CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2003
Chao-Yu Miao
Summary 1.,It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak ,1 -adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR). 2.,It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 µg/rat, i.c.v.). 3.,Prazosin, an ,1 -adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 ug/rat). Ritanserin (0.625 mg/kg, i.v.; 40 'ug/rat, i.c.v.), a 5-HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level. 4.,Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v. 5.,The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically. 6.,It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5-HT2A receptors and is probably attributable to the restoration of arterial baroreflex function. [source]

Simultaneous administration of a low-dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long-term survival of cardiac allograft in rats

IMMUNOLOGY, Issue 2 2003
Yongzhu Jin
Summary T-cell costimulatory blockade combined with donor bone marrow transfusion may induce mixed chimerism, rendering robust tolerance in transplanted organs and cells. However, most protocols entail high doses of donor bone marrow cells (BMCs) or repeated administration of costly agents that block costimulatory pathways, thus delaying clinical development. To circumvent these shortcomings, we developed a strategy in which the dosage of donor BMCs was reduced but compensated by donor splenocytes (SPLCs). Furthermore, repeated administration of costly agents was replaced with a single injection of adenovirus expressing a gene of interest. In rat cardiac transplantation models, cardiac allografts from DA (RT-1a) rats were transplanted heterotopically into the abdomen of LEW (RT-11) recipient rats. Immediately after cardiac transplantation, an adenovirus vector (AdCTLA4Ig; 5 × 109 plaque-forming units) containing the gene for CTLA4Ig was administered to recipients (n = 6) simultaneously with a low dose of donor BMCs (1 × 108/rat) and SPLCs (5 × 107/rat) via the portal vein. The treated LEW recipient rats developed long-lasting mixed chimerism (>10% at >100 days) and exhibited long-term cardiac allografts (mean survival time of > 200 days) compared with control recipients. Moreover, recipients displaying long-lasting mixed chimerism accepted subsequent donor skin allografts while promptly rejecting third-party skin allografts. These results suggest that blockade of the CD28-B7 pathway, using adenovirus-mediated CTLA4Ig gene transfer, in concert with a low dosage of donor BMCs and SPLCs, may represent a feasible strategy to induce stable mixed chimerism and permit long-term survival of cardiac allografts. [source]

Assessment of the access selection gain in multi-radio access networks

EUROPEAN TRANSACTIONS ON TELECOMMUNICATIONS, Issue 3 2009
Joachim Sachs
In this paper, we investigate the capacity gain of access selection in a multi-radio access network with heterogeneous radio access technologies (RATs). We classify the kinds of gain that can be achieved by access selection: statistical multiplexing in the multi-access system leads to a trunking gain, spatial transmission diversity results from the geographic capacity distribution of the cell layout, stochastic transmission diversity exploits the multi-path fading characteristics. We show how these different properties are affected by the cell layout of the different RATs, the characteristics of each RAT and the traffic load distribution in the network. In a simulation environment the system capacity for the combination of two wide-area access technologies, as well as, for the combination of a wide-area and a local-area access technology is investigated. For this, we compare two different access selection algorithms. One uses the radio link quality as an input parameter, while the other also considers the cell load. We derive quantitative figures for the capacity gain in a large number of scenarios and show that load-based access selection can significantly increase the capacity. We show that the gain of an overlay of local-area access cells provides little capacity gain for uniform geographic load distribution, whereas significant gain can be achieved when most users are located at hotspots. Copyright © 2007 John Wiley & Sons, Ltd. [source]

RAT in vivo models of taxanes' peripheral neurotoxicity following chronic intravenous administration

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2004
A Canta
The "taxanes" family includes some widely used antineoplastic agents, such as paclitaxel and docetaxel. Treatment with these microtubule-stabilizing drugs is often associated with neurotoxicity, a potentially severe side effect limiting the clinical utility of these agents. To study the pathogenesis of taxanes' neurotoxicity and to compare it to the effect of new agents, the availability of reliable in vivo models is warranted. In this study we developed chronic iv models for the assessment of "taxanes" peripheral neurotoxicity. Forty-eight adult Wistar rats were divided into six groups of 8 animals each and treated as follows: paclitaxel or docetaxel at doses of 5, 10, 12.5 mg/kg 1q7d × 4 via a chronic jugular vein implant. The evaluation was based on the assessment of body weight and survival as a measure of general tolerability, and on the measurement of tail nerve conduction velocity, a neurophysiological method previously used in animal models of toxic peripheral neuropathies. The results were compared with those obtained in untreated or vehicle-treated control rats. A clear dose-dependent effect was evident both on general toxicity, and on neurophysiological changes measured at the end of the treatment (untreated controls = 41,9 m/sec, vehicle = 40,3 m/sec; paclitaxel 5 mg/kg = 32,5 m/sec, 10 mg/kg = 28,5 m/sec, 12.5 m/kg = 27,4 m/sec; docetaxel 5 mg/kg = 33,6 m/sec, 10 mg/kg = 27,8 m/sec, 12.5 mg/kg = 27,0 m/sec), demonstrating the usefulness of this new model system to investigate peripheral neurotoxicity mediated by taxanes, and potentially other drugs, under chronic treatment schedules. [source]

Characterization of RAT, an autolysis regulator in Staphylococcus aureus

MOLECULAR MICROBIOLOGY, Issue 6 2003
S. S. Ingavale
Summary In trying to identify genetic loci involved in the regulation of cap5 genes in Staphylococcus aureus, we isolated a transposon mutant that exhibited a growth defect, enhanced autolysis and increased sensitivity to Triton X-100 and penicillin, attributable in part to increased murein hydrolase activity. Analysis of the chromosomal sequence flanking the transposon insertion site revealed that the gene disrupted in the mutant encodes an open reading frame of 147 amino acids. We named this gene rat, which stands for regulator of autolytic activity. Sequence analysis indicated that Rat is homologous to the MarR and, to a lesser extent, the SarA protein families. Mutations in rat resulted in decreased expression of known autolytic regulators lytSR, lrgAB and arlRS. Gel shift studies indicated that Rat binds to the lytRS and arlRS promoters, thus confirming Rat as a DNA-binding protein to these known repressors of autolytic activity. As anticipated, rat appears to be a negative regulator of autolysin genes including lytM and lytN. These data suggest that the rat gene product is an important regulator of autolytic activity in S. aureus. [source]

