Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a potent endogenous antioxidant and free radical scavenger that has attracted much attention as a consequence of its multiple biological functions. In addition to other physiological properties, it has clear antiproliferative activity in several types of cancer cell. The concentration of melatonin necessary to inhibit cell growth is much higher than its blood physiological concentrations in some tumor types. For years its indolic nature has impeded proper monitoring, by molecular or immunological techniques, of its uptake by cancer cells. In this work we developed a simple, rapid, and validated analytical method for detection and quantification of MEL inside normal and cancer cells. For this purpose we performed high-performance liquid chromatographic analysis after liquid-liquid extraction of the indole from biological samples. The method was validated, and the correlation coefficient for amounts from 0.12<em>5</em> to 1.2<em>5</em> microg was higher than 0.999, with a range of recovery near 100%. Precision was evaluated as repeatability, and for intermediate precision, the relative standard deviation was less than <em>5</em>%. The method was used to study the stability of the indole in solution and to determine intracellular melatonin concentrations in normal (P<em>N</em>T1A) and several cancer (L<em>N</em>CaP, DU-14<em>5</em>, PC-3) prostate cell lines. Intracellular LOQ/LOD were 7.23/2.83, 23.17/9.07, 4.03/1.83, and 6.<em>5</em>1/2.<em>5</em>3 nmol L(-1), or 1.82/4.66, 0.<em>5</em>6/1.4<em>5</em>, 3.26/8.34, and 2.02/<em>5</em>.17 attogram in each cell in P<em>N</em>T1A, L<em>N</em>CaP, DU14<em>5</em>, and PC-3 cells, respectively. Because there was no information about intracellular levels of melatonin inside normal or tumor prostate cells after treatment with the indole, nor a relationship between its antiproliferative activity and its intracellular concentration, this is the first time that, by using an analytical method combined with measurement of cellular volume by flow cytometry, the intracellular concentration of MEL has been estimated. Also, data obtained here explain why the antiproliferative properties of MEL vary in different cell types. This is, moreover, the first time that by increasing the intracellular concentration of melatonin, its antitumor properties have been promoted in prostate cancer cells. This process can be monitored by the method developed here.

Melatonin binding sites in the goldfish brain were characterized by radioreceptor assay using 2-[12<em>5</em>I]iodomelatonin as the radioligand. Specific binding of 2-[12<em>5</em>I]iodomelatonin was rapid, stable, saturable and reversible. Saturation experiments demonstrated that 2-[12<em>5</em>I]iodomelatonin binds to a single class of receptor site with an affinity constant (Kd) of 29.8 +/- 0.7 pM and a total binding capacity (Bmax) of 11.47 +/- 0.33 fmol/mg protein at mid-light. At mid-dark, the Bmax value decreased significantly to 7.90 +/- 0.23 fmol/mg protein (P < 0.01) with no significant variation in the Kd value (33.8 +/- 1.<em>5</em> pM). Competition experiments revealed the following order of pharmacological affinities: 2-iodomelatonin>> melatonin>> 6-hydroxymelatonin>> <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptamine>> <em>5</em>-<em>methoxytryptamine</em>>> <em>5</em>-methoxytryptophol>> <em>5</em>-methoxyindole-3-acetic acid. <em>5</em>-Hydroxytryptamine, <em>5</em>-hydroxytryptophol, <em>5</em>-hydroxyindole-3-acetic acid, norepinephrine and <em>acetyl</em>choline exhibited no inhibition. Subcellular distribution of melatonin binding sites was demonstrated to be greatest in the P2 and P3 fractions as compared with the P1 fraction. Localization of melatonin binding sites in discrete brain areas was determined to be highest in the optic tectum-thalamus and hypothalamus, intermediate in the telencephalon, cerebellum and medulla oblongata, and lowest in the olfactory bulbs and pituitary gland. These results suggest that characteristics of melatonin receptors are highly conserved during evolution and that in this species melatonin plays neuromodulatory roles in the central nervous system through specific receptors.

