Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes.

Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance.

Examination of Self-Esteem, Body Image, Eating Attitudes and Cardiorespiratory Performance in Adolescents.

Self-esteem, body image and eating attitudes are important characteristics regarding adolescent mental health. In our present work, we aimed to investigate these psychological items in adolescent boys and girls examining gender differences and correlations with the BMI-for-age and cardiorespiratory performance. 374 students (209 girls with an average age of 16.4 ± 1.08 years, and 165 boys with an average age of 16.5 ± 1.03 years) underwent investigation using the Rosenberg self-esteem scale, EAT-26 and BAT questionnaires. The BMI-for-age was calculated with BMI growth charts and the cardiorespiratory performance was measured with the 20 m shuttle run test. Our results showed that adolescent girls scored lower self-esteem and higher values for BAT and each scale of eating behaviors, such as uncontrolled eating, cognitive restraints and emotional eating compared to boys despite the fact, that obesity and overweight were more common among boys. No significant correlation was found between BMI and psychological test results in either boys or girls, however, subjective body shape and gender predicted self-esteem and BAT scores and the cognitive restraints in the eating attitudes. Uncontrolled and emotional eating were primarily influenced by gender, in which BMI played only a weaker role. Cardiorespiratory performance was positively associated with self-esteem and body image among boys, and it had a negative correlation regarding BMI in both genders.

Association between Obesity and Overweight and Cardiorespiratory and Muscle Performance in Adolescents.

The high prevalence of obesity in childhood and adolescence has major public health consequences, since it is associated with various chronic diseases in the short- and long-term. The goal of our study was to examine the possible association between obesity and overweight and cardiorespiratory and muscle performance during a 4-year follow up period in adolescents. The body mass index (BMI) and physical performance of adolescents (360 girls and 348 boys) between 14-18 years of age was measured twice a year, and the possible correlation between overweight and obesity and cardiorespiratory and muscle performances were investigated. Our results revealed that cardiorespiratory performance increased significantly in boys during the 4 years (p < 0.001), but the aerobic performance of girls only showed seasonal fluctuation. Muscle performance significantly increased both in boys and girls (p < 0.001). Inverse association between obesity and cardiorespiratory and muscle performance was proved. Overweight was also inversely correlated with cardiorespiratory performance, but it demonstrated no correlation with muscle strength. Avoiding increased BMI and decreased physical fitness is essential for adolescents' health to prevent short- and long-term adverse effects.

PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3ß and several PKC isoforms.

Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3ß(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3ß(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/ßII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

Alcohol-free red wine inhibits isoproterenol-induced cardiac remodeling in rats by the regulation of Akt1 and protein kinase C alpha/beta II.

There is increasing evidence that moderate consumption of red wine containing high amount of polyphenols and anthocyanins is associated with decreased incidence of cardiovascular morbidity and mortality. Therefore, we hypothesized that cardiac hypertrophy and fibrosis as well as Akt (protein kinase B, PKB) and protein kinase C (PKC) cascades can be beneficially influenced by an alcohol-free red wine (AFRW) extract rich in 14 types of polyphenols and 4 types of anthocyanins during cardiac remodeling. To test this assumption, rats were treated with isoproterenol (ISO) to induce postinfarction remodeling and were given tap water or AFRW ad libitum for 8 weeks. Control rats received vehicle instead of ISO. Heart mass/body mass and ventricle mass/body mass ratios, diameter of cardiomyocytes, phosphorylation of PKC alpha/beta II and protein kinase B/Akt, and deposition of collagen type III were determined from the hearts of all four groups of rats. All measured gravimetric parameters, myocyte diameters and the amount of collagen type III decreased, and the phosphorylation of PKC alpha/beta II was reduced in the ISO+AFRW group compared to the ISO group. AFRW induced activation of Akt, one of the best characterized cytoprotective pathways even without ISO treatment, and this activation was further increased in the ISO+AFRW group. These data suggest that AFRW treatment has a protective effect on hearts undergoing postinfarction remodeling by repressing hypertrophy-associated increased phosphorylation of PKC alpha/beta II and by activating Akt, providing a molecular mechanism for the cardioprotective effect of red wine polyphenols.

Circadian variability of blood pressure in obese children.