Catalysis of intumescent flame retardancy of polypropylene by metallic compounds,

POLYMERS FOR ADVANCED TECHNOLOGIES, Issue 1 2003
Menachem Lewin
Abstract Divalent and multivalent metallic compounds catalyze the flame retardancy performance of intumescent systems based on ammonium polyphosphate (APP) and pentaerythritol (petol) in poly(propylene) (PP). The catalytic effect is shown by increases in the oxygen index (OI) and UL-94 ratings. The effect is exerted by small concentrations of the metallic compounds in the range of 0.1,2.5 wt% of the compositions. The effect increases with the concentration of the catalyst until a maximum is reached. At higher concentrations of the catalyst a decrease in the flame retardancy parameters is observed, accompanied in several cases by a degradation and discoloration of the composition. The catalyst replaces melamine in intumescent systems. Catalytic effectiveness is defined and calculated for a number of compounds. Thermogravimetric parameters, such as initial decomposition temperature, temperature of the transition point and residue-after-transitions (RAT) change in parallel with the catalytic effect of the metal compound concentration. Metal compounds investigated include oxides, acetates, acetyl acetonates, borates and sulfates of Mn, Zn, Mg, Al, Ca, Ba,,V, Co, Ni, Cu, Mo, Zr, and Cr. Mechanistic considerations on the activity of the catalysts are presented. Copyright © 2003 John Wiley & Sons, Ltd. [source]

Microbiology of Healthy and Diseased Adenoids

THE LARYNGOSCOPE, Issue 6 2000
Itzhak Brook MD
Abstract Objective To determine the qualitative and quantitative microbiology of core adenoid tissue obtained from four groups of 15 children each, with recurrent otitis media (ROM), recurrent adenotonsillitis (RAT), obstructive adenoid hypertrophy (OAH), and occlusion or speech abnormalities (controls). Methods Core cultures of surgically removed diseased adenoids and of healthy controls were cultured for aerobic and anaerobic bacteria. Results Polymicrobial aerobic-anaerobic flora were present in all instances. Ninety-four organisms were isolated from control specimens, and 148 from ROM, 142 from RAT, and 149 from OAH specimens. The predominant aerobes in all groups were ,-hemolytic and ,-hemolytic streptococci, Haemophilus influenzae, Staphylococcus aureus, group A ,-hemolytic streptococci, and Moraxella catarrhalis. The prominent anaerobes were Peptostreptococcus, Prevotella, and Fusobacterium species. The number, concentration and distribution of types of most organisms did not vary among the three groups of diseased adenoids. However, the number of those that are potential pathogens and those that produced ,-lactamase was lower in the control than the diseased adenoids (P < .001). Conclusion The study highlights the importance of the bacterial load in the adenoids in contributing to the etiology of ROM, RAT, and OAH. [source]

s -CARBOXYMETHYLCYSTEINE INHIBITS CARBACHOL-INDUCED CONSTRICTION OF EPITHELIUM-DENUDED RAT AND HUMAN AIRWAY PREPARATIONS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2008
Dragan Pavlovic
SUMMARY 1The effects of s-carboxymethyl-l-cysteine (S-CMC), either administered orally to rats or incubated with tissue preparations from rats and humans, on isometric contractions of tracheal smooth muscle were investigated in the present study using an improved in vitro model of tracheal tube or ring preparations. The involvement of the tracheal epithelium in the observed effects was also investigated. 2The experimental model permitted selective perfusion of the airway tube, luminal-IN or serosal,OUT, and measurement of airway smooth muscle contraction or relaxation in preparations with (+) or without (,) epithelium (Ep), excluding direct effects of airway mucus. 3We found that oral pretreatment of rats with S-CMC (mixed with water; 200 mg/kg per day for 2 weeks), but not short pre-incubation of preparations in vitro (10,3 mol/L S-CMC for 1 h), diminished the sensitivity of ,Ep preparations to carbachol compared with controls (EC50 (,log10 mol/L) values: 5.5 ± 0.1 vs 5.8 ± 0.1, respectively, for IN perfusion (P < 0.005); 5.6 ± 0.1 vs 5.9 ± 0.1, respectively, for OUT perfusion (P < 0.005)), whereas the sensitivity of preparations to aminophylline was not affected. Normal sensitivity to carbachol stimulation was re-established if preparations were pre-incubated with capsaicin. 4It was also found that longer pre-incubation (4 h) of ring-preparations of human bronchus with S-CMC (10,5 mol/L) in vitro resulted in a diminished response to carbachol stimulation. 5In conclusion, S-CMC had small inhibitory effects on the sensitivity of rat and human airway smooth muscle to carbachol, particularly in endothelium-denuded preparations. Whether the epithelium was responding to S-CMC by producing some contracting factor(s) requires further investigation. [source]