At a temperature of 1<em>5</em> degrees C, Gonyaulax polyedra responds to short days (light less than or equal to 10 h) by transition to the stage of a resting cyst. At 20 degrees C, even an light:dark (LD) cycle of 6:18 is incapable of inducing this process. In otherwise cyst-inducing conditions (1<em>5</em> degrees C; 10 h of light per day), an interruption of the scotophase by 2 h of light (LDLD 8:2:2:12 or 2:2:8:12) prevented encystment. Cyst induction is, therefore, initiated by a photoperiodic mechanism rather than by light deficiency. In Gonyaulax, photoperiodism may be mediated by the action of indoleamines. Melatonin, which exhibits a circadian rhythmicity in this organism, leads to encystment when given 1 h before lights-off in LD 11:13 at 1<em>5</em> degrees C, i.e., under otherwise noninducing conditions. Again, at 20 degrees C, melatonin is inefficient. Some analogues of melatonin, in particular, <em>5</em>-<em>methoxytryptamine</em> and <em>N</em>,<em>N</em>-dimethyl-<em>5</em>-<em>methoxytryptamine</em>, and, at high concentrations, their respective precursors, serotonin and bufotenin, are capable of inducing cyst formation at 20 degrees C and in LD 12:12, whereas <em>N</em>-<em>acetyl</em>-serotonin does not show this effect.

Spermatogenesis, an intricate process occurring in the testis, is responsible for ongoing production of spermatozoa and thus the cornerstone of lifelong male fertility. In the testis, spermatogenesis occurs optimally at a temperature 2-4°C lower than that of the core body. Increased scrotal temperature generates testicular heat stress and later causes testicular atrophy and spermatogenic arrest, resulting in a lower sperm yield and therefore impaired male fertility. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a small neuro-hormone synthesized and secreted by the pineal gland and the testis, is widely known as a potent free-radical scavenger; it has been reported that melatonin protects the testis against inflammation and reactive oxygen species generation thereby playing anti-inflammatory, -oxidative and -apoptotic roles in the testis. <em>N</em>evertheless, the role of melatonin in the testicular response to heat stress has not been studied. Here, by employing a mouse model of testicular hyperthermia, we systematically investigated the testicular response to heat stress as well as the occurrence of autophagy, apoptosis and oxidative stress in the testis. Importantly, we found that pre-treatment with melatonin attenuated heat-induced apoptosis and oxidative stress in the testis. Also, post-treatment with melatonin promoted recovery of the testes from heat-induced damage, probably by maintaining the integrity of the Sertoli cell tight-junction. Thus, we for the first time provide the proof-of-concept that melatonin can protect the testis against heat-induced damage, supporting the potential future use of melatonin as a therapeutic drug in men for sub/infertility incurred by various testicular hyperthermia factors.

<em>N</em>ew in vitro studies have demonstrated that <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> (Melatonin) has cytotoxic and apoptotic effects on various cell types although most of the previous investigations document that it is a potent antioxidant. However, the precise molecular mechanism(s) of its effects are not fully elucidated. In this study, we examined dose-dependent cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of melatonin in human epidermoid carcinoma cells (A-431) and human normal skin fibroblastic cells (CCD-1079Sk). The cells were incubated with different doses of melatonin (0.031-<em>5</em> mM) for 24 h. Cell viability was assessed based on luminometric ATP cell viability assay. Intracellular ROS was detected using 2,7-dichlorodihydrofluorescein-diacetate (H2DCF-DA) fluorescent probes. Genotoxicity was evaluated by alkaline single cell gel electrophoresis assay (Comet Assay). Apoptosis was evaluated by western blotting, DAPI staining, acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide double staining methods Mitochondrial membrane potentials were measured by flow cytometry. Although lower doses of melatonin (0.031-0.06 mM) increased cell proliferation and decreased ROS generation, higher doses (0.12<em>5</em>-<em>5</em> mM) markedly inhibited the cell viability, induced D<em>N</em>A damage, apoptosis and ROS generation. Cytotoxic, genotoxic, apoptotic and ROS generating effects were significantly higher in cancer cells than those observed in normal cells. Melatonin-induced cell death, and ROS generating activity were effectively inhibited by <em>N</em>-<em>acetyl</em>-l-cysteine (<em>N</em>AC) In conclusion, at low doses, melatonin has proliferative effects on both cancer and normal cells, whereas high concentrations have cytotoxic effects. Cytotoxic, genotoxic and apoptotic effects at higher doses of melatonin may be due to its ROS production capacity.

