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    The long-term effect of pinealectomy on the crypts of the rat gastrointestinal tract. Callaghan B D Journal of pineal research Previously it has been found that rat small bowel crypt cell hyperplasia occurred several weeks after pinealectomy. To determine if this effect was longer-lasting (because of the possible role of the pineal in bowel malignancy) the crypt cell proliferation rate was determined in rat small bowel and colon 6 months after pinealectomy, using a stathmokinetic technique. Although the hyperproliferative effect of pinealectomy was well maintained in the small bowel crypts after 6 months, the hyperproliferative effect in the colonic crypts was much less marked. There is no obvious explanation for these findings, although it is possible that regional differences in levels of gut neuropeptides or melatonin are involved. The mechanism of the effect of pinealectomy on the crypts remains unexplained--in particular, why the effect is so prolonged.
    A unique central tryptophan hydroxylase isoform. Walther Diego J,Bader Michael Biochemical pharmacology Serotonin (5-hydroxytryptophan, 5-HT) is a neurotransmitter synthesized in the raphe nuclei of the brain stem and involved in the central control of food intake, sleep, and mood. Accordingly, dysfunction of the serotonin system has been implicated in the pathogenesis of psychiatric diseases. At the same time, serotonin is a peripheral hormone produced mainly by enterochromaffin cells in the intestine and stored in platelets, where it is involved in vasoconstriction, haemostasis, and the control of immune responses. Moreover, serotonin is a precursor for melatonin and is therefore synthesized in high amounts in the pineal gland. Tryptophan hydroxylase (TPH) catalyzes the rate limiting step in 5-HT synthesis. Until recently, only one gene encoding TPH was described for vertebrates. By gene targeting, we functionally ablated this gene in mice. To our surprise, the resulting animals, although being deficient for serotonin in the periphery and in the pineal gland, exhibited close to normal levels of 5-HT in the brain stem. This led us to the detection of a second TPH gene in the genome of humans, mice, and rats, called TPH2. This gene is predominantly expressed in the brain stem, while the classical TPH gene, now called TPH1, is expressed in the gut, pineal gland, spleen, and thymus. These findings clarify puzzling data, which have been collected over the last decades about partially purified TPH proteins with different characteristics and justify a new concept of the serotonin system. In fact, there are two serotonin systems in vertebrates, independently regulated and with distinct functions. 10.1016/s0006-2952(03)00556-2
    5-hydroxyoxindole, an indole metabolite, is present at high concentrations in brain. Crumeyrolle-Arias Michèle,Tournaire Marie-Claude,Rabot Sylvie,Malpaux Benoît,Thiéry Jean-Claude Journal of neuroscience research 5-Hydroxyoxindole has been identified as a urinary metabolite of indole, which is produced from tryptophane via the tryptophanase activity of gut bacteria. We have demonstrated recently that 5-hydroxyoxindole is an endogenous compound in blood and tissues of mammals, including humans. To date, 5-hydroxyoxindole's role is unknown. The aim of this study was to compare 5-hydroxyoxindole levels in plasma and cerebrospinal fluid (CSF) during day-night and seasonal changes, as a common approach to pilot physiological characterization of any compound. Simultaneous blood and CSF sampling was performed in the ewe, because its size allows collection in quantities suitable for 5-hydroxyoxindole assay (HPLC-ED) in awake animals, without obvious physiological or behavioral disturbance. 5-Hydroxyoxindole concentration was quite stable in plasma (2-6 nM range), whereas, in CSF, it displayed marked day-night and photoperiodic variations (4-116 nM range). 5-Hydroxyoxindole levels in CSF were twofold higher at night than during the day and at least one order of magnitude higher during the long compared with the short photoperiod. These day/night and photoperiodic variations persisted after pinealectomy, indicating that 5-hydroxyoxindole rhythms in CSF are independent of melatonin formation. In conclusion, high levels of 5-hydroxyoxindole in the CSF during long photoperiod and its daily modulation suggest physiological involvement of 5-hydroxyoxindole in rhythmic adjustments in the brain, independently of the pineal gland. 10.1002/jnr.21475
    Irritable bowel syndrome: recent and novel therapeutic approaches. Andresen Viola,Camilleri Michael Drugs Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder affecting up to 3-15% of the general population in Western countries. It is characterised by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits. The pathophysiology of IBS is considered to be multifactorial, involving disturbances of the brain-gut-axis: IBS has been associated with abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Hence, there is a need for new treatment strategies. Increasing knowledge of brain-gut physiology, mechanisms, and neurotransmitters and receptors involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches. This article provides a systematic overview of recently approved or novel medications that show promise for the treatment of IBS; classification is based on the physiological systems targeted by the medication. The article includes agents acting on the serotonin receptor or serotonin transporter system, novel selective anticholinergics, alpha-adrenergic agonists, opioid agents, cholecystokinin antagonists, neurokinin antagonists, somatostatin receptor agonists, neurotrophin-3, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin and atypical benzodiazepines. Finally, the role of probiotics and antibacterials in the treatment of IBS is summarised. 10.2165/00003495-200666080-00004
    Effect of N-Acetylserotonin on Intestinal Recovery Following Intestinal Ischemia-Reperfusion Injury in a Rat. Ben Shahar Yoav,Sukhotnik Igor,Bitterman Nir,Pollak Yulia,Bejar Jacob,Chepurov Dmitriy,Coran Arnold,Bitterman Arie European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie OBJECTIVE:N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. Extensive studies in various experimental models have established that treatment with NAS significantly protects heart and kidney injury from ischemia-reperfusion (IR). The purpose of the present study was to examine the effect of NAS on intestinal recovery and enterocyte turnover after intestinal IR injury in rats. METHODS:Male Sprague-Dawley rats were divided into four experimental groups: (1) Sham rats underwent laparotomy, (2) sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); (3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 30 minutes, followed by 48 hours of reperfusion, and (4) IR-NAS rats underwent IR and were treated with IP NAS (20 mg/kg) immediately before abdominal closure. Intestinal structural changes, Park injury score, enterocyte proliferation, and enterocyte apoptosis were determined 24 hours following IR. The expression of Bax, Bcl-2, p-ERK, and caspase-3 in the intestinal mucosa was determined using real-time polymerase chain reaction, Western blot, and immunohistochemistry. A nonparametric Kruskal-Wallis analysis of variance test was used for statistical analysis with p less than 0.05 considered statistically significant. RESULTS:Treatment with NAS resulted in a significant increase in mucosal weight in jejunum and ileum, villus height in the ileum, and crypt depth in jejunum and ileum compared with IR animals. IR-NAS rats also had a significantly proliferation rates as well as a lower apoptotic index in jejunum and ileum which was accompanied by higher Bcl-2 levels compared with IR animals. CONCLUSIONS:Treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal IR in a rat. 10.1055/s-0035-1559886
    Effect of N-Acetylserotonin on TLR-4 and MyD88 Expression during Intestinal Ischemia-Reperfusion in a Rat Model. Sukhotnik Igor,Ben Shahar Yoav,Halabi Salim,Bitterman Nir,Dorfman Tatiana,Pollak Yulia,Coran Arnold,Bitterman Arie European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie BACKGROUND: Accumulating evidence indicates that changes in intestinal toll-like receptors (TLRs) precede histological injury in a rodent model of necrotizing enterocolitis. N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. A recent study has shown that treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal ischemia-reperfusion (IR). The objective of this study was to determine the effects of NAS on TLR-4, myeloid differentiation factor 88 (Myd88), and TNF-α receptor-associated factor 6 (TRAF6) expression in intestinal mucosa following intestinal IR in a rat. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly assigned to one of the four experimental groups: 1) Sham rats underwent laparotomy; 2) Sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); 3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 20 minutes followed by 48 hours of reperfusion; and 4) IR-NAS rats underwent IR and were treated with IP NAS immediately before abdominal closure. Intestinal structural changes, mucosal TLR-4, MyD88, and TRAF6 mucosal gene, and protein expression were examined using real-time PCR, Western blot, and immunohistochemistry. RESULTS: Significant mucosal damage in IR rats was accompanied by a significant upregulation of TLR-4, MyD88, and TRAF6 gene and protein expression in intestinal mucosa compared with control animals. The administration of NAS decreased the intestinal injury score, inhibited cell apoptosis, and significantly reduced the expression of TLR-4, MyD88, and TRAF6. CONCLUSION: Treatment with NAS is associated with downregulation of TLR-4, MyD88, and TRAF6 expression along with a concomitant decrease in intestinal mucosal injury caused by intestinal IR in a rat. 10.1055/s-0037-1618593
    Pituitary prolactin-secreting tumor formation: recent developments. Xu R K,Wu X M,Di A K,Xu J N,Pang C S,Pang S F Biological signals and receptors Prolactinoma is the most common type of primary pituitary tumors. It occurs more frequently in women than in men. Dopaminergic agonists are effective in the shrinkage of prolactin-secreting pituitary tumor and are preferred in some patients. However, pituitary radiotherapy may enable the long-term removal of prolactin-secreting tumor cells. Recent evidence suggests that prolactinoma is a heterogeneous disorder with complicated and multifactorial etiology and pathogenesis. Apparently, a thorough understanding of prolactinoma tumorigenesis would be important. To facilitate investigations on tumorigenesis of prolactinoma, animal models for prolactinomas have been developed. These models have expedited our progress in the recent years. Many researchers consider the F(344) rat to be the most sensitive strain of rats to estrogen (E(2))-induced prolactinoma formation. Nonetheless, E(2) treatment for 60 days also induces the formation of pituitary prolactin-secreting adenoma in male Sprague-Dawley (SD) rats. Evidently, the SD rat is also a good animal for prolactinoma investigations. Following E(2) implantation, prolactinomas developed in the eutopic adenohypophysis in situ and/or ectopic pituitary grafted under the renal capsule in SD rats. These observations favor the hypothesis that prolactinoma growth is the result of pathological changes in the adenohypophysis and/or hypothalamus. In the latter case, abnormal release of hypothalamic dopamine, GABA, or brain-gut peptides (such as cholecystokinin, vasoactive intestinal polypeptide, galanin, angiotensin, opioid peptide, gastrin, gastrin-releasing peptide, pancreatic polypeptide, and adrenocorticotropic hormone) results in some of the pathological changes that may lead to hyperprolactinemia and/or prolactinoma development. Dysregulation of prolactin synthesis and secretion may be the result of prolactin gene modulation. In E(2)-induced rat prolactinomas, prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc and c-ras, TGFalpha and TGFbeta1 mRNA were significantly changed. The above findings are consistent with results in human prolactinoma development. In addition, in rats abnormal expression of the prolactin gene was correlated with hypomethylated status of CpG sites in exons 1, 2 and 4 of the prolactin gene, as well as the increase in hypersensitive sites to DNase 1 in the encoding region of the prolactin gene. In E(2)-treated rats, a point mutation with a base substitution from cytidine (C) to adenine (A) was found at the -36-bp site of the proximal promoter of the prolactin gene in eutopic pituitary prolactinomas, but no change was observed in the same sequence of the prolactin gene in ectopic prolactinoma. The association of a base substitution with the hyperexpression of the prolactin gene in eutopic prolactinomas suggests that different mechanisms may mediate the formation of eutopic and ectopic prolactin-secreting tumors. Melatonin decreases the expression of the prolactin gene in vitro suggesting that this pineal hormone may be a potential anticarcinogen in vivo. It has also been shown that MT(2) (Mel(1b)) melatonin receptors are expressed in anterior pituitary cells. The use of melatonin as a preventive or therapeutic drug for prolactinomas should be further investigated. In summary, improved knowledge on tumorigenesis of prolactinomas, especially in the rat model, was noted. These E(2)-induced rat prolactinoma models would facilitate future investigations, and expected results shall be fruitful and exciting for the development of future drug designs for the prevention and/or treatment of prolactin-secreting pituitary tumors. 10.1159/000014618
    The effect of food deprivation on brain and gastrointestinal tissue levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. Bubenik G A,Ball R O,Pang S F Journal of pineal research In order to investigate the effect of food deprivation on the levels of indoles in the brain and the gastrointestinal tissues, we have determined tissue levels of tryptophan (TRP), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and melatonin in the brain and the gastrointestinal tract (GIT) of mice on ad libitum diet as well as in mice deprived of food for 24 and 48 hr. The reduction of food intake 1) had no effect on TRP levels in the brain, but increased TRP concentrations in the stomach and the gut, especially in the colon; 2) decreased 5-HT levels in the brain, but increased values in the stomach and the intestines; 3) decreased 5-HIAA levels in the brain, but increased them in the stomach and the intestines; 4) did not change 5-HT conversion to 5-HIAA in the brain, stomach, and the jejunum, but increased the conversion in the ileum and colon and; 5) increased melatonin levels in all tissues investigated, particularly in the stomach and the brain. The changes of indole levels induced by food deprivation were compared to their known function in the brain and the individual segments of the GIT. A possible serotonin-melatonin antagonism in the brain and GIT function is considered.
    Diurnal variation and binding characteristics of melatonin in the mouse brain and gastrointestinal tissues. Bubenik G A,Niles L P,Pang S F,Pentney P J Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology 1. Compared to night time values, levels of melatonin (M), determined by specific RIA, were lower in the brain and the duodenum-jejunum segment of mice sacrificed in mid-photophase. In other parts of the gut no significant diurnal difference was observed. 2. Highest daytime levels were detected in the stomach (569 pg/ml), lowest in the brain (62 pg/ml). 3. Preliminary studies indicate the presence of specific binding sites for [125I]iodo-melatonin in the colon, ileum, jejunum, stomach and brain. These sites, which exhibit an affinity of about 1 nM, may be involved in mediating the gastrointestinal and central effects of melatonin in this species. 10.1016/0742-8413(93)90027-i
    Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestine. Harlow H J,Weekley B L Journal of pineal research Segments from various locations of the small and large intestine of the rat were removed, bathed in Tyrode's solution and attached to a force displacement transducer. Melatonin, while not influencing the frequency of contraction, did reduce the force of spontaneous contractions of duodenal and colon segments of rat intestine by 92 and 52%, respectively compared to only 25 and 22% for the ileum and jejunum, respectively. Areas with greatest responsiveness to melatonin were those that previous studies have shown to contain the largest concentrations of endogenous melatonin. Cyclic guanosine monophosphate, when tested in similar preparations, did not produce an inhibitory response characteristic of melatonin. It is hypothesized, therefore, that this hormone has physiological action within the gut, including motility; however, its action may not be directly on smooth muscle contraction but may be through an indirect action inhibiting the contractile response of serotonin, as suggested by other investigators.
    Influence of serotonin and melatonin on some parameters of gastrointestinal activity. Bubenik G A,Dhanvantari S Journal of pineal research 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.
    Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Huether G,Poeggeler B,Reimer A,George A Life sciences The administration of L-tryptophan (Trp, 150-300 mg/kg) to rats and chicks causes a rapid and dose-dependent elevation of circulating melatonin. The elevation of serum melatonin was greater after oral compared to the intraperitoneal route of administration of the same dose of Trp (150 mg/kg). The Trp-induced increase of circulating melatonin was unaffected by prior pinealectomy but was almost abolished by a partial ligature of the portal vein. The Trp-induced increase of melatonin in the portal blood preceded that in the systemic circulation. The gut contains considerable amounts of melatonin and the Trp-induced elevation of melatonin was greater in the duodenum compared to the pineal or the blood. The enterochromaffin cells of the gastrointestinal tract appear to be the major source of the Trp-induced increment of circulating melatonin. The possibility is discussed that the sedating, sleep inducing effects of Trp are mediated by the Trp-induced elevation of circulating melatonin. 10.1016/0024-3205(92)90402-b
    Recent developments in the therapy of irritable bowel syndrome. Saad Richard J,Chey William D Expert opinion on investigational drugs There is tremendous activity and excitement in the arena of drug development for the treatment of the irritable bowel syndrome (IBS). Pharmacologic therapy has been largely limited to gut acting therapeutic agents including antidiarrheals, laxatives and antispasmodics that primarily target individual symptoms. Various antidepressants have gained popularity although their efficacy in clinical trials has been modest and their clinical utility is limited by untoward side effects. Serotonergic agents have demonstrated efficacy on the global symptoms of IBS; however, recent concerns about safety have severely limited their use. Recent discoveries regarding the pathophysiology of IBS have revealed numerous potential therapeutic targets. Agents under development include newer serotonergic agents and antidepressants; chloride channel, guanylate cyclase, opioid and motilin receptor ligands; various central, peripheral and autonomic neural receptor ligands; and gut immune modulators. 10.1517/13543784.17.2.117
    Melatonin reduces the severity of dextran-induced colitis in mice. Pentney P T,Bubenik G A Journal of pineal research Melatonin administration reduces the severity of dextran sodium sulphate (DSS)-induced colitis in mice. After 7 weeks of daily intraperitoneal melatonin administration (150 micrograms/kg), rectal bleeding and occult blood was eliminated in all mice in which colitis was induced by DSS. In addition the frequency and severity of focal lesions in the mucosa was dramatically reduced. Furthermore, weight loss and higher food consumption observed in DSS-treated mice was reversed in DSS-treated mice injected with melatonin. All treated groups exhibited significant alterations in goblet cell distribution as a result of DSS or melatonin administration. Surprisingly, serum melatonin levels were more than 10 times higher in mice that received DSS as compared to controls. The significant improvement in the conditions of melatonin-treated mice might be due to its effect on the smooth muscles of the colon, the blood supply in the mucosa, its capability as an antioxidant and scavenger of free radicals, or its effect on the immune system of the gut. The higher plasma levels of melatonin in DSS-treated mice might be due to a stress-induced increase in the production of gastrointestinal (GIT) melatonin.
