Can pulsed ultrasound increase tissue damage during ischemia? A study of the effects of ultrasound on infarcted and non-infarcted myocardium in anesthetized pigs

Background

Natural history of paroxysmal atrial fibrillation (AF) is not very well documented. Clinical experience suggests that paroxysmal AF could progress to chronic AF with estimates ranging between 15 and 30% over a period of 1–3 years. We performed an epidemiologic study to elucidate the natural history of paroxysmal AF, this study estimated its incidence in a general practice setting, identified associated factors and analyzed the progression into chronic AF as well as the mortality rate.

Methods

Using the UK General Practice Research Database (GPRD), we identified patients aged 40–89 years with a first-recorded episode of paroxysmal AF during 1996. Risk factors were assessed using 525 incident paroxysmal AF cases confirmed by the general practitioner (GP) and a random sample of controls. We follow-up paroxysmal AF patients and estimated their mortality rate and progression to chronic AF.

Results

The incidence of paroxysmal AF was 1.0 per 1,000 person-years. Major risk factors for paroxysmal AF were age and prior valvular heart disease, ischaemic heart disease, heart failure and hyperthyroidism. During a mean follow-up of 2.7 years, 70 of 418 paroxysmal AF patients with complete information progressed to chronic AF. Risk factors associated with progression were valvular heart disease (OR 2.7, 95% CI 1.2–6.0) and moderate to high alcohol consumption (OR 3.0, 95% CI 1.1–8.0). Paroxysmal AF patients did not carry an increased risk of mortality, compared to an age and sex matched sample of the general population. There was a suggestion of a small increased risk among patients progressing to chronic AF (RR 1.5, 96% CI 0.8–2.9).

Conclusion

Paroxysmal AF is a common arrhythmia in the general practice setting, increasing with age and commonly associated with other heart diseases. It sometimes is the initial presentation and then progress to chronic AF. A history of valvular heart disease and alcohol consumption are associated with this progression.     

Is the sarcolemmal or mitochondrial KATP channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemia/reperfusion in the intact anesthetized rabbit model?

The relative contributions of cardiomyocyte sarcolemmal ATP-sensitive K(+) (K(ATP)) and mitochondrial K(ATP) channels in the cardioprotection and antiarrhythmic activity induced by K(ATP) channel openers remain obscure, though the mitochondrial K(ATP) channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we sought to investigate the effects of administration of ATP-sensitive K(+) channel (K(ATP)) openers (nicorandil and minoxidil), a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal K(ATP) channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to coronary occlusion as well as prior to post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n=88), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias was achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n=206), arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. Both in Group I and Group II, intravenous (i.v.) administration of nicorandil (0.47 mg/kg), minoxidil (0.5 mg/kg), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/minoxidil before coronary artery occlusion increased survival rate (86%, 75%, 75% and 86% vs. 55% in the control subgroup in Group I; 75%, 67%, 67% and 75% vs. 46% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias. In Group II, i.v. administration of nicorandil and minoxidil before coronary artery occlusion significantly decreased myocardial infarct size. However, i.v. administration of nicorandil or minoxidil before reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and minoxidil were abolished by pretreating the rabbits with 5-HD (5 mg/kg, i.v. bolus), a selective mitochondrial K(ATP) channel blocker but not by HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and minoxidil. We conclude that intervention by intravenous administration of nicorandil and minoxidil (through the selective activation of mitochondrial K(ATP) channels) increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to coronary occlusion. The cardiomyocyte mitochondrial K(ATP) channel may be a pharmacologically modulable target of cardioprotection and antiarrhythmic activity.     

