bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Ca2+entry and Ca2+stores in atypical smooth muscle cell autorhythmicity in the mouse renal pelvis
Authors: Lang R J , Hashitani H , Tonta M A , Suzuki H , Parkington H C 
Published: October 2007

Background and purpose:Electrically active atypical smooth muscle cells (ASMCs) within the renal pelvis have long been considered to act as pacemaker cells driving pelviureteric peristalsis. We have investigated the role of Ca2+entry and uptake into and release from internal stores in the generation of Ca2+transients and spontaneous transient depolarizations (STDs) in ASMCs.Experimental approach:The electrical activity and separately visualized changes in intracellular Ca2+concentration in typical smooth muscle cells (TSMCs), ASMCs and interstitial cells of Cajal‐like cells (ICC‐LCs) were recorded using intracellular microelectrodes and a fluorescent Ca2+indicator, fluo‐4.Results:In 1 μMnifedipine, high frequency (10–30 min−1) Ca2+transients and STDs were recorded in ASMCs, while ICC‐LCs displayed low frequency (1–3 min−1) Ca2+transients. All spontaneous electrical activity and Ca2+transients were blocked upon removal of Ca2+from the bathing solution, blockade of Ca2+store uptake with cyclopiazonic acid (CPA) and with 2‐aminoethoxy‐diphenylborate (2‐APB). STD amplitudes were reduced upon removal of the extracellular Na+or blockade of IP3dependent Ca2+store release with neomycin or U73122. Blockade of ryanodine‐sensitive Ca2+release blocked ICC‐LC Ca2+transients but only reduced Ca2+transient discharge in ASMCs. STDs in ASMCS were also little affected by DIDS, La3+, Gd3+or by the replacement of extracellular Cl‐with isethionate.Conclusions:ASMCs generated Ca2+transients and cation‐selective STDs via mechanisms involving Ca2+release from IP3‐dependent Ca2+stores, STD stimulation of TSMCs was supported by Ca2+entry through L type Ca2+channels and Ca2+release from ryanodine‐sensitive stores.British Journal of Pharmacology(2007)152, 1248–1259; doi:10.1038/sj.bjp.0707535; published online 29 October 2007
Relevance of anaesthesia for dofetilide‐induced torsades de pointes in α1‐adrenoceptor‐stimulated rabbits
Authors: Vincze D , Farkas A S , Rudas L , Makra P , Csík N , Leprán I , Forster T , Csanády M , Papp J G , Varró A , Farkas A 
Published: October 2007

Background and purpose:No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro‐arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α‐chloralose anaesthesia on the pro‐arrhythmic activity of the class III anti‐arrhythmic dofetilide in α1‐adrenoceptor‐stimulated rabbits.Experimental approach:Rabbits anaesthetized intravenously with pentobarbital, propofol or α‐chloralose were infused simultaneously with the α1‐adrenoceptor agonist phenylephrine (15 μg kg−1 min−1, i.v.) and dofetilide (0.04 mg kg−1 min−1, i.v.). The electrocardiographic QT interval, the T
peak–T
end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15–0.5 Hz to assess the sympathetic activity.Key results:Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide‐induced torsades de pointes (TdP) as compared with the results with α‐chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α‐chloralose. None of the repolarization‐related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α‐chloralose and propofol anaesthesia groups.Conclusions and implications:In rabbits, anaesthetics may affect drug‐induced TdP genesis differently, which must be considered when results of different studies are compared.British Journal of Pharmacology (2008) 153, 75–89; doi:10.1038/sj.bjp.0707536; published online 29 October 2007
Effects of angiotensin II blockade on inflammation‐induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers
Authors: Hanafy S , Dagenais N J , Dryden W F , Jamali F 
Published: October 2007

