bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of Interleukin‐8 by Hypoxia in Human Ovaries
Authors: Yoshino Osamu , Osuga Yutaka , Koga Kaori , Hirota Yasushi , Yano Tetsu , Tsutsumi Osamu , Fujimoto Akihisa , Kugu Koji , Momoeda Mikio , Fujiwara Toshihiro , Taketani Yuji 
Published: September 2003

Problem: To evaluate the effect of hypoxia on interleukin (IL)‐8 expression in human ovarian follicles.Method of study: Follicular fluid (FF) from each follicle was separately collected from women undergoing in vitro fertilization and embryo transfer. Concentrations of oxygen, progesterone, estradiol, IL‐1α/β, IL‐8, and tumor necrosis factor (TNF)‐α in FF were measured. Isolated granulosa‐lutein cells (GLC) from obtained FF were cultured under normoxic or hypoxic conditions, and concentrations of IL‐8 in culture media were measured.Results: Simple regression analysis demonstrated a significant negative correlation between the concentrations of IL‐8 and oxygen in FF (r = 0.50, P < 0.0001). However, none of the concentrations of progesterone, estradiol, IL‐1β, and TNF‐α in FF showed a significant correlation with IL‐8 concentrations. Hypoxia stimulated the secretion of IL‐8 by cultured GLC over twofolds compared with a normoxic control (P < 0.05).Conclusions: These findings suggest that IL‐8, like other angiogenic factors, is upregulated under hypoxic condition, which argues that hypoxia in the ovarian follicles comes into play in ovarian functions by inducing a range of proangiogenic and chemoattractive substances.
Pre‐conceptional Natural Killer Cell Activity and Percentage as Predictors of Biochemical Pregnancy and Spontaneous Abortion with Normal Chromosome Karyotype
Authors: Yamada Hideto , Morikawa Mamoru , Kato Emi H. , Shimada Shigeki , Kobashi Gen , Minakami Hisanori 
Published: September 2003

Problem: The aim of the present study was to determine whether pre‐conceptional natural killer (NK) cell activity and percentage are predictive of subsequent spontaneous abortion in women with recurrent spontaneous abortion (RSA).Method of study: Pre‐conceptional NK cell activity and percentage in peripheral blood of women who had a history of two or more RSA was prospectively assessed. The 51Cr release assay and flow cytometric analysis were performed. A total of 113 RSA women were recruited, and 85 conceived later.Results: Pre‐conceptional NK cell activity/percentage values in women whose next pregnancies ended in biochemical pregnancy and spontaneous abortion with normal fetal karyotype (n = 17, median 47%/17.1%), but spontaneous abortion with abnormal karyotype (n = 9, 27%/15.7%), were higher than those in live births (n = 59, 33%/13.1%). High values of pre‐conceptional NK cell activity (>46%; relative risk 3.6, 95%CI 1.6–8.0) and percentage (>16.4%; 4.9, 1.7–13.8) were found to predict biochemical pregnancy and spontaneous abortion with normal karyotype in the next pregnancy.Conclusion: Pre‐conceptional NK cell abnormalities were predictive of spontaneous abortion with normal fetal karyotype.
Identification of CD4‐independent HIV Receptors on Spermatozoa
Authors: Bandivdekar Atmaram H. , Velhal Shilpa M. , Raghavan Vijaya P. 
Published: September 2003

Problem: Human immunodeficiency virus (HIV) has been demonstrated to bind and enter into the spermatozoa facilitating the transmission into urogenital cells. However, spermatozoa has been reported to be devoid of the conventional CD4 receptors for HIV. This suggests that there exists an alternate modality of HIV entry into spermatozoa using receptors other than CD4. Present communication describes the identification of HIV receptors on the spermatozoa.Method of Study: The sperm proteins were solubilized using Triton X‐100 and subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by Western blot analysis, using cell‐free HIV or gp120 envelope glycoprotein as a probe. HIV or gp120 bound protein band was then visualized by using alkaline phosphatase (AP) labeled anti‐gp120 antibody as well as by using anti‐gp120 antibody and subsequently by AP‐labeled anti‐rabbit gamma globulin.Results: The results obtained demonstrate for the first time that cell‐free HIV and gp120 protein bind specifically to 160 kDa sperm protein that could be the receptor for HIV entry into spermatozoa.Conclusion: A 160 kDa sperm protein could be the CD4‐independent HIV receptor for HIV to bind and enter into the spermatozoa. Further characterization of this 160 kDa HIV receptor on sperm will provide an insight in understanding the mechanism and probable mode of intervention or prevention of HIV transmission at the initial stage of infection.
Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin‐diabetic rat
Authors: Abdouh Mohamed , Khanjari Ashraf , Abdelazziz Nadia , Ongali Brice , Couture Réjean , Hasséssian Haroutioun M 
Published: September 2003

