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Modulatory Role (modulatory + role)
Selected AbstractsPigment-dispersing factor in the locust abdominal ganglia may have roles as circulating neurohormone and central neuromodulatorDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001Magnus G. S. Persson Abstract Pigment-dispersing factor (PDF) is a neuropeptide that has been indicated as a likely output signal from the circadian clock neurons in the brain of Drosophila. In addition to these brain neurons, there are PDF-immunoreactive (PDFI) neurons in the abdominal ganglia of Drosophila and other insects; the function of these neurons is not known. We have analyzed PDFI neurons in the abdominal ganglia of the locust Locusta migratoria. These PDFI neurons can first be detected at about 45% embryonic development and have an adult appearance at about 80%. In each of the abdominal ganglia (A3,A7) there is one pair of lateral PDFI neurons and in each of the A5,A7 ganglia there is additionally a pair of median neurons. The lateral neurons supply varicose branches to neurohemal areas of the lateral heart nerves and perisympathetic organs, whereas the median cells form processes in the terminal abdominal ganglion and supply terminals on the hindgut. Because PDF does not influence hindgut contractility, it is possible that also these median neurons release PDF into the circulation. Release from one or both the PDFI neuron types was confirmed by measurements of PDF-immunoreactivity in hemolymph by enzyme immunoassay. PDF applied to the terminal abdominal ganglion triggers firing of action potentials in motoneurons with axons in the genital nerves of males and the 8th ventral nerve of females. Because this action is blocked in calcium-free saline, it is likely that PDF acts via interneurons. Thus, PDF seems to have a modulatory role in central neuronal circuits of the terminal abdominal ganglion that control muscles of genital organs. © 2001 John Wiley & Sons, Inc. J Neurobiol 48: 19,41, 2001 [source] Electrochemical Nitric Oxide Sensors for Biological Samples , Principle, Selected Examples and ApplicationsELECTROANALYSIS, Issue 1 2003Fethi Bedioui Abstract The discoveries made in the 1980s that NO could be synthesized by mammalian cells and could act as physiological messenger and cytotoxic agent had elevated the importance of its detection. The numerous properties of NO, that enable it to carry out its diverse functions, also present considerable problems when attempting its detection and quantification in biological systems. Indeed, its total free concentration in physiological conditions has been established to be in nanomolar range. Thus, detection of nitric oxide remains a challenge, pointing out the difficult dual requirements for specificity and sensitivity. Exception made for the electrochemical techniques, most of the approaches (namely UV-visible spectroscopy, fluorescence, electron paramagnetic resonance spectroscopy) use indirect methods for estimating endogenous NO, relying on measurements of secondary species such as nitrite and nitrate or NO-adducts. They also suffer from allowing only ex situ measurements. So, the only strategies that allow a direct and in vivo detection of NO are those based on the use of ultramicroelectrodes. The reality is that surface electrode modification is needed to make the ultramicroelectrode material selective for NO. Therefore, the design of modified electrode surfaces using organized layers is very attractive and provides the ideal strategy. This review addresses a global description of the various approaches that have involved chemically modified microelectrodes specially designed for the electrochemical detection of NO in biological media. Selected significant examples of applications in biological tissues are also reported in order to highlight the importance of this approach in having new insights into the modulatory role of NO in physiology and pathophysiology. [source] REVIEW: Behavioral evidence for the significance of serotoninergic (5-HT) receptors in cocaine addictionADDICTION BIOLOGY, Issue 3 2010gorzata Filip ABSTRACT Cocaine addiction has somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Presently, there is no medication approved for the treatment of cocaine addiction. In recent years, data from the literature (pre-clinical studies and clinical trials) have provided several lines of evidence that serotonin (5-HT) and 5-HT receptors play a modulatory role in the mechanisms of action of cocaine. Here we review the contribution of 5-HT receptor subtypes to cocaine sensitization, discrimination, conditioned