Studies on Venom of the fish Scatophagus Argus from Cochin Estuary-A Biochemical Approach

Studies reveal the presence of enzymes and different proteins in the venom of S.argus. The present study detected the presence of phosphodiesterase in S. argus venom. S. argus venom has displayed the presence of micromolar concentration of acetylcholine. Phospholipase activity in S. argus venom shows values below the detection threshold indicating that the venom does not possess this enzyme. The proteolylic activity of S. argus venom on casein and gelatin were assayed due to the probable involvement of proteases in causing the instability of biological activities of the fish venom. Caseinase and gelatinase enzymes were detected in S. argus venom. Though exact relationships of these enzymes and proteins in envenomation are not traced, the involvement of enzymes in envenomation cannot be ruled out. Further studies are required to find the mechanism of action of these enzymes and proteins present in S. argus venom. The present study opens new dimensions for isolation of the lethal compound present in S. argus venom. The preliminary study carried out here shows the presence of a lethal factor between 6.5 KDa - 68 KDa. Studies conclude that fish venom possesses many bioactive substances, especially peptides, proteases and enzymes that bind with high affinity to physiological targets and can be trapped for therapeutic purposes in the near future. Even though this study reveals the conundrums of S. argus venom, it opens new vistas of research on the venom components and the application and design of the venom as a drug.

Neuronal degeneration in streptozotocin induced diabetic rats: Effect of Aegle marmelose and pyridoxine in pancreatic cell proliferation and neuronal Surviva

This thesis Entitled Neuronal degeneration in streptozotocin induced diabetic rats: effect of aegle marmelose and pyridoxine in pancreatic B cell proliferation and neuronal survival. Diabetes mellitus, a chronic metabolic disorder results in neurological dysfunctions and structural changes in the CNS. Antioxidant therapy is a challenging but necessary dimension in the management of diabetes and neurodegenerative changes associated with it. Our results showed regional variation and imbalance in the expression pattern of dopaminergic receptor subtypes in diabetes and its role in imbalanced insulin signaling and glucose regulation. Disrupted dopaminergic signaling and increased hyperglycemic stress in diabetes contributed to the neuronal loss. Neuronal loss in diabetic rats mediated through the expression of pattern of GLUT-3, CREB, IGF-1, Akt-1, NF,B, second messengers- cAMP, cGMP, IP3 and activation of apoptotic factors factors- TNF-a,caspase-8. Disrupted dopaminergic receptor expressions and its signaling in pancreas contributed defective insulin secretion in diabetes. Activation of apoptotic factors- TNF- a,caspase-8 and defective functioning of neuronal survival factors, disrupted second messenger signaling modulated neuronal viability in diabetes. Hyperglycemic stress activated the expression of TNF-a,caspase-8, BAX and differential expression of anti oxidant enzymes- SOD and GPx in liver lead to apoptosis. Treatment of diabetic rats with insulin, Aegle marmelose and pyridoxine significantly reversed the altered dopaminergic neurotransmission, GLUT3, GLUT2, IGF-1 and second messenger signaling. Antihyperglycemic and antioxidant activity of Aegle marmelose and pyridoxine enhanced pancreatic B cell proliferation, increased insulin synthesis and secretion in diabetic rats. Thus our results conclude the neuroprotective and regenerating ability of Aegle marmelose and pyridoxine which in turn has a novel therapeutic role in the management of diabetes.

Cholinergic receptor subtypes functional regulation in spinal cord injured monoplegic rats