INVESTIGATION OF THE MICROCIRCULATION AND THE STATE OF OXIDATIVE STRESS IN THE RAT AFTER SCORPION ENVENOMATION

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2007
Z Sahnoun
SUMMARY 1Severe cases of scorpion envenomation (SE) generally show both respiratory and cardiocirculatory dysfunction. However, the pathophysiology of SE remains controversial. In the present study, we tried to explain the pathophysiology of the haemodynamic perturbations and cardiac failure in rats poisoned by the venom of Buthus occitanus tunetanus through a histomorphometric study of myocardial and muscular skeletal microcirculation and analysis of the oxidative stress state in order to evaluate the implication of the inflammatory process in the pathogenesis of SE. 2Experiments were performed on 96 rats divided into 16 groups (n = 6 in each group). Two groups were used to determine the optimum conditions of venom administration and times when to measure haemodynamic parameters. The B. occitanus tunetanus venom was administered at a dose of 800 µg/kg and tissues were removed 5 and 20 min after envenomation. Six groups were used for histomorphometric study: two control groups, two poisoned groups an two melatonin-pretreated and poisoned groups. The histomorphometric study was performed on isolated hearts and skeletal muscles. The final eight groups of rats (two control groups, two envenomated groups, two control groups pretreated with melatonin and two groups pretreated and envenomated) were used to investigate the state of tissue oxidative stress during SE and to evaluate the anti-oxidant effect of melatonin on rats poisoned with B. occitanus tunetanus venom. This study was based on the determination of tissue malondialdehyde in isolated organs as an indicator of thiobarbituric acid-reactive substances (TBARS). Melatonin was injected at a dose of 5 mg/kg, i.v., 15 min before the administration of serum or venom. Data were compared using analysis of variance and Tukey's test for multiple pair-wise comparisons. 3Five minutes after venom injection, a significant reduction in the mean relative volume of venules and arterioles in the heart and skeletal muscles of poisoned rats was noted. Twenty minutes after venom injection, these volumes were significantly increased in the heart and skeletal muscles of poisoned rats. Pretreatment of envenomated rats with melatonin resulted in a significant decrease in the mean relative volume of the venules and arterioles in the heart and skeletal muscles 5 and 20 min after venom injection compared with untreated envenomated rats. Investigation of the oxidative stress state showed a highly significant increase in TBARS in poisoned rats compared with control groups 5 and 20 min after venom injection. Melatonin pretreatment of rats poisoned with B. occitanus tunetanus venom resulted in an important and highly significant reduction of TBARS compared with untreated envenomated rats. 4It appears from the results of the present study that administration of B. occitanus tunetanus venom engendered an excessive myocardial and skeletal muscular vasoconstriction attributed to massive catecholamine release followed by arteriolar and venular vasodilatation. This venous stasis at the muscular microcirculation could be due to myocardiac failure. However, the concomitant presence of arteriolar vasodilatation suggests an inflammatory process in the pathophysiology of SE. This process was suggested by the genesis of a state of oxidative stress in relation to the important lipoperoxidation, which was inhibited by administration of the anti-oxidant melatonin. Thus, melatonin pretreatment seemed to accentuate the first phase of vascular reactivity in envenomed rats and inhibit the second vasodilator phase observed 20 min after administration of the venom. [source]

DUAL ACTIVATION OF CARDIAC SYMPATHETIC AND PARASYMPATHETIC COMPONENTS DURING CONDITIONED FEAR TO CONTEXT IN THE RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2006
Pascal Carrive
SUMMARY 1The present study investigates the contribution of the sympathetic and vagal parasympathetic systems to the tachycardic response of long-lasting (40 min) conditioned fear responses to context. 2The conditioned fear response evoked by re-exposure to a footshock chamber was tested 10 min after intravenous injection of the ,-adrenoceptor antagonist propranolol (2 mg/kg) or the muscarinic antagonist atropine methyl nitrate (2 mg/kg) in rats implanted with radiotelemetric probes. 3Compared with saline controls, the drugs did not change the behavioural component of the response (freezing, 22 kHz ultrasonic vocalizations) or its pressor component (+28 mmHg). 4Propranolol abolished the tachycardic response of fear, whereas atropine more than doubled it (from +75 to +175 b.p.m. above resting baseline). 5The results demonstrate that both sympathetic and vagal parasympathetic outflows to the heart are strongly activated during conditioned fear. The vagal activation may act to hold back cardiac acceleration while the animal waits for the aversive stimulus to come. [source]

NG -NITRO- l -ARGININE METHYL ESTER POTENTIATES ANAPHYLACTIC VENOCONSTRICTION IN RAT PERFUSED LIVERS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2006
Toshishige Shibamoto
SUMMARY 1The effects of the nitric oxide (NO) synthase inhibitor NG -nitro- l -arginine methyl ester (l -NAME) on anaphylaxis-induced venoconstriction were examined in rat isolated livers perfused with blood-free solutions in order to clarify the role of NO in anaphylactic venoconstriction. 2Rats were sensitized with ovalbumin (1 mg) and, 2 weeks later, livers were excised and perfused portally in a recirculating manner at a constant flow with Krebs',Henseleit solution. The antigen (ovalbumin; 0.1 mg) was injected into the reservoir 10 min after pretreatment with l-NAME (100 mmol/L) or d -NAME (100 mmol/L) and changes in portal vein pressure (Ppv), hepatic vein pressure (Phv) and perfusate flow were monitored. In addition, concentrations of the stable metabolites of NO ( and ) were determined in the perfusate using an HPLC,Griess system. 3The antigen caused hepatic venoconstriction, as evidenced by an increase in Ppv from a mean (SEM) baseline value of 7.7 ± 0.1 cmH2O to a peak of 21.4 ± 1.1 cmH2O at 3 min in d -NAME-pretreated livers. Pretreatment with l-NAME augmented anaphylactic venoconstriction, as reflected by a higher Ppv (27.4 ± 0.8 cmH2O) after antigen than observed following d -NAME pretreatment. The addition of l -arginine, a precursor for the synthesis of NO, reversed the augmentation of anaphylactic venoconstricion by l -NAME. This suggests that hepatic anaphylaxis increased the production of NO, which consequently attenuated anaphylactic venoconstriction. However, perfusate NOx levels did not increase significantly after antigen in livers pretreated with either l -NAME or d -NAME. 4In conclusion, l -NAME potentiates rat anaphylactic hepatic venoconstriction, suggesting that NO contributes to the attenuation of the venoconstriction. However, this functional evidence was not accompanied by corresponding changes in perfusate NOx concentrations. [source]

