Q85363022
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The efficacy of fenofibrate in the treatment of hepatic steatosis has not been clearly demonstrated. In this study, we investigated the effects of fenofibrate and silymarin, administered as monotherapy and in combination to existing hepatic steatosis in a unique strain of hereditary hypertriglyceridemic rats (HHTg), a non-obese model of metabolic syndrome. HHTg rats were fed a standard diet without or with fenofibrate (100 mg/kg b.wt./day) or with silymarin (1%) or with a combination of fenofibrate with silymarin for four weeks. Fenofibrate alone and in combination with silymarin decreased serum and liver triglycerides and cholesterol and increased HDL cholesterol. These effects were associated with the decreased gene expression of enzymes involved in lipid synthesis and transport, while enzymes of lipid conversion were upregulated. The combination treatment had a beneficial effect on the gene expression of hepatic cytochrome P450 (CYP) enzymes. The expression of the CYP2E1 enzyme, which is source of hepatic reactive oxygen species, was reduced. In addition, fenofibrate-induced increased CYP4A1 expression was decreased, suggesting a reduction in the pro-inflammatory effects of fenofibrate. These results show high efficacy and mechanisms of action of the combination of fenofibrate with silymarin in treating hepatic steatosis and indicate the possibility of protection against disorders in which oxidative stress and inflammation are involved.
- Publikační typ
- časopisecké články MeSH
The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin-silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.
- Publikační typ
- časopisecké články MeSH
Hypolipidemic and cardioprotective effects of statins can be associated with the development of myopathies and new-onset type 2 diabetes. These adverse effects may be related to increased oxidative stress. The plant extract silymarin (SM) is known for its antioxidant and anti-inflammatory actions. We tested the hypothesis that the combination of atorvastatin (ATV) with SM could improve therapy efficacy and eliminate some negative effects of statin on hypertriglyceridemia-induced metabolic disorders. Hereditary hypertriglyceridemic rats were fed a standard diet for four weeks without supplementation; supplemented with ATV (5 mg/kg b. wt./day) or a combination of ATV with 1 % micronized SM (ATV+SM). ATV treatment elevated plasma levels of HDL-cholesterol (p<0.01), glucose and insulin and decreased triglycerides (p<0.001). The combination of ATV+SM led to a significant reduction in insulin, an improvement of glucose tolerance, and the hypolipidemic effect was enhanced compared to ATV alone. Furthermore, ATV supplementation increased skeletal muscle triglycerides but its combination with SM decreased triglycerides accumulation in the muscle (p<0.05) and the liver (p<0.01). In the liver, ATV+SM treatment increased the activities of antioxidant enzymes, glutathione and reduced lipid peroxidation (p<0.001). The combined administration of ATV with SM potentiated the hypolipidemic effect, reduced ectopic lipid accumulation, improved glucose metabolism, and increased antioxidant and anti-inflammatory actions. Our results show that SM increased the effectiveness of statin therapy in a hypertriglyceridemic rat model of metabolic syndrome.
- MeSH
- anticholesteremika škodlivé účinky MeSH
- antioxidancia farmakologie MeSH
- atorvastatin škodlivé účinky MeSH
- diabetes mellitus 2. typu chemicky indukované farmakoterapie patologie MeSH
- hypercholesterolemie krev MeSH
- hyperlipidemie farmakoterapie MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- metabolický syndrom farmakoterapie genetika patologie MeSH
- modely nemocí na zvířatech MeSH
- oxidační stres účinky léků MeSH
- silymarin farmakologie MeSH
- triglyceridy krev MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
An evaluation of possible interactions with enzymes of drug metabolism (cytochromes P450, CYP) is an important part of studies on safety and, in general, on the properties of any drug or biologically active compound. The article is focused on the preliminary metabolic study of selected 2,6,9-trisubstituted purine kinase inhibitors with significant anticancer activities which we have developed. The compounds BP-21 and BP-117 represent strong CDK inhibitors and the compound BPA-302 was developed as selective FLT3-ITD kinase inhibitor. Here, emphasis is placed on interactions of these compounds with the nine most important forms of CYP to evaluate the possibility of inhibition of these enzymes. The possibility of their inhibitory effect was studied in vitro on selected human liver microsomal CYP enzymes. The most affected enzyme was CYP2C19. Its activity dropped to 22 % of its original value by BPA 302, to 13 % by BP-21 and to 6 % by BP-117 at the highest concentration tested (250 µmol·l(-1)). The results suggest that the metabolism of concomitantly administered drugs should not be significantly affected at lower doses. Molecular docking of BPA-302 indicated that it can bind to active site of both CYP2C19 and CYP2D6 enzymes above the heme cofactor corroborating the experimental data.