Mammalian Target of Rapamycin (mTOR) signaling pathway has important roles in the regulation of puberty onset, gonadotropin secretion, follicular development and ovulation. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a lipophilic hormone has multiple functions in regulating the fertility. Recent studies have shown that melatonin affected the number or maturation of follicles in the ovary. The aim of this study was to investigate the effects of melatonin on mTOR expression and quantity of follicle in rat ovary. In the present study, a total of 4<em>5</em> female rats were randomly divided into three groups. Group 1; Control (C), Group 2: Vehicle (V) and Group 3; Melatonin (M). Melatonin was administered intraperitoneally at a dose of <em>5</em>0 mg/kg/day for 30 days in Melatonin group. The effects of Melatonin on the expression of mTOR and downstream components were determined by Western Blot and Reverse Transcriptase PCR analysis. Upon Western Blot and RT-PCR evaluations, we detected higher expression and activation of mTOR, P70S6K, PKCalpha, PC<em>N</em>A and higher numbers of primordial follicles in melatonin group compared with V and C group. In addition to this results, melatonin decreased oxidative stress markers, such as MDA, on the contrary, levels of antioxidative markers, such as CAT and GPx, were increased by melatonin in rat ovary. This study indicated that melatonin may have a significant protective effect on primordial follicles and increase the expression of mTOR and downstream components in rat ovary. Melatonin treatment may have a beneficial effect on fertility.

<b></b> Iodine is essential for thyroid hormone synthesis. Under normal iodine supply, calculated physiological iodine concentration in the thyroid is approx. 9 mM. Either potassium iodide (KI) or potassium iodate (KIO₃) are used in iodine prophylaxis. KI is confirmed as absolutely safe. KIO₃ possesses chemical properties suggesting its potential toxicity. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an effective antioxidant and free radical scavenger. Study aims: to evaluate potential protective effects of melatonin against oxidative damage to membrane lipids (lipid peroxidation, LPO) induced by KI or KIO₃ in porcine thyroid. Homogenates of twenty four (24) thyroids were incubated in presence of either KI or KIO₃ without/with melatonin (<em>5</em> mM). As melatonin was not effective against KI-induced LPO, in the next step only KIO₃ was used. Homogenates were incubated in presence of KIO₃ (200; 100; <em>5</em>0; 2<em>5</em>; 20; 1<em>5</em>; 10; 7.<em>5</em>; <em>5</em>.0; 2.<em>5</em>; 1.2<em>5</em> mM) without/with melatonin or 17ß-estradiol. Five experiments were performed with different concentrations of melatonin (<em>5</em>.0; 2.<em>5</em>; 1.2<em>5</em>; 1.0; 0.62<em>5</em> mM) and one with 17ß-estradiol (1.0 mM). Malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) concentration (LPO index) was measured spectrophotometrically. KIO₃ increased LPO with the strongest damaging effect (MDA + 4-HDA level: ≈1.28 nmol/mg protein, p < 0.0<em>5</em>) revealed at concentrations of around 1<em>5</em> mM, thus corresponding to physiological iodine concentrations in the thyroid. Melatonin reduced LPO (MDA + 4-HDA levels: from ≈0.97 to ≈0,76 and from ≈0,64 to ≈0,49 nmol/mg protein, p < 0.0<em>5</em>) induced by KIO₃ at concentrations of 10 mM or 7.<em>5</em> mM. Conclusion: Melatonin can reduce very strong oxidative damage to membrane lipids caused by KIO₃ used in doses resulting in physiological iodine concentrations in the thyroid.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a circadian hormone produced in vertebrates by the pineal gland and other organs. Melatonin is believed to influence immune cells leading to modulation of the proliferative response of stimulated lymphocytes as well as cytokine production. Due to the antioxidant and immunomodulatory effects of melatonin, it is suggested that this molecule could be a therapeutic alternative agent to fight bacterial, viral, and parasitic infections by a variety of mechanisms. Herein, we review the effects of melatonin on the cell biology of protozoan parasites and host's immune response. In toxoplasmosis, African trypanosomiasis and Chagas' disease, melatonin enhances host's immune response against the parasite via regulating the secretion of inflammatory mediators. In amoebiasis, melatonin reduces the amoebic lesions as well as increasing the leukophagocytosis and the number of dead amoebae. In giardiasis, serum melatonin levels are elevated in these patients; this suggests a positive correlation between the level of melatonin and phagocytic activity in the G. duodenalis infected patients, possibly related to melatonin's immunomodulatory effect. In leishmaniasis, melatonin arrests parasite replication accompanied by releasing mitochondrial Ca2+ into the cytosol, increasing the level of mitochondrial nitrites as well as reducing superoxide dismutase (SOD) activity. In malaria, melatonin synchronizes the Plasmodium cell cycle via modulating cAMP-PKA and IP3-Ca2+ pathways. Thus, simultaneous administration of melatonin agonists or giving pharmacological doses of melatonin may be considered a novel approach for treatment of malarial infection.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. <em>N</em>umerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research.

