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Motilin-induced concentration–response curves and effects of pretreatment with ritanserin, ondansetron, naloxone, FK888, verapamil, and l-NAME. (A) Ritanserin (10−7 mol L−1) showed no antagonistic effect on motilin-induced contraction. (B) Ondansetron treatment (10−5 mol L−1) significant reduced motilin-induced contraction (from 10−9 to 10−8 mol L−1). (C) Naloxone (10−6 mol L−1) showed significantly inhibited 10−9 mol L−1 motilin-induced contraction. (D) FK888 had no significant effect on motilin-induced contraction. (E) Verapamil significantly inhibited motilin-induced contraction (from 10−9 to 10−7 mol L−1). (F) l-NAME significantly potentiated the contraction at the dose of 3 × 10−10 mol L−1 motilin. Each value is the mean ± SEM (N = 4). ♦, control; ○, antagonists or inhibitor treatment; *P < 0.05.
Source publication
It has been shown in human and canine studies that motilin, a gastroprokinetic hormone, induces gastric phase III contractions via the enteric nervous; however, the center of motilin action in the stomach has not been clearly revealed. In the present study, we investigated the neural pathway of motilin-induced gastric contraction by using Suncus mu...
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... to previous studies, 5-hydroxytryptamine (5-HT) is involved in motilin action in the dog GI tract. 20 In the present study, ritanserin, a 5-HT 2 receptor antagonist (Fig. 4A), did not decrease the motilin-induced contraction at each concentration but markedly suppressed the spontaneous contractile activity (data not shown). In contrast to ritanserin, ondansetron, a 5-HT 3 receptor antagonist, significantly suppressed the contraction induced by motilin at 10 )9 and 10 )8 mol L )1 (Fig. ...
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... a 5-HT 2 receptor antagonist (Fig. 4A), did not decrease the motilin-induced contraction at each concentration but markedly suppressed the spontaneous contractile activity (data not shown). In contrast to ritanserin, ondansetron, a 5-HT 3 receptor antagonist, significantly suppressed the contraction induced by motilin at 10 )9 and 10 )8 mol L )1 (Fig. ...
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... effects of other receptor antagonists and nitric oxide synthase inhibitors were also investigated for further characterization of the response to motilin. Naloxone, an opiate receptor antagonist, significantly suppressed the contraction induced by a low dose of motilin (10 )9 mol L )1 ; Fig. 4C) but did not affect the spontaneously occurring phasic contractions (data not shown). Neither spontaneously occurring contractions nor motilin-induced contractions were decreased by FK888, a neurokinin 1 (NK1) receptor antagonist (Fig. 4D). Pretreatment with verapamil, an inhibitor of calcium inflow, significantly decreased the ...
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... antagonist, significantly suppressed the contraction induced by a low dose of motilin (10 )9 mol L )1 ; Fig. 4C) but did not affect the spontaneously occurring phasic contractions (data not shown). Neither spontaneously occurring contractions nor motilin-induced contractions were decreased by FK888, a neurokinin 1 (NK1) receptor antagonist (Fig. 4D). Pretreatment with verapamil, an inhibitor of calcium inflow, significantly decreased the motilin- induced contraction (Fig. ...
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... affect the spontaneously occurring phasic contractions (data not shown). Neither spontaneously occurring contractions nor motilin-induced contractions were decreased by FK888, a neurokinin 1 (NK1) receptor antagonist (Fig. 4D). Pretreatment with verapamil, an inhibitor of calcium inflow, significantly decreased the motilin- induced contraction (Fig. ...
Citations
... MLN acts as a physiological mediator of phase III gastric migrating myoelectric complex in humans and dogs (Itoh et al. 1976(Itoh et al. , 1978Vantrappen et al. 1979;Itoh 1997;Ogawa et al. 2012). Subsequently, in vitro contractile activity of gastrointestinal strips of rabbits and house musk shrews was reported (Kitazawa et al. 1994;Mondal et al. 2011), which suggests a similar action of MLN in these species. The activity of MLN is mediated by a specific G-protein-coupled receptor (GPR38 or MLNR) (Feighner et al. 1999). ...