- MeSH
- inhibitory cytochromu P450 chemie farmakologie MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- izoenzymy MeSH
- jaterní mikrozomy účinky léků enzymologie MeSH
- kinetika MeSH
- konformace proteinů MeSH
- lékové interakce MeSH
- lidé MeSH
- puriny chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- systém (enzymů) cytochromů P-450 chemie metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The risk of development of metabolic syndrome can be increased by hypertriglyceridemia. A search for effective therapy is a subject of considerable attention. Therefore, our hypothesis is that the fish oil (containing polyunsaturated fatty acids; n-3 PUFA) in a combination with silymarin can more effectively protect against hypertriglyceridemia-induced metabolic disturbances. The study was conducted using a unique non-obese strain of rats with hereditary hypertriglyceridemia an accepted model of metabolic syndrome. Adult male rats were treated with n-3 PUFA (300 mg/kg/day) without or with 1 % micronized silymarin in a diet for 4 weeks. The treatment with the diet containing n-3 PUFA and silymarin significantly reduced concentrations of serum triglycerides (-45 %), total cholesterol (-18 %), non-esterified fatty acids (-33 %), and ectopic lipid accumulation in skeletal muscle (-35 %) compared to controls. In addition, an increase in Abcg5 and Abcg8 mRNA expression (as genes affecting lipid homeostasis) as well as in protein content of ABCG5 (+78 %) and ABCG8 (+232 %) transporters have been determined in the liver of treated rats. Our findings suggest that this combined diet could be used in the prevention of hypertriglyceridemia-induced metabolic disorders.
- MeSH
- antioxidancia metabolismus MeSH
- dieta * MeSH
- dyslipidemie terapie MeSH
- exprese genu účinky léků MeSH
- hypertriglyceridemie komplikace farmakoterapie genetika MeSH
- krysa rodu rattus MeSH
- lipidy krev MeSH
- metabolický syndrom etiologie prevence a kontrola MeSH
- metabolismus lipidů účinky léků genetika MeSH
- modely nemocí na zvířatech MeSH
- omega-3 mastné kyseliny aplikace a dávkování MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- potkani Wistar MeSH
- rybí oleje MeSH
- silymarin aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Troxerutin (TRX) has a beneficial effect on blood viscosity and platelet aggregation, and is currently used for the treatment of chronic varicosity. Recently, TRX can improve lipid abnormalities, glucose intolerance and oxidative stress in high-fat diet-induced metabolic disorders. In this study, we tested the effect of TRX on metabolic syndrome-associated disorders using a non-obese model of metabolic syndrome-the Hereditary Hypertriglyceridaemic rats (HHTg). METHODS: Adult male HHTg rats were fed standard diet without or with TRX (150 mg/kg bwt/day for 4 weeks). RESULTS: Compared to untreated rats, TRX supplementation in HHTg rats decreased serum glucose (p<0.05) and insulin (p<0.05). Although blood lipids were not affected, TRX decreased hepatic cholesterol concentrations (p<0.01) and reduced gene expression of HMGCR, SREBP2 and SCD1 (p<0.01), involved in cholesterol synthesis and lipid homeostasis. TRX-treated rats exhibited decreased lipoperoxidation and increased activity of antioxidant enzymes SOD and GPx (p<0.05) in the liver. In addition, TRX supplementation increased insulin sensitivity in muscles and epididymal adipose tissue (p<0.05). Elevated serum adiponectin (p<0.05) and decreased muscle triglyceride (p<0.05) helped improve insulin sensitivity. Among the beneficial effects of TRX were changes to cytochrome P450 family enzymes. Hepatic gene expression of CYP4A1, CYP4A3 and CYP5A1 (p<0.01) decreased, while there was a marked elevation in gene expression of CYP1A1 (p<0.01). CONCLUSION: Our results indicate that TRX improves hepatic lipid metabolism and insulin sensitivity in peripheral tissues. As well as ameliorating oxidative stress, TRX can reduce ectopic lipid deposition, affect genes involved in lipid metabolism, and influence the activity of CYP family enzymes.
- MeSH
- glukosa metabolismus MeSH
- glykogen metabolismus MeSH
- hydroxyethylrutosid analogy a deriváty terapeutické užití MeSH
- hypolipidemika terapeutické užití MeSH
- inbrední kmeny potkanů MeSH
- inzulinová rezistence MeSH
- kosterní svaly metabolismus MeSH
- krysa rodu rattus MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- metabolický syndrom farmakoterapie MeSH
- metabolismus lipidů účinky léků MeSH
- modely nemocí na zvířatech MeSH
- oxidační stres účinky léků MeSH
- transkriptom účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Vaccinium myrtillus L. (bilberry) fruit is a blue-colored berry with a high content of anthocyanins. These bioactive secondary metabolites are considered to play a major role in the health-promoting properties of bilberries. Our in vivo study was designed to assess the possible influence of bilberry extract on drug-metabolizing enzymes (DMEs). Rats were exposed to bilberry extract in drinking water at two concentrations (0.15 and 1.5 g/L). Selected DMEs were determined (mRNA expression and enzymatic activity) after 29 and 58 days in rat liver. In addition, a panel of antioxidant, physiological, biochemical and hematological parameters was studied; these parameters did not demonstrate any impact of bilberry extract on the health status of rats. A significant increase in activity was observed in cytochrome P450 (CYP) 2C11 (131% of control) and CYP2E1 (122% of control) after a 29-day administration, while the consumption of a higher concentration for a longer time led to a mild activity decrease. Slight changes were observed in some other DMEs, but they remained insignificant from a physiological perspective. According to our results, we conclude that the consumption of bilberries as a food supplement should not pose a risk of interacting with co-administered drugs based on their metabolism.
- MeSH
- antioxidancia farmakologie MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- rostlinné extrakty farmakologie MeSH
- systém (enzymů) cytochromů P-450 účinky léků metabolismus MeSH
- Vaccinium myrtillus chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
