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Abstract

After being discovered from the bovine pineal gland by Aaron Lerner and co-workers in the year 1958, various distinguished researchers have reported melatonin (5-methoxy-N-acetyl-tryptamine) from several extra-pineal sources, including the gastrointestinal tract (GIT). In the year 1974, Raikhlin and Kvetnoy first detected this molecule in the gastrointestinal tissue. Later, within the last 45 years, many renowned investigators found that the GIT is a rich source of melatonin, in addition to the pineal gland. In the carp gut, the estimation of Arylalkylamine-N-acetyltransferase (AANAT) mRNA/protein levels, which is the rate-determining enzyme for melatonin biosynthesis in the pineal gland, confirmed the endogenous synthesis of melatonin. The remarkable feature of the pineal gland melatonin is its rhythmic synthesis with a peak at dark-phase and lowest at light-phase in synchronization with seasonal environmental light-dark (LD) cycle. Recent studies on carp demonstrated that the melatonin concentrations and the AANAT protein intensities in different gut segments underwent significant daily fluctuations. However, compared to the melatonin rhythm in the pineal gland, the melatonin profiles in gut tissue displayed daily rhythm in parallel with the feeding cycle of the carp, irrespective of LD conditions of the environment. Notably, in carp, the temporal pattern of the gut melatoninergic system found to vary with the environmental non-photic signal(s), such as food entrainment factors (availability of food/timing of food supply/number(s) of feed per day/quality of food) those act as the most dependable synchronizer(s) in daily rhythm characteristics of gut melatonin and AANAT. Thereby in this review, it appears meaningful to highlight the existing data on the mode of synthesis of melatonin in cells of the digestive tract, and most importantly, the regulation of its synthesis. Finally, in comparison with the dynamic actions of melatonin derived from the pineal gland, this review will lead to underline the role of gut-derived melatonin in a variety of physiological functions.

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... Melatonin is a hormone that affects circadian rhythms and increases intestinal motility (Falcón et al., 2010). Various melatonin receptors have been described in the intestine, as well as high melatonin synthesis with circadian patterns determined by food but independent of ambient light (Yasmin et al., 2021). Increased melatonin levels in the intestine after 2-4 h post-feeding in carp (Mukherjee et al., 2014) suggests its key roles in the passage of food through the gastrointestinal tract. ...
... Increased melatonin levels in the intestine after 2-4 h post-feeding in carp (Mukherjee et al., 2014) suggests its key roles in the passage of food through the gastrointestinal tract. However, the information relating feed passage and melatonin levels is still limited in fish (Acharyya et al., 2021;Yasmin et al., 2021). ...
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Eleginops maclovinus is a native species with potential for Chilean aquaculture. Understanding the variations between the post-prandial and fasted metabolic responses can contribute to improving the aquaculture of this species. This study aimed to characterize variations in intermediate metabolism during the course of the day in the liver, serum, and gills of fed and unfed fish. For this, 72 fish were assigned to two experimental groups, “fed” and “fasted”. The first group was fed “ad libitum” at 8.30, while the fasted group was not fed for 24 h. Samples were taken from both groups at 9:00, and every 2 h: 11:00, 13:00, 15:00, 17:00, and 19:00. In the fed group, food spent a long time in the gastrointestinal tract, with a large increase in stomach size and without evidence of complete emptying of the stomach at 19:00 (10.5 h post-feeding). In serum, the levels of amino acids, glucose, and triglycerides presented significant differences with peak levels at different times of day in the fed group. The cortisol in the fasted group presented a diurnal pattern with high levels during the morning and very low levels after 13:00, while in the fed group, the high cortisol variability did not allow a clear pattern to be established. In the liver, the effect of time on the enzymatic activity of the intermediary metabolism was greater compared to the effect of feeding. In the liver, enzyme activity decreased at later hours of the day, while glycogen levels increased at later hours of the day in both groups: but its levels were higher in the fed group. In gills, as well as in the liver, time had a greater effect than feeding on intermediate metabolism, since feeding only had a significant effect on the levels of hexokinase, lactate, and amino acids, suggesting an effect on carbohydrate metabolism. Meanwhile, time significantly affected the levels of Na⁺, K⁺-ATPase, glutamate dehydrogenase, aspartate aminotransferase, amino acids, and proteins, suggesting an effect on amino acid metabolism. In conclusion, the intermediate metabolism of E. maclovinus presents variations according to the time of day, with an increased metabolism during the morning and decreased metabolism as the day progresses, especially at the hepatic level. The gill tissue, despite not being a metabolic organ, presents feeding-dependent variations in its metabolism. Additional studies will be required to corroborate if coordinating a feeding strategy during the first hours of the day when metabolism is greater would improve the growth of E. maclovinus.
... In the current state of knowledge, there are reasons to suggest that food composition, feeding habits, and feeding time may be the critical factors in aquaculture for the synchronization of MEL synthesis within the gastrointestinal tissues (Mukherjee and Maitra, 2018;Pal and Maitra, 2018;Yasmin et al., 2021). It is wellproclaimed that the poor quality of flesh and poor performance of fish growth are related to imbalanced food composition in aquaculture (Maitra, 2011). ...
... Endogenous MEL synthesis from its precursor tryptophan in fish gut is well-established by various researchers. Dietary L-Trp supplementation in variable amounts with conventional fish meal has been shown to modulate the synthesis of MEL from digestive tissues (Yasmin et al., 2021). In the juvenile rainbow trout (O. ...
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In vertebrates, melatonin ( N -acetyl-5-methoxy-tryptamine, MEL) is synthesized from L-tryptophan (L-Trp), primarily in the pineal gland and additionally in several non-pineal tissues, including enterochromaffin cells of the gastrointestinal tract. The biosynthesis of MEL in the pinealocytes exhibits a daily rhythm with a nocturnal peak in synchronization with the dark phase of an environment. However, the temporal pattern of the gut melatoninergic system in fish is known to be synchronized with one or more non-photic external cue(s), of which most notable include the components of food and feeding time in a daily cycle. Experimental findings on the use of L-Trp (5-fold to −8-fold higher with respect to standard) as a fish food supplement suggest that it has a stimulatory influence on gut MEL synthesis that ultimately leads to elevated levels of plasma MEL. Several studies employing MEL as a fish feed additive report variable responses in relation to the physiological functions of the fish and its doses of application and modes of exposure. Oral administration of MEL (validated dose in general: 200 mg/kg fish food) causes an increase in gut MEL concentrations, food intake capacity, and micronutrient selection ability of fish, as well as enhanced activity of antioxidative enzymes and/or reduced levels of biological stress markers like plasma cortisol and lactate. The application of MEL with the doses of 50 and 250 mg/kg fish food to balanced diet results in precious maturation of gonads, high live sperm rate, and good quality seeds in catfish. A few studies on different fish groups administered with MEL through tank water reveal a significant increase in the fecundity rate, percentage of fertilization, and the number of hatched embryos. MEL injection through intraperitoneal or intramuscular routes also elicits variable responses in fish. Several studies suggest a major protective role of endogenous MEL against gastric ulcer induced by pathogenic bacterial infection. Taken together, MEL seems to be a multipotent physiological candidate involved in the regulation of a variety of body functions ranging from the synchronization of vital activities with environmental variables to the timing of reproduction in a changing system, from the acceleration of body growth to the determination of a pattern of development, and from the reduction of oxidative stress to the protection against microbial infections. Because aquaculture aims at substantially improving the quality and quantity of available aquatic resources employing convenient, consistent, and commercially exploitable measures, we find the reasons to suggest that the use of MEL or its precursor L-Trp as a fish food supplement may open up a new vista of aquaculture and, hence, present this review with an attempt to present the basic information on this area of interest to justify the hypothesis.
... Therefore, melatonin was previously reported to be mainly synthesized in pinealocytes and then released into the bloodstream to reach central and peripheral organs for diverse roles. However, recent reports indicate that a majority of melatonin is synthesized in other tissues such as gut and skin rather than the pineal gland (Yasmin et al., 2021;Sevilla et al., 2022), suggesting that it can also regulate biological activities by binding to its specific receptors in target tissues (Shi et al., 2004;Isorna et al., 2009;Kuz'mina, 2020). ...
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As an important hormone, melatonin participates in endocrine regulation of diverse functions in vertebrates. Its biosynthesis is catalyzed by four cascaded enzymes, among them, arylalkylamine N-acetyltransferase (AANAT) is the most critical one. Although only single aanat gene has been identified in most groups of vertebrates, researchers including us have determined that fish have the most diverse of aanat genes (aanat1a, aanat1b, and aanat2), playing various potential roles such as seasonal migration, amphibious aerial vision, and cave or deep-sea adaptation. With the rapid development of genome and transcriptome sequencing, more and more putative sequences of fish aanat genes are going to be available. Related phylogeny and functional investigations will enrich our understanding of AANAT functions in various fish species.