Retinal microvessel responses to kinin B1 and B2 receptor agonists and antagonists were investigated in streptozotocin (STZ)‐diabetic rats and age‐matched controls. In addition, quantitative in vitro autoradiography was performed on retinas from control and STZ‐diabetic rats with radioligands specific for B2 ([125I]HPP‐Hoe 140), and B1 receptors ([125I]HPP‐[des‐Arg10]‐Hoe 140).
In control rats, the B2 receptor agonist bradykinin (BK, 0.1–50 nM) vasodilated retinal vessels in a concentration and time‐dependent manner. This effect was completely blocked by the B2 receptor antagonist Hoe140 (1 μM). In contrast, the B1 receptor agonist des‐Arg9‐BK (0.1–50 nM) was without effect.
Des‐Arg9‐BK was able to produce a concentration‐dependent vasodilatation as early as 4 days after STZ injection, and the effect of 1 nM des‐Arg9‐BK was inhibited by the B1 receptor antagonist des‐Arg10‐Hoe140 (1 μM). Low‐level B1 receptor binding sites were detected in control rats, but densities were 256% higher in retinas from 4‐ to 21‐day STZ‐diabetic rats.
In control rats, the vasodilatation in response to 1 nM BK involved neither calcium influx nor nitric oxide (NO) as GdCl3 and L‐NAME were without effect. However, the vasodilatation did involve intracellular calcium mobilization as well as products of the cyclooxygenase‐2 (COX‐2) pathway as 2,5‐di‐t‐butylhydroquinone (BHQ), cADP ribose and L‐745 337 inhibited this response. The vasodilatation response was blocked by trans‐2‐phenyl cyclopropylamine (TPC) demonstrating that prostacyclins mediate this response.
In STZ‐diabetic rats, the vasodilatation in response to des‐Arg9‐BK involved both calcium influx and intracellular calcium mobilization from stores both IP3 sensitive and non‐IP3 sensitive. Indeed, the effect was blocked by GdCl3, BHQ and cADP ribose. Furthermore, NO production and products of the COX‐2 pathway including prostacyclin are involved as the response was inhibited by L‐NAME, L‐745 377 and TPC.
Vasodilatation in response to either 1 nM BK or 1 nM des‐Arg9‐BK were blocked by NF023 demonstrating that a Go/Gi G‐protein transduces both these effects.
This is the first report on the retinal circulation which provides evidence for vasodilator B2 receptors and the upregulation of B1 receptors very early following induction of diabetes with STZ rats. These results suggest that kinin receptors may be potential targets for therapeutics to treat retinopathies.

British Journal of Pharmacology (2003) 140, 33–40. doi:10.1038/sj.bjp.0705210
Electrical properties of detrusor smooth muscles from the pig and human urinary bladder
Authors: Hashitani Hikaru , Brading Alison F 
Published: September 2003

The electrophysiological properties of detrusor smooth muscles have been studied almost exclusively in small mammals and the relevance of the information to the human bladder has been questioned. In the present study, electrical properties of detrusor smooth muscles of the pig and human were investigated using intracellular recording techniques.
Bladder smooth muscles of the pig and human exhibited nifedipine (10 μM)‐sensitive spontaneous action potentials, and their frequency was highly sensitive to membrane polarization.
During bursts of action potentials, each action potential was followed by a fast after‐hyperpolarization (fast AHP). Charybdotoxin (CTX, 50 nM) increased the amplitude and duration of action potentials but failed to inhibit the fast AHPs, while apamin (0.1 μM) blocked the fast AHPs and induced action potential complexes, which were followed by slow AHPs. 4‐Aminopyridine (4‐AP, 1 mM) suppressed the slow AHP and increased action potential frequency.
In the human bladder, transmural stimuli initiated inhibitory junction potential‐like hyperpolarizations, which were followed by action potential discharges. The hyperpolarizations were blocked by atropine (1 μM) and by apamin (0.1 μM) but not by CTX (50 nM). In the pig bladder, transmural stimuli evoked excitatory junction potentials (EJPs), which triggered action potentials. After desensitizing P2x receptors with α,β methylene‐ATP (10 μM), nerve‐evoked responses were similar to those of human bladder.
These results indicate that detrusor smooth muscles of the pig share many features of electrical properties with those of the human. In addition to large conductance (BK) and small conductance (SK) Ca2+‐activated K+ channels, voltage‐dependent K+ (VK) channels may play an important role in the regulation of electrical activity of detrusor smooth muscles.

