37 research outputs found
Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HTagonist – tegaserod-1
No full text<p><b>Copyright information:</b></p><p>Taken from "Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HTagonist – tegaserod"</p><p>BMC Gastroenterology 2006;6():8-8.</p><p>Published online 23 Feb 2006</p><p>PMCID:PMC1434748.</p><p>Copyright © 2006 Mathison and Shaffer; licensee BioMed Central Ltd.</p> & D) cholesterol diet. The animals were treated with either vehicle (A & B) or tegaserod (C & D). The action potential blocker tetrodotoxin (TTX; 10M) was added to the jejunal tissue segments 10 min before constructing a cumulative dose-response curve to the cholinergic agonist, carbachol. * TTX greater than No TTX (P < 0.05). N = 8–9
A Tree-Based Algorithm for Determining the Effects of Solvation on the Structure of Salivary Gland Tripeptide NH3+-D-PHE-D-GLU-GLY-COO−
No full textAbstractA D-enantiomeric analog of the submandibular gland rat-1 tripeptide FEG (Seq: NH3+-Phe-Glu-Gly-COO−) called feG (Seq: NH3+-D-Phe-D-Glu-Gly-COO−) was examined by molecular dynamics simulations in water. Previous in vacuo simulations suggested a conformation consisting predominantly of interactions between the Phe side chain and glutamyl-carboxyl group and a carboxyl/amino termini interaction. The solvated peptide was simulated using two approaches which were compared—a single 400-ns simulation and a “simulation tree.” The “tree” approach utilized 45 10-ns simulations with different conformations used as initial structures for given trajectories. We demonstrate that multiple short duration simulations are able to describe the same conformational space as that described by longer simulations. Furthermore, previously described in vacuo interactions were confirmed with amendments: the previously described head-to-tail arrangement of the amino and carboxyl termini, was not observed; the interaction between the glutamyl carboxyl and Phe side chain describes only one of a continuum of conformations present wherein the aromatic residue remains in close proximity to the glutamyl carbonyl group, and also interacts with either of the two available carboxyl groups. Finally, utilizing only two separate 10-ns trajectories, we were able to better describe the conformational space than a single 60-ns trajectory, realizing a threefold decrease in the computational complexity of the problem
The tripeptide feG inhibits leukocyte adhesion
No full textAbstract Background The tripeptide feG (D-Phe-D-Glu-Gly) is a potent anti-inflammatory peptide that reduces the severity of type I immediate hypersensitivity reactions, and inhibits neutrophil chemotaxis and adhesion to tissues. feG also reduces the expression of β1-integrin on circulating neutrophils, but the counter ligands involved in the anti-adhesive actions of the peptide are not known. In this study the effects of feG on the adhesion of rat peritoneal leukocytes and extravasated neutrophils to several different integrin selective substrates were evaluated. Results The adhesion of peritoneal leukocytes and extravasated neutrophils from rats to adhesive proteins coated to 96-well plates was dependent upon magnesium (Mg2+) ion, suggestive of integrin-mediated adhesion. feG inhibited leukocyte adhesion, but only if the cells were stimulated with PAF (10-9M), indicating that feG's actions in vitro require cell activation. In the dose range of 10-10M to 10-12M feG inhibited the adhesion of peritoneal leukocytes to fibrinogen and fibronectin, but not IgG, vitronectin or ICAM-1. feG inhibited the binding of extravasated neutrophils to heparin, IgG, fibronectin and CD16 antibody. Antigen-challenge of sensitized rats reduced the adhesion of peritoneal leukocytes to most substrates and abolished the inhibitory effects of feG. However, pretreating the animals with intraperitoneal feG (100 μg/kg) 18 h before collecting the cells from the antigen-challenged animal restored the inhibition of adhesion by in vitro feG of peritoneal leukocytes and extravasated neutrophils to fibronectin. Conclusion The modulation of leukocyte adhesion by feG appears to involve actions on αMβ2 integrin, with a possible interaction with the low affinity FcγRIII receptor (CD16). The modulation of cell adhesion by feG is dual in nature. When administered in vivo, feG prevents inflammation-induced reductions in cell adhesion, as well as restoring its inhibitory effect in vitro. The mechanism by which in vivo treatment with feG exerts these effects remains to be elucidated.</p
The tripeptide feG regulates the production of intracellular reactive oxygen species by neutrophils