place preference, self-administration, reinstatement of seeking behavior and withdrawal symptoms in laboratory animals. Additionally, the consequences of chronic cocaine exposure on particular 5-HT receptor-assigned functions in pre-clinical studies are presented. [source] Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatumEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Ingrid Strömberg Abstract It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P < 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function. [source] A modulatory role for protein phosphatase 2B (calcineurin) in the regulation of Ca2+ entryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2000J. Russell Burley Abstract The Ca2+/calmodulin-dependent protein phosphatase 2B (PP2B) also known as calcineurin (CN) has been implicated in the Ca2+ -dependent inactivation of Ca2+ channels in several cell types. To study the role of calcineurin in the regulation of Ca2+ -channel activity, phosphatase expression was altered in NG108-15 cells by transfection of sense and antisense plasmid constructs carrying the catalytic subunit of human PP2B,3. Relative to mock-transfected (wild-type) controls, cells overexpressing calcineurin showed dramatically reduced high-voltage-activated Ca2+ currents which were recoverable by the inclusion of 1 ,m FK506 in the patch pipette. Conversely, in cells with reduced calcineurin expression, high-voltage-activated Ca2+ currents were larger relative to controls. Additionally in these cells, low-voltage-activated currents were significantly reduced. Analysis of high-voltage-activated Ca2+ currents revealed that the kinetics of inactivation were significantly accelerated in cells overexpressing calcineurin. Following the delivery of a train of depolarizing pulses in experiments designed to produce large-scale Ca2+ influx across the cell membrane, Ca2+ -dependent inactivation of high-voltage-activated Ca2+ currents was increased in sense cells, and this increase could be reduced by intracellular application of 1 m m BAPTA or 1 ,m FK506. These data support a role of calcineurin in the negative feedback regulation of Ca2+ entry through voltage-operated Ca2+ channels. [source] Effect of H. pylori on the Expression of TRAIL, FasL and their Receptor Subtypes in Human Gastric Epithelial Cells and their Role in ApoptosisHELICOBACTER, Issue 5 2004Jan Hendrik Martin ABSTRACT Background and Aims., In the human stomach expression of TNF-related apoptosis inducing ligand (TRAIL) and its receptors and the modulatory role of Helicobacter pylori are not well described. Therefore, we investigated the effect of H. pylori on the expression of TRAIL, FasL and their receptors (TRAIL-R1-R4, Fas) in gastric epithelial cells and examined their role in apoptosis. Materials and Methods., mRNA and protein expression of TRAIL, FasL and their receptors were analyzed in human gastric epithelial cells using RT-PCR, Western blot, and immunohistochemistry. Gastric epithelial cells were incubated with FasL, TRAIL and/or H. pylori, and effects on expression, cell viability and epithelial apoptosis were monitored. Apoptosis was analyzed by histone ELISA, DAPI staining and immunohistochemistry. Results., TRAIL, FasL and their receptor subtypes were expressed in human gastric mucosa, gastric epithelial cell primary cultures and gastric cancer cells. TRAIL, FasL and H. pylori caused a time- and concentration-dependent induction of DNA fragmentation in gastric cancer cells with synergistic effects. In addition, H. pylori caused a selective up-regulation of TRAIL, TRAIL-R1 and Fas mRNA and protein expression in gastric cancer cells. Conclusions., Next to FasL and Fas, TRAIL and all of its receptor subtypes are expressed in the human stomach and differentially modulated by H. pylori. TRAIL, FasL and H. pylori show complex interaction mediating apoptosis in human gastric epithelial cells. These findings might be important for the understanding of gastric epithelial cell kinetics in patients with H. pylori infection. [source] IL-6 levels decrease with SSRI treatment in patients with major depressionHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2005Ayse Devrim Basterzi Abstract Objective Some evidence indicates that an immune response with an increased production of proinflammatory cytokines often accompanies major depression. The objective of this study was to examine the serum levels of IL-6 in patients with major depression and the changes occurring in IL-6 levels during treatment with selective serotonin reuptake inhibitors (SSRI). Method Twenty-three patients with a DSM-IV