutura-Atividade
7.
Artigo em Inglês | MEDLINE | ID: mdl-29885532

RESUMO

Lipid metabolism involves complex pathways, which are regulated in a similar way across vertebrates. Hormonal and hypolipidemic deregulations cause lipid imbalance from fish to humans, but the underlying mechanisms are far from understood. This study explores the potential of using juvenile brown trout to evaluate the in vivo interferences caused by estrogenic (17α-ethinylestradiol - EE2), androgenic (testosterone - T), and hypolipidemic (clofibrate - CLF) compounds in lipidic and/or peroxisomal pathways. Studied endpoints were from blood/plasma biochemistry, plasma fatty acid profile, ultrastructure of hepatocytes and abundance of their peroxisomes to mRNA expression in the liver. Both T and CLF caused minimal effects when compared to EE2. Estrogenized fish had significantly higher hepatosomatic indexes, increased triglycerides and very-low density lipoproteins (VLDL) in plasma, compared with solvent control. Morphologically, EE2 fish showed increased lipid droplets in hepatocytes, and EE2 and T reduced volume density of peroxisomes in relation to the hepatic parenchyma. Polyunsaturated fatty acids (PUFA) in plasma, namely n-3 PUFA, increased with EE2. EE2 animals had increased mRNA levels of vitellogenin A (VtgA), estrogen receptor alpha (ERα), peroxisome proliferator-activated receptor alpha (PPARα), PPARαBa and acyl-CoA long chain synthetase 1 (Acsl1), while ERß-1, acyl-CoA oxidase 1-3I (Acox1-3I), Acox3, PPARγ, catalase (Cat), urate oxidase (Uox), fatty acid binding protein 1 (Fabp1) and apolipoprotein AI (ApoAI) were down-regulated. In summary, in vivo EE2 exposure altered lipid metabolism and peroxisome dynamics in brown trout, namely by changing the mRNA levels of several genes. Our model can be used to study possible organism-level impacts, viz. in gonadogenesis.


Assuntos
Estrogênios/efeitos adversos , Hipolipemiantes/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Peroxissomos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Testosterona/efeitos adversos , Androgênios/efeitos adversos , Animais , Aquicultura , Clofibrato/efeitos adversos , Etinilestradiol/efeitos adversos , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/ultraestrutura , Lipídeos/sangue , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Fígado/ultraestrutura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Peroxissomos/metabolismo , Peroxissomos/ultraestrutura , Portugal , Distribuição Aleatória , Testes de Toxicidade Subaguda , Truta
8.
Urol J ; 15(2): 38-43, 2018 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-29299890

RESUMO

PURPOSE: Fibrates are drugs widely used for the treatment of hyperlipidemic disorders. Previous studies on a novel analogue of clofibrate, called silafibrate, have shown good lipid lowering effects. This study was designed to assess the role of silafibrate as a peroxisome proliferator-activated receptors (PPARs) agonist on sperm health and spermatogenesis in adult male rats. MATERIAL AND METHODS: Seventy male Wistar rats were randomly allocated into 7 groups: Cl-10, Cl-20, and Cl-40 mg/kg/day (clofibrate); Si-10, Si-20, and Si-40 mg/kg/day (silafibrate); and C, control. After a 28-day treatment, all rats were euthanized. Blood samples were taken for determination of testosterone, total antioxidant capacity, levels of malondialdehyde, and oxidized low-density lipoprotein. Reproductive organs were dissected and spermatozoa collected from the epididymis for analysis. RESULT: Sperm parameters (count, motility, viability, and morphology) and total serum testosterone decreased significantly in clofibrate-treated (20 and 40 mg/kg) rats (P < 0.05) as compared with normal rats. CONCLUSION: We conclude that PPARs agonists have significant adverse effect on sperm viability, motility, and total serum testosterone, and could be harmful for sperm parameters and male reproductive function in rats.


Assuntos
Clofibrato/análogos & derivados , Clofibrato/farmacologia , Hipolipemiantes/farmacologia , Contagem de Espermatozoides , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Hormônio Foliculoestimulante/sangue , Lipoproteínas LDL/sangue , Hormônio Luteinizante/sangue , Masculino , Malondialdeído/sangue , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Distribuição Aleatória , Ratos , Espermatozoides/patologia , Espermatozoides/fisiologia , Testosterona/sangue
9.
Toxicol Appl Pharmacol ; 338: 112-123, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29175453

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.


