Current Pharmaceutical Design - Volume 20, Issue 16, 2014

Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical “tastes” as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.

In the oral cavity, taste receptor cells dedicate to detecting chemical compounds in foodstuffs and transmitting their signals to gustatory nerve fibers. Heretofore, five taste qualities (sweet, umami, bitter, salty and sour) are generally accepted as basic tastes. Each of these may have a specific role in the detection of nutritious and poisonous substances; sweet for carbohydrate sources of calories, umami for protein and amino acid contents, bitter for harmful compounds, salty for minerals and sour for ripeness of fruits and spoiled foods. Recent studies have revealed molecular mechanisms for reception and transduction of these five basic tastes. Sweet, umami and bitter tastes are mediated by G-protein coupled receptors (GPCRs) and second-messenger signaling cascades. Salty and sour tastes are mediated by channel-type receptors. In addition to five basic tastes, taste receptor cells may have the ability to detect fat taste, which is elicited by fatty acids, and calcium taste, which is elicited by calcium. Taste compounds eliciting either fat taste or calcium taste may be detected by specific GPCRs expressed in taste receptor cells. This review will focus on transduction mechanisms and cellular characteristics responsible for each of basic tastes, fat taste and calcium taste.

A number of nutrient sensing seven trans-membrane (7TM) receptors have been identified and characterized over the past few years. While the sensing mechanisms to carbohydrates and free fatty acids are well understood, the molecular basis of amino acid sensing has recently come to the limelight. The present review describes the current status of promiscuous L-α-amino acid sensors, the calcium sensing receptor (CaSR), the GPRC6A receptor, the T1R1/T1R3 receptor and also their molecular pharmacology, expression pattern and physiological significance.

Nausea and vomiting are biological systems for defense against food poisoning that are also provoked by numerous drugs (e.g., chemotherapy, anesthesia) and chronic diseases (e.g., cancer, diabetic gastroparesis). The sensory pathways that stimulate nausea and vomiting include vestibular, area postrema, and forebrain inputs, but gastrointestinal vagal afferent fibers arguably play the most prominent role as a first-line defense. Vagal sensory neurons detect toxins that enter the gastrointestinal lumen and transmit information to the hindbrain, leading to nausea (an unconditioned stimulus that serves to facilitate the avoidance of offending foods) and vomiting (a mechanism to clear contents from the stomach). Despite the major importance of these systems to human physiology, progress on the biological basis of nausea and vomiting has been slow – partly because laboratory rats and mice, which represent the largest thrust of preclinical biomedical research, lack a vomiting reflex (although they appear to have indices of nausea, e.g., conditioned food aversion). Several established models are a mainstay of preclinical nausea and vomiting research in academia and pharmaceutical companies, including the dog, cat, ferret, and musk shrew. An argument is made for broader testing across species since each model possesses often unique experimental advantages and sensitivity to emetic and antiemetic agents. This review focuses on the state of knowledge on the neural pathways for nausea and vomiting, behavioral indices of nausea used in preclinical models, role of vagal afferent fibers, current antiemetic and antinausea treatments, and potential future directions.

Digestion and the absorption of food and nutrients have been considered the only functions of the gastrointestinal (GI) tract. However, recent studies suggest that taste cells in the oral cavity and taste-like cells in the GI tract share many common characteristics (taste receptors and transduction signaling). Over the last two decades, it has been revealed that the GI tract is a chemosensory organ that transfers nutrient information via GI hormone secretion (glucagon-like peptide-1, Peptide YY, oxyntomodulin, glucose-dependent insulinotropic polypeptide and others) and the activation of abdominal vagus afferents. In addition, the information relayed via the abdominal vagus nerve plays an important role in autonomic reflexes. This information, both humoral and neural, contributes to the maintenance of homeostasis (digestion, absorption, metabolism and food intake) in the body. In this review, we provide a brief overview of the following: GI chemosensory molecules, their distribution, the effect of nutrients on GI hormone secretion and the activation of vagus afferent nerves. We also focus on the possibility of clinical applications that control abdominal vagus activity.