... In the present study, mlnr mRNA expression was not observed in the gut, suggesting that MLN does not directly contribute to gastrointestinal motility, which supports the results described above. Potential active sites of MLN for stimulating the gastrointestinal tract in mammals are the gastrointestinal smooth muscle, myenteric plexus, and vagus nerve, based on immunohistochemical and pharmacological studies in mammals (Broad et al. 2012;Mondal et al. 2011;Inatomi et al. 1996); however, other sites are not apparent. In this study, mlnr expression was observed primarily in the brain, eye, and kidney, suggesting that MLN produced in the intestine may be transported to these organs in an endocrine manner to perform some unidentified functions. ...
Motilin (MLN) is a peptide hormone originally isolated from the mucosa of the porcine intestine. Its orthologs have been identified in various vertebrates. Although MLN regulates gastrointestinal motility in tetrapods from amphibians to mammals, recent studies indicate that MLN is not involved in the regulation of isolated intestinal motility in zebrafish, at least in vitro. To determine the unknown function of MLN in teleosts, we examined the expression of MLN and the MLN receptor (MLNR) at the cellular level in Japanese medaka (Oryzias latipes). Quantitative PCR revealed that mln mRNA was limitedly expressed in the gut, whereas mlnr mRNA was not detected in the gut but was expressed in the brain and kidney. By in situ hybridization and immunohistochemistry, mlnr mRNA was detected in the dopaminergic neurons of the area postrema in the brain and the noradrenaline-producing cells in the interrenal gland of the kidney. Furthermore, we observed efferent projections of mlnr-expressing dopaminergic neurons in the lobus vagi (XL) and nucleus motorius nervi vagi (NXm) of the medulla oblongata by establishing a transgenic medaka expressing the enhanced green fluorescence protein driven by the mlnr promoter. The expression of dopamine receptor mRNAs in the XL and cholinergic neurons in NXm was confirmed by in situ hybridization. These results indicate novel sites of MLN activity other than the gastrointestinal tract. MLN may exert central and peripheral actions through the regulation of catecholamine release in medaka.
... Finally, there is a last step, phase III, in which the maximum levels of contraction occur, and subsequently, the cycle restarts again [114,115]. Thus, the molecule that seems to be most important in MMC regulation is motilin, which is formed in the small intestine and causes gastric contraction [116,117]. In this line, several researchers pointed out how motilin values oscillate depending on the MMC phases, reaching the maximum gastric levels before phase III [118][119][120]. ...
This comprehensive narrative review explores the concept of neuro-vulnerability in energy metabolism regulation and its implications for metabolic disorders. The review highlights the complex interactions among the neural, hormonal, and metabolic pathways involved in the regulation of energy metabolism. The key topics discussed include the role of organs, hormones, and neural circuits in maintaining metabolic balance. The review investigates the association between neuro-vulnerability and metabolic disorders, such as obesity, insulin resistance, and eating disorders, considering genetic, epigenetic, and environmental factors that influence neuro-vulnerability and subsequent metabolic dysregulation. Neuroendocrine interactions and the neural regulation of food intake and energy expenditure are examined, with a focus on the impact of neuro-vulnerability on appetite dysregulation and altered energy expenditure. The role of neuroinflammation in metabolic health and neuro-vulnerability is discussed, emphasizing the bidirectional relationship between metabolic dysregulation and neuroinflammatory processes. This review also evaluates the use of neuroimaging techniques in studying neuro-vulnerability and their potential applications in clinical settings. Furthermore, the association between neuro-vulnerability and eating disorders, as well as its contribution to obesity, is examined. Potential therapeutic interventions targeting neuro-vulnerability, including pharmacological treatments and lifestyle modifications, are reviewed. In conclusion, understanding the concept of neuro-vulnerability in energy metabolism regulation is crucial for addressing metabolic disorders. This review provides valuable insights into the underlying neurobiological mechanisms and their implications for metabolic health. Targeting neuro-vulnerability holds promise for developing innovative strategies in the prevention and treatment of metabolic disorders, ultimately improving metabolic health outcomes.
... Later, MA2029, a 10-times potent and selective MLN-R antagonist was also reported (70). Using these MLN-R antagonists, involvement of endogenous motilin in the phase III of gastric MMC initiated in fasted dogs or Suncus was confirmed (71,72). ...