No full textAbstract Background The D-isomeric form of the tripeptide FEG (feG) is a potent anti-inflammatory agent that suppresses type I hypersensitivity (IgE-mediated allergic) reactions in several animal species. One of feG's primary actions is to inhibit leukocyte activation resulting in loss of their adhesive and migratory properties. Since activation of neutrophils is often associated with an increase in respiratory burst with the generation of reactive oxygen species (ROS), we examined the effect of feG on the respiratory burst in neutrophils of antigen-sensitized rats. A role for protein kinase C (PKC) in the actions of feG was evaluated by using selective isoform inhibitors for PKC. Results At 18h after antigen (ovalbumin) challenge of sensitized Sprague-Dawley rats a pronounced neutrophilia occurred; a response that was reduced in animals treated with feG (100 μg/kg). With antigen-challenged animals the protein kinase C (PKC) activator, PMA, significantly increased intracellular ROS of circulating neutrophils, as determined by flow cytometry using the fluorescent probe dihydrorhodamine-123. This increase was prevented by treatment with feG at the time of antigen challenge. The inhibitor of PKCδ, rottlerin, which effectively prevented intracellular ROS production by circulating neutrophils of animals receiving a naïve antigen, failed to inhibit PMA-stimulated ROS production if the animals were challenged with antigen. feG treatment, however, re-established the inhibitory effects of the PKCδ inhibitor on intracellular ROS production. The extracellular release of superoxide anion, evaluated by measuring the oxidative reduction of cytochrome C, was neither modified by antigen challenge nor feG treatment. However, hispidin, an inhibitor of PKCβ, inhibited the release of superoxide anion from circulating leukocytes in all groups of animals. feG prevented the increased expression of the β1-integrin CD49d on the circulating neutrophils elicited by antigen challenge. Conclusion feG reduces the capacity of circulating neutrophils to generate intracellular ROS consequent to an allergic reaction by preventing the deregulation of PKCδ. This action of feG may be related to the reduction in antigen-induced up-regulation of CD49d expression on circulating neutrophils.</p
Submandibular gland peptides and the modulation of anaphylactic and endotoxic reactions
No full textSubmandibular gland peptide-T (SGP-T), a heptapeptide with the sequence of threonine, aspartate, isoleucine, phenylalanine, glutamate, glycine, glycine (TDIFEGG), was isolated from the submandibular glands of rats based on the ability of extracts of these glands to reduce the hypotension induced by bacterial lipopolysaccharide. SGP-T was also found to decrease the severity of the cardiovascular shock provoked by antigen administration to ovalbumin-sensitized rats. An analysis of the structure-activity relationship revealed that three amino acids, phenylalanine, glutamate, glycine (FEG), located in the carboxy terminal of SGP-T were sufficient to inhibit intestinal anaphylaxis in vitro. Interestingly, the D-isomeric form of FEG (feG) did not inhibit anaphylaxis in the in vitro assay. However, both tripeptides, FEG and feG, significantly reduced anaphylactic hypotension and intestinal anaphylaxis in vivo. SGP-T may be a prototype of a family of small peptides that modulate the immune and smooth muscle reactions to severe inflammatory stress. SGP-T preferentially inhibits cardiovascular anaphylaxis, whereas feG exhibits a high degree of selectivity for inhibiting intestinal anaphylaxis in vivo.Biomedical Reviews 1998; 9: 101-106
Salivary glands and adipobiology
No full textThis review explores the functional relationships between salivary glands and adipose tissue. Since salivary glands, and in particular the submandibular glands, exert profound systemic effects on organs and inflammatory responses outside the gastrointestinal tract, the question arises if these glands also impact the body's physiological response to increases in adipose tissue deposition and secretion. And, if the adipose tissue deposition and secretion impact the salivary gland's physiological response. To date the evidence is relatively weak that salivary glands significantly impact obesity, or that their function is dramatically altered by obesity, and that the measurement of metabolic peptides in saliva will lead to diagnostic and treatment strategies for obesity and related cardiometabolic diseases. Although obesity detrimentally impacts oral health causative linkages and associations have not been conclusively made between periodontitis and obesity. The most intriguing connections between adipobiology and saliva (or salivary glands) have emerged from unexpected quarters. It was recently reported that adiponectin, resistin and visfatin (adipose tissue-derived signaling proteins collectively termed adipokines) are found in saliva and that their amount correlates with that of circulating level of these adipokines. These observations suggest that the introduction of salivary determinations of adipokines may contribute to the study of pathogenesis of various obesity-related diseases. Receptors for adipokines and obesity-related hormones, especially for polypeptide Y (PYY (3-36)), in the mouth and in particular the taste buds, may be a primary signal for satiety. This observation offers new avenues for investigating the physiology of satiety along with potential treatment strategies for obesity. Another unexpected finding, and to date unrelated to obesity - the transplantation of adipose-derived stromal cells has the potential to restore salivary gland function after their destruction by radiation therapy.Adipobiology 2012; 4: 51-58
