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General Physiology and Biophysics

Volume 31, 2012, No. 4


  Molecular biology of toll-like receptors
Zoltan Szatmary 1)

1)Slovak Medical University, Limbová 12, 833 03 Bratislava, Slovak Republic.

Toll-like receptors (TLRs) play important roles in host resistance to infections, but also act as mediators of pathologies in autoimmunity, septic shock, metabolic disease and cancer. TLRs are expressed in sentinel cells of the immune system (most notably dendritic cells and macrophages) and are key sensors of bacteria, viruses, fungi and protozoa (O'Neill 2006). TLRs also recognize endogenous ligands present in tissues and cells in the absence of infection (Kawai and Akira 2005; Nizet 2006; Kim et al. 2009). In this review, the TLRs are characterized at the cellular level with emphasis on TLR-mediated signaling pathways along with their negative regulation, including specificity of the response(s) at the promoter level.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 357-366.

  Glucocorticoid excess and disturbed hemodynamics in advanced age: the extent to which soy isoflavones may be beneficial
Vladimir Ajdžanović 1), Verica Milosevic, Ivan Spasojević

1)Institute for Biological Research “Siniša Stanković”, University of Belgrade, Belgrade, Serbia.

Advanced age is often accompanied by glucocorticoid excess which contributes to the pathogenesis of the metabolic syndrome associated with some hemodynamic disorders. Impaired central regulation of stress hormones secretion and increased glucocorticoids/adrenal androgens ratio trigger hyperglycemia, elevated blood lipids and visceral fat accumulation, associated with hypertension and increased blood viscosity, all of which represent cardiovascular morbidity factors in this age. Finding the adequate therapeutic solutions is set as an imperative in the treatment of listed symptoms. Biologically active soy isoflavones, exhibiting estrogen- and membrane-receptor agonistic/antagonistic activity, and antioxidative and tyrosine kinase/steroidogenic enzyme inhibiting effects, appear as alternative therapeutics for various ageing-related diseases. It has been shown that soy isoflavones reduce some of the listed risk factors, while affecting the hemodynamic group of cardiovascular parameters directly, as well as indirectly via endocrine perturbations. Soy isoflavones may reverse the glucocorticoids/adrenal androgens ratio, lower serum cholesterol, slow the development of atherosclerotic plaque formation, inhibit platelet aggregation, increase cardiac contractility, but they may have diverse effects on blood viscosity and may increase triglyceride levels. Herein, we present the projection of soy isoflavones-based therapy of glucocorticoid excess and disturbed hemodynamics in advanced age, concluding that although promising, it requires the impartial approach and certain precautions.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 367-374.

  Calcium transporters and their role in the development of neuronal disease and neuronal damage
Katarina Jaskova 1), Michaela Pavlovicova, Dana Jurkovicova

1)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 833 34 Bratislava, Slovak Republic.

Neurodegeneration comprises assembly of pathophysiological events that gives rise to a progressive loss of neuronal structure and function including cellular damage, diseases development or cellular death. Neurons respond by adjusting signaling pathways, from gene expression to morphological changes. In most of these processes, Ca2+ signaling plays a pivotal role. By increasing the Ca2+ concentration, the cell responds to neuronal, neurotrophic and other growth factor stimuli, however, the molecular mechanism of Ca2+-dependent neurite outgrowth and development yet requires further elucidation. Here we focus on the role of Ca2+ and selected Ca2+ transporters involved in processes of CNS neurodegeneration – inositol 1,4,5-trisphosphate (IP3Rs) and ryanodine receptors (RyRs), considering the fact that these receptors may be important “sensors” of disturbed intracellular calcium homeostasis. We propose that in vitro cellular models could serve as suitable experimental systems for the determination of the role that these receptors play in neuropathological conditions. Recognition of the principles, key players and regulatory processes may elucidate the role of Ca2+ in the regulation of neuronal proliferation, development and differentiation, growth and axon navigation in neurodegenerative and regenerative processes. This may provide a new insight and also discovery of novel therapeutic-targeting possibilities for severe neurological disorders and pathophysiological changes.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 375-382.

  The role of endothelin-1 and its receptor blockers on the liver function
Łukasz Michalski 1), Paulina Kleniewska, Aleksandra Piechota-Polańczyk, Anna Gorąca

1)Department of Cardiovascular Physiology, Medical University of Łódź, Mazowiecka 6/8, 92-215 Łódź, Poland.