The present study deals with the Cholinergic Receptor subtypes functional regulation in spinal cord injured monoplegic rats: Effect of 5-HT GABA and bone marrow cells.Spinal cord injury causes permanent and irrevocable motor deficits and neurodegeneration. Disruption of the spinal cord leads to diminished transmission of descending control from the brain to motor neurons and ascending sensory information. Behavioural studies showed deficits in motor control and coordination in SCI rats. Cholinergic system plays an important role in SCI, the evaluation of which provides valuable insight on the underlying mechanisms of motor deficit that occur during SCI. The cholinergic transmission was studied by assessing the muscarinic and nicotinic receptors; cholinergic enzymes- ChAT and AChE; second messenger enzyme PLC; transcription factor CREB and second messengers - IP3, cAMP and cGMP. We observed a decrease in the cholinergic transmission in the brain and spinal cord of SCI rats. The disrupted cholinergic system is the indicative of motor deficit and neuronal degeneration in the spinal cord and brain regions. SCI mediated oxidative stress and apoptosis leads to neuronal degeneration in SCI rats. The decreased expression of anti oxidant enzymes – SOD, GPx and neuronal cell survival factors - BDNF, GDNF, IGF-1, Akt and cyclin D2 along with increased expression of apoptotic factors – Bax, caspase-8, TNFa and NF-kB augmented the neuronal degeneration in SCI condition. BMC administration in combination with 5-HT and GABA in SCI rats showed a reversal in the impaired cholinergic neurotransmission and reduced the oxidative stress and apoptosis. It also enhanced the expression of cell survival factors in the spinal cord region. In SCI rats treated with 5-HT and GABA, the transplanted BMC expressed NeuN confirming that 5-HT and GABA induced the differentiation and proliferation of BMC to neurons in the spinal cord. Neurotrophic factors and anti-apoptotic elements in SCI rats treated with 5-HT and GABA along with BMC rendered neuroprotective effects accompanied by improvement in behavioural deficits. This resulted in a significant reversal of altered cholinergic neurotransmission in SCI. The restorative and neuro protective effects of BMC in combination with 5-HT and GABA are of immense therapeutic significance in the clinical management of SCI.

Adrenergic and muscarinic receptor subtypes functional regulation during diabetogenesis: Effect of curcumin and vitamin D3 pre-treatment

In the present study, the initial phase was directed to confirm the effects of curcumin and vitamin D3 in preventing or delaying diabetes onset by studying the blood glucose and insulin levels in the pre-treated and diabetic groups. Behavioural studies were conducted to evaluate the cognitive and motor function in experimental rats. The major focus of the study was to understand the cellular and neuronal mechanisms that ensure the prophylactic capability of curcumin and vitamin D3. To elucidate the mechanisms involved in conferring the antidiabetogenesis effect, we examined the DNA and protein profiles using radioactive incorporation studies for DNA synthesis, DNA methylation and protein synthesis. Furthermore the gene expression studies of Akt-1, Pax, Pdx-1, Neuro D1, insulin like growth factor-1 and NF-κB were done to monitor pancreatic beta cell proliferation and differentiation. The antioxidant and antiapoptotic actions of curcumin and vitamin D3 were examined by studying the expression of antioxidant enzymes - SOD and GPx, and apoptotic mediators like Bax, caspase 3, caspase 8 and TNF-α. In order to understand the signalling pathways involved in curcumin and vitamin D3 action, the second messengers, cAMP, cGMP and IP3 were studied along with the expression of vitamin D receptor in the pancreas. The neuronal regulation of pancreatic beta cell maintenance, proliferation and insulin release was studied by assessing the adrenergic and muscarinic receptor functional regulation in the pancreas, brain stem, hippocampus and hypothalamus. The receptor number and binding affinity of total muscarinic, muscarinic M1, muscarinic M3, total adrenergic, α adrenergic and β adrenergic receptor subtypes were studied in pancreas, brain stem and hippocampus of experimental rats. The mRNA expression of muscarinic and adrenergic receptor subtypes were determined using Real Time PCR. Immunohistochemistry studies using confocal microscope were carried out to confirm receptor density and gene expression results. Cell signalling alterations in the pancreas and brain regions associated with diabetogenesis and antidiabetogenesis were assessed by examining the gene expression profiles of vitamin D receptor, CREB, phospholipase C, insulin receptor and GLUT. This study will establish the anti-diabetogenesis activity of curcumin and vitamin D3 pre-treatment and will attempt to understand the cellular, molecular and neuronal control mechanism in the onset of diabetes.Administration of MLD-STZ to curcumin and vitamin D3 pre-treated rats induced only an incidental prediabetic condition. Curcumin and vitamin D3 pretreated groups injected with MLD-STZ exhibited improved circulating insulin levels and behavioural responses when compared to MLD-STZ induced diabetic group. Activation of beta cell compensatory response induces an increase in pancreatic insulin output and beta cell mass expansion in the pre-treated group. Cell signalling proteins that regulate pancreatic beta cell survival, insulin release, proliferation and differentiation showed a significant increase in curcumin and vitamin D3 pre-treated rats. Marked decline in α2 adrenergic receptor function in pancreas helps to relent sympathetic inhibition of insulin release. Neuronal stimulation of hyperglycemia induced beta cell compensatory response is mediated by escalated signalling through β adrenergic, muscarinic M1 and M3 receptors. Pre-treatment mediated functional regulation of adrenergic and cholinergic receptors, key cell signalling proteins and second messengers improves pancreatic glucose sensing, insulin gene expression, insulin secretion, cell survival and beta cell mass expansion in pancreas. Curcumin and vitamin D3 pre-treatment induced modulation of adrenergic and cholinergic signalling in brain stem, hippocampus and hypothalamus promotes insulin secretion, beta cell compensatory response, insulin sensitivity and energy balance to resist diabetogenesis. Pre-treatment improved second messenger levels and the gene expression of intracellular signalling molecules in brain stem, hippocampus and hypothalamus, to retain a functional neuronal response to hyperglycemia. Curcumin and vitamin D3 protect pancreas and brain regions from oxidative stress by their indigenous antioxidant properties and by their ability to stimulate cellular free radical defence system. The present study demonstrates the role of adrenergic and muscarinic receptor subtypes functional regulation in curcumin and vitamin D3 mediated anti-diabetogenesis. This will have immense clinical significance in developing effective strategies to delay or prevent the onset of diabetes.