British Journal of Pharmacology (2003) 140, 146–158. doi:10.1038/sj.bjp.0705319
Ionic basis for the regulation of spontaneous excitation in detrusor smooth muscle cells of the guinea‐pig urinary bladder
Authors: Hashitani Hikaru , Brading Alison F 
Published: September 2003

The regulatory mechanisms of spontaneous excitation in detrusor smooth muscles of the guinea‐pig urinary bladder were investigated using intracellular microelectrode and muscle tension recording techniques.
Detrusor smooth muscle cells exhibited nifedipine‐sensitive spontaneous action potentials. Their frequency was highly sensitive to membrane polarization and was reduced by lowering the temperature. Lowering the temperature also reduced the frequency of spontaneous contractions and increased their amplitude.
Charybdotoxin (50 nM) and iberiotoxin (0.1 μM) increased the amplitude and duration of action potentials, and abolished after hyperpolarizations (AHPs). Both agents also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. Apamin (0.1 μM) did not change the shape of action potentials but often converted individual action potentials into bursts. It also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. 4‐aminopyrideine (4‐AP, 1 mM) increased the frequency of action potentials without affecting their shape, and increased the amplitude and frequency of spontaneous contractions.
Cyclopiazonic acid (CPA, 10 μM) and ryanodine (50 μM) increased the amplitude of action potentials, and suppressed AHPs. Both agents also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. 1,2‐(Bis (2‐aminophenoxy) ethane‐N,N,N′, N′‐tetraacetic acid tetrakis (acetoxymethyl ester) (50 μM) dramatically increased the amplitude and duration of the action potential, and abolished AHPs.
Spontaneous action potentials in detrusor smooth muscles cells result from the opening of L‐type Ca2+ channels, and their frequency is regulated by voltage‐dependent mechanisms and by some metabolic process. Both the activation of large conductance Ca2+‐activated K+ (BK) channels and Ca2+‐mediated inactivation of the Ca2+ channels are involved in the repolarizing phase of action potentials. The Ca2+ influx through L‐type Ca2+ channels triggers calcium‐induced calcium release via ryanodine receptors and activates BK channels to generate AHPs. Both small conductance Ca2+‐activated K+ channels and voltage‐sensitive K+ channels may contribute to the resting membrane potential and regulate the frequency of action potentials. The regulatory mechanisms of action potentials are closely related to the regulation of spontaneous contractions.

British Journal of Pharmacology (2003) 140, 159–169. doi:10.1038/sj.bjp.0705320
GLP‐1 derivative liraglutide in rats with β‐cell deficiencies: influence of metabolic state on β‐cell mass dynamics
Authors: Sturis Jeppe , Gotfredsen Carsten F , Rømer John , Rolin Bidda , Ribel Ulla , Brand Christian L , Wilken Michael , Wassermann Karsten , Deacon Carolyn F , Carr Richard D , Knudsen Lotte Bjerre 
Published: September 2003

Liraglutide is a long‐acting GLP‐1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and β‐cell mass in rat models of β‐cell deficiencies, studies were performed in male Zucker diabetic fatty (ZDF) rats and in 60% pancreatectomized rats.
When liraglutide was dosed s.c. at 150 μg kg−1 b.i.d. for 6 weeks in ZDF rats 6–8 weeks of age at study start, diabetes development was markedly attenuated. Blood glucose was approximately 12 mM lower compared to vehicle (P<0.0002), and plasma insulin was 2–3‐fold higher during a normal 24‐h feeding period (P<0.001). Judged by pair feeding, approximately 53% of the antihyperglycemic effect observed on 24‐h glucose profiles was mediated by a reduction in food intake, which persisted throughout the study and averaged 16% (P<0.02).
Histological analyses revealed that β‐cell mass and proliferation were significantly lower in prediabetic animals still normoglycemic after 2 weeks treatment compared to vehicle‐treated animals that had begun to develop diabetes. When the treatment period was 6 weeks, the liraglutide‐treated animals were no longer completely normoglycemic and the β‐cell mass was significantly increased compared to overtly diabetic vehicle‐treated animals, while β‐cell proliferation was unaffected.
In the experiments with 60% pancreatectomized rats, 8 days treatment with liraglutide resulted in a significantly lower glucose excursion in response to oral glucose compared to vehicle treatment. Again, part of the antihyperglycemic effect was due to reduced food intake. No effect of liraglutide on β‐cell mass was observed in these virtually normoglycemic animals.
In conclusion, treatment with liraglutide has marked antihyperglycemic effects in rodent models of β‐cell deficiencies, and the in vivo effect of liraglutide on β‐cell mass may in part depend on the metabolic state of the animals.