Pavlov’s seminal findings in the early twentieth century showed that the sight, smell or taste of food in dogs with chronic esophagostomy induces a vagal-dependent gastric acid secretion. These observations established the concept of the cephalic phase of digestion. Compelling experimental evidence in rats indicates that the three amino acid peptide thyrotropin-releasing hormone (TRH) expressed in the brainstem plays a key role in the vagal stimulation of gastric function. Neurons in the dorsal motor nucleus of the vagus (DMN) expressed TRH receptor subtype (TRH-R1) and received efferent input from TRH containing fibers arising from TRH synthesizing neurons in the raphe pallidus, raphe obscurus, and the parapyramidal regions. TRH microinjected into the DMN or intracisternally excites the firing of DMN neurons and stimulates efferent activity in the gastric branch of the vagus nerve and gastric myenteric cholinergic neurons. At the functional level, this results in a vagally-mediated and atropine-sensitive stimulation of gastric epithelial and endocrine cells secreting acid, pepsin, serotonin, histamine and ghrelin, and enteric neurons leading to increased gastric motility and emptying. Importantly, the blockade of TRH or TRH-R1 in the brainstem by pretreatment into the cisterna magna or the DMN with TRH antibody or TRH-R1 oligodeoxynucleotide antisense respectively abolishes the stimulation of gastric acid induced by sham-feeding. The gastric response to TRH injected into the DMN is potentiated by serotonin and the proTRH flanking peptide, Ps4 and suppressed by a number of brainstem peptides and cytokines activated during stress or immune response and inhibiting food intake and gastric acid secretion. These convergent data strongly support a physiological involvement of TRH signaling pathway in the brainstem to stimulate vagal activity and identified TRH-TRH-R1 system as a major effector in the dorsal vagal complex to drive the vagally mediated gut response triggered by the cephalic phase.

In the stomach, pre-absorptive perception of food constituents is of particular importance in maintaining secretion and motility that matches the quantity and quality of nutrients. Products of food protein hydrolysis, free amino acids and short peptides, are the most potent chemical stimulants of the gastric phase of digestion. They are recognized by a variety of extracellular receptors belonging to the G-protein-coupled receptor superfamily, which are expressed by gastric mucosal exocrine and endocrine cells. Enteroendocrine G and D cells are likely the first level of integration of amino-acid-induced signals influencing a balance of endocrine activation and inhibition of gastric functions. This review focuses mainly on the physiological significance of dietary L-glutamate (Glu) in control of the gastric phase of digestion. The Glu signaling system in the stomach is linked to activation of the vagal afferents. In contrast to other natural amino acids, luminal Glu activates a paracrine cascade led by nitric oxide and followed by serotonin (5-HT), interacting in turn with 5- HT3 receptors on the afferent endings in the sub-mucosal layer. Glu, the only amino acid regularly ingested in a free form, enhances secretory and gastroprokinetic responses to protein- and amino-acid-rich diets but has no effect when applied alone or with carbohydrates. Possible mechanisms are discussed.

Nutrient perception in the gut is important for the maintenance of nutrient and energy balance in the body. Recently, nutrient perception has attracted the attention of medical researchers, as it may provide an opportunity to prevent obesity and associated disease. Recent progress in functional MRI (fMRI) techniques have enabled noninvasive investigation of whole brain function during the processing of information regarding ingested nutrients from the gut depending on the feeding status in both rodents and human subjects. However, the fMRI technique still has substantial problems because it relies on blood oxygenation levels. Here, a novel fMRI technique is introduced that solves this problem for rodent fMRI studies and fMRI studies of the gut-brain axis.

Neurons and neuroendocrine cells store nucleotides in vesicles and release them upon stimulation, leading to intercellular purinergic signaling. The molecular machinery responsible for the vesicular storage of nucleotides was a long standing enigma, however, recently the transporter involving in the process was identified. This article summarizes the history of vesicular storage of nucleotides and the identification of the vesicular nucleotide transporter (VNUT) responsible for the process. The significance of VNUT as a drug target to control purinergic chemical transmission is also discussed.