Background and purpose:Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro‐inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation.Experimental approach:We used 4 groups of male Sprague–Dawley rats (220–280 g): inflamed‐placebo, inflamed‐treated, control‐placebo and control‐treated. Inflammation as pre‐adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg−1 oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg−1 verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor‐verapamil analysis. The amounts of the target protein Cav1.2 subunit of L‐type calcium channels in heart was measured by Western blotting and ligand binding with 3H‐nitrendipine.Key results:Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down‐regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein.Conclusions and implications:Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan.British Journal of Pharmacology (2008) 153, 90–99; doi:10.1038/sj.bjp.0707538; published online 29 October 2007
Electromechanical characterization of cinnamophilin, a natural thromboxane A2 receptor antagonist with anti‐arrhythmic activity, in guinea‐pig heart
Authors: Chang G‐J , Su M‐J , Wu T‐S , Chen W‐P , Kuo C‐M 
Published: October 2007

Background and purpose:Cinnamophilin, a thromboxane A2 receptor antagonist, has been identified as a prominent anti‐arrhythmic agent in rat heart. This study aimed to determine its electromechanical and anti‐arrhythmic effects in guinea‐pig hearts.Experimental approach:Microelectrodes were used to study action potentials in ventricular papillary muscles. Fluo‐3 fluorimetric ratio and whole‐cell voltage‐clamp techniques were used to record calcium transients and membrane currents in single ventricular myocytes, respectively. Intracardiac electrocardiograms were obtained and the anti‐arrhythmic efficacy was determined from isolated perfused hearts.Key results:In papillary muscles, cinnamophilin decreased the maximal rate of upstroke (Vmax) and duration of action potential, and reduced the contractile force. In single ventricular myocytes, cinnamophilin reduced Ca2+ transient amplitude. Cinnamophilin decreased the L‐type Ca2+ current (ICa,L)(IC50=7.5 μM) with use‐dependency, induced a negative shift of the voltage‐dependent inactivation and retarded recovery from inactivation. Cinnamophilin also decreased the Na+ current (INa) (IC50=2.7 μM) and to a lesser extent, the delayed outward (IK), inward rectifier (IK1), and ATP‐sensitive (IK,ATP) K+ currents. In isolated perfused hearts, cinnamophilin prolonged the AV nodal conduction interval and Wenckebach cycle length and the refractory periods of the AV node, His‐Purkinje system and ventricle, while shortening the ventricular repolarization time. Additionally, cinnamophilin reduced the occurrence of reperfusion‐induced ventricular fibrillation.Conclusions and implications:These results suggest that the promising anti‐arrhythmic effect and the changes in the electromechanical function induced by cinnamophilin in guinea‐pig heart can be chiefly accounted for by inhibition of ICa,L and INa.British Journal of Pharmacology (2008) 153, 110–123; doi:10.1038/sj.bjp.0707541; published online 29 October 2007
Effects of chronic in vivo administration of nitroglycerine on ACh‐induced endothelium‐dependent relaxation in rabbit cerebral arteries
Authors: Watanabe Y , Kusama N , Itoh T 
Published: October 2007

Background and purpose:In the setting of nitrate tolerance, endothelium‐dependent relaxation is reduced in several types of peripheral vessels. However, it is unknown whether chronic in vivo administration of nitroglycerine modulates such relaxation in cerebral arteries.Experimental approach:Isometric force and smooth muscle cell membrane potential were measured in endothelium‐intact strips from rabbit middle cerebral artery (MCA) and posterior cerebral artery (PCA).Key results:ACh (0.1–10 μM) concentration‐dependently induced endothelium‐dependent relaxation during the contraction induced by histamine in both MCA and PCA. Chronic (10 days) in vivo administration of nitroglycerine reduced the ACh‐induced relaxation in PCA but not in MCA, in the presence of the cyclooxygenase inhibitor diclofenac (3 μM). In the presence of the NO‐synthase inhibitor N
ω‐nitro‐L‐arginine (L‐NNA, 0.1 mM) plus diclofenac, in MCA from both nitroglycerine‐untreated control and ‐treated rabbits, ACh (0.1–10 μM) induced a smooth muscle cell hyperpolarization and relaxation, and these were blocked by the small‐conductance Ca2+‐activated K+‐channel inhibitor apamin (0.1 μM), but not by the large‐ and intermediate‐conductance Ca2+‐activated K+‐channel inhibitor charybdotoxin (0.1 μM). In contrast, in PCA, ACh (<3 μM) induced neither hyperpolarization nor relaxation under these conditions, suggesting that the endothelium‐derived relaxing factor is NO in PCA, whereas endothelium‐derived hyperpolarizing factor (EDHF) plays a significant role in MCA.Conclusions and implications:It is suggested that in rabbit cerebral arteries, the function of the endothelium‐derived relaxing factor NO and that of EDHF may be modulated differently by chronic in vivo administration of nitroglycerine.British Journal of Pharmacology (2008) 153, 132–139; doi:10.1038/sj.bjp.0707562; published online 29 October 2007
Investigation of the redox centres of periplasmic selenate reductase from Thauera selenatis by EPR spectroscopy
Authors: Dridge Elizabeth J. , Watts Carys A. , Jepson Brian J. N. , Line Kirsty , Santini Joanne M. , Richardson David J. , Butler Clive S. 
Published: October 2007