RELATIVE CONTRIBUTION OF THE PRENATAL VERSUS POSTNATAL PERIOD ON DEVELOPMENT OF HYPERTENSION AND GROWTH RATE OF THE SPONTANEOUSLY HYPERTENSIVE RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006
Robert Di Nicolantonio
SUMMARY 1To determine the relative roles of the prenatal and postnatal (preweaning) environment on the development of blood pressure and growth rate in the spontaneously hypertensive rat (SHR) of the Okamoto strain, we used combined embryo transfer and cross-fostering techniques between SHR and normotensive Wistar-Kyoto (WKY) rats to produce offspring whose development was examined during the first 20 weeks of life. 2We measured litter sizes, bodyweights and tail-cuff blood pressures in offspring at 4, 8, 12 and 20 weeks of age. We also recorded heart, kidney and adrenal weights at 20 weeks of age, when the study concluded. 3We found that both the in utero and postnatal environments provided by the SHR mother could significantly affect WKY rat offspring growth rates, but blood pressure was unaffected in this strain. In SHR offspring, the SHR maternal in utero and suckling period both contributed to the rate of blood pressure development in the SHR, but not the final blood pressure of offspring at 20 weeks of age. This effect was greater for male than female offspring. Organ weights were largely unaffected by the perinatal environment in either strain. 4We conclude that although the SHR maternal in utero and immediate postnatal environment both contribute to the rate of blood pressure development in the SHR, they do not appear to contribute to the final blood pressure of offspring at maturity. The SHR maternal environment also alters growth rate that may, in turn, underlie these effects on SHR blood pressure development, particularly in males. [source]

AUTONOMIC and RESPIRATORY RESPONSES TO MICROINJECTION OF ATP INTO THE INTERMEDIATE OR CAUDAL NUCLEUS TRACTUS SOLITARIUS IN THE WORKING HEART,BRAINSTEM PREPARATION OF THE RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2005
Vagner R Antunes
SUMMARY 1.,Activation of peripheral chemoreceptors with KCN in the working heart,brainstem preparation from young male Wistar rats (70,90 g) increases phrenic (PNA; +105 ± 18%) and thoracic (tSNA; +44 ± 6%) sympathetic nerve activity compared with baseline and reduces heart rate (HR; from 377 ± 27 to 83 ± 6 b.p.m.). 2.,Microinjections of increasing doses of ATP (1, 5, 25, 100 and 500 mmol/L; n = 7) into the intermediate nucleus tractus solitarius (NTS) produced a dose-dependent reduction in PNA (from ,6 ± 3 to ,82 ± 1%) and in HR (from ,12 ± 4 to ,179 ± 47 b.p.m.). Microinjections of ATP into the intermediate NTS also produced a reduction in tSNA (from ,3 ± 3 to ,26 ± 5%), which was not dose dependent. 3.,Microinjections of ATP into the caudal NTS (n = 5) produced a dose-dependent increase in PNA (from 0.2 ± 3 to 115 ± 27%) and minor changes in HR and tSNA, which were not dose dependent. 4.,The data show that microinjection of ATP into distinct subregions of the NTS produces different respiratory and autonomic responses and suggest that ATP in the caudal NTS is involved in the respiratory but not in the sympathoexcitatory component of the chemoreflex. [source]

DIFFERENTIAL REGULATION OF ANGIOTENSIN II RECEPTORS DURING RENAL INJURY AND COMPENSATORY HYPERTROPHY IN THE RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2005
Emma Joly
SUMMARY 1.,The renin-angiotensin system may be involved in the compensatory adaptations occurring after the reduction of renal mass and during the consecutive changes leading to chronic renal failure. We therefore investigated the regulation of angiotensin II receptors in two models of renal hypertrophy in the rat: hypertrophy following uninephrectomy (UNx) or subtotal nephrectomy (STNx). The level of angiotensin type 1 (AT1A -R and AT1B -R) and type 2 (AT2 -R) receptor mRNA was quantified by competitive reverse transcription-polymerase chain reaction (RT-PCR) in specific renal zones and the intrarenal distribution of angiotensin II receptors was analysed by immunohistochemistry. 2.,In the UNx rats, AT1 -R mRNA expression was not modified in the cortex or in the inner stripe of the outer medulla of the residual kidney at any time after the surgery (1, 4 and 12 weeks). In contrast, AT1 -R mRNA expression was significantly reduced in these zones in STNx rats (,33% and ,40%, respectively). This downregulation was organ-specific, as AT1 -R mRNA levels were not modified in the liver. The proportions of AT1 -R subtype (AT1A and AT1B) mRNA were unchanged by UNx or STNx. Very low levels of AT2 -R mRNA were found in the cortex of all groups. Immunostaining revealed a similar localization of AT1 -R in mesangial cells, proximal tubule, basolateral membrane of thick ascending limb, in both models of hypertrophy. AT1 -R labelling was also detected in the apical membrane of intercalated cells of cortical collecting ducts. 3.,This differential mRNA expression of angiotensin II receptors during compensatory hypertrophy and renal injury suggests that the development of renal hypertrophy is independent of AT1 -R and AT2 -R gene expression levels. [source]

DYSFUNCTION OF PURINERGIC REGULATION OF SYMPATHETIC NEUROTRANSMISSION IN SHR/NDMCR-CP (SHR-CP) RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 2004
Naoko Tanaka
SUMMARY 1.,The effect of 2-chloroadenosine (2CA), a P1 receptor agonist and ,,,-methylene ATP (,,mATP), a P2 receptor agonist, on the overflow of endogenous noradrenaline (NE) and the contractile response were examined in the electrically field-stimulated (EFS) (1 Hz) caudal artery obtained from Wistar-Kyoto (WKY) and SHR/NDmcr-cp (SHR-cp) rats. 2.,Both 2CA and ,,mATP reduced the EFS-evoked release of NE from the arteries of WKY. Also, 2CA significantly reduced the EFS-evoked contractile response in WKY, while it had no effect at all in SHR-cp. ,,mATP significantly reduced the EFS-evoked contractile response in both WKY and SHR-cp. Both 2CA and ,,mATP did not affect the contractile response induced by NE at 1 µmol/L. 3.,These results indicate that in the caudal arteries of SHR-cp, the P2 agonist but not the P1 agonist is functional in the prejunctional inhibitory regulation of adrenergic neurotransmission. This P1 dysfunction may play a role in the sympathetic hyperinnervation in metabolic syndrome. [source]