Effect of simvastatin on collagen I deposition in non-infarcted myocardium: role of NF-κB and osteopontin

The novel biological effect of statins in alleviating myocardium fibrosis following infarction has been increasingly recognized, yet the underlying mechanisms are not fully understood. The purpose of this study was to characterize the effect of simvastatin on myocardial fibrosis and collagen I deposition in the non-infarcted region after myocardial infarction (MI) and to identify the role of NF-κB and osteopontin in simvastatin-mediated inhibition of post-MI collagen over-expression. A rat model of MI was generated by ligating the left anterior descending coronary artery. The rats surviving the MI operation were randomly divided into the following 3 groups: myocardial infarction (MI, vehicle), simvastatin (Sim, 30 mg·kg-1·day-1), and pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB, 100 mg·kg-1·day-1). Four weeks after MI, cardiac function, mRNAs, and protein expression in non-infarcted myocardium were analyzed. Myocardial fibrosis and collagen I over-expression were observed following MI, accompanied by an increase of NF-κB and osteopontin. Simvastatin improved post-MI left ventricular dysfunction and ameliorated post-MI associated changes to several cardiac parameters, including the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure development (+dP/dtmax), and the maximal rate of pressure decline (-dP/dtmax). Concurrently, simvastatin significantly suppressed the over-expression of NF-κB, osteopontin, and collagen I in the non-infarcted region following MI. Inhibition of NF-κB by PDTC also reduced osteopontin over-expression and excessive collagen I production and improved the above functional myocardial parameters. These results show that post-MI myocardial fibrosis and collagen I over-expression in the non-infarcted region is associated with activation of NF-κB and osteopontin up-regulation. The anti-fibrotic effect of simvastatin following MI is associated with the attenuation of the expression of osteopontin and NF-κB. The inhibition of NF-κB activation could be the process upstream of osteopontin suppression in the simvastatin-mediated effect.     

Can diving-induced tissue nitrogen supersaturation increase the chance of acoustically driven bubble growth in marine mammals?

The potential for acoustically mediated causes of stranding in cetaceans (whales and dolphins) is of increasing concern given recent stranding events associated with anthropogenic acoustic activity. We examine a potentially debilitating non-auditory mechanism called rectified diffusion. Rectified diffusion causes gas bubble growth, which in an insonified animal may produce emboli, tissue separation and high, localized pressure in nervous tissue. Using the results of a dolphin dive study and a model of rectified diffusion for low-frequency exposure, we demonstrate that the diving behavior of cetaceans prior to an intense acoustic exposure may increase the chance of rectified diffusion. Specifically, deep diving and slow ascent/descent speed contributes to increased gas-tissue saturation, a condition that amplifies the likelihood of rectified diffusion. The depth of lung collapse limits nitrogen uptake per dive and the surface interval duration influences the amount of nitrogen washout from tissues between dives. Model results suggest that low-frequency rectified diffusion models need to be advanced, that the diving behavior of marine mammals of concern needs to be investigated to identify at-risk animals, and that more intensive studies of gas dynamics within diving marine mammals should be undertaken.     

Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia–reperfusion injury in cardio-pulmonary bypass in dogs

During cardiac pulmonary bypass (CPB), myocardial ischemia–reperfusion (I/R) induces heart glucose metabolism impairment. Our previous research showed that the decreased glucose utilization is due to decreased glucose transporter-4 (Glut-4) expression and translocation to myocyte surface membranes. This study further examined whether rosiglitazone, a synthetic agonist of peroxisome proliferator-activated receptor γ, could intervene glucose metabolism by regulating Glut-4 mRNA during I/R in dogs. Cardiac ischemia was induced by cardiopulmonary bypass for 30 or 120 min. Plasma insulin and glucose concentrations were measured at pre-bypass (control), aortic cross-clamp off (I/R) at 15, 45, and 75 min. The left ventricle biopsies were taken for the expression of Glut-4 mRNA by real-time RT-PCR. In dogs receiving 120 min ischemia, coronary arterial, venous glucose concentrations, plasma insulin levels, and insulin resistant index (IRI) were increased, but the expression of Glut-4 mRNA was decreased obviously at 15 min of reperfusion, and recovered gradually. On the other hand, these changes were relatively mild in dogs treated with rosiglitazone in cardioplegic solution and expression of Glut-4 mRNA was increased remarkably. It is concluded that the decrease in total amount of Glut-4 mRNA expression could be one of the important molecular mechanisms, which causes the myocardium insulin resistance. The longer the ischemia period, the decrease in amount of Glut-4 mRNA was more dramatic. Adding rosiglitazone into the cardioplegic solution during I/R can increase the amount of Glut-4 mRNA expression, mitigate the myocardium insulin resistance and improve the myocardium I/R injury during CPB.     

