INFLAMMATORY BOWEL DISEASES, Issue 4 2005
Charles N Bernstein MD
Abstract Background: There is a potential interface between osteoporosis and the chronic inflammation of inflammatory bowel disease (IBD), and the osteoprotegerin (OPG)/receptor for activated nuclear factor-,B (RANK)/RANK ligand (RANKL) signaling pathway may be an important mediator, although data are limited. Methods: We conducted a population-based case-control seroassay study to look for alterations in serum OPG and soluble RANKL (sRANKL). The study population included IBD patients who were 18 to 50 years old with Crohn's disease (CD; n = 287) or ulcerative colitis (UC; n = 166), age-matched healthy controls (n = 368), and nonaffected siblings of IBD patients (n = 146). Serum OPG and sRANKL were measured by enzyme-linked immunoassay. Sex-specific reference ranges were derived from the healthy controls. Results: Analysis of variance (ANOVA) confirmed significant group differences in women for mean serum OPG (P = 0.018). CD women had higher values of OPG than UC women (P = 0.028) or healthy controls (P = 0.045), whereas the other groups were similar. OPG levels were above the reference range in 13/173 (8%) of CD women, exceeding the expected proportion (P = 0.032). In contrast, no differences in OPG were seen in men between controls, CD, or UC. Estrogen use in women (P = 0.000002) and corticosteroid use in men (P = 0.026) were associated with higher OPG levels. In multivariate analysis, CD diagnosis (P = 0.031) and estrogen use (P = 0.000002) were independently associated with higher OPG levels. No group differences were seen in mean serum sRANKL measurements. Conclusions: An OPG:sRANKL imbalance with OPG exceeding sRANKL should inhibit osteoclastogenesis and promote bone formation. CD is associated with increased fracture risk, and possibly, the paradoxically higher OPG is a counterregulatory response to factors such as inflammatory cytokines, promoting high bone turnover. Alternatively, elevated OPG in CD may reflect T-cell activation. [source]

Thymoquinone protects renal tubular cells against tubular injury

CELL BIOCHEMISTRY AND FUNCTION, Issue 3 2008
Ahmed Amir Radwan Sayed
Abstract In this work the effect of angiotensin II (AT II) on proximal tubular epithelial cells (pTECs) in vitro was studied. AT II was found to activate the nuclear factor ,B (NF- ,B) and its controlled genes, for example, interleukin 6 (IL-6) of pTECs in a time-dependent manner. Two points with maximum NF- ,B activation were found, the first after 12,h and the second after 3.5 days. The first point may be due to activation of NF- ,B in pTECs in response to AT II while the second may be due to activation of the advanced glycation end product (AGE)/receptor of the AGE (RAGE) system. Thymoquinone (TQ) was found to decrease NF- ,B activation in a dose-dependant manner with maximum inhibitory effect at a concentration of 500,nM. Also, pre-incubation of pTECs with TQ leads to disappearance of the second peak of NF- ,B. These data are consistent with results obtained from IL-6 enzyme-linked immunosorbent assay (ELISA) and transient transfection experiments. The results explain the therapeutic value of TQ which can be used to delay end stage renal diseases in diabetics. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Polymorphisms in innate immunity genes and lung cancer risk in Xuanwei, China,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2009
Min Shen
Abstract The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population-based case,control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% CI: 0.16,0.55; P: 0.0001; false discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value <0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; Pinteraction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; Pinteraction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH-containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy. Environ. Mol. Mutagen., 2009. Published 2009 Wiley-Liss, Inc. [source]

INSULIN-LIKE GROWTH FACTOR-I RECEPTOR AS A CANDIDATE FOR A NOVEL MOLECULAR TARGET IN GASTROINTESTINAL CANCERS

DIGESTIVE ENDOSCOPY, Issue 4 2006
Yasushi Adachi
Abnormal activation of growth factor receptors and their signal pathways are required for neoplastic transformation and tumor progression. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, such as those acting against HER2/neu, epidermal growth factor receptor 1, and c-Kit. In this review, we focus on the next promising therapeutic molecular target of insulin-like growth factor (IGF)-I receptor (IGF-Ir). The IGF/IGF-Ir system is an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity in a number of neoplastic diseases, including human gastrointestinal carcinomas. Preclinical studies demonstrated that downregulation of IGF-Ir signals reversed the neoplastic phenotype and sensitized cells to antitumor treatments. We summarize a variety of ways to disrupt IGF-Ir function. Then, we introduce our strategy of adenoviruses expressing dominant negative of IGF-Ir (IGF-Ir/dn) against gastrointestinal cancers, including stomach, colon, and pancreas. IGF-Ir/dn suppresses tumorigenicity both in vitro and in vivo and increases stressor-induced apoptosis. IGF-Ir/dn expression upregulates chemotherapy-induced apoptosis and these combination therapies with chemotherapy are very effective against tumors in mice. Some drugs blocking IGF-Ir function are now entering clinical trial, thus IGF-Ir might be a candidate for a therapeutic target in several gastrointestinal malignancies. [source]

