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This simulation study was designed to predict the torsadogenicity of sevoflurane and propofol in healthy control, as well as type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), using the O'Hara-Rudy dynamic model. LQT1 and LQT2 models were simulated by decreasing the conductances of slowly and rapidly activating delayed rectifier K.sup.+ currents (I.sub.Ks and I.sub.Kr, respectively) by 50%, respectively. Action potential duration at 50% repolarization level (APD.sub.50) and diastolic intracellular Ca.sup.2+ concentration were measured in epicardial cell during administration of sevoflurane (1 ~ 5%) and propofol (1 ~ 10 [mu]M). Torsadogenicity can be predicted from the relationship between APD.sub.50 and diastolic intracellular Ca.sup.2+ concentration, which is classified by the decision boundary. Whereas the relationships in control and LQT1 models were distributed on nontorsadogenic side in the presence of sevoflurane at all tested concentrations, those in LQT2 models were shifted to torsadogenic side by concentrations of [greater than or equal to] 2%. In all three models, propofol shifted the relationships in a direction away from the decision boundary on nontorsadogenic side. Our findings suggest that sevoflurane, but not propofol, exerts torsadogenicity in patients with reduced I.sub.Kr, such as LQT2 patients. Caution should be paid to the occurrence of arrhythmia during sevoflurane anesthesia in patients with reduced I.sub.Kr., Author(s): Akiko Kojima [sup.1], Yutaka Fukushima [sup.1], Hiroshi Matsuura [sup.2] Author Affiliations: (1) https://ror.org/00d8gp927, grid.410827.8, 0000 0000 9747 6806, Department of Anesthesiology, Shiga University of Medical Science, , 520-2192, Otsu, [...]

Propofol is a broadly used intravenous anesthetic agent that can cause cardiovascular effects, including bradycardia and asystole. A possible mechanism for these effects is slowing cardiac pacemaker activity due to inhibition of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. However, it remains unclear how propofol affects the allosteric nature of the voltage- and cAMP-dependent gating mechanism in HCN channels. To address this aim, we investigated the effect of propofol on HCN channels (HCN4 and HCN2) in heterologous expression systems using a whole-cell patch clamp technique. The extracellular application of propofol substantially suppressed the maximum current at clinical concentrations. This was accompanied by a hyperpolarizing shift in the voltage dependence of channel opening. These effects were significantly attenuated by intracellular loading of cAMP, even after considering the current modification by cAMP in opposite directions. The differential degree of propofol effects in the presence and absence of cAMP was rationalized by an allosteric gating model for HCN channels, where we assumed that propofol affects allosteric couplings between the pore, voltage-sensor, and cyclic nucleotide-binding domain (CNBD). The model predicted that propofol enhanced autoinhibition of pore opening by unliganded CNBD, which was relieved by the activation of CNBD by cAMP. Taken together, these findings reveal that propofol acts as an allosteric modulator of cAMP-dependent gating in HCN channels, which may help us to better understand the clinical action of this anesthetic drug. [ABSTRACT FROM AUTHOR]

The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (IKr and IKs) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the IKr and IKs current. The expression of IKr or IKs was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of IKr and IKs, respectively. The nonselective β-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the IKs inhibitor HMR-1556 than by the IKr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and β-adrenoceptor–stimulated conditions. IKr was not significantly influenced by β-adrenoceptor stimulation, but IKs was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the IKr and IKs channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the β-adrenoceptor is activated, IKs modulation may become more important. [ABSTRACT FROM AUTHOR]