    Melatonin receptors in peripheral tissues: a new area of melatonin research. Pang S F,Dubocovich M L,Brown G M Biological signals Melatonin is synthesized and secreted by pineal gland, retina, harderian gland, lacrimal gland, and gut. It is a lipid-soluble molecule with ubiquitous distribution and multifarious functions. Thus, along with the better established sites of melatonin action, such as brain, retina, and pituitary, direct melatonin actions on other peripheral tissues should also be considered. The presence of melatonin receptors in peripheral tissues was rightfully hypothesized. Earlier studies on melatonin receptors had limited success. The advent of 2-[125I]iodomelatonin, a labelled melatonin agonist with a specific activity as high as 2,200 Ci/mmol, has allowed the studies of melatonin receptors with picomolar affinity and femtomolar density. Putative melatonin receptors demonstrated by autoradiography and/or radioreceptor assay in gut, kidney, lung, heart, vas deferens, and blood vessels are discussed. 10.1159/000109490
    Nuclear localization of melatonin in different mammalian tissues: immunocytochemical and radioimmunoassay evidence. Menendez-Pelaez A,Poeggeler B,Reiter R J,Barlow-Walden L,Pablos M I,Tan D X Journal of cellular biochemistry Melatonin was detected by an improved immunocytochemical technique in the cell nuclei of most tissues studied including several brain areas, pineal gland, Harderian gland, gut, liver, kidney, and spleen from rodents and primates. Cryostat sections from tissues fixed in Bouin's fluid, formalin, or acetone/ethanol were used. The nuclear staining appeared primarily associated with the chromatin. The nucleoli did not exhibit a positive reaction. The melatonin antiserum was used in the range of 1:500 to 1:5,000. Incubation of the antibody with an excess of melatonin resulted in the complete blockade of nuclear staining. Pretreatment of the sections with proteinase K (200-1,000 ng/ml) prevented the positive immunoreaction. In a second aspect of the study, we estimated the concentration of melatonin by means of radioimmunoassay in the nuclear fraction of several tissues including cerebral cortex, liver, and gut. The subcutaneous injection of melatonin (500 micrograms/kg) to rats resulted, after 30 min, in a rapid increase in the nuclear concentration of immunoreactive melatonin which varied in a tissue-dependent manner. However, samples collected 3 h after the injection showed that melatonin levels had decreased to control values. Pinealectomy in rats resulted in a clear reduction in the nuclear content of melatonin in the cerebral cortex and liver but not in the gut. The results of these studies suggest that melatonin may interact with nuclear proteins and that the indole may have an important function at the nuclear level in a variety of mammalian tissues. 10.1002/jcb.240530415
    Iron decreases the nuclear but not the cytosolic content of the neurohormone melatonin in several tissues in chicks. Pablos M I,Agapito M T,Menéndez-Pelaez A,Acuña-Castroviejo D,Reiter R J,Recio J M Journal of cellular biochemistry This paper describes the influence of iron on both nuclear and cytosolic melatonin contents in several tissues of chicks. The neurohormone melatonin was estimated by means of radioimmunoassay. Iron, administered as FeCl3, decreased the nuclear melatonin level in a variety of tissues, including brain, heart, lung, kidney, and erythrocytes (nucleated cells in chicks) but was not seen in either the liver or gut. All variations related with iron were seen in the nuclear fraction, while only in the pineal gland did the melatonin content of the cytosol change as a result of iron treatment. We also observed a day-night rhythm in the nuclear melatonin: high nuclear levels of melatonin at night and low levels during the light period. This is the first report of nuclear localization of melatonin in any avian cell. 10.1002/(sici)1097-4644(19960301)60:3<317::aid-jcb3>3.0.co;2-z
    Melatonin modulates cholinergic transmission by blocking nicotinic channels in the guinea-pig submucous plexus. Barajas-López C,Peres A L,Espinosa-Luna R,Reyes-Vázquez C,Prieto-Gómez B European journal of pharmacology Melatonin, a hormone produced and released by the pineal gland is also synthesized by cells of the gastrointestinal wall, where it might be a local regulator of gut functions. In this study, we investigated the possible role of melatonin as a modulator of the enteric nervous system. Intracellular recordings were made in neurons of the submucosal plexus from the guinea-pig ileum to measure the melatonin effects on their electrophysiological properties. Melatonin did not alter the membrane potential, the membrane resistance and the noradrenergic inhibitory postsynaptic potentials. However, melatonin (30-3000 microM) reversibly decreased the amplitude of nicotinic excitatory postynaptic potentials (EPSPs) in a concentration-dependent manner (IC50 = 247 microM). These actions of melatonin were not modified by the presence of idazoxan and atropine indicating that they are not mediated by endogenous release of acetylcholine, noradrenaline, or by direct activation of alpha 2-adrenoceptors or muscarinic receptors. The superfusion of melatonin also blocked the nicotinic depolarizations induced by locally applied acetylcholine, indicating that at least part of its effects are postsynaptic. In voltage-clamp experiments, using the whole-cell configuration, melatonin also inhibited the nicotinic inward currents induced by acetylcholine (IACh) in a concentration-dependent manner (IC50 = 257 microM). Melatonin decreased the maximal IACh but did not affect the potency of acetylcholine to induce this current, indicating a noncompetitive antagonism. This effect was voltage-dependent. Our observations indicate that melatonin inhibits the fast EPSPs by directly and specifically blocking the nicotinic channels. The relative high concentrations of melatonin required to produce such an effect rules this out as one of its humoral actions. Such an effect, however, might be of physiological significance close to the cells that release melatonin in the gastrointestinal wall or in other organs. 10.1016/0014-2999(96)00481-5
    Melatonin affords protection against gastric lesions induced by ischemia-reperfusion possibly due to its antioxidant and mucosal microcirculatory effects. Konturek P C,Konturek S J,Majka J,Zembala M,Hahn E G European journal of pharmacology Melatonin, a pineal hormone, is known to scavenge oxygen free radicals and to be present in the gut but little is known about its role in the protection of gastric mucosa against the damage accompanied by a marked increase in these radicals. This study was designed to determine the effects of melatonin on the formation of acute gastric lesions induced by ischemia-reperfusion and, for comparison, by a topical irritant such as 100% ethanol. It was found that pretreatment with melatonin at a dose of 5 mg/kg given intragastrically reduced significantly gastric lesions induced by ischemia-reperfusion and this was accompanied by a reduction in free radicals in the blood and by attenuation of the fall in gastric blood flow. In contrast, melatonin failed to affect acute gastric lesions induced by 100% ethanol. We conclude that melatonin is capable of protecting gastric mucosa from the damage caused by ischemia-reperfusion and that this action is mediated, at least in part, by limitation of the generation of free radicals and by attenuation of the fall in gastric blood flow. 10.1016/s0014-2999(97)00051-4
    Gastroprotective activity of melatonin and its precursor, L-tryptophan, against stress-induced and ischaemia-induced lesions is mediated by scavenge of oxygen radicals. Konturek P C,Konturek S J,Brzozowski T,Dembinski A,Zembala M,Mytar B,Hahn E G Scandinavian journal of gastroenterology BACKGROUND:Melatonin, a pineal hormone that is biosynthesized from L-tryptophan, is known to scavenge oxygen free radicals and to be present in the gut, but little is known about the role of this hormone and its precursor, L-tryptophan, in protecting the gastric mucosa from damage accompanied by increase in the generation of oxygen radicals. METHODS:This study was designed to determine the effects of melatonin and L-tryptophan on the formation of acute gastric lesions induced by stress and ischaemia reperfusion and, for comparison, by topical irritants such as 100% ethanol or acidified acetylsalicylic acid. RESULTS:It was found that pretreatment with melatonin in doses ranging from 1.2 to 10 mg/kg dose-dependently reduced the stress-induced gastric lesions and was accompanied by a reduction in blood-free radicals and by attenuation of the fall in gastric blood flow. L-tryptophan applied intragastrically in doses ranging from 1 to 100 mg/kg also reduced dose-dependently the lesions induced by stress; this effect too was accompanied by a rise in gastric blood flow. Pretreatment with indomethacin, to block the biosynthesis of prostaglandins, significantly augmented the lesions produced by stress and completely abolished the protective effects of melatonin or L-tryptophan. Both melatonin and tryptophan reduced the formation of acute gastric lesions provoked by ischaemia reperfusion; this was accompanied by an increase in gastric blood flow. In contrast, melatonin and L-tryptophan failed to influence acute gastric lesions induced by topical irritants such as 100% ethanol or acidified aspirin. CONCLUSIONS:Melatonin and L-tryptophan protect the gastric mucosa from damage by stress and ischaemia reperfusion, and this action is mediated, at least in part, by the limitation in the free radicals, the stimulation of mucosal generation of PG and by the increase in gastric blood flow.
    Gut neuroendocrine cells: relationship to the proliferative activity and apoptosis of mucous epitheliocytes in aging. Kvetnoy I,Popuichiev V,Mikhina L,Anisimov V,Yuzhakov V,Konovalov S,Pogudina N,Franceschi C,Piantanelli L,Rossolini G,Zaia A,Kvetnaia T,Hernandez-Yago J,Blesa J R Neuro endocrinology letters OBJECTIVES:Diffuse neuroendocrine system (DNES) cells regulate homeostasis via neurocrine, endocrine and paracrine mechanisms. Extensive effects of peptide hormones and biogenic amines necessitate studying of DNES cell biology in aging. In this connection, the functional morphology of gut neuroendocrine cells (NEC), proliferative activity and apoptosis of mucous epithelial cells in aging have been studied. MATERIAL AND METHODS:The study was performed on BALB/c-nu mice of 4, 21 and 34 months of age. NEC, proliferative activity and apoptosis of mucous epitheliocytes in stomach and duodenum have been studied by histochemical, immunohistochemical and morphometrical methods. RESULTS:The total number of NEC shows an increasing trend with advancing age. However, the different types of NEC elicit differential patterns. The total number of epithelial cell nuclei does not show any statistically significant difference during aging. The proliferative activity of mucous epitheliocytes also shows no difference among the three animal groups studied. On the contrary, the apoptotic index increases with advancing age. CONCLUSIONS:The results demonstrate that various gut NEC show differential behavior with age and their time-courses are dependent on the site of location (stomach or duodenum). The picture seems quite complex to allow a comprehensive interpretation, nonetheless it gives us some useful indications for further investigation. In fact, since the gut does not show evident gross age-related physiological changes, modifications with age in specific biological parameters can suggest the key mechanisms of compensative regulatory processes possibly acting during aging.
    The role of melatonin and L-tryptophan in prevention of acute gastric lesions induced by stress, ethanol, ischemia, and aspirin. Brzozowski T,Konturek P C,Konturek S J,Pajdo R,Bielanski W,Brzozowska I,Stachura J,Hahn E G Journal of pineal research Melatonin, a pineal hormone, synthesized from L-tryptophan, is known to exist in the gut and to scavenge oxygen free radicals but its role in gastroprotection against acute lesions induced by various strong irritants has been little studied. In this study, we determined the effects of melatonin and L-tryptophan on gastric secretion and the formation of acute gastric lesions induced by absolute ethanol, acidified aspirin (ASA), stress, and ischemia-reperfusion (I/R). Area of gastric lesions was determined by planimetry, gastric blood flow (GBF) was measured using a H2-gas clearance technique, and blood was withdrawn for the measurement of free radicals, plasma gastrin, and melatonin concentration by specific radioimmunoassay. Intragastric (i.g.) administration of melatonin (2.5-10 mg/kg) or L-tryptophan (25-200 mg/kg) failed to affect gastric lesions by ethanol and ASA but dose-dependently reduced the lesions provoked by stress and I/R; this protective effect was accompanied by a significant rise in plasma melatonin level, GBF, and DNA synthesis and by a marked fall in blood free radicals. L-tryptophan, which significantly elevated the plasma melatonin by about 3-5-fold, also reduced the stress and I/R-induced lesions and blood levels of free radicals, while increasing the GBF, DNA synthesis, and plasma gastrin levels. Inhibition of mucosal generation of PGE2 by indomethacin abolished the protection and the rise of GBF afforded by melatonin and L-tryptophan, whereas pretreatment with N(G)-nitro-L-arginine (L-NNA), to suppress nitric oxide (NO) synthase, was without any effect. We conclude that melatonin applied exogenously in pharmacological doses and that released by the administration of its precursor, L-tryptophan, protect gastric mucosa from the damage induced by stress and I/R possibly by a mechanism involving the scavenging of free radicals and gastric hyperemia probably mediated by endogenous prostaglandin but not NO.
    The footprints of gut microbial-mammalian co-metabolism. Zheng Xiaojiao,Xie Guoxiang,Zhao Aihua,Zhao Linjing,Yao Chun,Chiu Norman H L,Zhou Zhanxiang,Bao Yuqian,Jia Weiping,Nicholson Jeremy K,Jia Wei Journal of proteome research Gut microbiota are associated with essential various biological functions in humans through a "network" of microbial-host co-metabolism to process nutrients and drugs and modulate the activities of multiple pathways in organ systems that are linked to different diseases. The microbiome impacts strongly on the metabolic phenotypes of the host, and hence, metabolic readouts can give insights into functional metagenomic activity. We applied an untargeted mass spectrometry (MS) based metabonomics approach to profile normal Wistar rats exposed to a broad spectrum β-lactam antibiotic imipenem/cilastatin sodium, at 50 mg/kg/daily for 4 days followed by a 14-day recovery period. In-depth metabolic phenotyping allowed identification of a panel of 202 urinary and 223 fecal metabolites significantly related to end points of a functional metagenome (p < 0.05 in at least one day), many of which have not been previously reported such as oligopeptides and carbohydrates. This study shows extensive gut microbiota modulation of host systemic metabolism involving short-chain fatty acids, tryptophan, tyrosine metabolism, and possibly a compensatory mechanism of indole-melatonin production. Given the integral nature of the mammalian genome and metagenome, this panel of metabolites will provide a new platform for potential therapeutic markers and mechanistic solutions to complex problems commonly encountered in pathology, toxicology, or drug metabolism studies. 10.1021/pr2007945
    Exposure to continuous darkness ameliorates gastric and colonic inflammation in the rat: both receptor and non-receptor-mediated processes. Cevík Hülya,Erkanli Gözde,Ercan Feríha,Işman Cağla A,Yeğen Berrak C Journal of gastroenterology and hepatology BACKGROUND AND AIM:Melatonin is a hormone involved in the transduction of photoperiodic information, and appears to modulate a variety of neural and endocrine functions. The present study was designed to determine the impact of continuous darkness (CD) on acute gastric and colonic inflammation and the involvement of melatonin receptors in the darkness-related alterations in oxidant gut injury. METHODS:Rats were housed either in CD or in standardized light/dark (12/12 h) cycles for 15 days before the induction of colitis or gastric ulcer. Luzindole (MT(2) receptor antagonist) was given at a dose of 0.25 mg/kg intraperitoneally 30 min before and 6 and 18 h following the induction of colitis with acetic acid or gastric ulcer with ethanol. Rats were decapitated at 24 h, and the colons and stomachs were removed for macroscopic scoring, histologic assessment and for the determination of tissue malondialdehyde and glutathione levels. RESULTS:All inflammation parameters were increased by acetic acid-induced colitis or ethanol-induced gastric ulcer compared with the control group. Our results indicate that the severity of both gastric and colonic injury is reduced by a 2-week exposure to CD prior to the induction of inflammatory event, while luzindole treatment reversed the protective effect of CD on the colonic and gastric injury. However, darkness-related alterations in malondialdehyde and glutathione levels were not altered by luzindole. CONCLUSION:Although the CD-induced amelioration of gut injury involves melatonin receptors, the direct antioxidant effects on melatonin appear to be independent of receptor activity. 10.1111/j.1440-1746.2004.03579.x
    Extrapineal melatonin: location and role within diffuse neuroendocrine system. Kvetnoy I M The Histochemical journal During the last decade, much attention has centred on melatonin, one of the hormones of the diffuse neuroendocrine system. For many years it was considered to be only a hormone of the pineal gland. As soon as highly sensitive antibodies to indolealkylamines became available, melatonin was identified not only in pineal gland, but also in extrapineal tissues. These included the retina, Harderian gland, gut mucosa, cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, ovary, carotid body, placenta and endometrium. It has also been localized in non-neuroendocrine cells such as mast cells, natural killer cells, eosinophilic leukocytes, platelets and endothelial cells. This list of cells indicates that melatonin has a unique position among the hormones of the diffuse neuroendocrine system. It is found in practically all organ systems. Functionally, melatonin-producing cells are part and parcel of the diffuse neuroendocrine system as a universal system of response, control and organism protection. Taking into account the large number of such melatonin-producing cells in many organs, the wide spectrum of biological activities of melatonin and especially its main property as a universal regulator of biological rhythms, it is now possible to consider extrapineal melatonin as a key paracrine signal molecule for the local co-ordination of intercellular relationships.
    Effect of continuous melatonin infusions on steady-state plasma melatonin levels, metabolic fate and tissue retention in rats under near physiological conditions. Messner M,Hardeland R,Rodenbeck A,Huether G Advances in experimental medicine and biology The fate and disposition of melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after one single, often very large dose of labeled melatonin. In continuous infusion experiments in freely moving rats, 500 ng melatonin/mL hr had to be infused in order to elevate the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady state concentrations. To study the fate and tissue accumulation of the infused melatonin, tritiated melatonin was added to the infusion solution, and the retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites were measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and six hours later. A considerable amount of the infused melatonin was found in the gut and in all tissues, some melatonin was covalently attached to proteins. 10.1007/978-1-4615-4709-9_39
    Melatonin and the gastrointestinal tract. Martin M T,Azpiroz F,Malagelada J R Therapie Melatonin has been detected in the digestive tract of several species and appears to be synthesized by the enterochromaffin cells of the gut. Although a diurnal rhythm of melatonin release has been observed in gastrointestinal tissues of birds, in other species it seems to depend on the presence of nutritional elements. Melatonin binding sites have been identified in the digestive tract of several species and it has been suggested that melatonin could act as a protecting agent of the gastrointestinal mucosa. Moreover, the potential role of melatonin as a local regulator of gastrointestinal motility has been investigated. It seems that at least some effects of melatonin on gut activity depend on an antagonistic relationship between serotonin and melatonin. The effects of melatonin on segmental gut transit both in the fasting and in the fed state, as well as on the electromyographic pattern of the small intestine in rats, are described.
    High physiological levels of melatonin in the bile of mammals. Tan D,Manchester L C,Reiter R J,Qi W,Hanes M A,Farley N J Life sciences Bile is an important physiological bodily fluid which functions in the regulation of cholesterol metabolism, promotes the absorption of lipid and fat-soluble vitamins by the gut and serves in the excretion of toxic substances from the liver. Conversely, due to autooxidative processes bile is highly toxic to the hepatocyte and gastrointestinal epithelium. In this investigation, extremely high day time physiological levels of the endogenous antioxidant, melatonin, were measured in the bile of several mammals including rat, guinea pig, rabbit, pig, monkey and humans. Melatonin concentrations in the bile samples ranged from 2,000 to 11,000 pg/ml when measured by radioimmunoassay (RIA). These melatonin levels in bile are 2 to 3 orders of magnitude higher than those in day time serum. The presence of melatonin in bile was confirmed by HPLC with an electrochemical detector. This method, like the RIA, also documented very high levels of melatonin in bile. The presence of high levels of melatonin in bile may be essential to prevent oxidative damage to biliary and small intestinal epithelium induced by bile acids and oxidized cholesterol derivatives. 10.1016/s0024-3205(99)00519-6
    Effect of melatonin on motility pattern of small intestine in rats and its inhibition by melatonin receptor antagonist S 22153. Merle A,Delagrange P,Renard P,Lesieur D,Cuber J C,Roche M,Pellissier S Journal of pineal research Melatonin is synthesized during the night by the pineal gland. Recently, melatonin binding sites have been identified in the gut. Despite few studies, the physiological role of melatonin in gut function remains unclear. The objective of the present study was to investigate the effects of melatonin in the regulation of intestinal motility by using the melatonin receptor antagonist S 22153 in rats. Twenty-four male Wistar rats (400 +/- 25 g) were equipped with intraparietal electrodes along the small intestine. Rats were subjected to a 12:12 hr light:dark schedule. During the dark phase, intestinal migrating motor complexes (MMCs) frequency increased (P < 0.05) by 20% in the duodenum and in the jejunum compared with daylight. This effect is due to a significant reduction in the irregular spiking activity (ISA) of MMCs. Concurrently, at night, the duration of the postprandial motor response is reduced by 30% in the duodenum and 50% in the jejunum and ileum. The administration of S 22153 (2 mg/kg sc) at night suppressed these nocturnal variations and restored the daylight values. In contrast, S 22153 was ineffective during daylight whatever the digestive state. Administration of melatonin (1 mg/kg iv) during the preprandial state, 3 hr after light onset, decreased (-80%) the duration of the ISA of MMCs at the three intestinal levels. During the satiety phase, melatonin administered 10 min before or 15 min after food onset induced the appearance of a transitory preprandial-like motor profile in the entire small intestine. In contrast, when administered at the end of the meal it was ineffective. Preprandial and postprandial melatonin effects were prevented by S 22153 pretreatment. In conclusion, these findings reveal, first, that endogenous melatonin is physiologically involved in the pre- and postprandial changes of intestinal motility at night. Second, exogenous melatonin produces pharmacological effects on pre- and postprandial intestinal motility. In both cases, the action of melatonin corresponds to an inhibition of ISA and a reinforcement of the cyclic MMC pattern.
    Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Bubenik G A Biological signals and receptors The gastrointestinal tract (GIT) is a major source of extrapineal melatonin. In some animals, tissue concentrations of melatonin in the GIT surpass blood levels by 10-100 times and the digestive tract contributes significantly to melatonin concentrations in the peripheral blood, particularly during the day. Some melatonin found in the GIT may originate from the pineal gland, as the organs of the digestive system contain binding sites, which in some species exhibit circadian variation. Unlike the production of pineal melatonin, which is under the photoperiodic control, release of GI melatonin seems to be related to periodicity of food intake. Melatonin and melatonin binding sites were localized in all GI tissues of mammalian and avian embryos. Postnatally, melatonin was localized in the GIT of newborn mice and rats. Phylogenetically, melatonin and melatonin binding sites were detected in GIT of numerous mammals, birds and lower vertebrates. Melatonin is probably produced in the serotonin-rich enterochromaffin cells (EC) of the GI mucosa and can be released into the portal vein postprandially. In addition, melatonin can act as an autocrine or a paracrine hormone affecting the function of GI epithelium, lymphatic tissues of the immune system and the smooth muscles of the digestive tube. Finally, melatonin may act as a luminal hormone, synchronizing the sequential digestive processes. Higher peripheral and tissue levels of melatonin were observed not only after food intake but also after a long-term food deprivation. Such melatonin release may have a direct effect on the various GI tissues but may also act indirectly via the CNS; such action might be mediated by sympathetic or parasympathetic nerves. Melatonin can protect GI mucosa from ulceration by its antioxidant action, stimulation of the immune system and by fostering microcirculation and epithelial regeneration. Melatonin may reduce the secretion of pepsin and the hydrochloric acid and influence the activity of the myoelectric complexes of the gut via its action in the CNS. Tissue or blood levels of melatonin may serve as a marker of GI lesions or tumors. Clinically, melatonin has a potential for a prevention or treatment of colorectal cancer, ulcerative colitis, irritable bowel syndrome, children colic and diarrhea. 10.1159/000046903
    Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. Konturek Peter C,Brzozowski T,Konturek S J Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 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.
