Modulating activity of fullerol C60(OH)22 on doxorubicin-induced cytotoxicity.

Paper presents the effects of the newly synthesized fullerol C60(OH)22 on the growth of tumor cells in vitro and its modulating activity on doxorubicin (DOX)-induced cytotoxicity in human breast cancer cell lines. Cell growth inhibition was evaluated by tetrazolium colorimetric WST1 assay. Electron spin resonance (ESR) "trapping" method was used to investigate OH-radical scavenger activity of fullerol during Fenton's reaction. At a range of nanomolar concentrations fullerol induced cell growth inhibition, which was cell line, dose and time dependent. Fullerol also strongly suppressed DOX-induced cytotoxicity at all concentrations regardless the time of fullerol addition. Proanthocyanidins added as single agent to MCF-7 cell culture for 48 h induced low growth inhibition but in combination with DOX strongly decreased DOX cytotoxicity. Fullerol was found to be a potent hydroxyl radical scavenger: the relative intensity of ESR signals of DMPO-hydroxyl radical (DMPO-OH) spin adduct decreased by 88% in the presence of 0.5 microg/ml of fullerol. The obtained results suggest that antiproliferative effect of the fullerol and its protective effect on DOX-induced cytotoxicity might be mediated through hydroxyl-radical scavenger activity of C60(OH)22.     

Can physical activity improve the mental health of older adults?

The world population is aging rapidly. Whilst this dramatic demographic change is a desirable and welcome phenomenon, particularly in view of people's increasing longevity, it's social, financial and health consequences can not be ignored. In addition to an increase of many age related physical illnesses, this demographic change will also lead to an increase of a number of mental health problems in older adults and in particular of dementia and depression. Therefore, any health promotion approach that could facilitate introduction of effective primary, secondary and even tertiary prevention strategies in old age psychiatry would be of significant importance. This paper explores physical activity as one of possible health promotion strategies and evaluates the existing evidence that supports its positive effect on cognitive impairment and depression in later life.     

Effects of nonpeptide and selective V1 and V2 antagonists on blood pressure short-term variability in spontaneously hypertensive rats

Effects of V(1) (OPC-21268) and V(2) (OPC-31260) vasopressin antagonists on blood pressure (BP) short-term variability were investigated in adult spontaneously hypertensive rats (SHR) under basal conditions and after the stimulation of vasopressin release by hemorrhage. BP was recorded intra-arterially and sampled at 20 Hz to be analyzed on a personal computer. BP time spectra were calculated on 30 stationary overlapping 2048 point-time series. Spectral power was estimated in total (0.00976 - 3 Hz), very low frequency (VLF: 0.00976 - 0.195 Hz), low frequency (LF: 0.195 - 0.605 Hz), and high frequency (HF: 0.8 - 3 Hz) regions. Under basal conditions a V(1) antagonist (5 mg/kg, i.v.) decreased BP without affecting BP variability, while combined (V(1) + V(2)) blockade or V(2) blockade (1 mg/kg, i.v.) alone did not affect cardiovascular parameters. Mild hemorrhage (5 ml/kg per min) increased HF-BP variability, while moderate (10 ml/kg per min) and massive (15 ml/kg per min) hemorrhage did not affect it. In V(1), but not V(2), antagonist pre-treated SHR HF-BP increased significantly after moderate and massive hemorrhage. V(1) or V(2) antagonist pre-treatment also enhanced VLF-BP variability during massive hemorrhage. Moreover V(1) blockade prevented hemorrhage-induced bradycardia, while V(2) blockade potentiated it. It follows that in adult SHR, vasopressin buffers BP oscillations in HF and VLF frequency domains only in hypovolaemic conditions and that the modulation of the autonomic adjustment of the HR to hemorrhage by vasopressin is preserved.     

Progress in the development of melanocortin receptor selective ligands

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors (GPCRs), and auxiliary proteins. This pathway has been identified to participate physiologically in numerous biological pathways including energy homeostasis, pigmentation, sexual function, inflammation, cardiovascular function, adrenal function, sebaceous gland lipid production, just to list a few. During this past decade, a clear link between the melanocortin-4 receptor (MC4R) and obesity, in both mice and humans via the regulation of food intake and energy homeostasis, has made this pathway the target of many academic and industrial research endeavors in attempts to develop potent and selective MC4R small molecules as anti-obesity therapeutic agents. Herein, we attempt to summarize the known proteins that constitute the melanocortin system and discuss advances in peptide and non-peptide drug discovery.     

Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene

1 A novel animal model of spontaneous colonic inflammation, the multiple drug-resistant (mdr1) a(-/-) mouse, was identified by Panwala and colleagues in 1998. The aim of our study was to further characterise this model, specifically by measuring cytokines that have been implicated in inflammatory bowel disease (IBD) (IL-8 and IFN-gamma) in the colon/rectum of mdr1a(-/-) mice, and by determining the sensitivity of these, together with the macroscopic, microscopic and disease signs of colitis, to dexamethasone (0.05, 0.3 and 2 mg kg(-1) subcutaneously (s.c.) daily for 7 days). 2 All mdr1a(-/-) mice had microscopic evidence of inflammation in the caecum and colon/rectum, while control mice with the same genetic background did not. Significant increases in colon/rectum and caecal weights and also in cytokine levels (both IFN-gamma and IL-8) in homogenised colon/rectum were observed in mdr1a(-/-) mice compared to mdr1a(+/+) mice. 3 Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN-gamma or IL-8. 4 This study supports the similarity of the gastrointestinal inflammation present in mdr1a(-/-) mice to that of human IBD, in particular Crohn's disease. This has been demonstrated at the macroscopic and microscopic levels, and was supported further by elevations in colonic levels of IFN-gamma and IL-8 and the disease signs observed. The incidence of colitis was much higher than previously reported, with all mice having microscopic evidence of colitis. The limited variance between animals in the parameters measured suggests that this model is reproducible.     

Hyperbaric oxygen treatment does not affect left ventricular chamber stiffness after myocardial infarction treated with thrombolysis

Background

It has been shown that transient increase in left ventricular stiffness, assessed by Doppler-derived early filling deceleration time, occurs during the first 24 to 48 hours after myocardial infarction but returns to normal within several days. It has been reported that hyperbaric oxygen treatment has a favorable effect on left ventricular systolic function in patients with acute myocardial infarction treated with thrombolysis. However, there are no data on the effects of hyperbaric oxygen on diastolic function after myocardial infarction.

Methods

To assess acute and short-term effects of hyperbaric oxygen on left ventricular chamber stiffness, we studied 74 consecutive patients with first acute myocardial infarction who were randomly assigned to treatment with hyperbaric oxygen combined with streptokinase or streptokinase alone. After thrombolysis, patients in the hyperbaric oxygen group received 100% oxygen at 2 atm for 60 minutes in a hyperbaric chamber. All patients underwent 2-dimensional and Doppler echocardiography 1 (after thrombolysis), 2, 3, 7, 21, and 42 days after myocardial infarction.

Results

Patient characteristics, including age, sex, risk factors, adjunctive postinfarction therapy, infarct location, and baseline left ventricular volumes and ejection fraction, were similar between groups (P > .05 for all). For both groups, deceleration time decreased nonsignificantly from day 1 to day 3 and increased on day 7 (P < .001, for both groups), increasing nonsignificantly subsequently. The E/A ratio increased in the entire study group throughout the time of study (P < .001, for both groups). The pattern of changes of deceleration time was similar in both groups (P > .05 by analysis of variance), as was in subgroups determined by early reperfusion success.

Conclusions

These data in a small clinical trial do not support a benefit of hyperbaric oxygen on left ventricular diastolic filling in patients with acute myocardial infarction treated with thrombolysis.     

Effect of rat pretreatment with aqueous solutions of stevioside and bile acids on the action of certain cardioactive drugs.

The interaction of aqueous solutions of stevioside and bile acids with cardioactive drugs was studied in rats by registering changes in their electrocardiograms (ECG). Wistar rats of both sexes received daily doses of 20 mg/kg (i.p.) of an aqueous solution of stevioside or physiological solution (controls), then were narcotized with urethane and connected to the ECG apparatus for the first recording. The jugular vein was prepared and connected to an infusion pump to administer one of the drugs: adrenaline (0.1 mg/ml), verapamil (2.5 mg/ml) or metoprolol (1 mg/ml) to rats in both groups, while recording their ECGs. In the second part of the study, the animals were treated in the same way but instead of the stevioside solution received a single dose of 4 mg/kg of monoketocholic acid methyl ester (ME) or sodium salt of the same bile acid (MKHNa), 30 minutes before cardioactive drug infusion. The infusion rate of cardioactive drugs was 0.2 ml/min, except for verapamil (0.1 ml/min). The events observed on ECG recordings were the first myocardial reaction to drug infusion, the second longer-lasting reaction (observed as more extended extrasystoles, decrease in intensity of the QRS complex, or changes in heart rate frequency), and toxicity effect. In the control animals, adrenaline induced a decrease in heart rate frequency at a dose of 0.094 mg/kg, while with stevioside-pretreated rats this effect appeared significantly earlier (at a dose of 0.018 mg/kg). No toxic effect of adrenaline was observed, either in control or stevioside-pretreated group. Bile acids caused no changes in myocardial reaction to adrenaline. Only in the group of animals that received MKHNa, a significant decrease in the QRS complex was observed. Finally, the infusion of stevioside to intact animals at doses of 45 and 55 mg/kg caused no significant changes in the ECG patterns. The myocardial reaction to metoprolol remained unchanged in rats of all groups when compared with controls except for a mild decrease in heart rate frequency. Stevioside induced/produced a significant increase in myocardial sensitivity to verapamil, but no toxic effect was observed in any of the cases. A similar conclusion also holds for the interaction with MKHNa, whereas ME caused an increase in the toxicity of verapamil.