CHARACTERIZATION OF A DINOFLAGELLATE CRYPTOCHROME BLUE-LIGHT RECEPTOR WITH A POSSIBLE ROLE IN CIRCADIAN CONTROL OF THE CELL CYCLE,

JOURNAL OF PHYCOLOGY, Issue 3 2007
Stephanie A. Brunelle
Karenia brevis (C. C. Davis) G. Hansen et Moestrup is a dinoflagellate responsible for red tides in the Gulf of Mexico. The signaling pathways regulating its cell cycle are of interest because they are the key to the formation of toxic blooms that cause mass marine animal die-offs and human illness. Karenia brevis displays phased cell division, in which cells enter S phase at precise times relative to the onset of light. Here, we demonstrate that a circadian rhythm underlies this behavior and that light quality affects the rate of cell-cycle progression: in blue light, K. brevis entered the S phase early relative to its behavior in white light of similar intensity, whereas in red light, K. brevis was not affected. A data base of 25,000 K. brevis expressed sequence tags (ESTs) revealed several sequences with similarity to cryptochrome blue-light receptors, but none related to known red-light receptors. We characterized the K. brevis cryptochrome (Kb CRY) and modeled its three-dimensional protein structure. Phylogenetic analysis of the photolyase/CRY gene family showed that Kb CRY is a member of the cryptochrome DASH (CRY DASH) clade. Western blotting with an antibody designed to bind a conserved peptide within Kb CRY identified a single band at ,55 kDa. Immunolocalization showed that Kb CRY, like CRY DASH in Arabidopsis, is localized to the chloroplast. This is the first blue-light receptor to be characterized in a dinoflagellate. As the Kb CRY appears to be the only blue-light receptor expressed, it is a likely candidate for circadian entrainment of the cell cycle. [source]

NERVE GROWTH FACTOR RESCUE OF CISPLATIN NEUROTOXICITY IS MEDIATED THROUGH THE HIGH AFFINITY RECEPTOR: STUDIES IN PC12 CELLS AND P75 NULL MOUSE DORSAL ROOT GANGLIA

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002
SJ Fischer
Nerve growth factor (NGF) rescues dorsal root ganglion neurons and PC12 cells from cisplatin-induced cell death. Two model systems were used to demonstrate that rescue is mediated through the high affinity NGF receptor. In dorsal root ganglion (DRG) neurons isolated from p75(,/,) and control mice, 20 ng/ml NGF completely prevented cisplatin-induced death. In PC12 cells, we overexpressed receptor chimeras between the tumor necrosis factor and NGF receptors. We demonstrated that activation of the intracellular domain of Trk A is responsible for the NGF rescue effect. [source]

LOSS OF ESTROGEN RECEPTOR- , (ER,) IN PROSTATE CANCER

PATHOLOGY INTERNATIONAL, Issue 12 2001
Horvath LG
No abstract is available for this article. [source]

THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2009
Masamune Kuno
SUMMARY 1TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1,3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis. [source]

ANGIOTENSIN AT2 RECEPTOR AS A POTENTIAL THERAPEUTIC TARGET IN HYPERTENSION

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2009
Wing Tak Wong
No abstract is available for this article. [source]

PIOGLITAZONE INHIBITS HOMOCYSTEINE-INDUCED MIGRATION OF VASCULAR SMOOTH MUSCLE CELLS THROUGH A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ,-INDEPENDENT MECHANISM