Differential effects of thyroid hormone manipulation and �� adrenoceptor agonist administration on uncoupling protein mRNA abundance in adipose tissue and thermoregulation in neonatal pigs

We have shown that there is significant disparity in the expression of uncoupling proteins (UCP) 2 and 3 between modern-commercial and ancient-Meishan porcine genotypes, commercial pigs also have higher plasma triiodothyronine (T₃) in on the first day of life. T₃ and the sympathetic nervous system are both known to regulate UCPs in rodents and humans; their role in regulating these proteins in the pig is unknown. This study examined whether thyroid hormone manipulation or administration of a selective β3 adrenoceptor agonist (ZD) influenced plasma hormones, colonic temperature and UCP expression in adipose tissue of two breeds of pig. To mimic the differences observed in thyroid hormone status, piglets from Meishan and commercial litters were randomly assigned to control (1 ml/kg water), T₃ (10 mg/kg) (Meishan only), methimazole (a commonly used antithyroid drug) (50 mg/kg) (commercial only) or ZD (10 mg/kg) oral administration for the first 4 days of postnatal life. Adipose tissue UCP2/3 mRNA abundance was measured on day 4 using PCR. T₃ administration raised plasma T₃ concentrations and increased colonic temperature on day 4. UCP3 mRNA abundance was higher in Meishan, than commercial piglets (p = 0.042) and was downregulated following T₃ administration (p = 0.014). Irrespective of genotype, ZD increased UCP2 mRNA abundance (Meishan p = 0.05, commercial p = 0.03). Expression of neither UCP2 nor 3 was related to colonic temperature, regardless of treatment. In conclusion, we have demonstrated a dissociation between thyroid hormones and the sympathetic nervous system in the regulation of UCPs in porcine adipose tissue. We have also suggested that expression of adipose tissue UCP2 and 3 are not related to body temperature in piglets.Key words: mitochondria, postnatal growth, metabolism     

Differential effects of thyroid hormone manipulation and β adrenoceptor agonist administration on uncoupling protein mRNA abundance in adipose tissue and thermoregulation in neonatal pigs

We have shown that there is significant disparity in the expression of uncoupling proteins (UCP) 2 and 3 between modern-commercial and ancient-Meishan porcine genotypes, commercial pigs also have higher plasma triiodothyronine (T₃) in on the first day of life. T₃ and the sympathetic nervous system are both known to regulate UCPs in rodents and humans; their role in regulating these proteins in the pig is unknown. This study examined whether thyroid hormone manipulation or administration of a selective β3 adrenoceptor agonist (ZD) influenced plasma hormones, colonic temperature and UCP expression in adipose tissue of two breeds of pig. To mimic the differences observed in thyroid hormone status, piglets from Meishan and commercial litters were randomly assigned to control (1 ml/kg water), T₃ (10 mg/kg) (Meishan only), methimazole (a commonly used antithyroid drug) (50 mg/kg) (commercial only) or ZD (10 mg/kg) oral administration for the first 4 days of postnatal life. Adipose tissue UCP2/3 mRNA abundance was measured on day 4 using PCR. T₃ administration raised plasma T₃ concentrations and increased colonic temperature on day 4. UCP3 mRNA abundance was higher in Meishan, than commercial piglets and was downregulated following T₃ administration. Irrespective of genotype, ZD increased UCP2 mRNA abundance. Expression of neither UCP2 nor 3 was related to colonic temperature, regardless of treatment. In conclusion, we have demonstrated a dissociation between thyroid hormones and the sympathetic nervous system in the regulation of UCPs in porcine adipose tissue. We have also suggested that expression of adipose tissue UCP2 and 3 are not related to body temperature in piglets.     