Assuntos
Ácidos e Sais Biliares/metabolismo , Bile/metabolismo , Fígado/metabolismo , PPAR alfa/fisiologia , Animais , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Clofibrato/farmacologia , Feminino , Íleo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
10.
Kidney Int ; 93(2): 375-389, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28760335

RESUMO

Cardiovascular events are the leading cause of death in patients with chronic kidney disease (CKD), although the pathological mechanisms are poorly understood. Here we longitudinally characterized left ventricle pathology in a 5/6 nephrectomy rat model of CKD and identify novel molecular mediators. Next-generation sequencing of left ventricle mRNA and microRNA (miRNA) was performed at physiologically distinct points in disease progression, identifying alterations in genes in numerous immune, lipid metabolism, and inflammatory pathways, as well as several miRNAs. MiRNA miR-21-5p was increased in our dataset and has been reported to regulate many identified pathways. Suppression of miR-21-5p protected rats with 5/6 nephrectomy from developing left ventricle hypertrophy and improved left ventricle function. Next-generation mRNA sequencing revealed that miR-21-5p suppression altered gene expression in peroxisome proliferator-activated receptor alpha (PPARα) regulated pathways in the left ventricle. PPARα, a miR-21-5p target, is the primary PPAR isoform in the heart, importantly involved in regulating fatty acid metabolism. Therapeutic delivery of low-dose PPARα agonist (clofibrate) to rats with 5/6 nephrectomy improved cardiac function and prevented left ventricle dilation. Thus, comprehensive characterization of left ventricle molecular changes highlights the involvement of numerous signaling pathways not previously explored in CKD models and identified PPARα as a potential therapeutic target for CKD-related cardiac dysfunction.


Assuntos
Síndrome Cardiorrenal/metabolismo , Ventrículos do Coração/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , MicroRNAs/metabolismo , PPAR alfa/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Síndrome Cardiorrenal/genética , Síndrome Cardiorrenal/patologia , Síndrome Cardiorrenal/prevenção & controle , Clofibrato/farmacologia , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fibrose , Regulação da Expressão Gênica , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , MicroRNAs/genética , PPAR alfa/agonistas , PPAR alfa/genética , Ratos Sprague-Dawley , Transdução de Sinais , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
11.
Oncogene ; 37(7): 953-962, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29059162

RESUMO

Radiotherapy is emerging as an important modality for the local control of pancreatic cancer, but pancreatic cancer cell radioresistance remains a serious concern. Peroxisome proliferator-activated receptor α (PPARα) is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. The clinical relevance of PPARα and its biological function in pancreatic cancer radiosensitivity have not been previously described. In this study, we examined PPARα expression in tissue samples of pancreatic cancer patients. We found significantly higher expression of PPARα in pancreatic cancer tissues than in tumor-adjacent tissues and that the PPARα expression level is inversely associated with higher overall patient survival rate. We further observed that PPARα activation by its agonist clofibrate sensitizes pancreatic cancer cells to radiation by modulating cell cycle progression and apoptosis in several pancreatic cancer cell lines. Small interfering RNA-mediated PPARα silencing and PPARα blockade by the antagonist GW6471 abolish the effect of clofibrate on radiosensitization. An in vivo study showed that PANC1 xenografts treated with clofibrate are more sensitive to radiation than untreated xenografts. mRNA profiling by microarray analysis revealed that the expression of PTPRZ1 and Wnt8a, two core components of the ß-catenin pathway, is downregulated by clofibrate. Chromatin immunoprecipitation analysis confirmed that clofibrate abrogates the binding of nuclear factor-κB to the PTPRZ1 and Wnt8a promoters, ultimately decreasing Wnt/ß-catenin signaling activity, which is associated with radiosensitivity. Overall, we demonstrate that PPARα is overexpressed in pancreatic cancer tissues and clofibrate-mediated PPARα activation sensitizes pancreatic cancer cells to radiation through the Wnt/ß-catenin pathway.


Assuntos
Clofibrato/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , PPAR alfa/metabolismo , Neoplasias Pancreáticas/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Apoptose , Biomarcadores Tumorais , Proliferação de Células , Seguimentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , PPAR alfa/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Radiação Ionizante , Células Tumorais Cultivadas , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
12.
PLoS One ; 12(11): e0187507, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29095960