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2008
Li Li
SUMMARY 1Peroxisome proliferator-activated receptor (PPAR)-, agonists have been demonstrated to exert protective effects against homocysteine (Hcy)-induced pathogenesis. However, the effects of PPAR-, agonists on Hcy-induced migration are unknown. In the present study, we examined the effect of pioglitazone on the migration of vascular smooth muscle cells (VSMC) induced by Hcy and the possible mechanism involved. 2Vascular smooth muscle cells were isolated from the thoracic aortas of male Sprague-Dawley rats. The migration of VSMC was examined using a transwell technique. The generation of intracellular reactive oxygen species (ROS) was measured using the ROS-sensitive fluoroprobe 2,,7,-dichlorodihydrofluorescein diacetate. The activity of NAD(P)H oxidase was assessed by lucigenin enhanced chemiluminescence. Activation of p38 mitogen-activated protein kinase (MAPK) was determined by western blotting. 3The results showed that pioglitazone dose-dependently inhibited the migration of VSMC induced by Hcy. This was not reversed by the PPAR-, antagonist GW9662. In addition, pretreatment with the NAD(P)H oxidase inhibitor diphenylene iodonium (DPI), the free radical scavenger N -acetylcysteine and the p38 MAPK inhibitor SB202190 blocked Hcy-induced VSMC migration. Furthermore, we observed that pioglitazone suppressed Hcy-induced intracellular ROS production; similar effects were observed with DPI and NAC. Pioglitazone attenuated Hcy-induced activation of NAD(P)H oxidase. Moreover, pioglitazone blocked Hcy-induced p38 MAPK phosphorylation; similar effects were observed for DPI, NAC and SB202190. 4The data demonstrate that pioglitazone inhibits Hcy-induced VSMC migration that is independent of PPAR-,. Furthermore, part of the biological effect of pioglitazone involves a decrease in the levels of NAD(P)H oxidase derived-ROS and p38 MAPK activation. [source]

AN S296R MUTATION IN THE HUMAN ANDROGEN RECEPTOR CAUSES ACTIVATION OF THE RECEPTOR BY NON-ANDROGENIC STEROIDS AND STRONGER INHIBITION BY THE NUCLEAR RECEPTOR COREPRESSOR N-coR

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008
Yi-Dong Li
SUMMARY 1Mutation of the androgen receptor (AR) is believed to contribute to androgen-independent growth of prostate cancer. In the present study, we examined the functional changes associated with the novel somatic mutation S296R in the N-terminal domain of the AR identified from one recurrent prostate cancer sample. 2The results indicate that the S296R mutation does not differ obviously from the wild-type AR in its ability to bind the synthetic androgen methyltrienolone, or in its transcriptional activity induced by dihydrotestosterone (DHT) in the absence or presence of the overexpression of coactivators (steroid receptor coactivator-1, transcription intermediary factor-2, cAMP response element-binding protein-binding protein and p300). However, S296R was found to differ from wild-type AR in that its transcriptional activity could be activated by high concentrations (1 µmol/L) of 17,-oestradiol and progesterone and its transactivity induced by DHT was more obviously inhibited by overexpression of the nuclear receptor corepressor N-coR in CV-1 cells. 3These findings indicate that a point mutation (S296R) in the N-terminal domain of the AR can decrease the ligand specificity of the AR and alter the interaction between S296R and the corepressor N-coR. [source]

WHAT MAKES A CGRP2 RECEPTOR?

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2007
DL Hay
SUMMARY 1Heterogeneity in the receptors for the neuropeptide calcitonin gene-related peptide (CGRP) has been apparent for nearly 20 years. This is most clearly manifested in the observation of CGRP8,37 -sensitive and -insensitive populations of CGRP-activated receptors. The pA2 values for CGRP8,37 in excess of 7 are widely considered to be the result of antagonism of CGRP1 receptors, whereas those below 7 are believed to be the consequence of antagonism of a second population of receptors, namely CGRP2 receptors. 2However, a multitude of pA2 values exist for CGRP8,37, spanning several log units, and as such no obvious clusters of values are apparent. Understanding the molecular nature of the receptors that underlie this phenomenon is likely to aid the development of selective pharmacological tools to progress our understanding of the physiology of CGRP and related peptides. Because there is active development of CGRP agonists and antagonists as therapeutics, such information would also further this pursuit. 3The CGRP1 receptor is pharmacologically and molecularly well defined as a heterodimer of the calcitonin receptor-like receptor (CL) and receptor activity modifying protein (RAMP) 1. The CL/RAMP1 complex is highly sensitive to CGRP8,37. Conversely, the constituents of the CGRP2 receptor have not been identified. In fact, there is little evidence for a distinct molecular entity that represents the CGRP2 receptor. 4Recent pharmacological characterization of receptors related to CGRP1 has revealed that some of these receptors may explain CGRP2 receptor pharmacology. Specifically, AMY1(a) (calcitonin receptor/RAMP1) and AM2 (CL/RAMP3) receptors can be activated by CGRP but are relatively insensitive to CGRP8,37. 5This, along with other supporting data, suggests that the ,CGRP2 receptor' that has been extensively reported in the literature may, in fact, be an amalgamation of contributions from a variety of CGRP-activated receptors. The use of appropriate combinations of agonists and antagonists, along with receptor expression studies, could allow such receptors to be separated. [source]

IMMUNOLOCALIZATION OF FIBROBLAST GROWTH FACTOR RECEPTORS IN THE ADULT RAT KIDNEY

NEPHROLOGY, Issue 3 2000
John F Bertram
[source]