Does climatic warming increase the risk of frost damage in northern trees?

Abstract. The effect of climatic warming on the timing of bud burst and the subsequent risk of frost damage on trees in central Finland was assessed with the aid of a computer model, 73 years of temperature data and a climatic scenario corresponding to doubled level of atmospheric CO₂. In general, climatic warming hastened bud burst, due to ontogenetic development during warm spells in autumn, winter and spring. During the years with the warmest winters in the scenario conditions: (a) bud burst took place during mid-winter; and (2) depending on the year, the trees were subsequently exposed to temperatures between −27 and −10°C. This finding suggests that the risk of frost damage to trees will be increased if the predicted climatic warming occurs. Because of the assumptions used in the model, the results are not conclusive, but they do point out the importance of further experimental studies on genetic and environmental regulation of timing of bud burst in trees.     

Protective effects of salusin-α and salusin-β on renal ischemia/reperfusion damage and their levels in ischemic acute renal failure

Salusin-α and salusin-β are expressed in many tissues including the central nervous system, vessels and kidneys; they have been shown to decrease endoplasmic reticulum stress during heart ischemia/reperfusion (I/R) and to decrease apoptosis. We investigated the relation of salusin-α and salusin-β levels to acute ischemic renal failure. We also investigated whether these peptides are protective against renal I/R damage. Fifty-three rats were divided into six groups: control, I/R, I/R + salusin-α1, I/R + salusin-α10, I/R + salusin-β1 and I/R + salusin-β10. After removing the right kidney, the left kidney was subjected to ischemia for 1 h and reperfusion for 23 h. The treatment groups were injected subcutaneously at the beginning of ischemia with 1 or 10 μg/kg salusin-α, and 1 or 10 μg/kg salusin-β. Histopathology was assessed at the end of the experiment. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) levels were measured in the kidney tissue. Serum levels of blood urea nitrogen (BUN), creatinine (Cre), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) also were measured. Levels of salusin-α and salusin-β were measured in the serum and kidney tissues of the control and I/R groups. SOD, CAT and GSH-PX activities were decreased and the levels of MDA, TNF-α, IL-6, IL-1β, BUN and Cre were increased in the I/R group compared to controls. Severe glomerular and tubular damage was apparent in the I/R group compared to controls. The level of salusin-β was decreased in the serum and kidney tissue of the I/R group compared to controls, whereas the level of salusin-α was decreased in the serum and increased in the kidney tissue. Salusin-α and salusin-β administration increased SOD and GSH-PX enzyme activation and decreased the levels of MDA, TNF-α, IL-6 and IL-1β compared to the I/R group. BUN and Cre levels were decreased in the I/R + salusin-α1 group and the level of Cre was decreased in I/R + salusin-β10 group compared to the I/R group. We demonstrated a protective effect of salusin-α and salusin-β against renal I/R damage. Changes in the levels of salusin-α and salusin-β in the I/R group suggest that these peptides may be associated with acute renal failure.     

When can refuges mediate the genetic effects of fire regimes? A simulation study of the effects of topography and weather on neutral and adaptive genetic diversity in fire‐prone landscapes

Understanding how landscape heterogeneity mediates the effects of fire on biodiversity is increasingly important under global changes in fire regimes. We used a simulation experiment to investigate how fire regimes interact with topography and weather to shape neutral and selection‐driven genetic diversity under alternative dispersal scenarios, and to explore the conditions under which microrefuges can maintain genetic diversity of populations exposed to recurrent fire. Spatial heterogeneity in simulated fire frequency occurred in topographically complex landscapes, with fire refuges and fire‐prone “hotspots” apparent. Interannual weather variability reduced the effect of topography on fire patterns, with refuges less apparent under high weather variability. Neutral genetic diversity was correlated with long‐term fire frequency under spatially heterogeneous fire regimes, being higher in fire refuges than fire‐prone areas, except under high dispersal or low fire severity (low mortality). This generated different spatial genetic structures in fire‐prone and fire‐refuge components of the landscape, despite similar dispersal. In contrast, genetic diversity was only associated with time since the most recent fire in flat landscapes without predictable refuges and hotspots. Genetic effects of selection driven by fire‐related conditions depended on selection pressure, migration distance and spatial heterogeneity in fire regimes. Allele frequencies at a locus conferring higher fitness under successional environmental conditions followed a pattern of “temporal adaptation” to contemporary conditions under strong selection pressure and high migration. However, selected allele frequencies were correlated with spatial variation in long‐term mean fire frequency (relating to environmental predictability) under weak dispersal, low selection pressure and strong spatial heterogeneity in fire regimes.     