Our newly developed umami taste sensitivity test revealed the loss of only the umami taste sensation in some elderly patients, whereas the other four basic taste sensations (sweet, salty, sour, bitter) were normal. Such patients all complained of appetite loss and weight loss, resulting in poor overall health. As a treatment for taste disorder patients, improvement of salivary flow has been adopted in our clinic. Umami taste stimulation increases salivary flow rate of not only major but also minor salivary glands. After treatment with umami taste stimulation, patients remarkably regained their appetite, weight and overall health. Sensitivity to umami taste seems to contribute to good overall health in elderly people.

Despite the development of strong antibiotics, the pneumonia death is increasing all over the world in these decades. Among the people who died of pneumonia, the majority were 65 years old or over. Although pneumonia is recently categorized into several entities, aspiration pneumonia includes all entities. Therefore, targeting dysphagia and aspiration to treat pneumonia is a promising strategy and anti-aspiration drugs will be a part of pneumonia treatment. The swallowing reflex in elderly people was temperature-sensitive and the improvement of swallowing reflex by temperature stimuli could be mediated by the thermosensing TRP channels at pharynx. The administration of capsaicin as an agonist stimulus of TRPV1, a warm temperature receptor, decreased the delay in swallowing reflex. Red wine polyphenols improved swallowing reflex by enhancing TRPV1 response. Food with menthol, agonist of TRPM8 which is a cold temperature receptor, also decreased the delay in swallowing reflex. Olfactory stimulation such as black pepper was useful to improve the swallowing reflex for people with low ADL levels or with decreased consciousness. Thus, recent advancement of geriatrics found several anti-aspiration drugs such as thermosensing TRP channel agonists, black pepper odor, amantadine, cilostazol, theophylline and angiotensin- converting enzymes inhibitors. Thermosensing TRP channel agonists include capsaicin, capsiate, menthol, and red wine polyphenols. Controls of swallowing are mediated by various stages of neural system from peripheral sensory nerves to the entire cerebral cortex. Each anti-aspiration drug acts on various sites of neural axis of swallowing reflex. The combination of various anti-aspiration drugs may improve dysphagia and prevent aspiration pneumonia.

Intestinal chemosensing of endogenous and exogenous luminal compounds, including acid, CO2, bile acids and nutrients is an emerging area of gastrointestinal research, since gut hormones, particularly including incretins and glucagon-like peptide-2 (GLP-2) are released in response to luminal nutrients. Identification of luminal chemosensors such as nutrient-ligand G-protein coupled receptors (GPCRs) in enteroendocrine cells has linked luminal compounds to the corresponding gut hormone release. Mucosal chemical sensors are necessary to exert physiological responses such as secretion, digestion, absorption, and motility. We have been studying the mechanisms by which luminal compounds are sensed via mucosal acid sensors and GPCRs, which trigger mucosal defense mechanisms. In addition to luminal acid/CO2 sensing in the duodenum, recent studies also show that compounds present post-prandially such as amino acids, bile acids and fatty acids, enhance duodenal mucosal defenses, with digestion following the initial gastric processing. These studies may form the basis for therapies in which luminal nutrients release gut hormones that affect the mucosal protection, appetite, satiety, and systemic metabolisms.

The colonic lumen is continually exposed to many compounds, including beneficial and harmful compounds that are produced by colonic microflora. The intestinal epithelia form a barrier between the internal and luminal (external) environments. Chemical receptors that sense the luminal environment are thought to play important roles as sensors and as modulators of epithelial cell functions. The recent molecular identification of various membrane receptor proteins has revealed the sensory role of intestinal epithelial cells. Nutrient sensing by these receptors in the small intestine is implicated in nutrient absorption and metabolism. However, little is known about the physiological roles of chemosensors in the large intestine. Since 1980s, researchers have examined the effects of short-chain fatty acids (SCFA), the primary products of commensal bacteria, on gut motility, secretion, and incretin release, for example. In this decade, the SCFA receptor genes and their expression were identified in the mammalian colon. Furthermore, many other chemical receptors, including taste and olfactory receptors have been found in colonic epithelial cells. These findings indicate that the large intestinal epithelia express chemosensors that detect the luminal contents, particularly bacterial metabolites, and induce the host defense systems and the modulation of systemic metabolism via incretin release. In this review, we describe the local effects of chemical stimuli on the lumen associated with the expression pattern of sensory receptors. We propose that sensory receptors expressed in the colonic mucosa play important roles in luminal chemosensing to maintain homeostasis.