... Although the roles of serotonin and melatonin for various aspects of liver physiology have been well described [50,51], the synthesis of melatonin in the liver has been shown only in fish [52]. This seems to be in contrast with the mammalian intestine, in which the high basal levels of serotonin and melatonin and their physiological functions are well understood [45,53]. ...
Article
Amino acid tryptophan is catabolised via the kynurenine and serotonin–melatonin pathways, leading to various biologically active metabolites involved in regulating immunity, metabolism, and neuronal function. The levels of these metabolites are determined by the enzymes, which respond to altered homeostasis and pathological processes in the body. For the pineal gland, most work has centred on the serotonin–melatonin pathway. Still, no information exists on the expression of kynurenine pathway enzymes (KPEs), which may compete for the same substrate. Therefore, in this study, we investigated the physiological expression of KPEs in the rat pineal gland and their alterations in response to acute inflammation. We further compared the pineal expression profiles with the KPE expression in the rat liver and heart. Our data indicate the basal, non-induced expression of KPEs in the pineal gland, liver, and hearts, with a few first-step enzyme exceptions, such as Tdo and Ido1, and the first-step enzyme of serotonin pathway Tph1. This physiological expression was regulated in a circadian manner in the pineal gland and liver but not in the heart. Peripheral treatment with lipopolysaccharide resulted in mild upregulation of Tph1 in the pineal gland and heart, more robust upregulation of KPEs in the pineal gland and heart, but downregulation of Kmo, KatII, and Kynu in the liver. Altogether, our data provide evidence on the physiological expression of KPEs in the pineal gland, liver, and heart, which is regulated by the circadian clock in a tissue-specific manner. Furthermore, we show the temporal dynamics and bidirectional change in the transcriptional patterns of KPEs, Tph1, Per2, Nr1d1, and Stat3 in response to systemic administration of lipopolysaccharide in these tissues.
... MT produced by enterochromaffin cells of the gastrointestinal mucosa is released into blood vessels or, through diffusion, reaches the outer layers of smooth muscles, where it acts as an antagonist of serotonin contractile effects, causing relaxation [90]. It regulates the transmembrane transport of electrolytes and ions, water content in the intestine, and mitotic activity [91]. ...
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Much attention has been recently drawn to studying melatonin – a hormone whose synthesis was first found in the epiphysis (pineal gland). This interest can be due to discovering the role of melatonin in numerous physiological processes. It was the discovery of melatonin synthesis in endocrine organs (pineal gland), neural structures (Purkinje cells in the cerebellum, retinal photoreceptors), and immunocompetent cells (T lymphocytes, NK cells, mast cells) that triggered the evolution of new approaches to the unifield signal regulation of homeostasis, which, at the turn of the 21st century, lead to the creation of a new integral biomedical discipline—neuroimmunoendocrinology. While numerous hormones have been verified over the last decade outside the “classical” locations of their formation, melatonin occupies an exclusive position with regard to the diversity of locations where it is synthesized and secreted. This review provides an overview and discussion of the major data regarding the role of melatonin in various physiological and pathological processes, which affords grounds for considering melatonin as the “cornerstone” on which neuroimmunoendocrinology has been built as an integral concept of homeostasis regulation.
... Gut melatonin levels can be influenced by food intake [7,22]. After consuming melatonin-rich foods, dietary melatonin may contribute to serum melatonin concentration [7]. ...
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Intestinal melatonin exerts diverse biological effects on the body. Our previous research showed that the abundance of the butyrate-producing bacteria, Roseburia, is positively related to the expression of colonic mucosal melatonin. However, the detailed relationship is unclear. Therefore, we aimed to explore whether Roseburia regulates intestinal melatonin and its underlying mechanisms. Male Sprague–Dawley germfree rats were orally administered with or without Roseburia hominis. R. hominis treatment significantly increased the intestinal melatonin level. The concentrations of propionate and butyrate in the intestinal contents were significantly elevated after gavage of R. hominis. Propionate or butyrate treatment increased melatonin, 5-hydroxytryptamine (5-HT), arylalkylamine N-acetyltransferase (AANAT), and phosphorylated cAMP-response element-binding protein (p-CREB) levels. When pretreated with telotristat ethyl, the inhibitor of tryptophan hydroxylase (TPH), or siRNA of Aanat, or 666-15, i.e., an inhibitor of CREB, propionate, or butyrate, could not promote melatonin production in the pheochromocytoma cell line BON-1. Metabolomics analysis showed that propionate and butyrate stimulation regulated levels of some metabolites and some metabolic pathways in BON-1 cell supernatants. In conclusion, propionate and butyrate, i.e., metabolites of R. hominis, can promote intestinal melatonin synthesis by increasing 5-HT levels and promoting p-CREB-mediated Aanat transcription, thereby offering a potential target for ameliorating intestinal diseases.
... Since 1976, it has been known that the enterochromaffin cells of the gastrointestinal mucosa synthesize melatonin [60]. Melatonin in the gut follows the distribution of serotonin and enterochromaffin cells and modulates local inflammation [61]. Higher concentrations are found in the colon and rectum, while lower concentrations have been found in the jejunum and ileum [62]. ...
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Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune–pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.
... Melatonin as a signal molecule of stress can be induced by the pathogenic (but not the beneficial) bacteria invasion and the increased melatonin level in hosts can improve the protective effects or tolerance to the bacteria (179). In addition to inhibiting pathogenic bacteria, melatonin has a beneficial effect on intestinal flora (180,181). For example, melatonin reprogramming of gut microbiota improves lipid dysmetabolism to prevent obesity in mice (182)(183)(184)(185). ...
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Diseases caused by pathogenic bacteria in animals (e.g., bacterial pneumonia, meningitis and sepsis) and plants (e.g., bacterial wilt, angular spot and canker) lead to high prevalence and mortality, and decomposition of plant leaves, respectively. Melatonin, an endogenous molecule, is highly pleiotropic, and accumulating evidence supports the notion that melatonin's actions in bacterial infection deserve particular attention. Here, we summarize the antibacterial effects of melatonin in vitro, in animals as well as plants, and discuss the potential mechanisms. Melatonin exerts antibacterial activities not only on classic gram-negative and-positive bacteria, but also on members of other bacterial groups, such as Mycobacterium tuberculosis. Protective actions against bacterial infections can occur at different levels. Direct actions of melatonin may occur only at very high concentrations, which is at the borderline of practical applicability. However, various indirect functions comprise activation of hosts' defense mechanisms or, in sepsis, attenuation of bacterially induced inflammation. In plants, its antibacterial functions involve the mitogen-activated protein kinase (MAPK) pathway; in animals, protection by melatonin against bacterially induced damage is associated with inhibition or activation of various signaling pathways, including key regulators such as NF-kB, STAT-1, Nrf2, NLRP3 inflammasome, MAPK and TLR-2/4. Moreover, melatonin can reduce formation of reactive oxygen and nitrogen species (ROS, RNS), promote detoxification and protect mitochondrial damage. Altogether, we propose that melatonin could be an effective approach against various pathogenic bacterial infections.
Chapter
Circadian rhythms are integral to life at all levels. However, only in the last few decades have their roles and importance in promoting health and implications for preventing disease begun to be fully explored. Circadian rhythms have a profound effect on daily living in all organisms and strongly influence everything from the cell cycle and gene expression for numerous genes up through human behaviors such as timing of food consumption and how nutrients are utilized, including in mounting effective inflammatory and immune responses. The effect of circadian rhythm disruption, both in the brain's central clock, known as the suprachiasmatic nucleus (SCN), and peripheral tissues, has been studied extensively. Of late, there has been growing interest in the relationship between diet (both quality and timing) and various circadian rhythms, primarily in peripheral tissues. In this chapter we provide an overview of the molecular and genetic underpinnings of the SCN and a molecular overview to peripheral rhythms, providing a biological framework through which behaviors act to influence inflammation. We discuss chrononutrition, as well as various fasting diets and their association with inflammation. We highlight sleep's and chronotype's relationship with circadian rhythms, diet, and inflammation, respectively. Finally, we discuss these relationships from a shift-working perspective, as shift workers commonly experience circadian disruption and abnormal eating times, which may lead to chronic systemic inflammation and inability to mount a competent immune response.