MELATONIN REDUCES BLOOD PRESSURE IN RATS WITH STRESS-INDUCED HYPERTENSION VIA GABAA RECEPTORS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2009
Hua-Li Li
SUMMARY 1Several groups have reported that melatonin produces a significant decrease in blood pressure in mammals and that pinealectomy in rats causes hypertension. The purpose of the present study was to investigate the effects of melatonin and bicuculline methiodide on the blood pressure of rats, both in the developing and fully developed stage of stress-induced hypertension (SIH). 2Rats with SIH were generated by mild electric foot shocks for 15 days, after which tail arterial systolic pressure and plasma angiotensin (Ang) II levels were measured. The effects of melatonin injections (i.p. or i.c.v.) on mean arterial pressure (MAP) in rats with SIH were also determined. 3Pretreatment with 1 mg/kg, i.p., melatonin significantly diminished the elevated tail arterial systolic pressure and plasma AngII levels caused by 15 days stress. The suppressive effects of melatonin were blocked by i.p. injection of 1 mg/kg bicuculline methiodide, an antagonist of the GABAA receptor. 4Intraperitoneal (0.2, 0.5 and 1 mg/kg) or i.c.v. (0.15 and 1.5 µg/3 µL) injection of melatonin produced a dose-dependent lowering of MAP in rats with SIH. The antihypertensive response induced by melatonin was blocked by injection of both 1 mg/kg, i.p., and 1.5 × 106 µg/3 µL, i.c.v., bicuculline methiodide. 5In conclusion, melatonin not only prevents increases in blood pressure during the developing stage of SIH, but can also reduce the blood pressure of rats that have already developed SIH. The antihypertensive effect of melatonin may be mediated by GABAA receptors through inhibition of plasma AngII levels. [source]

ILLUMINATING THE STRUCTURE AND FUNCTION OF CYS-LOOP RECEPTORS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008
Stephan A Pless
SUMMARY 1Cys-loop receptors are an important class of ligand-gated ion channels. They mediate fast synaptic neurotransmission, are implicated in various ,channelopathies' and are important pharmacological targets. Recent progress in X-ray crystallography and electron microscopy has provided a considerable insight into the structure of Cys-loop receptors. However, data from these experiments only provide ,snapshots' of the proteins under investigation. They cannot provide information about the various conformations the protein adopts during transition from the closed to the open and desensitized states. 2Voltage-clamp fluorometry helps overcome this problem by simultaneously monitoring movements at the channel gate (through changes in current) and conformational rearrangements in a domain of interest (through changes in fluorescence) in real time. Thus, the technique can provide information on both transitional and steady state conformations and serves as a real time correlate of the channel structure and its function. 3Voltage-clamp fluorometry experiments on Cys-loop receptors have yielded a large body of data concerning the mechanisms by which agonists, antagonists and modulators act on these receptors. They have shed new light on the conformational mobility of both the ligand-binding and the transmembrane domain of Cys-loop receptors. [source]

KETANSERIN-INDUCED BAROREFLEX ENHANCEMENT IN SPONTANEOUSLY HYPERTENSIVE RATS DEPENDS ON CENTRAL 5-HT2A RECEPTORS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 8 2007
Fu-Ming Shen
SUMMARY 1Ketanserin may influence baroreflex function by blocking 5-HT2A receptors and/or ,1 -adrenoceptors through central and/or peripheral mechanisms. 2In the present study, we tested the hypothesis that the baroreflex sensitivity (BRS)-enhancing effects of ketanserin are mediated by central 5-HT2A receptors in spontaneously hypertensive rats (SHR). 3Using a conjugate of a monoclonal antibody to the serotonin reuptake transporter (SERT) and the toxin saporin (anti-SERT-SAP), which specifically eliminates the neurons that express SERT, the effects of ketanserin (0.3 and 3.0 mg/kg, i.g.) on BRS, blood pressure (BP), heart period (HP) and blood pressure variability (BPV) were compared between conscious intact SHR and SHR pretreated with anti-SERT-SAP. 4Immunochemistry showed that, 2 weeks after intracerebroventricular injection of the toxin, 5-HT expression was strikingly attenuated in the brain, whereas values of BRS, BPV and BP were similar to those in the sham group. In intact SHR, 0.3 mg/kg ketanserin significantly improved BRS (191% control) and reduced BPV without affecting BP; at 3.0 mg/kg, ketanserin significantly increased BRS (197% control) and decreased BPV and BP. In toxin-pretreated SHR, only the high dose of ketanserin improved BRS (132% control), neither of the ketanserin doses reduced BPV, but both significantly decreased BP. 5We conclude that the BRS-enhancing effects of ketanserin are mediated largely by central 5-HT2A receptors, whereas the antihypertensive effect of ketanserin persists even after destruction of serotonergic neurons in the central nervous system. [source]