Endothelin-1 (ET-1) was first described by Yanagisawa et al. (1988) as a 21-amino acid peptide present in the extract from the aorta endothelial cells. It is known that ET-1 is one of the most potent vasoconstrictor compounds and also causes proliferation of many of the vascular cells involved in vascular remodeling. This peptide exerts its action through interactions with its membrane receptors – ETA and ETB. These receptors are expressed in the vascular smooth muscle cells, endothelial cells, intestines and the brain. Secretion of ET-1 results in long-lasting vasoconstriction, increased blood pressure and, in turn, overproduction of free radicals. As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis, hypertension and endotoxic shock, the ETA and ETB receptors are attractive therapeutic targets for treatment of these disorders. Recently, several clinical trials have provided evidence that ET-1 receptor antagonism influences liver function and has therapeutic potential in the treatment of liver impairment. Therefore, this review summarizes recent clinical trials on the role of ET-1 receptor blockers with respect to the modulation of liver function.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 383-388.

  Thyroid hormones decrease the affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a competitive antagonist, for the guinea pig atrial A1 adenosine receptor
Rudolf Gesztelyi 1), Zsuzsa Kiss, Judit Zsuga, Krisztian Pak, Csaba Papp, Zoltan Galajda, Klara Branzaniuc, Andras Szentmiklosi, Arpad Tosaki

1)Department of Pharmacology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.

The aim of the present study was to investigate whether or not thyroxine (T4) treatment affects KB, the equilibrium dissociation constant of the antagonist-receptor complex, for the interaction between CPX, a selective and competitive orthosteric antagonist, and the guinea pig atrial A1 adenosine receptor A1 receptor). The inotropic response to adenosine, a nonselective adenosine receptor agonist, or CPA, a selective A1 receptor agonist, was investigated in the absence or presence of CPX in paced left atria isolated from 8-day solvent- or T4-treated guinea pigs. To obtain KB values, adenosine and CPA concentration-response curves were evaluated by Schild analysis. CPA but not adenosine obeyed the requirements of the Schild analysis to provide correct KB values for CPX. According to the CPA concentration-response curves, affinity of CPX for the hyperthyroid guinea pig atrial A1 receptor (KB = 44.16 nM) was lower than that for the euthyroid one (KB = 16.63 nM). Regarding the intense reduction in the negative inotropic effect of adenosine and CPA in hyperthyroid atria, it is reasonable to assume that the moderate decrease in affinity of the guinea pig atrial A1 receptor is only in part responsible for the diminished A1 receptor-mediated effect in hyperthyroidism.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 389-400.

  Estimation of the fractional sarcoplasmic reticulum Ca2+ release in intact cardiomyocytes using integrated Ca2+ fluxes
Rosana Bassani 1), Rafael Ricardo, José Bassani

1)Center for Biomedical Engineering, University of Campinas, Campinas, Sao Paulo, Brazil.

The sarcoplasmic reticulum (SR) is the main source of contraction-activating Ca2+ in the adult mammalian myocardium. The fraction of the SR Ca2+ content released at a twitch (fractional SR Ca2+ release, FR) is an important parameter for assessing the efficiency of excitation-contraction coupling under physiological and pathophysiological conditions, as well as for identification of modulators of this process. We here describe and propose an approach for FR quantitation based on the estimation of integrated Ca2+ fluxes mediated by different transporters that remove the ion from the cytosol. These fluxes may be calculated solely from the measurement of cytosolic free Ca2+ concentration ([Ca2+]i) during Ca2+ transients evoked under selective inhibition of the transporters, and from the cell Ca2+ buffering parameters available in the literature. The FR values obtained with this approach in intact rat ventricular myocytes (0.63 ± 0.04; n = 12) were comparable to those estimated in the same cell type with an already established method, based on electrophysiological measurements with the patch-clamp technique, in addition to [Ca2+]i measurement (0.69 ± 0.05; n = 6; p > 0.40). We conclude that the proposed method might be a suitable and technically simpler alternative to the electrophysiological method for FR estimation.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 401-408.

  Mg2+-induced adenosine-receptor mediated relaxations in mesenteric vascular beds of diabetic rats
Roya Tavasoli 1), Nepton Soltani, Mansoor Keshavarz, Shahla Shorabipour

1)Department of Biology, Faculty of Science, Arsanjan Azad University, Shiraz, Iran.