Regulation of leukocyte adhesion to heart by the tripeptides feG and feG(NH<sub>2</sub>)
No full text The role of the D-isomeric form of the salivary gland tripeptide FEG (feG) and its carboxyl-amidated derivative, feG(NH2), in regulating leukocyte adherence to nonfixed atrial slices from Sprague-Dawley rats was examined under static conditions. Optimal binding of the leukocytes was seen if the leukocytes were treated with platelet activating factor (PAF; 10-9M). The increased adherence of PAF-treated peripheral blood leukocytes was totally inhibited by both feG and feG(NH2) (10-9M), as well as by antibodies against CD18 and CD49d. In contrast, the binding of peritoneal leukocytes was blocked only by CD49d antibody. Circulating leukocytes obtained from lipopolysaccharide (LPS) treated (2 mg/kg ip) rats did not bind to atrial slices obtained from normal hearts, but readily bound to atrial slices obtained from LPS-treated rats. This leukocyte binding was inhibited by in vivo feG treatment (100 µg/kg ip, 24 h before harvest) or by treating the isolated cells with feG (10-9M). The amidated peptide feG(NH2) reduced neutrophil accumulation in the atrium elicited by ip injection of LPS, whereas feG was ineffective. The reduction in neutrophil infiltration into the myocardium by feG(NH2) and the prevention of leukocyte interaction with myocytes seen with both feG and feG(NH2) probably results in hindered leukocyte migration in the inflamed heart, resulting in less tissue damage. The inhibition by these tripeptides on neutrophil adhesion to myocytes suggests that salivary glands hormones regulate the severity of cardiac inflammation.Key words: endotoxemia, inflammation, salivary glands, leukocytes, heart, adhesion. </jats:p
The Computability-Theoretic Content of Emergence
No full textIn dealing with emergent phenomena, a common task is to identify useful descriptions of them in terms of the underlying atomic processes, and to extract enough computational content from these descriptions to enable predictions to be made. Generally, the underlying atomic processes are quite well understood, and (with important exceptions) captured by mathematics from which it is relatively easy to extract algorithmic con- tent. A widespread view is that the difficulty in describing transitions from algorithmic activity to the emergence associated with chaotic situations is a simple case of complexity outstripping computational resources and human ingenuity. Or, on the other hand, that phenomena transcending the standard Turing model of computation, if they exist, must necessarily lie outside the domain of classical computability theory. In this article we suggest that much of the current confusion arises from conceptual gaps and the lack of a suitably fundamental model within which to situate emergence. We examine the potential for placing emer- gent relations in a familiar context based on Turing's 1939 model for interactive computation over structures described in terms of reals. The explanatory power of this model is explored, formalising informal descrip- tions in terms of mathematical definability and invariance, and relating a range of basic scientific puzzles to results and intractable problems in computability theory
Modulation of neutrophil function by the tripeptide feG
No full textAbstract Background Neutrophils are critical in the defense against potentially harmful microorganisms, but their excessive and inappropriate activation can contribute significantly to tissue damage and a worsening pathology. Through the release of endocrine factors submandibular glands contribute to achieving a balance in neutrophil function by modulating the state of activation and migratory potential of circulating neutrophils. A putative hormonal candidate for these effects on neutrophils was identified as a heptapeptide named submandibular gland peptide T (SGP-T; sequence = TDIFEGG). Since the tripeptide FEG, derived from SGP-T, and its D-amino acid analogue feG had similar inhibitory effects on inflammatory reactions, we investigated the effects of feG on human and rat neutrophil function. Results With human neutrophils feG had no discernible effect on oxidative burst or phagocytosis, but in picomolar amounts it reduced PAF-induced neutrophil movement and adhesion, and the binding of CD11b by 34% and that of CD16b close to control values. In the rat feG (10-11M) reduced the binding of CD11b and CD16 antibodies to PAF-stimulated circulating neutrophils by 35% and 43%, respectively, and at 100 micrograms/kilograms intraperitoneally feG reduced neutrophil in vivo migration by 40%. With ovalbumin-sensitized rats that were challenged with antigen, feG inhibited binding of antibodies against CD16b but not CD11b, on peritoneal leukocytes. Conclusions The inhibitory effect of feG on neutrophil movement may be mediated by alterations in the co-stimulatory molecules CD11b and CD16.</p
Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein
No full textAbstract The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 μg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs.</p