... In in vitro experiments, on the other hand, the local actions of motilin on smooth muscle cells and enteric neurons can be examined. Based on the results of functional studies mainly used dogs, rabbits and Suncus, the mechanisms of GI motility-stimulating actions by motilin are divided into three pathways (6,7,71,99,116,117) (Figure 3): (i) the action on MLN-Rs located on smooth muscle cells; (ii) the action on MLN-Rs located on enteric neurons although detailed neural networks have not been proven, as a result, ACh released from cholinergic neurons causes contraction through the muscarinic receptor; and (iii) the activation of the vago-vagal reflex pathways followed by stimulating vagal efferent neurons connecting to the enteric neurons. The presence of 5-HT 3 receptors has been demonstrated in the terminals of vagus afferent neurons (115), and motilin-induced contraction in the vagus-intact stomach, but not in the vagotomized stomach, was decreased by a 5-HT 3 receptor antagonist (94). ...
... Sanger et al. (12) reported that the motilin system is correlated with the ability to vomit with some species exceptions. Suncus motilin and ghrelin (44,172) and their receptors (78) have been identified, and functions of motilin in regulation of GI motility have been investigated in both in vivo and in vitro (15,71,99,173). ...
Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs and house musk shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes to the maintenance of normal GI functions and transmits a hunger signal from the stomach to the brain. Motilin has been identified in various mammals, but the physiological roles of motilin in regulating GI motility in these mammals are well not understood due to inconsistencies between studies conducted on different species using a range of experimental conditions. Motilin orthologs have been identified in non-mammalian vertebrates, and the sequence of avian motilin is relatively close to that of mammals, but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R has also been identified in mammals and non-mammalian vertebrates, and can be divided into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50 years have passed since discovery of motilin, here we reviewed the structure, distribution, receptor and the GI motility regulatory function of motilin in vertebrates from fish to mammals.
... Des-acyl rat GHRL, an inactive form of GHRL, did not cause contraction in the stomach or upper intestine, indicating that the contraction by rat GHRL is due to activation of GHRL receptor. Contraction caused by GHRL in the non-stimulated GI tract has already been demonstrated in the chicken, rat and suncus (Kitazawa et al., 2007;Edholm et al., 2004;Mondal et al., 2011). GHRL caused contraction in the chicken crop but not in the quail or pheasant crop, suggesting species-specific responses to GHRL in birds (Kitazawa et al., 2007(Kitazawa et al., , 2009Zhang et al., 2020). ...
... But physiological meaning of species-dependent actions of GHRL in GI tract was not clear in this study. GHRL-induced contraction in the non-stimulated rat intestine, chicken proventriculus and suncus stomach was decreased by TTX, but that in the non-stimulated chicken crop was insensitive to TTX (Edholm et al., 2004;Kitazawa et al., 2007;Mondal et al., 2011). GHRL receptor is thought to be located on enteric neurons in the rat intestine and chicken proventriculus as suggested by the results of an immunohistochemical study (Dass et al., 2003), but it located on smooth muscle cells in the chicken crop (Kitazawa et al., 2007). ...
Ghrelin (GHRL) and motilin (MLN), gut peptides isolated from the mucosa of the stomach and duodenum, respectively, stimulate gastrointestinal (GI) motility in mammals and birds. However, the functions of MLN and GHRL in amphibian GI tracts have not been examined in detail. To clarify the regulation of GI motility by the two peptides, the effects of human MLN and rat GHRL on contractility of isolated GI strips from three species of frogs, the black-spotted pond frog (pond frog; Pelophylax nigromaculata), bullfrog (Lithobates catesbeiana) and Western clawed frog (Xenopus; Xenopus tropicalis), were examined in in vitro experiments. The GI tract of each frog was divided into the stomach, upper intestine, middle intestine and lower intestine. Human MLN caused contractions of the stomach in the pond frog and upper intestine in the bullfrog and Xenopus, but other GI regions were insensitive to human MLN. Erythromycin did not cause contraction of the upper intestine of the bullfrog and Xenopus. Rat GHRL did not cause contraction of the stomach and small intestines in the pond frog and bullfrog, but it caused a concentration-dependent contraction in the stomach and upper intestine of Xenopus, while des-acyl rat GHRL did not cause any contraction of them. In conclusion, human MLN caused the contraction of the stomach or upper intestine in the three species of frogs, but GHRL was effective only in the stomach and upper intestine of Xenopus. On the basis of these data, MLN but not GHRL causes the GI region-dependent contractions in the frogs.