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The gut microbiota is strongly shaped by a high-fat diet, and obese humans and animals are characterized by low gut microbial diversity and impaired gut microbiota compositions. Comprehensive data on mammalian gut metagenomes shows gut microbiota exhibit circadian rhythms, which is disturbed by a high-fat diet. On the other hand, melatonin is a natural and ubiquitous molecule showing multiple mechanisms of regulating the circadian clock and lipid metabolism, while the role of melatonin in the regulation of the diurnal patterns of gut microbial structure and function in obese animals is not yet known. This study delineates an intricate picture of melatonin-gut microbiota circadian rhythms and may provide insight for obesity intervention.
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Background Melatonin regulates metabolism and metabolism related hormones in mammalians. Castration has some adverse effects on the metabolic hormones of dog. This study was conducted to determine the effects of oral melatonin administration on metabolic hormones, as well as to compare changes of these hormones after administration of melatonin in castrated and intact dogs. Twenty healthy mixed breed mature male dogs were divided randomly into four groups (n = 5): melatonin (3 mg/10 kg(, castrated, castrated and melatonin treated, and negative control. Blood sample was collected from jugular vein weekly for 1 month. Results T3 and T4 hormones had a significant decrease within 1 month following administration of melatonin. No significant change was observed in concentration of FT3 and FT4 hormones. Leptin and ghrelin hormones also had a significant decrease in this period. Leptin and ghrelin had a more significant decrease in “non-castrated and melatonin treated” group compared to “castrated and melatonin treated” group. Galanin had a significant decrease but this neurotransmitter had no significant change in “non-castrated and melatonin treated” group in comparison to “castrated and melatonin treated” group. Conclusions It seems that daily administration of melatonin capsule in all dogs can probably decrease concentration of T3 and T4 hormones and balance other metabolic hormones following castration. Methods The dogs underwent castration, melatonin treatment and blood sampling.
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Present study provided the first information on temporal relationship between melatonin concentrations and oxidative status of the liver in any fish. Accordingly, the liver tissue homogenates of carp Catla catla were used to measure the diurnal levels of melatonin, malondialdehyde (MDA) – an intra-cellular stress marker, and different antioxidants [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRd), glutathione S-transferase (GST), reduced glutathione (GSH)] during four distinct reproductive seasons of an annual cycle. The hepatic melatonin titres exhibited significant daily variations with a peak in early dark-phase and nadir at midday in each season, though its diurnal values were highest in post-spawning phase and lowest during spawning. Likewise, the activities/levels of different antioxidants, other than GSH, displayed diurnal peak in early dark-phase and seasonal peak during post-spawning phase. The hepatic MDA levels were diurnally maximum in midday, and seasonally highest during spawning and lowest in post-spawning phase. Although hepatic melatonin titres were positively correlated with the levels of each antioxidant, MDA levels were negatively correlated with the levels of both melatonin and each antioxidant. Collectively, current study underlines possible influences of endogenous hepatic melatonin on the oxidative status of liver relating to seasonal reproductive events in a fish species.
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The purpose of present study was to ascertain whether the response of gastrointestinal (gut) melatonin to altered feeding conditions was related to the levels of different antioxidants and digestive enzymes in the same gut tissues of a sub-tropical carp (Catla catla). Accordingly, the fish were subjected to food deprivation for 4 or 8 days and separately to re-feeding for 4 or 8 or 12 days after deprivation of food for 8 days, and their gut tissue homogenates were used to measure the levels of melatonin, both enzymatic [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST)] and non-enzymatic [reduced glutathione (GSH)] antioxidants, as well as different digestive enzymes (α-amylase, cellulase, protease, and lipase). Notably, the gut levels of melatonin, SOD, CAT, GPx, and GST underwent gradual increase with the progress of food deprivation, but a sudden fall after restoration of food supply for 4 days and a rise thereafter. Conversely, the activity of all the digestive enzymes significantly decreased after deprivation of food, but started increasing when food supply was reinforced. Gut melatonin concentrations by showing a positive correlation with the titers of different antioxidants (in both food-deprived and re-fed fish groups) and a negative (in food-deprived fish) or a positive (in re-fed fish) correlation with the activity of each digestive enzyme underlined possible physiological interplay between them. Collectively, our findings lend support to the hypothesis that gut melatonin response to altered feeding conditions in carp might be associated with the oxidative status as well as the digestive functions of the gastrointestinal tissues itself.
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Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin’s free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA.
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Influences of daytime (~10:00 h) or night-time (~22:00 h) supply of L-tryptophan (Trp)-rich diet on daily rhythm features of melatonin and arylalkylamine-N-acetyltransferase (AANAT) protein (key regulator of melatonin biosynthesis) in gastrointestinal (gut) tissue extracts, and melatonin in serum were studied in carp (Catla catla). Analysis of obtained data revealed that the mesor and amplitude values of both melatonin and AANAT in gut tissue-extracts were higher in daytime-fed fish than those supplied with food at night, and their acrophase varied from ~2 h in the daytime-fed carp to ~10 h in night-time-fed fish. Notably, initiation of stimulatory response of melatonin and AANAT in gut to Trp-rich diet varied from ~2 h (following food supply in day) to ~6 h (after food supply during night). However, in either case, their elevated levels were maintained for ~12 h. Trp-rich diet also caused increase in serum melatonin levels, and the duration of such response varied with the time of food supply. Collectively, present study not only demonstrates the role of Trp-rich diet as a potential inducer of gut melatoninergic system and modulator of daily serum melatonin profiles, but underlines the importance of the time of food supply as a determining factor of its influence as well.
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Abstract Introduction Demonstration of the role of food and feeding time in determining daily rhythm profiles of gut derived melatonin in carp(Catlacatla) led to present study on the mechanism of neural regulation of its gut melatoninergic system. In this in vitro study, different pharmacological agents were used to demonstrate the role of adrenergic, dopaminergic and cholinergic signals in the post-prandial regulation of AANAT and melatonin titres in the carp gut. Methods The gut tissues of carp, which were supplied daily with an equal amount of food at a fixed time point in the morning and sacrificed 2 hours thereafter, were used for in vitrostudy. The gut tissues were incubated initially in the culture medium for 2 hours and then separately with specific agonists and antagonists of adrenergic, dopaminergic and cholinergic receptors for 2 hours before using them for measuring their levels of AANAT and melatonin. Results Gut levels of AANAT and melatonin were significantly increased following incubation with nor-epinephrine or agonists of its α1and β1 receptors, but decreased when incubated with their antagonists. Gut melatoninergic system was stimulated by dopamine or its D1 agonist, but inhibited by antagonist of D1receptor. While acetylcholine or, agonist of its nicotinic receptor or, muscarinic receptor significantly reduced the levels of AANAT and melatonin, antagonists of respective receptors caused an opposite effect. AANAT and melatonin levels in gut were elevated by cAMP or adenylatecyclase activator, but reduced by its inhibitor. Conclusion This study provides the first evidence that different neuronal signals, by employing a signal transduction pathway where cAMP seems to act as an intracellular messenger, play important role in regulating post-prandial synthesis of AANAT and melatonin in any fish gut.
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The study demonstrates the temporal pattern of expression of melatonin bio-synthesizing enzyme genes (Tph1, Aanat1, Aanat2, and Hiomt) in the brain and gut of a tropical carp (Catla catla) on a daily and seasonal basis under natural photo-thermal conditions. The measurement of melatonin in brain and gut (both in vivo and in vitro) demonstrated a higher content in gut, with evidence of melatonin bio-synthesizing machinery in both tissues. All melatonin bio-synthesizing gene expressions in these two tissues were negatively correlated (except Aanat1 in brain and Hiomt in the gut) with the water temperature on an annual cycle. The higher expression of Aanat2 gene, rather than Aanat1, signifies the importance of Aanat2 isoform in the melatonin production in tropical carp. Furthermore, the Aanat2 and Hiomt genes are highly expressed in the gut. Analysis of the rhythm and acrophase of expression of these genes in the brain and gut imply a pineal-independent melatonin synthesizing machinery in these two organs, possibly involving both environmental and endogenous cues for the regulation of melatonin rhythm to synchronize the physiology of the animal.
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Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its anti-radical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely-diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule. This article is protected by copyright. All rights reserved.