EFFECT OF BUTYRIC ACID SUPPLEMENTATION ON SERUM AND RENAL ANTIOXIDANT ENZYME ACTIVITIES IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

JOURNAL OF FOOD BIOCHEMISTRY, Issue 2010
A. PUNEETH KUMAR
ABSTRACT Reactive oxygen metabolites, which are constant products of normal aerobic cell metabolism, play a key role in worsening the pathophysiological complications of diabetes. The present investigation was aimed at understanding the effect of butyric acid supplementation along with wheatbran and guar gum on serum and renal antioxidant enzyme activities and lipid peroxidation in streptozotocin (STZ)-induced diabetic rats. Activities of superoxide dismutase, catalase, glutathione peroxidase were evaluated in serum and kidney of control and experimental rats. Results clearly showed that the altered activity of the enzymes during diabetes was significantly ameliorated by butyric acid (500 mg/kg body weight/day) supplementation compared with other experimental groups. Further, the increased lipid peroxidation in serum and kidney of diabetic rats was also significantly reduced in butyric acid-supplemented diabetic rats. The study led us to conclude that butyric acid exert antioxidant property, thereby minimizing oxidative stress induced diabetes and its related complications. PRACTICAL APPLICATIONS Butyric acid , a product of dietary fiber fermentation , is a four-carbon fatty acid, which has wide range of application in disease management. This product is involved in various physiological functions of body like cell differentiation, apoptosis, colonic homeostasis, histone acetylation, etc. It is also known to decrease the incidence of bowel cancer and some of its analogues are shown to selectively improve glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. This study aims to evaluate the beneficial effects of butyric acid supplementation on oxidative stress-induced diabetic complications in rats. [source]

LIPID-LOWERING EFFECTS OF ARONIA MELANOCARPA FRUIT JUICE IN RATS FED CHOLESTEROL-CONTAINING DIETS

JOURNAL OF FOOD BIOCHEMISTRY, Issue 5 2007
S. VALCHEVA-KUZMANOVA
ABSTRACT Aronia melanocarpa fruit juice (AMFJ) is very rich in phenolic antioxidants, mainly flavonoids from the subclass anthocyanins. The aim of this study was to assess the influence of AMFJ on body and liver mass, plasma lipids and lipoprotein profiles, and the histopathology of liver and aorta in rats fed with cholesterol diets. AMFJ was applied orally for 30 days at doses of 5, 10 and 20 mL/kg. In rats fed the cholesterol-containing diets, AMFJ significantly hindered an increase in plasma lipids (total cholesterol, low-density lipoprotein cholesterol and triglycerides) because of cholesterol feeding. Body weight gains, liver weights, and liver and aorta histopathology were not influenced either by high-cholesterol diets or by AMFJ treatment. In conclusion, AMFJ showed lipid-lowering effects in rats with experimentally induced hyperlipidemia, and could be valuable in reducing lipidemia as a factor of cardiovascular risk. PRACTICAL APPLICATIONS Hyperlipidemia characterized by an increase in low-density lipoprotein (LDL) cholesterol and a decrease in high-density lipoprotein cholesterol is one of the major risk factors for atherosclerosis and cardiovascular disease. Plant foods with high contents of phenolic phytochemicals are reported to be inversely correlated with plasma total cholesterol (TC) and LDL cholesterol. Aronia melanocarpa fruits are remarkably rich in phenolic substances. They are used for human consumption as juice, syrup, jam and wine. Our research demonstrated that A. melanocarpa fruit juice hindered the dietary-induced elevation of plasma TC, LDL cholesterol and triglycerides in rats. In view of the results from our experiment, we can suppose that the juice may be further tested for reducing hyperlipidemia in humans and possibly approved a valuable dietary supplement. [source]

LIPID-LOWERING EFFICACY OF PIPERINE FROM PIPER NIGRUM L. IN HIGH-FAT DIET AND ANTITHYROID DRUG-INDUCED HYPERCHOLESTEROLEMIC RATS

JOURNAL OF FOOD BIOCHEMISTRY, Issue 4 2006
RAMASAMY SUBRAMANIAM VIJAYAKUMAR
ABSTRACT Male Wistar rats were divided into two groups: control diet group and high-fat diet group (HFD). Both groups were divided into four subgroups, each consisted of 10 animals, and the diets were supplemented with the following ingredients for 10 weeks: (1) 1% carboxymethyl cellulose; (2) 10 mg carbimazole (CM)/kg body weight; (3) 10 mg CM + 40 mg piperine/kg body weight; and (4) 10 mg CM + 2 mg atorvastatin/kg body weight. Feeding HFD to rats significantly (P < 0.05) elevated plasma total cholesterol, triglycerides, phospholipids, free fatty acids, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and the activity of 3-hydroxy 3-methyl glutaryl coenzyme A (HMG CoA) reductase in the liver, heart and aorta, while the activities of plasma and tissue lipoprotein lipase (LPL) and plasma lecithin cholesterol acyl transferase (LCAT) and high-density lipoprotein were significantly (P < 0.05) lowered compared to control rats. Supplementing piperine with HFD significantly (P < 0.05) reduced the levels of plasma total cholesterol, LDL, VLDL tissue HMG CoA reductase and significantly (P < 0.05) elevated the levels of LPL and LCAT compared to rats that did not receive piperine. Fecal bile acids and neutral sterols were also elevated in HFD-fed rats as compared to control animals, while simultaneous supplementation of piperine significantly (P < 0.05) enhanced further excretion of bile acids and neutral sterols. The results indicate that piperine can prevent the accumulation of plasma lipids and lipoproteins significantly by modulating the enzymes of lipid metabolism. [source]