British Journal of Pharmacology (2003) 140, 123–132. doi:10.1038/sj.bjp.0705397
Effect of selective PKC isoform activation and inhibition on TNF‐α‐induced injury and apoptosis in human intestinal epithelial cells
Authors: Chang Q , Tepperman B L 
Published: September 2003

We have investigated the effects of specific PKC isoforms in TNF‐α mediated cellular damage using a human intestinal cell line (SCBN).
TNF‐α treatment induced a decrease in the extent of intestinal cellular viability as determined by a formazan‐based assay and an increase in the apoptotic index as assessed by immunohistology. These changes in cellular integrity were found to be related to the degradation of I‐κBα, mobilization of NF‐κB and release of mitochondrial cytochrome c.
TNF‐α treatment also induced the activation of selective PKC isoforms which were associated with the decrease in cellular viability and an increase of cellular apoptosis.
Nonselective PKC antagonists, such as GF109203X and Gö6976 as well as isoform‐selective PKC‐inhibiting peptides would reverse the cellular injury as well as reduce the degradation of I‐κBα and mitochondrial cytochrome c release. These effects were most highly correlated with changes in PKCδ and ɛ primarily.
Intestinal cellular injury could be induced by treating cells with agonists selective for PKCδ and ɛ mainly.
In conclusion, this study has shown that TNF‐α treatment can induce the activation of PKCδ and ɛ in the human intestinal cell line, SCBN, and this response is closely associated with an increase in cellular damage and apoptosis. PKCδ and ɛ primarily mediate the release of mitochondrial cytochrome c and degradation of I‐κBα and hence mobilization of NF‐κB, which are responsible for the pathway leading to cell injury.

British Journal of Pharmacology (2003) 140, 41–52. doi:10.1038/sj.bjp.0705398
Evidence for the involvement of central 5‐HT7 receptors in the micturition reflex in anaesthetized female rats
Authors: Read Kate E , Sanger Gareth J , Ramage Andrew G 
Published: September 2003

The effects of the selective 5‐HT7 receptor antagonists SB‐269970 (3‐300 μg kg−1; n=5–6) and SB‐656104 (30 μg kg−1; n=5) administered centrally (i.c.v.) were investigated on the ‘micturition reflex’ in the urethane anaesthetized female rat.
In cystometric recordings, SB‐269970 caused significant increases in volume of 58±15 and 138±33% and pressure of 140±46 and 149±60% thresholds at 10 and 30 μg kg−1. These changes were associated with significant decreases in distension‐induced bladder contraction of 62±14 and 60±11%, respectively. However, there was no change in residual volume. At the higher doses, SB‐269970 blocked the micturition reflex. SB‐656104 had similar effects to SB‐269970 but in addition significantly increased the residual volume.
SB‐269970 (10 μg kg−1; n=5) given i.v. had no effect on the micturition reflex.
SB‐269970 (30 μg kg−1; n=4) given intrathecally (i.t.) had no effect on micturition reflex, although the selective 5‐HT1A receptor antagonist WAY‐100635 given i.t. after SB‐269970 caused a significant increase in the volume threshold.
Using an isovolumetric method in which urethral changes were measured, SB‐269970 (30 μg kg−1; n=4; i.c.v.) failed to have any effect on these urethral‐evoked changes although they significantly reduced the amplitude of the bladder contraction.
These data demonstrate that 5‐HT7 receptors located supraspinally in the rat are involved in the control of micturition.

British Journal of Pharmacology (2003) 140, 53–60. doi:10.1038/sj.bjp.0705399
Partial agonist behaviour depends upon the level of nociceptin/orphanin FQ receptor expression: studies using the ecdysone‐inducible mammalian expression system
Authors: McDonald J , Barnes T A , Okawa H , Williams J , Calo' G , Rowbotham D J , Lambert D G 
Published: September 2003