RESUMO

We tested the hypothesis that prenatal administration of PPARα agonist clofibrate may permanently increase browning capacity of developing white adipose tissue (WAT). Pregnant C57BL/6J mice were fed a basal diet, without (C) or with 0.5% clofibrate (CF, a PPARα agonist) throughout pregnancy. After parturition, only male offspring were used; all suckled their mothers (who were eating the C diet) and after weaning, they ate a standard chow diet for 4 wk, followed by a high-fat diet (HFD) for 5 wk. Administration of CF up-regulated serum concentrations and hepatic expression of FGF21 in fetuses, with a return to basal levels after CF withdrawal. At postnatal day 84 (P84), CF-offspring had significantly higher expression of thermogenic genes (Ucp1, Cidea, Ppara Ppargc1a, Cpt1b) and UCP1 protein levels in response to HFD in inguinal fat, but not in retroperitoneal (combined with perirenal) or epididymal fat. Based on UCP1 levels in inguinal fat on P7, P14, and P21, appearance of the transient brown-adipocyte phenotype seemed to be hastened by CF exposure. We concluded that giving CF to pregnant mice programmed greater HFD-induced WAT browning in subcutaneous, but not in visceral fat, in their male offspring at adulthood.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Clofibrato/farmacologia , Dieta Hiperlipídica , PPAR alfa/agonistas , Tecido Adiposo Marrom/crescimento & desenvolvimento , Animais , Feminino , Crescimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
13.
Toxicol Sci ; 160(2): 351-360, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973556

RESUMO

Fibrates and their receptor, namely peroxisome proliferator-activated receptor α (PPARα), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARα activation on BA homeostasis remains controversial. In this study, both wild-type (WT) and PPARα-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-term PPARα activation on BA homeostasis. Although a decrease in total BAs (ΣBAs) was observed in livers of CLOF-treated WT mice, it was not observed in PPARα-null mice. CLOF-mediated decrease in ΣBAs in the liver was not likely due to the reduction in BA synthesis or BA uptake, as evidenced by an increase in the BA synthetic enzyme (Cyp7a1) and 2 BA uptake transporters (Na (+)-taurocholate cotransporting polypeptide [Ntcp] and organic anion transporting polypeptide [Oatp]1b2). Instead, the decrease in liver BAs by CLOF is largely a result of increased biliary excretion of BAs, which was associated with a significant induction of the canalicular efflux transporter (bile salt export pump [Bsep]) in the liver. The PPARα-mediated increase in Cyp7a1 in CLOF-treated WT mice was not due to farnesoid X receptor (Fxr)-small heterodimer partner (Shp) signaling in the liver, but due to suppression of Fxr- fibroblast growth factor15 signaling in the ileum. Additionally, CLOF also suppressed intestinal BA transporters (apical sodium-dependent bile acid transporter and organic solute transporterß) and cholesterol efflux transporters (Abcg5 and Abcg8) in a PPARα-dependent manner. In summary, this study provides the first comprehensive analysis on the effect of a short-term CLOF treatment on BA homeostasis, and revealed an essential role of PPARα in regulating BA synthesis, transport and signaling.


Assuntos
Ácidos e Sais Biliares/metabolismo , Clofibrato/farmacologia , Fármacos Gastrointestinais/farmacologia , Fígado/efeitos dos fármacos , PPAR alfa/agonistas , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Genótipo , Homeostase , Íleo/efeitos dos fármacos , Íleo/metabolismo , Lipoproteínas/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Fenótipo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/metabolismo , Simportadores/metabolismo , Fatores de Tempo
14.
J Pharm Pharm Sci ; 20(0): 239-251, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28810950

RESUMO

PURPOSE: To investigate the effect of clofibrate on inducing liver fatty acid binding protein (FABP1) following a high-fat load in a hepatocyte cell culture model. METHODS: Rat hepatoma cells (CRL-1548) were treated with a fatty acid (FA) mixture consisting of oleate:palmitate (2:1) in the presence of 3% albumin. Cells were treated with 0, 0.5, 1, 2, or 3 mM FA for 24 and 48 hr, or further treated with 500 µM clofibrate (CLO) to induce FABP1 levels. Cytotoxicity was determined using the WST-1 assay. Intracellular lipid droplets were quantitated following staining with Nile Red. Dichlorofluorescein (DCF) was used to assess the extent of intracellular reactive oxygen species (ROS). RESULTS: Cell viability decreased (p < 0.01) with an increase in lipid concentration. Intracellular lipid droplets accumulated significantly (p < 0.001) with an increase in long-chain fatty acid load, which was associated with a statistical increase (p < 0.05) in ROS levels. Early clofibrate treatment showed significant increases in intracellular FABP1 levels with significant decreases in ROS levels (p < 0.05). Silencing FABP1 expression using siRNA revealed that FABP1 was the main contributor for the observed intracellular ROS clearance. CONCLUSIONS: Characteristic cellular damage resulted from released ROS following a high fat load to hepatoma cells. The damage was attenuated through early treatment with clofibrate, which may act as a hepatoprotectant by inducing FABP1 expression and in this manner, suppress intracellular ROS levels. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Assuntos
Clofibrato/farmacologia , Lipídeos/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/biossíntese , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/farmacologia , Lipídeos/administração & dosagem , Lipídeos/química , Tamanho da Partícula , RNA Interferente Pequeno/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Environ Mol Mutagen ; 58(7): 485-493, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28714084

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.