DOSE-DEPENDENT EFFECT OF LUMINAL BUTYRATE ON EPITHELIAL PROLIFERATION IN THE DISTAL COLON OF RATS

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2001
S Sengupta
Butyrate, a major product of bacterial fermentation of dietary fibre, is trophic to the colonic epithelium, when deprived of dietary fibre or faecal stream. However, the dose,response relationship of butyrate to this trophic effect is not known. The mechanism of this effect is still debated and how it relates to the antitumorigenic action of butyrate is unclear. Aim, To characterise the dose,response relationship of the effect of butyrate delivered topically to the distal colon on fibre-deprived atrophic colonic epithelium in rats. Methods, Sixty-four male Sprague,Dawley rats were maintained on a fibre-free AIN 93G diet for 3 weeks to induce mucosal atrophy in the colon. The rats then underwent laparotomy for colonic intubation, in which a polyethylene tube was positioned at the proximal end of the distal colon via a caecotomy. After recovering from surgery, they were randomly divided into five groups, which were given for 4 days twice daily infusions of 0.5 mL butyrate at doses of 0, 10, 20, 40 or 80 mm (at which complete reversal of atrophy has been previously observed). Prior to sacrifice, the rats were injected intraperitoneally with vincristine to induce mitotic arrest. Crypt column heights and mitotic arrests were quantified by light microscopy. Results, All treatment groups were healthy and stress-free. The mucosa of vehicle-infused rats was atrophic (mean 38 cells/crypt). Effects of twice daily infusions of butyrate were first observed on cell proliferation (number of mitotic arrests per crypt column) at 10 mm, and increased linearly to 80 mm. Crypt column height increased linearly from 20 mm to 80 mm, at which a mean of 45 cells/crypt were observed (the number usually observed in chow-fed healthy rats). The mitotic index (number of mitotic arrests per 100 crypt cells) also increased linearly from 10 mm. Conclusions, Butyrate's trophic effect showed a linear dose,dependent relationship. Although a maximal effect was not convincingly demonstrated, the results indicate that very small amounts of butyrate are required to affect epithelial proliferation. Since much higher luminal delivery is required to suppress tumorigenesis in this model, the mechanism by which butyrate exerts its trophic and antitumorigenic effects are likely to be different. [source]

MYELINATION DEFICIT IN NERVE OF SUCKLING RATS DUE TO CYCLOLEUCINE -INDUCED DEFICIENCY OF METHYL DONORS

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000
R. Bianchi
We used cycloleucine (CL) , which prevents methionine conversion to S-adenosyl-methionine (SAMe) by inhibiting ATP-L-methionine-adenosyl-transferase (MAT) , to characterize the lipid and protein changes induced by methyl donors deficit in peripheral nerve and brain myelin in rats during development. We have previously shown that CL (400 mg/kg ip) given to suckling rats at days 7, 8, 12, and 13 after birth reduced brain and sciatic nerve weight gain, brain myelin content, protein, phospholipid (PL), and galactolipid concentration in comparison to control. Among PLs, only sphingomyelin (SPH) significantly increased by 35,50%. SAMe p-toluensulphonate (SAMe-SD4) (100 mg/kg, ip) given daily from day 7, as with exogenous SAMe, partially prevented some lipid alterations induced by CL, particularly galactolipid and SPH. To test the ability of CL to affect PL metabolism we have measured de novo PL biosynthesis, ex vivo in nerve homogenates (in comparison with brain homogenates) from control and CL-treated animals killed at day 18 after birth, starting from labelled substrates ([3H]-choline, specific activity 20 mCi/mmol) in a Tris/HCl buffer, containing 5 mM MgCl2, 0.2 mM EDTA, 0.1 mM ATP, and 0.5 mM of the labelled substrates. After 60 min incubation, lipids were extracted, PL separated by TLC, and corresponding silica gel fractions scraped and counted in a liquid scintillator. Phosphatidylcholine enrichment in labelled choline resulted in slight increases in brain and sciatic nerve of CL-treated rats, suggesting an increased synthesis rate via the Kennedy pathway, possibly due to the reduced availability of methyl donors. Interestingly, choline incorporation into SPH in brain and nerve myelin resulted in significant increases of 30,40%. In agreement with the observed decrease of galactolipid content and the relative increase in SPH, these data suggest an alteration in sphingolipid metabolism after CL. Among proteins, in sciatic nerves of CL-treated pups the relative content of a number of polypeptides, namely the 116, 90, 66, 58, and 56 kDa bands, decreased, whereas others increased; the most abundant PNS protein, protein zero, remained unchanged. The analyses of myelin basic protein isoforms revealed a dramatic increase in the 14.0 and 18.5 forms, indicating early active myelination. SAMe-SD4 treatment counteracted, and in some cases normalized, these changes. In summary, methyl donor deficiency induced by MAT inhibition produces myelin lipid and protein alterations, partly counteracted by SAMe-SD4 administration. The financial support of Telethon-Italy (grant No. D 51) is gratefully acknowledged. [source]

MACROPHAGE INFILTRATION AND INDUCTION OF P75 NTR AND IL-1B IN THE NERVE OF DIABETIC RATS

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000
G. Conti
Recently, inflammation has been involved in the pathogenesis of diabetic neuropathy, and activated macrophages have been found in the peripheral nervous system of diabetic rats, with a possible role in chemotaxis and regeneration. In this study, we obtained sciatic nerve specimens from diabetic rats at different time points following STZ administration. Macrophages infiltration, IL-1b and p75NTR induction were analyzed by immunocytochemistry on frozen sections and on teased nerve fibers. Apoptosis was detected on teased nerve fibers by TUNEL and DAPI staining. Cell phenotype was characterized by double-staining with antibodies specific for Schwann cells and macrophages. The nerves obtained from STZ-diabetic rats showed macrophages infiltration by day 14 following STZ administration, with complete clearance by day 35. Fifteen percent of these cells were TUNEL positive. IL-1B induction was concomitant with macrophages infiltration and not detectable by day 35. p75NTR expression began by day 21, peaking by day 35, and dropping to barely detectable levels by day 105. These findings seem to indicate that the concomitance of these processes may be crucial in the regulation of nerve damage and in promoting an attempt of regeneration at the early stages of STZ diabetic neuropathy. [source]