Can paternal preconceptional radiation account for the increase of leukaemia and non-Hodgkin's lymphoma in Seascale?

OBJECTIVE--To determine if the excess of leukaemia and non-Hodgkin''s lymphoma in Seascale is restricted to those born in the parish and whether it might be explained by the postulated relation with paternal preconceptional radiation. DESIGN--Comparison, separately for those born in the parish and those born elsewhere, of the numbers of these malignancies observed in Seascale with those expected on the basis of reference rates for England and Wales. Details of paternal radiation levels were sought for each case. SETTING--The parish of Seascale in west Cumbria. SUBJECTS--Residents of Seascale below age 25 years in the years 1951-91. MAIN OUTCOME MEASURES--The observed and expected numbers of cases of leukaemia and non-Hodgkin''s lymphoma within Seascale among those born there and among those born elsewhere. Also, the levels of any paternal preconceptional radiation associated with each case. RESULTS--A significant excess of leukaemia and non-Hodgkin''s lymphoma at ages 0-24 was found in Seascale in those who were born there (ratio of observed to expected cases 8.6 and 20.2 respectively; p < 0.01). This also applied to those not born there (7.2 and 16.5; p < 0.01), a group often regarded as not showing an excess. The estimates were then conservatively recalculated so as to overestimate the risks among those born in Seascale and underestimate them among those born elsewhere. On this basis the six cases in those born in Seascale compare with 0.38 expected (15.8; p < 0.001), of which two were associated with paternal preconceptional life-time levels of 100 mSv or greater and three others with levels of 90-99 mSv. Among those born elsewhere, there were five cases (expected 0.74; ratio 6.7, p < 0.01), of which only one was associated with a high level of such radiation. CONCLUSIONS--Paternal preconceptional radiation cannot be the sole cause of the excess in Seascale since it will not explain the excess among those born outside Seascale. It follows that, unless two causes are to be postulated, any single cause must be a factor other than paternal preconceptional radiation. On this basis, the association found among those born there, if not partly due to chance, may reflect an indirect relation with the true cause. The recent hypothesis about such paternal radiation has originated in a subgroup of the excess cases that have aroused concern.     

DFT study on the effects of β-cyclodextrin in synthesis of 2-phenylbenzimidazole via benzaldehyde and o-phenylenediamine

The conversion of 2-phenylbenzimidazole using o-phenylenediamine and benzaldehyde can be improved significantly under β-cyclodextrin (β-CD). The density functional theory (DFT) method was applied to study the whole process. According to energy parameters (binding energy, deformation energy) and structural deformation, entry models and the reaction process can be pinpointed, with o-phenylenediamine embedding β-CD from a wide rim, and then benzaldehyde passing into the inclusion from the narrow rim. Subsequently, natural bonding orbital (NBO), Mulliken charge, frontier orbital, FuKui function and nuclear magnetic resonance (NMR) methods were employed to reveal the mechanism of electron transfer. The results illustrate that β-CD plays a catalytic role in synthesis reaction mechanism on the secondary side, improving the reactivity and selectivity of the process.