Melatonin, <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, is an indole mainly synthesized from tryptophan in the pineal gland and secreted exclusively during the night in all the animals reported to date. While the pineal gland is the major source responsible for this night rise, it is not at all the exclusive production site and many other tissues and organs produce melatonin as well. Likewise, melatonin is not restricted to vertebrates, as its presence has been reported in almost all the phyla from protozoa to mammals. Melatonin displays a large set of functions including adaptation to light: dark cycles, free radical scavenging ability, antioxidant enzyme modulation, immunomodulatory actions or differentiation⁻proliferation regulatory effects, among others. However, in addition to those important functions, this evolutionary 'ancient' molecule still hides further tools with important cellular implications. The major goal of the present review is to discuss the data and experiments that have addressed the relationship between the indole and glucose. Classically, the pineal gland and a pinealectomy were associated with glucose homeostasis even before melatonin was chemically isolated. <em>N</em>umerous reports have provided the molecular components underlying the regulatory actions of melatonin on insulin secretion in pancreatic beta-cells, mainly involving membrane receptors MT<em>N</em>R1A/B, which would be partially responsible for the circadian rhythmicity of insulin in the organism. More recently, a new line of evidence has shown that glucose transporters GLUT/SLC2A are linked to melatonin uptake and its cellular internalization. Beside its binding to membrane receptors, melatonin transportation into the cytoplasm, required for its free radical scavenging abilities, still generates a great deal of debate. Thus, GLUT transporters might constitute at least one of the keys to explain the relationship between glucose and melatonin. These and other potential mechanisms responsible for such interaction are also discussed here.

<strong class="sub-title"> Background and aim: </strong> The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (<em>N</em>F-κB) signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 7<em>5</em> μg/kg combined with melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, MLT) could produce hepatic protection against HIR injury.

<strong class="sub-title"> Methods: </strong> Rats were randomized into sham, HIR, OCT (<em>5</em>0, 7<em>5</em>, and 100 μg/kg, respectively), MLT, and MLT + OCT7<em>5</em> groups. Ischemia was induced for 30 min followed by 24 h reperfusion.

<strong class="sub-title"> Results: </strong> OCT pretreatment at doses (<em>5</em>0 or 7<em>5</em> μg/kg), MLT alone, and MLT + OCT7<em>5</em> significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers with downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-<em>N</em>F-κBp6<em>5</em> (S<em>5</em>36), <em>N</em>LRP3, ASC, caspase-1(p20), and GSDMD-<em>N</em> expressions compared with HIR group. Lastly, Octreotide showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-<em>N</em>LRP3-mediated pyroptosis in rats. As well, OCT7<em>5</em> was more effective than MLT and was not enhanced after the addition of MLT through downregulation of TLR4/MyD88/<em>N</em>F-κB/<em>N</em>LRP3 inflammasome pathway.

Keywords: Hepatic ischemia/reperfusion injury; Melatonin; NLRP3; Octreotide; Pyroptosis; TLR4.

Aluminium (Al) toxicity is a major chemical constraint limiting plant growth and production on acidic soils. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a ubiquitous molecule that plays crucial roles in plant growth and stress tolerance. However, there is no knowledge regarding whether melatonin is involved in plant responses to Al stress. Here, we show that optimal concentrations of melatonin could effectively ameliorate Al-induced phytotoxicity in soybean (Glycine max L.). The concentration of melatonin in roots was significantly increased by the <em>5</em>0μM Al treatment. Such an increase in endogenous melatonin coincided with the upregulation of the gene encoding <em>acetyl</em>transferase <em>N</em>SI-like (nuclear shuttle protein-interacting) in soybean roots. Supplementation with low concentrations of melatonin (0.1 and 1μM) conferred Al resistance as evident in partial alleviation of root growth inhibition and decreased H2O2 production: in contrast, high concentrations of melatonin (100 and 200μM) had an opposite effect and even decreased root growth in Al-exposed seedlings. Mitigation of Al stress by the 1μM melatonin root treatment was associated with enhanced activities of the antioxidant enzymes and increased exudation of malate and citrate. In conclusion, melatonin might play a critical role in soybean resistance to Al toxicity.