VEGF GENE EXPRESSION IN PROTEINURIC RATS

NEPHROLOGY, Issue 1 2002
Kelly Dj
[source]

A NOVEL IMMUNOSUPPRESSANT, LF15-0195c, PREVENTS THE DEVELOPMENT OF ANTI-GBM DISEASE IN RATS

NEPHROLOGY, Issue 3 2000
Tesch Gh
[source]

THE IMPORTANCE OF BLOCKADE OF THE RENIN ANGIOTENSIN AND ENDOTHELIN SYSTEMS ON PROGRESSIVE RENAL INJURY IN SUBTOTALLY NEPHRECTOMISED RATS: USE OF COMBINATION REGIMENS

NEPHROLOGY, Issue 3 2000
Zemin Cao
[source]

RATS, We Should Have Used Clinton: Subliminal Priming in Political Campaigns

POLITICAL PSYCHOLOGY, Issue 5 2008
Joel Weinberger
Political strategists decide daily how to market their candidates. Growing recognition of the importance of implicit processes (processes occurring outside of awareness) suggests limitations to focus groups and polling, which rely on conscious self-report. Two experiments, inspired by national political campaigns, employed Internet-presented subliminal primes to study evaluations of politicians. In Experiment 1, the subliminal word "RATS" increased negative ratings of an unknown politician. In Experiment 2, conducted during former California Governor Gray Davis's recall referendum, a subliminal photo of Clinton affected ratings of Davis, primarily among Independents. Results showed that subliminal stimuli can affect ratings of well-known as well as unknown politicians. Further, subliminal studies can be conducted in a mass media outlet (the Internet) in real time and supplement voter self-report, supporting the potential utility of implicit measures for campaign decision making. [source]

EPIGALLOCATECHIN-3-GALLATE ATTENUATES CARDIAC HYPERTROPHY IN HYPERTENSIVE RATS IN PART BY MODULATION OF MITOGEN-ACTIVATED PROTEIN KINASE SIGNALS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2009
Dan-Dan Chen
SUMMARY 1It has been demonstrated that epigallocatechin-3-gallate (EGCG) inhibits cardiac hypertrophy through its antihypertensive and anti-oxidant effects. However, the underlying molecular mechanism is not clear. 2In the present study, we tested the hypothesis that EGCG attenuates transaortic abdominal aortic constriction (TAC)-induced ventricular hypertrophy by regulating mitogen-activated protein kinase (MAPK) signal pathways in hypertensive rats. Four groups of rats were used: (i) a sham-operated control group; (ii) an EGCG-treated (50 mg/kg per day, i.p., for 21 days) sham-operated group; (iii) a TAC group; and (iv) an EGCG-treated TAC group. Histological analysis of whole hearts and biochemical analyses of left ventricular (LV) tissue were used to investigate the effects of EGCG. 3The results showed that the LV myocyte diameter and the expression of atrial natriuretic peptide, brain natriuretic peptide and ,-myocardial heavy chain were significantly decreased in the EGCG-treated (50 mg/kg per day, i.p.) TAC group. Levels of reactive oxygen species and malondialdehyde in the lV were significantly reduced by EGCG in the TAC group. Total superoxide dismutase, catalase and glutathione peroxidase activities were decreased in the TAC group, and this decrease was significantly restored by EGCG treatment. Phosphorylation of extracellular signal-regulated kinase 2, p38 and c-Jun N-terminal kinase 1 was significantly reversed in the LV of EGCG-treated TAC rats (40%, 53% and 52%vs TAC, respectively), accompanied by significant inhibition of nuclear factor-,B and activator protein-1. Transaortic abdominal aortic constriction significantly upregulated LV expression of matrix metalloproteinase-9 from 32 ± 6 to 100 ± 12% and this increase was inhibited by EGCG treatment (from 100 ± 12 to 50 ± 15%). In addition, TAC decreased mitochondrial DNA copy number and the activity of respiratory chain complexes I (from 100 ± 7 to 68 ± 5%), III (from 100 ± 4 to 2 ± 5%) and IV (from 766 ± 2 to 100 ± 5%); this decrease was reversed by EGCG treatment to levels seen in sham-operated rats. 4In conclusion, EGCG attenuates TAC-induced ventricular hypertrophy in hypertensive rats in part by suppression of anti-oxidant enzymes and regulation of MAPK signals. [source]

INHIBITION OF BRAIN RENIN,ANGIOTENSIN SYSTEM IMPROVES DIASTOLIC CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009
IG Araujo
SUMMARY 1Recently, we demonstrated that oral captopril treatment improved diastolic function and attenuated cardiac remodelling after myocardial infarction (MI) in rats. Considering the feasible role of the brain renin,angiotensin system (RAS) in heart failure, in the present study we investigated the role of the captopril injected intracerebroventricularly (i.c.v.) on the progression of cardiac dysfunction. 2Male Wistar rats underwent experimental MI or sham operation. Infarcted animals received daily i.c.v. injections of captopril (approximately 200 mg/kg; MI + Cap) or saline (MI) from 11 to 18 days after infarction. Electro- and echocardiogram assessments were performed before and after i.c.v. treatment (10 and 18 days after MI, respectively). Water and hypertonic saline ingestion were determined daily between 12 and 16 days after MI. 3Electrocardiograms from the MI and MI + Cap groups showed signs that resembled large MI before and after i.c.v. treatment. However, despite similar systolic dysfunction observed in both groups, only captopril-treated rats exhibited reduced left ventricular (LV) dilatation and improved LV filling, as assessed by echocardiograms, and low levels of water ingestion compared with the saline-treated control group. 4The results of the present study suggest that the brain RAS may participate in the development of cardiac dysfunction induced by ischaemia and that inhibition of the brain RAS may provide a new strategy for the prevention of diastolic dysfunction. [source]