    New insights into tryptophan and its metabolites in the regulation of bone metabolism. Michalowska M,Znorko B,Kaminski T,Oksztulska-Kolanek E,Pawlak D Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Osteoporosis, a debilitating disease caused by an imbalance between the action of osteoblasts and osteoclasts, is becoming an increasing problem in today's aging population. Although many advances in this field have addressed certain aspects of disease progression and pain management, new approaches to treatment are required. This review focuses on the influence of tryptophan, its metabolites and their influence on bone remodeling. Tryptophan is a precursor to serotonin, melatonin, kynurenines and niacin. Changes of tryptophan levels were noticed in bone metabolic diseases. Moreover, some works indicate that tryptophan plays a role in osteoblastic differentiation. Serotonin can exert different effects on bones, which depend on site of serotonin synthesis. Gut-derived serotonin inhibits bone formation, whereas brain-derived serotonin enhances bone formation and decreases bone resorption. Melatonin, increased differentiation of human mesenchymal stem cells into the osteoblastic cell lineage. Results of melatonin action on bone are anabolic and antiresorptive. Activation of the second tryptophan metabolic pathway, the kynurenine pathway, is associated with osteoblastogenesis and can be implicated in the occurrence of bone diseases. Oxidation products like kynurenine stopped proliferation of bone marrow mesenchymal stem cells. This may result in inhibition of osteoblastic proliferation and differentiation. Kynurenic acid acts as an antagonist at glutamate receptors, which are expressed on osteoclasts. Quinolinic acid activates N-methyl-D-aspartate receptors. 3-hydroxyanthranilic acid exhibits pro-oxidant and antioxidant activity. Decreased concentration of 3-hydroxyanthranilic acid can be one of the causes of osteoporosis. 3-hydroxykynurenine reduced the viability of osteoblast-like cells. Picolinic acid exerted osteogenic effect in vitro. Kynurenine derivatives exert various effects on bones. Discovery of the exact mechanism of action of tryptophan metabolites on bones may take us a step closer to understanding the complicated mechanism of bone metabolism, which in turn may result in finding a new, effective therapy for treating bone diseases.
    Gut-Brain Axis in Gastric Mucosal Damage and Protection. Sgambato Dolores,Capuano Annalisa,Sullo Maria Giuseppa,Miranda Agnese,Federico Alessandro,Romano Marco Current neuropharmacology BACKGROUND:The gut-brain axis plays a potential role in numerous physiological and pathological conditions. Several substances link stomach with central nervous system. In particular, hypothalamo-pituitary-adrenocortical axis, thyrotropinreleasing factor-containing nerve fibers and capsaicin-sensitive nerves are principal mediators of the harmful and protective central nervous system-mediated effects on gastric mucosa. Also, existing evidence indicates that nitric oxide, prostaglandins and calcitonin gene-related peptide play a role as final effectors of gastric protection. METHODS:We undertook a structured search of bibliographic databases for peerreviewed research literature with the aim of focusing on the role of gut-brain axis in gastric damage and protection. In particular, we examined manuscripts dealing with the role of steroids, thyrotropin-releasing hormone, prostaglandins, melatonin, hydrogen sulfide and peptides influencing food intake (i.e. leptin, cholecystokinin, peptide YY, central glucagon-like peptide-1, and ghrelin). Also, the role of GABAergic and glutamatergic pathways in gastric mucosal protection have been examined. RESULTS:We found and reviewed 61 peer-reviewed papers dealing with the major aspects related to the role of gut brain axis in gastric mucosal damage and protection. CONCLUSIONS:A dense neuronal network links stomach with central nervous system and a number of neurotransmitters and peptides functionally and anatomically related to central nervous system play a major role in contributing to gastric mucosal integrity. Exploiting the mechanisms underlying the connection between brain and gut may lead to a better understanding of the pathophysiology of gastric mucosal injury and to an improvement in the prevention and, eventually, management of gastric damage. 10.2174/1570159x14666160223120742
    Small doses of melatonin increase intestinal motility in rats. Drago Filippo,Macauda Silvia,Salehi Soudabeh Digestive diseases and sciences Since melatonin receptors are present in the intestines, the possibility that this hormone may affect intestinal motility has been studied in the rat. Sprague-Dawley male rats were given a carmine cochineal powder meal and were injected intraperitoneally with 1, 10, 100, or 1000 microg/kg melatonin. Sixty minutes after treatment, intestinal transit was found to be faster in animals treated with small doses of melatonin (1 or 10 microg/kg) than in saline-injected controls. This effect, however, appear to be clearly reversed with 100 or 1000 microg/kg melatonin. In fact, these doses of the hormone reduced intestinal transit in rats. The nonselective melatonin receptor antagonist, luzindole (administered intraperitoneally in a dose of 0.25 mg/kg, 15 min prior to melatonin injection) totally prevented the accelerating effect of melatonin (10 microg/kg) on intestinal transit. Luzindole per se failed to affect gut motility. Injection of the reversible acetylcholinesterase inhibitor and cholinergic agent, neostigmine, accelerated intestinal transit but failed to influence melatonin effect on this parameter. In contrast, intraperitoneal injection of the muscarinic receptor antagonist atropine delayed intestinal transit per se but did not reduce the stimulating effect of melatonin on this parameter. Intestinal myoelectrical recording revealed that intestinal myoelectrical activity was increased by intraperitoneal injection of melatonin (10 microg/kg). Administration of luzindole totally prevented melatonin-induced increase of intestinal myoelectrical activity. These results indicate that melatonin may affect intestinal motility in rats when administered in small doses. This effect might be mediated by melatonin receptors in the intestines, although the involvement of central receptors for the hormone is also possible. 10.1023/a:1019696006677
    Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion. Jaworek Jolanta,Leja-Szpak Anna,Bonior Joanna,Nawrot Katarzyna,Tomaszewska Romana,Stachura Jerzy,Sendur Ryszard,Pawlik Wiesław,Brzozowski Tomasz,Konturek Stanisław J Journal of pineal research Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.
    Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract. Reiter R J,Tan D-X,Mayo J C,Sainz R M,Leon J,Bandyopadhyay D Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.
    Amelioration of methotrexate-induced enteritis by melatonin in rats. Jahovic Nermina,Sener Göksel,Cevik Hülya,Ersoy Yasemin,Arbak Serap,Yeğen Berrak C Cell biochemistry and function The anti-tumour drug methotrexate (MTX) induces intestinal mucosa injury resulting in malabsorption and diarrhoea. The purpose of this study was to investigate whether exogenous melatonin could protect the gut from MTX-induced damage in rats. A single dose of MTX (20 mg kg(-1), i.p.) was followed by i.p. saline or melatonin injections (10 mg kg(-1), MTX + Mel) for the next 5 days. On the fifth day, intestinal transit was assessed using charcoal propagation. Rats were decapitated and small intestinal segments were fixed for light (LM) and scanning electron microscope (SEM) examinations. Other intestinal segments were stored to measure glutathione (GSH) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) and ATPase activity. MTX led to loss of more than 10% of the initial body weight (p < 0.01). Conversely, weight loss was markedly less in the melatonin-treated MTX group (p < 0.05). Bowel motility was increased in MTX-treated rats, while the transit index in the MTX-Mel group was not different from the control group. MTX caused decreases in GSH levels and ATPase activity, with increases in MDA levels and MPO activity. These changes were reversed in MTX-Mel-treated rats (p < 0.05-p < 0.001). LM and SEM in the MTX group revealed desquamation of surface epithelium and glandular degeneration, while the epithelium was slightly damaged in the MTX-Mel group. In conclusion, the present study demonstrates that melatonin is capable of reversing MTX-induced intestinal dysfunctions, indicating that it may be beneficial in ameliorating the symptoms of chemotherapy-induced enteritis. 10.1002/cbf.1071
    Melatonin as a modulator of the ileal brake mechanism. Teresa Martín Maria,Azpiroz Fernando,Malagelada Juan-R Scandinavian journal of gastroenterology OBJECTIVE:The gastrointestinal tract represents the most important extrapineal source of melatonin. Intestinal melatonin release is induced by the ileal passage of nutrients and could play a part in the control of postprandial gut motility. The specific aim of this study was to determine the putative role of melatonin in the "ileal brake" reflex, an important mechanism released by ileal lipids that regulates the gastric emptying of chyme. MATERIAL AND METHODS:Under general anaesthesia rats were fitted with ileal cannula exteriorized at the back of the neck. After a 1-week recovery, experiments were performed in conscious fasted animals. Rats were fed by gavage 1.5 ml casein hydrolyse plus 0.05% phenol red and either saline or Intralipid were continuously infused (2 ml/h) into the ileum. Gastric emptying was measured 50 min after ingestion by gastric lavage and determination of phenol red by spectrophotometry. The effects of melatonin (1 mg/kg) and melatonin antagonist S-22153 (dose-response study 0.2-25 mg/kg) were tested versus vehicle in paired experiments at 1-week intervals. RESULTS:Ileal infusion of lipids delayed gastric emptying. During ileal infusion of lipids, melatonin antagonist S-22153, but not melatonin, potentiated the delay in gastric emptying induced by the ileal brake mechanism. The inhibition of gastric emptying induced by S-22153 was dose related. Neither melatonin nor S-22153 had noticeable effects on gastric emptying during ileal infusion of saline. CONCLUSIONS:Our data suggest that melatonin, released in response to ileal lipids, exerts a modulatory influence that decreases the inhibitory effects of the ileal brake on gastric emptying of nutrients. 10.1080/00365520510012316
    Continuous amperometric detection of co-released serotonin and melatonin from the mucosa in the ileum. Patel Bhavik Anil The Analyst Serotonin (5-HT) and melatonin (MEL) are well known neurotransmitters and paracrine signalling molecules. Both compounds are present in enterochromaffin (EC) cells in the mucosa of the gastrointestinal tract and are thought to play a role in controlling gut motility. To date there are no real-time analytical methods for the detection of these two molecules and it is not clear if MEL is actually released from the EC cells. In this paper, I used boron-doped diamond (BDD) microelectrodes to record 5-HT and MEL overflow from EC cells in the mucosa of rabbit ileum. The BDD microelectrode was extremely stable and sensitive for measurements of both compounds when assessed using differential pulse voltammetry (DPV) and flow injection analysis (FIA) using amperometric detection. MEL release was detected in the mucosa, where it is most likely from the EC cells. Mechanical stimulation of individual villi increased 5-HT but not MEL overflow. Application of the serotonin transporter (SERT) inhibitor, fluoxetine, elevated the 5-HT but not the MEL signal. Differences in the amounts of the two gastrointestinal compounds released and the mechanism of which they are released will provide insights to the physiology of the EC cell and disease states. 10.1039/b717034c
    Importance of the pineal gland, endogenous prostaglandins and sensory nerves in the gastroprotective actions of central and peripheral melatonin against stress-induced damage. Brzozowski Tomasz,Konturek Peter C,Zwirska-Korczala Krystyna,Konturek Stanislaw J,Brzozowska Iwona,Drozdowicz Danuta,Sliwowski Zbigniew,Pawlik Michal,Pawlik Wieslaw W,Hahn Eckhart G Journal of pineal research Melatonin attenuates acute gastric lesions induced by topical strong irritants because of scavenging of free radicals, but its role in the pathogenesis of stress-induced gastric lesions has been sparingly investigated. In this study we compared the effects of intragastric (i.g.) or intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on gastric lesions induced by water immersion and restraint stress (WRS). The involvement of pineal gland, endogenous prostaglandins (PG) and sensory nerves in gastroprotective action of melatonin and L-tryptophan against WRS was studied in intact or pinealectomized rats or those treated with indomethacin or rofecoxib to suppress cyclooxygenase (COX)-1 and COX-2, respectively, and with capsaicin to induce functional ablation of the sensory nerves. In addition, the influence of i.c.v. and i.g. melatonin on gastric secretion was tested in a separate group of rats equipped with gastric fistulas. At 3.5 hr after the end of WRS, the number of gastric lesions was counted, the gastric blood flow (GBF) was determined by H2-gas clearance technique and plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for determination of expression of mRNA for COX-1 and COX-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) and of the mucosal generation of prostaglandin E2 (PGE2) by RIA. Melatonin applied i.g. (1.25-10 mg/kg) or i.c.v. (1.25-10 microg/kg) dose-dependently inhibited gastric acid secretion and significantly attenuated the WRS-induced gastric damage. This protective effect of melatonin was accompanied by a significant rise in the GBF and plasma melatonin and gastrin levels and in mucosal generation of PGE2. Pinealectomy, which suppressed plasma melatonin levels, aggravated the gastric lesions induced by WRS and these effects were counteracted by i.g. or i.c.v. application of melatonin. Luzindole abolished completely the gastroprotective effects of melatonin and L-tryptophan and attenuated significantly the rise in GBF evoked by the indoleamine and its precursor. Indomethacin and rofecoxib, which diminished PGE2 biosynthesis by c. 90 and 75% or capsaicin denervation, attenuated significantly melatonin- and L-tryptophan-induced protection and the rise in the GBF. Both the protection and the hyperemia were restored by addition of exogenous CGRP to capsaicin-denervated animals. COX-1 mRNA was detected by RT-PCR in the intact and melatonin-treated gastric mucosa, while COX-2 mRNA, which was undetectable in the intact gastric mucosa, appeared in WRS-exposed mucosa, especially in the melatonin-treated animals and this was accompanied by increased generation of PGE2 in gastric mucosa. Pinealectomy downregulated COX-2 mRNA and this effect was reversed by supplementation of pinealectomized animals with melatonin. We conclude that, (a) exogenous melatonin and its precursor, L-tryptophan, attenuates WRS-induced gastric lesions via interaction with MT2 receptors, (b) this protective action of melatonin is because of an enhancement of gastric microcirculation, probably mediated by PGE2 derived from COX-2 overexpression and activity, the activation of brain-gut axis involving CGRP released from sensory nerves, and the release of gastrin and (c) the pineal plays an important role in the limitation of WRS-induced gastric lesions via releasing melatonin, which exerts gastroprotective and hyperemic activities against stress ulcerogenesis. 10.1111/j.1600-079X.2005.00264.x
    Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors. Kasimay O,Cakir B,Devseren E,Yegen B C Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Pineal hormone melatonin is proposed as a potential treatment for severe sleep disturbances, and various gastrointestinal disorders. It was shown that melatonin increases intestinal motility and influences the activity of myoelectric complexes of the gut. The aim of the study was to evaluate the mechanisms of the effect of exogenous melatonin on gastric emptying rate. Male Sprague-Dawley rats were fitted with gastric cannulas under anesthesia. The rate of gastric emptying of saline was determined after instillation into the gastric fistula, from the volume and phenol red concentrations recovered after 5 min. Melatonin injected intraperitoneally (ip; 0.001-100 mg/kg) delayed gastric emptying rate of saline at 3 and 10 mg/kg doses. When administered ip 15 min before melatonin (10 mg/kg) injections, CCK2 (L-365,260, 1 mg/kg) or 5-HT3 receptor (ramosetrone, 50 microg/kg) blockers abolished melatonin-induced delay in gastric emptying rate, while the blockade of sympathetic ganglia (bretylium tosylate, 15 mg/kg) significantly reduced the delay in gastric emptying rate. CCK1 receptor blocker (L-364,718, 1 mg/kg) had no significant effect on the delaying action of melatonin. Our results indicate that pharmacological doses of melatonin delay gastric emptying via mechanisms that involve CCK2 and 5-HT3 receptors. Moreover, it appears that exogenous melatonin inhibits gastric motility in part by activating sympathetic neurons.
    Melatonin reduces apoptosis and necrosis induced by ischemia/reperfusion injury of the pancreas. Muñoz-Casares Francisco C,Padillo Francisco J,Briceño Javier,Collado Juan A,Muñoz-Castañeda Juan R,Ortega Rosa,Cruz Adolfo,Túnez Isaac,Montilla Pedro,Pera Carlos,Muntané Jordi Journal of pineal research The pancreas is highly susceptible to the oxidative stress induced by ischemia/reperfusion (IR) injury leading to the generation of acute pancreatitis. Melatonin has been shown to be useful in the prevention of the damage by ischemia-reperfusion in liver, brain, myocardium, gut and kidney. The aim of the study was to evaluate the cytoprotective properties of melatonin against injury induced by IR in pancreas. The obstruction of gastro-duodenal and inferior splenic arteries induced pancreatic IR in male Wistar rats. Melatonin was intraperitoneally administered before or/and after IR injury. The animals were killed at 24 and 48 hr after reperfusion and there were evaluated parameters of oxidative stress (lipoperoxides, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione), glandular endocrine and exocrine function (lipase, amylase, insulin) and cell injury (apoptosis and necrosis). The IR induced a marked enhancement of oxidative stress and impaired pancreatic function. The histological analysis showed that IR induced acute pancreatitis with the accumulation of inflammatory infiltrate, disruption of tissue structure, cell necrosis and hemorrhage. Melatonin administration before or after pancreatic IR prevented all tissue markers of oxidative stress, biochemical and histological signs of apoptosis and necrosis, and restored glandular function. No histological signs of pancreatitis were observed 48 hr after reperfusion in 80% of the animals treated with melatonin, with only a mild edematous pancreatitis being observed in the remaining rats. Preventive or therapeutic administration of melatonin protected against the induction of oxidative stress and tissue injury, and restored cell function in experimental pancreatic IR in rats. 10.1111/j.1600-079X.2005.00291.x
    Brain-gut axis in the modulation of pancreatic enzyme secretion. Jaworek J,Nawrot-Porabka K,Leja-Szpak A,Konturek S J Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Pancreatic enzyme secretion is controlled by complex of neurohormonal mechanisms, activated by nutrients. Food components in the duodenum acts as the signals for activation of intestinal phase of pancreatic secretion. Direct stimulation of pancreatic exocrine function involves several hormones, which bind to the receptors on pancreatic acinar cell. Indirect mechanism depends on the activation of autonomic nervous reflexes. Brain is also implicated in the regulation of pancreatic exocrine function. Dorsal vagal complex of the brainstem (DVC) appears the center of long vago-vagal cholinergic entero-pancreatic reflex. Mucosal terminals, which initiates entro-pancreatic reflex could be stimulated by CCK, serotonin and perhaps others peptides, which are released into duodenum from the enteroendocrine (EE) cells of the gastrointestinal mucosa. Melatonin, leptin and ghrelin are released from the EE cells into the gastrointestinal lumen. These substances given intraduodenally to the rats produced dose-dependent stimulation of pancreatic enzyme secretion, but they failed to affect directly amylase release from isolated pancreatic acini. Intraluminal application of melatonin, its precursor: L-tryptophan, leptin or ghrelin dose-dependently increased plasma CCK level. Above stimulatory effects of investigated substances on CCK release were completely abolished by bilateral, subdiaphragmatic vagotomy, capsaicin-deactivation of afferent nerves as well as blockade of CCK receptors. We conclude that melatonin, leptin or ghrelin, which are released into duodenal lumen by nutrients, stimulate pancreatic enzyme secretion by activation of CCK release and activation of duodeno-pancreatic reflex.