Digestive tract motility patterns are closely related to the pathophysiology of functional gastrointestinal diseases (FGID), and these patterns differ markedly between the interdigestive period and the postprandial period. The characteristic motility pattern in the interdigestive period is so-called interdigestive migrating contraction (IMC). IMCs have a housekeeping role in the intestinal tract, and could also be related to FGID. IMCs arising from the stomach are called gastrointestinal IMCs (GI-IMC), while IMCs arising from the duodenum without associated gastric contractions are called intestinal IMCs (I-IMC). It is thought that I-IMCs are abnormal in FGID. Transport of food residue to the duodenum via gastric emptying is one of the most important postprandial functions of the stomach. In patients with functional dyspepsia (FD), abnormal gastric emptying is a possible mechanism of gastric dysfunction. Accordingly, delayed gastric emptying has attracted attention, with prokinetic agents and herbal medicines often being administered in Japan to accelerate gastric emptying in patients who have anorexia associated with dyspepsia. Recently, we found that addition of monosodium L-glutamate (MSG) to a high-calorie liquid diet rich in casein promoted gastric emptying in healthy men. Therefore, another potential method of improving delayed gastric emptying could be activation of chemosensors that stimulate the autonomic nervous system of the gastrointestinal tract, suggesting a role for MSG in the management of delayed gastric emptying in patients with FD.

We reviewed the prophylactic effect of monosodium glutamate (MSG), a substance known as the “umami”, on NSAIDinduced small intestinal damage in rats. Loxoprofen, one of the NSAIDs frequently used in Asian countries, given orally at 60 mg/kg, caused hemorrhagic damage in the small intestine, mainly jejunum and ileum, concomitant with a down-regulation of Muc2 expression/ mucus secretion and an up-regulation of enterobacterial invasion and neutrophil migration as well as inducible nitric oxide synthase (iNOS) expression. The severity of these lesions was reduced by pretreatment with MSG (0.1~5%) given as a mixture of powder food (10 g/rat/day) for 5 days before administration of loxoprofen. The effect of MSG was accompanied by an up-regulation of Muc2 expression/ mucus secretion as well as a suppression of bacterial invasion, iNOS expression and myeloperoxidase activity. On the other hand, these lesions spontaneously healed within 7 days, but this process was hampered by loxoprofen at low doses (>10 mg/kg) given repeatedly for 5 days after ulceration. The healing-impairment effect of loxoprofen was accompanied by the down-regulation of vascular endothelium- derived growth factor (VEGF) expression and angiogenic response, and these responses were all antagonized by feeding diet containing 5% MSG for 5 days after ulceration. It is suggested that MSG exhibits a prophylactic effect against loxoprofen-induced small intestinal lesions, this effect is functionally associated with the up-regulation of Muc2 expression/mucus secretion, resulting in suppression of enterobacterial invasion and iNOS expression, the major pathogenic events in NSAID-induced enteropathy, and MSG also has the healing promoting effect on these lesions through enhancement of VEGF expression and angiogenesis.

The principal objective of this paper is to demonstrate the role of taste and flavor in health from the ancient science of Ayurveda to modern medicine; specifically their mechanisms and roles in space medicine and their clinical relevance in modern heath care. It also describes the brief history of the use of the monosodium glutamate or flavor enhancers (“Umami substance”) that improve the quality of food intake by stimulating chemosensory perception. In addition, the dietary nucleotides are known to be the components of “Umami substance” and the benefit of their use has been proposed in various types of patients with cancer, radiation therapy, organ transplantation, and for application inspace medicine.