Background and Purpose: The slowly activating delayed rectifier K+ channel (IKs ), composed of pore-forming KCNQ1 α-subunits and ancillary KCNE1 β-subunits, regulates ventricular repolarization in human heart. Propofol, at clinically used concentrations, modestly inhibits the intact (wild-type) IKs channels and is therefore unlikely to appreciably prolong QT interval in ECG during anaesthesia. However, little information is available concerning the inhibitory effect of propofol on IKs channel associated with its gene variants implicated in QT prolongation. The KCNE1 single nucleotide polymorphism leading to D85N is associated with drug-induced QT prolongation and therefore regarded as a clinically important genetic variant. This study examined whether KCNE1-D85N affects the sensitivity of IKs to inhibition by propofol.Experimental Approach: Whole-cell patch-clamp and immunostaining experiments were conducted in HEK293 cells and/or mouse cardiomyocyte-derived HL-1 cells, transfected with wild-type KCNQ1, wild-type or variant KCNE1 cDNAs.Key Results: Propofol inhibited KCNQ1/KCNE1-D85N current more potently than KCNQ1/KCNE1 current in HEK293 cells and HL-1 cells. Immunostaining experiments in HEK293 cells revealed that pretreatment with propofol (10 μM) did not appreciably affect cell membrane expression of KCNQ1 and KCNE1 proteins in KCNQ1/KCNE1 and KCNQ1/KCNE1-D85N channels.Conclusion and Implications: The KCNE1 polymorphism D85N significantly elevates the sensitivity of IKs to inhibition by propofol. This study detects a functionally important role of KCNE1-D85N polymorphism in conferring genetic susceptibility to propofol-induced QT prolongation and further suggests the possibility that the inhibitory action of anaesthetics on ionic currents becomes exaggerated in patients carrying variants in genes encoding ion channels. [ABSTRACT FROM AUTHOR]

Aim: Although numerous studies have demonstrated promising results for the cognitive rehabilitation in subjects with schizophrenia, the efficacy of cognitive rehabilitation for everyday and social functioning is not yet sufficient. Although consideration of the contents and methods are vital, the timing for implementing cognitive rehabilitation also seems to be crucial. The aim of this study was to examine the feasibility and acceptability of cognitive rehabilitation during the acute phase of schizophrenia. Methods: Patients were recruited from consecutive acute admissions to the inpatient unit during a 15‐month period and were evaluated to determine whether they could be enrolled in an 8‐week cognitive rehabilitation program within 14 days of their hospital admission. Cognitive rehabilitation programs with a workbook style were adopted, taking the patients' conditions and burdens into consideration. Results: Eighty‐three patients were newly admitted during the entry period, and 49 patients (59.0%) were eligible for inclusion. Of them, 22 patients (44.9%) agreed to participate and started the program. Sixteen patients completed the program and underwent a second assessment. Thus, 32.7% (16/49) of all the eligible patients actually completed the study. The participants were quite satisfied with the program. Conclusions: This preliminary study yielded encouraging data demonstrating the feasibility and acceptability of cognitive remediation for patients with schizophrenia during the acute phase. The provision of cognitive rehabilitation during the acute phase of the first episode can reasonably be expected to lead to better functional outcomes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv 1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv 1.5 (hKv 1.5) channels.Experimental Approach: Thirteen single-point mutations were constructed within pore domain of hKv 1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hKv 1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv 1.5 channel.Key Results: Both desflurane and sevoflurane increased hKv 1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hKv 1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv 1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv 1.5 channels was significantly attenuated in T480A, V505A, and I508A mutant channels, compared with wild-type channel. Computational docking simulation predicted that desflurane or sevoflurane resides within the inner cavity of channel pore and has contact with Thr479, Thr480, Val505, and Ile508.Conclusion and Implications: Desflurane and sevoflurane exert an open-channel blocking action on hKv 1.5 channels by functionally interacting with specific amino acids located within the channel pore. This study thus identifies a novel molecular basis mediating inhibitory modulation of hKv 1.5 channels by desflurane and sevoflurane. [ABSTRACT FROM AUTHOR]

Hydroxytyrosol (HT) and oleuropein (OLE) are natural polyphenols found in extra virgin olive oil. Accumulating evidence indicates that ingestion of olive oil contributes to reduce the risk of cardiovascular diseases and stroke. It has been reported that HT and OLE inhibit human platelet aggregation. We have shown that collagen induces the phosphorylation of heat shock protein 27 (HSP27) in human platelets, resulting in the release of HSP27, an extracellular pro-inflammatory agent. In this study, we investigated the effects of HT and OLE on the collagen-stimulated human platelet activation. The PDGF-AB secretion and the soluble CD40 ligand (sCD40L) release by collagen were reduced by HT or OLE. HT and OLE significantly suppressed the phosphorylation of HSP27 and the release of phosphorylated-HSP27. These findings suggest that olive polyphenol reduces the collagen-stimulated phosphorylation of HSP27 in human platelets and the release. Our results may provide a novel anti- inflammatory effect of olive polyphenol. Olive polyphenol reduces the collagen-stimulated phosphorylation of HSP27 in human platelets and the release. [ABSTRACT FROM AUTHOR]