diagnosis of major depressive disorder and 23 healthy matched controls were included in the study. The severity of depression was measured with the Hamilton rating scale for depression. Blood samples for IL-6 levels were obtained at baseline and at week 6 of treatment and IL-6 concentrations were evaluated using a solid phase sandwich enzyme immunoassay. All patients were treated with an SSRI. Results The IL-6 levels showed no statistically significant difference between the patients and the controls at baseline. However, IL-6 levels after treatment with SSRIs were significantly lower compared with the baseline IL-6 levels of both the patients and the controls. Conclusion The results of this study suggest that proinflammatory cytokines show some changes during the course of treatment of major depression. These findings might also be considered as supporting the hypothesis of a modulatory role of antidepressants on the immune system. Copyright © 2005 John Wiley & Sons, Ltd. [source] Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune responseINFLAMMATORY BOWEL DISEASES, Issue 9 2005Nicolas Cenac PhD Abstract Background: Activation of colonic proteinase activated receptor-1 (PAR1) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is not neurogenic like in the paw of rats but depends on PAR1 -mediated activation monocytic cells. PAR1 activation in the colon increases the release of lymphocyte T helper-1 (TH1) cytokines. Moreover, PAR1 expression is increased in biopsies from patients with inflammatory bowel disease, and its activation during TH1-mediated colitis in mice increases all of the hallmarks of inflammation. Methods: This study aimed to characterize the effects of PAR1 activation in oxazolone-mediated colitis, involving a TH2 cytokine profile. Results: Intracolonic administration of oxazolone increased myeloperoxidase activity, damage score, and interleukin (IL)-4, IL-10, tumor necrosis factor ,, and IL-1, mRNA expression but lowered interferon-, mRNA expression, indicating colonic inflammation of a TH2 profile. The concurrent intracolonic administration of a PAR1 agonist in oxazolone-treated mice inhibited colitis, resulting in a reduction of myeloperoxidase activity, damage score, and inflammatory cytokine mRNA expression. Using PAR1 -deficient mice, we confirmed that the anti-inflammatory effects of PAR1 agonists were mediated by PAR1. Moreover, in PAR1 -deficient mice or in mice treated with a PAR1 antagonist, oxazolone-induced colitis was exacerbated, showing an endogenous modulatory role for PAR1 in this TH2 cytokine profile of colitis. Conclusions: Thus, as opposed to a previously shown proinflammatory role for PAR1 in a TH1 cytokine-mediated colitis, our new data show anti-inflammatory role for PAR1 activation in the setting of TH2 cytokine colitis model. [source] Tachykinins and their possible modulatory role on testicular function: a reviewINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2003Luciano Debeljuk Summary Tachykinins are vasoactive and smooth muscle-contracting peptides with widespread localizations. Tachykinins have been localized in the nerve fibres that supply the testes, in the Leydig cells of different animal species, and also in Sertoli cells of the Siberian hamster testes. The presence of substance P (SP) has also been demonstrated in ejaculated human spermatozoa and in the seminal plasma. Tachykinins have been shown to inhibit the release of testosterone by testicular fragments or by isolated Leydig cells in vitro. Acting on Sertoli cells, tachykinins have been shown to stimulate the release of lactate and transferrin by these cells in vitro, and also to stimulate aromatase activity. Leydig and Sertoli cells express the Preprotachykinin A gene, and this fact strongly suggests that tachykinins can be synthesized in the testes. These findings suggest that tachykinins may have a physiological function in the testes as modulators of the functions of the different cell types contained in these organs. [source] Levels of soluble HLA-G in amniotic fluid are related to the sex of the offspringINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2003P. M. Emmer Summary Although HLA-G is thought to play a modulatory role in the immune system, its function and expression require to be elucidated. We analysed soluble HLA-G levels in mid-trimester amniotic fluid (n = 64) from uncomplicated pregnancies. We found a decrease in soluble HLA-G levels for female offspring as compared to male offspring (P < 0.007). This may be a consequence of the immuno-modulatory capacity of HLA-G. [source] Cholinergic modulation of angiogenesis: Role of the 7 nicotinic acetylcholine receptorJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009Jenny C.F. Wu Abstract Pathological angiogenesis contributes to tobacco-related diseases such as malignancy, atherosclerosis and age-related macular degeneration. Nicotine acts on endothelial nicotinic acetylcholine receptors (nAChRs) to activate endothelial cells and to augment pathological angiogenesis. In the current study, we studied nAChR subunits involved in these actions. We detected mRNA for all mammalian nAChR subunits except ,2, ,4, ,, and , in four different types of ECs. Using siRNA methodology, we found that the ,7 nAChR plays a dominant role in nicotine-induced cell signaling (assessed by intracellular calcium and NO imaging, and studies of protein expression and phosphorylation), as well as nicotine-activated EC functions (proliferation, survival, migration, and tube formation). The ,9 and ,7 nAChRs have opposing effects on nicotine-induced cell proliferation and survival. Our studies reveal a critical role for the ,7 nAChR in mediating the effects of nicotine on the endothelium. Other subunits play a modulatory role. These findings may have therapeutic implications for diseases characterized by pathological angiogenesis. J. Cell. Biochem. 108: 433,446, 2009. © 2009 Wiley-Liss, Inc. [source] Response to Male Odours in Progestin Receptor- and Oestrogen Receptor-Containing Cells in Female Rat BrainJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2002A. L. Bennett Abstract Sensory cues from male rats, such as odours and vaginal-cervical stimulation (VCS), play a modulatory role in female rat sexual behaviour. For example, exposure to male odours and VCS appears to be at least partially responsible for increases in sexual behaviour following repeated mating of oestradiol-primed female rats. Although there is evidence that VCS influences sexual behaviour via a ligand-independent progestin receptor (PR)-dependent mechanism, the mechanism by which odours influence sexual behaviour is not known. We tested the hypothesis that, similar to VCS, the effects of male odours on sexual behaviour are mediated by progestin receptors. Female rats were injected with the progestin antagonist, RU486, or oil vehicle and were then exposed to male-soiled bedding or clean bedding. Although exposure to male-soiled bedding resulted in higher levels of Fos immunoreactivity in brain areas associated with female sexual behaviour, the progestin antagonist did not reduce this effect. Furthermore, there was minimal coexpression of odour-induced Fos and progestin receptors in brain areas associated with female sexual behaviour. Together, these results suggest that the effects of male odours are not mediated by a PR-dependent mechanism. Therefore, we tested the hypothesis that oestrogen receptor (ER)-containing cells are involved in the effects of olfactory cues. Although there was virtually no coexpression of ER, and odour-induced Fos in brain areas associated with female sexual behaviour, exposure to male odours slightly increased the number of cells coexpressing ER, and odour-induced Fos in the posterodorsal medial amygdala. Although, these results do not support the hypothesis that the effects of odours are mediated by a PR-dependent mechanism, they suggest that integration of male odours and hormonal cues may occur in ER,-containing cells in the posterodorsal medial amygdala. [source] Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitroJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2003N. David Ĺberg Abstract Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I,at which stimulation of proliferation occurred,did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism. © 2003 Wiley-Liss, Inc. [source] Dose-response efficacy of caraway (Carum carvi L.) on tissue lipid peroxidation and antioxidant profile in rat colon carcinogenesisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2006Muthaiyan Kamaleeswari Colon cancer is a leading cause of cancer death and its prevention is of great interest throughout the world. This study was conducted to examine the efficacy of different doses of dietary caraway (Carum carvi L.) on tissue lipid peroxidation (LPO) and antioxidant profile in rat colon carcinogenesis. Wistar male rats were divided into 6 groups and were fed a modified pellet diet for the whole of 30 weeks. To induce colon cancer, rats were given a weekly subcutaneous injection of 1,2-dimethylhydrazine (DMH) at a dose of 20 mg kg,1 (based on body weight) for the first 15 weeks. Caraway was supplemented every day orally at doses of 30, 60 and 90 mg kg,1 for