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Melatonin is synthesized in peripheral locations of vertebrates, including the gastrointestinal tract (GIT). In teleost, information regarding this topic is scarce. Here we studied the presence and synthesis of melatonin at the rainbow trout GIT. Different sections of trout GIT (from esophagus to hindgut) were dissected out and assayed for contents of melatonin, serotonin (5-HT) and its metabolite, 5-hydroxyindole acetic acid, as well as for aanat1, aanat2 and hiomt mRNA abundance. A trout group was pinealectomized to evaluate changes in plasma and gut melatonin content. Finally, the daily profile of melatonin and 5-HT content, and aanat1, aanat2 and hiomt mRNA abundance were analyzed in gut of trout kept under normal lighting, and then under constant darkness. Melatonin was detected in all GIT regions with higher concentrations in the muscular wall than in the mucosa, a similar trend to that of 5-HT. In contrast, transcripts of melatonin synthesis enzymes were more abundant in the mucosa. Pinealectomy did not affect melatonin levels in midgut and hindgut either at day or at night. Additionally, no daily rhythms could be defined for melatonin content in gut tissues but increases during late light phase and at midnight occurred. However, aanat1, aanat2 and hiomt mRNA abundance showed clear daily rhythms with peaks at night. These rhythms remained with a 3-h phase advanced peak in fish exposed to constant darkness. Our results provide clear evidence for a local synthesis of melatonin in trout GIT that might be influenced by the content of 5-HT in the tissue. The process is affected by environmental light cycle and is likely to be under circadian regulation.
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The purpose of present study was to demonstrate the response of gut melatoninergic system to Aeromonas hydrophila infection for 3 or 6 days and search for its correlation with the activity of different antioxidative and digestive enzymes to focus their interplay under pathophysiological conditions in carp (Catla catla). Microscopic study of gut in infected fish revealed degenerative changes in the tunica mucosa and lamina propria layers with sloughed off epithelial cells in the lumen. The activity of each digestive enzyme was reduced, but the levels of melatonin, arylalkylamine-N-acetyl transferase protein, the key regulator of melatonin biosynthesis, and different enzymatic antioxidants in gut were gradually and significantly increased with the progress of infection. Gut melatonin concentrations in A. hydrophila challenged carp by showing a positive correlation with the activity of each antioxidative enzyme, and a negative correlation with different digestive enzymes argued in favor of their functional relation, at least, during pathological stress. Moreover, parallel changes in the gut and serum melatonin titers indicated possible contribution of gut to circulating melatonin. Collectively, present carp study provided the first data to suggest that endogenous gut melatonin may be implicated to the mechanism of response to microbial infections in any fish species.
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Influences of starvation, re-feeding and time of food supply on daily rhythm features of melatonin (5-methoxy-N-acetyltryptamine) and its key regulator AANAT (arylalkylamine N-acetyltransferase) protein in the gut tissues were separately evaluated in carp Catla catla. The first experiment was aimed at demonstration of duration dependent effects of starvation and re-feeding after starvation on the daily profiles and rhythm features of gut melatonin and AANAT. Accordingly, juvenile carp were randomly distributed in three groups, which were (a) provided with balanced diet daily at a fixed time, that is, 10:00 clock hour or zeitgeber time (ZT) 4 (control), or (b) starved (for 2-, 4-, 6- or 8 days), or (c) initially starved for 8 days and then re-fed (for 2-, 4-, 6-, 8-, 12- or 16 days) daily with the same food and at the time (ZT4) used for control fish. The carp in each group were sampled for collection of gut tissues at six different time points at a regular interval of 4 h in a daily cycle. In another experiment, the influences of timing of food supply were separately examined in four fish groups, which were provided with a fixed amount of food once daily either at 06:00 or 12:00 or 18:00 or 24:00 clock hour corresponding to ZT0 or ZT6 or ZT12 or ZT18, respectively, for 7 days before sampling at 12 different time points with a regular interval of 2 h in a 24-h cycle. The study revealed a gradual increase in the mesor and amplitude values of melatonin and AANAT in gut with the progress of starvation till their values reached maximum at day-6 and remained steady thereafter. In contrast, re-feeding of 8-day starved fish resulted in a sharp decrease in their mesor and amplitude values after 2 days and then followed by a steady-state increase till re-attainment of their values close to control fish at the end of 16 days. The acrophase of these gut variables in each control, starved and re-fed fish was noted mostly at midday or ZT6. However, the results of another experiment demonstrated that a shift of food supply time led to a shift in their acrophase. The amount of residual food in the gut lumen in each, but not starved, fish by showing a significant positive correlation independently with the gut levels of melatonin and AANAT also indicated possible role of food as the synchronizer for their daily rhythms. Collectively, it appears reasonable to argue that daily profiles of gut melatonin and AANAT are strongly influenced by the availability of food, while their daily rhythm features seem to be dependent mostly on the time of food supply in carp.
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The objectives of this study were to test the effects of light on melatonin rhythms in the pineal gland and gut of goldfish Carassius auratus and to investigate whether melatonin function differed in these two tissues, which are photosensitive and non-photosensitive respectively. Rhythms were evaluated by measuring arylalkylamine N-acetyltransferase (AANAT2) and melatonin receptor 1 (MT-R1) mRNA expression and melatonin concentration in the pineal gland, gut (in vivo), and cell cultures of the two tissues (in vitro). Compared to control, pineal gland melatonin secretion was higher at night, whereas the 24-h dark and ophthalmectomy groups maintained higher AANAT2 and MT-R1 mRNA expression during the day. Melatonin levels and AANAT2 and MT-R1 mRNA expression in the gut were also the highest at night, but the 24-h light, dark, and ophthalmectomy groups did not significantly differ from control. Furthermore, we measured AANAT2 and MT-R1 mRNA expression in high temperature water (30 °C) to investigate differences in the antioxidant capacity of pineal gland vs. gut melatonin. Melatonin and H2O2 levels, as well as AANAT2 and MT-R1 mRNA expression, were all higher in the two tissues under thermal stress, compared with their levels at 22 °C. Taken together, our results suggest that light has no effect on melatonin patterns in the gut, which appears to exhibit its own circadian rhythm, but both gut and pineal gland melatonin exhibit similar antioxidant function.
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Melatonin, following discovery in the bovine pineal gland, has been detected in several extra-pineal sources including gastrointestinal tract or gut. Arylalkylamine N-acetyltransferase (AANAT) is the key regulator of its biosynthesis. Melatonin in pineal is rhythmically produced with a nocturnal peak in synchronization with environmental light–dark cycle. A recent study on carp reported first that melatonin levels and intensity of a ~23 kDa AANAT protein in each gut segment also exhibit significant daily variations but, unlike pineal, show a peak at midday in all seasons. Extensive experimental studies ruled out direct role of light–dark conditions in determining temporal pattern of gut melatoninergic system in carp, and opened up possible role of environmental non-photic cue(s) as its synchronizer. Based on mammalian findings, physiological significance of gut-derived melatonin also appears unique because its actions at local levels sharing paracrine and/or autocrine functions have been emphasized. The purpose of this mini review is to summarize the existing data on the chronobiology and physiology of gut melatonin and to emphasize their relation with the same hormone derived in the pineal in vertebrates including fish.
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The daily profiles of melatonin and arylalkylamine N-acetyltransferase (AANAT) protein, the key enzyme of the melatoninergic pathway, in three anatomical segments of gut were studied in carp which were held under natural (NP) or long (LP; LD 16:08) or short (SP; LD 08:16) photoperiods or continuous light (LL; LD 24:00) or continuous darkness (DD; LD 00:24) for 30 days. The levels of melatonin and the density of a ~23 kDa AANAT protein, in each gut segment, exhibited a daily rhythm with a peak at midday, irrespective of LD regimens to which the carp were held. None of the photo schedules had any significant effects on mesor values of gut melatonin and AANAT. However, compared to the rhythm features in NP fish, a significant reduction in the amplitude and a significant phase delay in the midday peak, as depicted by the value of acrophase (Ø), were noted in the gut of SP and DD carp. Collectively, it appears reasonable to argue that environmental lighting conditions may not be the synchronizer of daily periodicity in gut melatoninergic system, though the secondary effects of available light in determining its rhythm features in carp may not be ignored.
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A temporal relationship between the daily and seasonal profiles of melatonin (N-acetyl-5-methoxytryptamine) in three different parts of gut, pineal, and serum as well as the density of arylalkylamine N-acetyltransferase (AANAT) protein, the key regulator of melatoninergic pathway in the pineal and respective regions of gut has been sought in a tropical carp Catla catla under natural photo-thermal conditions. The tissue samples were collected at four different clock hours in a daily cycle and the same was repeated in four different seasons in an annual cycle. In a daily cycle, concentrations of melatonin as well as the band intensity of a ∼23 kDa AANAT protein in each segment of gut, irrespective of sampling months, exhibited a peak at midday, while both the variables in the pineal and melatonin in serum showed a peak either in late dark phase (in March) or at midnight (in the remaining seasons). The simple correlation coefficient analysis of values revealed a negative correlation between the melatoninergic system in the gut and the pineal. Notably, seasonal fluctuations of photoperiod as well as water temperature exhibited a negative correlation with the daily peak values of pineal and serum melatonin, but no significant correlation with the respective values of gut melatonin. In conclusion, attainment of a daily peak in melatonin in the gut, unlike in the pineal and serum, does not seem to be a dark-dependent phenomenon.