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Graphical Abstract Density functional theory study of the effects of β-cyclodextrin in synthesis of 2-phenylbenzimidazole via benzaldehyde and o-phenylenediamine

     

Synergic effects of NO and oxygen free radicals in the injury of ischemia-reperfused myocardium——ESR studies on NO free radicals generated from ischemia-reperfused myocardium

The ESR signal of NO bound to hemoglobin was detected during the ischemia-reperfusion of myocardium with low temperature ESR technique, and the synergic effects of NO and oxygen free radicals in the injury of the process were studied with this technique. Oxygen free radicals and NO bound to β-subunit of hemoglobin (β-NO complex) could be detected simultaneously in the ischemia-reperfused myocardium. Those signals could not be detected from the normal myocardium even in the presence of L-arginme. However, those signals could be detected and were dose-dependent with L-arginine in the ischemia-reperfused myocardiums and the signal could be suppressed with the inhibitor of NO synthetase, NG-nitro-L-arginine methylester (NAME). Measurement of the activities of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary artery effluent of ischemia-reperfused heart showed that L-arginine at lower concentration (<1 mmol/L) could protect the heart from the ischemia-reperfusion injury but at higher con     

A case–control study on the effects of the apolipoprotein E genotypes in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions being the most common cause of chronic liver disease in Western countries. The Apolipoprotein E (ApoE) gene has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. The role of apoE genotypes on NAFLD has been previously investigated with conflicting results. Our hospital-based case-control study conducted in Italy aims to explore the effect of the apoE genotypes on NAFLD risk and their effect on the clinical features of NAFLD patients. 310 NAFLD cases and 422 controls were genotyped for apoE. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between NAFLD and apoE genotypes, as well as their interaction with selected demographic and lifestyle factors. ApoE ε4 allele carriers showed a statistically significant two-fold reduction of NAFLD risk (OR = 0.51, 95% CI: 0.28-0.93) compared with ε3 homozygotes. A statistically significant lower HDL cholesterol level was observed for ApoE ε4 carriers if compared with ε3/ε3 genotype or ApoE ε2 carriers with a nearly linear decreasing trend from ApoE ε2 to ApoE ε4 carriers. Our study reports for the first time a protective effect of the ε4 allele towards NAFLD that might be attributable to its role in the regulation of hepatic triglycerides rich very low-density lipoproteins secretion.     

Protective effects of the volatile oil of Nigella sativa seeds on β-cell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study

The aim of this study was to evaluate the possible protective effects of the volatile oil of Nigella sativa (NS) seeds on insulin immunoreactivity and ultrastructural changes of pancreatic β-cells in STZ-induced diabetic rats. STZ was injected intraperitoneally at a single dose of 50 mg/kg to induce diabetes. The rats in NS treated groups were given NS (0.2 ml/kg) once a day orally for 4 weeks starting 3 days prior to STZ injection. To date, no ultrastructural changes of pancreatic β-cells in STZ induced diabetic rats by NS treatment have been reported. Islet cell degeneration and weak insulin immunohistochemical staining was observed in rats with STZ-induced diabetes. Increased intensity of staining for insulin, and preservation of β-cell numbers were apparent in the NS-treated diabetic rats. The protective effect of NS on STZ-diabetic rats was evident by a moderate increase in the lowered secretory vesicles with granules and also slight destruction with loss of cristae within the mitochondria of β-cell when compared to control rats. These findings suggest that NS treatment exerts a therapeutic protective effect in diabetes by decreasing morphological changes and preserving pancreatic β-cell integrity. Consequently, NS may be clinically useful for protecting β-cells against oxidative stress.     

Combined effects of quercetin and α-tocopherol on lipids and glycoprotein components in isoproterenol induced myocardial infarcted Wistar rats