different groups of rats for the total period of 30 weeks. All rats were sacrificed at the end of 30 weeks, the colons were examined visually for masses and were subsequently evaluated histologically. The results showed diminished levels of intestinal, colonic and caecal LPO products, such as conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS) and also the antioxidants superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione reductase (GR) in DMH treated rats, which were significantly reversed (P < 0.05) on caraway supplementation. Moreover, enhanced activity of intestinal, colonic and caecal glutathione peroxidase (GPx), glutathione S-transferase (GST) and colonic ascorbic acid and ,-tocopherol levels were observed in carcinogen-treated rats, which were significantly (P < 0.05) reduced on caraway supplementation. Thus, our study showed that caraway supplementation at a dose of 60 mg kg,1 had a modulatory role on tissue LPO, antioxidant profile and prevented DMH-induced histopathological lesions in colon cancer rats. [source] Investigations into the antinociceptive activity of Sapindus trifoliatus in various pain modelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2004D. K. Arulmozhi The effect of the aqueous extract of Sapindus trifoliatus (ST) on chemical, thermal-induced pain, nitroglycerin-induced hyperalgesia and pain on inflamed tissue was investigated. The extract (20 and 100 mg kg,1, i.p.) significantly inhibited acetic-acid-induced abdominal constrictions, formalin-induced pain licking and hotplate-induced pain in mice. Furthermore, the extract significantly increased the response latencies of nitroglycerin-induced hyperalgesia by the tail-flick method and mechanical pain on carrageenan-induced inflamed paw in rats. The data suggest that ST has an inhibitory activity on both peripheral and central pain mechanisms and has a modulatory role in NO-mediated nociceptive transmission. [source] Melatonin decreases TLR3-mediated inflammatory factor expression via inhibition of NF-,B activation in respiratory syncytial virus-infected RAW264.7 macrophagesJOURNAL OF PINEAL RESEARCH, Issue 1 2008Sheng-Hai Huang Abstract:, Double-stranded (ds) RNA has been identified as a ligand for Toll-like receptor 3 (TLR3). Respiratory syncytial virus (RSV), a single-stranded RNA virus and a major respiratory pathogen and pneumovirus in human infants pathogenesis of which relies on early inflammatory and immune events of the host in response to RSV, could be recognized by TLR3 sensing viral dsRNA produced during replication. The downstream signaling pathway from TLR3 leads to activation of IFN regulatory factor (IRF)-3 and/or NF-,B and subsequent expression of numerous proinflammatory factors. Melatonin (MT) is an effective regulator of the immune system. To determine the molecular mechanisms responsible for the suppressive effect of MT on RSV infection, we analyzed signaling molecules involved in the TLR3-mediated activation of inflammatory factors in macrophages infected with RSV and the modulatory role of MT on these mediators. We report that RSV infection of RAW264.7 macrophages time-dependently stimulate the rapid activation of TLR3 and NF-,B, as well as subsequent NF-,B-dependent gene expression such as those encoding TNF-, and inducible nitric oxide synthase. Moreover, we demonstrate that MT decreased TLR3-mediated downstream gene expression in RSV-infected macrophages in a dose- and time-dependent manner, and that MT inhibition of NF-,B activity seemed to be the key event required to explain the reduction in inflammatory gene expression caused by MT. But MT did not influence TLR3 at either the protein or mRNA level or MyD88 transcription. These results could be related to the beneficial immunoregulatory role of MT in RSV-infected macrophages and address the possible therapeutic potential of this indoleamine in human RSV diseases. [source] Angiostatin K1-3 induces E-selectin via AP1 and Ets1: a mediator for anti-angiogenic action of K1-3JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2008Y.