<em>N</em>itrate reductase is a nitric oxide (<em>N</em>O) induced enzyme in plants, <em>N</em>O acts as a signaling molecule under ZnO <em>N</em>Ps-induced stress whereas melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) could improve morpho-physiological attributes of plants under adverse conditions. In present study, seedlings of two rice genotypes differed regarding nitrate reductase activities i.e., transgenic '<em>N</em>R' and wild type 'WT' were applied with two melatonin levels i.e., 0, 10 μΜ regarded as M0, M10, respectively and three levels of ZnO <em>N</em>Ps i.e., 0, <em>5</em>0, <em>5</em>00 mg L^-1 regarded as ZnO <em>N</em>Ps0, ZnO <em>N</em>Ps<em>5</em>0 and ZnO <em>N</em>Ps<em>5</em>00, respectively. Results revealed that melatonin application substantially increased the dry biomass accumulation of both rice genotypes under all ZnO <em>N</em>Ps levels. The root growth, mineral absorption as well as the antioxidant responses were also improved by melatonin application under ZnO <em>N</em>Ps stress. The interactive effects of melatonin and genotype on plant growth, antioxidant responses and mineral contents i.e., Zn, <em>N</em>a, Fe and Mn were also found significant under different ZnO <em>N</em>Ps stress. Furthermore, total plant dry weight was significantly correlated with the leaf dry weight, root volume, catalase (CAT) activity in leaves, <em>N</em>a accumulation in stem sheath and Fe accumulation in root under both M0 and M10 treatments. Moreover, the comparative transcriptome analysis identified key genes which were responsible for melatonin and <em>N</em>O-induced modulations in plant growth under ZnO <em>N</em>Ps stress. Overall, melatonin could improve the morphological growth of the rice plants by modulating root-shoot characteristics, antioxidant activities and mineral uptake in root and shoot of rice.

Melatonin (<em>N</em>‑<em>acetyl</em>‑<em>5</em>‑<em>methoxytryptamine</em>; MT) has been shown to have a protective effect against sepsis‑induced renal injury, however, the mechanisms underlying the function of MT remain to be elucidated. Therefore, in the present study, the potential mechanisms underlying the preventive role of MT in sepsis‑induced renal injury were investigated. Hematoxylin and eosin staining was used to detect the effect of MT on the reduction of renal tissue damage, and immunohistochemistry (IHC), ELISA and western blot analysis were performed to determine the influence of MT on the protein expression of PTE<em>N</em>‑induced putative kinase 1 (PI<em>N</em>K1), nucleotide‑oligomerization binding domain and leucine‑rich repeat pyrin domain‑containing 3 (<em>N</em>LRP3), apoptosis‑associated speck‑like protein containing a C‑terminal caspase recruitment domain (ASC1), interleukin (IL)‑18, IL‑1β, IL‑6 and cleaved caspase‑1. Finally, a TU<em>N</em>EL assay was used to compare the rate of apoptosis of renal tissues among the sham, cecal ligation and puncture (CLP), and CLP + MT groups. The extent of tissue damage in the CLP group was the highest and the extent of tissue damage in the sham group was the lowest. The IHC and western blot analysis showed that the sham group had the highest protein level of PI<em>N</em>K1, whereas the CLP group had the lowest protein level of PI<em>N</em>K1. By contrast, the sham group had the lowest protein level of <em>N</em>LRP, whereas the CLP group had the highest level of <em>N</em>LRP3. Furthermore, CLP treatment enhanced the protein expression of ASC1 and cleaved caspase‑1, whereas the administration of MT reduced the protein expression of ASC1 and cleaved caspase‑1 to a certain degree. Finally, the apoptotic rate was found to be the highest in the CLP group and the lowest in the sham group. Taken together, in evaluating the therapeutic effect of MT on sepsis‑induced renal injury, the results of the present study showed that MT alleviated sepsis‑induced renal injury by regulating the expression of PI<em>N</em>K1, Parkin1, <em>N</em>LRP3, ASC and cleaved caspase‑1 in rats.

Melatonin (MT; <i><em>N</em></i>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a pleiotropic signaling molecule that has been demonstrated to play an important role in plant growth, development, and regulation of environmental stress responses. Studies have been conducted on the role of the exogenous application of MT in a few species, but the potential mechanisms of MT-mediated stress tolerance under salt stress are still largely unknown. In this study, naked oat seedlings under salt stress (1<em>5</em>0 mM <em>N</em>aCl) were pretreated with two different concentrations of MT (<em>5</em>0 and 100 μM), and the effects of MT on the growth and antioxidant capacity of naked oat seedlings were analyzed to explore the regulatory effect of MT on salt tolerance. The results showed that pretreating with different concentrations of MT promoted the growth of seedlings in response to 1<em>5</em>0 mM <em>N</em>aCl. Different concentrations of MT reduced hydrogen peroxide, superoxide anion, and malondialdehyde contents. The exogenous application of MT also increased superoxide dismutase, peroxidase, catalase, and ascorbate peroxide activities. Chlorophyll content, leaf area, leaf volume, and proline increased in the leaves of naked oat seedlings under 1<em>5</em>0 mM <em>N</em>aCl stress. MT upregulated the expression levels of the lipid peroxidase genes <i>lipoxygenase</i> and <i>peroxygenase</i>, a chlorophyll biosynthase gene (<i>ChlG</i>), the mitogen-activated protein kinase genes <i>Asmap1</i> and <i>Aspk11</i>, and the transcription factor genes (except <i>DREB2</i>), <i><em>N</em>AC</i>, <i>WRKY1</i>, <i>WRKY3</i>, and <i>MYB</i> in salt-exposed MT-pretreated seedlings when compared with seedlings exposed to salt stress alone. These results demonstrate an important role of MT in the relief of salt stress and, therefore, provide a reference for managing salinity in naked oat.