CONTRIBUTION OF PROSTANOID TP RECEPTORS TO THE PRESSOR AND INTRARENAL HAEMODYNAMIC RESPONSE TO ENDOTHELIN

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2006
Jan Michael Williams
SUMMARY 1Previous studies have shown that endothelin (ET)-1 stimulates thromboxane (Tx)A2 production and so we hypothesized that inhibiting prostanoid TP receptors would prevent the pressor and intrarenal haemodynamic response to an acute infusion of ET-1. 2Male Sprague-Dawley rats were anaesthetized with Inactin (Sigma Chemical, St Louis, MO, USA; 50 mg/kg) and catheters were inserted into the femoral artery and vein for recording mean arterial pressure (MAP) and infusion of ET-1 and receptor antagonists, respectively. A jugular vein catheter was used for the infusion of bovine serum albumin (6.2% in saline) during surgery (1.25% bodyweight). The pressor response to a 1 h infusion of ET-1 (6 pmol/kg per min) was determined in rats that had been pretreated with vehicle (0.9% NaCl) or the TP receptor antagonist SQ29548 (2 mg/kg per h). Laser Doppler single-optic fibres were implanted in the left kidney for the measurement of medullary blood flow (MBF) and cortical blood flow (CBF). 3Prostanoid TP receptor blockade completely inhibited the acute pressor response to ET-1; the change in MAP was 14 2% versus -3 4% in vehicle and SQ29548 groups, respectively (P < 0.05). Endothelin-1 reduced CBF (-15.2 3.3%), a response that was not significantly changed by SQ29548 (-6.2 7.6%). Similarly, the ET-1-mediated response in MBF was not altered by the TP receptor antagonist (7.7 4.9 vs 6.5 5.2%). 4To determine the influence of the ETB receptor in modulating the response to ET-1 during TP receptor blockade, additional groups were pretreated with A-192621, an ETB receptor-selective antagonist (10 mg/kg, i.v.). A-192621 potentiated the increase in MAP produced by ET-1 (32 5%; P < 0.05 vs ET-1 alone). SQ29548 significantly inhibited, but did not completely block, the increase in MAP produced by ET-1 during ETB antagonist treatment (18 4%; P < 0.05). Endothelin-1-induced decreases in CBF were significantly enhanced in rats that were pretreated with A-192621, whereas ET-1 also significantly decreased MBF following A-192621 treatment. During ETB receptor blockade, TP receptor inhibition had no effect on the ET-1-mediated response of CBF and MBF. 5These results suggest that TP receptor activation is not involved in the renal haemodynamic responses to ET-1. However, TP receptor activation contributes to the acute pressor response to ET-1, but does not account for the potentiated increase in MAP during ETB receptor blockade. [source]

INVOLVEMENT OF N -METHYL- d -ASPARTATE RECEPTORS and NITRIC OXIDE IN THE ROSTRAL VENTROMEDIAL MEDULLA IN MODULATING MORPHINE PAIN-INHIBITORY SIGNALS FROM THE PERIAQUEDUCTAL GREY MATTER IN RATS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2005
Kazem Javanmardi
SUMMARY 1.,Supraspinal opioid antinociception is mediated, in part, by connections between the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM). Morphine antinociception from the PAG is decreased by serotonin, N -methyl- d -aspartate (NMDA) and opioid receptor antagonists administered into the RVM. Because the brain isoform of nitric oxide synthase (NOS) is also prominent in the RVM, the present study was designed to evaluate the effects of microinjection of the non-selective NOS inhibitor NG -nitro- l -arginine methyl ester (l -NAME) and the non-competitive NMDA receptor antagonist MK-801 into the RVM on PAG morphine antinociception and their potential interactions, as measured by the tail-flick test. 2.,Rats were anaesthetized with sodium pentobarbital and then special cannulas were inserted stereotaxically into the RVM and PAG. After 1 week recovery, the effects of microinjection of MK-801 and l -NAME into the RVM and their interactions in altering PAG morphine (2.5 µg) antinociception elicited from the PAG were assessed. 3.,Mesencephalic morphine antinociception was significantly reduced after pretreatment with l -NAME (0.6,1.3 µmol) or MK-801 (0.8 nmol). The reduction in mesencephalic morphine antinociception when MK-801 (0.8 nmol) and l -NAME (1 µmol) were microinjected sequentially into the RVM was not significantly different from the effects of MK-801 (0.8 nmol) or l -NAME (1 µmol) administered alone. 4.,These data imply that NMDA receptors and nitric oxide production in the RVM modulate the transmission of opioid pain-inhibitory signals from the PAG. [source]

