• MeSH
• endokrinní systém účinky léků   MeSH
• imunita účinky záření   MeSH
• metabolismus účinky léků   MeSH
• racionální návrh léčiv MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• chemie, klinická chemie
• endokrinologie
• vnitřní lékařství
• NLK Publikační typ
• elektronické časopisy

Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, medium- and large-scale metabolic networks models.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• biologické modely MeSH
• fruktosadifosfáty metabolismus   MeSH
• Lactococcus lactis metabolismus   MeSH
• metabolické sítě a dráhy MeSH
• metabolismus sacharidů * MeSH
• metoda Monte Carlo MeSH
• počítačová simulace MeSH
• statistické modely MeSH
• zpětná vazba fyziologická MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• endokrinní systém účinky léků   MeSH
• farmaceutická chemie MeSH
• imunita účinky léků   MeSH
• metabolismus účinky léků   MeSH
• racionální návrh léčiv MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmakoterapie
• farmacie a farmakologie
• farmacie a farmakologie
• endokrinologie
• vnitřní lékařství
• NLK Publikační typ
• elektronické časopisy

• MeSH
• biologické modely MeSH
• inzulinová rezistence MeSH
• krysa rodu rattus MeSH
• metabolický syndrom etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• AIDS farmakoterapie   MeSH
• lékové transportní systémy MeSH
• metabolické nemoci farmakoterapie   MeSH
• nemoci endokrinního systému farmakoterapie   MeSH
• racionální návrh léčiv MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmakoterapie
• vnitřní lékařství
• endokrinologie
• NLK Publikační typ
• elektronické časopisy

• MeSH
• kultivované buňky MeSH
• metabolismus MeSH
• myokard cytologie   metabolismus   MeSH
• teoretické modely MeSH
• Publikační typ
• přehledy MeSH

Fatty liver is extremely common in insulin-resistant patients with either obesity or lipodystrophy and it has been proposed that hepatic steatosis be considered an additional feature of the metabolic syndrome. Although insulin resistance can promote fatty liver, excessive hepatic accumulation of fat can also promote insulin resistance and could contribute to the pathogenesis of the metabolic syndrome. We sought to create a new nonobese rat model with hypertension, hepatic steatosis, and the metabolic syndrome by transgenic overexpression of a sterol-regulatory element-binding protein (SREBP-1a) in the spontaneously hypertensive rat (SHR). SREBPs are transcription factors that activate the expression of multiple genes involved in the hepatic synthesis of cholesterol, triglycerides, and fatty acids. The new transgenic strain of SHR overexpressing a dominant-positive form of human SREBP-1a under control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhibited marked hepatic steatosis with major biochemical features of the metabolic syndrome, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Both oxidative and nonoxidative skeletal muscle glucose metabolism were significantly impaired in the SHR transgenic strain and glucose tolerance deteriorated as the animals aged. The SHR transgenic strain also exhibited reduced body weight and reduced adipose tissue stores; however, the level of hypertension in the transgenic SHR was similar to that in the nontransgenic SHR control. The transgenic SHR overexpressing SREBP-1a represents a nonobese rat model of fatty liver, disordered glucose and lipid metabolism, and hypertension that may provide new opportunities for studying the pathogenesis and treatment of the metabolic syndrome associated with hepatic steatosis.

• MeSH
• adiponektin MeSH
• DNA vazebné proteiny * genetika   MeSH
• exprese genu MeSH
• geneticky modifikovaná zvířata * MeSH
• hypertenze genetika   patofyziologie   MeSH
• játra patologie   MeSH
• krevní tlak MeSH
• leptin krev   MeSH
• lidé MeSH
• metabolický syndrom * genetika   MeSH
• mezibuněčné signální peptidy a proteiny krev   MeSH
• modely nemocí na zvířatech * MeSH
• potkani inbrední SHR * MeSH
• protein SREBP1 MeSH
• proteiny vázající zesilovač transkripce CCAAT * genetika   MeSH
• stárnutí metabolismus   MeSH
• transgeny MeSH
• transkripční faktory * genetika   MeSH
• tuková tkáň patologie   MeSH
• ztučnělá játra * genetika   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

The survival and proliferation of cells and organisms require a highly coordinated allocation of cellular resources to ensure the efficient synthesis of cellular components. In particular, the total enzymatic capacity for cellular metabolism is limited by finite resources that are shared between all enzymes, such as cytosolic space, energy expenditure for amino-acid synthesis, or micro-nutrients. While extensive work has been done to study constrained optimization problems based only on stoichiometric information, mathematical results that characterize the optimal flux in kinetic metabolic networks are still scarce. Here, we study constrained enzyme allocation problems with general kinetics, using the theory of oriented matroids. We give a rigorous proof for the fact that optimal solutions of the non-linear optimization problem are elementary flux modes. This finding has significant consequences for our understanding of optimality in metabolic networks as well as for the identification of metabolic switches and the computation of optimal flux distributions in kinetic metabolic networks.

• MeSH
• kinetika MeSH
• metabolismus * MeSH
• teoretické modely * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• lékařství MeSH
• počítače MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• lékařství
• lékařská informatika

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