Analyse von Protein-Ligand Interaktionen zur Charakterisierung zyklonukleotidbindender Proteine

Hyperpolarisations-aktivierte zyklonukleotid-gesteuerte (HCN) Kanäle übernehmen wichtige Funktionen in der Regulation der Herz- und Neuronalaktivität und können über einen dualen Mechanismus aus Membranhyperpolarisation und der Bindung von zyklischen Nukleotiden aktiviert werden. Ein großes Ziel der aktuellen Forschung ist die Entwicklung neuartiger Inhibitoren, die einer Fehlregulation der Kanäle entgegenwirken. In der vorliegenden Arbeit wurde die Regulation von HCN Kanälen durch zyklische Nukleotide im Detail analysiert, indem erstmals ein umfassender Screen mit 48 unterschiedlichen Zyklonukleotid-Analoga am C-terminalen Bereich (bestehend aus C-Linker und Zyklonukleotid-Bindedomäne) der drei Isoformen HCN1, HCN2 und HCN4 durchgeführt wurde. Mit Hilfe eines Fluoreszenzpolarisations-Assays wurde der Einfluss von Modifikationen in der Base, der Ribose und dem zyklischen Phosphat auf die Bindungsaffinitäten innerhalb der Zyklonukleotid-Bindedomäne untersucht. Zyklonukleotid-Analoga mit Modifikationen an der Position 7 und 8 der Base verschoben die apparenten Affinitäten im Vergleich zu den beiden natürlich vorkommenden Zyklonukleotiden cAMP und cGMP vom mikromolaren in den nanomolaren Bereich. Selektiv für die HCN4 Isoform erwiesen sich Zyklonukleotid-Analoga mit Modifikationen an der Position 6 der Base, während Modifikationen an der Position 8 der Base zu einer höheren Affinität für die HCN2 Isoform führten. Im Gegensatz zu HCN2 und HCN4 zeigte die HCN1 Isoform besonders hohe Affinitäten für Zyklonukleotid-Analoga mit Modifikationen an der Position 8 von cGMP. Eine Substitution der 2’-Hydroxylgruppe erlaubte keine Bindung an die HCN Kanäle. Mit 7-CH-cAMP konnte ein hochaffines Bindemolekül für HCN Kanäle identifiziert werden, denn der Austausch eines Stickstoffs gegen eine CH-Einheit an Position 7 der Base führte zu einer 100-fachen Steigerung der Affinität im Vergleich zu cAMP. In Übereinstimmung mit der hochaffinen Bindung konnte in kinetischen Analysen eine langsamere Dissoziationsrate für 7-CH-cAMP gemessen werden. Anhand thermodynamischer Messungen konnte ein entropisch favorisierter Bindungsmodus für 7-CH-cAMP im Vergleich zu cAMP identifiziert werden. Basierend auf einer Kristallstruktur des HCN4 CNBD:7-CH-cAMP Komplexes (2,5 Å) lässt sich erklären, dass 7-CH-cAMP durch seine höhere Lipohilie im Vergleich zu cAMP eine stärkere Präferenz für das hydrophobe Netzwerk zwischen Protein und Base besitzt. In detaillierten, vergleichenden Analysen mit den zyklonukleotidbindenden Proteinen PKA Typ I und II, hPKGIβ und Epac 1 und 2 konnte gezeigt werden, dass 7-CH-cAMP die höchsten Affinitäten für die drei Isoformen der HCN Kanäle aufwies. Somit könnte sich 7-CH-cAMP als vielversprechender Kandidat für die selektive Regulation von HCN Kanälen in vitro und in lebenden Zellen eignen und möglicherweise einen wichtigen Beitrag als krankheitsrelevanter Effektor leisten.

