Inzulinovou rezistenci (IR) definujeme jako stav, při němž normální koncentrace volného plazmatického inzulinu vyvolává sníženou odpověď organizmu. V užším slova smyslu IR chápeme jako poruchu účinku inzulinu v cílové struktuře, která může vzniknout na kterékoli úrovni inzulinové signalizační kaskády. V klinických podmínkách ji obvykle definujeme jako poruchu účinku inzulinu v metabolizmu glukózy, i když platí, že porucha se může se týkat různých účinků inzulinu a různých buněčných struktur. Charakteristickým rysem IR svázané s metabolickým syndromem či diabetem 2. typu je defektní signalizace, která postihuje PI3-kinázovou větev inzulinové signalizační kaskády. Další účinky inzulinu, které závisí na signalizaci vedoucí přes Ras komplex a MAP-kinázu, nemusí být postiženy. Vlivem kompenzatorní hyperinzulinemie mohou být dokonce zvýšeny. Článek shrnuje některé novější poznatky týkající struktury a regulací inzulinové signalizační kaskády a rozebírá vybrané primární a sekundární příčiny IR, které zahrnují faktory genetické a epigenetické, regulační roli mikroRNA a metabolické, humorální a imunologické faktory. Detailní poznání příčin IR nabízí možnosti její racionální léčby. Ta se v současné době opírá o léčbu odstranitelných příčin IR, tj. důslednou kompenzaci diabetu, redukci hmotnosti, režimová opatření (dieta, fyzická aktivita), přehodnocení potřeby léčby kortikoidy, léčbu přidružených onemocnění, a případně podání metforminu či pioglitazonu. Klíčová slova: cytokiny – inzulinová rezistence – inzulinová signalizační kaskáda, Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re-assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone. Key words: cytokines – insulin resistance – insulin signalling cascade, and Terezie Pelikánová
As traditional risk factors are unable to fully explain the pathogenesis of coronary artery disease (CAD), novel mechanisms became a target of many investigations. Our aim was to study the response of selected markers to physical exercise. High-sensitive C-reactive protein (hs-CRP), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), advanced oxidation protein products (AOPP), soluble receptor for advanced glycation end-products (sRAGE), pregnancy-associated plasma protein A (PAPP-A), E-selectin, vascular endothelial growth factor (VEGF) and B-type natriuretic peptide (BNP) levels were measured in serum of 21 CAD patients and in 22 healthy controls at rest and after exercise bicycle stress test performed up to the maximal tolerated effort. At rest, hs-CRP, AOPP, MMP-9 and BNP were significantly elevated in the CAD patients as compared with controls. In contrast, P-selectin was significantly lower in CAD patients and a tendency to lower levels of sRAGE was noted. After exercise MMP-9 and BNP, increased significantly in both groups. In conclusions, CAD patients have elevated hs-CRP, AOPP, MMP-9 and BNP - novel markers related to cardiovascular risk or left ventricular overload. MMP-9 and BNP increase significantly with exercise in both healthy individuals and CAD patients., V. Danzig ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Homeostasis of reactive oxygen species (ROS) in cardiomyocytes is critical for elucidation of normal heart physiology and pathology. Mitochondrial phospholipases A2 (mt-PLA2) have been previously suggested to be activated by ROS. Therefore, we have attempted to elucidate physiological role of such activation. We have found that function of a specific i-isoform of mitochondrial phospholipase A2 (mt-iPLA2) is activated by tert-butylhydroperoxide in isolated rat heart mitochondria. Isoform specificity was judged from the inhibition by bromoenol lactone (BEL), a specific iPLA2 inhibitor. Concomitant uncoupling has been caused by free fatty acids, since it was inhibited by bovine serum albumin. The uncoupling was manifested as a respiration burst accompanied by a slight decrease in mitochondrial inner membrane potential. Since this uncoupling was sensitive to carboxyatractyloside and purine nucleotide di- and triphosphates, we conclude that it originated from the onset of fatty acid cycling mediated by the adenine nucleotide translocase (major contribution) and mitochondrial uncoupling protein(s) (minor contribution), respectively. Such a mild uncoupling may provide a feedback downregulation of oxidative stress, since it can further attenuate mitochondrial production of ROS. In conclusion, ROS-induced function of cardiac mt-iPLA2 may stand on a pro-survival side of ischemia-reperfusion injury., Ježek, J. ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The study aimed to evaluate if the monitoring of advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), lipoperoxides (LPO) and interleukin-6 (IL-6) in plasma could help to predict development of diabetic complications (DC). Clinical and biochemical parameters including AGEs, AOPP, LPO and IL-6 were investigated in patients with type 2 diabetes mellitus (DM2) with (+DC) and without (-DC) complications. AGEs were significantly higher in both diabetic groups compared to controls. AGEs were also significantly higher in group +DC compared to -DC. AGEs significantly correlated with HbA1c. We observed significantly higher AOPP in both diabetic groups in comparison with controls, but the difference between -DC and +DC was not significant. LPO significantly correlated with BMI. IL-6 were significantly increased in both diabetic groups compared to controls, but the difference between -DC and +DC was not significant. There was no significant correlation between IL-6 and clinical and biochemical parameters. These results do not exclude the association between IL-6 and onset of DC. We suggest that the measurement of not only HbA1c, but also AGEs may be useful to predict the risk of DC development in clinical practice. Furthermore, the measurement of IL-6 should be studied as adjunct to HbA1c monitoring., V. Jakuš, E. Šándorová, J. Kalninová, B. Krahulec., and Obsahuje bibliografii
Hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play an important role in brain control of blood pressure (BP). One of the important mechanisms involved in the pathogenesis of hypertension is the elevation of reactive oxygen species (ROS) production by nicotine adenine dinucleotide phosphate (NADPH) oxidase. The aim of our present study was to investigate NADPH oxidase -mediated superoxide (O 2 - ) production and to search for the signs of lipid peroxidation in hypothalamus and medulla oblongata as well as in renal medulla and cortex of hypertensive male rats transgenic for the murine Ren -2 renin gene (Ren -2 TGR) and their age -matched normotensive controls ‒ Hannover Sprague Dawley rats (HanSD) . We found no difference in the activity of NADPH oxidase measured as a lucigenin -mediated O 2 - production in the hypothalamus and medulla oblongata. However, we observed significantly elevated NADPH oxidase in both renal cortex and medulla of Ren -2 TGR com pared with HanSD. Losartan (LOS) treatment (10 mg/kg body weight/day) for 2 months (Ren -2 TGR+LOS) did not change NADPH oxidase -dependent O 2 - production in the kidney. We detected significantly elevated indirect m arkers of lipid peroxidation measured as th iobarbituric acid -reactive substance s (TBARS) in Ren -2 TGR, while they were significantly decreased in Ren -2 TGR +LOS. In conclusion, the present study shows increased NADPH oxidase activities in renal cortex and medulla with significantly increased TBARS in renal cortex. No significant changes of NADPH oxidase and markers of lipid peroxidation were detected in the studied brain regions., M. Vokurková, H. Rauchová, L. Řezáčová, I. Vaněčková, J. Zicha., and Obsahuje bibliografii
The review concerns a number of basic molecular pathways that play a crucial role in perception, transmission, and modulation of the stress signals, and mediate the adaptation of the vital processes in the cardiovascular system (CVS). These highly complex systems for intracellular transfer of information include stress hormones and their receptors, stress-activated phosphoprotein kinases, stress-activated heat shock proteins, and antioxidant enzymes maintaining oxidoreductive homeostasis of the CVS. Failure to compensate for the deleterious effects of stress may result in the development of different pathophysiological states of the CVS, such as ischemia, hypertension, atherosclerosis and infarction. Stress-induced dysbalance in each of the CVS molecular signaling systems and their contribution to the CVS malfunctioning is reviewed. The general picture of the molecular mechanisms of the stress-induced pathophysiology in the CVS pointed out the importance of stress duration and intensity as etiological factors, and suggested that future studies should be complemented by the careful insights into the individual factors of susceptibility to stress, prophylactic effects of 'healthy' life styles and beneficial action of antioxidant-rich nutrition., S. B. Pajović, M. B. Radojčić, D. T. Kanazir., and Obsahuje bibliografii a bibliografické odkazy
Excessive production of reactive oxygen species (ROS) are implicated in the pathogenesis of numerous disease states. However, direct measurement of in vivo ROS in humans has remained elusive due to limited access to appropriate tissue beds and the inherently short half-lives and high reactivity of ROS. Herein, we describe a novel technique by which to measure in vivo ROS in human skeletal muscle. Microdialysis probes were inserted into the vastus lateralis of eight healthy volunteers. Amplex Ultrared, a highly specific fluorogenic substrate for hydrogen peroxide (H2O2), and horseradish peroxidase (HRP), were perfused through microdialysis probes, and outflowing dialysate was collected and fluorescence was measured. Extracellular H2O2 that crossed the microdialysis membrane was measured via fluorescence of the dialysate. Superoxide dismutase (SOD) was then added to the inflowing perfusion media to convert any superoxide crossing the microdialysis membrane to H2O2 within the microdialysis probe. Fluorescence significantly increased (P=0.005) upon SOD addition. These data demonstrate the feasibility of measuring both in vivo H2O2 and superoxide in the extracellular environment of human skeletal muscle, providing a technique with a potential application to a wide range of circulatory and metabolic studies of oxidative stress., J. D. La Favor, E. J. Anderson, R. C. Hickner., and Obsahuje bibliografii
The oxidative stress plays an important role in the development of cardiovascular diseases (CVD). In CVD progression an aberrant redox regulation was observed. In this regulation levels of reactive oxygen species (ROS) play an important role in cellular signaling, where Nrf2 is the key regulator of redox homeostasis. Keap1-Nrf2-ARE system regulates a great set of detoxificant and antioxidant enzymes in cells after ROS and electrophiles exposure. In this review we focus on radical-generating systems in cardiovascular system as well as on Nrf2 as a target against oxidative stress and a key player of redox regulation in cardiovascular diseases. We also summarize the current knowledge about the role of Nrf2 in pathophysiology of several CVD (hypertension, cardiac hypertrophy, cardiomyopathies) as well as in cardioprotection against myocardial ischemia/ reperfusion injury., M. Barančík, L. Grešová, M. Barteková, I. Dovinová., and Obsahuje bibliografii
In this study we analyzed the effects of melatonin (Mel, 1 mg/kg ip) on behavioral changes as well as cell and oxidative damage prompted by bilaterally olfactory bulbectomy. Olfactory bulbectomy caused an increase in lipid peroxidation products and caspase-3, whereas it prompted a decrease of reduced glutathione (GSH) content and antioxidative enzymes activities. Additionally, olfactory bulbectomy induced behavioral changes characterized by the enhancement of immobility time in the forced swim test and hyperactivity in the open field test. All these changes were normalized by treatment of Mel (14 days). Our data show that Mel has a beneficial neuropsychiatric action against oxidative stress, cell damage and behavior alterations., I. Tasset ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy