UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was shown previously that platelet-activating factor receptors (PAF-Rs) inhibit invasiveness of colonic and kidney epithelial cells induced by the src and Met oncogenes via a pertussis toxin-sensitive mechanism. Therefore, Madin-Darby canine kidney (MDCKts.src) cells were stably transfected with constitutively activated forms of Galphao, Galphai1, Galphai2, Galphai3 (AGalphao/i), two Gbetagamma sequestering proteins [C-terminal end of beta-adrenergic receptor kinase (ct-betaARK) and the Galphat subunit of retinal G-protein transducin], and Gbeta1-Ggamma2 subunits alone or in combination. Cellular invasion induced by src, Met, and leptin was abrogated by the AGalphao/i, ct-betaARK, and Galphat-positive clones, but was induced by coexpression of Gbeta1gamma2. In contrast, invasion stimulated by the trefoil factors (TFFs) pS2 and intestinal trefoil factor in MDCKts.src cells or human colonic epithelial cells PCmsrc and HCT8/S11 was insensitive to PAF, AGalphao, AGalphai1, and AGalphai2, but was abolished by AGalphai3 and the protease-activated receptor-1 (PAR-1) agonist thrombin receptor-activating peptide. Depletion of free Gbetagamma heterodimers by ct-betaARK resulted in a remarkable decrease of cellular adhesion and spreading on collagen matrix. Our data demonstrate the following: 1) PAF-Rs impair cellular invasion induced by src, Met, and leptin via the activation of Galphao and Galphai1 to -3; 2) invasion induced by TFFs is selectively inhibited by PAR-1 receptors and Galphai3 activation; and 3) Gbetagamma dimers are required as positive effectors of invasion pathways induced by oncogenes and epigenetic factors. Thus, redistribution of Galphao/Galphai and Gbeta/gamma heterotrimeric G-proteins by PAF-R and PAR-1 exert differential functions on positive and negative signaling pathways involved in cellular invasion and may serve as potential targets for anticancer therapy.
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PMID:Suppression of cellular invasion by activated G-protein subunits Galphao, Galphai1, Galphai2, and Galphai3 and sequestration of Gbetagamma. 1145 24

Thrombin and proteinase-activated receptors (PAR) specifically regulate several functions that markedly enhance the transformation phenotype such as inflammation, cell proliferation, tumor growth, and metastasis. We recently reported that thrombin inhibits cellular invasion induced by src, hepatocyte growth factor (HGF), and leptin in kidney and colonic epithelial cells via predominant activation of the pertussis toxin (PTx) -sensitive G-proteins Galphao/Galphai. We provide pharmacological and biochemical evidence that in the presence of PTx, PAR-1 induced cellular invasion through Galpha12/Galpha13- and RhoA/Rho kinase (ROCK) -dependent signaling. However, inhibition of the endogenous small GTPase RhoA by the C3 exoenzyme, dominant-negative N19-RhoA, activated G26V-RhoD, and activators of the nitric oxide/cGMP pathways conferred invasive activity to PAR-1 via a signaling cascade using Galphaq, phospholipase C (PLC), Ca(2+)/calmodulin myosin light chain kinase (CaM-MLCK), and phosphorylation of MLC. We found that cellular invasion induced by the src oncogene is abrogated by inhibitors of the RhoA/ROCK pathway and is independent of PLC/CaM-MLCK signaling. Our data demonstrate that the RhoA and RhoD small GTPases are acting as a molecular switch of cellular invasion and reveal a novel critical mechanism by which PAR-1 bypass Galphao/i and RhoA inhibition via differential coupling to heterotrimeric G-proteins linked to divergent or convergent biological responses. Our data also indicate that Rho GTPases and ROCK mediate a src-dependent invasion signal in kidney and colonic cancer cells. We conclude that dynamic regulation of Rho GTPases activation and inactivation by oncogenes, growth factors, cGMP-inducing agents, and adhesion molecules can initiate convergent invasion signals controlled by the thrombin PAR-1 in cancer cells.-Nguyen, Q.-D., Faivre, S., Bruyneel, E., Rivat, C., Seto, M., Endo, T., Mareel, M., Emami, S., Gespach, C. RhoA- and RhoD-dependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion.
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PMID:RhoA- and RhoD-dependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. 1191 59

An attenuated severity of infections is among the well-documented benefits of breast-feeding. The degree to which this attenuated severity extends to the amelioration of anorexia is understood incompletely, and possible underlying mechanisms have received limited evaluation. This study was designed to test whether breast-feeding attenuates reductions in energy intake associated with a mild immunologic stimulus and to assess poststimulus relationships among putative reductions in energy intake and serum interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and leptin concentrations. A quasi-experimental, hospital-based study was conducted in 23 healthy fully breast- (BF) and formula-fed (FF) infants who received the quadruple diphtheria, pertussis, tetanus and hemophilus influenza (DPTH) immunization as an immunologic challenge. Only FF infants had decreased energy intakes (12 +/- 2%, P = 0.001) after immunization. Leptin concentrations increased after immunization only in FF infants (30 +/- 7%, P = 0.03). Correlations between postimmunization increases in IL-beta and reductions in energy intake were of borderline significance (r = -0.56, P = 0.08). These findings support the view that breast-feeding protects against anorectic responses to mild immunologic stimuli. Increases in leptin are associated with reductions in energy consumption in the postimmunization period in FF infants and postimmunization changes in IL-1beta concentrations likely are related to reductions in energy intake in response to immunologic stimuli.
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PMID:Breastfeeding attenuates reductions in energy intake induced by a mild immunologic stimulus represented by DPTH immunization: possible roles of interleukin-1beta, tumor necrosis factor-alpha and leptin. 1204 49

The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.
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PMID:Mechanisms of leptin secretion from white adipocytes. 1205 93

The basal release of leptin by adipocytes from massively obese human subjects incubated for 48 hours in serum-free suspension culture was comparable to that by explants of subcutaneous adipose tissue from the same obese individuals. There was no stimulation due to dexamethasone or insulin alone of leptin release by adipocytes. However, the combination of insulin and dexamethasone doubled leptin release by adipocytes. The release of leptin was also stimulated by agonists of G(i)-coupled receptors (prostaglandin E(2) [PGE(2)], brimonidine [an alpha(2) catecholamine agonist] and cyclopentyladenosine [CPA]) in the presence of dexamethasone. Leptin release by these agents was further enhanced by insulin in both adipocytes and adipose tissue. Pertussis toxin, which irreversibly inactivates G(i) heterotrimers, inhibited leptin release and abolished the stimulatory effects of G(i)-coupled receptor agonists. However, pertussis toxin did not block the stimulation of leptin release by insulin in either adipose tissue or adipocytes. These data indicate that the release of leptin by human adipocytes cultured for 48 hours in a serum-free medium is comparable to that by explants of adipose tissue except that dexamethasone stimulation of leptin release requires the presence of insulin.
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PMID:Regulation of leptin release by insulin, glucocorticoids, G(i)-coupled receptor agonists, and pertussis toxin in adipocytes and adipose tissue explants from obese humans in primary culture. 1252 63

Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of orexins in rats. Immunohistochemical methods showed that orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca(2+)](i) were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca(2+) uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca(2+)](i) in NPY neurons were greater with orexin-A than with orexin-B, indicative of involvement of the orexin-1 receptor (OX(1)R). In contrast, orexin-A and -B equipotently attenuated [Ca(2+)](i) oscillations and decreased [Ca(2+)](i) levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca(2+)](i) levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that orexins directly regulate NPY, POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca(2+) signaling in NPY neurons via OX(1)R-PLC-PKC and IP(3) pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of orexins.
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PMID:Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. 1506 49

Dietary conjugated linoleic acid (CLA) reduces body fat in animals and some humans. Here we show that trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, when added to cultures of stromal vascular cells containing newly differentiated human adipocytes, caused a time-dependent decrease in triglyceride content, insulin-stimulated glucose and fatty acid uptake, incorporation into lipid, and oxidation compared with controls. In parallel, gene expression of peroxisome proliferator-activated receptor-gamma and many of its downstream targets were diminished by trans-10, cis-12 CLA, whereas leptin gene expression was increased. Prior to changes in gene expression and metabolism, trans-10, cis-12 CLA caused a robust and sustained activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling. Furthermore, the trans-10, cis-12 CLA-mediated activation of MEK/ERK could be attenuated by pretreatment with U0126 and pertussis toxin. In parallel, pretreatment with U0126 blocked the ability of trans-10, cis-12 CLA to alter gene expression and attenuate glucose and fatty acid uptake of the cultures. Intriguingly, the induction by CLA of MEK/ERK signaling was linked to hypersecretion of adipocytokines interleukin-6 and interleukin-8. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA decreases the triglyceride content of newly differentiated human adipocytes by inducing MEK/ERK signaling through the autocrine/paracrine actions of interleukins-6 and 8.
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PMID:Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines. 1506 15