Analysis of second messengers in peripheral and central circadian pacemakers

In früheren Experimenten konnte gezeigt werden, dass die sekundären Botenstoffe cAMP, cGMP und IP3 in der olfaktorischen Signaltransduktionskaskade bei Manduca sexta involviert sind. Während cGMP Perfusionen in die Antenne die Pheromonwahrnehmung tageszeitabhängig adaptierten, führten cAMP Perfusionen zu einer tageszeitabhängigen Sensitisierung, ähnlicher der von Octopamin (OA). Daher wurde hypothetisiert, dass eine tageszeitabhängige Oszillation antennaler OA Level sowie der intrazelluläre Kalziumkonzentration in einer Schwankung von sekundären Botenstoffen resultieren könnte. Diese Hypothese wurde mittels biochemischen Nachweißverfahren in der Antenne von M. sexta und Rhyparobia maderae überprüft. Tatsächlich konnten in der Antenne des Tabakschwärmers tageszeitabhängige Unterschiede in der OA-, cAMP- und IP3-, aber nicht in der cGMP Konzentration, nachgewiesen werden. Während die cAMP- und OA Oszillationen einander sehr ähnelten und die Maxima in der Paarungsphase aufzeigten, korrelierte der IP3 Verlauf sehr stark mit dem Flug- bzw. Fressverhalten. Diese Korrelationen konnten auch in der Madeira Schabe beobachtet werden, in der darüber hinaus gezeigt werden konnte, dass antennale cAMP- und IP3 Level von dem circadianen Uhrwerk gesteuert werden. Zudem wurde herausgefunden, dass OA die cAMP- und teilweise auch die IP3- Spiegel reguliert. Demgegenüber beeinflusste Kalzium die Konzentration aller untersuchten sekundären Botenstoffe. Daher wird angenommen, dass die intrazelluläre Kalziumkonzentration aber auch der antennale OA Level kritische Faktoren bei der Regelung der olfaktorischen Sensitivität sind. Da Oszillationen von sekundären Botenstoffen in mutmaßlichen, peripheren Schrittmacher nachgewiesen wurden, wurde untersucht, ob sie auch im circadianen Schrittmacher der Madeira Schabe oszillieren und ob das Neuropeptid pigment-dispersing factor (PDF), ein entscheidender Kopplungsfaktor des Uhrwerks in Insekten, diese Rhythmen generieren könnte. Es konnte gezeigt werden, dass PDF die cAMP Synthese steigert. Darüber hinaus wurden bimodale cAMP Oszillationen unter licht-dunkel Bedingungen beobachtet, welche unter konstanten Umweltbedingungen verblieben. Daher wird angenommen, dass PDF Freisetzung zelluläres cAMP erhöht über das das circadiane Uhrwerk synchronisiert wird.

Manejo de cardiomiopatia chagasica : revisión sistemática (1996-2010)