Highlights • Rho-kinase inhibitors enhanced TGF-β-stimulated release of IL-6 from astrocytes. • Inhibition of Rac activity amplified TGF-β-stimulated-IL-6 release. • TGF-β-stimulated IL-6 release was upregulated in RhoA- or Rac-knockdown astrocytes. • Inhibition of Rho-kinase or Rac failed to affect Smad2 phosphorylation by TGF-β. • Rho-kinase and Rac limit TGF-β-induced L-6 release independently of Smad pathway. Abstract Transforming growth factor (TGF)-β stimulates release of interleukin (IL)-6, which is recognized to function as both a pro- and anti- inflammatory cytokine in the central nervous system, from astrocytes. It is generally recognized that effects of TGF-β are mediated through Smad-independent as well as Smad-dependent pathways. Small GTPases regulate a variety of cell functions. In the present study, we investigated whether or not Rho-kinase, a downstream effector of Rho, and Rac are implicated in TGF-β-stimulated IL-6 release from astrocytes (C8D1A cells). Y-27632 or fasudil (Rho-kinase inhibitors) or NSC23766 (an inhibitor of Rac-guanine nucleotide exchange factor interaction) significantly enhanced TGF-β-stimulated IL-6 release from these cells. TGF-β-stimulated IL-6 release was markedly upregulated in RhoA- or Rac-knockdown C8D1A cells. We found that SIS3 (a specific inhibitor of TGF-β-dependent Smad3 phosphorylation) or LY364947 (a TGF-β type I receptor kinase inhibitor) significantly reduced the IL-6 release. However, TGF-β-induced-Smad2 and Smad3 phosphorylation was not affected by Y-27632, fasudil or NSC23766. In conclusion, our results strongly suggest that Rho-kinase and Rac limit TGF-β-induced IL-6 release from astrocytes, and the suppressive effects are exerted independently of the Smad pathway or at a point downstream of Smad2/3 complex. [ABSTRACT FROM AUTHOR]

Aim: The importance of early intervention in psychiatry is widely recognized among psychiatrists. However, it is unknown whether precise knowledge of at‐risk mental state has been disseminated. With this survey, we aimed to reveal how Japanese psychiatrists diagnose patients with at‐risk mental state and prescribe treatment strategies for them. Methods: Using fictional case vignettes, we conducted a questionnaire survey of psychiatrists (n = 1399) who worked in Tokyo. We mailed study documents to all eligible participants in November 2015 with a requested return date in December. Results: Two hundred and sixty (19.3%) psychiatrists responded to the survey. Their correct diagnosis rates for the patients in the at‐risk mental state vignettes were low (14.6% for the vignette describing at‐risk mental state with attenuated positive symptom syndrome; 13.1% for the vignette describing at‐risk mental state with brief intermittent psychotic syndrome). Many psychiatrists selected pharmacotherapy and antipsychotics to treat patients in the at‐risk mental state vignettes. The psychiatrists who correctly diagnosed patients in the at‐risk mental state vignettes had significantly fewer years of clinical psychiatric experience than did those who diagnosed them as having a non‐at‐risk mental state (12.5 years vs 22.7 years for the vignette describing at‐risk mental state with attenuated positive symptom syndrome, P < 0.01; 14.3 years vs 22.2 years for the vignette describing at‐risk mental state with brief intermittent psychotic syndrome, P < 0.01). Conclusion: This study suggests that precise knowledge of at‐risk mental state has not been disseminated among Japanese psychiatrists. [ABSTRACT FROM AUTHOR]

