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Mechanism Contributing (mechanism + contributing)
Selected AbstractsThe Anticonvulsant SGB-017 (ADCI) Blocks Voltage-Gated Sodium Channels in Rat and Human Neurons: Comparison with CarbamazepineEPILEPSIA, Issue 3 2000Lucy Sun Summary: Purpose: SGB-017 (ADCI) is a novel anticonvul-sant that blocks both voltage-activated sodium channels and N -methyl- d -aspartate (NMDA)-receptor-gated channels. Results by Rogawski et al. suggested that SGB-017 produces its anticonvulsant action primarily by inhibition of NMDA-receptor channels. However, SGB-017 is effective in several animal models of epilepsy that are unresponsive to NMDA antagonists. These results indicate that block of NMDA-receptor channels is not the only mechanism contributing to its anticonvulsant activity. Thus the effects of SGB-017 on neu-ronal sodium channels were investigated. Methods: Whole cell voltage-clamp techniques were used to record sodium currents in freshly dissociated rat superior cervical ganglion (SCG) and hippocampal neurons and cultured human NT2 neurons. The effects of SGB-017 on the amplitude of sodium currents, elicited by a depolarizing pulse to 0 mV from different holding potentials, were measured and compared with those of carbamazepine (CBZ). Results: SGB-017 inhibited sodium currents in rat SCG and hippocampal neurons with a similar potency to CBZ. Like CBZ, the inhibition of sodium channels by SGB-017 was voltage dependent. Its median inhibitory concentration (IC50) for inhibition of sodium channels at depolarized holding potentials is similar to that for its inhibition of NMDA receptor channels. In human hNT2 neurons, SGB-017 was more potent than CBZ at inhibiting sodium currents. Conclusions: SGB-017 produces its anticonvulsant activity by blocking both sodium- and NMDA-receptor channels in a voltage- and use-dependent manner. The combination of these two mechanisms of action makes SGB-017 an effective AED in several different animal models of epilepsy. [source] Source,sink dynamics sustain central stonerollers (Campostoma anomalum) in a heavily urbanized catchmentFRESHWATER BIOLOGY, Issue 10 2008ERIC R. WAITS Summary 1. The influence of spatial structure on population dynamics within river,stream networks is poorly understood. Utilizing spatially explicit analyses of temporal genetic variance, we tested whether persistence of central stonerollers (Campostoma anomalum) reflects differences in habitat quality and location within a highly modified urban catchment in southwestern Ohio, U.S.A. 2. Estimates of genetic diversity did not vary with habitat quality. Nevertheless, evidence of weak but temporally stable genetic structure, location-dependent effective population sizes and rates of immigration among sites, together suggest that persistence of central stonerollers within the catchment may be attributable to source,sink dynamics driven by habitat heterogeneity. 3. Under this scenario, migrant-pool colonization from areas of relatively high habitat quality in the upper catchment sustains the presence of central stonerollers at degraded sites in the main stem and dampens population subdivision within the catchment. However, because intact habitat is restricted to the upper portion of the catchment, it is not possible to preclude net downstream dispersal as a mechanism contributing to source,sink dynamics. The slight genetic structure that persists appears to reflect weak isolation by distance diminished by high rates of immigration. 4. This study suggests that without a systems perspective of the conditions that sustain populations in degraded waterways, environmental assessments may underestimate levels of impairment. Conservation and management of stream fishes could be improved by maintaining habitat in areas that are net exporters of migrants or by remediation of impaired habitat. [source] Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in miceFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009C. Girish Abstract Oxidative stress is implicated as a common pathologic mechanism contributing to the initiation and progression of hepatic damage in a variety of liver disorders. Present study attempts to evaluate the hepatoprotective activity of picroliv, curcumin and ellagic acid in comparison to silymarin using paracetamol (PCM) induced acute liver damage. Hepatotoxicity was induced by administering a single oral dose of PCM (500 mg/kg) and was assessed by quantifying the serum enzyme activities, phenobarbitone induced sleeping time and histopathological analysis of liver tissues. The antioxidant parameters, malondialdehyde (MDA), reduced glutathione (GSH) and catalase of the liver tissue were also assessed. The herbal drugs were administered for 7 days by oral route at 50 and 100 mg/kg. PCM induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase) in serum and MDA level