BACKGROUND AND AIMS: The aim of the present study was to evaluate the circadian rhythm of blood pressure pattern in obese children, and to investigate if the lack of normal diurnal rhythm of blood pressure is associated with cardiovascular risk factors. METHODS AND RESULTS: 73 obese children (body weight [mean+/-SD]: 89.0+/-17.8 kg; age [mean+/-SD]: 14.2+/-2.3 years), 42 dippers and 31 non-dippers were investigated. Following ambulatory blood pressure monitoring (ABPM), physical fitness testing was performed on a treadmill. Physical working capacity at 130, -150, -170 beat/min (PWC-130, -150, -170), resting and peak oxygen consumption (VO(2)rest, VO(2)peak) were determined. Forty-two percent of obese children were non-dipper. PWC-130 (74.8+/-48.8 watts; 48.0+/-38.5 watts), PWC-150 (132.9+/-52.1 watts; 104.2+/-49.3 watts), PWC-170 (185.9+/-49.5 watts; 154.9+/-53.4 watts) and VO(2)rest, ([mean+/-SD]: 0.29+/-0.08 L/min; 0.26+/-0.07 L/min), and VO(2) peak (2.77+/-0.61 L/min; 2.44+/-0.62 L/min) were significantly lower in the non-dipper group, as compared to dippers (p<0.05). The prevalence of hypertension, on the basis of ABPM, was significantly higher in the non-dipper group (45.2% vs 83.9%, p<0.001). This is due to increased prevalence of masked hypertension in the non-dipper group (19.0% vs 32.3%, p<0.001). CONCLUSION: The normal circadian variation of the blood pressure is frequently absent in obese children. Most of the non-dipper obese children are hypertensive, and their physical fitness is decreased.

A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death.

In ischemia-reperfusion injuries, elevated calcium and reactive oxygen species (ROS) induce mitochondrial permeability transition (mPT), which plays a pivotal role in mediating damages and cell death. Inhibition of mPT decreases necrotic cell death; however, during reperfusion, the continuous production of ROS may contribute to the temporary opening of the pore and thus the onset of the delayed apoptotic cell death. Based on amiodarone structure, we developed the first SOD-mimetic mPT inhibitor (HO-3538) that can eliminate ROS in the microenvironment of the permeability pore. In isolated mitochondria, HO-3538 inhibited mPT and the release of proapoptotic mitochondrial proteins. It had a ROS scavenging effect and antiapoptotic effect in a cardiomyocyte line and it diminished release of mitochondrial proapoptotic proteins. Furthermore, HO-3538 significantly enhanced the recovery of mitochondrial energy metabolism and functional cardiac parameters; decreased infarct size, lipid peroxidation, and protein oxidation; and suppressed necrotic as well as apoptotic cell death pathways in Langendorff-perfused hearts. In these respects it was somewhat superior to its two constituents, amiodarone and a pyrrol-derivative free radical scavenger. These data suggest that the SOD-mimetic mPT inhibitors are ideal candidates for drug development for the alleviation of postinfarct myocardial injuries.

PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway.

The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

The role of Akt and mitogen-activated protein kinase systems in the protective effect of poly(ADP-ribose) polymerase inhibition in Langendorff perfused and in isoproterenol-damaged rat hearts.

Blocking poly(ADP-ribosyl)ation of nuclear proteins protects the heart from ischemia-reperfusion injury. In addition, activation of Akt and mitogen-activated protein kinase (MAPK) cascades also plays a pivotal role in the survival of cardiomyocytes during ischemia-reperfusion; however, the potential interplay between these pathways is yet to be elucidated. We therefore tested the hypothesis whether poly(ADP-ribose) polymerase (PARP) inhibition can modulate Akt and MAPK signaling of ischemic-reperfused rat hearts. A novel PARP inhibitor, L-2286 [2-[(2-piperidin-1-yletil)thio]quinazolin-4(3H)-one] was administered during ischemia-reperfusion in Langendorff perfused rat hearts and in isoproterenol-induced myocardial infarction. Thereafter, the cardiac energy metabolism, oxidative damage, and the phosphorylation state of Akt and MAPK cascades were monitored. L-2286 exerted significant protective effect against ischemia-reperfusion-induced myocardial injury in both experimental models. More importantly, L-2286 facilitated the ischemia-reperfusion-induced activation of Akt, extracellular signal-regulated kinase, and p38-MAPK in both isolated hearts and in vivo cardiac injury. By contrast, isoproterenol-induced rapid c-Jun N-termainal kinase activation was repressed by L-2286. Here, we provide evidence for the first time that PARP inhibition beneficially modulates the cardiac Akt and MAPK signaling in ex vivo and in vivo ischemia-reperfusion models. We therefore propose that this novel mechanism may contribute to the cardioprotective properties of PARP inhibitors.

Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives.

Several amiodarone analogues were synthesized varying the 2-substituent on the benzofuran ring and diethylaminoethyl side chain of phenolether by introducing 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole and 1,2,5,6-tetrahydropyridine nitroxides or their amino or hydroxylamino precursors. The new compounds were screened on isolated mitochondria and perfused heart and their toxicity was evaluated on WRL-68 liver cells and H9C2 cardiomyocytes. Most of the newly synthesized derivatives exerted uncoupling effect on the mitochondrial oxidative phosphorilation at higher concentrations, compared to amiodarone and one of the modified amiodarone analogues showed an effect similar to that of amiodarone on the mitochondrial permeability transition and on restoring of mitochondrial high-energy phosphate metabolites in perfused hearts. This amiodarone analogue can be new leading compound among the experimental amiodarone analogues with the same or enhanced efficiency of amiodarone, but with less side effects.

Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound.

Doxorubicin is a widely used anticancer agent, but its application is restricted by its cardiotoxic side effects. The current theory of its cardiotoxicity is based on free radical formation. The compound H-2545, having a 3-carboxamido-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole moiety, was reported to exhibit antioxidant properties and accumulate in cell membranes, scavenging free radicals at the site of formation. Therefore, we hypothesized that H-2545 could reduce the doxorubicin-induced acute deterioration of cardiac function. Langendorff-perfused rat hearts were treated with doxorubicin and/or H-2545, its metabolite H-2954, or dihydrolipoamide. High-energy phosphate levels, contractile function, lipid peroxidation, protein oxidation, and Akt phosphorylation were investigated. We also determined whether the antioxidants influenced doxorubicin toxicity on malignant cells. During perfusion with doxorubicin, the energetic and functional parameters of the myocardium were improved by adding H-2545. H-2545 significantly diminished doxorubicin-induced lipid and protein damage. On H-2545 treatment, the doxorubicin-triggered Akt phosphorylation was markedly reduced, whereas dihydrolipoamide had such an effect only at higher concentrations. H-2545 did not alter the anticancer effect of doxorubicin on malignant cell lines. We propose that the coadministration of the antioxidant H-2545 attenuates doxorubicin-induced acute cardiotoxicity without interfering with its anticancer effects. Prevention of the acute adverse effects of doxorubicin on myocardium may hinder the later development of cardiomyopathy.

[Effects of cardiovascular risk factors on hemorheologic parameters in cerebrovascular patients]. / A kardiovaszkuláris rizikófaktorok hatása az agyérbetegek hemoreológiai viszonyaira.

INTRODUCTION: Hemorheological factors are of significance in the determination of flow characteristics of blood and play an important role in the pathogenesis of cerebrovascular diseases. AIMS AND METHODS: In this study the changes of rheological factors--hematocrit (Hct), plasma fibrinogen concentration (PFC), whole blood (WBV) and plasma viscosity (PV), red blood cell aggregation (AI) and deformability and the association between these parameters and cardiovascular risk factors were investigated in 297 patients (173 males, 124 females, mean age: 60 11 years) with chronic phase (3 months after onset) ischemic cerebrovascular diseases, and in 68 healthy volunteers (30 males, 38 females, mean age: 36 6 years). RESULTS: All investigated hemorheological factors were significantly (p < 0.05-0.0001) elevated in cerebrovascular patients compared to normal controls, the rise in Hct, WBV and PV are some of the most prominent findings. In the group of hypertensive, hyperlipidemic patients, smokers and alcoholics Hct, PFC, WBV, PV and AI were significantly (p < 0.05-0.0001) higher compared to healthy controls, the same factors except plasma fibrinogen concentration showed association with diabetic history. Comparing cerebrovascular patients with or without risk factors, the most severe hemorheological deficit was observed in patients with hyperlipidemia and smoking habits. CONCLUSIONS: In this study the authors proved in chronic ischemic cerebrovascular patients that hemorheological abnormalities persist in most cases for a long time after an acute stroke, significant correlation could be seen between blood rheology and cardiovascular risk factors. Examination of rheological parameters can support to choose the optimal medical treatment in the secondary prevention of stroke, correction of hemorheological disturbances can reduce the risk of recurrent stroke.