    Indoles - Gut Bacteria Metabolites of Tryptophan with Pharmacotherapeutic Potential. Konopelski Piotr,Ufnal Marcin Current drug metabolism BACKGROUND:Increasing evidence proves the pivotal role of gut microbiota in mammals' homeostasis. Gut bacterial metabolites may exert local effects on the intestines, and may enter the circulation, affecting the functions of virtually all organs. Here, we review the available evidence on metabolism and biological effects of gut microbiota- derived indoles. METHODS:The PUBMED database and Google Scholar were searched to identify experimental and clinical studies investigating biological effects of gut bacteria-derived indoles. Key words included: gut microbiota, indoles, indole and tryptophan. RESULTS:Indoles represent a wide group of gut bacteria-derived compounds produced from tryptophan, an essential amino acid and the precursor of endogenous synthesis of tryptamine, serotonin and melatonin. Ample evidence suggests that indoles derived from gut microbiota metabolism exert significant biological effects and may contribute to the etiology of cardiovascular, metabolic, and psychiatric diseases. However, a majority of the research is limited to experimental studies and only a small number of clinical trials. CONCLUSION:Bacterial indoles affect the function of many biological systems. Whether gut-derived indoles contribute to pathogenesis of cardiovascular, metabolic and other diseases, requires further clinical studies. 10.2174/1389200219666180427164731
    Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism. Gao Jing,Xu Kang,Liu Hongnan,Liu Gang,Bai Miaomiao,Peng Can,Li Tiejun,Yin Yulong Frontiers in cellular and infection microbiology The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature. 10.3389/fcimb.2018.00013
    Protective effect of melatonin in acetic acid induced colitis in rats. Nosál'ová Viera,Zeman Michal,Cerná Silvia,Navarová Jana,Zakálová Monika Journal of pineal research Possible protective effects of exogenous melatonin on colonic inflammation were studied in rats. Colitis was induced by intracolonic (i.c.) instillation of 4% acetic acid (AA) and the resulting injury was assessed after 1 and 48 hr. Diffuse hyperemia and bleeding with erosions and ulcerations were observed in the colons of vehicle-treated rats. Melatonin administered in doses of 5 and 10 mg/kg reduced significantly the extent of gross mucosal damage after intraperitoneal as well as i.c. dosing. The inflammation induced increase in colonic wet weight was also reduced by melatonin treatment. In the early phase of colonic inflammation (60 min), melatonin partly prevented the decrease of reduced glutathione (GSH) content and limited lysosomal enzyme, N-acetyl-glucosaminidase and cathepsin D, activities induced by AA, with no changes in proteins or acid phosphatase activity. Increase of myeloperoxidase activity (MPO) caused by colonic inflammation was prevented by melatonin given i.c. As observed 48 hr after AA exposure, there was no difference between the effect of vehicle and melatonin on the content of GSH. Colitis did not influence the melatonin content of the colon. After administration of exogenous melatonin, plasma, pineal and gut melatonin tended to increase. The results indicate that melatonin participates in various defense mechanisms against colonic inflammatory processes by preserving the important endogenous antioxidant reserve of GSH, by preventing lysosomal enzyme disruption, by inhibiting enhanced MPO activity, thus reducing the extent of colonic damage, mainly in the early phase of colitis. 10.1111/j.1600-079X.2007.00428.x
    Chronic disruptions of circadian sleep regulation induce specific proinflammatory responses in the rat colon. Polidarová Lenka,Houdek Pavel,Sumová Alena Chronobiology international Exposure to environmental conditions that disturb the daily rhythms has been shown to enhance the proinflammatory responses of immunostimulant-challenged immune system. However, it is not known whether circadian disturbances may stimulate unchallenged immune responses and thus contribute per se to the development of inflammation-related diseases. Our aim was to ascertain an effect of various conditions threatening the behavioral activity/rest cycle regulation, namely aging with or without melatonin, 6 h advance/delay phase shifts in the light/dark cycle repeated with a 2-day frequency and constant light, on expression of immune markers in the rat colon. The impact of these conditions on parameters of behavioral activity and mRNA levels of selected immune markers in the colonic mucosa of Wistar rats, namely TNFα (Tnf), IL1a (Il1a), IL17RA (Il17ra), STAT3 (Stat3) and Rgs16 (Rsg16), were detected. Our results demonstrate that aging with or without melatonin as well as repeated 6 h advance/delay phase shifts in the light/dark cycle, which increased inactivity as a correlate of sleep during the dark phase of the light/dark cycle (i.e. during the active phase for nocturnal animals), had a minor effect on immune state in the colonic mucosa; all these conditions caused downregulation of gene Rgs16 which is involved in attenuation of the inflammatory response in the colon but did not affect expression of the other immune markers. Interestingly, a long-term absence of melatonin facilitated the aging-induced effect on immune state in the colon. In contrast, exposure to constant light, which perturbed the interval of inactivity (sleep) and led to the complete abolishment of activity/inactivity cycles, activated robustly proinflammatory state in the colon selectively via Stat3-dependent pathway. In spite all these experimental conditions (aging with or without melatonin, shifts in light/dark cycles, constant light) perturbed the activity/rest cycles, none of them induced sleep deprivation. These results provided the first evidence that disruptions in the behavioral activity/inactivity cycles may spontaneously (without immuno-stimulant) induce selective proinflammatory responses in the colonic mucosa. Such effects may take part in the mechanisms of modern lifestyle-induced inflammatory diseases of the gut. ABBREVIATIONS:B2M: β2-microglobulin; DSS: dextran sodium sulfate; Gapdh: glyceraldehyde-3-phosphate dehydrogenase; Ifng: interferon g; Il1a: interleukin 1a; Il1b: interleukin 1b; Il2: interleukin 2; Il6: interleukin 6; Il17ra: interleukin 17 receptor a; LD: light/dark cycle; LL: constant light; LPS: lipopolysaccharide; Mntr1a: melatonin receptor 1a; PINX: pinealectomy; Rgs16: regulator of G protein signaling 16; RT qPCR: quantitative reverse transcription polymerase chain reaction; Stat3: signal transducer and activator of transcription 3; Th17: type 17 T helper cells; Tnfα: tumor necrosis factor α; Tnfrsf1b: tumor necrosis factor receptor superfamily member 1b. 10.1080/07420528.2017.1361436
    Determination of serotonin, melatonin and metabolites in gastrointestinal tissue using high-performance liquid chromatography with electrochemical detection. Chau Rosanna M W,Patel Bhavik Anil Biomedical chromatography : BMC In this paper we show a simple isocratic chromatographic method for the detection of serotonin and its precursors and metabolites from various types of gastrointestinal tissue. The paper measures for the first time basal measurements of melatonin in the gastrointestinal tract, which has recently been shown to be released from the musosal lining of the gut. Tissue samples were stable following sample preparation in either 0.1 m perchloric acid or mobile phase. Analysis was carried out using a mobile phase consisting of 10% acetonitrile-90% acetate acid buffer pH 4.0 with 2 mm decane-sulfonic acid sodium salt at a column temperature of 50 degrees C. Electrochemical detection was utilized at a potential of +850 mV vs Ag/AgCl reference electrode at 10 microA full-scale deflection. The detection limit of 5-HT and melatonin was 241 and 308 nm respectively for a 10 microL injection. As a result of the method optimization, total analysis was reduced to 30 min. Accurate responses of the tissue samples following sample preparation could be obtained following a week after storage at -80 degrees C. This method is capable of preparing and analysing of samples from all regions of the gastrointestinal tract. 10.1002/bmc.1100
    Left Ventricular Hypertrophy: Roles of Mitochondria CYP1B1 and Melatonergic Pathways in Co-Ordinating Wider Pathophysiology. Anderson George,Mazzoccoli Gianluigi International journal of molecular sciences Left ventricular hypertrophy (LVH) can be adaptive, as arising from exercise, or pathological, most commonly when driven by hypertension. The pathophysiology of LVH is consistently associated with an increase in cytochrome P450 (CYP)1B1 and mitogen-activated protein kinases (MAPKs) and a decrease in sirtuins and mitochondria functioning. Treatment is usually targeted to hypertension management, although it is widely accepted that treatment outcomes could be improved with cardiomyocyte hypertrophy targeted interventions. The current article reviews the wide, but disparate, bodies of data pertaining to LVH pathoetiology and pathophysiology, proposing a significant role for variations in the N-acetylserotonin (NAS)/melatonin ratio within mitochondria in driving the biological underpinnings of LVH. Heightened levels of mitochondria CYP1B1 drive the 'backward' conversion of melatonin to NAS, resulting in a loss of the co-operative interactions of melatonin and sirtuin-3 within mitochondria. NAS activates the brain-derived neurotrophic factor receptor, TrkB, leading to raised trophic signalling via cyclic adenosine 3',5'-monophosphate (cAMP)-response element binding protein (CREB) and the MAPKs, which are significantly increased in LVH. The gut microbiome may be intimately linked to how stress and depression associate with LVH and hypertension, with gut microbiome derived butyrate, and other histone deacetylase inhibitors, significant modulators of the melatonergic pathways and LVH more generally. This provides a model of LVH that has significant treatment and research implications. 10.3390/ijms20164068
    Melatonin protects against hydrogen peroxide-induced gastric injury in rats. Mohamadin Ahmed M,Ashour Osama M,El-Sherbeny Nagla A,Alahdal Abdulrahman M,Morsy Gehan M,Abdel-Naim Ashraf B Clinical and experimental pharmacology & physiology 1. Melatonin (MT) is a pineal hormone that is also abundant in the gut and has a well known role in scavenging oxygen free radicals. The aim of the present study was to evaluate the potential protective effects of MT against H(2)O(2)-induced gastric lesions in rats. 2. An experimental model of gastric ulceration was established in rats using 15% H(2)O(2). Melatonin (12.5, 25 or 50 mg/kg, intagastrically) was administered to rats 30 min before H(2)O(2) challenge. 3. Intragastric administration of H(2)O(2) resulted in haemorrhagic lesions in the fundic area of the stomach. Furthermore, H(2)O(2) induced gastric oxidative stress, as indicated by depletion of reduced glutathione (GSH), inhibition of glutathione peroxidase (GPx) activity and elevation of malonedialdehyde (MDA) levels. These effects were accompanied by decreased gastric tissue levels of prostaglandin (PG) E(2) and nitric oxide (NO), as well as increased levels of tumour necrosis factor (TNF)-alpha. Administration of MT (12.5, 25 or 50 mg/kg) 30 min before H(2)O(2) significantly attenuated the development of gastric lesions in a dose-dependent manner. The protective effects of MT were accompanied by significant inhibition of the H(2)O(2)-induced reduction in gastric content of GSH and GPx activity and elevation in MDA levels. Furthermore, MT antagonized H(2)O(2)-induced reduction of gastric PGE(2) and NO levels and elevation of TNF-alpha. 4. In conclusion, MT protects rat gastric mucosa against H(2)O(2)-induced damage. The observed protective effects of MT can be attributed, at least in part, to its anti-oxidant properties, preservation of PGE(2) and NO levels, as well as inhibition of TNF-alpha induction in gastric tissues. 10.1111/j.1440-1681.2008.05072.x
    Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector. Jaworek J,Nawrot-Porabka K,Leja-Szpak A,Bonior J,Szklarczyk J,Kot M,Konturek S J,Pawlik W W Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Melatonin, the main product of the pineal gland, is also released from the gastrointestinal endocrine-neurocrine (EE) cells. The concentrations of melatonin produced in the gut exceeds that originating from central nervous system. In spite of the presence of melatonin receptors in the pancreatic tissue little is known about the role of this indole in the pancreas. Our experimental studies have shown that exogenous melatonin, as well as this produced endogenously from its precursor; L-tryptophan, strongly stimulates pancreatic amylase secretion when given intraperitoneally, or into the gut lumen. This was accompanied by significant increases of CCK plasma level. Above pancreatostimulatory effects of luminal administration of melatonin, were completely reversed by bilateral vagotomy, capsaicin deactivation of sensory nerves or pretreatment of the rats with CCK1 receptor antagonist; tarazepide as well as serotonin antagonist; ketanserin. Melatonin, as well as its precursor; L-tryptophan, effectively protects the pancreas against the damage induced by caerulein overstimulation or ischemia/reperfusion. The beneficial effects of melatonin or L-tryptophan on acute pancreatitis could be related to the ability of melatonin to scavenge the free radicals, to activate antioxidative enzymes and to modulate the cytokine production.
    Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation. Bertrand P P,Bertrand R L,Camello P J,Pozo M J Journal of pineal research Ageing is associated with important changes in gastrointestinal function and in the levels of intestinal hormones secreted. Enterochromaffin (EC) cells containing serotonin (5-HT) and melatonin may play a major role in maintaining gut function during ageing. Our aim was to characterise the mucosal availability of 5-HT and melatonin in the ileum and colon of a mouse model of ageing. Female young mice (2-5 month; n = 6), aged mice (22-24 months; n = 6) and aged mice treated with melatonin (n = 6; 10 mg/kg/day) were examined. Electrochemical methods were used to measure 5-HT and melatonin concentrations near the mucosal surface of ileum and distal colon. Amperometry studies showed that steady state levels of 5-HT from ileum and colon were decreased in aged mice treated with melatonin when compared to aged mice, while compression-evoked 5-HT release was unchanged. Differential pulse voltammetry studies showed that young mice had concentrations of 5-HT of 4.8 +/- 0.8 mum in the ileum and 4.9 +/- 1.0 mum in the colon. Concentrations of melatonin were 5.7 +/- 1.4 mum in the ileum and 5.6 +/- 1.9 mum in the colon. Compared to young mice, the levels of 5-HT and melatonin were increased in aged mice (combined ileum and colon: 5-HT = 130% and melatonin = 126% of young mice) and decreased in melatonin-treated mice (5-HT = 94% and melatonin = 82%). In conclusion, our data show that the availability of gut 5-HT and melatonin is increased in aged mice and melatonin treatment suppresses natural gastrointestinal production of 5-HT and melatonin in the aged mouse intestine. 10.1111/j.1600-079X.2010.00760.x
    Antioxidant and antiapoptotic properties of melatonin restore intestinal calcium absorption altered by menadione. Carpentieri A,Marchionatti A,Areco V,Perez A,Centeno V,Tolosa de Talamoni N Molecular and cellular biochemistry The intestinal Ca²⁺ absorption is inhibited by menadione (MEN) through oxidative stress and apoptosis. The aim of this study was to elucidate whether the antioxidant and antiapoptotic properties of melatonin (MEL) could protect the gut against the oxidant MEN. For this purpose, 4-week-old chicks were divided into four groups: (1) controls, (2) treated i.p. with MEN (2.5 μmol/kg of b.w.), (3) treated i.p. with MEL (10 mg/kg of b.w.), and (4) treated with 10 mg MEL/kg of b.w after 2.5 μmol MEN/kg of b.w. Oxidative stress was assessed by determination of glutathione (GSH) and protein carbonyl contents as well as antioxidant enzyme activities. Apoptosis was assayed by the TUNEL technique, protein expression, and activity of caspase 3. The data show that MEL restores the intestinal Ca²⁺ absorption altered by MEN. In addition, MEL reversed the effects caused by MEN such as decrease in GSH levels, increase in the carbonyl content, alteration in mitochondrial membrane permeability, and enhancement of superoxide dismutase and catalase activities. Apoptosis triggered by MEN in the intestinal cells was arrested by MEL, as indicated by normalization of the mitochondrial membrane permeability, caspase 3 activity, and DNA fragmentation. In conclusion, MEL reverses the inhibition of intestinal Ca²⁺ absorption produced by MEN counteracting oxidative stress and apoptosis. These findings suggest that MEL could be a potential drug of choice for the reversal of impaired intestinal Ca²⁺ absorption in certain gut disorders that occur with oxidative stress and apoptosis. 10.1007/s11010-013-1885-2
    Melatonin attenuates stress-induced defecation: lesson from a rat model of stress-induced gut dysfunction. Song G H,Gwee K A,Moochhala S M,Ho K Y Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society Melatonin is known to alleviate stress and modulate gut motility. We investigated the modulating effects of melatonin on stress-induced gut dysfunction. One hundred Wistar rats were randomly assigned to five equal groups, receiving intraperitoneal injections of 0, 1, 10, 100 or 1000 microg kg(-1) melatonin, respectively. Fifteen minutes later, each group was divided again into four subgroups receiving no treatment, 0.25 mg luzindole (a non-selective melatonin receptor antagonist) intraperitoneally, wrap-restraint stress, and 10 mg kg(-1) serotonin intraperitoneally, respectively. Two hours later, serum serotonin, corticotropin-releasing factor (CRF) and melatonin levels, and faecal output were recorded. Results showed that intraperitoneal melatonin increased faecal output, but this effect was abolished by luzindole. In wrap-restraint group, prior intraperitoneal melatonin at doses of 100 or 1000 microg kg(-1) significantly inhibited stress-induced defecation. This effect was associated with corresponding reductions in serum serotonin and CRF concentrations. In serotonin-treated group, serotonin-induced defecation was also inhibited by melatonin. In conclusion, melatonin exhibited an excitatory effect on bowel output in rats placed under resting state, while attenuated defecation in those subjected to wrap-restraint stress or serotonin treatment. The inhibitory effects of melatonin on stress-induced defecation may stem from its antagonistic effect on stress-induced enhancement of serotonin and CRF secretion. 10.1111/j.1365-2982.2005.00653.x
    Selected biomarkers as predictive tools in testing efficacy of melatonin and coenzyme Q on propionic acid - induced neurotoxicity in rodent model of autism. Al-Ghamdi Mashael,Al-Ayadhi Laila,El-Ansary Afaf BMC neuroscience BACKGROUND:Exposures to environmental toxins are now thought to contribute to the development of autism spectrum disorder. Propionic acid (PA) found as a metabolic product of gut bacteria has been reported to mimic/mediate the neurotoxic effects of autism. Results from animal studies may guide investigations on human populations toward identifying environmental contaminants that produce or drugs that protect from neurotoxicity. Forty-eight young male Western Albino rats were used in the present study. They were grouped into six equal groups 8 rats each. The first group received a neurotoxic dose of buffered PA (250 mg/Kg body weight/day for 3 consecutive days). The second group received only phosphate buffered saline (control group). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for one week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for one week prior to PA (protected groups). Heat shock protein70 (Hsp70), Gamma amino-butyric acid (GABA), serotonin, dopamine, oxytocin and interferon γ-inducible protein 16 together with Comet DNA assay were measured in brain tissues of the six studied groups. RESULTS:The obtained data showed that PA caused multiple signs of brain toxicity revealed in depletion of GABA, serotonin, and dopamine, are which important neurotransmitters that reflect brain function, interferon γ-inducible protein 16 and oxytocin. A high significant increase in tail length, tail DNA% damage and tail moment was reported indicating the genotoxic effect of PA. Administration of melatonin or coenzyme Q showed both protective and therapeutic effects on PA-treated rats demonstrated in a remarkable amelioration of most of the measured parameters. CONCLUSION:In conclusion, melatonin and coenzyme Q have potential protective and restorative effects against PA-induced brain injury, confirmed by improvement in biochemical markers and DNA double strand breaks. 10.1186/1471-2202-15-34
    Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo. Sommansson Anna,Nylander Olof,Sjöblom Markus Journal of pineal research Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of (51)Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier. 10.1111/jpi.12013
    Melatonin reduces ulcerative colitis-associated local and systemic damage in mice: investigation on possible mechanisms. Trivedi P P,Jena G B Digestive diseases and sciences BACKGROUND AND AIMS:Ulcerative colitis (UC) is a chronic gastrointestinal disorder. Substantial research reveals that melatonin has beneficial effects in ulcerative colitis both experimentally and clinically. We have previously reported that ulcerative colitis was associated with local and systemic damage in mice. The purpose of this study was to reveal the novel targets of melatonin in its protective mechanism against ulcerative colitis in mice. We also wished to determine whether or not melatonin protected against ulcerative colitis-induced systemic damage in mice. METHODS:Ulcerative colitis was induced in mice by use of 3% (w/v) dextran sulfate sodium for two cycles. One cycle comprised 7 days of DSS-treated water followed by 14 days of normal drinking water. Melatonin was administered at doses of 2, 4, or 8 mg/kg bw/day, po throughout. The effect of melatonin in mice with UC was evaluated by use of biochemical data, histological evaluation, comet and micronucleus assays, immunohistochemistry, and western blot analysis. RESULTS:The results indicated that melatonin treatment ameliorated the severity of ulcerative colitis by modulating a variety of molecular targets, for example nuclear factor kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, matrix metalloproteinase-9, and connective tissue growth factor. Further, ulcerative colitis increased gut permeability, plasma lipopolysaccharide level, systemic inflammation, and genotoxicity. Melatonin treatment led to mucosal healing and reduced ulcerative colitis-induced elevated gut permeability and reduced the plasma LPS level, systemic inflammation, and genotoxicity. CONCLUSION:Melatonin ameliorated ulcerative colitis-associated local and systemic damage in mice. 10.1007/s10620-013-2831-6
    Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Sommansson Anna,Saudi Wan Salman Wan,Nylander Olof,Sjöblom Markus American journal of physiology. Gastrointestinal and liver physiology Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a ~30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of ⁵¹Cr-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol- and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol- and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions. 10.1152/ajpgi.00074.2013
    Melatonin for the treatment of irritable bowel syndrome. Siah Kewin Tien Ho,Wong Reuben Kong Min,Ho Khek Yu World journal of gastroenterology Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain or discomfort, in combination with disturbed bowel habits in the absence of identifiable organic cause. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland and also large number by enterochromaffin cells of the digestive mucosa. Melatonin plays an important part in gastrointestinal physiology which includes regulation of gastrointestinal motility, local anti-inflammatory reaction as well as moderation of visceral sensation. Melatonin is commonly given orally. It is categorized by the United States Food and Drug Administration as a dietary supplement. Melatonin treatment has an extremely wide margin of safety though it may cause minor adverse effects, such as headache, rash and nightmares. Melatonin was touted as a potential effective candidate for IBS treatment. Putative role of melatonin in IBS treatment include analgesic effects, regulator of gastrointestinal motility and sensation to sleep promoter. Placebo-controlled studies in melatonin suffered from heterogeneity in methodology. Most studies utilized 3 mg at bedtime as the standard dose of trial. However, all studies had consistently showed improvement in abdominal pain, some showed improvement in quality of life of IBS patients. Melatonin is a relatively safe drug that possesses potential in treating IBS. Future studies should focus on melatonin effect on gut mobility as well as its central nervous system effect to elucidate its role in IBS patients. 10.3748/wjg.v20.i10.2492