PROTECTIVE EFFECTS OF ICARIIN ON COGNITIVE DEFICITS INDUCED BY CHRONIC CEREBRAL HYPOPERFUSION IN RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009
Rui-Xia Xu
SUMMARY 1Icariin is a major constituent of flavonoids derived from the Chinese medicinal herb Epimedium revicornum Maxim. The aim of the present study was to investigate whether icariin has protective effects on learning ability and memory in a rat model of chronic cerebral hypoperfusion. 2Chronic cerebral hypoperfusion was induced by permanent ligation of the common carotid artery in Wistar rats for 4 months. One month after permanent artery occlusion, rats were adminitered icariin at doses of 0, 30, 60 or 120 mg/kg per day, p.o., for 3 months. Neurobehavioural and neurobiochemical parameters were examined to evaluate the effects of icariin on cognitive deficits induced by chronic cerebral hypoperfusion. 3The Morris water maze test revealed that learning ability and memory were severely impaired in untreated rats, but were significantly improved in icariin-treated rats. Icariin treatment also ameliorated chronic cerebral hypoperfusion-induced oxidative stress in the brain, as evidenced by reduced malondialdehyde formation and maintained superoxide dismutase activity. In addition, the decreased hippocampal levels of acetylcholine, acetylcholinesterase and choline acetyltransferase associated with chronic cerebral hypoperfusion were significantly prevented by icariin treatment. 4In conclusion, icariin protects against cognitive deficits induced by chronic cerebral hypoperfusion in rats. These effects appear to be mediated through its anti-oxidant effects, as well as its effects on the circulatory and cholinergic systems. [source]

CONTINUOUS FLUOXETINE ADMINISTRATION PREVENTS RECURRENCE OF PULMONARY ARTERIAL HYPERTENSION AND PROLONGS SURVIVAL IN RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2009
Shao-Ping Zhu
SUMMARY 1The serotonin transporter (SERT) is strongly implicated in the pathogenesis of pulmonary arterial hypertension (PAH) in patients and animal models. Inhibitors of SERT have been reported to attenuate or reverse experimental PAH, which makes them potential therapeutic options for the treatment of PAH in humans. However, little is known about pathophysiological features after reversal or attenuation of PAH; moreover, the long-term therapeutic effects of SERT inhibitors on PAH remain undetermined. Thus, the aim of the present study was to investigate the short- and long-term effects of fluoxetine on monocrotaline (MCT)-induced PAH and associated pathophysiological changes in PAH models. 2Rats were randomly divided into four groups as follows: (i) an M + F group, in which rats received a single injection of MCT (60 mg/kg, s.c.) and then after 3 weeks were given fluoxetine (10 mg/kg) once daily by gavage from Week 4 to Week 12; (ii) an M/F group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection, rats were given fluoxetine (10 mg/kg) by daily gavage from Week 4 to Week 6 and were then given an equivalent volume of saline once daily by gavage from Week 7 to Week 12; (iii) an MCT group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection rats were given an equivalent volume of saline by gavage from Week 4 to Week 12; and (iv) a saline group, in which rats received an equivalent volume of saline injection or gavage over the 12 week treatment period. Morphometric changes, pulmonary arterial pressure, percentage wall thickness, right ventricular hypertrophy index and SERT expression were detected at various times during the 12 week treatment period. Survival analysis was performed in each group. 3After 12 weeks treatment, it was found that even through fluoxetine treatment resulted in complete reversal of PAH, PAH recurred after fluoxetine withdrawal. In contrast, continuous administration of fluoxetine prevented the recurrence of PAH and prolonged survival. Analysis of SERT protein levels in rat lung indicated that, compared with values obtained at Week 0, SERT protein increased significantly after discontinuation of fluoxetine but continuous fluoxetine administration inhibited this increase. 4In conclusion, SERT overexpression correlates with the recurrence of PAH after withdrawal of fluoxetine in rats. Continuous fluoxetine administration prevents recurrence of PAH and prolongs survival. [source]

ENDOPLASMIC RETICULUM STRESS INVOLVED IN HEART AND LIVER INJURY IN IRON-LOADED RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2009
Li-Xia Lou
SUMMARY 1Iron overload contributes to the pathogenesis of various diseases and directly induces tissue injury. In the present study, we investigated the relationship between heart and liver injury induced by iron overload and cellular endoplasmic reticulum (ER) stress to explore the molecular mechanism of iron overload-induced cellular injury. 2Iron overload in rats was generated by intraperitoneal injection of iron,dextran chronically (30 mg/kg per day for 9 weeks) or acutely (300 mg/kg once). Tissue injury was assessed by determining serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, as well as malondialdehyde (MDA) content in the heart and liver. The ER stress response was analysed by expression of glucose-response protein 78 (GRP78) and activation of caspase 12. 3In chronic iron-loaded rats, iron levels in the heart and liver were higher, by approximately 2-and 7.8-fold, respectively (P < 0.01), compared with control. Serum LDH, ALT and AST activity, as well as MDA content, GRP78 expression and caspase 12 activity in the heart and liver, were upregulated in chronically iron-loaded rats. In acute iron-loaded rats, iron content in the heart and liver was 51% and 63% higher than in controls (both P < 0.01). Serum LDH, ALT and AST activity, MDA content in the heart and liver and levels of ER stress markers were all increased in acute iron-loaded rats. N -Acetylcysteine (150 mg/kg, s.c.) lowered the levels of these parameters in acute iron-loaded rats. 4The results of the present study indicate that ER stress may play an important role in iron-induced tissue injury and that reactive oxygen species may mediate the ER stress response in the pathogenesis of iron-overload cellular injury. [source]