DIFFERENTIAL REGULATION OF ANGIOTENSIN II RECEPTORS DURING RENAL INJURY AND COMPENSATORY HYPERTROPHY IN THE RAT

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2005
Emma Joly
SUMMARY 1.,The renin-angiotensin system may be involved in the compensatory adaptations occurring after the reduction of renal mass and during the consecutive changes leading to chronic renal failure. We therefore investigated the regulation of angiotensin II receptors in two models of renal hypertrophy in the rat: hypertrophy following uninephrectomy (UNx) or subtotal nephrectomy (STNx). The level of angiotensin type 1 (AT1A -R and AT1B -R) and type 2 (AT2 -R) receptor mRNA was quantified by competitive reverse transcription-polymerase chain reaction (RT-PCR) in specific renal zones and the intrarenal distribution of angiotensin II receptors was analysed by immunohistochemistry. 2.,In the UNx rats, AT1 -R mRNA expression was not modified in the cortex or in the inner stripe of the outer medulla of the residual kidney at any time after the surgery (1, 4 and 12 weeks). In contrast, AT1 -R mRNA expression was significantly reduced in these zones in STNx rats (,33% and ,40%, respectively). This downregulation was organ-specific, as AT1 -R mRNA levels were not modified in the liver. The proportions of AT1 -R subtype (AT1A and AT1B) mRNA were unchanged by UNx or STNx. Very low levels of AT2 -R mRNA were found in the cortex of all groups. Immunostaining revealed a similar localization of AT1 -R in mesangial cells, proximal tubule, basolateral membrane of thick ascending limb, in both models of hypertrophy. AT1 -R labelling was also detected in the apical membrane of intercalated cells of cortical collecting ducts. 3.,This differential mRNA expression of angiotensin II receptors during compensatory hypertrophy and renal injury suggests that the development of renal hypertrophy is independent of AT1 -R and AT2 -R gene expression levels. [source]

DOPAMINERGIC RECEPTORS IN RAT DURA MATER: PHARMACOLOGICAL CHARACTERISTICS

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2004
C Cavallotti
SUMMARY 1.,The location and distribution of dopaminergic receptors in rat dura mater was studied by examining several dural zones (vascular, perivascular, intervascular) in different cranial and spinal regions. 2.,The pharmacological characteristics and anatomical distribution of dopamine D1- and D2-like receptors sites were investigated using combined pharmacological techniques and immunofluorescent microscopy. 3.,Samples of rat dura mater were obtained from 10 adult Wistar rats. On frozen slices, dopaminergic D1 and D2 receptors were stained immunohistochemically using monoclonal antibodies. 4.,Inhibition studies were performed using fluorescent and non-fluorescent agonists or antagonists to define the pharmacological specificity of the immunostaining. 5.,The greater sensitivity to displacement by amisulpride, bromocryptine, domperidone, haloperidol, raclopride and l -sulpiride than to displacement by N -propyl-nor-apomorphine, quinpirole and clozapine suggests that the immunofluorescent sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype. 6.,Our observations provide evidence of the presence of D1 and D2 receptors in the wall of meningeal vessels. The dopaminergic receptors are located in the adventitia, media and intima of dural arteries. Furthermore, the density of receptors is higher in close proximity to arteries and decreases passing from the vascular to the perivascular and intervascular zones. 7.,In the rat dura mater, dopamine regulates the meningeal blood vessels and, through this action, dopamine and its receptors can play an important role in the pathogenesis of cephalalgia. [source]

Development of Amygdaloid Kindling in Histidine Decarboxylase,deficient and Histamine H1 Receptor,deficient Mice

EPILEPSIA, Issue 4 2004
Tadashi Hirai
Summary: Purpose: This study attempted to clarify the role of histamine or histamine H1 receptors in the development of amygdaloid kindling by using histidine decarboxylase (HDC)-deficient and histamine H1 receptor (H1R)-deficient mice. Methods: Under pentobarbital anesthesia, mice were fixed to a stereotaxic apparatus, and bipolar electrodes were implanted into the right amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. A bipolar electroencephalogram was recorded; bipolar stimulation of the amygdala was applied every day with a constant-current stimulator and continued until a generalized convulsion was obtained. Results: The development of amygdaloid kindling in HDC-deficient and H1R-deficient mice was significantly accelerated compared with that in their respective wild-type mice. In addition, the afterdischarge (AD) duration and generalized seizure duration in HDC-deficient and H1R-deficient mice were prolonged. Intraperitoneal injection of histidine resulted in an inhibition of amygdaloid kindled seizures in wild-type mice at doses that caused an increase in the histamine contents of the brain. However, no significant effect was observed with histidine in H1R-deficient mice at the same dose. Conclusions: These findings suggest that histaminergic mechanisms through H1 receptors play a crucial role not only in amygdaloid kindled seizures but also in the development of amygdaloid kindling. [source]