Melatonin (<i><em>N</em></i>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a pleiotropic signaling molecule that plays a crucial role in the regulation of various environmental stresses, including heat stress (HS). In this study, a 100 μM melatonin (MT) pretreatment followed by exposure to heat stress for different time periods was found to efficiently reduce oxidative stress by preventing the over-accumulation of hydrogen peroxide (H₂O₂), lowering the lipid peroxidation content (malondialdehyde (MDA) content), and increasing proline (Pro) biosynthesis. Moreover, the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), were increased substantially in MT-pretreated wheat seedlings. The presence of MT significantly improved the heat tolerance of wheat seedlings by modulating their antioxidant defense system, activating the ascorbate-glutathione (AsA-GSH) cycle comprising ascorbate peroxidase (APX), and increasing glutathione reductase (GR) activities. It also held the photosynthetic machinery stable by increasing the chlorophyll content. Enhancement in the endogenous MT contents was also observed in the MT+HS-treated plants. Furthermore, the expression of reactive oxygen species (ROS)-related genes TaSOD, TaPOD, and TaCAT<i>,</i> and anti-stress responsive genes, such as TaMYB80, TaWRKY26, and TaWRKY39, was also induced in MT-treated seedlings. Due to these notable changes, an improvement in stress resistance was observed in MT-treated seedlings compared with control. Taken together, our findings suggest that MT can play a key role in boosting the stress tolerance of plants by modulating the antioxidant defense system and regulating the transcription of stress-responsive genes.

Keywords: antioxidant enzymes; melatonin; reactive oxygen species; wheat (Triticum aestivum L).

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an evolutionary highly conserved molecule that plays an important role in conveying the clock and calendar information to all living organisms, including man. Melatonin is synthesized in the rhythmic fashion, primarily by the pineal gland, and, to a lesser degree, by extrapineal tissues-namely the retina, the Harderian gland, and the gastrointestinal tract. The rhythm of the hormone production, with maximal levels occurring at night in darkness, is generated by an endogenous circadian clock(s) and is synchronized with the photoperiodic environment to which animals are exposed. This brief outline surveys data on the regulation of rhythmic melatonin biosynthesis by a circadian pacemaker and light (full spectrum white light and monochromatic lights with wavelengths both in the visible and invisible range). Additionally, possible applications of this chronobiotic compound in agriculture and in medicine in the treatment of circadian rhythm sleep disorders are discussed.

The increasing salinity in soils and irrigation water is a major concern for growers of strawberry, a salt-sensitive horticultural crop. The hormone melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is involved in many biological processes and affects plant responses to environmental stresses. The effects of weekly 100 and 200 μM melatonin sprays on leaf composition parameters (photosynthetic pigment and macronutrient concentrations, oxidative stress markers, antioxidant defense systems and abscisic acid concentrations), fruit yield and quality parameters (soluble solids, total acidity, ascorbic acid, total antioxidants and phenolics and sugars), and leaf and fruit melatonin have been studied in strawberry grown under non-saline, moderate and intense salinity conditions (0, 40 and 80 mM <em>N</em>aCl, respectively). Salinity led to decreases in yield, fruit quality parameters and leaf photosynthetic pigments and macronutrient concentrations, as well as to increases in oxidative stress, with melatonin foliar application alleviating all these changes. On the other hand, salinity led to increases in the leaf levels of antioxidant enzymes, abscisic acid and melatonin, with foliar applications of melatonin boosting those increases. In the absence of salinity stress, melatonin led to smaller changes in all parameters in the same direction to that observed in the presence of salinity. Furthermore, melatonin resulted in increases in strawberry fruit yield and quality, especially in plants grown under salinity. Results indicate that the effects of melatonin application are associated with a boost in leaf antioxidant enzymes and abscisic acid, and support that the application of melatonin is a promising tool for mitigating salt stress in strawberry.