    Effects of theabrownin on serum metabolites and gut microbiome in rats with a high-sugar diet. Yue Suijuan,Zhao Dan,Peng Chunxiu,Tan Chao,Wang Qiuping,Gong Jiashun Food & function Evidence has proven that the gut microbiota is an important environmental factor contributing to obesity by altering host energy harvest and storage. We performed a high-throughput 16S rDNA sequencing association study and serum metabolomics profiling in rats with a high-sugar diet. Our studies revealed that the high sugar diet reduced the diversity of cecal microorganisms, while the combination of theabrownin and the high sugar diet increased the diversity of cecal microorganisms and promoted reproduction of Alloprevotella, Coprostanoligenes_group, Bacteroides, Prevotellaceae_NK3B31_group, Desulfovibrio, Intestinimonas, Alistipes, Bifidobacterium, Phascolarctobacterium, Ruminococcaceae_UCG-010 and Staphylococcus. The combination also inhibited the growth of Lactobacillus, Prevotellaceae_Ga6A1_group and Tyzzerella. The Firmicutes/Bacteroidetes (F/B) ratio can be significantly reduced after the intervention of theabrownin in high sugar diet rats, and the reproduction of Bacteroides acidifaciens (BA) and Staphylococcus saprophyticus subsp. saprophyticus can be promoted. We found that the obesity-associated gut microbial species were linked to the changes in circulating metabolites. Serum levels of deoxycholic acid, cholic acid, 1H-indole-3-acetic acid, 3-indole acrylic acid and melatonin were negatively correlated with BA and Staphylococcus saprophyticus subsp. saprophyticus, but positively correlated with Lactobacillus murinus, Leptum and Gut_metagenome. 2-Hydroxy-6-methylpyridin-3-carboxylic acid, l-homoserine, and 1,7-dimethylxanthine were positively correlated with BA and Staphylococcus saprophyticus subsp. saprophyticus, but negatively correlated with Lactobacillus murinus, Leptum, and Gut_metagenome. In a high sugar diet mode, theabrownin reduced the body weight and triglycerides and improved insulin resistance mainly by targeting the reproduction of intestinal microorganisms such as BA, Staphylococcus saprophyticus subsp. saprophyticus, Lactobacillus murinus, Leptum, Gut_metagenome and so on. A strong correlation between cecal microorganisms and serum metabolites, obesity and insulin resistance was observed. Theabrownin has high potential in reducing the risk of cardiovascular diseases such as diabetes and obesity. 10.1039/c9fo01334b
    Fundamental issues related to the origin of melatonin and melatonin isomers during evolution: relation to their biological functions. Tan Dun-Xian,Zheng Xiaodong,Kong Jin,Manchester Lucien C,Hardeland Ruediger,Kim Seok Joong,Xu Xiaoying,Reiter Russel J International journal of molecular sciences Melatonin and melatonin isomers exist and/or coexist in living organisms including yeasts, bacteria and plants. The levels of melatonin isomers are significantly higher than that of melatonin in some plants and in several fermented products such as in wine and bread. Currently, there are no reports documenting the presence of melatonin isomers in vertebrates. From an evolutionary point of view, it is unlikely that melatonin isomers do not exist in vertebrates. On the other hand, large quantities of the microbial flora exist in the gut of the vertebrates. These microorganisms frequently exchange materials with the host. Melatonin isomers, which are produced by these organisms inevitably enter the host's system. The origins of melatonin and its isomers can be traced back to photosynthetic bacteria and other primitive unicellular organisms. Since some of these bacteria are believed to be the precursors of mitochondria and chloroplasts these cellular organelles may be the primary sites of melatonin production in animals or in plants, respectively. Phylogenic analysis based on its rate-limiting synthetic enzyme, serotonin N-acetyltransferase (SNAT), indicates its multiple origins during evolution. Therefore, it is likely that melatonin and its isomer are also present in the domain of archaea, which perhaps require these molecules to protect them against hostile environments including extremely high or low temperature. Evidence indicates that the initial and primary function of melatonin and its isomers was to serve as the first-line of defence against oxidative stress and all other functions were acquired during evolution either by the process of adoption or by the extension of its antioxidative capacity. 10.3390/ijms150915858
    Protective effect of melatonin-supported adipose-derived mesenchymal stem cells against small bowel ischemia-reperfusion injury in rat. Chang Chia-Lo,Sung Pei-Hsun,Sun Cheuk-Kwan,Chen Chih-Hung,Chiang Hsin-Ju,Huang Tien-Hung,Chen Yi-Ling,Zhen Yen-Yi,Chai Han-Tan,Chung Sheng-Ying,Tong Meng-Shen,Chang Hsueh-Wen,Chen Hong-Hwa,Yip Hon-Kan Journal of pineal research We tested the hypothesis that combined melatonin and autologous adipose-derived mesenchymal stem cells (ADMSC) was superior to either alone against small bowel ischemia-reperfusion (SBIR) injury induced by superior mesenteric artery clamping for 30 min followed by reperfusion for 72 hr. Male adult Sprague Dawley rats (n = 50) were equally categorized into sham-operated controls SC, SBIR, SBIR-ADMSC (1.0 × 10(6) intravenous and 1.0 × 10(6) intrajejunal injection), SBIR-melatonin (intraperitoneal 20 mg/kg at 30 min after SI ischemia and 50 mg/kg at 6 and 18 hr after SI reperfusion), and SBIR-ADMSC-melatonin groups. The results demonstrated that the circulating levels of TNF-α, MPO, LyG6+ cells, CD68+ cells, WBC count, and gut permeability were highest in SBIR and lowest in SC, significantly higher in SBIR-ADMSC group and further increased in SBIR-melatonin group than in the combined therapy group (all P < 0.001). The ischemic mucosal damage score, the protein expressions of inflammation (TNF-α, NF-κB, MMP-9, MPO, and iNOS), oxidative stress (NOX-1, NOX-2, and oxidized protein), apoptosis (APAF-1, mitochondrial Bax, cleaved caspase-3 and PARP), mitochondrial damage (cytosolic cytochrome C) and DNA damage (γ-H2AX) markers, as well as cellular expressions of proliferation (PCNA), apoptosis (caspase-3, TUNEL assay), and DNA damage (γ-H2AX) showed an identical pattern, whereas mitochondrial cytochrome C exhibited an opposite pattern compared to that of inflammation among all groups (all P < 0.001). Besides, antioxidant expressions at protein (NQO-1, GR, and GPx) and cellular (HO-1) levels progressively increased from SC to the combined treatment group (all P < 0.001). In conclusion, combined melatonin-ADMSC treatment offered additive beneficial effect against SBIR injury. 10.1111/jpi.12251
    Potential benefits of melatonin in organ transplantation: a review. Esteban-Zubero Eduardo,García-Gil Francisco Agustín,López-Pingarrón Laura,Alatorre-Jiménez Moisés Alejandro,Iñigo-Gil Pablo,Tan Dun-Xian,García José Joaquín,Reiter Russel J The Journal of endocrinology Organ transplantation is a useful therapeutic tool for patients with end-stage organ failure; however, graft rejection is a major obstacle in terms of a successful treatment. Rejection is usually a consequence of a complex immunological and nonimmunological antigen-independent cascade of events, including free radical-mediated ischemia-reperfusion injury (IRI). To reduce the frequency of this outcome, continuing improvements in the efficacy of antirejection drugs are a top priority to enhance the long-term survival of transplant recipients. Melatonin (N-acetyl-5-methoxytryptamine) is a powerful antioxidant and ant-inflammatory agent synthesized from the essential amino acid l-tryptophan; it is produced by the pineal gland as well as by many other organs including ovary, testes, bone marrow, gut, placenta, and liver. Melatonin has proven to be a potentially useful therapeutic tool in the reduction of graft rejection. Its benefits are based on its direct actions as a free radical scavenger as well as its indirect antioxidative actions in the stimulation of the cellular antioxidant defense system. Moreover, it has significant anti-inflammatory activity. Melatonin has been found to improve the beneficial effects of preservation fluids when they are enriched with the indoleamine. This article reviews the experimental evidence that melatonin is useful in reducing graft failure, especially in cardiac, bone, otolaryngology, ovarian, testicular, lung, pancreas, kidney, and liver transplantation. 10.1530/JOE-16-0117
    Melatonin heals the gut. Eliasson L Acta physiologica (Oxford, England) 10.1111/apha.12364
    Changes in serum cytokine levels, hepatic and intestinal morphology in aflatoxin B1-induced injury: modulatory roles of melatonin and flavonoid-rich fractions from Chromolena odorata. Akinrinmade Fadeyemi Joseph,Akinrinde Akinleye Stephen,Amid Adetayo Mycotoxin research Aflatoxins are known to produce chronic carcinogenic, mutagenic, and teratogenic effects, as well as acute inflammatory effects, especially in the gastrointestinal tract. The potentials of the flavonoid-rich extract from Chromolena odorata (FCO) and melatonin (a standard anti-oxidant and anti-inflammatory agent) against aflatoxin B1 (AFB1)-induced alterations in pro-inflammatory cytokine levels and morphology of liver and small intestines were evaluated in this study. We utilized Wistar albino rats (200-230 g) randomly divided into five groups made up of group A, control rats; group B, rats given AFB1 (2.5 mg/kg, intraperitoneal) twice on days 5 and 7; rats in groups C, D, and E were treated with melatonin (10 mg/kg, intraperitoneal) or oral doses of FCO1 (50 mg/kg) and FCO2 (100 mg/kg) for 7 days, respectively, along with AFB1 injection on days 5 and 7. Serum levels of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were determined using commercial ELISA kits and histopathological evaluation of the liver, duodenum, and ileum were also carried out. We observed significant elevation (p < 0.05) in serum IL-1β correlating with hemorrhages and leucocytic and lymphocytic infiltration in the liver and intestines as evidences of an acute inflammatory response to AFB1 administration. All treatments yielded significant reduction (p < 0.05) in IL-1β levels, although TNF-α levels were not significantly altered in all rats that received AFB1, irrespective of the treatments. Melatonin and FCO2 produced considerable protection of hepatic tissues, although melatonin was not quite effective in protecting the intestinal lesions. Our findings suggest a modulation of cytokine expression that may, in part, be responsible for the abilities of C. odorata or melatonin in amelioration of hepatic and intestinal lesions associated with aflatoxin B1 injury. 10.1007/s12550-016-0239-9
    Melatonin attenuates Co γ-ray-induced hematopoietic, immunological and gastrointestinal injuries in C57BL/6 male mice. Khan Shahanshah,Adhikari Jawahar Singh,Rizvi Moshahid Alam,Chaudhury Nabo Kumar Environmental toxicology Protection of hematopoietic, immunological, and gastrointestinal injuries from deleterious effects of ionizing radiation is prime rational for developing radioprotector. The objective of this study, therefore, was to evaluate the radioprotective potential of melatonin against damaging effects of radiation-induced hematopoietic, immunological, and gastrointestinal injuries in mice. C57BL/6 male mice were intraperitoneally administered with melatonin (50-150 mg/kg) 30 min prior to whole-body radiation exposure of 5 and 7.5 Gy using Co-teletherapy unit. Thirty-day survival against 7.5 Gy was monitored. Melatonin (100 mg/kg) pretreatment showed 100% survival against 7.5 Gy radiation dose. Melatonin pretreatment expanded femoral HPSCs, and inhibited spleenocyte DNA strands breaks and apoptosis in irradiated mice. At this time, it also protected radiation-induced loss of T cell sub-populations in spleen. In addition, melatonin pretreatment enhanced crypts regeneration and increased villi number and length in irradiated mice. Translocation of gut bacteria to spleen, liver and kidney were controlled in irradiated mice pretreated with melatonin. Radiation-induced gastrointestinal DNA strand breaks, lipid peroxidation, and expression of proapoptotic-p53, Bax, and antiapoptotic-Bcl-xL proteins were reversed in melatonin pretreated mice. This increase of Bcl-xL was associated with the decrease of Bax/Bcl-xL ratio. ABTS and DPPH radical assays revealed that melatonin treatment alleviated total antioxidant capacity in hematopoietic and gastrointestinal tissues. Present study demonstrated that melatonin pretreatment was able to prevent hematopoietic, immunological, and gastrointestinal radiation-induced injury, therefore, overcoming lethality in mice. These results suggest potential of melatonin in developing radioprotector for protection of bone marrow, spleen, and gastrointestine in planned radiation exposure scenarios including radiotherapy. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 501-518, 2017. 10.1002/tox.22254
    Melatonin: Pharmacology, Functions and Therapeutic Benefits. Tordjman Sylvie,Chokron Sylvie,Delorme Richard,Charrier Annaëlle,Bellissant Eric,Jaafari Nemat,Fougerou Claire Current neuropharmacology BACKGROUND:Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. METHODS:First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. RESULTS:The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. CONCLUSION:This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects. 10.2174/1570159X14666161228122115
    The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin. Reiter R J,Rosales-Corral S,Coto-Montes A,Boga J A,Tan D-X,Davis J M,Konturek P C,Konturek S J,Brzozowski T Journal of physiology and pharmacology : an official journal of the Polish Physiological Society The current scientific literature is replete with investigations providing information on the molecular mechanisms governing the regulation of circadian rhythms by neurons in the suprachiasmatic nucleus (SCN), the master circadian generator. Virtually every function in an organism changes in a highly regular manner during every 24-hour period. These rhythms are believed to be a consequence of the SCN, via neural and humoral means, regulating the intrinsic clocks that perhaps all cells in organisms possess. These rhythms optimize the functions of cells and thereby prevent or lower the incidence of pathologies. Since these cyclic events are essential for improved cellular physiology, it is imperative that the SCN provide the peripheral cellular oscillators with the appropriate time cues. Inasmuch as the 24-hour light:dark cycle is a primary input to the central circadian clock, it is obvious that disturbances in the photoperiodic environment, e.g., light exposure at night, would cause disruption in the function of the SCN which would then pass this inappropriate information to cells in the periphery. One circadian rhythm that transfers time of day information to the organism is the melatonin cycle which is always at low levels in the blood during the day and at high levels during darkness. With light exposure at night the amount of melatonin produced is compromised and this important rhythm is disturbed. Another important source of melatonin is the gastrointestinal tract (GIT) that also influences the circulating melatonin is the generation of this hormone by the entero-endocrine (EE) cells in the gut following ingestion of tryptophan-containing meal. The consequences of the altered melatonin cycle with the chronodisruption as well as the alterations of GIT melatonin that have been linked to a variety of pathologies, including those of the gastrointestinal tract.
    Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett's Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives. Majka Jolanta,Wierdak Mateusz,Brzozowska Iwona,Magierowski Marcin,Szlachcic Aleksandra,Wojcik Dagmara,Kwiecien Slawomir,Magierowska Katarzyna,Zagajewski Jacek,Brzozowski Tomasz International journal of molecular sciences Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed. 10.3390/ijms19072033
    Melatonin protects rats from radiotherapy-induced small intestine toxicity. Fernández-Gil Beatriz,Moneim Ahmed E Abdel,Ortiz Francisco,Shen Ying-Qiang,Soto-Mercado Viviana,Mendivil-Perez Miguel,Guerra-Librero Ana,Acuña-Castroviejo Darío,Molina-Navarro María M,García-Verdugo José M,Sayed Ramy K A,Florido Javier,Luna Juan D,López Luis Carlos,Escames Germaine PloS one Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients. 10.1371/journal.pone.0174474
    Aging, melatonin biosynthesis, and circadian clockworks in the gastrointestinal system of the laboratory mouse. Paulose Jiffin K,Cassone Charles V,Cassone Vincent M Physiological genomics The gastrointestinal (GI) system is vital in its capacities for nutrient and water uptake, immune function, metabolism and detoxification, and stem-cell derived regeneration. Of significance to human health are a myriad of GI disorders associated with aging that integrate with the circadian clock. Here we present data from three groups of mice: young (3 mo old), middle aged (12 mo old), and old aged (24 mo old). Small intestine and colon samples taken every 4 h under light-dark (LD) conditions were assayed for gene expression related to molecular circadian rhythmicity, transcription, cell signaling, and immune function. Transcripts related to melatonin biosynthesis and signaling, as well as melatonin content from stool, were also included, as GI melatonin and aging have been associated in contexts outside of the circadian clock. With respect to circadian genes, the data here are congruent with data from other peripheral tissues: age does not affect the rhythmic expression of core clock genes in the gut. The same can be said for several clock-controlled transcripts. In contrast, diurnal patterns in the expression of nitric oxide synthase 1 and of immune factors irak4 and interleukin-8 were observed in the colon of young mice that were lost in middle-aged and aged animals. Furthermore, the diurnal pattern of melatonin synthesis genes was altered by age, and stool melatonin levels showed significant decline between young mice and aged cohorts. These data expand the evidence for the persistence of the circadian clock throughout the aging process and highlight its importance to health. 10.1152/physiolgenomics.00095.2018
    Role of melatonin in sleep deprivation-induced intestinal barrier dysfunction in mice. Gao Ting,Wang Zixu,Dong Yulan,Cao Jing,Lin Rutao,Wang Xintong,Yu Zhengquan,Chen Yaoxing Journal of pineal research Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress. 10.1111/jpi.12574
    Melatonin: Roles in influenza, Covid-19, and other viral infections. Anderson George,Reiter Russel J Reviews in medical virology There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections. 10.1002/rmv.2109
    Melatonin plays a protective role in postburn rodent gut pathophysiology. Al-Ghoul Walid M,Abu-Shaqra Steven,Park Byeong Gyu,Fazal Nadeem International journal of biological sciences Melatonin is a possible protective agent in postburn gut pathophysiological dynamics. We investigated the role of endogenously-produced versus exogenously-administered melatonin in a major thermal injury rat model with well-characterized gut inflammatory complications. Our rationale is that understanding in vivo melatonin mechanisms in control and inflamed tissues will improve our understanding of its potential as a safe anti-inflammatory/antioxidant therapeutic alternative. Towards this end, we tested the hypothesis that the gut is both a source and a target for melatonin and that mesenteric melatonin plays an anti-inflammatory role following major thermal injury in rats with 3rd degree hot water scald over 30% TBSA. Our methods for assessing the gut as a source of melatonin included plasma melatonin ELISA measurements in systemic and mesenteric circulation as well as rtPCR measurement of jejunum and terminal ileum expression of the melatonin synthesizing enzymes arylalkylamine N-acetyltransferase (AA-NAT) and 5-hydroxyindole-O-methyltransferase (HIOMT) in sham versus day-3 postburn rats. Our melatonin ELISA results revealed that mesenteric circulation has much higher melatonin than systemic circulation and that both mesenteric and systemic melatonin levels are increased three days following major thermal injury. Our rtPCR results complemented the ELISA data in showing that the melatonin synthesizing enzymes AA-NAT and HIOMT are expressed in the ileum and jejunum and that this expression is increased three days following major thermal injury. Interestingly, the rtPCR data also revealed negative feedback by melatonin as exogenous melatonin supplementation at a dose of 7.43 mg (32 micromole/kg), but not 1.86 mg/kg (8 micromole/kg) drastically suppressed AA-NAT mRNA expression. Our methods also included an assessment of the gut as a target for melatonin utilizing computerized immunohistochemical measurements to quantify the effects of exogenous melatonin supplementation on postburn gut mucosa barrier inflammatory profiles. Here, our results revealed that daily postburn intraperitoneal melatonin administration at a dose of 1.86 mg/kg (8 micromole/kg) significantly suppressed both neutrophil infiltration and tyrosine nitrosylation as revealed by Gr-1 and nitrotyrosine immunohistochemistry, respectively. In conclusion, our results provide support for high mesenteric melatonin levels and dynamic de novo gut melatonin production, both of which increase endogenously in response to major thermal injury, but appear to fall short of abrogating the excessive postburn hyper-inflammation. Moreover, supplementation by exogenous melatonin significantly suppresses gut inflammation, thus confirming that melatonin is protective against postburn inflammation. 10.7150/ijbs.6.282
    Multiple Sclerosis, Gut Microbiota and Permeability: Role of Tryptophan Catabolites, Depression and the Driving Down of Local Melatonin. Rodriguez Moses,Wootla Bharath,Anderson George Current pharmaceutical design BACKGROUND:Alterations in gut microbiota, coupled to increased gut permeability are now widely recognized as having a role in the etiology, course and treatment of many medical conditions, including autoimmune and neurodegenerative disorders. METHODS:In this review, the role that such gut changes play over the course of multiple sclerosis (MS) is detailed. RESULTS:Given the wide array of biological factors and processes that have been shown to be altered in MS, including changes in the gut, this allows for a better integration of the diverse array of pathophysiological processes linked to MS. Such pathophysiological processes include increases in oxidative and nitrosative stress, pro-inflammatory immune responses, especially T helper (Th)17 cell proliferation and activation, tryptophan catabolites, pain, fatigue and increased levels of depression. By raising levels of immune activation, increased gut permeability and alterations in gut microbiota impact on all of these MS-associated processes. Alterations in the regulation of local melatonergic pathway activation is proposed to be an important hub for such pathophysiological processes in MS, allowing for the increased frequency of depression that may be prodromal in MS, both in the first episode as well as in relapses, to become more intimately associated with the etiology and course of MS. We propose this occurs by decreasing serotonin availability as a precursor for the melatoninergic pathways. CONCLUSION:Changes in the gut are evident in the early stages of MS, including in paediatric MS, and may interact with pro-inflammatory genetic susceptibility genes to drive the biological underpinnings of MS. Such a conceptualization of the biological underpinnings of MS also has treatment implications.
    Short chain fatty acids contribute to gut microbiota-induced promotion of colonic melatonin receptor expression. Wang B,Zhang L,Zhu S W,Zhang J D,Duan L P Journal of biological regulators and homeostatic agents Melatonin plays an important role in various gut functions through melatonin receptors. The gutmicrobiota/gut hormone axis has recently received increasing attention. However, the relationship betweenthe gut microbiota and melatonin receptors has not yet been evaluated. We aimed to determine the effect ofthe gut microbiota on colonic melatonin receptor expression in germ-free (GF) rats and to further explorethe potential mechanism in Caco-2 cells. In this study, GF rats were transplanted with fecal samples froma healthy human donor. Subsequently, 16S rRNA sequencing was performed to analyze the microbialcommunities. Colon tissue was collected for immunohistochemical analysis. The correlations betweenmelatonin receptor expression and the gut microbiota were assessed. Melatonin receptor expression inCaco-2 cells was detected by Western blot. We found that fecal microbiota transplantation significantlyincreased the expression of colonic melatonin receptors in GF rats. The amount of fecal Short chainfatty acids (SCFAs) was significantly higher in fecal microbiota transplantation (FMT) rats than in GFrats. SCFA-producing bacteria, such as Alistipes and Blautia, were positively correlated with colonicmelatonin receptor expression in FMT rats. Additionally, acetate and propionate significantly increasedmelatonin receptor-1 expression in Caco-2 cells. Therefore, the gut microbiota may promote melatoninreceptor expression, and the mechanism may involve the action of SCFAs. This finding may facilitate thedevelopment of new therapeutic treatments for various gastrointestinal disorders.
