International Journal of Peptides最新文献

Ghrelin, a peptide hormone secreted by the stomach, has been shown to regulate energy homeostasis by modulating electrical activity of neurons in the central nervous system (CNS). Like many circulating satiety signals, ghrelin is a peptide hormone and is unable to cross the blood-brain barrier without a transport mechanism. In this review, we address the notion that the arcuate nucleus of the hypothalamus is the only site in the CNS that detects circulating ghrelin to trigger orexigenic responses. We consider the roles of a specialized group of CNS structures called the sensory circumventricular organs (CVOs), which are not protected by the blood-brain barrier. These areas include the subfornical organ and the area postrema and are already well known to be key areas for detection of other circulating hormones such as angiotensin II, cholecystokinin, and amylin. A growing body of evidence indicates a key role for the sensory CVOs in the regulation of energy homeostasis.

Ghrelin is 28-amino-acid peptide that was discovered from the rat and human stomach in 1999. Since the discovery of ghrelin, various functions of ghrelin, including growth hormone release, feeding behavior, glucose metabolism, memory, and also antidepressant effects, have been studied. It has also been reported that ghrelin in the gastrointestinal tract has an important physiological effect on gastric acid secretion and gastrointestinal motility. Ghrelin has a unique structure that is modified by O-acylation with n-octanoic acid at third serine residues, and this modification enzyme has recently been identified and named ghrelin O-acyl transferase (GOAT). Ghrelin is considered to be a gut-brain peptide and is abundantly produced from endocrine cells in the gastrointestinal mucosa. In the gastrointestinal tract, ghrelin cells are most abundant in the stomach and are localized in gastric mucosal layers. Ghrelin cells are also widely distributed throughout the gastrointestinal tract. In addition, abundance of ghrelin cells in the gastric mucosa is evolutionally conserved from mammals to lower vertebrates, indicating that gastric ghrelin plays important roles for fundamental physiological functions. Ghrelin cells in the gastrointestinal tract are a major source of circulating plasma ghrelin, and thus understanding the physiology of these cells would reveal the biological significance of ghrelin.

Ghrelin is a powerful orexigenic gut hormone with growth hormone releasing activity. It plays a pivotal role for long-term energy balance and short-term food intake. It is also recognized as a potent signal for meal initiation. Ghrelin levels rise sharply before feeding onset, and are strongly suppressed by food ingestion. Postprandial ghrelin response is totally macronutrient specific in normal weight subjects, but is rather independent of macronutrient composition in obese. In rodents and lean individuals, isoenergetic meals of different macronutrient content suppress ghrelin to a variable extent. Carbohydrate appears to be the most effective macronutrient for ghrelin suppression, because of its rapid absorption and insulin-secreting effect. Protein induces prolonged ghrelin suppression and is considered to be the most satiating macronutrient. Fat, on the other hand, exhibits rather weak and insufficient ghrelin-suppressing capacity. The principal mediators involved in meal-induced ghrelin regulation are glucose, insulin, gastrointestinal hormones released in the postabsorptive phase, vagal activity, gastric emptying rate, and postprandial alterations in intestinal osmolarity.

Patients with chronic kidney disease (CKD) often exhibit symptoms of anorexia and cachexia, which are associated with decreased quality of life and increased mortality. Chronic inflammation may be an important mechanism for the development of anorexia, cachexia, renal osteodystrophy, and increased cardiovascular risk in CKD. Ghrelin is a gastric hormone. The biological effects of ghrelin are mediated through the growth hormone secretagogue receptor (GHSR). The salutary effects of ghrelin on food intake and meal appreciation suggest that ghrelin could be an effective treatment for anorexic CKD patients. In addition to its appetite-stimulating effects, ghrelin has been shown to possess anti-inflammatory properties. The known metabolic effects of ghrelin and the potential implications in CKD will be discussed in this review. The strength, shortcomings, and unanswered questions related to ghrelin treatment in CKD will be addressed.