-H. CHEN Summary.,Background:,Angiostatin, a circulating angiogenic inhibitor, is an internal fragment of plasminogen and consists of several isoforms, K1-3 included. We previously showed that K1-3 was the most potent angiostatin to induce E-selectin mRNA expression. The purpose of this study was to identify the mechanism responsible for K1-3-induced E-selectin expression and investigate the role of E-selectin in the anti-angiogenic action of K1-3. Methods and results:,Quantitative real time RT-PCR and Western blotting analyses confirmed a time-dependent increase of E-selectin mRNA and protein induced by K1-3. Subcellular fractionation and immunofluorescence microscopy showed the co-localization of K1-3-induced E-selectin with caveolin 1 (Cav1) in lipid rafts in which E-selectin may behave as a signaling receptor. Promoter-driven reporter assays and site-directed mutagenesis showed that K1-3 induced E-selectin expression via promoter activation and AP1 and Ets-1 binding sites in the proximal E-selectin promoter were required for E-selectin induction. The in vivo binding of both protein complexes to the proximal promoter was confirmed by chromatin immunoprecipitation (ChIP). Although K1-3 induced the activation of ERK1/2 and JNK, only repression of JNK activation attenuated the induction of E-selectin by K1-3. A modulatory role of E-selectin in the anti-angiogenic action of K1-3 was manifested by both overexpression and knockdown of E-selectin followed by cell proliferation assay. Conclusions:,We show that K1-3 induced E-selectin expression via AP1 and Ets-1 binding to the proximal E-selectin promoter (,356/+1), which was positively mediated by JNK activation. Our findings also demonstrate E-selectin as a novel target for the anti-angiogenic therapy. [source] Neutrophils and B lymphocytes in ANCA-associated vasculitisAPMIS, Issue 2009VÉRONIQUE WITKO-SARSAT The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is unknown but is most consistent with a primary role for neutrophils in the acute injury. Thus, neutrophils are cardinal cells in the pathophysiological process in AAV because they are both effector cells responsible for endothelial damage and targets of autoimmunity. In addition, because of their capacity to synthesize a wide variety of cytokines and chemokines, neutrophils can be considered as important modulators of the inflammatory and potentially of the autoimmune process. ANCA directed against two main autoantigens, namely proteinase 3 and myeloperoxidase, are likely to play a modulatory role in the inflammatory process. Interestingly, neutrophils are an important source of lymphocyte stimulator (BLy), a cytokine that plays a fundamental role in B-cell physiology, including differentiation, proliferation and immunoglobulin production. The issue of B-cell activation and/or dysregulation in vasculitis will be discussed. [source] Investigation of sensory neurogenic components in a bleomycin-induced scleroderma model using transient receptor potential vanilloid 1 receptor, and calcitonin gene-related peptide,knockout miceARTHRITIS & RHEUMATISM, Issue 1 2008Árpád Szabó Objective Along with their classic afferent function (nociception), capsaicin-sensitive transient receptor potential vanilloid 1 (TRPV1) receptor,expressing sensory nerve terminals exert local and systemic efferent activities. Activation of TRPV1 causes sensory neuropeptide release, which modulates the inflammation process. The aim of the present study was to examine the role of this modulatory role of TRPV1 receptor and that of calcitonin gene-related peptide (CGRP) in bleomycin-induced scleroderma, using transgenic mice. Methods Cutaneous sclerosis was induced with daily subcutaneous injections of bleomycin for 30 days. Control groups were treated with phosphate buffered saline (PBS). TRPV1 receptor gene,deficient (TRPV1,/,) mice and CGRP-knockout (CGRP,/,) mice and their wild-type (WT) counterparts were investigated. A composite sclerosis score was calculated on the basis of thickening, leukocyte infiltration, and the amount/orientation of collagen bundles. Dermal thickness and the number of ,-smooth muscle actin (,-SMA),positive cells were also determined. The quantity of the collagen-specific amino acid hydroxyproline was measured by spectrophotometry. Results Bleomycin treatment induced marked cutaneous thickening and fibrosis compared with that observed in control mice treated with PBS. The composite sclerosis score was 18% higher, dermal thickness was 19% higher, the number of ,-SMA,positive cells was 47% higher, and the amount of hydroxyproline was 57% higher in TRPV1,/, mice than in their WT counterparts. Similarly, the composite sclerosis score was 47% higher, dermal thickness was 29% higher, the number of ,-SMA,positive cells was 76% higher, and the amount of hydroxyproline was 30% higher in CGRP,/, mice than in the respective WT groups. Conclusion These results suggest that activation of the TRPV1 receptor by mediators of inflammation induces sensory neuropeptide release, which might exert protective action against fibrosis. We confirmed the protective role of CGRP in the development of cutaneous sclerosis. [source] Different sensitivity of isoprenaline-induced responses in ventricular muscle to sodium nitroprusside in normotensive and spontaneously hypertensive rats 1AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2000A. M. Manso 1 The aim of the present work was to study the possible modulatory role of nitric oxide (NO) on the positive inotropic effect induced by the ,-adrenoceptor agonist isoprenaline in myocardial contractility, and whether this modulation is altered by hypertension. 