Leptin and melatonin play an important role in the regulation of body mass and energy balance. Both hormones show a circadian rhythm, with increasing values at night. In addition, melatonin receptors were recently described in adipocytes, where leptin is synthesized. Here, we investigated the influence of melatonin and its interaction with insulin and dexamethasone on leptin expression. Isolated rat adipocytes were incubated with melatonin (1 nM) alone or in combination with insulin (5 nM) and/or dexamethasone (7 nM) for 6 h. Melatonin or insulin alone did not affect leptin expression, but together they increased it by 120%. Dexamethasone increased leptin mRNA content (105%), and this effect was not enhanced by melatonin. Simultaneous treatment with the three hormones provoked a further increase in leptin release (250%) and leptin mRNA (100%). Melatonin prevented the forskolin-induced inhibition (95%) of leptin expression. In addition, melatonin's ability to stimulate leptin release (in the presence of insulin) was completely blocked by pertussis toxin and luzindole. To gain further insight into the molecular basis of melatonin and insulin synergism, the insulin-signaling pathway was investigated. Melatonin increased the insulin-induced insulin receptor-beta tyrosine phosphorylation, which led to an increased serine phosphorylation of the downstream convergent protein Akt. We concluded that melatonin interacts with insulin and upregulates insulin-stimulated leptin expression. These effects are caused by melatonin binding to the pertussis toxin-sensitive G(i) protein-coupled membrane receptor (MT1 subtype) and the cross talk with insulin, since insulin receptor and its convergent target Akt are coactivated by melatonin.
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PMID:Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. 1557 54

The present studies were designed to investigate the hormonal regulation of vascular endothelial growth factor (VEGF) release by human subcutaneous adipose tissue explants and adipocytes incubated in primary culture for 48 hours. Vascular endothelial growth factor and IL-8 release by adipocytes were less than 10% of that by tissue explants, whereas that of leptin in adipocytes was comparable to that by tissue. Dexamethasone inhibited VEGF formation by both adipose tissue explants and isolated adipocytes, whereas insulin stimulated VEGF release only in isolated adipocytes. Insulin also enhanced the formation of IL-8 and plasminogen activation inhibitor 1 (PAI-1), but not that of IL-6 by adipocytes although having little effect on that of IL-6 or PAI-1 by adipose tissue explants. Pertussis toxin stimulated lipolysis and inhibited leptin release by human adipose tissue or adipocytes but did not affect release of IL-8 or VEGF. Isoproterenol also stimulated lipolysis by human adipocytes, but this was not accompanied by any significant changes in VEGF, IL-8, IL-6, or PAI-1 release. In contrast, insulin stimulated VEGF release by human adipocytes, and this stimulation was enhanced in the presence of isoproterenol. Insulin stimulated VEGF formation as well as that of PAI-1 by human adipocytes, but not by explants under conditions where it had little effect on that of IL-6. The ability of insulin to stimulate VEGF formation by adipocytes suggests that the elevated circulating levels of insulin in obesity promote angiogenesis in adipose tissue as well as the enhanced accumulation of fat in human adipocytes.
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PMID:Insulin enhances vascular endothelial growth factor, interleukin-8, and plasminogen activator inhibitor 1 but not interleukin-6 release by human adipocytes. 1569 Mar 17

Sphingosine-1-phosphate (S1P) is a pluripotent lipid mediator that transmits signals through a family of G protein-coupled receptors to control diverse biological processes. Here, we investigated the effects of S1P on the levels of intracellular calcium and cAMP in differentiated rat white adipocytes and two important aspects of adipocyte-specific physiology, lipolysis and leptin production. In adipocytes, S1P signaling pathway was functionally linked to phospholipase C via pertussis-toxin-sensitive G protein. Interestingly, at higher S1P concentration (1-30 microM), it also induced cAMP generation in a concentration-dependent manner, which was pertussis toxin insensitive and was mimicked by dihydro-S1P and sphingosylphosphoryl-choline but not by its related metabolites, ceramide and sphingosine, or by its structural analogs, phyto-S1P and lysophosphatidic acid. Suramin, a known inhibitor of ligand-receptor interactions, reduced S1P-induced cAMP generation by 60% of control, whereas forskolin-induced cAMP increase was not affected by treatment with suramin. The S1P-induced cAMP generation was functionally linked to cAMP response element-binding protein phosphorylation. Finally, S1P significantly reduced insulin-induced mRNA of ob gene and leptin secretion, whereas S1P increased glycerol release from adipocytes. Both effects of S1P were reversed by a selective adenylyl cyclase inhibitor, SQ22536, without significantly affecting basal values. In conclusion, extracellular S1P elicits the elevation of cytosolic Ca2+ and cAMP with a distinct concentration dependency, and S1P-induced cAMP generation may be mediated by S1P-selective receptors rather than intracellular targets, and the activated adenylyl cyclase-cAMP signaling pathways subsequently increase lipolysis and decrease insulin-induced leptin production in rat white adipocytes.
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PMID:Sphingosine-1-phosphate modulates both lipolysis and leptin production in differentiated rat white adipocytes. 1697 28

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