    The effects of antibiotics and melatonin on hepato-intestinal inflammation and gut microbial dysbiosis induced by a short-term high-fat diet consumption in rats. Yildirim Alper,Arabacı Tamer Sevil,Sahin Duran,Bagriacik Fatma,Kahraman Merve M,Onur Nilsu D,Cayirli Yusuf B,Cilingir Kaya Özlem T,Aksu Burak,Akdeniz Esra,Yuksel Meral,Çetinel Şule,Yeğen Berrak Ç The British journal of nutrition High-fat diet (HFD) consumption leads to metabolic disorders, gastrointestinal dysfunction and intestinal dysbiosis. Antibiotics also disrupt the composition of intestinal microbiota. The aim of the present study was to investigate the impact of a short-term feeding with HFD on oxidative status, enteric microbiota, intestinal motility and the effects of antibiotics and/or melatonin treatments on diet-induced hepato-intestinal dysfunction and inflammation. Male Sprague-Dawley rats were pair-fed with either standard chow or HFD (45 % fat) and were given tap water or melatonin (4 mg/kg per d) or melatonin plus antibiotics (ABX; neomycin, ampicillin, metronidazole; each 1 g/l) in drinking water for 2 weeks. On the 14th day, colonic motility was measured and the next day intestinal transit was assessed using charcoal propagation. Trunk blood, liver and intestine samples were removed for biochemical and histopathological evaluations, and faeces were collected for microbiota analysis. A 2-week HFD feeding increased blood glucose level and perirenal fat weight, induced low-level hepatic and intestinal inflammation, delayed intestinal transit, led to deterioration of epithelial tight junctions and overgrowth of colonic bacteria. Melatonin intake in HFD-fed rats reduced ileal inflammation, colonic motility and perirenal fat accumulation. ABX abolished increases in fat accumulation and blood glucose, reduced ileal oxidative damage, suppressed HFD-induced overgrowth in colonic bacteria, and reversed HFD-induced delay in intestinal transit; however, hepatic neutrophil accumulation, hepatic injury and dysfunction were further enhanced. In conclusion, the results demonstrate that even a short-term HFD ingestion results in hepato-intestinal inflammatory state and alterations in bacterial populations, which may be worsened with antibiotic intake, but alleviated by melatonin. 10.1017/S0007114519001466
    Melatonin prevents obesity through modulation of gut microbiota in mice. Xu Pengfei,Wang Jialin,Hong Fan,Wang Sheng,Jin Xi,Xue Tingting,Jia Li,Zhai Yonggong Journal of pineal research Excess weight and obesity are severe public health threats worldwide. Recent evidence demonstrates that gut microbiota dysbiosis contributes to obesity and its comorbidities. The body weight-reducing and energy balancing effects of melatonin have been reported in several studies, but to date, no investigations toward examining whether the beneficial effects of melatonin are associated with gut microbiota have been carried out. In this study, we show that melatonin reduces body weight, liver steatosis, and low-grade inflammation as well as improving insulin resistance in high fat diet (HFD)-fed mice. High-throughput pyrosequencing of the 16S rRNA demonstrated that melatonin treatment significantly changed the composition of the gut microbiota in mice fed an HFD. The richness and diversity of gut microbiota were notably decreased by melatonin. HFD feeding altered 69 operational taxonomic units (OTUs) compare with a normal chow diet (NCD) group, and melatonin supplementation reversed 14 OTUs to the same configuration than those present in the NCD group, thereby impacting various functions, in particular through its ability to decrease the Firmicutes-to-Bacteroidetes ratio and increase the abundance of mucin-degrading bacteria Akkermansia, which is associated with healthy mucosa. Taken together, our results suggest that melatonin may be used as a probiotic agent to reverse HFD-induced gut microbiota dysbiosis and help us to gain a better understanding of the mechanisms governing the various melatonin beneficial effects. 10.1111/jpi.12399
    Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high-fat diet-fed mice. Yin Jie,Li Yuying,Han Hui,Chen Shuai,Gao Jing,Liu Gang,Wu Xin,Deng Jinping,Yu Qifang,Huang Xingguo,Fang Rejun,Li Tiejun,Reiter Russel J,Zhang Dong,Zhu Congrui,Zhu Guoqiang,Ren Wenkai,Yin Yulong Journal of pineal research Melatonin has been shown to improve lipid metabolism and gut microbiota communities in animals and humans; however, it remains to know whether melatonin prevents obesity through gut microbiota. Here, we found that high-fat diet promoted the lipid accumulation and intestinal microbiota dysbiosis in mice, while oral melatonin supplementation alleviated the lipid accumulation and reversed gut microbiota dysbiosis, including the diversity of intestinal microbiota, relative abundances of Bacteroides and Alistipes, and functional profiling of microbial communities, such as energy metabolism, lipid metabolism, and carbohydrate metabolism. Interestingly, melatonin failed to alleviate the high-fat-induced lipid accumulation in antibiotic-treated mice; however, microbiota transplantation from melatonin-treated mice alleviated high-fat diet-induced lipid metabolic disorders. Notably, short-chain fatty acids were decreased in high-fat diet-fed mice, while melatonin treatment improved the production of acetic acid. Correlation analysis found a marked correlation between production of acetic acid and relative abundances of Bacteroides and Alistipes. Importantly, sodium acetate treatment also alleviated high-fat diet-induced lipid metabolic disorders. Taken together, our results suggest that melatonin improves lipid metabolism in high-fat diet-fed mice, and the potential mechanisms may be associated with reprogramming gut microbiota, especially, Bacteroides and Alistipes-mediated acetic acid production. Future studies are needed for patients with metabolic syndrome to fully understand melatonin's effects on body weight and lipid profiles and the potential mechanism of gut microbiota. 10.1111/jpi.12524
    Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells. Anderson George,Rodriguez Moses,Reiter Russel J International journal of molecular sciences Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate. 10.3390/ijms20215500
    Plasma metabolite abundances are associated with urinary enterolactone excretion in healthy participants on controlled diets. Miles Fayth L,Navarro Sandi L,Schwarz Yvonne,Gu Haiwei,Djukovic Danijel,Randolph Timothy W,Shojaie Ali,Kratz Mario,Hullar Meredith A J,Lampe Paul D,Neuhouser Marian L,Raftery Daniel,Lampe Johanna W Food & function Enterolignans, products of gut bacterial metabolism of plant lignans, have been associated with reduced risk of chronic diseases, but their association with other plasma metabolites is unknown. We examined plasma metabolite profiles according to urinary enterolignan excretion in a cross-sectional analysis using data from a randomized crossover, controlled feeding study. Eighty healthy adult males and females completed two 28-day feeding periods differing by glycemic load, refined carbohydrate, and fiber content. Lignan intake was calculated from food records using a polyphenol database. Targeted metabolomics was performed by LC-MS on plasma from fasting blood samples collected at the end of each feeding period. Enterolactone (ENL) and enterodiol, were measured in 24 h urine samples collected on the penultimate day of each study period using GC-MS. Linear mixed models were used to test the association between enterolignan excretion and metabolite abundances. Pathway analyses were conducted using the Global Test. Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple testing. Of the metabolites assayed, 121 were detected in all samples. ENL excretion was associated positively with plasma hippuric acid and melatonin, and inversely with epinephrine, creatine, glycochenodeoxycholate, and glyceraldehyde (P < 0.05). Hippuric acid only satisfied the FDR of q < 0.1. END excretion was associated with myristic acid and glycine (q < 0.5). Two of 57 pathways tested were associated significantly with ENL, ubiquinone and terpenoid-quinone biosynthesis, and inositol phosphate metabolism. These results suggest a potential role for ENL or ENL-metabolizing gut bacteria in regulating plasma metabolites. 10.1039/c7fo00684e
    Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria. Ney Denise M,Murali Sangita G,Stroup Bridget M,Nair Nivedita,Sawin Emily A,Rohr Fran,Levy Harvey L Molecular genetics and metabolism BACKGROUND:Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). METHODS:Subjects with PKU consumed a low-Phe diet combined with AA-MF or GMP-MF for 3weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-h urine samples. RESULTS:Intake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA-MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF. CONCLUSIONS:The Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU. This trial is registered at www.clinicaltrials.gov as NCT01428258. 10.1016/j.ymgme.2017.04.003
    A preliminary study of melatonin in irritable bowel syndrome. Saha Lekha,Malhotra Samir,Rana Surinder,Bhasin Deepak,Pandhi Promila Journal of clinical gastroenterology BACKGROUND AND AIMS:Melatonin is involved in the regulation of gut motility and sensation. We aimed to determine if melatonin was effective in improving bowel symptoms, extracolonic symptoms, and quality of life (QOL) in irritable bowel syndrome (IBS) patients. METHODS:Eighteen patients (aged 18 to 65 y; 6 females) were randomly assigned to receive either melatonin 3 mg (n=9) or matching placebo (n=9) at bed time for 8 weeks. The overall IBS scores, extracolonic IBS scores, QOL scores were assessed at 2, 4, 6, and 8 weeks during treatment and at 16, 24, and 48 weeks during follow up. RESULTS:Compared with placebo, melatonin taken for 8 weeks significantly improved overall IBS score (45% vs. 16.66%, P<0.05). The posttreatment overall extracolonic IBS score was significantly lower (49.16% to 13.88%, P<0.05) when compared with placebo group. The overall improvement in QOL score was 43.63% in melatonin group and 14.64% in placebo group that is statistically significant. CONCLUSIONS:The result of this study showed that melatonin has some beneficial role in IBS. Further studies using large number of patients may provide a definite answer. 10.1097/MCG.0b013e31802df84c
    The effects of melatonin on colonic transit time in normal controls and IBS patients. Lu Wei-Zhen,Song Guang-Hui,Gwee Kok-Ann,Ho Khek-Yu Digestive diseases and sciences OBJECTIVES:The role of melatonin in regulating gut motility in human subjects is not clear. The aim of this study was to investigate the effects of exogenous melatonin on colonic transit time (CTT) in healthy subjects and in patients with irritable bowel syndrome (IBS). METHODS:Colonic transit time was measured in 17 healthy controls using the radio-opaque, blue dye, and Bristol stool form score method before and after 30 days of melatonin treatment 3 mg daily. A double blind cross-over study aimed at measuring CTT was also performed in 17 matched IBS patients using the blue dye and Bristol stool form score methods. The patients were randomized and received either melatonin 3 mg or placebo daily for 8 weeks, followed by a 4-week washout, and then placebo or melatonin in the reverse order for a second 8-week period. RESULTS:The melatonin treatment of the control subjects caused an increase in CTT (mean+/-SD) from 27.4+/-10.5 to 37.4+/-23.8 h (P=0.04). Compared with the CTT of the controls (25.2+/-7.7), that of the constipation-predominant IBS patients appeared prolonged-65.2+/-33.3 h (P<0.01). The CTT did not change significantly in IBS patients after melatonin treatment. CONCLUSION:Melatonin may be a promising candidate for the future research of agents that can modulate bowel motility. 10.1007/s10620-008-0463-z
    Evaluation of melatonin effectiveness in the adjuvant treatment of ulcerative colitis. Chojnacki C,Wisniewska-Jarosinska M,Walecka-Kapica E,Klupinska G,Jaworek J,Chojnacki J Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Ulcerative colitis (UC) is a chronic disease characterized by the variable clinical picture with the inflammatory changes which can involve the whole colon or its distal part. The current treatments for UC are mostly nonspecific, not always effective, and often accompanied by serious side effects. Therefore, there is a considerable interest in finding alternative and more tolerable treatments for this serious disease. Several lines of experimental studies have shown that melatonin (MEL) regulates the extensive gut immune system and exerts antiinflammatory and immunomodulatory effects suggesting its beneficial action in UC by reducing and controlling inflammation. The study aimed at evaluating the effect of MEL on the activity of inflammatory process and sustaining the remission in patients with UC. It comprised 60 patients with left-sided UC, divided in two equal groups of 30 patients each (38 women and 22 men, aged 26-49 years), similar in both groups, who were in clinical remission for the last 12 months. Patients, during a next period of 12 months, were given mesalazine in daily doses 2 x 1.0 g and melatonin 5 mg daily at bedtime (group I) or placebo (group II). All the patients on MEL adjuvant treatment remained in remission during 12 months of observation with The Mayo Clinic Disease Activity Index (MCDAI) values 1.50±0.51 at the beginning and 2.75±1.86 points after 12 months. In the placebo group significantly higher MCDAI values were observed than in patients on MEL after 6, 9 and 12 months. At the inclusion MCDAI was 1.61±0.68 points and at the end of observation it reached the value of 5.10±2.22 points. In MEL group CRP level remained within the normal range during the course of the study (from 3.49±1.40 to 4.17±2.10 mg/dl). Whereas in the placebo group from the end of the third month the steady rise in CRP blood concentration was noted from 3.85±1.29 to 13.13±6.08 mg/dl. Parallelly to CRP rise a significant decrease in hemoglobin concentration in blood from 12.05±0.69 to 10.93±0.81 g/dl was observed in patients receiving placebo and the values significantly differed between the groups after 3 (p<0.05), 6, 9 and 12 months (p<0.01). The level of anxiety and the intensity of depression in patients on adjuvant MEL decreased during the study but there were no statistical differences noted between the groups. The results of the study allowed drawing the conclusion that adjuvant melatonin therapy may help in sustaining remission in patients with UC.
    Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Song G H,Leng P H,Gwee K A,Moochhala S M,Ho K Y Gut BACKGROUND AND AIMS:Melatonin, a sleep promoting agent, is involved in the regulation of gastrointestinal motility and sensation. We aimed to determine if melatonin was effective in improving bowel symptoms and sleep disturbances in irritable bowel syndrome (IBS) patients with sleep disturbance. METHODS:Forty IBS patients (aged 20-64 years; 24 female) with sleep disturbances were randomly assigned to receive either melatonin 3 mg (n = 20) or matching placebo (n = 20) at bedtime for two weeks. Immediately before and after the treatment, subjects completed bowel, sleep, and psychological questionnaires, and underwent rectal manometry and overnight polysomnography. RESULTS:Compared with placebo, melatonin taken for two weeks significantly decreased mean abdominal pain score (2.35 v 0.70; p<0.001) and increased mean rectal pain threshold (8.9 v -1.2 mm Hg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not significantly differ after treatment in both groups. Data from sleep questionnaires and polysomnography showed that the two week course of melatonin did not influence sleep parameters, including total sleep time, sleep latency, sleep efficiency, sleep onset latency, arousals, duration of stages 1-4, rapid eye movement (REM) sleep, and REM onset latency. CONCLUSIONS:Administration of melatonin 3 mg at bedtime for two weeks significantly attenuated abdominal pain and reduced rectal pain sensitivity without improvements in sleep disturbance or psychological distress. The findings suggest that the beneficial effects of melatonin on abdominal pain in IBS patients with sleep disturbances are independent of its action on sleep disturbances or psychological profiles. 10.1136/gut.2004.062034
    Melatonin and hydroxytyrosol-rich wines influence the generation of DNA oxidation catabolites linked to mutagenesis after the ingestion of three types of wine by healthy volunteers. Marhuenda Javier,Medina Sonia,Martínez-Hernández Pedro,Arina Simón,Zafrilla Pilar,Mulero Juana,Genieser Hans-Gottfried,Ferreres Federico,Gil-Izquierdo Ángel Food & function The Mediterranean Diet (MD) has been proved to exert benefits with respect to the maintenance of the redox balance, and wine is a representative component. Bioactive compounds such as polyphenols, melatonin and hydroxytyrosol act as radical scavengers and regulate the oxidation status of organisms. Oxidative damage to DNA yields a large range of end products. The repair of oxidized DNA entails the removal of the useless bases and/or nucleotides as well as the release of circulating nucleotides and nucleosides. The current research aims to elucidate, for the first time, the DNA protection against oxidative stress provided by three types of red wine - relating it to the intake of bioactive compounds - after the intake of a serving of red wine/must by 18 healthy female volunteers during a short term double-blind, crossover and placebo-controlled study. The novelty of our work is to describe the importance of melatonin and hydroxytyrosol and its metabolites (from gut microflora) in comparison with polyphenols in a red wine matrix (excluding colon derivatives). The results show that the intake of red wine and must secondarily reduces oxidative stress and carcinogenesis due to their content of homovanillic acid, as measured by decreases in the plasmatic concentration of 8-hydroxy-2'deoxyguanosine, 8-hydroxyguanine, and 8-nitroguanosine. Moreover, the intake of wine appears to exert vasodilatory effects, mediated by the action of nitric oxide and increased plasma guanosine-3'-5'-cyclic monophosphate plasmatic levels, owing to the intake of wines higher in melatonin and homovanillic acid. Therefore, the results obtained in the present study revealed that polyphenols, despite being the major compounds in the red wine matrix, are not the most effective compounds protecting DNA from oxidative attack. 10.1039/c6fo01246a
    Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization. Anderson George,Maes Michael,Berk Michael Advances in protein chemistry and structural biology A recent study--comparing those with depression, somatization, comorbid depression+somatization, and controls--showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G-protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway-both centrally and peripherally-driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (γ-mangostin), N-acetyl cysteine, and pamoic acid. 10.1016/B978-0-12-398314-5.00002-7
    Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans. Palego Lionella,Betti Laura,Rossi Alessandra,Giannaccini Gino Journal of amino acids L-Tryptophan is the unique protein amino acid (AA) bearing an indole ring: its biotransformation in living organisms contributes either to keeping this chemical group in cells and tissues or to breaking it, by generating in both cases a variety of bioactive molecules. Investigations on the biology of Trp highlight the pleiotropic effects of its small derivatives on homeostasis processes. In addition to protein turn-over, in humans the pathways of Trp indole derivatives cover the synthesis of the neurotransmitter/hormone serotonin (5-HT), the pineal gland melatonin (MLT), and the trace amine tryptamine. The breakdown of the Trp indole ring defines instead the "kynurenine shunt" which produces cell-response adapters as L-kynurenine, kynurenic and quinolinic acids, or the coenzyme nicotinamide adenine dinucleotide (NAD(+)). This review aims therefore at tracing a "map" of the main molecular effectors in human tryptophan (Trp) research, starting from the chemistry of this AA, dealing then with its biosphere distribution and nutritional value for humans, also focusing on some proteins responsible for its tissue-dependent uptake and biotransformation. We will thus underscore the role of Trp biochemistry in the pathogenesis of human complex diseases/syndromes primarily involving the gut, neuroimmunoendocrine/stress responses, and the CNS, supporting the use of -Omics approaches in this field. 10.1155/2016/8952520
    An Endogenous Tachykinergic NK2/NK3 Receptor Cascade System Controlling the Release of Serotonin from Colonic Mucosa. Kojima Shu-ichi,Tohei Atsushi,Ikeda Masashi,Anzai Naohiko Current neuropharmacology 5-Hydroxytryptamine (5-HT) released from colonic mucosal enterochromaffin (EC) cells is a major signaling molecule, which participates in the pathophysiological regulation of colonic functions in gut disorder including irritable bowel syndrome (IBS), but the endogenous modulator system for the 5-HT release is not yet well elucidated. Our in vitro studies in guinea-pig colon have indicated that the cascade pathway of neuronal tachykinergic NK3 receptors and NK2 receptors on peptide YY (PYY)-containing endocrine L cells represents an endogenous modulator system for 5-HT release from EC cells and that melatonin, endogenous tachykinins and PYY play important roles in modulation of the release of 5-HT from EC cells via the endogenous NK2/NK3 receptor cascade system. This review aims at examining the potential role of the endogenous tachykinergic NK2/NK3 receptor cascade system controlling the release of 5-HT from EC cells, with special attention being paid to the pathophysiology of gut disorders including IBS. 10.2174/1570159x13666150825220524
    The implications of non-linear biological oscillations on human electrophysiology for electrohypersensitivity (EHS) and multiple chemical sensitivity (MCS). Sage Cindy Reviews on environmental health The 'informational content' of Earth's electromagnetic signaling is like a set of operating instructions for human life. These environmental cues are dynamic and involve exquisitely low inputs (intensities) of critical frequencies with which all life on Earth evolved. Circadian and other temporal biological rhythms depend on these fluctuating electromagnetic inputs to direct gene expression, cell communication and metabolism, neural development, brainwave activity, neural synchrony, a diversity of immune functions, sleep and wake cycles, behavior and cognition. Oscillation is also a universal phenomenon, and biological systems of the heart, brain and gut are dependent on the cooperative actions of cells that function according to principles of non-linear, coupled biological oscillations for their synchrony. They are dependent on exquisitely timed cues from the environment at vanishingly small levels. Altered 'informational content' of environmental cues can swamp natural electromagnetic cues and result in dysregulation of normal biological rhythms that direct growth, development, metabolism and repair mechanisms. Pulsed electromagnetic fields (PEMF) and radiofrequency radiation (RFR) can have the devastating biological effects of disrupting homeostasis and desynchronizing normal biological rhythms that maintain health. Non-linear, weak field biological oscillations govern body electrophysiology, organize cell and tissue functions and maintain organ systems. Artificial bioelectrical interference can give false information (disruptive signaling) sufficient to affect critical pacemaker cells (of the heart, gut and brain) and desynchronize functions of these important cells that orchestrate function and maintain health. Chronic physiological stress undermines homeostasis whether it is chemically induced or electromagnetically induced (or both exposures are simultaneous contributors). This can eventually break down adaptive biological responses critical to health maintenance; and resilience can be compromised. Electrohypersensitivity can be caused by successive assaults on human bioelectrochemical dynamics from exogenous electromagnetic fields (EMF) and RFR or a single acute exposure. Once sensitized, further exposures are widely reported to cause reactivity to lower and lower intensities of EMF/RFR, at which point thousand-fold lower levels can cause adverse health impacts to the electrosensitive person. Electrohypersensitivity (EHS) can be a precursor to, or linked with, multiple chemical sensitivity (MCS) based on reports of individuals who first develop one condition, then rapidly develop the other. Similarity of chemical biomarkers is seen in both conditions [histamines, markers of oxidative stress, auto-antibodies, heat shock protein (HSP), melatonin markers and leakage of the blood-brain barrier]. Low intensity pulsed microwave activation of voltage-gated calcium channels (VGCCs) is postulated as a mechanism of action for non-thermal health effects. 10.1515/reveh-2015-0007
