Gvozden Rosic

Histamine Blood Concentration in Ischemic Heart Disease Patients

The aim of this study was to investigate histamine blood concentration in subjects suffering from different types of ischemic heart diseases during the period of eight days. Our results showed that the histamine blood level was associated with different types of ischemic heart diseases. The blood histamine level in all investigated patients was significantly higher when compared to control subjects (44.87 ± 1.09 ng mL−1), indicating the increase of histamine release in patients suffering from coronary diseases. In patients suffering from ACS-UA and ACS-STEMI, the second day peak of histamine level occurs (90.85 ± 6.34 ng mL−1 and 121.7 ± 6.34 ng mL−1, resp.) probably as the reperfusion event. Furthermore, our data suggest that histamine can be additional parameter of myocardial ischemia along with cardiac specific enzymes and may prove to be an excellent single prognostic marker for multitude of ischemic heart diseases.

In vitro and in vivo assessment of meadowsweet (Filipendula ulmaria) as anti-inflammatory agent

ETHNOPHARMACOLOGICAL RELEVANCE Meadowsweet (Filipendula ulmaria (L.) Maxim, Rosaceae) has been traditionally used in most European countries for the treatment of inflammatory diseases due to its antipyretic, analgesic, astringent, and anti-rheumatic properties. However, there is little scientific evidence on F. ulmaria anti-inflammatory effects regarding its impact on cyclooxygenases enzymatic activity and in vivo assessment of anti-inflammatory potential. This study aims to reveal the anti-inflammatory activity of methanolic extracts from the aerial parts (FUA) and roots (FUR) of F. ulmaria, both in in vitro and in vivo conditions. MATERIALS AND METHODS The characteristic phenolic compounds in F. ulmaria extracts were monitored via high performance thin layer chromatography (HPTLC). The in vitro anti-inflammatory activity of F. ulmaria extracts was evaluated using cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme assays, and an assay for determining COX-2 gene expression. The in vivo anti-inflammatory effect of F. ulmaria extracts was determined in two doses (100 and 200 mg/kg b.w.) with hot plate test and carrageenan-induced paw edema test in rats. Inflammation was also evaluated by histopathological and immunohistochemical analysis. RESULTS FUA extract showed the presence of rutoside, spiraeoside, and isoquercitrin. Both F. ulmaria extracts at a concentration of 50μg/mL were able to inhibit COX-1 and -2 enzyme activities, whereby FUA extract (62.84% and 46.43% inhibition, respectively) was double as effective as the root extract (32.11% and 20.20%, respectively). Extracts hardly inhibited the level of COX-2 gene expression in THP-1 cells at a concentration of 25μg/mL (10.19% inhibition by FUA and 8.54% by FUR). In the hot plate test, both extracts in two doses (100 and 200mg/kg b.w.), exhibited an increase in latency time when compared with the control group (p<0.05). In the carrageenan-induced acute inflammation test, FUA at doses of 100 and 200mg/kg b.w., and FUR at 200mg/kg, were able to significantly reduce the mean maximal swelling of rat paw until 6h of treatment. Indomethacin, FUA, and FUR extracts significantly decreased inflammation score and this effect was more pronounced after 24h, compared to the control group (p<0.05). CONCLUSIONS The observed results of in vitro and, for the first time, in vivo anti-inflammatory activity of meadowsweet extracts, provide support of the traditional use of this plant in the treatment of different inflammatory conditions. Further investigation of the anti-inflammatory compounds could reveal the mechanism of anti-inflammatory action of these extracts.

The effects of N-acetylcysteine on cisplatin-induced changes of cardiodynamic parameters within coronary autoregulation range in isolated rat hearts.

The aim of this study was to evaluate the effects of chronic NAC administration along with cisplatin on cisplatin-induced cardiotoxicity by means of coronary flow (CF), cardiodynamic parameters, oxidative stress markers and morphological changes in isolated rat heart. Isolated hearts of Wistar albino rats (divided into four groups: control, cisplatin, NAC and cisplatin+NAC group) were perfused according to Langendorff technique at constant coronary perfusion pressure starting at 50 and gradually increased to 65, 80, 95 and 110 cm H2O to evaluate cardiodynamic parameters within autoregulation range. Samples of coronary venous effluent (CVE) were collected for determination of CF and biochemical assays, and heart tissue samples for biochemical assays and histopathological examination. Cisplatin treatment decreased CF and heart rate, and increased left ventricular systolic pressure and maximum left ventricular pressure development rate. Cisplatin increased H2O2 and TBARS, but decreased NO2(-) levels in CVE. In tissue samples, cisplatin reduced pathological alterations in myocardium and coronary vessels, with no changes in the amount of total glutathione, as well as in activity of glutathione peroxidase and glutathione reductase. NAC coadministration, by reducing oxidative damage, attenuated cisplatin-induced changes of cardiodynamic and oxidative stress parameters, as well as morphological changes in myocardium and coronary vasculature.