La cardiomiopatía chagásica es la más importante y severa manifestación de la enfermedad crónica, los pacientes pueden cursar con falla cardiaca, arritmias, bloqueos cardiacos, tromboembolismo y muerte súbita. El diagnóstico es tardío, debido a que se confunden con cardiopatías de otra etiología y el manejo se realiza con base en guías y protocolos dirigidos hacia el tratamiento de falla cardiaca de origen no chagásico. Métodos: Se realizó una revisión sistemática y tuvo como objetivo responder a las siguientes Preguntas clínicas: PREGUNTA 1. ¿El manejo actual para la cardiomiopatía chagásica (betabloqueadores, IECA, ARA II, Diuréticos, Inhibidores de la fosfodiesterasa, Estatinas, antiagragantes plaquetarios) que es extrapolado del manejo de falla cardiaca de origen no chagásico tiene impacto en la calidad de vida, sobrevida, seguridad, estancia hospitalaria y disminución del número de hospitalizaciones, mejoría de síntomas, de los pacientes adultos con cardiopatía chagásica?. PREGUNTA 2. ¿En pacientes con cardiomiopatía chagásica el uso de fármacos tripanocidas mejora la sobrevida, calidad de vida, estancia hospitalaria, disminución del número de hospitalizaciones, y resolución de síntomas? PREGUNTA 3. ¿En pacientes con cardiomiopatía chagásica el uso de cardiodesfibriladores mejora la sobrevida, calidad de vida, estancia hospitalaria, disminución del número de hospitalizaciones, y resolución de síntomas? PREGUNTA 4. ¿En pacientes con cardiomiopatía chagásica el uso de marcapasos mejora la sobrevida, calidad de vida, estancia hospitalaria, disminución del número de hospitalizaciones, y resolución de síntomas? PREGUNTA 5. ¿En pacientes con cardiomiopatía chagásica el uso de trasplante de corazón mejora la sobrevida, calidad de vida, estancia hospitalaria, disminución del número de hospitalizaciones, y resolución de síntomas? Se realizaron búsquedas en: MEDLINE, Colaboración Cochrane, Trip database, y otras importantes bases de datos desde 1996 hasta 2010, limitando la búsqueda. Los estudios se seleccionaron de acuerdo a criterios de pertinencia PICO y se evaluó la calidad, usando la metodología recomendada en Scottish Intercollegiate Guidelines Network. Resultados: Se encontraron 21 estudios, que incluyen revisiones sistemáticas, ensayos clínicos controlados y aleatorizados, ensayos clínicos, cohortes y, casos y controles. Estos estudios cumplieron con los criterios de inclusión. Discusión: En esta revisión sistemática se presenta un consolidado de la evidencia disponible acerca de la eficacia de las siguientes intervenciones: Betabloqueadores, IECAS, PDE, Digoxina, nitroderivados, cardiodesfibriladores, marcapasos y trasplante de corazón, en pacientes con cardiopatía chagásica; los estudios encontrados en su mayoría son de baja evidencia.

Toxina botulínica en manejo de síntomas del tracto urinario bajo en pacientes con hiperplasia prostática benigna - revisión sistemática de la literatura

Revisión sistemática de la literatura tomando ensayos clínicos aleatorizados sobre el uso de la inyección intraprostática de la toxina botulínica en los pacientes con hiperplasia prostática benigna evaluando una escala validada de síntomas del tracto urinario bajo como desenlace primario

Characterization of an escherichia coli elaC deletion mutant

The elaC gene of Escherichia coli encodes a binuclear zinc phosphodiesterase (ZiPD). ZiPD homologs from various species act as 3' tRNA processing endoribonucleases, and although the homologous gene in Bacillus subtilis is essential for viability [EMBO J. 22 (2003) 4534], the physiological function of E. coli ZiPD has remained enigmatic. In order to investigate the function of E. coli ZiPD we generated and characterized an E. coli elaC deletion mutant. Surprisingly, the E. coli elaC deletion mutant was viable and had wild-type like growth properties. Micro array-based transcriptional analysis indicated expression of the E. coli elaC gene at basal levels during aerobic growth. The elaC gene deletion had no effect on the expression of genes coding for RNases or amino-acyl tRNA synthetases or any other gene among a total of > 1300 genes probed. 2D-PAGE analysis showed that the elaC mutation, likewise, had no effect on the proteome. These results strengthen doubts about the involvement of E. coli ZiPD in tRNA maturation and suggest functional diversity within the ZiPD/ElaCl protein family. In addition to these unexpected features of the E. coli elaC deletion mutant, a sequence comparison of ZiPD (ElaCl) proteins revealed specific regions for either enterobacterial or mammalian ZiPD (ElaCl) proteins. (C) 2004 Elsevier Inc. All rights reserved.

Caseinoglycomacropeptide inhibits adhesion of pathogenic Escherichia coli strains to human cells in culture

Caseinoglycomacropeptide (CGMP) derived from kappa-casein was investigated for its ability to inhibit the adhesion of 3 strains of verotoxigenic Escherichia coli (VTEC) and 3 strains of enteropathogenic Escherichia coli (EPEC) to human HT29 tissue cell cultures. Effects on adhesion of Desulfovibrio desulfuricans, Lactobacillus pentosus, Lactobacillus casei, Lactobacillus acidophilus, and Lactobacillus gasseri were also investigated. Generally, CGMP exerted effective anti-adhesive properties at a dose of 2.5 mg/mL, albeit with a high degree of strain specificity. The CGMP reduced adhesion of VTEC strains to < 50% of the control and reduced adhesion of EPEC strains to between 80 and 10% of the control. The CGMP also reduced the adhesion of L. pentosus and L. casei to 44 and 42%, respectively. A slight but significant reduction of L. acidophilus, to 81%, was observed, but no significant effects were detected with either Dsv. desulfuricans or L. gasseri. Further investigation of the dose response relationships with the E. coli strains gave IC50 values ranging between 0.12 and 1.06 mg/mL.