Periplasmic SER (selenate reductase) from Thauera selenatis is classified as a member of the Tat (twin-arginine translocase)-translocated (Type II) molybdoenzymes and comprises three subunits each containing redox cofactors. Variable-temperature X-band EPR spectra of the purified SER complex showed features attributable to centres [3Fe–4S]1+, [4Fe–4S]1+, Mo(V) and haem-b. EPR-monitored redox-potentiometric titration of the SerABC complex (SerA–SerB–SerC, a hetero-trimetric complex of αβγ subunits) revealed that the [3Fe–4S] cluster (FS4, iron-sulfur cluster 4) titrated as n=1 Nernstian component with a midpoint redox potential (Em) of +118±10 mV for the [3Fe–4S]1+/0 couple. A [4Fe–4S]1+ cluster EPR signal developed over a range of potentials between 300 and −200 mV and was best fitted to two sequential Nernstian n=1 curves with midpoint redox potentials of +183±10 mV (FS1) and −51±10 mV (FS3) for the two [4Fe–4S]1+/2+ cluster couples. Upon further reduction, the observed signal intensity of the [4Fe–4S]1+ cluster decreases. This change in intensity can again be fitted to an n=1 Nernstian component with a midpoint potential (Em) of about −356 mV (FS2). It is considered likely that, at low redox potential (Em less than −300 mV), the remaining oxidized cluster is reduced (spin S=1/2) and strongly spin-couples to a neighbouring [4Fe–4S]1+ cluster rendering both centres EPR-silent. The involvement of both [3Fe–4S] and [4Fe–4S] clusters in electron transfer to the active site of the periplasmic SER was demonstrated by the re-oxidation of the clusters under anaerobic selenate turnover conditions. Attempts to detect a high-spin [4Fe–4S] cluster (FS0) in SerA at low temperature (5 K) and high power (100 mW) were unsuccessful. The Mo(V) EPR recorded at 60 K, in samples poised at pH 6.0, displays principal g values of g3∼1.999, g2∼1.996 and g1∼1.965 (gav 1.9867). The dominant features at g2 and g3 are not split, but hyperfine splitting is observed in the g1 region of the spectrum and can be best simulated as arising from a single proton with a coupling constant of A1 (1H)=1.014 mT. The presence of the haem-b moiety in SerC was demonstrated by the detection of a signal at g∼3.33 and is consistent with haem co-ordinated by methionine and lysine axial ligands. The combined evidence from EPR analysis and sequence alignments supports the assignment of the periplasmic SER as a member of the Type II molybdoenzymes and provides the first spectro-potentiometric insight into an enzyme that catalyses a key reductive reaction in the biogeochemical selenium cycle.
Understanding cisplatin resistance using cellular models
Authors: Stordal Britta , Davey Mary 
Published: October 2007

