Biomedical subjects

Benjamin Keserü

Publications and source records attributed to Benjamin Keserü.

3 recordsLinked to original sources

PubMed2007

Fluid shear stress and NO decrease the activity of the hydroxy-methylglutaryl coenzyme A reductase in endothelial cells via the AMP-activated protein kinase and FoxO1.

The rate-limiting enzyme for cholesterol synthesis, the hydroxy-methylglutaryl coenzyme A reductase (HCR), is phosphorylated by the AMP-activated protein kinase (AMPK). As shear stress activates the AMPK in endothelial cells, we determined whether it affects HCR activity and subsequent HCR-dependent signaling. Shear stress (12 dynes cm(-2)) rapidly increased the phosphorylation and activity (6.5- and 4-fold, respectively) of the AMPK in cultured endothelial cells and the activated AMPK phosphorylated the HCR in vitro. Moreover, shear stress and the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated endothelial HCR activity by 37% and 33%, respectively. Inhibition of NO production attenuated the acute shear stress-induced phosphorylation of the AMPK and the decrease in HCR activity. Prolonged shear stress (18 hours) led to a significant (50%) decrease in HCR mRNA expression that was dependent on NO, AMPK, and the subsequent phosphorylation and degradation of FoxO1a. Correspondingly, the downregulation of FoxO (small interfering RNA) decreased HCR expression. Prolonged shear stress also attenuated the bradykinin-induced activation of Ras and extracellular signal-regulated kinase 1/2, a phenomenon that was comparable to the effects of cerivastatin and that was reversed by mevalonate and thus attributed to HCR inhibition. A decrease (35%) in HCR expression was also detected in femoral arteries from mice following voluntary exercise, and the bradykinin-induced vasodilatation of the mouse hindlimb was attenuated by both exercise and the HCR inhibitor cerivastatin. These data indicate that fluid shear stress regulates the activity and expression of the HCR in endothelial cells and determines responsiveness to stimuli, such as bradykinin via a mechanism involving NO, AMPK, FoxO1a, and p21Ras.

AMP-Activated Protein Kinases↗

PubMed2005

The chemopreventive agent resveratrol stimulates cyclic AMP-dependent chloride secretion in vitro.

Resveratrol and its analogs are promising cancer chemoprevention agents, currently under investigation in clinical trials. However, patients administered other plant polyphenols experienced severe diarrhea, likely due to an increase in intracellular cyclic AMP (cAMP). Resveratrol itself raises intracellular cAMP levels in breast cancer cells in vitro. Its future use as a cancer chemopreventive agent could therefore be compromised by its severe side effects. The aim of the study was (a) to define the influence of resveratrol on intestinal Cl(-) secretion and (b) to elucidate possible intracellular transduction pathways involved. Resveratrol caused a dose- and time-dependent increase in DeltaIsc in T(84) cells. The specificity of resveratrol was confirmed by using piceatannol 100 mumol/L, the hydroxylated resveratrol analog, which did not alter DeltaIsc. A significant elevation of [cAMP](i) by resveratrol was assessed in T(84) cells. In mouse jejunum, resveratrol induced a time- and dose-dependent increase in DeltaIsc as well. In bilateral Cl(-)-free medium, as well as after inhibition of protein kinase A, resveratrol-induced DeltaIsc was reduced significantly. Preincubation of T(84) cells with butyrate 2 mmol/L (24 and 48 hours) significantly inhibited resveratrol as well as forskolin-induced Cl(-) secretion. In summary, the main mechanism of action of resveratrol in intestinal epithelia is cAMP-induced chloride secretion which can be suppressed by butyrate. It can therefore be suggested that in cancer chemoprevention, both agents should be combined to reduce an undesired side effect such as diarrhea and to benefit from the known agonistic effect of both agents on differentiation of colon cancer cells.

Animals↗

PubMed2005

Altered body composition and metabolism in the male offspring of high fat-fed rats.

An intrauterine environment may play a role in predisposing a developing fetus to metabolic diseases during adulthood. We investigated the hypothesis that a maternal diet high in omega-6 polyunsaturated fat can modify the programming of an offspring's glucose tolerance, insulin sensitivity, body composition, lipid metabolism, and insulin signaling. High omega-6 polyunsaturated fat diets were fed to female rats 4 weeks before mating and throughout the gestation period. The offspring were maintained on chow diet. At 3 months of age, indirect calorimetry, oral glucose tolerance tests, and dual x-ray absorptiometry measurements were performed. Triglyceride content and beta-hydroxyacyl coenzyme A dehydrogenase activity were determined in the liver and quadriceps muscle. Expression levels of key insulin signaling pathway proteins were measured in the liver and quadriceps muscle of the 3-month-old offspring. Offspring from the fat-fed dams had significantly increased proportions of both total body fat and abdominal fat. All offspring displayed normal insulin sensitivity and glucose tolerance, although the offspring from the fat-fed dams were significantly more hyperinsulinemic 15 minutes after an oral glucose challenge. Whole body fuel oxidation was not altered. The offspring of fat-fed dams had significantly elevated liver triglyceride content. Insulin signaling protein expression levels in the offspring of fat-fed dams were consistent with reduced hepatic insulin sensitivity but increased quadriceps insulin sensitivity. A maternal diet high in omega-6 polyunsaturated fat evokes programming within the metabolic processes of the offspring that may predispose the offspring to the development of metabolic diseases.

3-Hydroxyacyl CoA Dehydrogenases↗