in liver. There was also a significant decrease in activity of GSH and catalase levels. The histopathological examination on toxic models revealed centrizonal necrosis and fatty changes. Pretreatment of mice with picroliv, curcumin and ellagic acid reversed these altered parameters towards normal values, which were compared with silymarin. The normalization of phenobarbitone induced sleeping time suggests the restoration of liver cytochrome P450 enzymes. This study supports the use of these active phytochemicals against toxic liver injury, which may act by preventing the lipid peroxidation and augmenting the antioxidant defense system or regeneration of hepatocytes. These active phytochemicals may be developed as drugs for the treatment of liver diseases. [source] Osteoblast Function Is Compromised at Sites of Focal Bone Erosion in Inflammatory Arthritis,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2009Nicole C Walsh PhD Abstract In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA. [source] Calpain-mediated degradation of G-substrate plays a critical role in retinal excitotoxicity for amacrine cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2009Toru Nakazawa Abstract The role of neuronal N-methyl-D-aspartate (NMDA) receptor-mediated intracellular signaling has been elucidated in both physiological and pathological conditions. However, the details of relative vulnerability for excitotoxicity remain unknown. Retinal excitotoxicity is involved in various diseases leading to irreversible blindness. Here, we used the visual system and explored the mechanistic details of the NMDA-elicited intracellular events, especially in the amacrine cells, which are the most vulnerable type of neuron in the retina. G-substrate, a specific substrate of cyclic guanosine 3,,5,-monophosphate (cGMP)-dependent protein kinase, is colocalized with amacrine cells and acts as an endogenous inhibitor of protein phosphatase. To elucidate how G-substrate was involved in NMDA-induced amacrine cell death, the immunohistochemical analysis with G-substrate antibody was performed following NMDA injury. In vivo, NMDA immediately decreased G-substrate immunoreactivity, and the suppression of calpain activation using ALLN or calpain III, an inhibitor of calpain, blocked this decrease. In vitro, degraded fragments of G-substrate were detected within 10 min after coincubation of G-substrate and calpain. Moreover, G-substrate knockout (G-substrate,/,) mice were more susceptible to NMDA injury than wild-type mice. ALLN did not have a neuroprotective effect in G-substrate,/, mice. These data strongly suggest that calpain-mediated loss of G-substrate represents an important mechanism contributing to NMDA-induced amacrine cell death. © 2008 Wiley-Liss, Inc. [source] Proton release by N2 -fixing plant roots: A possible contribution to phytoremediation of calcareous sodic soilsJOURNAL OF PLANT NUTRITION AND SOIL SCIENCE, Issue 1 2003Manzoor Qadir Prof. Dr. Abstract With a world-wide occurrence on about 560 million hectares, sodic soils are characterized by the occurrence of excess sodium (Na+) to levels that can adversely affect crop growth and yield. Amelioration of such soils needs a source of calcium (Ca2+) to replace excess Na+ from the cation exchange sites. In addition, adequate levels of Ca2+ in ameliorated soils play a vital role in improving the structural and functional integrity of plant cell walls and membranes. As a low-cost and environmentally feasible strategy, phytoremediation of sodic soils , a plant-based amelioration , has gained increasing interest among scientists and farmers in recent years. Enhanced CO2 partial pressure (PCO2) in the root zone is considered as the principal mechanism contributing to phytoremediation of sodic soils. Aqueous CO2 produces protons (H+) and bicarbonate (HCO3 - ). In a subsequent reaction, H+ reacts with native soil calcite (CaCO3) to provide Ca2+ for Na+ Ca2+ exchange at the cation exchange sites. Another source of H+ may occur in such soils if cropped with N2 -fixing plant species because plants capable of fixing N2 release H+ in the root zone. In a lysimeter experiment on a calcareous sodic soil (pHs = 7.4, electrical conductivity of soil saturated paste extract (ECe) = 3.1 dS m -1, sodium adsorption ratio (SAR) = 28.4, exchangeable sodium percentage (ESP) = 27.6, CaCO3 = 50 g kg -1), we investigated the phytoremediation ability of alfalfa (Medicago sativa L.). There were two cropped treatments: Alfalfa relying on N2 fixation and alfalfa receiving NH4NO3 as mineral N source, respectively. Other treatments were non-cropped, including a control (without an amendment or crop), and soil application of gypsum or sulfuric acid. After two months of cropping, all lysimeters were leached by maintaining a water content at 130% waterholding capacity of the soil after every 24±1 h. The treatment efficiency