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A temporal relationship between the serum profiles of pineal-hormone melatonin (N-acetyl-5-methoxytryptamine) and two major ovarian steroids, i.e., 17-β estradiol (E2) and 17α, 20β-dihydroxy-4-pregnen-3-one (17α, 20β DHP) or maturation inducing hormone (MIH), has been sought for the first time in any free-living teleost. The study was carried under natural conditions in a carp Catla catla following collection of blood samples at different time-points in a diurnal cycle during each of the four distinct reproductive phases in an annual cycle. The levels of melatonin and the steroids were measured following specific RIA and ELISA techniques, respectively. A time-bound change in the serum melatonin was noted in a 24 h cycle, though the pattern of fluctuations was not identical throughout the reproductive cycle. Melatonin reached its peak during the mid-night in each reproductive phase, other than the preparatory phase (January–March) when the diurnal peak value was recorded in the late dark phase. In an annual cycle, melatonin titer was found to be maximum during the post-spawning phase (September–December). However, in each reproductive phase, a minimum daily value of melatonin was recorded in the mid-day. Serum E2, irrespective of reproductive phase, exhibited a daily peak in the mid-day and nadir in the early morning. However, in a seasonal cycle, E2 was found to be maximum in the spawning phase (July–August). The serum MIH, however, did not show any significant daily variations, and underwent significant changes in an annual cycle with a very low value in the preparatory phase followed by a gradual increase in the pre-spawning (April–June), a peak in the spawning phase, and was undetectable during the post-spawning phase. The simple correlation-coefficient analysis of the seasonal peak values of melatonin revealed a significant negative correlation with photoperiods, water temperature and serum E2, while a positive correlation was found between the seasonal values of serum E2, photoperiod and water temperature. In a seasonal cycle, serum MIH values exhibited a positive correlation with both water temperature and serum E2, and a negative correlation with melatonin. Collectively, the present study underlines the importance of environmental photo-thermal conditions, especially water temperature, as the functional correlate of seasonal changes in serum melatonin and ovarian steroids in carp.
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Histophysiological studies of the ovary in a hitherto unconsidered major carp Catla catla, included in this investigative treatise, have allowed the present investigators to demonstrate the pattern of annual events in ovarian functions, as well as the inter-relationship between changes in the ovary and environmental conditions. Month-wise studies of cytological features along with various biochemical features of ovarian functions in free-living Catla revealed the existence of precise annual cyclic changes. On the basis of the studies made on gonads, the annual breeding cycle of this fish has been divided into four different phases, namely (a) the preparatory phase (January–March), (b) the pre-spawning phase (April–June), (c) the spawning phase (July–August), and (d) the post-spawning phase (September–December). A detailed analysis of the data employing various exploratory data-analytic techniques was aimed at drawing a possible relationship between the indices of different reproductive events (oogenesis and oocyte maturation, vitellogenesis, steroidogene-sis) in mature free-living female Catla and the different components of the environ-ment in an annual cycle. The results of the study indicate that annual variations in photoperiod, alone or in association with water temperature, may be the major environmental component which plays a significant role in the regulation of seasonal maturation of ovary in Catla. These observations provided a basis for further experimental studies on the specific role of photoperiods in the regulation of ovarian activities in the currently considered most economically important species of Indian major carp.
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The most physiological processes that take place in the body have a circadian rhythm which is controlled by an internal biological clock located in the suprachiasmatic nucleus. The indole melatonin synthesized in the pineal gland, acts to synchronize these biological rhythms, and also it is synthesized and released following a circadian rhythm. The present study analyzed the levels of melatonin over a 24-hour period in Wistar rats in both basal and control conditions and after the oral administration of 125 mg/kg tryptophan, the amino acid that is the precursor of this indole, for 7 days. The levels of melatonin in the plasma and the pineal gland were measured by radioimmunoassay every hour during the night, and every 4 hours during the day. The results indicated that the tryptophan administration provoked raised levels of melatonin at all hours studied in both plasma and pineal. Of the chronobiological parameters studied, there were also increases in the values of the melatonin MESOR with respect to the values obtained in the basal and control groups (the respective increases being 45% and 52% in plasma, and 46% and 47% in the pineal), as well as an advanced acrophase with respect to the basal and control groups. In summary, our findings confirm that tryptophan intake one hour before lights-off increases melatonin levels in plasma and pineal over a 24-hour period, as well as advancing the peak of its synthesis.
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Current communication describes annual testicular events in free-living Indian major carp Catla catla and their probable environmental synchronizer(s). The study was initiated with month-wise evaluation of gametogenic and steroidogenic status of the testis, and thus dividing the annual testicular cycle into the preparatory spawning (November to March), the pre-spawning (April to June), the spawning (July to August) and the post-spawning (September to October) phases. An exhaustive statistical analysis of the data on the studied variables of testicular functions and various components of the environment indicated seasonal fluctuations of photoperiod as the major environmental factor associated with the seasonal reproductive activity of this carp. Ambient temperature appeared as a dependent variable of photoperiod, and thereby, may have substantial influences on the development of testis in Catla catla. Rainfall, on the other hand, showed significant correlation only with the peak reproductive activity, i.e. the act of spawning. Collectively, it appears logical to surmise that photo-thermal conditions may act as proximate and rainfall may play a role of ultimate environmental factor in the regulation of annual testicular events in Indian major carp Catla catla.
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The importance of photoperiods in the regulation of annual testicular events in the carp Catla catla was evaluated by subjecting them to either long (16 h light : 8 h dark) or short (8 h light : 16 h dark) photoperiods for 30 days during the preparatory, prespawning, spawning and postspawning phases of an annual gonadal cycle. In each reproductive phase, testicular responsiveness to subjected photoperiods was determined by comparing the gonadal status in corresponding groups of control or natural photoperiodic fish. The values of testicular weight, gametogenic index, as well as testicular activity of two steroidogenic enzymes (Δ53β-, and 17β-hydroxysteroid dehydrogenase), and the serum titre of testosterone were considered as the indices of functional status of the testis in the fish concerned. During the prespawning phase, exposure of fish to a daily long photoperiod schedule resulted in precocious maturation of testis, while retardation of testicular growth was noted under the influences of short photoperiod. However, none of the employed photo-schedules could influence the gametogenic and steroidogenic functions of the testis in the remaining part of the gonadal cycle. Collectively, the present study provides evidence for the first time that in the case of a commercially important carp, Catla catla, artificial, long photoperiods may be used for advanced testicular maturation, while reductions in maturation-associated growth and deterioration in flesh quality may be avoided by submitting the fish to shorter day lengths during the prespawning phase of the reproductive cycle.
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AbstrAct. -Melatonin is the time-keeping molecule of vertebrates. The daily and annual variations of its rhythmic production allow synchronizing metabolism, physiological functions and behaviour to the environment changes. In fish, melatonin is produced by the photoreceptors of the pineal organ and retina as well as by other retinal cell types in the inner nuclear and ganglion cell layers. In most species, the melatonin rhythm displays a high-at-night profile, resulting from the circadian control of the arylalkylamine n-acetyltranferase (aanaT) activity. aanaT is the penultimate enzyme in the melatonin biosynthesis pathway. This review summarizes our current knowledge on the molecular and cellular mecha-nisms controlling the rhythmic production of melatonin, as well as on the targets and modes of action of the hormone in fish, with special emphasis on neuroendocrine functions. résumé. -la mélatonine, l'hormone "donneuse de temps" : biosynthèse et rôles chez les poissons. la mélatonine est la molécule donneuse de temps des vertébrés. les variations journalières et annuelles de sa pro-duction rythmique permettent la synchronisation des métabolismes, fonctions physiologiques et comportements sur les changements de l'environnement. chez les poissons, elle est produite par les photorécepteurs de l'organe pinéal et de la rétine de même que par des cellules rétiniennes des couches nucléaire interne et ganglionnaire. chez la plupart des espè-ces étudiées, les taux de mélatonine sont élevés de nuit et faibles de jour. ce rythme résulte du contrôle par des horloges circadiennes de l'activité arylalkylamine n-acétyltranférase (aanaT), l'avant-dernière enzyme de la voie de synthèse de la mélatonine. ici sont résumées les connaissances actuelles sur les mécanismes moléculaires et cellulaires du contrôle rythmique de la production de mélatonine, ainsi que sur les cibles et modes d'action de l'hormone chez les poissons, en particulier sur les fonctions neuroendocrines.