... Although SST has inhibitory effects on motilin secretion (19,20), our results indicate that suppression of gastric contraction by SST is not involved in the inhibition of motilin secretion. In S. murinus, in vitro organ bath experiments showed that motilin-induced contractions are completely abolished by treatment with a muscarinic receptor antagonist and their occurrence is significantly reduced by a nicotine receptor antagonist (29). Taken together, our results suggest that the inhibitory effects of SST on motilininduced gastric contractions were exerted without affecting extrinsic nerves, and SST may primarily suppress motilin-induced contractions by acting on SSTRs to inhibit the release of ACh from cholinergic neurons in the myenteric plexus. ...
Gastric contractions show two specific patterns in many species, migrating motor contractions (MMC) and postprandial contractions (PPCs), that occur in the fasted and fed states, respectively. In this study, we examined the role of somatostatin (SST) in gastric motility both in vivo and in vitro using the Asian house shrew (Suncus murinus). We performed in vivo recordings of gastric motility and in vitro organ bath experiments using S. murinus, which was recently established as a small laboratory animal for use in tests of gastrointestinal motility. SST (1.65 µg kg⁻¹ min⁻¹) was intravenously administered during phase II of MMC and PPCs. Next, the effect of SST on motilin-induced gastric contractions at phase I of MMC was measured. Cyclosomatostatin (CSST), an SST receptor antagonist, was administered at the peak of phase III of MMC. In addition, the effect of SST (10⁻¹¹–10⁻⁹ M) on motilin-induced gastric contractions was evaluated using an organ bath experiment in vitro. In conscious, free-moving S. murinus, the administration of SST decreased the occurrence of the spontaneous phase II of MMC and PPCs. Pretreatment with SST and octreotide suppressed the induction of motilin-induced gastric contractions both in vivo and in vitro. Administration of CSST before the peak of spontaneous phase III contractions had no effect on gastric contractions. Endogenous SST is not involved in the regulation of gastric MMC and PPCs, but exogenous SST suppresses spontaneous gastric contractions. Thus, SST would be good for treating abnormal gastrointestinal motility disorders.
... Actually, MLN is known to contract the GI tract in several mammals through activation of smooth muscle cells, local enteric neurons and afferent terminals of vagus nerves (Figure 1). The mechanisms that have been identified depend on the experimental conditions (in vitro or in vivo) and animal species, such as dogs (Canis lupus familiaris), rabbits (Leporinae Trouessart) and Asian house musk shrews (Suncus murinus) (4,(16)(17)(18)(19)(20). The MLN receptor (MLN-R) was identified in the human (Homo sapiens) stomach as an orphan G protein-coupled receptor (GPR38) for which the ligand is direct action on smooth muscle (receptors being present on smooth muscle cells), action on enteric neurons in the myenteric plexus (receptors being present on enteric neurons), action on the nerve terminals of autonomic afferent neurons followed by excitation of the central nervous system (CNS), mainly the hypothalamus, which stimulates autonomic efferent neurons (receptors being present on afferent terminals) and direct action on central neurons (receptors being present on neurons of the CNS). ...
... The GI motility (circular muscle direction) of conscious dogs is measured by force transducers sutured on the serosal surface of the stomach and the intestine. Asian house musk shrew* Contraction Enteric neurons (18,19) Contraction (phase-III) Enteric neurons (20,54) *Motilin structure has been identified in the marked animal species. EFS, Electrical field stimulation for excitation of enteric neurons. ...
... MLN does not cause contraction in the digestive state in the vagus nerveintact animals but causes contraction in vagotomized animals, suggesting that the vagus nerve suppresses the action of MLN in the digestive state (20). MLN also causes contraction of gastric strips in an in vitro study, and the contraction was completely abolished by atropine and tetrodotoxin, indicating that MLNinduced response is a pure neural origin (18). Namely, the MLN-R is located only in enteric neurons in the house musk shrew and mediates the MLN-induced contraction (18). ...