Our previous studies showed that the magnesium Mg2+-induced relaxations were completely dependent on concentration of nitric oxide (NO) in non-diabetic rat mesenteric vascular beds, in diabetic rats other mechanisms may be involved. The present study was designed to determine the role of adenosine receptor in Mg2+-induced relaxation in streptozotocin (STZ)-induced diabetic rats vessels. Diabetes was induced by the intravenous injection of 60 mg/kg STZ. Eight weeks after diabetes induction, superior mesenteric arteries were isolated and perfused according to the McGregor method. Prepared vascular beds were constricted with phenylephrine to induce 70–75% of maximal constriction (0.001 M). Mg2+ at concentrations of 10-4 to 10-1 M were added into the medium and perfusion pressure was recorded. Theophylline (1 mM), and 3,7- dimethyl-1- propargylxanthine (0.01 μM) were added into medium 20 min before phenylephrine administration. In the presence of theophylline, vasorelaxation induced by high dose of Mg2+ (from 0.03 to 0.1 M) was totally suppressed. In presence of N(ω)-nitro-L-arginine methyl ester (L-NAME), the response of Mg2+ was completely inhibited at low dose of Mg2+. But, Mg2+-induced relaxation in the presence of adenosine A2a receptor blocker was significantly suppressed in high dose of Mg2+. Mg2+-induced relaxation in the presence of an A2a receptor blocker was not suppressed either by denudation of endothelium or presence of L-NAME. From the results of this study it may be concluded that Mg2+-induced relaxation at high concentrations is mediated by adenosine A2a receptors, but at low concentrations Mg2+-induced relaxation is dependent on NO.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 409-413.

  Analysis of genetic polymorphisms of brain-derived neurotrophic factor and methylenetetrahydrofolate reductase in depressed patients in a Slovak (Caucasian) population
Andrea Evinova 1), Eva Babusikova, Stanislav Straka, Igor Ondrejka, Ján Lehotský

1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University Bratislava, Slovak Republic.

Major depressive disorder (MDD) is a complex neuropsychiatric disorder where both gene-gene and gene-environment interactions play an important role, but the clues are still not fully understood. One carbon metabolism in the CNS plays a critical role in the synthesis and release of neurotransmitters which are relevant to depressive disorder. We studied genetic polymorphisms of the brain derived neurotrophic factor (BDNF) and the methylenetetrahydrofolate reductase (MTHFR) in association with major depressive disorder. We genotyped the BDNF G196A, the MTHFR C677T, and A1298C polymorphisms in 134 patients diagnosed with major depression and 143 control subjects in Slovak (Caucasian) cohort of patients and probands. We found no significant association of either the BDNF G196A or MTHFR C677T polymorphisms with major depressive disorder neither in female nor male group of patients. However, the MTHFR A1298C genotype distribution was 36.6% (for AA genotype), 48.5% (AC) and 14.9% (CC) for the depressed patients, and 48.9% (AA), 42.7% (AC) and 8.4% (CC), respectively, for the control subjects. Patients with MDD had a higher prevalence of the CC genotype (OR = 2.38; 95% CI = 1.07–5.32; p = 0.032) and the AC + CC genotype (OR = 1.67; 95% CI = 1.03–2.69; p = 0.037) in comparison with the control subjects. This study shows that CC genotype of the MTHFR A1298C is associated with higher risk of MDD in Slovak population.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 415-422.

  Protective effects of fenugreek (Trigonella foenum graecum L.) upon dieldrin-induced toxicity in male rat
Najla Hfaiedh 1), Hichem Alimi, Jean-Claude Murat, Abdelfattah Elfeki

1)Laboratory of Animal Ecophysiology, Faculty of Sciences, Sfax, Tunisia.

The purpose of this study was to evaluate the protective effects of fenugreek (Trigonella foenum graecum L.) upon dieldrin-induced perturbations of haematological parameters and damages to liver and kidney of male Wistar rats. Under our experimental conditions, dieldrin poisoning resulted in 1) an alteration of several haematological parameters, 2) an oxidative stress evidenced by an increase of lipids peroxidation level associated with an increase of superoxide dismutase activity and a decrease of glutathione peroxidase and catalase activities in hepatic and renal tissues, 3) increased levels of glucose, total cholesterol, triglycerides, creatinine, urea, uric acid and proteins in blood, 4) increased activities of lactate dehydrogenase, alkaline phosphatase and transaminases in blood. Previous administration of fenugreek was found to hinder these dieldrin-induced damages: all hematological, renal and hepatic biomarkers, level of lipids peroxidation and activities of catalase and glutathione-peroxidase in liver and kidney were kept close to control values. This protective effect is mainly attributed to antioxidant properties of fenugreek.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 423-430.