Several studies suggest that the peptide hormone ghrelin mediates some of the usual behavioral responses to acute and chronic stress. Circulating ghrelin levels have been found to rise following stress. It has been proposed that this elevated ghrelin helps animals cope with stress by generating antidepressant-like behavioral adaptations, although another study suggests that decreasing CNS ghrelin expression has antidepressant-like effects. Ghrelin also seems to have effects on anxiety, although these have been shown to be alternatively anxiogenic or anxiolytic. The current review discusses our current understanding of ghrelin's roles in stress, mood, and anxiety.

Rikkunshito is a popular Japanese traditional medicine that is prescribed in Japan to treat various gastrointestinal tract disorders. In a double-blind controlled study, rikkunshito significantly ameliorated dysmotility-like dyspepsia and brought about a generalized improvement in upper gastric symptoms such as nausea and anorexia when compared with a control group. Several studies in rats have shown enhanced gastric emptying and a protective effect on gastric mucosa injury with rikkunshito administration. In addition, rikkunshito in combination with an anti-emetic drug is effective against anorexia and vomiting that occur as adverse reactions to chemotherapy in patients with advanced breast cancer. However, the mechanism by which rikkunshito alleviates gastrointestinal disorders induced by anticancer agents remains unclear. It has recently been shown that rikkunshito ameliorates cisplatin-induced anorexia by mediating an increase in the circulating ghrelin concentration. Moreover, Fujitsuka et al. found that decreased contractions of the antrum and duodenum in rats treated with a selective serotonin reuptake inhibitor were reversed by rikkunshito via enhancement of the circulating ghrelin concentration. These findings show that rikkunshito may be useful for treatment of anorexia and may provide a new strategy for improvement of upper gastrointestinal dysfunction.

Side-chain oligo- and polyglutamylation represents an important posttranslational modification in tubulin physiology. The particular number of glutamate units is related to specific regulatory functions. In this work, we present a method for the synthesis of building blocks for the Fmoc synthesis of peptides containing main chain glutamic acid residues that carry side-chain branching with oligo-glutamic acid. The two model peptide sequences CYEEVGVDSVEGEG-E(E(x))-EEGEEY and CQDATADEQG-E(E(x))-FEEEEGEDEA from the C-termini of mammalian α1- and β1-tubulin, respectively, containing oligo-glutamic acid side-chain branching with lengths of 1 to 5 amino acids were assembled in good yield and purity. The products may lead to the generation of specific antibodies which should be important tools for a more detailed investigation of polyglutamylation processes.

The majority of patients with dyspepsia have no identifiable cause of their disease, leading to a diagnosis of functional dyspepsia (FD). While a number of different factors affect gut activity, components of the nervous and endocrine systems are essential for normal gut function. Communication between the brain and gut occurs via direct neural connections or endocrine signaling events. Ghrelin, a peptide produced by the stomach, affects gastric motility/emptying and secretion, suggesting it may play a pathophysiological role in FD. It is also possible that the functional abnormalities in FD may affect ghrelin production in the stomach. Plasma ghrelin levels are reported to be altered in FD, correlating with FD symptom score. Furthermore, some patients with FD suffer from anorexia with body-weight loss. As ghrelin increases gastric emptying and promotes feeding, ghrelin therapy may be a new approach to the treatment of FD.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized as a preprohormone and then proteolytically processed to yield a 28-amino acid peptide. This peptide was originally reported to induce growth hormone release; large evidence, however, has indicated many other physiological activities of ghrelin, including regulation of food intake and energy balance, as well as of lipid and glucose metabolism. Ghrelin receptors have been detected in the hypothalamus and the pituitary, but also in the cardiovascular system, where ghrelin exerts beneficial hemodynamic activities. Ghrelin administration acutely improves endothelial dysfunction by increasing nitric oxide bioavailability and normalizes the altered balance between endothelin-1 and nitric oxide within the vasculature of patients with metabolic syndrome. Other cardiovascular effects of ghrelin include improvement of left ventricular contractility and cardiac output, as well as reduction of arterial pressure and systemic vascular resistance. In addition, antinflammatory and antiapoptotic actions of ghrelin have been reported both in vivo and in vitro. This review summarizes the most recent findings on the metabolic and cardiovascular effects of ghrelin through GH-dependent and -independent mechanisms and the possible role of ghrelin as a therapeutic molecule for treating cardiovascular diseases.

Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development.