for Na+ removal in drainage water was in the order: sulfuric acid > gypsum = N2 -fixing alfalfa > NH4NO3-fed alfalfa > control. Both the alfalfa treatments produced statistically similar root and shoot biomass. We attribute better Na+ removal by the N2 -fixing alfalfa treatment to an additional source of H+ in the rhizosphere, which helped to dissolve additional CaCO3 and soil sodicity amelioration. Protonenabgabe durch N2 -fixierende Pflanzenwurzeln: ein möglicher Beitrag zur Phytomelioration von kalkreichen Natriumböden Bei einem weltweiten Vorkommen auf etwa 560 Millionen Hektar sind Natriumböden durch einen Überschuss an Natrium (Na+) gekennzeichnet, der das Wachstum und den Ertrag von Kulturpflanzenbeständen nachteilig beeinflussen kann. Die Melioration solcher Böden erfordert Calcium (Ca2+), um überschüssiges Na+ von Kationen-Austauscherplätzen zu verdrängen. Außerdem spielt Ca2+ eine wichtige Rolle bei der Verbesserung der strukturellen und funktionellen Integrität pflanzlicher Zellwände und Membranen. Als kostengünstige und umweltfreundliche Strategie hat die Phytomelioration von Natriumböden , eine auf Pflanzen beruhende Melioration , in den letzten Jahren zunehmendes Interesse bei Wissenschaftlern und Landwirten gefunden. Ein erhöhter CO2 -Partialdruck (PCO2) in der Rhizosphäre wird als hauptsächlicher Mechanismus angesehen, der zur Phytomelioration von Natriumböden beiträgt. In Wasser gelöst, erzeugt CO2 Protonen (H+) und Bikarbonate (HCO3 - ). Anschließend reagiert H+ mit nativem Calcit (CaCO3), wobei sich Ca2+ löst und Na+ von Austauscherplätzen verdrängt. Eine weitere H+ -Quelle könnte die H+ -Abgabe von Wurzeln N2 -fixierender Pflanzen sein, da diese in der Lage sind, H+ in die Rhizosphäre abzugeben. In einem Lysimeterversuch mit einem kalkreichen Natriumboden (pHs = 7, 4; ECe = 3, 1 dS m -1; SAR = 28, 4; ESP = 27, 6; CaCO3 = 50 g kg -1) wurde die Möglichkeit einer Phytomelioration mit N2 -fixierender Luzerne (Medicago sativa L.) im Vergleich zu einer mit mineralischem N ernährten Luzerne (NH4NO3) untersucht. In weiteren Varianten (Applikation von Gips bzw. Schwefelsäure) wurde die chemische Melioration einer nicht behandelten Kontrolle gegenübergestellt. Beide Ernährungsformen führten zu statistisch ähnlicher Wurzelund Sprossmasse der Luzerne. Nach zweimonatigem Pflanzenwachstum erfolgte alle 24±1 h eine Dränung der Lysimeter durch Zugabe einer Wassermenge von 130% der maximalen Wasserkapazität zum Boden. Hinsichtlich der Effizienz, Na+ über Auswaschung aus dem Boden zu entfernen, zeigte sich folgende Reihenfolge: Schwefelsäure > Gips = N2 -fixierende Luzerne > NH4NO3 -ernährte Luzerne > Kontrolle. Wir führen das bessere Meliorationsergebnis in der Variante der N2 -fixierenden Luzerne auf eine zusätzliche H+ -Quelle in der Rhizosphäre zurück, die zur Lösung von zusätzlichem CaCO3 beitrug. [source] Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2002KE Hall There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high-threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)-induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death. Using electrophysiologic and pharmacologic techniques, the present study provides evidence that significant impairment of G-protein-coupled modulation of calcium channel function may underlie the enhanced calcium entry in diabetes. N- and P-type voltage-activated, high-threshold calcium channels in DRGs are coupled to mu opiate receptors via inhibitory G(o)-type G proteins. The responsiveness of this receptor coupled model was tested in dorsal root ganglion (DRG) neurons from spontaneously-diabetic BB/W rats, and streptozotocin-induced (STZ) diabetic rats. Intracellular dialysis with GTPgammaS decreased calcium current amplitude in diabetic BB/W DRG neurons compared with those of age-matched, nondiabetic controls, suggesting that inhibitory G-protein activity was diminished in diabetes, resulting in larger calcium currents. Facilitation of calcium current density (I(DCa)) by large-amplitude depolarizing prepulses (proposed to transiently inactivate G proteins), was significantly less effective in neurons from BB/W and STZ-induced diabetic DRGs. Facilitation was enhanced by intracellular dialysis with GTPgammaS, decreased by pertussis toxin, and abolished by GDPbetaS within 5 min. Direct measurement of GTPase activity using opiate-mediated GTPgamma[(35)S] binding, confirmed that G-protein activity was significantly diminished in STZ-induced diabetic neurons compared with age-matched nondiabetic controls. Diabetes did not alter the level of expression of mu opiate receptors and G-protein alpha subunits. These studies indicate that impaired regulation of calcium channels by G proteins is an important mechanism contributing to enhanced calcium influx in diabetes. [source] Restless legs syndrome: Evidence for nocturnal hypothalamic-pituitary-adrenal system activation,MOVEMENT