Background and Purpose: In human heart, the Kv 1.5 channel contributes to repolarization of atrial action potentials. This study examined the electrophysiological and molecular mechanisms underlying arachidonic acid (AA)-induced inhibition of the human Kv 1.5 (hKv 1.5) channel.Experimental Approach: Site-directed mutagenesis was conducted to mutate amino acids that reside within the pore domain of the hKv 1.5 channel. Whole-cell patch-clamp method was used to record membrane currents through wild type and mutant hKv 1.5 channels heterologously expressed in CHO cells. Computer docking simulation was conducted to predict the putative binding site(s) of AA in an open-state model of the Kv 1.5 channel.Key Results: The hKv 1.5 current was minimally affected at the onset of depolarization but was progressively reduced during depolarization by the presence of AA, suggesting that AA acts as an open-channel blocker. AA itself affected the channel at extracellular sites independently of its metabolites and signalling pathways. The blocking effect of AA was attenuated at pH 8.0 but not at pH 6.4. The blocking action of AA developed rather rapidly by co-expression of Kv β1.3. The AA-induced block was significantly attenuated in H463C, T480A, R487V, I502A, I508A, V512A and V516A, but not in T462C, A501V and L510A mutants of the hKv 1.5 channel. Docking simulation predicted that H463, T480, R487, I508, V512 and V516 are potentially accessible for interaction with AA.Conclusions and Implications: AA itself interacts with multiple amino acids located in the pore domain of the hKv 1.5 channel. These findings may provide useful information for future development of selective blockers of hKv 1.5 channels. [ABSTRACT FROM AUTHOR]

We investigated the relationship between HSP27 phosphorylation and collagen-stimulated activation of platelets in patients with diabetes mellitus (DM). Platelet-rich plasma was prepared from blood of type 2 DM patients. The platelet aggregation was analyzed in size of aggregates by an aggregometer using a laser scattering method. The protein phosphorylation was analyzed by Western blotting. Phosphorylated-HSP27 and PDGF-AB released from platelets were measured by ELISA. The phosphorylated-HSP27 levels at Ser-78 and Ser-82 induced by collagen were directly proportional to the platelet aggregation. Total HSP27 levels in platelets were decreased concomitantly with the phosphorylation. The released HSP27 levels were significantly correlated with the phosphorylated levels of HSP27 in the platelets stimulated by 0.3 μg/ml collagen. The low dose collagen-stimulated release of HSP27 was detected but relatively small in healthy donors. The released levels of PDGF-AB were in parallel with the levels of released HSP27. Area under the curve (AUC) of small aggregation (9-25 μm) induced by 0.3 μg/ml collagen was inversely proportional to the levels of released HSP27. AUC of large aggregation (50-70 μm) was directly proportional to the levels of released HSP27. Exogenous recombinant phosphorylated- HSP27 hardly affected the aggregation or the released levels of PDGF-AB induced by collagen. These results strongly suggest that HSP27 is released from human platelets accompanied with its phosphorylation induced by collagen, which is correlated with the acceleration of platelet aggregation in type 2 DM patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Desflurane inhalation is associated with sympathetic activation and concomitant increase in heart rate in humans and experimental animals. There is, however, little information concerning the direct effects of desflurane on electrical activity of sinoatrial node pacemaker cells that determines the intrinsic heart rate. METHODS: Whole-cell patch-clamp experiments were conducted on guinea pig sinoatrial node pacemaker cells to record spontaneous action potentials and ionic currents contributing to sinoatrial node automaticity, namely, hyperpolarization-activated cation current (If), T-type and L-type Ca currents (ICa,T and ICa,L, respectively), Na/Ca exchange current (INCX), and rapidly and slowly activating delayed rectifier K currents (IKr and IKs, respectively). Electrocardiograms were recorded from ex vivo Langendorff-perfused hearts and in vivo hearts. RESULTS: Desflurane at 6 and 12% decreased spontaneous firing rate of sinoatrial node action potentials by 15.9% (n = 11) and 27.6% (n = 10), respectively, which was associated with 20.4% and 42.5% reductions in diastolic depolarization rate, respectively. Desflurane inhibited If, ICa,T, ICa,L, INCX, and IKs but had little effect on IKr. The negative chronotropic action of desflurane was reasonably well reproduced in sinoatrial node computer model. Desflurane reduced the heart rate in Langendorff-perfused hearts. High concentration (12%) of desflurane inhalation was associated with transient tachycardia, which was totally abolished by pretreatment with the [beta]-adrenergic blocker propranolol. CONCLUSIONS: Desflurane has a direct negative chronotropic action on sinoatrial node pacemaking activity, which is mediated by its inhibitory action on multiple ionic currents. This direct inhibitory action of desflurane on sinoatrial node automaticity seems to be counteracted by sympathetic activation associated with desflurane inhalation in vivo. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oxidative stress is implicated in pathogenesis of cardiac reperfusion injury, characterized by cellular Ca2+ overload and hypercontracture. Volatile anesthetics protect the heart against reperfusion injury primarily by attenuating Ca2+ overload. This study investigated electrophysiological mechanisms underlying cardioprotective effects of sevoflurane against oxidative stress-induced cellular injury. METHODS: The cytosolic Ca2+ levels and cell morphology were assessed in mouse ventricular myocytes, using confocal fluo-3 fluorescence imaging, whereas membrane potentials and L-type Ca2+ current (ICa,L) were recorded using wholecell patch-clamp techniques. Phosphorylation of Ca2+/calmodulin-dependent protein kinase II was examined by Western blotting. RESULTS: Exposure to H2O2 (100 [mu]m) for 15 min evoked cytosolic Ca2+ elevation and hypercontracture in 56.8% of ventricular myocytes in 11 experiments, which was partly but significantly reduced by nifedipine, tetracaine, or SEA0400. Sevoflurane prevented H2O2-induced cellular Ca2+ overload in a concentration-dependent way (IC50 = 1.35%). Isoflurane (2%) and desflurane (10%) also protected ventricular myocytes by a degree similar to sevoflurane (3%). Sevoflurane suppressed H2O2-induced electrophysiological disturbances, including early afterdepolarizations, voltage fluctuations in resting potential, and abnormal automaticities. H2O2 significantly enhanced ICa,L by activating Ca2+/calmodulin-dependent protein kinase II, and subsequent addition of sevoflurane, isoflurane, or desflurane similarly reduced ICa,L to below baseline levels. Phosphorylated Ca2+/calmodulin-dependent protein kinase II increased after 10-min incubation with H2O2, which was significantly prevented by concomitant administration of sevoflurane. CONCLUSIONS: Sevoflurane protected ventricular myocytes against H2O2-induced Ca2+ overload and hypercontracture, presumably by affecting multiple Ca2+ transport pathways, including ICa,L, Na+/Ca2+ exchanger and ryanodine receptor. These actions appear to mediate cardioprotection against reperfusion injury associated with oxidative stress. [ABSTRACT FROM AUTHOR]