2 The study was performed using right ventricular strips from the hearts of 6-month-old male Wistar,Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The contractile force of electrically-stimulated ventricular strips was measured by a force-displacement transducer. 3 Isoprenaline (from 10 nmol l,1 to 10 ,mol l,1) induced a concentration-dependent increase in cardiac contractility in strips from both rat strains. This positive inotropic effect to isoprenaline was reduced by the NO donor sodium nitroprusside (SNP, 0.1 mmol l,1) in muscles from WKY rats and slightly increased in those from SHR. The SNP-induced increase in strips from SHR was abolished by superoxide dismutase (100 U ml,1). 4 NG-nitro-arginine-methyl ester (L-NAME, 0.1 mmol l,1) and 1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one (ODQ, 10 ,mol l,1), respective inhibitors of NO synthase and guanylate cyclase, increased the response to isoprenaline in muscles from WKY rats, whereas it was unaltered in strips from SHR. 5 In strips from WKY rats, the combination of ODQ and SNP produced an increase in the response elicited by isoprenaline, which was similar to that observed with ODQ or L-NAME. 8-Br-cyclicGMP (8-Br-cGMP, 0.1 mmol l,1), a permeable and structural cGMP analogue, decreased the effect induced by isoprenaline only in muscles from WKY rats. 6 These results suggest that the positive inotropic response to isoprenaline in ventricular strips from WKY rats is negatively modulated by NO, and positively by superoxide anions in those from SHR. The lack of a modulatory response to NO in ventricular strips from SHR is probably a result of an alteration of mechanisms in NO-signalling pathway downstream of cGMP formation in SHR hearts. [source] Delayed neovascularization in inflammation-induced corneal neovascularization in interleukin-10-deficient miceACTA OPHTHALMOLOGICA, Issue 2 2010Branka Samolov Abstract. Purpose:, To investigate the potential modulatory role of interleukin-10 (IL-10) in the suture model for corneal neovascularization. Methods:, Neovascularized areas were measured on corneal flat-mounts in IL-10,/, and wild-type C57BL6 mice. The inflammatory cellular response was characterized with immunohistochemistry. Gene expression was measured by real-time polymerase chain reaction. Results:, IL-10,/, mice showed a delayed neovascular response compared to wild-type animals at day 6 after suture, when approximately half of the cornea was neovascularized. No apparent differences in inflammatory responses or in messenger RNA (mRNA) expression for proangiogenic factors were detected in IL-10,/, versus wild-type mice. Conclusion:, IL-10 appears to have a proangiogenic effect in the suture model for corneal neovascularization that cannot be explained by either IL-10's anti-inflammatory effect or apparent cross-talk with the angiogenic factors vascular endothelial growth factor (VEGF)-A, metalloproteinase (MMP)-2 and MMP-9, angiopoietin (Ang)-1 and Ang-2. [source] Modulation of Brain Endocannabinoid Levels by Voluntary Alcohol Consumption in Alcohol-Preferring AA RatsALCOHOLISM, Issue 10 2009Hanna Malinen Background:, The central nervous system cannabinoid CB1 receptors have been implicated in regulation of alcohol consumption. Less data are available on the role of the endogenous ligands for these receptors, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in alcohol-related behaviors. The purpose of this study was to assess the effects of voluntary alcohol consumption on the levels of these endocannabinoids in key brain areas mediating alcohol reinforcement. Methods:, Female and male alcohol-preferring AA (Alko, Alcohol) rats were trained to drink 10% (v/v) alcohol during 90-min limited access sessions every second day. Following establishment of stable alcohol drinking, half of the subjects were killed immediately before the daily alcohol access ("pre-session" group), while the other half was killed after the drinking session ("post-session" group). A separate control group consisted of water-drinking rats. AEA and 2-AG levels were measured from prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), amygdala, and