The energy balance of vertebrates is regulated by the difference in energy input and energy expenditure. Generally, most vertebrates obtain their energy from nutrients of foods through the gastrointestinal (GI) tract. Therefore, food intake and following food digestion, including motility of the GI tract, secretion and absorption, are crucial physiological events for energy homeostasis. GI motility changes depending on feeding, and GI motility is divided into fasting (interdigestive) and postprandial (digestive) contraction patterns. GI motility is controlled by contractility of smooth muscles of the GI tract, extrinsic and intrinsic neurons (motor and sensory) and some hormones. In mammals, ghrelin (GHRL) and motilin (MLN) stimulate appetite and GI motility and contribute to the regulation of energy homeostasis. GHRL and MLN are produced in the mucosal layer of the stomach and upper small intestine, respectively. GHRL is a multifunctional peptide and is involved in glucose metabolism, endocrine/exocrine functions and cardiovascular and reproductive functions, in addition to feeding and GI motility in mammals. On the other hand, the action of MLN is restricted and species such as rodentia, including mice and rats, lack MLN peptide and its receptor. From a phylogenetic point of view, GHRL and its receptor GHS-R1a have been identified in various vertebrates, and their structural features and various physiological functions have been revealed. On the other hand, MLN or MLN-like peptide (MLN-LP) and its receptors have been found only in some fish, birds and mammals. Here, we review the actions of GHRL and MLN with a focus on contractility of the GI tract of species from fish to mammals.
... Previous studies have demonstrated that MTLR is expressed in gastrointestinal muscle cells and the myenteric plexus, but not in the mucosa and submucosa of the gastrointestinal tract in humans [9,10]. These findings are consistent with results that suggest that the motilin-induced motor response is mediated through direct action on smooth muscle cells and the activation of cholinergic pathways [11][12][13]. Furthermore, the antibiotic drug erythromycin has been shown to stimulate MTLRs and mimic the motor response observed following treatment of motilin [14,15]. ...
... Interestingly, the acetylcholine muscarinic receptor antagonist atropine, and the neurotoxin tetrodotoxin, failed to attenuate the contractile responses to human motilin and erythromycin in hMTLR-Tg mice. Several studies have demonstrated that motilin-induced motor responses are mediated through direct action on smooth muscles and the activation of cholinergic pathways in dogs, rabbits, shrew and humans [11][12][13]34]. In contrast, Satoh et al. [33] showed that the contractile response induced by an erythromycin-derivative in human gastric antrum was not influenced by atropine and tetrodotoxin. ...
Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin receptors (MTLRs) are G protein-coupled receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of motilin are highly species-dependent and remain poorly understood. As a functional motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human motilin and erythromycin.
The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red.
hMTLR expression was abundant in the gastric smooth muscle layer. Interestingly, higher levels of hMTLR expression were observed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca²⁺-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice.
Human motilin and erythromycin stimulate gastric smooth muscle contraction in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca²⁺. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.
... Previous studies have demonstrated that MTLR is expressed in gastrointestinal muscle cells and the myenteric plexus, but not in the mucosa and submucosa of the gastrointestinal tract in humans [9,10]. These findings are consistent with results that suggest that the motilin-induced motor response is mediated through direct action on smooth muscle cells and the activation of cholinergic pathways [11][12][13]. Furthermore, the antibiotic drug erythromycin has been shown to stimulate MTLRs and mimic the motor response observed following treatment of motilin [14,15]. ...
... http://dx.doi.org/10.1101/436436 doi: bioRxiv preprint first posted online Oct. 5, 2018; in dogs, rabbits, shrew and humans [11][12][13]32]. In contrast, Satoh et al. [31] showed that the contractile response induced by an erythromycin-derivative in human gastric antrum was not influenced by atropine and tetrodotoxin. ...
Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin receptors (MTLRs) are G protein-coupled receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of motilin are highly species-dependent and remain poorly understood. As a functional motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human motilin and erythromycin.
The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red.
hMTLR expression was abundant in the gastric smooth muscle layer but more potently expressed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca2+-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice.
Human motilin and erythromycin stimulate the gastric motor response in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca2+. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.
... Motilin (MOT) modulates gastric contraction via cholinergic, adrenergic, serotonergic, and NO neurons (Mondal et al., 2011), and is associated with emptying the stomach during the interdigestive period (Dudani et al., 2016). Substance P (SP) belongs to an undecapeptide member of the tachykinin neuropeptide family. ...