Assuntos
Epididimo , Proteínas de Membrana/genética , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Espermatozoides/efeitos dos fármacos , 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
17.
Toxicol Pathol ; 45(4): 506-525, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28485676

RESUMO

Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity.


Assuntos
Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Clofibrato/efeitos adversos , Fígado/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Anticolesterolemiantes/administração & dosagem , Arginase/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Colesterol/sangue , Colinesterases/sangue , Clofibrato/administração & dosagem , Creatinina/sangue , Relação Dose-Resposta a Droga , Proteína 3 Ligante de Ácido Graxo/sangue , Glutamato Desidrogenase/sangue , Queratina-18/sangue , Fígado/metabolismo , Masculino , MicroRNAs/sangue , Músculo Esquelético/metabolismo , Cadeias Leves de Miosina/sangue , Ratos , Ratos Wistar , Triglicerídeos/sangue
18.
Indian J Pediatr ; 84(10): 763-767, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28512725

RESUMO

OBJECTIVE: To evaluate the efficacy of oral clofibrate as an adjunct to phototherapy for unconjugated hyperbilirubinemia in term neonates. METHODS: This randomized controlled trial was done in the level III neonatal intensive care unit (NICU) of a tertiary care hospital. Ninety term neonates with unconjugated hyperbilirubinemia with serum bilirubin 15-25 mg/dl were randomized to either intervention group (single dose of clofibrate in a dose of 50 mg/kg prior to starting phototherapy) or standard care group (only phototherapy). Primary outcome was absolute fall in bilirubin by 48 h. Secondary outcomes were duration of phototherapy, absolute fall in bilirubin levels at 12, 24, 36, 48 h, need for exchange transfusion and incidence of side-effects. RESULTS: After 48 h of intervention, significantly lower bilirubin levels were noted in the intervention group compared to standard care group with a mean difference of 7 mg/dl (95% CI 6.7 mg/dl to 7.2 mg/dl). Duration of phototherapy required was less in the intervention group compared to standard care group with mean difference of 23.82 h (95% CI 30.46 h to 17.18 h). Exchange transfusion was needed for 4 neonates in the standard care group and none in the intervention group. No side-effects were noted with clofibrate. CONCLUSIONS: Single dose clofibrate prior to starting phototherapy in term neonates with uncomplicated unconjugated hyperbilirubinemia reduces the duration of phototherapy significantly.


Assuntos
Clofibrato/uso terapêutico , Hiperbilirrubinemia Neonatal/terapia , Fototerapia/métodos , Clofibrato/administração & dosagem , Terapia Combinada , Feminino , Humanos , Hiperbilirrubinemia Neonatal/tratamento farmacológico , Recém-Nascido , Masculino
19.
Food Chem Toxicol ; 109(Pt 1): 690-702, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28495587

RESUMO

Identification of sensitive and novel biomarkers or endpoints associated with toxicity and carcinogenesis is of a high priority. There is increasing interest in the incorporation of epigenetic and metabolic biomarkers to complement apical data; however, a number of questions, including the tissue specificity, dose-response patterns, early detection of those endpoints, and the added value need to be addressed. In this study, we investigated the dose-response relationship between apical, epigenetic, and metabolomics endpoints following short-term exposure to experimental hepatotoxicants, clofibrate (CF) and phenobarbital (PB). Male F344 rats were exposed to PB (0, 5, 25, and 100 mg/kg/day) or CF (0, 10, 50, and 250 mg/kg/day) for seven days. Exposure to PB or CF resulted in dose-dependent increases in relative liver weights, hepatocellular hypertrophy and proliferation, and increases in Cyp2b1 and Cyp4a1 transcripts. These changes were associated with altered histone modifications within the regulatory units of cytochrome genes, LINE-1 DNA hypomethylation, and altered microRNA profiles. Metabolomics data indicated alterations in the metabolism of bile acids. This study provides the first comprehensive analysis of the apical, epigenetic and metabolic alterations, and suggests that the latter two occur within or near the dose response curve of apical endpoint alterations following exposure to experimental hepatotoxicants.


Assuntos
Clofibrato/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Fígado/efeitos dos fármacos , Fenobarbital/toxicidade , Animais , Clofibrato/análise , Sistema Enzimático do Citocromo P-450/metabolismo , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Epigenômica , Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , Masculino , Fenobarbital/análise , Ratos , Ratos Endogâmicos F344
20.
Mol Genet Genomics ; 292(4): 699-727, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28389698

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.


Assuntos
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 , 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
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