Glucagon Effects on Ischemic Vasodilatation in the Isolated Rat Heart

The myocardial reperfusion following ischemia leads to the ischemic vasodilation by affecting the release of various vasoactive substances, such as free radicals, NO, and histamine. In addition, some evidences suggest that glucagon itself may alter the release of those substances. In this study, we investigated the ischemic vasodilation of the isolated rat heart, as well as the concentrations of NO, TBARS, and histamine in the coronary venous effluent either in the presence or in the absence of glucagon. Our results showed that in the presence of glucagon, there was a faster restoration of coronary perfusion pressure during ischemic vasodilation compared to the absence of glucagon (124 ± 5.6 versus 81 ± 5.2 s) with no apparent changes in TBARS concentration. The glucagons administration leads to the decreased release of histamine by approximately 35%. Biphasic release of NO in the presence of glucagon initially showed augmentation by 60%, followed by the significant attenuation of 45%.

Mathematical analysis of the heart rate performance curve during incremental exercise testing.

In this study we performed laboratory treadmill protocols of increasing load. Heart rate was continuously recorded and blood lactate concentration was measured for determination of lactate threshold by means of LTD-max and LT4.0 methods.Our results indicate that the shape of heart rate performance curve (HRPC) during incremental testing depends on the applied exercise protocol (change of initial speed and the step of running speed increase, with the constant stage duration). Depending on the applied protocol, the HRPC can be described by linear, polynomial (S-shaped), and exponential mathematical expression.We presented mathematical procedure for estimation of heart rate threshold points at the level of LTD-max and LT4.0, by means of exponential curve and its relative deflection from the initial trend line (tangent line to exponential curve at the point of starting heart rate). The relative deflection of exponential curve from the initial trend line at the level of LTD-max and/or LT4.0 can be defined, based on the slope of the initial trend line. Using originally developed software that allows mathematical analysis of heart rate-load relation, LTD-max and/or LT4.0 can be estimated without direct measurement of blood lactate concentration.

The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin–positive interneurons

The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols.

The beneficial effects of sulfur-containing amino acids on cisplatin-induced cardiotoxicity and neurotoxicity in rodents

BACKGROUND Cisplatin is one the most frequently used chemotherapeutic drugs for several decades. Although its antineoplastic effect has been reported in treatment of numerous malignances, various adverse effects seem to be the crucial limiting factor for its administration. OBJECTIVE Beside the most commonly described nephro- and hepatotoxicity, cisplatin therapy is also accompanied with gastrointestinal, reproductive, hematological, cardiovascular and neurological side effects. Since it has been reported that cisplatin induce oxidative damage in various tissues, it seems reasonable to investigate an antioxidant supplementation as potential therapeutical approach for attenuation of cisplatin toxicities. METHODS We performed a structured search of bibliographic databases for research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers (101 in total) was appraised using standard tools. RESULTS Numerous antioxidants (such as thiol compounds, polyphenols, vitamins, etc.) had been reported for their beneficial effects on cisplatin-induced cardiotoxicity. The effects of various antioxidants, including sulfur-containing amino acids, have also been explored for mitigation of cisplatin neurotoxicity. However, the results for antioxidant supplementation in reduction of cisplatin-induced toxicities are still to be applied in clinical trials. CONCLUSION Considering the facts that sulfur-containing amino acids: (a) do not interfere with chemotherapeutics antitumor action; (b) do not exhibit any toxic effect (unless applied in dose several times above the recommended); and (c) produce significant protective effects on some cisplatin-induced toxicities connected to augmentation of oxidative damage - it seems that their administration can be harmless and protective supplementation against numerous adverse effects of certain antineoplastic agents.