Partial agonism is primarily dependent upon receptor density and coupling efficiency. As these parameters are tissue/model dependent, intrinsic activity in different tissues can vary. We have utilised the ecdysone‐inducible expression system containing the human nociceptin/orphanin FQ (N/OFQ) peptide receptor (hNOP) expressed in Chinese hamster ovary cells (CHOINDhNOP) to examine the activity of a range of partial agonists in receptor binding, GTPγ35S binding and inhibition of adenylyl cyclase studies.
Incubation of CHOINDhNOP cells with ponasterone A (PON) induced hNOP expression ([leucyl‐3H]N/OFQ binding) of 24, 68, 191 and 1101 fmol mg−1 protein at 1, 2, 5 and 10 μM PON, respectively. At 191 fmol mg−1, protein hNOP pharmacology was identical to that reported for other traditional expression systems.
pEC50 values for GTPγ35S binding ranged from 7.23 to 7.72 (2–10 μM PON) for the partial agonist [Phe1ψ(CH2–NH)Gly2]N/OFQ(1–13)–NH2 ([F/G]N/OFQ(1–13)–NH2) and 8.12–8.60 (1–10 μM PON) for N/OFQ(1–13)–NH2 and Emax values (stimulation factor relative to basal) ranged from 1.51 to 3.21 (2–10 μM PON) for [F/G]N/OFQ(1–13)–NH2 and 1.28–6.95 (1–10 μM) for N/OFQ(1–13)–NH2. Intrinsic activity of [F/G]N/OFQ(1–13)–NH2 relative to N/OFQ(1–13)–NH2 was 0.3–0.5. [F/G]N/OFQ(1–13)–NH2 did not stimulate GTPγ35S binding at 1 μM PON, but competitively antagonised the effects of N/OFQ(1–13)–NH2 with a pKB=7.62.
pEC50 values for cAMP inhibition ranged from 8.26 to 8.32 (2–10 μM PON) for [F/G]N/OFQ(1–13)–NH2 and 9.42–10.35 for N/OFQ(1–13)–NH2 and Emax values (% inhibition) ranged from 19.6 to 83.2 for [F/G]N/OFQ(1–13)–NH2 and 40.9–86.0 for N/OFQ(1–13)–NH2. The intrinsic activity of [F/G]N/OFQ(1–13)–NH2 relative to N/OFQ(1–13)–NH2 was 0.48–0.97.
In the same cellular environment with receptor density as the only variable, we show that the profile of [F/G]N/OFQ(1–13)–NH2 can be manipulated to encompass full and partial agonism along with antagonism.

British Journal of Pharmacology (2003) 140, 61–70. doi:10.1038/sj.bjp.0705401
Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX‐1 and COX‐2 selective inhibitors, and an LTC4receptor antagonist
Authors: Arumugam Thiruma V , Arnold Naomi , Proctor Lavinia M , Newman Michelle , Reid Robert C , Hansford Karl A , Fairlie David P , Shiels Ian A , Taylor Stephen M 
Published: September 2003

A new group IIa sPLA2inhibitor was compared with selective inhibitors of COX‐1, COX‐2 and an LTC4antagonist for effects on local and remote tissue injuries following ischaemia and reperfusion (I/R) of the small intestine in rats.In an acute model of ischaemia (30 min) and reperfusion (150 min) injury in the absence of inhibitors, there was significant intestinal haemorrhage, oedema and mucosal damage, neutropenia, elevated serum levels of aspartate aminotransferase (AST) and hypotension.Preischaemic treatment with the inhibitor of sPLA2(Group IIa), at 5 mg kg−1i.v. or 10 mg kg−1p.o. significantly inhibited I/R‐induced neutropenia, the elevation of serum levels of AST, intestinal oedema and hypotension.Pretreatment with the COX‐2 inhibitor celebrex (10 mg kg−1i.v.) and the LTC4antagonist zafirlukast (1 mg kg−1i.v.) also showed marked improvement with I/R‐induced AST, oedema and neutropenia. Hypotension was only reduced by the LTC4antagonist. The COX‐1 inhibitor flunixin (1 mg kg−1i.v.) did not effect improvement in the markers of tissue injury.Histological examination of rat I/R injury showed that all of the drugs offered some protection to the mucosal layer damage compared to no drug treatment. Given i.v., the sPLA2inhibitor was more effective than either the COX‐1 or COX‐2 inhibitors in preventing rat I/R injury.These results indicate that a potent new inhibitor of sPLA2(group IIa) protects the rat small intestine from I/R injury after oral or intravenous administration. COX‐2 and LTC4inhibitors also showed some beneficial effects against intestinal I/R injury. Our study suggests that sPLA2(Group IIa) may have a pathogenic role in intestinal I/R in rats.British Journal of Pharmacology(2003)140, 71–80. doi:10.1038/sj.bjp.0705402