Objectives: We assessed the association of family history of type 2 diabetes (T2D) with parameters used for health checkups in young Japanese women. Methods: The subjects were 497 nondiabetic women aged 19-39 years. Among them, the mothers of 34 subjects and fathers of 50 had T2D (MD group and PD group, respectively). The subjects were assessed for levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). Results: TC and LDL-C level showed a tendency to increase in the MD group compared with subjects without family history of T2D. LDL-C/HDL-C ratio ≥2.14 was found in 32.4 and 18.0 % of subjects in the MD and PD groups, respectively. When adjusted for differences in age, body mass index, smoking status, and drinking habits, the MD group was found to have a higher risk of abnormal TC and LDL-C levels than the PD group. LDL-C/HDL-C ratio was independently associated with maternal family history but not with paternal family history (odds ratio 3.44 [99 % confidence interval 1.11-10.6] and 1.21 [0.38-3.89], respectively). There was no association between TG/HDL-C ratio and family history type of T2D. Conclusions: Maternal family history of T2D had a more pronounced effect on the lipid parameters generally evaluated during health checkups than did paternal family history of T2D. Therefore, we recommend systematic screening for early detection and appropriate healthcare guidance for Japanese women, particularly those with maternal family history of T2D. [ABSTRACT FROM AUTHOR]