<stro<em>n</em>g class="sub-title"> Objective: </stro<em>n</em>g> This trial aims to evaluate the effective<em>n</em>ess of addi<em>n</em>g melato<em>n</em>i<em>n</em> to the treatme<em>n</em>t protocol of hospitalized COVID-19 patie<em>n</em>ts.

<stro<em>n</em>g class="sub-title"> Methods: </stro<em>n</em>g> This was a<em>n</em> ope<em>n</em>-label, ra<em>n</em>domized co<em>n</em>trolled cli<em>n</em>ical trial i<em>n</em> hospitalized COVID-19 patie<em>n</em>ts. Patie<em>n</em>ts were ra<em>n</em>domized i<em>n</em>to a treatme<em>n</em>t arm receivi<em>n</em>g melato<em>n</em>i<em>n</em> plus sta<em>n</em>dard care or a co<em>n</em>trol arm receivi<em>n</em>g sta<em>n</em>dard care alo<em>n</em>e. The trial's primary e<em>n</em>dpoi<em>n</em>t was sleep quality exami<em>n</em>ed by the Leeds Sleep Evaluatio<em>n</em> Questio<em>n</em><em>n</em>aire (LSEQ). The trial's seco<em>n</em>dary e<em>n</em>dpoi<em>n</em>ts were symptoms alleviatio<em>n</em> by day seve<em>n</em>, ICU admissio<em>n</em>, te<em>n</em>-day mortality, white blood cell cou<em>n</em>t, lymphocyte cou<em>n</em>t, C-reactive protei<em>n</em> status, a<em>n</em>d peripheral capillary oxyge<em>n</em> saturatio<em>n</em>.

<stro<em>n</em>g class="sub-title"> Results: </stro<em>n</em>g> <em>N</em>i<em>n</em>ety-six patie<em>n</em>ts were recruited a<em>n</em>d allocated to either the melato<em>n</em>i<em>n</em> arm (<em>n</em>=48) or co<em>n</em>trol arm (<em>n</em>=48). Baseli<em>n</em>e characteristics were similar across treatme<em>n</em>t arms. There was <em>n</em>o sig<em>n</em>ifica<em>n</em>t differe<em>n</em>ce i<em>n</em> symptoms o<em>n</em> day seve<em>n</em>. The mea<em>n</em> of the LSEQ scores were sig<em>n</em>ifica<em>n</em>tly higher i<em>n</em> the melato<em>n</em>i<em>n</em> group (p<0.001). There was <em>n</em>o sig<em>n</em>ifica<em>n</em>t differe<em>n</em>ce i<em>n</em> laboratory data, except for blood oxyge<em>n</em> saturatio<em>n</em>, which has improved sig<em>n</em>ifica<em>n</em>tly i<em>n</em> the melato<em>n</em>i<em>n</em> group compared to the co<em>n</em>trol group (9<em>5</em>.81% vs. 93.6<em>5</em>% respectively, p=0.003).

<stro<em>n</em>g class="sub-title"> Co<em>n</em>clusio<em>n</em>: </stro<em>n</em>g> This cli<em>n</em>ical trial study showed that the combi<em>n</em>atio<em>n</em> of oral melato<em>n</em>i<em>n</em> tablets a<em>n</em>d sta<em>n</em>dard treatme<em>n</em>t could substa<em>n</em>tially improve sleep quality a<em>n</em>d blood oxyge<em>n</em> saturatio<em>n</em> i<em>n</em> hospitalized COVID-19 patie<em>n</em>ts. This article is protected by copyright. All rights reserved.

<stro<em>n</em>g class="sub-title"> Keywords: </stro<em>n</em>g> 2019-<em>n</em>CoV; COVID-19; Melato<em>n</em>i<em>n</em>; <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>; SARS-CoV-2; Sleep Quality.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a hormone with multiple functions in humans, produced by the pineal gland and stimulated by beta-adrenergic receptors. Serum melatonin levels exhibit a circadian rhythm with low levels during the day, rise in the evening and maximum levels at night between 2 and 4 a.m. Melatonin participates in the regulation of several physiological processes such as seasonal biological rhythm, daily sleep induction, aging and modulation of immunobiological defence reactions. Furthermore, melatonin has a highly lipophilic molecular structure facilitating penetration of cell membranes and serving as an extra- and intracellular free radical scavenger. Melatonin seems to quench mainly hydroxyl radicals, the most damaging of all free radicals. Melatonin may play a role in the etiology and treatment of several dermatoses e.g. atopic eczema, psoriasis and malignant melanoma. The influence of melatonin on hair growth is another aspect. Topical application of melatonin inhibits the development of UV-erythema. Penetration through skin after topical application and oral bioavailability auxit further investigations on the pharmacokinetic and pharmacodynamic actions of melatonin.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is synthesized in the pineal organ and the retina of vertebrates. In some teleost species, ocular melatonin levels can exhibit a circadian periodicity with elevated levels during the dark phase under light-dark (LD) cycles and this periodicity can persist even under constant dark (DD) cycles. However, reversed melatonin profiles and an absence of circadian ocular melatonin rhythms have also been reported. In this study, we investigated the daily rhythms of ocular melatonin in 32 teleost species under LD cycles. The melatonin profiles could be classified into three types: (1) normal profiles, with higher melatonin levels during the dark phase than the light phase; (2) reversed profiles, with higher levels during the light phase than the dark phase; (3) no significant differences in melatonin levels. We also studied whether ocular melatonin exhibits circadian rhythms under DD in selected species. Our results showed that ocular melatonin exhibited circadian rhythms in some but not all of the species examined. These results indicate that ocular melatonin rhythms in teleost fish exhibit species-specific variations as a result of the changes in the regulatory mechanisms during the course of evolution.