Gastric ulcer (GU) is a main threat to public health. 1-Deoxynojirimycin (DNJ) has antioxidant and anti-inflammatory properties and may prevent GU but related mechanism remains unclear. DNJ was extracted from the supernatants of Bacillus subtilis by using ethanol and purified by using CM-Sepharose chromatography. A GU mouse model was induced by indomethacin. The functional role of DNJ in GU mice was explored by measuring the main molecules in the NF-KappaB pathway. After the model establishment, 40 GU mice were evenly assigned into five categories: IG (received vehicle control), LG (10 μg DNJ daily), MG (20 μg DNJ daily), HG (40 μg DNJ daily), and RG (0.5 mg ranitidine daily). Meanwhile, eight healthy mice were assigned as a control group (CG). After 1-month therapy, weight and gastric volume were investigated. The levels of serum inflammatory cytokines (IL-6 and TNF-α), antioxidant indices [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)], and oxidant biomarker malondialdehyde (MDA) were examined via ELISA. Meanwhile, inflammatory cytokine (IL-6 and TNF-α) levels, and key molecules (NF-κB p65), cyclooxygenase 1 (COX-1 and COX2) involved in NF-κB pathway, were analyzed by using Western Blot. COX-1 and COX-2 levels were further measured by immunohistochemistry. The effects of DNJ on gastric functions were explored by measuring the changes of Motilin (MOT), Substance P (SP), Somatostatin (SS), and Vasoactive intestinal peptide (VIP) in GU mouse models with ELISA Kits. The results indicated that DNJ prevented indomethacin-caused increase of gastric volume. DNJ improved histopathology of GU mice when compared with the mice from IG group (P < 0.05). DNJ consumption decreased the levels of IL-6 and TNF-α (P < 0.05). DNJ increased antioxidant indices of GU mice by improving the activities of SOD, CAT and reduced GSH, and reduced MDA levels (P < 0.05). DNJ increased the levels of prostaglandin E2, COX-1, COX2, and reduced the levels of and NF-κB p65 (P < 0.05). DNJ showed protection for gastric functions of GU mice by reducing the levels of MOT and SP, and increasing the levels of SS and VIP. DNJ treatment inactivates NF-κB signaling pathway, and increases anti-ulceration ability of the models.
... Motilin (MOT), a 22-amino-acid peptide, was first discovered from the mucosa of the porcine intestine (Brown et al., 1973), and it was shown that MOT stimulates gastrointestinal motility in several mammals through a direct action on smooth muscle cells and/or the activation of the cholinergic neural pathways (Kitazawa et al., 1993(Kitazawa et al., , 1994Van Assche et al., 1997;Mondal et al., 2011). Physiological effects of MOT are mediated by its cognate receptor GPR38, which was de-orphanized in1999 as the MOT receptor (Feighner et al., 1999). ...
Motilin (MOT), a 22-amino-acid peptide hormone produced in the duodenal mucosa, stimulates gastrointestinal motility in mammals and birds, and it is a mediator of interdigestive motor complexes. Recently, expression of MOT-like peptide (MOTLP) and its receptor mRNAs was identified in zebrafish. The aim of the present study was to determine whether the zebrafish MOTLP (zfMOTLP, HIAFFSPKEMRELREKE) affects zebrafish gastrointestinal motility, with comparison to the effect of human MOT, in which five amino acids are identical to zfMOTLP at positions 5, 9, 15, 16, and 17. zfMOTLP caused small contractions of the rabbit duodenum and chicken ileum but, the sensitivity was about 3000-times lower than that of human MOT. zfMOTLP-induced contraction in the rabbit duodenum was decreased by pretreatment of the MOT receptor antagonist GM109, indicating that zfMOTLP could bind to the MOT receptor. zfMOTLP (3-100 nM) increased the intracellular Ca²⁺concentration in zfMOT receptor-expressing HEK293 cells, but human MOT did not cause responses even at 100 nM. In in vitro study using isolated zebrafish gastrointestinal strips, zfMOTLP caused only small contractions even at high doses (1-10 μM). zfMOT receptor mRNA is detected in the gastrointestinal tract and brain to almost the same extent, and the expression level (40-70 copies/100 ng total RNA) is much lower than that in the chicken gastrointestinal tract. These results suggest that the MOTLP/MOT system is present in zebrafish, but its physiological role for regulation of gastrointestinal motility might be not significant due to the weak contractile activity and low expression level of the receptor.