DISORDERS, Issue 8 2010Claudia Schilling MD Abstract Epidemiological studies consistently point to a relationship between restless legs syndrome (RLS) and cardiovascular disease. The mechanism underlying this association is unclear. Activation of the hypothalamic-pituitary-adrenal (HPA) system has been shown to contribute to the metabolic syndrome and an enhanced cardiovascular risk. We investigated cortisol levels as an indicator of HPA system activity in RLS during the nighttime, when RLS symptoms are at their maximum. We assessed nocturnal urinary cortisol excretion in 73 patients with RLS and 34 healthy controls, controlling for age and gender. Urine sampling was paralleled by polysomnographic recordings. We found significantly enhanced nocturnal cortisol excretion in RLS, demonstrating nocturnal HPA system overactivity in RLS. HPA system overactivity is a possible mechanism contributing to the enhanced load of cardiovascular disease in RLS patients. Nocturnal cortisol release showed weak correlations with some polysomnographic parameters of disturbed sleep, making a potential contribution of RLS-induced sleep disruption to HPA system activation conceivable. © 2010 Movement Disorder Society [source] Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosisARTHRITIS & RHEUMATISM, Issue 11 2009Luca Dalle Carbonare Objective While the role of osteoclasts in bone loss has been well investigated, the involvement of osteoblast-lineage cells has not been completely elucidated. Several genes contribute to normal osteoblastic differentiation from mesenchymal stem cells (MSCs), but an understanding of their role in the pathogenesis of osteoporosis is still lacking. The present study was undertaken to evaluate a possible alteration of osteogenic gene expression as a mechanism contributing to bone loss. Methods We studied the osteogenic differentiation process in MSCs obtained from the peripheral blood of 31 patients with osteoporosis and 20 normal donors. The cells were evaluated by colony-forming unit,fibroblastic assay and cultured in osteogenic medium to analyze the transcription factors runt-related transcription factor 2 (RUNX-2) and Sp7 and the bone-related genes COL1A1, SPARC, and SPP1 after 3, 8, and 15 days of differentiation. In addition, to determine possible differences between the 2 groups in terms of osteoclastic and osteoblastic activation, we quantified the osteoprotegerin (OPG) and RANKL levels in the supernatants of osteoblastic culture. Results Circulating MSCs were increased in osteoporosis patients compared with normal donors. In contrast, gene expression analysis revealed down-regulation of RUNX2, Sp7, COL1A1, SPARC, and SPP1 in patients with osteoporosis, associated with a lower OPG:RANKL ratio. Conclusion These results suggest that an alteration of osteoblastic differentiation may contribute to the pathogenesis of osteoporosis. The noninvasive approach used in the present study could be proposed as a useful tool for studying mesenchymal involvement in bone diseases. [source] Osteopontin Mediates Dense Culture-Induced Proliferation and Adhesion of Prostate Tumour Cells: Role of Protein Kinase C, p38 Mitogen-Activated Protein Kinase and CalciumBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2009Hong Zhou Our results demonstrate that increasing cell density exerted stress on PC-3M cells, which decreased cell proliferation in dense cultures, but tended to facilitate tumour metastasis since cell adhesion ability was elevated and the cells showed an increased growth rate after being moved to a favourable growth environment. We conclude that higher cell density-mediated pericellular hypoxia was an important factor inducing expression of the intrinsic hypoxia marker osteopontin, another mechanism contributing to cell adhesion enhancement in PC-3M cells. In addition, cell density enhanced adhesion ability due to the activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C. Intracellular calcium also played positive roles at least partially through activating p38 MAPK. [source] Dose-dependent pharmacokinetics of 1-(2-Deoxy- , - D - ribofuranosyl)-2,4-difluoro-5-iodobenzene: A potential mimic of 5-iodo-2,-deoxyuridineBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2003Panteha Khalili Abstract The dose-range pharmacokinetics of l-(2-deoxy- , - D -ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C -aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from ,32 ml/min/kg at a dose of 15 mg/kg, to ,19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml,1) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% (,0.19 kg min ml,1) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from ,37 ml/min/kg to ,17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance. For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens. Copyright © 2003 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||