AbstractMany mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF‐CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7‐fold with a treatment dose of 1.6 μg/ml. Cisplatin resistance in these cells correlated with increases in the antioxidant glutathione, yet treatment with buthionine sulphoximine, an inhibitor of glutathione synthesis, had no effect on resistance, suggesting that the increase in glutathione was not directly involved in cisplatin resistance. Two models were developed from H69 SCLC cells, H69‐CP and H69CIS200 using 100 ng/ml or 200 ng/ml cisplatin respectively. Both cell models were 2‐4 fold resistant to cisplatin, and have decreased expression of p21 which may increase the cell's ability to progress through the cell cycle in the presence of DNA damage. Both the H69‐CP and H69CIS200 cells showed no decrease in cellular cisplatin accumulation. However, the H69‐CP cells have increased levels of cellular glutathione and are cross resistant to radiation whereas the H69CIS200 cells have neither of these changes. This suggests that increases in glutathione may contribute to cross‐resistance to other drugs and radiation, but not directly to cisplatin resistance. There are multiple resistance mechanisms induced by cisplatin treatment, even in the same cell type. How then should cisplatin‐resistant cancers be treated? Cisplatin‐resistant cell lines are often more sensitive to another chemotherapeutic drug paclitaxel (H69CIS200), or are able to be sensitized to cisplatin with paclitaxel pre‐treatment (H69‐CP). The understanding of this sensitization by paclitaxel using cell models of cisplatin resistance will lead to improvements in the clinical treatment of cisplatin resistant tumours. IUBMB Life, 59: 696‐699, 2007
Sirolimus Inhibits Human Pancreatic Carcinoma Cell Proliferation by a Mechanism Linked to the Targeting of mTOR/HIF‐1 Alpha/VEGF Signaling
Authors: Wang Yu , Zhao Qiu , Ma Songlin , Yang Fang , Gong Yong , Ke Changshu 
Published: October 2007

AbstractSirolimus(SRL, Rapamuneâ, rapamycin) is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Sirolimus exerts its biological activity by inhibiting the serine‐threonine kinase mammalian target of rapamycin (mTOR), which regulates important cellular processes such as control of cell cycle, cell size, translation initiation and transcription. The ability of sirolimus to inhibit cancer cell proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anticancer agents. Here, we made mTOR as a controlling target, using a new immunosuppressant named sirolimus, to investigate the inhibitory effects of sirolimus on cell proliferation and the expression of mTOR, Hypoxia‐inducible factor‐1 alpha(HIF‐1α) and vascular endothelial growth factor (VEGF) in human pancreatic carcinoma SW1990 cell line. Sirolimus is effective in vivo against pancreatic carcinoma and demonstrates that the effect of sirolimus on the inhibition of tumor cell proliferation is associated with the suppression of the mTOR/HIF‐1α/vascular endothelial growth factor (VEGF) pathway. Thus, the targeting of mTOR signaling has been exploited as a novel therapy for human cancers. IUBMB Life, 59: 717‐721, 2007
Vitamin B12 Transport Proteins: Crystallographic Analysis of β‐axial Ligand Substitutions in Cobalamin Bound to Transcobalamin
Authors: Wuerges Jochen , Geremia Silvano , Fedosov Sergey N. , Randaccio Lucio 
Published: October 2007

AbstractCobalamin (Cbl, vitamin B12) is an essential micronutrient that is synthesized only by bacteria. Mammals have developed a complex system for internalization of this vitamin from the diet. Three binding proteins (haptocorrin, intrinsic factor, transcobalamin (TC)) and several specific cell surface receptors are involved in the process of intestinal absorption, plasma transport and cellular uptake. The recent literature on the binding proteins is briefly reviewed. A structural study is presented addressing a unique feature of TC among the three proteins, i.e., the displacement of the weak Co(III)‐ligand H2O at the upper (or β) axial side of H2O‐Cbl by a histidine side chain. We have investigated crystallographically the β‐ligand exchange on Cbl bound to TC by crystallization of bovine holo‐TC in the presence of either cyanide or sulfite. The resulting electron density maps show that the histidine side chain has been displaced by an exogenous ligand CN‐ or to a lower extent than expected based on their higher affinity for Co and excess concentration with respect to histidine. This may reflect either reduced affinities of CN‐ and or the advantageous binding of the protein‐integrated His‐residue when competing for the β‐site of Cbl bound to TC. The loop hosting the histidine residue appears more flexible after disruption of the coordination bond His‐Cbl but no other differences are observed in the overall structure of holo‐TC. These structural results are discussed in relation to a possible physiological role of histidine substitution for H2O and regarding the role of β‐conjugated Cbl‐analogues recently proposed for targeted delivery of imaging agents. IUBMB Life, 59: 722‐729, 2007
Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma
Authors: Ogawa Yoshiaki , Tobinai Kensei , Ogura Michinori , Ando Kiyoshi , Tsuchiya Takahide , Kobayashi Yukio , Watanabe Takashi , Maruyama Dai , Morishima Yasuo , Kagami Yoshitoyo , Taji Hirofumi , Minami Hironobu , Itoh Kuniaki , Nakata Masanobu , Hotta Tomomitsu 
Published: October 2007