  Long-term treatment with resveratrol attenuates oxidative stress pro-inflammatory mediators and apoptosis in streptozotocin-nicotinamide-induced diabetic rats
Farhad Soufi 1), Mina Vardyani, Roghayeh Sheervalilou, Mustafa Mohammadi, Mohammad Somi

1)Department of Physiology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.

This study was designed to investigate the possible effectiveness of chronic resveratrol administration on redox state, inflammatory mediators and apoptosis rate in diabetic rats. Male Wistar rats were divided into four groups (n = 6): normal control, diabetic control, normal rats treated with resveratrol, and diabetic rats treated with resveratrol. Diabetes was induced by injection of streptozotocin (50 mg/kg; i.p.), 15 min after the prescription of nicotinamide (110 mg/kg; i.p.) in 12 h-fasted rats. Four-month oral resveratrol administration (5 mg/kg/day) significantly alleviated hyperglycemia, weight loss, enhancement of oxidative markers (lipid peroxidation index, nitrite/nitrate content and oxidized to reduced glutathione ratio) and superoxide dismutase activity in diabetic rats. Moreover, resveratrol administration to diabetic rats improved the elevated levels of plasma TNFα and IL-6 as well as NF-κB activity of polymorphonuclear cells. On the other hand, four months resveratrol administration decreased the apoptosis rate in the kidney, heart, retina, sciatic nerve and the polymorphonuclear cells of diabetic rats. These beneficial antidiabetic observations suggest that treatment with resveratrol may be considered as a therapeutic approach to reduce diabetic-related complications.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 431-438.

  Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation
Anna Severino 1), Maria Narducci, Daniela Pedicino, Vincenzo Pazzano, Ada Giglio, Luigi Biasucci, Giovanna Liuzzo, Michela Casella, Stefano Bartoletti, Antonio Russo, Gemma Pelargonio, Pasquale Santangeli, Luigi Di Biase, Andrea Natale, Filippo Crea

1)Institute of Cardiology, Catholic University of Sacred Heart, Rome, Italy.

Alteration of cardiomyocyte gap-junctions and component connexins (Cx) has been suggested to contribute to the development of atrial fibrillation (AF), including postoperative AF. We tested different possible stimuli, such as hypoxia and ischemia, influencing Cx43 and Cx40 expression and distribution in cultured atrial cells (HL-1) and reversibility of these processes after reoxygenation. Western-blot analysis and immunostaining using anti-Cx43, anti-Cx40 and anti-zonula occludens polyclonal antibodies were performed. HL-1 cells exposed to hypoxia for 24 and 48 h showed a reduction of Cx43 protein levels by 75% and 90% respectively (p < 0.001). During reoxygenation following 24 h of hypoxia, Cx43 levels increased to reach the basal level within 48 h, while they remained at low level during reoxygenation following 48 h of hypoxia. Furthermore, atrial cardiomyocytes subjected to simulated ischemia (SI) were incubated in normoxic and hypoxic conditions for 3, 6, 9, 12 h. Atrial cardiomyocytes subjected to SI in addition to normoxia showed a progressive reduction of Cx43 levels beginning from 3 h. During SI and hypoxia, atrial Cx43 levels showed an initial decrease after 3 h with a subsequent rescue beginning from 6 h of exposure (p = 0.001). Hypoxia and ischemia per se downregulate Cx43 protein expression in atrial cardiomyocytes, but protein downregulation is reversible, depending on hypoxia duration and the association of the two triggers. These alterations characterize several conditions and might contribute to the generation of an arrhythmogenic substrate leading to AF onset and/or maintenance.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 439-448.

  Evaluation of protein change and oxidative stress index after photodynamic therapy of corneal neovascularization
Salwa Abdelkawi 1), Aziza Hassan

1)Department of Vision Science, Biophysics and Laser Science Unit, Research Institute of Ophthalmology, Giza, Egypt.