Surface activity of surfactin recovered and purified from fermentation broth using a two-step ultrafiltration (UF) process

B. subtilis under certain types of media and fermentation conditions can produce surfactin, a biosurfactant which belongs to the lipopeptide class. Surfactin has exceptional surfactant activity, and exhibits some interesting biological characteristics such as antibacterial activity, antitumoral activity against ascites carcinoma cells, and a hypocholesterolemic activity that inhibits cAMP phosphodiesterase, as well as having anti-HIV properties. A cost effective recovery and purification of surfactin from fermentation broth using a two-step ultrafiltration (UF) process has been developed in order to reduce the cost of surfactin production. In this study, competitive adsorption of surfactin and proteins at the air-water interface was studied using surface pressure measurements. Small volumes of bovine serum albumin (BSA) and β-casein solutions were added to the air-water interface on a Langmuir trough and allowed to stabilise before the addition of surfactin to the subphase. Contrasting interfacial behaviour of proteins was observed with β-casein showing faster initial adsorption compared to BSA. On introduction of surfactin both proteins were displaced but a longer time were taken to displace β-casein. Overall the results showed surfactin were highly surface-active by forming a β-sheet structure at the air-water interface after reaching its critical micelle concentration (CMC) and were effective in removing both protein films, which can be explained following the orogenic mechanism. Results showed that the two-step UF process was effective to achieve high purity and fully functional surfactin.

Variation in root-associated phosphatase activities in wheat contributes to the utilization of organic P substrates in vitro, but does not explain differences in the P-nutrition of plants when grown in soils

To understand whether genotypic variation in root-associated phosphatase activities in wheat impacts on its ability to acquire phosphorus (P), various phosphatase activities of roots were measured in relation to the utilization of organic P substrates in agar, and the P-nutrition of plants was investigated in a range of soils. Root-associated phosphatase activities of plants grown in hydroponics were measured against different organic P substrates. Representative genotypes were then grown in both agar culture and in soils with differing organic P contents and plant biomass and P uptake were determined. Differences in the activities of both root-associated and exuded phosphodiesterase and phosphomonoesterase were observed, and were related to the P content of plants supplied with either ribonucleic acid or glucose 6-phosphate, respectively, as the sole form of P. When the cereal lines were grown in different soils, however, there was little relationship between any root-associated phosphatase activity and plant P uptake. This indicates that despite differences in phosphatase activities of cereal roots, such variability appears to play no significant role in the P-nutrition of the plant grown in soil, and that any benefit derived from the hydrolysis of soil organic P is common to all genotypes.

Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation.

Aims: While much data exist for the effects of flavonoid-rich foods on spatial memory in rodents, there are no such data for foods/beverages predominantly containing hydroxycinnamates and phenolic acids. To address this, we investigated the effects of moderate Champagne wine intake, which is rich in these components, on spatial memory and related mechanisms relative to the alcohol- and energy-matched controls. Results: In contrast to the isocaloric and alcohol-matched controls, supplementation with Champagne wine (1.78 ml/kg BW, alcohol 12.5% vol.) for 6 weeks led to an improvement in spatial working memory in aged rodents. Targeted protein arrays indicated that these behavioral effects were paralleled by the differential expression of a number of hippocampal and cortical proteins (relative to the isocaloric control group), including those involved in signal transduction, neuroplasticity, apoptosis, and cell cycle regulation. Western immunoblotting confirmed the differential modulation of brain-derived neurotrophic factor, cAMP response-element-binding protein (CREB), p38, dystrophin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, mammalian target of rapamycin (mTOR), and Bcl-xL in response to Champagne supplementation compared to the control drink, and the modulation of mTOR, Bcl-xL, and CREB in response to alcohol supplementation. Innovation: Our data suggest that smaller phenolics such as gallic acid, protocatechuic acid, tyrosol, caftaric acid, and caffeic acid, in addition to flavonoids, are capable of exerting improvements in spatial memory via the modulation in hippocampal signaling and protein expression. Conclusion: Changes in spatial working memory induced by the Champagne supplementation are linked to the effects of absorbed phenolics on cytoskeletal proteins, neurotrophin expression, and the effects of alcohol on the regulation of apoptotic events in the hippocampus and cortex. Antioxid. Redox Signal. 00, 000-000.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, nitric oxide and cGMP levels, as well as regulate MAP kinase signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.