    How important is tryptophan in human health? Kałużna-Czaplińska Joanna,Gątarek Paulina,Chirumbolo Salvatore,Chartrand Max Stanley,Bjørklund Geir Critical reviews in food science and nutrition Tryptophan (Trp) is an amino acid and an essential component of the human diet. It plays a crucial role in many metabolic functions. Clinicians can use Trp levels in the course of diagnosing various metabolic disorders and the symptoms associated with those diseases. Furthermore, supplementation with this amino acid is considered in the treatment of depression and sleep disorders, mainly due to the Trp relationship with the synthesis of serotonin (5-HT) and melatonin. It is also used in helping to resolve cognitive disorders, anxiety, or neurodegenerative diseases. Reduced secretion of serotonin is associated with autism spectrum disorder, obesity, anorexia and bulimia nervosa, and other diseases presenting peripherals symptoms. The literature strongly suggests that Trp has a significant role in the correct functionality of the brain-gut axis and immunology. This information leads to the consideration of Trp as an essential dietary component due to its role in the serotonin pathway. A reduced availability of Trp in diet and nutraceutical supplementation should be considered with greater concern than one might expect. This paper constitutes a review of the more salient aspects gleaned from the current knowledge base about the role of Trp in diseases, associated nutritional disorders, and food science, in general. 10.1080/10408398.2017.1357534
    Tryptophan in health and disease. Comai Stefano,Bertazzo Antonella,Brughera Martina,Crotti Sara Advances in clinical chemistry Tryptophan (TRP), an essential amino acid in mammals, is involved in several physiological processes including neuronal function, immunity, and gut homeostasis. In humans, TRP is metabolized via the kynurenine and serotonin pathways, leading to the generation of biologically active compounds, such as serotonin, melatonin and niacin. In addition to endogenous TRP metabolism, resident gut microbiota also contributes to the production of specific TRP metabolites and indirectly influences host physiology. The variety of physiologic functions regulated by TRP reflects the complex pattern of diseases associated with altered homeostasis. Indeed, an imbalance in the synthesis of TRP metabolites has been associated with pathophysiologic mechanisms occurring in neurologic and psychiatric disorders, in chronic immune activation and in the immune escape of cancer. In this chapter, the role of TRP metabolism in health and disease is presented. Disorders involving the central nervous system, malignancy, inflammatory bowel and cardiovascular disease are discussed. 10.1016/bs.acc.2019.08.005
    Neuroendocrine control of photoperiodic changes in immune function. Weil Zachary M,Borniger Jeremy C,Cisse Yasmine M,Abi Salloum Bachir A,Nelson Randy J Frontiers in neuroendocrinology Seasonal variation in immune function putatively maximizes survival and reproductive success. Day length (photoperiod) is the most potent signal for time of year. Animals typically organize breeding, growth, and behavior to adapt to spatial and temporal niches. Outside the tropics individuals monitor photoperiod to support adaptations favoring survival and reproductive success. Changes in day length allow anticipation of seasonal changes in temperature and food availability that are critical for reproductive success. Immune function is typically bolstered during winter, whereas reproduction and growth are favored during summer. We provide an overview of how photoperiod influences neuronal function and melatonin secretion, how melatonin acts directly and indirectly to govern seasonal changes in immune function, and the manner by which other neuroendocrine effectors such as glucocorticoids, prolactin, thyroid, and sex steroid hormones modulate seasonal variations in immune function. Potential future research avenues include commensal gut microbiota and light pollution influences on photoperiodic responses. 10.1016/j.yfrne.2014.10.001
    Oxidative stress, antioxidants and intestinal calcium absorption. Diaz de Barboza Gabriela,Guizzardi Solange,Moine Luciana,Tolosa de Talamoni Nori World journal of gastroenterology The disequilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and their elimination by protective mechanisms leads to oxidative stress. Mitochondria are the main source of ROS as by-products of electron transport chain. Most of the time the intestine responds adequately against the oxidative stress, but with aging or under conditions that exacerbate the ROS and/or RNS production, the defenses are not enough and contribute to developing intestinal pathologies. The endogenous antioxidant defense system in gut includes glutathione (GSH) and GSH-dependent enzymes as major components. When the ROS and/or RNS production is exacerbated, oxidative stress occurs and the intestinal Ca absorption is inhibited. GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione and sodium deoxycholate inhibit the Ca transport from lumen to blood by alteration in the protein expression and/or activity of molecules involved in the Ca transcellular and paracellular pathways through mechanisms of oxidative stress, apoptosis and/or autophagy. Quercetin, melatonin, lithocholic and ursodeoxycholic acids block the effect of those drugs in experimental animals by their antioxidant, anti-apoptotic and/or anti-autophagic properties. Therefore, they may become drugs of choice for treatment of deteriorated intestinal Ca absorption under oxidant conditions such as aging, diabetes, gut inflammation and other intestinal disorders. 10.3748/wjg.v23.i16.2841
    A Perspective on the Safety of Supplemental Tryptophan Based on Its Metabolic Fates. Fernstrom John D The Journal of nutrition Over the past 50 y, tryptophan has been ingested in amounts well in excess of its dietary requirement. This use is based on extensive findings that ingesting tryptophan increases brain tryptophan concentrations, which stimulates the synthesis and release of the neurotransmitter serotonin, from which it is derived. Such increases in serotonin function may improve mood and sleep. However, tryptophan ingestion has other effects, such as increasing serotonin production in the gut, increasing serotonin concentrations in blood, stimulating the production of the hormone melatonin (a tryptophan metabolite), stimulating tryptophan metabolism via the kynurenine pathway, and possibly stimulating the production of tryptophan metabolites in the gut microbiome. Several of the kynurenine metabolites have actions on excitatory glutamate receptors in the gut and brain and on cells of the immune system. In addition, metabolites of tryptophan produced by colonic bacteria are reported to cause adverse effects in some species. This review examines each of these tryptophan pathways to determine if any of the metabolites increase after tryptophan ingestion, and if so, whether effects are seen on target body functions. In this regard, recent research suggests that it may be useful to examine kynurenine pathway metabolites and some microbial tryptophan metabolites to determine whether supplemental tryptophan consumption increases their concentrations in the body and amplifies their actions. 10.3945/jn.115.228643
    The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Huether G Experientia While the production of melatonin in higher vertebrates occurs in other organs and tissues besides the pineal, the contribution of extrapineal sites of melatonin synthesis such as the retina, the Harderian glands and the gut to circulating melatonin levels is still a matter of debate. The amount of melatonin found in the gastrointestinal tract is much higher than in any other organ including the pineal and the gut appears to make a significant contribution to circulating melatonin at least under certain conditions. The gut has been identified to be the major source of the elevated plasma concentrations of melatonin seen after tryptophan administration and of the changes of circulating melatonin level induced by the feeding regimen. Whereas the circadian and circannual fluctuations of the concentration of melatonin in the blood seem to be triggered by changes of the photoenvironment and its effect of pineal melatonin formation, basal daytime melatonin levels and the extent of their elevation at nighttime appear to be additionally controlled by nutritional factors, such as the amount and the composition of ingested food and therefore availability of tryptophan as a rate-limiting precursor of melatonin formation by the enterochromaffin cells of the gastrointestinal tract. 10.1007/bf01923948
    Melatonin and its receptors in the gastrointestinal tract. Lee P P,Pang S F Biological signals Melatonin and its synthesizing enzymes have been demonstrated in the gastrointestinal tract, suggesting the in situ biosynthesis of melatonin by the gut tissues. There appears to be a diurnal rhythm of melatonin in the gastrointestinal tissues of birds and rodents, with high levels in the dark period. Release of gut melatonin into the general circulation, however, was recorded following tryptophan treatment. Melatonin has direct gastrointestinal functions: it decreased serotonin-induced gut concentration, alleviated serotonin-induced reduction in gastric glandular mucosal blood flow, diminished epithelial sodium absorption, and inhibited the proliferation of jejunal epithelium. The use of a radiolabeled melatonin agonist, 2-[125I]iodomelatonin, has allowed the study of putative melatonin receptors in the gut of duck, mouse, chicken and human. The gastrointestinal 2-[125I]iodomelatonin binding to the duck, chicken and human was rapid, stable, saturable, reversible, specific and with a high affinity. The 2-[125I]iodomelatonin binding sites in the mouse gut were of a much lower affinity. In the duck gut, there was a significant variation in the densities of 2-[125I]iodomelatonin binding sites in different regions of the gut, with the following descending order of density: ileum, jejunum > duodenum, colon > cecum > esophagus. Autoradiographical studies have showed that the highest concentration of 2-[125I]iodomelatonin binding sites was in the villi of the small intestine and also in the mucosal layers of the cecum and colon. In contrast to the diurnal rhythms of 2-[125I]iodomelatonin binding sites reported in other tissues, 2-[125I]iodomelatonin binding in the duck gut showed no daily rhythm. The subcellular distribution of binding sites was in the following descending order: nuclear > microsomal > mitochondrial >> cytosolic fraction. These findings are consistent with a paracrine and/or hormonal action of melatonin in the gastrointestinal tract. 10.1159/000109491
    Melatonin and biological rhythms. Pévet P Biological signals and receptors Circadian and seasonal rhythms are a fundamental feature of all living organisms. The functional mechanism involved is built around internal biological clock(s) and the hormone melatonin (Mel) is one of its critical components. Although numerous other sources have been identified (retina, harderian gland, gut), in vertebrates Mel is primarily produced by the pineal gland during the dark period of the light-dark cycle. This rhythmic Mel is generated directly by circadian clock(s). The Mel rhythm is thus an important efferent hormonal signal from the clock. The periodic secretion of Mel might thus be used as a circadian mediator of a system that can 'read' the message. The duration of the nocturnal Mel production is directly proportional to the length of the dark period. It is through these changes in duration that the brain integrates the photoperiodic information. In essence, the Mel rhythm appears to be an endocrine code of the environmental light-dark cycle conveying photic information that is used by organisms for both circadian and seasonal temporal organization. The major question arising from this effect of Mel concerns it precise mechanism of action. From the data reported in the present minireview, it appears that the photoneuroendocrine mechanism is not fundamentally different in vertebrates at least as far as the role of Mel is concerned. 10.1159/000014640
    Neuroactive compounds in foods: Occurrence, mechanism and potential health effects. Yılmaz Cemile,Gökmen Vural Food research international (Ottawa, Ont.) Neuroactive compounds are synthesized by certain plants and microorganisms by undertaking different tasks, especially as a stress response. Most common neuroactive compounds in foods are gamma-aminobutyric acid (GABA), serotonin, melatonin, kynurenine, kynurenic acid, dopamine, norepinephrine, histamine, tryptamine, tyramine and β-phenylethylamine. Fermented foods contain some of these compounds, which can affect human health and mood. Moreover, food processing such as roasting and malting alter amount and profile of neuroactive compounds in foods. In addition to plant-origin and microbially-formed neuroactive compounds in foods, these substances are also formed by gut microbiota, which is the most attractive subject to assess the interaction between gut microbiota and mental health. The discovery of microbiota-gut-brain axis calls for the investigation of the effects of diet on the formation of neuroactive compounds in the gut. Furthermore, probiotics and prebiotics are indispensable elements for the understanding of the food-mood relationship. The focus of this comprehensive review is to investigate the neuroactive compounds found naturally in foods or formed during fermentation. Their formation pathways in humans, plants and microorganisms, potential health effects, effects of diet on the formation of microbial metabolites including neuroactive compounds in the gut are discussed throughout this review. Furthermore, the importance of gut-brain axis, probiotics and prebiotics are discussed. 10.1016/j.foodres.2019.108744
    Influence of photoperiod on hormones, behavior, and immune function. Walton James C,Weil Zachary M,Nelson Randy J Frontiers in neuroendocrinology Photoperiodism is the ability of plants and animals to measure environmental day length to ascertain time of year. Central to the evolution of photoperiodism in animals is the adaptive distribution of energetically challenging activities across the year to optimize reproductive fitness while balancing the energetic tradeoffs necessary for seasonally-appropriate survival strategies. The ability to accurately predict future events requires endogenous mechanisms to permit physiological anticipation of annual conditions. Day length provides a virtually noise free environmental signal to monitor and accurately predict time of the year. In mammals, melatonin provides the hormonal signal transducing day length. Duration of pineal melatonin is inversely related to day length and its secretion drives enduring changes in many physiological systems, including the HPA, HPG, and brain-gut axes, the autonomic nervous system, and the immune system. Thus, melatonin is the fulcrum mediating redistribution of energetic investment among physiological processes to maximize fitness and survival. 10.1016/j.yfrne.2010.12.003
    Timing of Breakfast, Lunch, and Dinner. Effects on Obesity and Metabolic Risk. Lopez-Minguez Jesus,Gómez-Abellán Purificación,Garaulet Marta Nutrients (1) Background: Eating is fundamental to survival. Animals choose when to eat depending on food availability. The timing of eating can synchronize different organs and tissues that are related to food digestion, absorption, or metabolism, such as the stomach, gut, liver, pancreas, or adipose tissue. Studies performed in experimental animal models suggest that food intake is a major external synchronizer of peripheral clocks. Therefore, the timing of eating may be decisive in fat accumulation and mobilization and affect the effectiveness of weight loss treatments. (2) Results: We will review multiple studies about the timing of the three main meals of the day, breakfast, lunch and dinner, and its potential impact on metabolism, glucose tolerance, and obesity-related factors. We will also delve into several mechanisms that may be implicated in the obesogenic effect of eating late. Conclusion: Unusual eating time can produce a disruption in the circadian system that might lead to unhealthy consequences. 10.3390/nu11112624
    Gastrointestinal melatonin: localization, function, and clinical relevance. Bubenik George A Digestive diseases and sciences The gastrointestinal tract of vertebrate species is a rich source of extrapineal melatonin. The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10-100 times and there is at least 400x more melatonin in the gastrointestinal tract than in the pineal gland. The gastrointestinal tract contributes significantly to circulating concentrations of melatonin, especially during the daytime and melatonin may serve as an endocrine, paracrine, or autocrine hormone influencing the regeneration and function of epithelium, enhancing the immune system of the gut, and reducing the tone of gastrointestinal muscles. As binding sites for melatonin exhibit circadian variation in various species, it has been hypothesized that some melatonin found in the gastrointestinal tract might be of pineal origin. Unlike the photoperiodically regulated production of melatonin in the pineal, the release of gastrointestinal melatonin seems to be related to the periodicity of food intake. Phylogenetically, melatonin and its binding sites were detected in the gastrointestinal tract of lower vertebrates, birds, and mammals. Melatonin was found also in large quantities in the embryonic tissue of the mammalian and avian gastrointestinal tract. Food intake and, paradoxically, also longterm food deprivation resulted in an increase of tissue and plasma concentrations of melatonin. Melatonin release may have a direct effect on many gastrointestinal tissues but may also well influence the digestive tract indirectly, via the central nervous system and the sympathetic and parasympathetic nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by an antioxidant action, reduction of secretion of hydrochloric acid, stimulation of the immune system, fostering epithelial regeneration, and increasing microcirculation. Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic. 10.1023/a:1020107915919
    Circadian rhythms, alcohol and gut interactions. Forsyth Christopher B,Voigt Robin M,Burgess Helen J,Swanson Garth R,Keshavarzian Ali Alcohol (Fayetteville, N.Y.) The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock(▵19) mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our data support circadian mechanisms for alcohol-induced gut leakiness that could provide new therapeutic targets for ALD. 10.1016/j.alcohol.2014.07.021
    Melatonin as an organoprotector in the stomach and the pancreas. Jaworek Jolanta,Brzozowski Tomasz,Konturek Stanislaw Jan Journal of pineal research Melatonin was thought to originate primarily from the pineal gland and to be secreted during the night, but recent studies revealed that gastrointestinal (GI) tract presents another, many times larger, source of melatonin that contributes significantly to the circulating concentration of this indole. Melatonin may exert a direct effect on GI tissues but its major influence on GI organs seems to occur indirectly, via the brain-gut axis including peripheral receptors, sensory afferent (vagal or sympathetic) pathways and central nervous system (CNS) acting on these organs via autonomic efferents and neuromediators. This article reviews and updates our experience with the fascinating molecule, as related to GI organs, with special focus on secretory activity of the stomach and pancreas and the maintenance of their tissue integrity. In addition to being released into the circulation, melatonin is also discharged into the gut lumen and this appears to be implicated in the postprandial stimulation of pancreatic enzyme secretion, mediated by melatonin-induced release of cholecystokinin, acting through entero-gastro-pancreatic reflexes. Although exerting certain differences in the mechanism of action on gastric and pancreatic secretory activities, melatonin derived from its precursor L-tryptophan, exhibits similar highly protective actions against the damage of both the stomach and the pancreas and accelerates the healing of chronic gastric ulcerations by stimulating the microcirculation and cooperating with arachidonate metabolites such as prostaglandins, with nitric oxide released from vascular endothelium, and/or sensory nerves and with their neuropeptides such as calcitonin gene related peptide. The beneficial effects of melatonin results in gastro- and pancreato-protection, prevents various forms of gastritis and pancreatitis through the activation of specific MT2-receptors and scavenges reactive oxygen species (ROS). Melatonin counteracts the increase in the ROS-induced lipid peroxidation and preserves, at least in part, the activity of key anti-oxidizing enzymes such as superoxide dismutase. It is proposed that melatonin should be considered as the agent exerting an important role in prevention of gastric and pancreatic damage and in accelerating healing of gastric ulcers. 10.1111/j.1600-079X.2004.00179.x
    Melatonin. Hardeland Rüdiger,Pandi-Perumal S R,Cardinali Daniel P The international journal of biochemistry & cell biology Melatonin, originally discovered as a hormone of the pineal gland, is produced by bacteria, protozoa, plants, fungi, invertebrates, and various extrapineal sites of vertebrates, including gut, skin, Harderian gland, and leukocytes. Biosynthetic pathways seem to be identical. Actions are pleiotropic, mediated by membrane and nuclear receptors, other binding sites or chemical interactions. Melatonin regulates the sleep/wake cycle, other circadian and seasonal rhythms, and acts as an immunostimulator and cytoprotective agent. Circulating melatonin is mostly 6-hydroxylated by hepatic P450 monooxygenases and excreted as 6-sulfatoxymelatonin. Pyrrole-ring cleavage is of higher importance in other tissues, especially the brain. The product, N1-acetyl-N2-formyl-5-methoxykynuramine, is formed by enzymatic, pseudoenzymatic, photocatalytic, and numerous free-radical reactions. Additional metabolites result from hydroxylation and nitrosation. The secondary metabolite, N1-acetyl-5-methoxykynuramine, supports mitochondrial function and downregulates cyclooxygenase 2. Antioxidative protection, safeguarding of mitochondrial electron flux, and in particular, neuroprotection, have been demonstrated in many experimental systems. Findings are encouraging to use melatonin as a sleep promoter and in preventing progression of neurodegenerative diseases. 10.1016/j.biocel.2005.08.020
    Melatonin in gastroprotection against stress-induced acute gastric lesions and in healing of chronic gastric ulcers. Konturek S J,Konturek P C,Brzozowski T Journal of physiology and pharmacology : an official journal of the Polish Physiological Society The degree of gastric damage following to exposition of the mucosa to noxious agents depends upon a balance between the factors promoting this damage and those activating the natural defense mechanisms. Recent findings, presented in this review, provide evidence that melatonin prevents the formation of acute gastric lesions induced by stress and accelerates healing of chronic gastric ulcers due to increase in the activity of nitric oxide (NO) synthase (NOS)-NO and cyclooxygenase (COX)-prostaglandin E(2) (PGE(2)) systems resulting in the increase of mucosal blood flow and mucosal integrity. Melatonin is produced and released into the circulation by the pineal gland and, in many times larger amounts, by the gastrointestinal tract. Due to its anti-inflammatory and anti-oxidant properties, melatonin may be one of the most efficient protective factors preventing the development of acute gastric damage and accelerating healing of chronic gastric ulcers probably due to reduction in proinflammatory cytokine production, scavenging of the radical oxygen species and activation of COX-PG and NOS-NO systems as well as stimulating the afferent sensory nerves in the brain-gut axis.