The aim of the present study was to evaluate the change in corneal protein and oxidative stress state after using photodynamic therapy (PDT) for treatment of experimental corneal neovascularization (NV) with benzoporphyrin derivative (BPD). One group was considered as control (N = 10 eyes), corneal NV was induced in 25 New Zealand male rabbits (N = 50 eyes) after placing silk sutures in the corneal limbus. Five rabbits with corneal NV were left without any treatment, and 20 rabbits were administered by intravenous injection with Verteporfin at a dose of 1.5 mg/kg. Diode laser (660 nm) was applied for 5 minutes with a power of 50 mW/cm2. For a period of 4 weeks, five rabbits were selected and sacrificed weekly (N = 10 eyes each). The corneas were isolated for determination of protein content, SDS-PAGE, total antioxidant capacity (TAC), total oxidative capacity (TOC), malondialdhyde (MDA) and oxidative stress index (OSI). The results indicated that corneal NV induced changes in the content and composition on the corneal protein and gradual improvement of the cornea after the 3rd and 4th week of PDT was detected. Furthermore, the oxidative/antioxidative balance shifted towards the antioxidative status that helped to prevent further damage.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 449-455.

  Differential actions of proteinases and neuraminidase on mammalian erythrocyte surface and its impact on erythrocyte agglutination by concanavalin A
Savita Sharma 1), Sadashiv Gokhale

1)School of Biochemistry, Devi Ahilya University, Khandwa Road, Indore 452017, India.

Action of proteinases viz. trypsin and chymotrypsin, and neuraminidase on intact erythrocyte membrane proteins and glycophorins (sialoglycoproteins) exposed to cell surface and its impact on lectin (concanavalin A)-mediated agglutination were studied in Homo sapiens (human), Capra aegagrus hircus (goat) and Bubalus bubalis (buffalo). Membrane proteins and glycophorins analysis by SDS-PAGE as visualized by coomassie brilliant blue and periodic acid-schiff stains, respectively, and agglutination behaviour revealed marked differences: 1) there were prominent dissimilarities in the number and molecular weights of glycophorins in human, goat and buffalo erythrocyte membranes; 2) proteinase action(s) on human and buffalo erythrocyte surface membrane proteins and glycophorins showed similarity but was found different in goat; 3) significant differences in erythrocyte agglutinability with concanavalin A can be attributed to differences in membrane composition and alterations in the surface proteins after enzyme treatment; 4) a direct correlation was found between degradation of glycophorins and concanavalin A agglutinability; 5) action of neuraminidase specifically indicated the negative role of cell surface sialic acids in determining concanavalin A agglutinability of goat and buffalo erythrocytes, similar to human. Present studies clearly indicate that there are some basic differences in human, goat and buffalo erythrocyte membrane proteins, especially with respect to glycophorins, which determine the concanavalin A-mediated agglutination in enzyme treated erythrocytes.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 457-468.

  Increased ubiquinone concentration after intracerebroventricularly-administered ubiquinol to selected rat brain regions
Anna Gvozdjáková 1), Boris Mravec, Jarmila Kucharská, Lubica Lackovičová, Katarína Ondičová, Martin Tkačov, Ram Singh

1)Pharmacobiochemical Laboratory of 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic.

Brain coenzyme Q10 (CoQ10) concentration can influence the activity of several brain regions, including those which participate in the regulation of cardiovascular circadian rhythms, food intake, neuroendocrine stress response, activity and sleep regulation. However, the effect of supplemented ubiquinol (reduced CoQ) into brain regions is not known. This study determined baseline levels of ubiquinone (oxidized CoQ) in various rat brain regions and proved the bioavailability of the liposomal ubiquinol to selected brain regions after its administration into right brain ventricle. Our data indicate that administration of ubiquinol may create the basis for modulation of neuronal activities in specific brain regions.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 469-472.

  NGF-induced neurite outgrowth in PC12 cells is independent of calcium entry through L-type calcium channels
Lucia Lichvárová 1), Katarína Jašková, Ľubica Lacinová

1)Institute of Molecular Physiology and Genetics, VVCE Biomembranes, Slovak Academy of Sciences, Bratislava, Slovak Republic.

Neuronal growth factor (NGF) induces neurodifferentiation of PC12 cells into cholinergic neurons-like cells. It was shown that intracellular Ca2+ ions participate in regulation of the differentiation of PC12 cells. We tested whether L-type calcium channels contribute to Ca2+ entry which supports neurite outgrowth accompanying NGF-activated differentiation process. Development of morphological changes did correlate with increase of functional expression of L-type calcium channels. However, inhibition of L-type calcium channels by 1 μM of isradipine did not affect significantly an NGF-activated neurite outgrowth.

General Physiology and Biophysics. Volume 31, 2012, No. 4: 473-478.