Dose-dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

EPILEPSIA, Issue 12 2003
Srikanth C. Nallani
Summary:,Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose-dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. Methods: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 ,M) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 ,M). The rate of testosterone 6,-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell-based reporter gene assay. Results: Compared with controls, TPM (50,500 ,M),treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6- to 8.2-fold), protein levels (4.6- to 17.3-fold), and mRNA levels (1.9- to 13.3-fold). Comparatively, rifampicin (10 ,M) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50,500 ,M) caused 1.3- to 3-fold activation of the hPXR, whereas rifampicin (10 ,M) caused a 6-fold activation. Conclusions: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used. [source]

Receptor versus Counterion: Capability of N,N, -Bis(2-aminobenzyl)-diazacrowns for Giving Endo- and/or Exocyclic Coordination of ZnII

EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2007
Lea Vaiana
Abstract The structure of ZnII complexes with receptors L1 and L2[L1 = N,N, -bis(2-aminobenzyl)-1,10-diaza-15-crown-5 and L2 = N,N, -bis(2-aminobenzyl)-4,13-diaza-18-crown-6] was studied both in the solid state and in acetonitrile solution. Both receptors form mononuclear ZnII complexes in this solvent, while no evidence for the formation of dinuclear complexes was obtained. This is in contrast with previous investigations that demonstrated the formation of dinuclear complexes of L2 with first-row transition metals such as NiII, CoII and CuII. Compounds of formula [Zn(L1)](ClO4)2 (1), [Zn(L1)](NO3)2·2CH3CN (2), [Zn(L2)](ClO4)2 (3) and [Zn(L2)(NO3)2] (4) were isolated and structurally characterised by X-ray diffraction analyses. L1 forms seven-coordinate ZnII complexes in the presence of both nitrate and perchlorate anions, as a consequence of the good fit between the macrocyclic cavity and the ionic radius of the metal ion. The ZnII ion is deeply buried into the receptor cavity and the anions are forced to remain out of the metal coordination sphere. The cation [Zn(L1)]2+ present in 1 and 2 is one of the very few examples of seven-coordinate Zn complexes. Receptor L2 provides a very rare example of a macrocyclic receptor allowing endocyclic and exocyclic coordination on the same guest cation, depending on the nature of the anion present. Thus, in 3 the ZnII ion is endocyclically coordinated, placed inside the crown hole coordinated to four donor atoms of the ligand in a distorted tetrahedral environment, whereas in 4, the presence of a strongly coordinating anion such as nitrate results in an exocyclic coordination of ZnII, which is directly bound only to the two primarily amine groups of L2 and two nitrate ligands. Spectrophotometric titrations of [Zn(L2)]2+ with tetrabutylammonium nitrate in acetonitrile solution demonstrate the stepwise formation of 1:1 and 1:2 adducts with this anion in acetonitrile solution. The [Zn(L1)]2+, [Zn(L2)]2+ and [Zn(L2)(NO3)2] systems were characterised by means of DFT calculations (B3LYP model). The calculated geometries show an excellent agreement with the experimental structures obtained from X-ray diffraction analyses. Calculated binding energies of the macrocyclic ligands to ZnII are also consistent with the experimental data.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source]

A Highly Enantioselective Receptor for Carbamoyl Lactic Acid,

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 31 2009
Francisco M. Muñiz
Abstract A new receptor based on a 9,9-dimethylxanthene framework was synthesized. Owing to its suitable oxyanion hole structure, this receptor is able to associate carboxylic acids and anions. The introduction of a chiral center provides enantioselective properties to this receptor as a result of its different interactions with both enantiomers of the substrate. The combination of this skeleton with a fluorescent unit such as dansyl allows the detection of small amounts of carboxylic acids by making use of fluorescent techniques.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

Synthesis and Hormonal Activity of the (25S)-Cholesten-26-oic Acids , Potent Ligands for the DAF-12 Receptor in Caenorhabditis elegans

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2009
René Martin
Abstract Using a highly stereoselective Evans aldol reaction for the introduction of the stereogenic center at C-25, we describe an efficient synthesis of the orthogonally diprotected (25S)-26-hydroxycholesterol 11. In a few synthetic steps, this crucial intermediate 11 has been converted into the four (25S)-cholesten-26-oic acids 1,4, which have been obtained in 12,15 steps and 19,53,% overall yield based on commercially available 3,-hydroxychol-5-en-24-oic acid (5). Our biological studies of the compounds 1,4 reveal that (25S)-,7 -dafachronic acid (1) represents the most active steroidal ligand for the hormonal receptor DAF-12 in Caenorhabditis elegans. Moreover, the saturated (25S)-dafachronic acid (3) represents a new ligand for this receptor and the (25S)-steroidal acids are more active as compared to their corresponding (25R)-counterparts.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