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The aim of the present study was to investigate how photocycle and feeding-time cues regulate the daily expression of Per1a, Per2a, Per3, and Cry3 in the goldfish hindgut. For this purpose, we studied the daily rhythmicity of these genes in fish maintained under different lighting conditions and under different feeding regimes (scheduled or not). We also studied whether the timing of just one meal is able to reset the hindgut molecular clock. In a first experiment, randomly fed fish were divided into four groups and kept under different light conditions for 30 d: 12 h light and 12 h dark (12L:12D), an inverted photoperiod (12D:12L), constant darkness (24D), and constant light (24L). In a second study, fish maintained under 24L were divided into four groups fed at different time points for 35 d: (1) fish scheduled-fed once a day (at 10:00 h); (2) fish fed with a 12-h shifted schedule (at 22:00 h), (3) fish fed at 10:00 h throughout the experiment, except the last day when fed at 22:00 h; and (4) a randomly fed group of fish. Fish were sacrificed every 6 h throughout a 24-h cycle. In both experiments, gPer1a, gPer2a, gPer3, and gCry3 transcripts were quantified using Real Time-qPCR in the hindgut. Results show the clock genes gPer1a, gPer2a, and gCry3 are synchronized by both zeitgebers, the photocycle and feeding regime, in goldfish hindgut. Moreover, such clock genes anticipate light-on and food delivery, when these cues appear in a cyclic manner. In the absence of both zeitgebers, gCry3 and gPer2a rhythmicity disappeared. In contrast, the gPer1 rhythm was maintained under 24L and random feeding conditions, but not always, suggesting that food when randomly supplied is able to reset the clock depending on other factors, such as the energetic and metabolic conditions of the fish. The expression of gPer2a was not activated during the light phase of the cycle, suggesting the hindgut of goldfish is a non-direct photosensitive organ. In contrast to the other three genes, gPer3 expression in the goldfish hindgut seemed to be dependent on the timing of the last food delivery, even in the presence of a photocycle. This gene was the only one that maintained daily rhythms under both constant lighting conditions (24D and 24L), although with lower amplitude than when a photocycle was present. This indicates that, although the acrophase (peak time) of the gPer3 expression rhythm seems to be driven by feeding time, there is an interaction of both zeitgebers, food and light, to regulate its expression. In conclusion, present data indicate: (1) the hindgut of goldfish can be synchronized in vivo by both the photocycle and feeding time; (2) food is a potent signal that entrains this peripheral oscillator; and (3) both environmental cues seems to target different elements of the molecular clock.
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In vitro melatonin (M) reduced the tone of gut muscles and counteracted the tonic effect of serotonin (5-HT). In vivo 0.1 to 4 mg of 5-HT (contained in beeswax implants) decreased the food transit time (FTT) in a dose-dependent manner, but higher doses (5 and 6 mg) increased the FTT. Melatonin injected intraperitoneally into mice bearing 5-HT implants (2 mg per animal) blocked partly the serotonin effect and increased FTT by 50%; however, no dose-dependent effect was observed when doses between 0.01 and 1 mg were used. Surprisingly, M injected into intact mice decreased FTT to levels comparable to those observed in 5-HT implanted, M-treated mice. Again, this significant decrease was not dose-dependent between 0.02 and 1 mg. Although in vitro the maximal inhibition of serotonin-induced spasm was achieved when the M: 5-HT ratio was 50–100: 1, in vivo the effective ratio was about 1: 1. This may indicate that part of M action on the gut movement is mediated by extraintestinal mechanisms. A hypothetical, counterbalancing system of M and 5-HT regulation of gut activity (similar to adrenaline-acetylcholine system) is proposed.
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Characteristics and functional efficacy of digestive proteases of Catla catla, catla, Labeo rohita, rohu and Hypophthalmichthys molitrix, silver carp were studied. Total protease activity was significantly (P < 0.05) higher in rohu (1.219 ± 0.059 U mg protein−1 min−1) followed by silver carp (1.084 ± 0.061 U mg protein−1 min−1), and catla (0.193 ± 0.006 U mg protein−1 min−1). Trypsin activity of silver carp and rohu was 89–91% higher than catla. Chymotrypsin activity was significantly (P < 0.05) higher in silver carp compared with rohu and catla. The protease activity of rohu and silver carp displayed bell-shaped curves with maximum activity at pH 9; whereas in catla, maximum activity was found between pH 8 and 11. Inhibition of protease activity with soybean trypsin inhibitor (SBTI), phenylmethylsulfonyl fluoride (PMSF) revealed the presence of serine proteases and inhibition of activity with N--p-tosyl-L-lysine-chloromethyl ketone (TLCK) and N-tosyl-L-phenylalanychloromethane (TPCK) indicated the presence of trypsin-like and chymotrypsin-like enzymes in all these three carps. SDS-PAGE showed the presence of several protein bands ranging from 15.3 to 121.9 kDa in enzyme extracts of catla, rohu and silver carp. The substrate SDS-PAGE evidenced the presence of various protease activity bands ranging from 21.6–93.7, 21.6–63.8 and 26.7–98.5 kDa for catla, rohu and silver carp respectively. In pH-stat hydrolysis of Chilean fishmeal showed significantly (P < 0.05) higher degree of hydrolysis compared with soybean meal, silver cup (a commercial fish feed of Mexico) and wheat flour, with enzyme preparations of three fishes. The rate of hydrolysis was significantly (P < 0.05) higher in silver carp compared with others.
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Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.
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Melatonin synthesis is controlled by aralkylamine N-acetyltransferase (AANAT: EC 2.3.1.87) acetylating serotonin (5-hydroxytryptamine; 5-HT) to N-acetylserotonin (NAS), and N-acetylserotonin O-methyltransferase (ASMT: EC 2.1.1.4) methylating NAS to melatonin (Mel; N-acetyl-5-methoxytryptamine). We examined the levels of expression of the aanat and asmt genes, Mel concentrations as well as AANAT isozyme activity in the eyeball (with retina) and skin of the three-spined stickleback (Gasterosteus aculeatus), at noon and midnight. We found mRNA of four genes (aanat1a, snat, asmt and asmt2) in the eyeball, and two (aanat1a and asmt2) in the skin. The presence of two transcripts of genes encoding AANAT and two of ASMT in the eyeball at noon and midnight, suggests activity of AANAT and ASMT isozymes in metabolic pathways besides "the way to melatonin", all the more so because day/night changes in Mel concentration do not follow the changes in either the expression of genes or the activity of AANAT. The high effectiveness of noon NAS synthesis in the eyeball at low substrate concentrations, which is not reflected in high Mel production, suggests the function of eye NAS beyond that of a precursor to the biosynthesis of Mel. The inhibition of AANAT isozyme activity by product observed in the eyeball may be one of the mechanisms of 5-HT husbanding in the eye (retina). The presence of transcripts of genes encoding both AANAT and ASMT and the activity of AANAT, at noon and midnight, supports a local Mel synthesis in the sticklebacks' skin.
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The stress hormone cortisol, together with antioxidants, melatonin (Mel) and its biologically active metabolites, 5-methoxykynuramines, including AFMK, set up a local stress response system in mammalian skin. Our in vitro study of the European flounder (Platichthys flesus) was designed to examine whether Mel and AFMK would respond to cortisol while a glucocorticoid is added to the incubation medium. The concentrations of cortisol in the incubation medium mimic plasma cortisol levels seen in fish exposed to different types of stresses such as handling, confinement, high density, food-deprivation or air-exposure. We measured Mel and AFMK in skin explants and culture media using high-performance liquid chromatography (HPLC) with fluorescence detection. We also analyzed melanosome response (dispersion/aggregation) in the explants subjected to the different treatments. Cortisol stimulated the release of Mel and AFMK from skin explants in a dose-dependent manner. Melanosome dispersion and a darkening of the skin explants were observed after incubation with cortisol. This study is the first to demonstrate the interrelationship between cortisol and Mel/AFMK in fish skin. Our data strongly suggest that the cutaneous stress response system (CSRS) is present in fish. The question remains whether Mel, AFMK or cortisol are synthetized locally in fish skin and/or transported by the bloodstream. The presence of the CSRS should be taken into account during elaboration of new indicators of fish welfare both in aquaculture and in the wild.
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Melatonin (N-acetyl-5-methoxy tryptamine), following discovery from the extracts of bovine pineal gland, has been detected in the pineal as well as several extra-pineal tissues/organs of different vertebrates including fish. The unique feature of melatonin in the pineal gland is its rhythmic biosynthesis and release in blood in synchronization with the environmental light-–dark cycle. Accordingly, melatonin produced in the pineal of an animal living in a changing environment is implicated to the regulation of seasonal reproduction by acting as a hormone at one or more levels of hypothalamo-hypophyseal-gonadal axis. Additionally, melatonin is known to act as a potent free-radical scavenger or antioxidant to influence maturation of oocytes. However, possible relationship between extra-pineal melatonin and seasonality of reproduction in any animal remains enigmatic. Perhaps, carp is the only known animal in which temporal patterns of melatonin levels in the serum as well as in the extracts of pineal, retina, ovary, gut, and liver have been studied in relation to the reproductive events in an annual cycle. The purpose of current review is to bring those fascinating, and arguably most important data together to underline their significance in the control of seasonal reproduction in subtropical fish in general and in carp in particular.
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In vertebrates, aralkylamine N-acetyltransferase (AANAT; EC 2.3.1.87) is a time-keeping enzyme in melatonin (Mel) biosynthesis. Uniquely in fish, there are several AANAT isozymes belonging to two AANAT subfamilies, AANAT1 and AANAT2, which are encoded by distinct genes. The different substrate preferences, kinetics and spatial expression patterns of isozymes indicate that they may have different functions. In the three-spined stickleback (Gasterosteus aculeatus), there are three genes encoding three AANAT isozymes. In this study, for the first time, the levels of aanat1a, aanat1b and aanat2 mRNAs are measured by absolute RT-qPCR in the brain, eye, skin, stomach, gut, heart and kidney collected at noon and midnight. Melatonin levels are analysed by HPLC with fluorescence detection in homogenates of the brain, eye, skin and kidney. The levels of aanats mRNAs differ significantly within and among organs. In the brain, eye, stomach and gut, there are day/night variations in aanats mRNAs levels. The highest levels of aanat1a and aanat1b mRNAs are in the eye. The extremely high expressions of these genes which are reflected in the highest Mel concentrations at this site at noon and midnight strongly suggest that the eye is an important source of the hormone in the three-spined sticklebacks. A very low level of aanat2 mRNA in all organs may suggest that AANAT1a and/or AANAT1b are principal isozymes in the three-spine sticklebacks. A presence of the isozymes of defined substrate preferences provides opportunity for control of acetylation of amines by modulation of individual aanat expression and permits the fine-tuning of indolethylamines and phenylethylamines metabolism to meet the particular needs of a given organ.
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The tropical carp Catla catla is gaining importance for the studies of the impact of environmental changes on aquatic animals due to its surface dwelling habitat. Till date, there is no information about the transcriptional profile of melatonin bio-synthesizing enzyme genes in any tropical carp under either natural or artificial photo-thermal conditions in pineal and retina. The present study is an attempt to demonstrate the temporal pattern of expression of melatonin bio-synthesizing enzyme genes, Tryptophan hydroxylase 1 (tph1), Arylalkylamine N-acetyltransferase (aanat1 and aanat2) and Hydroxyindole-O-methyltransferase (hiomt) collectively and simultaneously in pineal organ and retina in tropical fish, Catla catla, on a daily and seasonal basis under natural environmental conditions along with the serum melatonin levels. Depending upon the changes of the natural photo-thermal conditions, in four phases of an annual cycle, the variation and/or shifting of the rhythm parameters of different melatonin bio-synthesizing enzyme genes in these two organs are different. Moreover, relative expression of these genes varies based on tissue and season. The serum melatonin levels correspond to the expression pattern of pineal aanat2 and hiomt. This finding indicates a possible organization of melatonin bio-synthesizing enzyme genes with reproductive phases differently in these two photoreceptive organs for maintaining its physiological functions.
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The present study demonstrated a temporal relationship between the concentrations of melatonin, oxidative status and digestive physiology in the gut of a tropical carp Catla catla. We measured the levels of gut melatonin, malondialdehyde (MDA) – a faithful marker of intracellular stress, different antioxidants and major digestive enzymes in the carp gut at four different clock hours in a daily cycle under natural photo-thermal conditions. A correlation between the gut variables was sought to point their possible functional relationship. Gut melatonin titers displayed significant diurnal variations with a peak at midday. An identical temporal pattern with the highest value at midday and nadir at midnight was noted in the activities of superoxide dismutase, catalase and glutathione peroxidase. In contrast, levels of MDA and reduced glutathione (GSH) were highest at midnight and lowest at midday. The activity of all the studied digestive enzymes (α-amylase, cellulase, protease and lipase) showed significant daily variations with a peak at midday. Gut melatonin concentrations by showing a positive correlation with the activity of both enzymatic antioxidants and digestive enzymes, and a negative correlation with the levels of GSH and MDA indicated their possible physiological interplay in a daily cycle. Collectively, our study presented the first information on the daily profiles of oxidative stress, different antioxidants and digestive enzymes in the gut tissues of any fish species, and suggested their functional relationship with the concentrations of gut melatonin in carp Catla catla.
Article
The major objective of present study was to demonstrate the actions of exogenous melatonin on ovaprim (synthetic GnRH and domperidone)-induced final oocyte maturation focusing oxidative status of pre-ovulatory follicles in carp Catla catla. Accordingly, gravid carp during early spawning phase of reproductive cycle were injected with melatonin and/or ovaprim at different time intervals, or luzindole (a pharmacological blocker of melatonin receptors) before them. The effects were studied on the latency period, the rate of germinal vesicle breakdown (GVBD; a visual marker of final oocyte maturation) in the oocytes, and the levels of maturation promoting factor (MPF), oxidative stress, different antioxidants, melatonin and MT1 melatonin receptor protein in the extracts of pre-ovulatory follicles as well. Notably, melatonin treatment two hours before ovaprim injection resulted in shortest latency period as well as highest rate of GVBD and MPF formation. Exogenous melatonin, irrespective of injection schedule, caused significant reduction in intra-follicular oxidative stress and an increase in the levels of both enzymatic and non-enzymatic antioxidants, melatonin and its receptor protein. Concentrations of ovarian melatonin in each fish exhibited a significant negative correlation with the level of oxidative stress, but a positive correlation with the rate of GVBD and the activity/level of different antioxidants. However, no significant effects of melatonin and/or ovaprim were detected in luzindole pre-treated carp. Collectively, current study provides the first evidence that melatonin pre-treatment in carp ameliorates ovaprim actions on the process of final oocyte maturation by MPF formation and alleviates oxidative stress in pre-ovulatory follicles by stimulating different antioxidants.
Article
Melatonin is an important component of the vertebrates circadian system, synthetized from serotonin by the successive action of the arylalkylamine N-acetyltransferase (Aanat: serotonin?N-acetylserotonin) and acetylserotonin-O-methyltransferase (Asmt: N-acetylserotonin?melatonin). Aanat is responsible for the daily rhythm in melatonin production. Teleost fish are unique because they express two Aanat genes, aanat1 and aanat2, mainly expressed in the retina and pineal gland, respectively. In silico analysis indicated that the teleost-specific whole-genome duplication generated Aanat1 duplicates (aanat1a and aanat1b); some fish express both of them, while others express either one of the isoforms. Here, we bring the first information on the structure, function, and distribution of Aanat1a and Aanat1b in a teleost, the sea bass Dicentrarchus labrax. Aanat1a and Aanat1b displayed a wide and distinct distribution in the nervous system and peripheral tissues, while Aanat2 appeared as a pineal enzyme. Co-expression of Aanats with asmt was found in the pineal gland and the three retinal nuclear layers. Enzyme kinetics indicated subtle differences in the affinity and catalytic efficiency of Aanat1a and Aanat1b for indolethylamines and phenylethylamines, respectively. Our data are consistent with the idea that Aanat2 is a pineal enzyme involved in melatonin production, while Aanat1 enzymes have a broader range of functions including melatonin synthesis in the retina, and catabolism of serotonin and dopamine in the retina and other tissues. The data are discussed in light of the recently uncovered roles of N-acetylserotonin and N-acetyldopamine as antioxidants, neuroprotectants, and modulators of cell proliferation and enzyme activities.
Article
Melatonin is remarkably functionally-diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immuno-regulating molecule and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary since photosynthesis is associated with the generation of toxic free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple non-sulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
The immunofluorescent method (Coons' indirect method) with the use of a specific antisera for melatonin and N-acetylserotonin has been used to show the localization of melatonin in the enterochromaffine cells of the gastrointestinal tract. Despite the fact that in a number of cases antisera will apparently give cross-reactions to melatonin+N-acetylserotonin, it is possible that the active synthesis of melatonin does take place in the enterochromaffine cells. Herein, it is suggested that melatonin-producing cells (epiphysis pinealocytes, corresponding cells in the cerebellum, enterochromaffine cells of the gastro-intestinal tract) be united into a single group of cells, respresenting the main part of the“APUD”-system which plays an important role in homeostasis of the body.