hippocampus using liquid chromatography,tandem mass spectrometry (LC/MS/MS). Results:, Voluntary alcohol drinking caused widespread alterations in the levels of both AEA and 2-AG. Compared to the water group, increased AEA levels were seen in the pre-session group, but they were decreased immediately following limited access drinking in the female AA rats. Also 2-AG levels were significantly elevated after long alcohol exposure, and an additional increase was found after limited access drinking in PFC. In males, however, the only alterations caused by alcohol drinking were significantly elevated AEA levels in NAc and CPu in the post-session group. No changes were seen in the levels of 2-AG. Conclusions:, These results demonstrate that voluntary alcohol drinking modulates the levels of endocannabinoids in several brain areas implicated in alcohol reinforcement. AEA and 2-AG were differentially affected, suggesting that they could have partially separate modulatory roles. Alterations were more widespread in females than males, possibly reflecting their higher alcohol intake. Taken together, alcohol-induced release of endocannabinoids may have an important role in alcohol reinforcement and development of alcohol addiction. [source] Release of ATP in the central nervous system during systemic inflammation: real-time measurement in the hypothalamus of conscious rabbitsTHE JOURNAL OF PHYSIOLOGY, Issue 1 2007Alexander V. Gourine Receptors for extracellular ATP (both ionotropic and metabotropic) are widely expressed in the CNS both in neurones and glia. ATP can modulate neuronal activity in many parts of the brain and contributes to the central nervous control of several physiological functions. Here we show that during the systemic inflammatory response the extracellular concentrations of ATP increase in the anterior hypothalamus and this has a profound effect on the development of the thermoregulatory febrile response. In conscious rabbits we measured ATP release in real time with novel amperometric biosensors and monitored a marked increase in the concentration of ATP (4.0 ± 0.7 ,m) in the anterior hypothalamus in response to intravenous injection of bacterial endotoxin , lipopolysaccharide (LPS). No ATP release was observed in the posterior hypothalamus. The release of ATP coincided with the development of the initial phase of the febrile response, starting 18 ± 2 min and reaching its peak 45 ± 2 min after LPS injection. Application of the ATP receptor antagonists pyridoxal-5,-phosphate-6-azophenyl-2,,4,-disulphonic acid, Brilliant Blue G or periodate oxidized ATP dialdehyde to the site of ATP release in the anterior hypothalamus markedly augmented and prolonged the febrile response. These data indicate that during the development of the systemic inflammation, ATP is released in the anterior hypothalamus to limit the magnitude and duration of fever. This release may also have a profound effect on the hypothalamic control of other physiological functions in which ATP and related purines have been implicated to play modulatory roles, such as food intake, hormone secretion, cardiovascular activity and sleep. [source] RIC-3 and nicotinic acetylcholine receptors: Biogenesis, properties, and diversityBIOTECHNOLOGY JOURNAL, Issue 12 2008Millet Treinin Dr.Article first published online: 27 OCT 200 Abstract Nicotinic acetylcholine receptors (nAChRs) belong to a diverse and widely expressed family of ion channels. These receptors are pentamers assembled from multiple combinations of subunits, with different subunit compositions producing receptors having different properties and functions. The diverse functions of nAChRs include an essential role in excitation of skeletal muscles and many modulatory roles throughout the central nervous system. Nicotinic receptors are also implicated in a number of brain pathologies such as epilepsy, schizophrenia, and Alzheimer's disease. Thus, it is important to understand the cellular mechanisms controlling both the numbers and the properties of surface expressed nAChRs. Genetic analysis in Caenorhabditis elegans identified a number of proteins specifically needed for biogenesis of nAChRs. Among these proteins is RIC-3, a member of a family of proteins having conserved structure and function. RIC-3 influences both surface expression and properties of nAChRs and its effects are subtype specific. Here we suggest that receptor-specific chaperones such as RIC-3 may play important roles in controlling receptor diversity by selectively regulating surface expression of nAChRs having specific subunit compositions. [source] | |||||||||||||