A pH-responsive amphiphilic hydrogel with interpenetrating polymer networks (IP<em>N</em>) structure for controlled drug release was proposed. The IP<em>N</em> was constructed with hydrophilic poly(acrylic acid) (PAA) and hydrophobic poly(butyl acrylate) (PBA). Using drug <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> (melatonin, MEL) as a model molecule, the controlled drug release behaviors of the IP<em>N</em> were investigated. It is found that not only the release of MEL from the IP<em>N</em> can respond to change in pH, but also the presence of hydrophobic network can overcome disadvantageous burst effect of hydrophilic network. This may be a result of hydrophobic aggregation encapsulating MEL molecules.

Pineal organ and its hormone melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is likely involved in timing and synchronisation of many internal processes, such as reproduction, with annual changes in environmental cues, i.e., photoperiod and water temperature. The seasonal changes in melatonin profile in stickleback brains related to the following reproductive phases were examined, and the link between melatonin concentrations and the stages of spawning cycle was analysed. Two wild populations of sticklebacks were exposed to annual environmental changes in their natural habitats. Brains, gonads, kidneys and livers were collected over 2 years. Melatonin was measured using RIA and the indices, gonadosomatic (GSI), nephrosomatic (<em>N</em>SI) and hepatosomatic (HSI), were calculated. The role of melatonin, as a component of internal calendar engaged in the control of seasonal breeding in this species, is discussed. The extremely high melatonin levels observed in early spring (March) and autumn (October) seem to mark out a time frame for spawning in sticklebacks. The seasonal pattern of melatonin production and identified development stages of gonads suggests the potential inhibitory effect of the hormone on stickleback reproduction in shortening photoperiod and stimulatory effect in lengthening photoperiod.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) plays critical roles in plant growth and development and during the response to multiple abiotic stresses. However, the roles of melatonin in plant response to K+ deficiency remain largely unknown. In the present study, we observed that the endogenous melatonin contents in bermudagrass were remarkably increased by low K+ (LK) treatment, suggesting that melatonin was involved in bermudagrass response to LK stress. Further phenotype analysis revealed that exogenous melatonin application conferred Bermudagrass enhanced tolerance to LK stress. Interestingly, exogenous melatonin application also promoted bermudagrass growth and development at normal condition. Furthermore, the K+ contents measurement revealed that melatonin-treated plants accumulated more K+ in both shoot (under both control and LK condition) and root tissues (under LK condition) compared with those of melatonin non-treated plants. Expression analysis indicated that the transcripts of K+ transport genes were significantly induced by exogenous melatonin treatment in bermudagrass under both control and LK stress conditions, especially under a combined treatment of LK stress and melatonin, which may increase accumulation of K+ content profoundly under LK stress and thereby contributed to the LK-tolerant phenotype. In addition, we investigated the role of melatonin in the regulation of photosystem II (PSII) activities under LK stress. The chlorophyll fluorescence transient (OJIP) curves were obviously higher in plants grown in LK with melatonin (LK+Mel) than those of plants grown in LK medium without melatonin application for 1 or 2 weeks, suggesting that melatonin plays important roles in PSII against LK stress. After a combined treatment of LK stress and melatonin, the values for performance indexes (PIABS, PITotal, and PICS), flux ratios (φP0, ΨE0, and φE0) and specific energy fluxes (ETO/RC) were significantly improved compared with those of LK stress alone, suggesting that melatonin plays positive roles in protecting PSII activity under LK stress. Collectively, this study reveals an important role of melatonin in regulating bermudagrass response to LK stress.