Objectives: Japanese public health policies on the prevention of atherosclerotic diseases have focused on controlling obesity. The aim of this study was to assess the prevalence of abnormality in risk factors for atherosclerotic disease among young Japanese classified according to body mass index (BMI). Methods: Data were obtained from 359 men (mean age 32 ± 5 years) and 1,108 women (mean age 33 ± 4 years) between 2005 and 2010. Abnormal levels of aspartate aminotransferase, alanine aminotransferase, and/or gamma-glutamyltranspeptidase were considered to indicate liver dysfunction, and abnormal levels of low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and/or triglycerides were considered to indicate dyslipidemia. The cutoff points for high blood pressure (HBP) and hyperglycemia were set as a reference in the high-normal range. Results: No significant difference was observed in both sexes in all items among each year. In men, HBP (12.9 %), liver dysfunction (33.9 %), dyslipidemia (29.9 %), and hyperglycemia (2.7 %) were observed in the normal BMI group (18.5 < BMI ≤ 25 kg/m). In women, these abnormalities were observed in both the normal BMI group and lean group. Conclusions: Asymptomatic abnormalities, particularly liver dysfunction and dyslipidemia, were observed in a substantial percentage of subjects without obesity. Therefore, we recommend that the comprehensive public health policy should be directed at all individuals, including the non-obese group, for the early prevention/detection against atherosclerotic diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The Ca(2+) paradox is an important phenomenon associated with Ca(2+) overload-mediated cellular injury in myocardium. The present study was undertaken to elucidate molecular and cellular mechanisms for the development of the Ca(2+) paradox. EXPERIMENTAL APPROACH Fluorescence imaging was performed on fluo-3 loaded quiescent mouse ventricular myocytes using confocal laser scanning microscope. KEY RESULTS The Ca(2+) paradox was readily evoked by restoration of the extracellular Ca(2+) following 10-20 min of nominally Ca(2+)-free superfusion. The Ca(2+) paradox was significantly reduced by blockers of transient receptor potential canonical (TRPC) channels (2-aminoethoxydiphenyl borate, Gd(3+), La(3+)) and anti-TRPC1 antibody. The sarcoplasmic reticulum (SR) Ca(2+) content, assessed by caffeine application, gradually declined during Ca(2+)-free superfusion, which was further accelerated by metabolic inhibition. Block of SR Ca(2+) leak by tetracaine prevented Ca(2+) paradox. The Na(+) /Ca(2+) exchange (NCX) blocker KB-R7943 significantly inhibited Ca(2+) paradox when applied throughout superfusion period, but had little effect when added for a period of 3 min before and during Ca(2+) restoration. The SR Ca(2+) content was better preserved during Ca(2+) depletion by KB-R7943. Immunocytochemistry confirmed the expression of TRPC1, in addition to TRPC3 and TRPC4, in mouse ventricular myocytes. CONCLUSIONS AND IMPLICATIONS These results provide evidence that (i) the Ca(2+) paradox is primarily mediated by Ca(2+) entry through TRPC (probably TRPC1) channels that are presumably activated by SR Ca(2+) depletion; and (ii) reverse mode NCX contributes little to the Ca(2+) paradox, whereas inhibition of NCX during Ca(2+) depletion improves SR Ca(2+) loading, and is associated with reduced incidence of Ca(2+) paradox in mouse ventricular myocytes. [ABSTRACT FROM AUTHOR]

As is well known, liquid crystalline polymers often show an electro-rheological (ER) effect. The polymers show a remarkable viscosity increment and a relatively long response time when an electric field is applied. However, for low molecular weight liquid crystals, the ER effect is small although the response time is fast. These facts suggest that the ER effect depends on the molecular weight of the constituent materials. Diglycerol derivatives are designed and synthesized as oligomeric liquid crystals. These materials show considerably large ER effect and short response time. Consequently, it is considered that these derivatives are expected to be useful ER fluids for many industrial purposes. [ABSTRACT FROM AUTHOR]

The metastable ion dissociations of the (M − COOCH3)+ ions (m/z 135) generated upon electron ionization from dimethyl phthalate (1), isophthalate (2) and terephthalate (3), have been studied by use of mass-analyzed ion kinetic energy (MIKE) spectrometry and D-labeling. These ions all show as primary fragmentation channels the losses of methyl and carbon monoxide to give the ions m/z 120 and 107, respectively. The latter ions decompose further by the losses of another molecule of carbon monoxide or a molecule of formaldehyde to generate the ions at m/z 79 and 77, respectively. An additional dissociation channel is observed for the (M − COOCH3)+ ions from 2⋅+ and 3⋅+, the loss of methanol to give the ions m/z 103. The dissociation mechanism of the (M − COOCH3)+ ions from 1⋅+ is shown to be identical to that of the (M − CH3)+ ions from ionized 2-methoxyacetophenone. The latter ions have the 2-methoxybenzoyl cation structure demonstrating a methoxy migration in the (M − COOCH3)+ ions from 1⋅+ precedes their metastable ion dissociations. Part of the (M − COOCH3)+ ions from 2⋅+ and 3⋅+ has also rearranged to the 2-methoxybenzoyl cation structure prior to dissociation, but the significantly enhanced loss of methyl and the loss of methanol from these ions occur from the unrearranged structures as indicated by comparison with the dissociation behavior of the (M − CH3)+ ions from ionized 3- and 4-methoxyacetophenones. [Copyright &y& Elsevier]

