The submandibular glands: a role in homeostasis and allostasis

The salivary glands are important exocrine and endocrine organs, whose role in oral health is well recognized. Only within the last 15 years has it become apparent that these glands also contribute to maintenance of systemic health. Salivary gland polypeptides promote health and well-being by aiding in wound healing, mucosal protection, tissue and organ regeneration, and immunomodulation. It is proposed that salivary gland factors form an integral part of the body's homeostatic processes. In the their absence, a condition promoted by many diseases or by artificially removing the glands (sialadenectomy), oral and systemic health is jeopardized. When the salivary glands do not secrete their hormones properly the organism is no longer able to normally regulate several functions since important homeostatic mechanisms become dysfunctional. This breakdown in homeostatic mechanisms results in the establishment of an alternative state, that of allostasis, which is generally associated with illness or susceptibility to illness. It is proposed that the dysfunctional salivary glands facilitate the development of the pathologies associated with various disorders, such as diabetes mellitus and enhanced sensitivity to endotoxin.Biomedical Reviews 1995; 4: 61-69

Submandibular gland peptides and the modulation of anaphylactic and endotoxic reactions

Submandibular 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

This 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

The tripeptide feG regulates the production of intracellular reactive oxygen species by neutrophils

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

The tripeptide feG inhibits leukocyte adhesion

© 2008 Mathison et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Effects of tegaserod on bile composition and hepatic secretion in Richardson ground squirrels on an enriched cholesterol diet

BACKGROUND: Tegaserod is effective in treating IBS patients with constipation, and does not alter gallbladder motility in healthy individuals or in patients with IBS. However, it is not known if tegaserod affects the biliary tract in gallstone disease, so to this end the effects of tegaserod on bile composition and hepatic secretion of Richardson ground squirrels maintained on an enriched cholesterol diet were examined. RESULTS: Animals were fed either a control (0.03%) or enriched (1%) cholesterol diet for 28 days, and treated s.c. with tegaserod (0.1 mg/kg BID) or vehicle. Bile flow, bile acid, phospholipids and cholesterol secretion were measured with standard methods. Tegaserod treatment or enriched cholesterol diet, alone or combination, did not alter body or liver weights. The enriched cholesterol diet increased cholesterol saturation index (CSI), cholesterol concentrations in gallbladder and hepatic duct bile by ~50% and decreased bile acids in gallbladder bile by 17%. Tegaserod treatment reversed these cholesterol-induced changes. None of the treatments, drug or diet, altered fasting gallbladder volume, bile flow and bile salts or phospholipid secretion in normal diet and cholesterol-fed animals. However, tegaserod treatment prevented the decreases in bile acid pool size and cycling frequency caused by the enriched cholesterol diet, consequent to re-establishing normal bile acid to concentrations in the gall bladder. Tegaserod had no effect on these parameters with normal diet animals. CONCLUSION: Tegaserod treatment results in increased enterohepatic cycling and lowers cholesterol saturation in the bile of cholesterol-fed animals. These effects would decrease conditions favorable to cholesterol gallstone formation

Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein

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

Modulation of neutrophil function by the tripeptide feG

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(-11)M) 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

Increased cholinergic contractions of jejunal smooth muscle caused by a high cholesterol diet are prevented by the 5-HT(4 )agonist – tegaserod

BACKGROUND: Excess cholesterol in bile and in blood is a major risk factor for the respective development of gallbladder disease and atherosclerosis. This lipid in excess negatively impacts the functioning of other smooth muscles, including the intestine. Serotonin is an important mediator of the contractile responses of the small intestine. Drugs targeting the serotonin receptor are used as prokinetic agents to manage intestinal motor disorders, in particular irritable bowel syndrome. Thus, tegaserod, acting on 5-HT(4 )receptor, ideally should obviate detrimental effects of excessive cholesterol on gastrointestinal smooth muscle. In this study we examined the effect of tegaserod on cholesterol-induced changes in the contractile responses of intestinal smooth muscle. METHODS: The effects of a high cholesterol (1%) diet on the in vitro contractile responses of jejunal longitudinal smooth muscle from Richardson ground squirrels to the cholinergic agonist carbachol were examined in the presence or absence of tetrodrodotoxin (TTX). Two groups of animals, fed either low (0.03%) or high cholesterol rat chow diet, were further divided into two subgroups and treated for 28 days with either vehicle or tegaserod. RESULTS: The high cholesterol diet increased, by nearly 2-fold, contractions of the jejunal longitudinal smooth muscle elicited by carbachol. These cholinergic contractions were mediated by muscarinic receptors since they were blocked by scopolamine, a muscarinic receptor antagonist, but not by the nicotinic receptor antagonist, hexamethonium. Tegaserod treatment, which did not affect cholinergic contractions of tissues from low cholesterol fed animals, abrogated the increase caused by the high cholesterol diet. With low cholesterol diet TTX enhanced carbachol-evoked contractions, whereas this action potential blocker did not affect the augmented cholinergic contractions seen with tissues from animals on the high cholesterol diet. Tegaserod-treatment removed the effects of a high cholesterol diet on neuronal muscarinic receptors, as the potentiating effect of TTX on carbachol-elicited contractions was maintained in these animals. CONCLUSION: A high cholesterol diet causes significant changes to cholinergic neurotransmission in the enteric nerves of the jejunum. The mechanisms by which these effects of cholesterol are reversed by tegaserod are unknown, but relate to removal of an inhibitory effect of cholesterol on enteric nerves