An Acyclic Aminonaphthyridine-Based Receptor for Carbohydrate Recognition: Binding Studies in Competitive Solvents

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2007
Monika Mazik
Abstract 1H NMR spectroscopic and microcalorimetric titrations revealed that receptor 3b, consisting of three protonated 2-amino-1,8-naphthyridine units, binds N -acetylneuraminic acid (Neu5Ac), the most commonly occurring sialic acid, with high affinity in competitive solvents such as water/dimethyl sulfoxide. Receptor 3b is able to form neutral/charge-reinforced hydrogen bonds and ion pairs with Neu5Ac, similar to sialic acid-binding proteins. Furthermore, indications for weak binding of neutral sugars, such as methyl ,- D -glucopyranoside, D -maltose and D -cellobiose were provided by NMR spectroscopy. Molecular modelling calculations, synthesis and binding studies in aqueous media are described. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source]

Structural Studies on Hydrogen-Bonding Receptors for Barbiturate Guests That Use Metal Ions as Allosteric Inhibitors

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 1 2004
Mohammad H. Al-Sayah
Abstract Receptor 1 was designed to bind barbiturate substrates through a six-point hydrogen-bonding motif only in the absence of metal allosteric cofactors. It was predicted that the binding of metal ions by bipyridine ligands in 1 would result in a geometric change in the receptor to inhibit substrate recognition. However, receptor 1 showed minimal affinity for the barbiturate guests even in the absence of the metal. Binding studies on model compounds 2, 3, 5, and 6 revealed that the inactivity of 1 is due to an intramolecular hydrogen bond between the N,H donor groups and the nitrogen atoms on the first heterocycle of the bipyridine ligands. This intramolecular hydrogen-bonding was eliminated by altering the position of the tether between the bipyridine ligands and the active site to produce receptor 7. Consequently, the high affinity exhibited by 7 for the barbiturate substrate (Ka = 2.8±0.7 × 103M,1 in 9:1 CD2Cl2/CD3CN) was significantly reduced by the addition of ZnII ions as a negative allosteric co-factor. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source]

Anatomy of Primary Afferents and Projection Neurones in the Rat Spinal Dorsal Horn with Particular Emphasis on Substance P and the Neurokinin 1 Receptor

EXPERIMENTAL PHYSIOLOGY, Issue 2 2002
A. J. Todd
The dorsal horn of the spinal cord plays an important role in transmitting information from nociceptive primary afferent neurones to the brain; however, our knowledge of its neuronal and synaptic organisation is still limited. Nociceptive afferents terminate mainly in laminae I and II and some of these contain substance P. Many projection neurones are located in lamina I and these send axons to various parts of the brain, including the caudal ventrolateral medulla (CVLM), parabrachial area, periaqueductal grey matter and thalamus. The neurokinin 1 (NK1) receptor on which substance P acts is expressed by certain neurones in the dorsal horn, including approximately 80% of lamina I projection neurones. There is also a population of large NK1 receptor-immunoreactive neurones with cell bodies in laminae III and IV which project to the CVLM and parabrachial area. It has been shown that the lamina III/IV NK1 receptor-immunoreactive projection neurones are densely and selectively innervated by substance P-containing primary afferent neurones, and there is evidence that these afferents also target lamina I projection neurones with the receptor. Both types of neurone are innervated by descending serotoninergic axons from the medullary raphe nuclei. The lamina III/IV neurones also receive numerous synapses from axons of local inhibitory interneurones which contain GABA and neuropeptide Y, and again this input shows some specificity since post-synaptic dorsal column neurones which also have cell bodies in laminae III and IV receive few contacts from neuropeptide Y-containing axons. These observations indicate that there are specific patterns of synaptic connectivity within the spinal dorsal horn. [source]

NMDA Receptor Blockade Prevents Nitroglycerin-Induced Headaches

HEADACHE, Issue 7 2001
Peter Roffey MD
No abstract is available for this article. [source]

Single-Carbon-Atomic-Resolution Detection of Odorant Molecules using a Human Olfactory Receptor-based Bioelectronic Nose,

ADVANCED MATERIALS, Issue 1 2009
Tae Hyun Kim
Single-carbon-atomic-resolution detection of odorant molecules has been demonstrated using a human olfactory receptor-based bioelectric nose. Furthermore, since the human olfactory receptor is a G-protein-coupled receptor (GPCR), these sensor systems may be a new powerful platform for the development of new drugs and fragrances. [source]