This study was aimed to evaluate the combined effects of quercetin and α-tocopherol on lipid metabolism and glycoprotein components in isoproterenol induced myocardial infarction in Wistar rats. Myocardial infarction in rats was induced by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) were given to rats as pretreatment for 14 days orally using an intragastric tube. Quercetin and α-tocopherol significantly reduced the levels of cholesterol, triglycerides and free fatty acids in the serum and heart and serum phospholipids and significantly increased the levels of heart phospholipids in isoproterenol induced rats. They also significantly decreased the activity of plasma and liver 3-hydroxy-3-methylglutaryl-coenzyme-A reductase and increased the activity of plasma and liver lecithin cholesterol acyl transferase in isoproterenol treated rats. In addition to this, they also significantly reduced the levels of hexose, hexosamine, fucose and sialic acid in the serum and heart of isoproterenol treated rats. Quercetin and α-tocopherol also showed significant decrease in plasma lipid peroxidation products (thiobarbituric acid reactive substances and lipid hydroperoxides). Pretreatment with quercetin alone and α-tocopherol alone showed significant effect in all the biochemical parameters in myocardial infarcted rats. But, combined pretreatment with quercetin and α-tocopherol normalized all the above mentioned biochemical parameters in isoproterenol treated myocardial infarction in rats. Thus, the experiment clearly showed that quercetin and α-tocopherol prevented the accumulation of lipids and glycoprotein components in myocardial infarcted rats by their anti-lipid peroxidative effect. This study also showed that combined pretreatment was better than single pretreatment.     

Variability of glutathione during the menstrual cycle-due to estrogen effects on hepatocytes?

Oxidative stress and alterations in the antioxidative defense system may be involved in carcinogenesis. We have previously shown that the levels of glutathione (GSH) in vivo in both breast tissue and subcutaneous fat were higher in the luteal phase compared with the follicular phase, suggesting an overall increase in GSH. This result was confirmed in the present study. Moreover, we exposed normal breast tissue in vivo, breast epithelial cells in vitro, and hepatocytes in culture to ovarian hormones. We found that local perfusion with estradiol, using microdialysis, in normal human breast tissue did not alter the local GSH levels in vivo. In vitro, treatment with estradiol and progesterone of normal human breast epithelial cells did not alter GSH levels. However, levels of GSH in hepatocytes were after 8 h estradiol exposure initially decreased, 76.6 +/- 5% of control cells, p <.05, whereas 20 h exposure more than doubled GSH, 209 +/- 26% compared with control cells, p <.01. Progesterone had no additional effect. Exposure of hepatocytes to estradiol increased the cellular content of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis. In conclusion we suggest that estradiol affects the GSH homeostasis mainly by effects on hepatocytes, whereas local production in the breast is unaffected by estradiol.     

In?vitro and in?vivo study on the effect of antifungal agents on hematopoietic cells in mice

Liposomal amphotericin B, voriconazole, and caspofungin are currently used for systemic and severe fungal infections. Patients with malignant diseases are treated with granulocyte-colony stimulating factor (G-CSF) for the recovery of granulocytes after chemotherapy or hematopoietic cell (HC) transplantation. Since they have a high incidence of fungal infections, they inevitably receive antifungal drugs for treatment and prophylaxis. Despite their proven less toxicity for various cell types comparatively with amphotericin B and the decrease in the number of leukocytes that has been reported as a possible complication in clinical studies, the effect of liposomal amphotericin B, voriconazole, and caspofungin on HCs has not been clarified. The present study aimed to examine the in vitro and in vivo effect of these three modern antifungals on HCs. Colony-forming unit (CFU) assays of murine bone marrow cells were performed in methylcellulose medium with or without cytokines and in the presence or absence of various concentrations of liposomal amphotericin B, voriconazole, and caspofungin. In the in vivo experiments, the absolute number of granulocytes was determined during leukocyte recovery in sublethally irradiated mice receiving each antifungal agent separately, with or without G-CSF. In vitro, all three antifungal drugs were nontoxic and, interestingly, they significantly increased the number of CFU-granulocyte-macrophage colonies in the presence of cytokines, at all concentrations tested. This was contrary to the concentration-dependent toxicity and the significant decrease caused by conventional amphotericin B. In vivo, the number of granulocytes was significantly higher with caspofungin plus G-CSF treatment, higher and to a lesser extent higher, but not statistically significantly, with voriconazole plus G-CSF and liposomal amphotericin B plus G-CSF treatments, respectively, as compared with G-CSF alone. These data indicate a potential synergistic effect of these antifungals with the cytokines, in vitro and in vivo, with subsequent positive effect on hematopoiesis.