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose‐escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty‐four patients were enrolled. A dose‐limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest‐dose cohort in phase I and led to the selection of 1.3 mg/m2 as the recommended dose. Adverse events ≥ grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16–49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration–time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules. (Cancer Sci 2008; 99: 140–144)
Prostate cancer antigen‐1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer
Authors: Shimada Keiji , Nakamura Mitsutoshi , Ishida Eiwa , Higuchi Tomonori , Yamamoto Hiroshi , Tsujikawa Kazutake , Konishi Noboru 
Published: October 2007

A novel gene, prostate cancer antigen (PCA)‐1, was recently reported to be expressed in the prostate; however, its biological roles remain unclear. Knockdown of the PCA‐1 gene by small interfering RNA transfection induced apoptosis through reducing the expression of the anti‐apoptotic molecule Bcl‐xl and cytoplasmic release of cytochrome c in the androgen‐independent prostate cancer cell line PC3. Moreover, in vitro matrigel and in vivo chorioallantoic membrane assays showed that silencing of PCA‐1 significantly downregulated discoidin receptor (DDR)‐1 expression, resulting in suppression of cancer‐cell invasion. Transfection with PCA‐1 increased the levels of both Bcl‐xl and DDR1, which made the cells more invasive through the upregulation of matrix metalloproteinase 9 in DU145. Interestingly, long‐term culture using androgen‐free medium increased the level of PCA‐1 and the related expression of Bcl‐xl and DDR‐1 in the androgen‐sensitive cancer cell line LNCaP, suggesting that PCA‐1 signaling is associated with androgen independence. Immunohistochemical analysis in a series of 169 prostate carcinomas showed that PCA‐1 and DDR1 were strongly expressed in prostate cancer cells, including preneoplastic lesions, but there was little or no expression in normal epithelium. Moreover, the expression of PCA‐1 and DDR‐1 was associated with a hormone‐independent state of prostate cancer. Taken together, we propose that PCA‐1–DDR‐1 signaling is a new important axis involved in malignant potential prostate cancer associated with hormone‐refractory status. (Cancer Sci 2008; 99: 39–45)
CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura
Authors: Li Shuguang , Wang Lin , Zhao Chunhong , Li Lizhen , Peng Jun , Hou Ming 
Published: October 2007

SummaryTo investigate the effect and mechanism of the CD8+ T cells in bone marrow on autologous megakaryocytopoiesis in idiopathic thrombocytopenic purpura (ITP) patients, we prepared bone marrow mononuclear cells (MNCs) from 15 chronic ITP patients and 13 controls. MNCs were cultured in vitro directly (MNC group) or after depleting CD8+ T cells (CD8+ T‐dep group) or adding purified autologous CD8+ T cells to CD8+ T‐dep MNCs (Coculture group) or adding dexamethasone to the coculture (DEX group) all in semi‐solid and liquid culture systems. The quantity and quality of megakaryocytes were measured. The megakaryocyte count was increased in the presence of autologous CD8+ T cells of patients with chronic ITP, while platelet production was reduced. In addition, lower percentages of polyploidy and apoptotic megakaryocytes, and higher levels of soluble Fas (sFas) in supernatant were observed. Dexamethasone successfully corrected this effect of CD8+ T cells on autologous megakaryocytopoiesis. These studies provide evidence that activated CD8+ T cells in bone marrow of patients with chronic ITP might suppress megakaryocyte apoptosis, leading to impaired platelet production. Megakaryocyte apoptosis would be a novel target for the management of ITP.