The effects of N-acetylcysteine on cisplatin-induced cardiotoxicity on isolated rat hearts after short-term global ischemia

The aim of this study was to estimate the protective effect of N-acetyl-l-cysteine (NAC) against cisplatin-induced cardiotoxicity under conditions of ischemic-reperfusion injury. Wistar albino rats were randomly divided into three groups (n = 8): control, cisplatin (5 mg/kg/w, i.p., 5 weeks) and cisplatin + NAC group (cisplatin – 5 mg/kg/w, i.p. and NAC – 500 mg/kg/w, i.p., 5 weeks). Isolated hearts were perfused according to the modified Langendorff technique at constant pressure (70 cmH2O). Following cardiodynamic parameters were measured: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, left ventricular systolic pressure (SLVP), left ventricular diastolic pressure and heart rate. The ischemic vasodilation episodes were induced by the complete interruption of coronary inflow for 30, 60 and 120 s. The samples of the coronary venous effluent (CVE) were continuously collected during the reperfusion period for determination of coronary flow (CF) rate and oxidative stress markers (H2O2, O2−, NO2− and thiobarbituric acid reactive substances – TBARS). Cisplatin reduced CF, heart rate and overflow (total, maximal and duration of overflow) during reperfusion, and increased SLVP (under basal conditions and after global ischemias). Cisplatin increased levels of H2O2 (under basal conditions), O2− and TBARS (under basal conditions and after ischemia), but decreased NO2− levels (during reperfusion) in CVE, and decreased superoxide dismutase and reduced glutathione in serum. NAC attenuated cisplatin-induced changes of cardiodynamic parameters (except CF under basal conditions) and oxidative stress parameters. Those results suggest that NAC, by decreasing oxidative stress, may be useful in cardioprotection during cisplatin therapy.

Summer savory (Satureja hortensis L.) extract: Phytochemical profile and modulation of cisplatin-induced liver, renal and testicular toxicity

The aim of our study was to examine the potential ameliorating effect of the methanolic extract of Satureja hortensis L. (summer savory) aerial parts against cisplatin-induced oxidative damage in renal, hepatic, and testicular tissues. S. hortensis methanol extract at the doses of 50, 100 and 200 mg/kg of body weight were orally administered to Wistar rats once daily for 10 days. Toxicity was induced by intraperitoneal injection of a single dose of cisplatin (7.5 mg/kg of body weight) on the 5th day of the experiment. Applied treatment with S. hortensis extract restored tissue morphology, ameliorated levels of serum parameters for liver, renal and testes function, tissue oxidative stress parameters, and increased Bcl-2/Bax ratio as an indicator of apoptosis in experimental animals caused by application of cisplatin. UHPLC/DAD/HESI-MS/MS analysis revealed that S. hortensis extract was rich in phenolic compounds with rosmarinic acid (24.9 mg/g) as the main compound, followed by caffeic acid (1.28 mg/g) and naringenin (1.06 mg/g). Our findings suggest that S. hortensis may be a valuable source of dietary and pharmacologically important phenolic compounds, especially rosmarinic acid, in pharmaceutical and functional food formulations in order to maintain normal health conditions or as a remedy in various diseases caused by oxidative damage.

The role of neuropeptide-Y in nandrolone decanoate-induced attenuation of antidepressant effect of exercise

Since the increased prevalence of anabolic androgenic steroids abuse in last few decades is usually accompanied by various exercise protocols, the scope of our study was to evaluate the effects of chronic nandrolone decanoate administration in supraphysiological dose and a prolonged swimming protocol (alone and simultaneously with nandrolone decanoate) on depressive state in male rats. Simultaneously, we investigated the possible alterations in neuropeptide Y (NPY) content in blood and the hippocampus, in order to determine the role of NPY in the modulation of depressive-like behavior.Exercise induced antidepressant effects in tail suspension test (decrease of the total duration of immobility), as well as significant increase in the number of hippocampal NPY-interneurons in CA1 region. Chronic nandrolone decanoate treatment attenuated the beneficial antidepressant effects of exercise as measured by the tail suspension test parameters. Simultaneously, nandrolone decanoate treatment resulted in diminution of NPY content both in blood (decreased serum levels) and in hippocampus (the significant decrease in NPY expression in all three investigated hippocampal regions—CA1, CA2/3 and DG). Our findings indicate that alterations in serum and hippocampal NPY contents may underlie the changes in depressive state in rats. The exercise was beneficial as it exerted antidepressant effect, while chronic nandrolone decanoate treatment resulted in depressive-like behavior. Furthermore, the behavioral indicators of depression showed strong correlations with the serum levels and the hippocampal content of NPY.