Article
Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin®) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ. Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 μm increased (P < 0.05) the secretion from 7.20 ± 1.35 to 13.20 ± 1.51 μEq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 ± 0.82 to 12.35 ± 1.51 μEq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion.
Article
The action of a supernatant obtained after extraction of a homogenate of the mucosa and submucosa of the human appendix with 95% acetone on the melanophores of the frog skin was investigated. A bleaching action was found, indicating that the homogenate contained melatonin. Considering the high content of the melatonin precursor, 5-hydroxytryptamine (serotonin), in the enterochromaffin cells, the possibility of melatonin biosynthesis in these cells during serotonin metabolism can be postulated.
Article
Abstract Melatonin is a neuroendocrine transducer of circadian/circannual rhythms able to synchronize organism's physiological activity. On the basis of our recent findings on appetite regulation by melatonin in the zebrafish brain, the aim of this study was to evaluate melatonin's role in peripheral circuitries regulating food intake, growth, and lipid metabolism. For this purpose, the effect of two melatonin doses (100 nM and 1 μM) administered for 10 days, via water, to adult zebrafish was evaluated at both physiological and molecular levels. The major signals controlling energy homeostasis were analyzed together. Additionally, the effect of melatonin doses on muscle metabolic resources was evaluated. The results obtained indicate that melatonin reduces food intake by stimulating molecules involved in appetite inhibition, such as leptin (LPT), in the liver and intestine and MC4R, a melanocortin system receptor, in the liver. Moreover, melatonin decreases hepatic insulin-like growth factor-I (IGF-I) gene expression, involved in growth process and other signals involved in lipid metabolism such as proliferator-activated receptors (PPARα, β, and γ) and sterol regulatory element-binding protein (SREBP). These results were correlated with lower levels of lipids in the muscles as evidenced by the macromolecular pools analyses. The findings obtained in this study could be of great interest for a better understanding of the molecular mechanisms as the basis of food intake control and, in turn, can be a useful tool for medical and aquaculture applications.
Article
Using highly specific antibodies, melatonin was identified in the gastrointestinal tract of the rat as early as several hours of postnatal life. Its amount progressively increased and reached the adult levels around day 21. Exogenously administered melatonin concentrates in all parts of the gastrointestinal tract with most pronounced accumulation in the colon and the rectum. Diurnal variations were not clearly demonstrated in any part of the alimentary canal. Pinealectomy had no visible effect on the levels of melatonin in the tissues investigated. A hypothesis of ontogenic as well as phylogenic development of production of N-acetylated indolealkylamines in the pineal and the extrapineal tissues and their physiological role is presented.
Article
Mammals have developed an endogenous circadian clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus that responds to the environmental light-dark cycle. Similar clocks are found in peripheral tissues, such as the liver and adipose tissue, regulating cellular and physiological functions. The circadian clock has been reported to regulate metabolism and energy homeostasis, including lipogenic and adipogenic pathways. This is achieved by mediating the expression and/or activity of certain metabolic enzymes and transport systems. In return, enzymes and transcription activators interact with and affect the core clock mechanism. Animals with clock gene mutations that disrupt cellular rhythmicity have provided evidence to the relationship between the circadian clock and metabolic homeostasis. In addition, clinical studies in obese patients accentuate the link between the circadian clock and metabolism. This review will focus on the inter-connection between the circadian clock and metabolism with implications for body weight and how the circadian clock is influenced by hormones that regulate metabolism.
Article
Effects of melatonin and serotonin on ethanol ulceration and mucosal blood flow in the rat stomach were investigated. Melatonin and serotonin (5-HT) administration did not produce observable gastric injury in the ex vivo stomach, but the 5-HT dose dependently reduced glandular mucosal blood flow (GMBF) in this organ. Ethanol depressed GMBF and induced visible glandular mucosal injury. The latter effect was prevented by melatonin preincubation. Serotonin pretreatment aggravated the gastric mucosal injury and GMBF changes induced by ethanol; these actions were partially reversed by melatonin. The findings indicate that the GMBF and gastric injury are related; the reduction in GMBF, however, may not be the sole factor responsible for ulceration. The antagonistic effects of melatonin on 5-HT action on the stomach suggest that melatonin may act as a modulator for 5-HT action on the gastrointestinal tract.
Article
Although several studies have described effects of meal frequency and timing of meals on growth performance and body composition of different species of fishes, the mechanisms by which such variables influence the energy partitioning processes is not known. They may interact with the natural feeding rhythm of the fish, or with various behavioural and physiological parameters that exhibit circadian-like patterns; however, in most cases, the endogenous character of such rhythms is not clear. The time of feeding, perse, can act as a Zeitgeber and override the effect of the light/dark alternation. Fish that are fed always at the same time of day show typical pre-feeding activity. Blood levels of some nutrients and hormones also show peaks or troughs at the time of feeding, but whether these are pre-feeding or post-prandial events is not clear. These results from fish are compared with similar studies with mammals. The existence and location of an endogenous multi-oscillator system is also discussed.
Article
Periodic food availability can act as a potent zeitgeber capable of synchronizing many biological rhythms in fishes, including locomotor activity rhythms. In the present paper we investigated entrainment of locomotor rhythms to scheduled feeding under different light and feeding regimes. In experiment 1, fish were exposed to a 12:12 h light/dark cycle and fed one single daily meal in the middle of the light phase. In experiment 2, we tested the effect of random versus scheduled feeding on the daily distribution of activity. During random feeding, meals were randomly scheduled with intervals ranging from 12 to 36 h, while scheduled feeding consisted of one single daily meal set in the middle of the light or dark phase. Finally, in experiment 3, we studied the synchronization of activity rhythms to feeding under constant darkness (DD) and after shifting the feeding cycle by either advancing or delaying the feeding cycle by 9 h. The results revealed that goldfish synchronized to feeding, overcame light entrainment and significantly changed their daily distribution of activity according to their feeding schedule. In addition, the daily activity pattern modulated by feeding differed between layers: a peak of activity being noticeable directly after feeding at the bottom, while an anticipatory behaviour was obvious at the surface of the tank. Under DD and no food, free-running rhythms averaging 25.5 ± 1.9 h (mean ± SD) were detected. In conclusion, some properties of feeding entrainment (e.g. anticipation of the feeding time, free-running rhythms following termination of periodic feeding, and the stability of ø after shifting the feeding cycle) suggested that goldfish have (a) separate but tightly coupled light- and food-entrainable oscillators, or (b) a single oscillator that is entrainable by both light and food (one synchronizer being eventually stronger than the other).
Article
Stress, which is defined as an acute threat to homeostasis, shows both short- and long-term effects on the functions of the gastrointestinal tract. Exposure to stress results in alterations of the brain-gut interactions ("brain-gut axis") ultimately leading to the development of a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases, food antigen-related adverse responses, peptic ulcer and gastroesophageal reflux disease (GERD). The major effects of stress on gut physiology include: 1) alterations in gastrointestinal motility; 2) increase in visceral perception; 3) changes in gastrointestinal secretion; 4) increase in intestinal permeability; 5) negative effects on regenerative capacity of gastrointestinal mucosa and mucosal blood flow; and 6) negative effects on intestinal microbiota. Mast cells (MC) are important effectors of brain-gut axis that translate the stress signals into the release of a wide range of neurotransmitters and proinflammatory cytokines, which may profoundly affect the gastrointestinal physiology. IBS represents the most important gastrointestinal disorder in humans, and is characterized by chronic or recurrent pain associated with altered bowel motility. The diagnostic testing for IBS patients include routine blood tests, stool tests, celiac disease serology, abdominal sonography, breath testing to rule out carbohydrate (lactose, fructose, etc.) intolerance and small intestinal bacterial overgrowth. Colonoscopy is recommended if alarming symptoms are present or to obtain colonic biopsies especially in patients with diarrhoea predominant IBS. The management of IBS is based on a multifactorial approach and includes pharmacotherapy targeted against the predominant symptom, behavioural and psychological treatment, dietary alterations, education, reassurance and effective patient-physician relationship. When evaluating for the stress-induced condition in the upper GI tract, the diagnostic testing includes mainly blood tests and gastroscopy to rule out GERD and peptic ulcer disease. The therapy for these conditions is mainly based on the inhibition of gastric acid by proton pump inhibitors and eradication of Helicobacter pylori-infection. Additionally, melatonin an important mediator of brain gut axis has been shown to exhibit important protective effects against stress-induced lesions in the gastrointestinal tract. Finally, probiotics may profoundly affect the brain-gut interactions ("microbiome-gut-brain axis") and attenuate the development of stress-induced disorders in both the upper and lower gastrointestinal tract. Further studies on the brain-gut axis are needed to open new therapeutic avenues in the future.