Tea polyphenols have been shown to inhibit tumor cell growth, but there is limited information on their effects on cell signaling and cell cycle control pathways. We have shown the involvement of such mechanisms as activation of mitogenic activated protein kinases, decreases in ornithine decarboxylase activity and in cellular thiol levels, elicitation of mitochondrial cytochrome c release, and activation of caspases by the green tea galloyl polyphenol, epigallocatechin (EGC). In the current study, we sought to determine how EGC alters cell cycle and its related control factors in its growth inhibitory effect in Ehrlich ascites tumor cells. The significant finding here is that EGC caused a dose-dependent accumulation of cells in the G1 phase and a decrease in the phosphorylation of the retinoblastoma (Rb) protein, which was also in a cellular thiol-dependent manner. The involvement of a cellular thiol-dependent modulation in Rb phosphorylation leading to the regulation of tumor cell growth by a green tea polyphenol is a novel observation, to the best of our knowledge. [Copyright &y& Elsevier]

The efficacy of the antitumor activity of 1′-acetoxychavicol acetate (ACA), reported to be a suppressor of chemically induced carcinogenesis, was evaluated in Ehrlich ascites tumor cells. ACA treatment resulted in changes in morphology and a dose-dependent suppression of cell viability. Apoptosis, characterized by nuclear condensation, membrane blebbing, cell shrinkage and a significant induction of caspase-3-like protease activity at 8 h in a time-course study were observed. Formation of apoptotic bodies was preceded by lowering of intracellular polyamines, particularly putrescine, and both dose- and time-dependent inhibitory and activation effect by ACA on ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT), respectively. Administration of exogenous polyamines prevented ACA-induced apoptosis represented by a reduction in the number of apoptotic bodies and also caused reduction in the induced caspase-3-like protease activity at 8 h. These findings suggest that the anticarcinogenic effects of ACA might be partly due to perturbation of the polyamine metabolic pathway and triggering of caspase-3-like activity, which result in apoptosis. [ABSTRACT FROM PUBLISHER]

The slowly and rapidly activating delayed rectifier K+ channels (I Ks and I Kr , respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding I Ks and I Kr cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of I Ks and I Kr , respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on I Ks was primarily responsible for its QT-prolonging effect. In LQT2 model , I Ks was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of I Kr and relative contribution of I Ks to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings. [ABSTRACT FROM AUTHOR]

Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. To further evaluate the efficacy of the anticancer activity of 1′-acetoxychavicol acetate (ACA), this study investigates the underlying mechanisms by which ACA induces death of Ehrlich ascites tumor cells. ACA treatment induced loss of cell viability, and Western blotting analysis revealed that the compound stimulated tyrosine phosphorylation of several proteins with 27 and 70 kDa proteins being regulated in both dose- and time-dependent manner prior to loss of viability. Protein tyrosine kinase inhibitor herbimycin A moderately protected cells from ACA-induced toxicity. In addition, cellular glutathione and protein sulfydryl groups were also significantly reduced both dose- and time-dependently during evidence of cell death. Replenishing thiol levels by antioxidant, N-acetylcysteine (NAC), an excellent supplier of glutathione and precursor of glutathione, substantially recovered the viability loss, but the recovery being time-dependent, as late addition of NAC (at least 30 min after ACA addition to cultures) was, however, ineffective. Addition of NAC to ACA treated cultures also abolished tyrosine phophorylation of the 27 kDa protein. These results, at least partly, identify cellular sulfhydryl groups and protein tyrosine phosphorylation as targets of ACA cytotoxicity in tumor cells. [Copyright &y& Elsevier]