    Ghrelin and melatonin in the regulation of pancreatic exocrine secretion and maintaining of integrity. Jaworek J Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Ghrelin and melatonin are produced in the central nervous system and in the gastrointestinal tissues; ghrelin in the stomach, and melatonin - in the liver and in the intestine. Both ghrelin and melatonin have been reported to protect the gastric mucosa against acute lesions and to influence gastrointestinal motility and secretions, however the physiological significance of these peptides in the gastrointestinal tissues remains unknown. In spite of the presence of ghrelin and melatonin receptors in the pancreatic tissue little is known about the role of these peptides in the pancreas. It is very likely that both ghrelin and melatonin, which are released from the gastrointestinal tract in relation to food ingestion, could be implicated in the postprandial stimulation of pancreatic enzyme secretion though the activation of cholinergic entero-pancreatic reflex and CCK release. Our experimental studies have shown that exogenous melatonin, as well as this produced endogenously from its precursor; L-tryptophan, strongly stimulates pancreatic amylase secretion when given intraperitoneally, or into the gut lumen. Intraduodenal administration of ghrelin also increases pancreatic enzyme secretion. This was accompanied by significant increases of CCK plasma levels. Above pancreatostimulatory effects of luminal administration of melatonin or ghrelin were completely reversed by bilateral vagotomy, capsaicin deactivation of sensory nerves or pretreatment of the rats with CCK1 receptor antagonist; tarazepide. Our previous findings have revealed that melatonin, as well as its precursor; L-tryptophan, effectively protects the pancreas against the damage induced by caerulein overstimulation. The beneficial effects of melatonin and L-tryptophan on the pancreas have been related to the ability of melatonin to scavenge the radical oxygen species (ROS), to activate antioxidative enzymes and to modulate the cytokine production. It has been previously shown that systemic application of ghrelin attenuated acute pancreatitis activating the immune defense mechanisms. Our recent data demonstrate that ghrelin is able to prevent pancreatic inflammatory damage though the activation of central nervous mechanisms leading to the improvement of antioxidative properties of pancreatic tissue. The results of experimental studies indicated that melatonin and ghrelin could take a part in the protection of pancreatic tissue against the damage under physiological conditions.
    One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? Tan Dun-Xian,Manchester Lucien C,Terron Maria P,Flores Luis J,Reiter Russel J Journal of pineal research Melatonin is a highly conserved molecule. Its presence can be traced back to ancient photosynthetic prokaryotes. A primitive and primary function of melatonin is that it acts as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. The receptor-dependent functions of melatonin were subsequently acquired during evolution. In the current review, we focus on melatonin metabolism which includes the synthetic rate-limiting enzymes, synthetic sites, potential regulatory mechanisms, bioavailability in humans, mechanisms of breakdown and functions of its metabolites. Recent evidence indicates that the original melatonin metabolite may be N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) rather than its commonly measured urinary excretory product 6-hydroxymelatonin sulfate. Numerous pathways for AFMK formation have been identified both in vitro and in vivo. These include enzymatic and pseudo-enzymatic pathways, interactions with reactive oxygen species (ROS)/reactive nitrogen species (RNS) and with ultraviolet irradiation. AFMK is present in mammals including humans, and is the only detectable melatonin metabolite in unicellular organisms and metazoans. 6-hydroxymelatonin sulfate has not been observed in these low evolutionary-ranked organisms. This implies that AFMK evolved earlier in evolution than 6-hydroxymelatonin sulfate as a melatonin metabolite. Via the AFMK pathway, a single melatonin molecule is reported to scavenge up to 10 ROS/RNS. That the free radical scavenging capacity of melatonin extends to its secondary, tertiary and quaternary metabolites is now documented. It appears that melatonin's interaction with ROS/RNS is a prolonged process that involves many of its derivatives. The process by which melatonin and its metabolites successively scavenge ROS/RNS is referred as the free radical scavenging cascade. This cascade reaction is a novel property of melatonin and explains how it differs from other conventional antioxidants. This cascade reaction makes melatonin highly effective, even at low concentrations, in protecting organisms from oxidative stress. In accordance with its protective function, substantial amounts of melatonin are found in tissues and organs which are frequently exposed to the hostile environmental insults such as the gut and skin or organs which have high oxygen consumption such as the brain. In addition, melatonin production may be upregulated by low intensity stressors such as dietary restriction in rats and exercise in humans. Intensive oxidative stress results in a rapid drop of circulating melatonin levels. This melatonin decline is not related to its reduced synthesis but to its rapid consumption, i.e. circulating melatonin is rapidly metabolized by interaction with ROS/RNS induced by stress. Rapid melatonin consumption during elevated stress may serve as a protective mechanism of organisms in which melatonin is used as a first-line defensive molecule against oxidative damage. The oxidative status of organisms modifies melatonin metabolism. It has been reported that the higher the oxidative state, the more AFMK is produced. The ratio of AFMK and another melatonin metabolite, cyclic 3-hydroxymelatonin, may serve as an indicator of the level of oxidative stress in organisms. 10.1111/j.1600-079X.2006.00407.x
    Gut clock: implication of circadian rhythms in the gastrointestinal tract. Konturek P C,Brzozowski T,Konturek S J Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Circadian and seasonal rhythms are a fundamental feature of all living organisms and their organelles. Biological rhythms are responsible for daily food intake; the period of hunger and satiety is controlled by the central pacemaker, which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and communicates with tissues via bidirectional neuronal and humoral pathways. The molecular basis for circadian timing in the gastrointestinal tract (GIT) involves interlocking transcriptional/translational feedback loops which culminate in the rhythmic expression and activity of a set of clock genes and related hormones. Interestingly, it has been found that clocks in the GIT are responsible for the periodic activity (PA) of its various segments and transit along the GIT; they are localized in special interstitial cells, with unstable membrane potentials located between the longitudinal and circular muscle layers. The rhythm of slow waves is controlled in various segments of the GIT: in the stomach (about 3 cycles per min), in the duodenum (12 cycle per min), in the jejunum and ileum (from 7 to 10 cycles per min), and in the colon (12 cycles per min). The migrating motor complex (MMC) starts in the stomach and moves along the gut causing peristaltic contractions when the electrical activity spikes are superimposed on the slow waves. GIT hormones, such as motilin and ghrelin, are involved in the generation of MMCs, while others (gastrin, ghrelin, cholecystokinin, serotonin) are involved in the generation of spikes upon the slow waves, resulting in peristaltic or segmental contractions in the small (duodenum, jejunum ileum) and large bowel (colon). Additionally, melatonin, produced by neuro-endocrine cells of the GIT mucosa, plays an important role in the internal biological clock, related to food intake (hunger and satiety) and the myoelectric rhythm (produced primarily by the pineal gland during the dark period of the light-dark cycle). This appears to be an endocrine encoding of the environmental light-dark cycle, conveying photic information which is used by organisms for both circadian and seasonal organization. Motor and secretory activity, as well as the rhythm of cell proliferation in the GIT and liver, are subject to many circadian rhythms, mediated by autonomic cells and some enterohormones (gastrin, ghrelin and somatostatin). Disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD) or peptic ulcer disease. In addition, circadian disruption accelerates aging, and promotes tumorigenesis in the liver and GIT. Identification of the molecular basis and role of melatonin in the regulation of circadian rhythm allows researchers and clinicians to approach gastrointestinal diseases from a chronobiological perspective. Clinical studies have demonstrated that the administration of melatonin improves symptoms in patients with IBS and GERD. Moreover, our own studies indicate that melatonin significantly protects gastrointestinal mucosa, and has strong protective effects on the liver in patients with non-alcoholic steatohepatitis (NASH). Recently, it has been postulated that disruption of circadian regulation may lead to obesity by shifting food intake schedules. Future research should focus on the role of clock genes in the pathophysiology of the GIT and liver.
    Pathoetiology and pathophysiology of borderline personality: Role of prenatal factors, gut microbiome, mu- and kappa-opioid receptors in amygdala-PFC interactions. Anderson George Progress in neuro-psychopharmacology & biological psychiatry The pathoetiology and pathophysiology of borderline personality disorder (BPD) have been relatively under-explored. Consequently, no targetted pharmaceutical treatments or preventative interventions are available. The current article reviews the available data on the biological underpinnings of BPD, highlighting a role for early developmental processes, including prenatal stress and maternal dysbiosis, in BPD pathoetiology. Such factors are proposed to drive alterations in the infant's gut microbiome, in turn modulating amygdala development and the amygdala's two-way interactions with other brain regions. Alterations in opioidergic activity, including variations in the ratio of the mu-and kappa-opioid receptors seem a significant aspect of BPD pathophysiology, contributing to its comorbidities with depression, anxiety, impulsivity and addiction. Stress and dysphoria are commonly experienced in people classed with BPD. A growing body of data, across a host of medical conditions, indicate that stress and mood dysregulation may be intimately associated with gut dysbiosis and increased gut permeability, coupled to heightened levels of oxidative stress and immune-inflammatory activity. It urgently requires investigation as to the relevance of such gut changes in the course of BPD symptomatology. Accumulating data indicates that BPD symptom exacerbations may be linked to cyclical variations in estrogen, in turn decreasing serotonin and local melatonin synthesis, and thereby overlapping with the pathophysiology of migraine and endometriosis, which also have a heightened association with BPD. Future research directions and treatment implications are indicated. 10.1016/j.pnpbp.2019.109782
    Melatonin's role as a co-adjuvant treatment in colonic diseases: A review. Esteban-Zubero Eduardo,López-Pingarrón Laura,Alatorre-Jiménez Moisés Alejandro,Ochoa-Moneo Purificación,Buisac-Ramón Celia,Rivas-Jiménez Miguel,Castán-Ruiz Silvia,Antoñanzas-Lombarte Ángel,Tan Dun-Xian,García José Joaquín,Reiter Russel J Life sciences Melatonin is produced in the pineal gland as well as many other organs, including the enterochromaffin cells of the digestive mucosa. Melatonin is a powerful antioxidant that resists oxidative stress due to its capacity to directly scavenge reactive species, to modulate the antioxidant defense system by increasing the activities of antioxidant enzymes, and to stimulate the innate immune response through its direct and indirect actions. In addition, the dysregulation of the circadian system is observed to be related with alterations in colonic motility and cell disruptions due to the modifications of clock genes expression. In the gastrointestinal tract, the activities of melatonin are mediated by melatonin receptors (MT2), serotonin (5-HT), and cholecystokinin B (CCK2) receptors and via receptor-independent processes. The levels of melatonin in the gastrointestinal tract exceed by 10-100 times the blood concentrations. Also, there is an estimated 400 times more melatonin in the gut than in the pineal gland. Gut melatonin secretion is suggested to be influenced by the food intake. Low dose melatonin treatment accelerates intestinal transit time whereas high doses may decrease gut motility. Melatonin has been studied as a co-adjuvant treatment in several gastrointestinal diseases including irritable bowel syndrome (IBS), constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), Crohn's disease, ulcerative colitis, and necrotizing enterocolitis. The purpose of this review is to provide information regarding the potential benefits of melatonin as a co-adjuvant treatment in gastrointestinal diseases, especially IBS, Crohn's disease, ulcerative colitis, and necrotizing enterocolitis. 10.1016/j.lfs.2016.11.031
    Impact of Melatonin on Skeletal Muscle and Exercise. Stacchiotti Alessandra,Favero Gaia,Rodella Luigi Fabrizio Cells Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut-muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of melatonin as a safe nutraceutical that limits skeletal muscle frailty and prolongs physical performance. 10.3390/cells9020288
    Endometriosis Pathoetiology and Pathophysiology: Roles of Vitamin A, Estrogen, Immunity, Adipocytes, Gut Microbiome and Melatonergic Pathway on Mitochondria Regulation. Anderson George Biomolecular concepts Endometriosis is a common, often painful, condition that has significant implications for a woman's fertility. Classically, endometriosis has been conceptualized as a local estrogen-mediated uterine condition driven by retrograde menstruation. However, recent work suggests that endometriosis may be a systemic condition modulated, if not driven, by prenatal processes. Although a diverse array of factors have been associated with endometriosis pathophysiology, recent data indicate that the low body mass index and decreased adipogenesis may be indicative of an early developmental etiology with alterations in metabolic function crucial to endometriosis pathoetiology. The present article reviews the data on the pathoetiology and pathophysiology of endometriosis, suggesting key roles for alterations in mitochondria functioning across a number of cell types and body systems, including the immune system and gut microbiome. These changes are importantly regulated by decreases in vitamin A and its retinoic acid metabolites as well as increases in mitochondria estrogen receptor-beta and the N-acetylserotonin/melatonin ratio across development. This has treatment and future research implications for this still poorly managed condition, as well as for the association of endometriosis with a number of cancers. 10.1515/bmc-2019-0017
    Immune-pineal axis: nuclear factor κB (NF-kB) mediates the shift in the melatonin source from pinealocytes to immune competent cells. Markus Regina P,Cecon Erika,Pires-Lapa Marco Antonio International journal of molecular sciences Pineal gland melatonin is the darkness hormone, while extra-pineal melatonin produced by the gonads, gut, retina, and immune competent cells acts as a paracrine or autocrine mediator. The well-known immunomodulatory effect of melatonin is observed either as an endocrine, a paracrine or an autocrine response. In mammals, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) blocks noradrenaline-induced melatonin synthesis in pinealocytes, which induces melatonin synthesis in macrophages. In addition, melatonin reduces NF-κB activation in pinealocytes and immune competent cells. Therefore, pathogen- or danger-associated molecular patterns transiently switch the synthesis of melatonin from pinealocytes to immune competent cells, and as the response progresses melatonin inhibition of NF-κB activity leads these cells to a more quiescent state. The opposite effect of NF-κB in pinealocytes and immune competent cells is due to different NF-κB dimers recruited in each phase of the defense response. This coordinated shift of the source of melatonin driven by NF-κB is called the immune-pineal axis. Finally, we discuss how this concept might be relevant to a better understanding of pathological conditions with impaired melatonin rhythms and hope it opens new horizons for the research of side effects of melatonin-based therapies. 10.3390/ijms140610979
    Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: A therapeutic target to reduce intestinal inflammation. Ma Ning,Zhang Jie,Reiter Russel J,Ma Xi Medicinal research reviews Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co-adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T-cell differentiation, intervening T/B cell interaction and attenuating the production of pro-inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid-β peptides via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune-pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF-κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut-microbiome-immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases. 10.1002/med.21628
    The Role of Prenatal Melatonin in the Regulation of Childhood Obesity. Ivanov Dmitry O,Evsyukova Inna I,Mazzoccoli Gianluigi,Anderson George,Polyakova Victoria O,Kvetnoy Igor M,Carbone Annalucia,Nasyrov Ruslan A Biology There is a growing awareness that pregnancy can set the foundations for an array of diverse medical conditions in the offspring, including obesity. A wide assortment of factors, including genetic, epigenetic, lifestyle, and diet can influence foetal outcomes. This article reviews the role of melatonin in the prenatal modulation of offspring obesity. A growing number of studies show that many prenatal risk factors for poor foetal metabolic outcomes, including gestational diabetes and night-shift work, are associated with a decrease in pineal gland-derived melatonin and associated alterations in the circadian rhythm. An important aspect of circadian melatonin's effects is mediated via the circadian gene, BMAL1, including in the regulation of mitochondrial metabolism and the mitochondrial melatoninergic pathway. Alterations in the regulation of mitochondrial metabolic shifts between glycolysis and oxidative phosphorylation in immune and glia cells seem crucial to a host of human medical conditions, including in the development of obesity and the association of obesity with the risk of other medical conditions. The gut microbiome is another important hub in the pathoetiology and pathophysiology of many medical conditions, with negative consequences mediated by a decrease in the short-chain fatty acid, butyrate. The effects of butyrate are partly mediated via an increase in the melatoninergic pathway, indicating interactions of the gut microbiome with melatonin. Some of the effects of melatonin seem mediated via the alpha 7 nicotinic receptor, whilst both melatonin and butyrate may regulate obesity through the opioidergic system. Oxytocin, a recently recognized inhibitor of obesity, may also be acting via the opioidergic system. The early developmental regulation of these processes and factors by melatonin are crucial to the development of obesity and many diverse comorbidities. 10.3390/biology9040072
    Gut Permeability and Microbiota in Parkinson's Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatonergic Pathways. Anderson George,Seo Moonsang,Berk Michael,Carvalho Andre F,Maes Michael Current pharmaceutical design BACKGROUND:Increased gut permeability (leaky gut) and alterations in gut microbiota are now widely accepted as relevant to the etiology, course and treatment of many neuropsychiatric disorders, including Parkinson disease (PD). Although a wide array of data on the biological underpinnings of PD has not yet been linked to such gut-associated changes, increased gut permeability and dysregulated microbiota alter many pathways germane to PD. METHODS:In this article we review and integrate these wider biological changes in PD, including increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways. RESULTS:These wider biological changes in PD are compatible with alterations in gut permeability and changes in gut microbiota. By driving tryptophan down the kynurenine pathway, pro-inflammatory cytokines and chronic stress-driven activation of the hypothalamic-pituitary-adrenal axis decrease the availability of serotonin as a precursor for activation of the melatonergic pathways. CONCLUSION:Decreased local melatonin synthesis in glia, gut, neuronal and immune cells is likely to be important to the etiology, course and management of PD.
    Beyond the thin ideal: Development and validation of the Fit Ideal Internalization Test (FIIT) for women. Uhlmann Laura R,Donovan Caroline L,Zimmer-Gembeck Melanie J Psychological assessment [Correction Notice: An Erratum for this article was reported in Vol 32(2) of (see record 2020-04120-001). In the article, there are two errors in the Method section for Study 2. First, in the "Body dissatisfaction" subsection, the range of total scores for the Body-Image Ideals Questionnaire was incorrectly listed as being "between 0 and 99." The correct range is from - 3 to 9. Second, in the "Dieting and bulimia" subsection, the reference for the Eating Attitudes Test (EAT-26) was incorrectly cited as "Garner et al., 1983." Garner, D. M., Olmsted, M. P., Bohr, Y., & Garfinkel, P. E. (1982). The Eating Attitudes Test: Psychometric features and clinical correlates. , 12, 871-878. http://dx.doi .org/10.1017/s0033291700049163.] Females are at risk for body image and eating disturbance when they internalize societally prescribed standards of Western beauty. With respect to messages to be thin or muscular, numerous scales are available that measure internalization. However, many women are now receiving messages about the desirability of being both thin and toned, yet no self-report measure of internalization of a fit female body ideal exists. Our aim was to develop a multidimensional tool (i.e., the Fit Ideal Internalization Test; FIIT) useful for assessing women's internalization of the fit ideal (i.e., a lean and toned body ideal). Three studies were conducted, recruiting independent groups of women attending university to complete surveys. In Study 1 ( = 300, age 16-51), women completed the FIIT items, and a 3-factor structure of fit idealization (8 items), fit overvaluation (8 items), and fit behavioral drive (4 items) was established through exploratory factor analysis. Also, items loading highly on each of the factors had good interitem correlations. In Study 2 ( = 354, age 16-63), women completed the 20-item FIIT and validation measures. The 3-factor structure of the FIIT was confirmed, and findings supported convergent, discriminant, and incremental validity of the FIIT subscale scores (and a total score). In Study 3 ( = 67, age 17-50), the 2-week test-retest reliability of the FIIT scores was high. Overall, the 3 FIIT subscales are related but also distinct domains of fit ideal internalization that conform to theory and may be used as individual subscales or potentially as a composite score. (PsycINFO Database Record (c) 2020 APA, all rights reserved). 10.1037/pas0000773
    Gut Melatonin in Vertebrates: Chronobiology and Physiology. Mukherjee Sourav,Maitra Saumen Kumar Frontiers in endocrinology 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. 10.3389/fendo.2015.00112
    Breastfeeding and the gut-brain axis: is there a role for melatonin? Anderson George,Vaillancourt Cathy,Maes Michael,Reiter Russel J Biomolecular concepts The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions. 10.1515/bmc-2017-0009
    Latitude, Vitamin D, Melatonin, and Gut Microbiota Act in Concert to Initiate Multiple Sclerosis: A New Mechanistic Pathway. Ghareghani Majid,Reiter Russel J,Zibara Kazem,Farhadi Naser Frontiers in immunology Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease. Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels. Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system. While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion. On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability. The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood. LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland. This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS. We also propose a new mechanistic pathway for the initiation of MS. 10.3389/fimmu.2018.02484