RESUMO
Perinatal maternal high-fat diet (HFD) increases susceptibility to obesity and fatty liver diseases in adult offspring, which can be attenuated by the potent hypolipidaemic action of fish oil (FO), an n-3 PUFA source, during adult life. Previously, we described that adolescent HFD offspring showed resistance to FO hypolipidaemic effects, although FO promoted hepatic molecular changes suggestive of reduced lipid accumulation. Here, we investigated whether this FO intervention only during the adolescence period could affect offspring metabolism in adulthood. Then, female Wistar rats received isoenergetic, standard (STD: 9 % fat) or high-fat (HFD: 28·6 % fat) diet before mating, and throughout pregnancy and lactation. After weaning, male offspring received the standard diet; and from 25 to 45 d old they received oral administration of soyabean oil or FO. At 150 d old, serum and hepatic metabolic parameters were evaluated. Maternal HFD adult offspring showed increased body weight, visceral adiposity, hyperleptinaemia and decreased hepatic pSTAT3/STAT3 ratio, suggestive of hepatic leptin resistance. FO intake only during the adolescence period reduced visceral adiposity and serum leptin, regardless of maternal diet. Maternal HFD promoted dyslipidaemia and hepatic TAG accumulation, which was correlated with reduced hepatic carnitine palmitoyl transferase-1a content, suggesting lipid oxidation impairment. FO intake did not change serum lipids; however, it restored hepatic TAG content and hepatic markers of lipid oxidation to STD offspring levels. Therefore, we concluded that FO intake exclusively during adolescence programmed STD offspring and reprogrammed HFD offspring male rats to a healthier metabolic phenotype in adult life, reducing visceral adiposity, serum leptin and hepatic TAG content in offspring adulthood.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Dislipidemias/prevenção & controle , Óleos de Peixe/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Dislipidemias/etiologia , Ácidos Graxos Ômega-3/metabolismo , Feminino , Gordura Intra-Abdominal/metabolismo , Leptina/sangue , Fígado/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar , Triglicerídeos/metabolismoRESUMO
In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 µM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.
Assuntos
Antituberculosos/química , Proteínas de Bactérias/química , Benzofuranos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Policetídeo Sintases/química , Aminoácidos , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Benzofuranos/farmacologia , Sítios de Ligação , Descoberta de Drogas , Ligação de Hidrogênio , Estrutura Molecular , Policetídeo Sintases/antagonistas & inibidores , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Conjugated linoleic acid (CLA) might regulate the lipid depots in liver and adipose tissue. As there is an association between maternal nutrition, fat depots and risk of offspring chronic disease, the aim was to investigate the effect of maternal CLA consumption on TAG regulation and some inflammatory parameters in adult male rat offspring receiving or not receiving CLA. Female Wistar rats were fed control (C) or CLA-supplemented (1 %, w/w) diets during 4 weeks before and throughout pregnancy and lactation. After weaning, male offspring of CLA rats were fed C or CLA diets (CLA/C and CLA/CLA groups, respectively), whereas C male rat offspring were fed a C diet (C/C group) for 9 weeks. Serum TAG levels were increased in the CLA/CLA and CLA/C groups, associated with a reduction of lipoprotein lipase activity and weights of adipose tissue. The liver TAG levels were decreased in the CLA/CLA group, related to a significant reduction of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and glucose-6-phosphate dehydrogenase enzyme activities, as well as to the mRNA levels of FAS, ACC, stearoyl-CoA desaturase-1 and sterol regulatory element-binding protein-1c. Even though normal TAG levels were found in the liver of CLA/C rats, a reduction of lipogenesis was also observed. Thus, these results demonstrated a programming effect of CLA on the lipid metabolic pathways leading to a preventive effect on the TAG accretion in adipose tissue and the liver of male rat offspring. This knowledge could be important to develop some dietary strategies leading to a reduced incidence of obesity and fatty acid liver disease in humans.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Ácidos Linoleicos Conjugados/farmacologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Dieta , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/sangue , Feminino , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , 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/metabolismoRESUMO
C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (-)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (-)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (-)-UB006 that has no anorexigenic side effects.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Furanos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ingestão de Alimentos/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Ácido Graxo Sintases/metabolismo , Furanos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-DawleyRESUMO
The aim of this study was to investigate the effects of trans-fatty acids (TFA) on liver and serum TAG regulation in mice fed diets containing different proportions of n-3, n-6 and n-9 unsaturated fatty acids (UFA) from olive (O), maize (C) or rapeseed (R) oils partially substituted or not with TFA (Ot, Ct and Rt, respectively). Male CF1 mice were fed (30 d) one of these diets. The effects of the partial substitution (1 %, w/w) of different UFA with TFA on the activity and expression of hepatic enzymes involved in lipogenesis and fatty acids oxidation were evaluated, as well as their transcription factor expressions. Some of the mechanisms involved in the serum TAG regulation, hepatic VLDL rich in TAG (VLDL-TAG) secretion rate and lipoprotein lipase (LPL) activity were assessed. In liver, TFA induced an increase in TAG content in the Ot and Rt groups, and this effect was associated with an imbalance between lipogenesis and ß-oxidation. In the Ot group, exacerbated lipogenesis may be one of the mechanisms responsible for the liver steatosis induced by TFA, whereas in Rt it has been related to a decreased ß-oxidation, compared with their respective controls. The enhanced hepatic VLDL-TAG secretion in the Ot and Rt groups was compensated with a differential removal of TAG by LPL enzyme in extrahepatic tissues, leading to unchanged serum TAG levels. In brief, the effects of low levels of TFA on liver and serum TAG regulation in mice depend on the dietary proportions of n-3, n-6 and n-9 UFA.