Melatonin Receptor Research Articles

Enantioselective Synthesis of Chiral 1,4-Dihydroquinolines via Iridium-Catalyzed Asymmetric Partial Hydrogenation of Quinolines.

Chiral 1,4-dihydroquinolines are frequently found in natural products and pharmaceuticals, yet a generally useful route for their synthesis remains elusive. Here, we present an asymmetric partial hydrogenation strategy to access enantioenriched 1,4-dihydroquinolines from quinolines. Our strategy involves incorporating an ester group at position 3 of the quinoline ring, thereby enhancing the electronic deficiency and polarity of the C3-C4 double bond. Employing a chiral Ir-SpiroPAP catalyst facilitated the hydrogenation of a wide variety of 4-substituted 3-ethoxycarbonylquinolines, yielding chiral 1,4-dihydroquinolines in high yields (up to 95%) with exceptional enantioselectivity and efficiency (up to 99% ee and 1840 TONs). Noteworthy for its scalability and practicality, the method provides a robust avenue for the synthesis of valuable compounds such as 9-aryl aza-podophyllotoxins and melatonin MT2 receptor modulators. Density functional theory calculations were performed to gain insights into the reaction mechanism and the origins of the enantioselectivity.

Cellular signalling of melatonin and its role in metabolic disorders.

Melatonin released from the pineal gland plays an important role in maintaining the light/dark cycle. Melatonin exerts its effects on various organs through receptor and nonreceptor pathways. Recently, the role of melatonin in various metabolic disorders has been investigated. This review focuses on the molecular pathways associated with melatonin and its role in metabolic disorders. In humans, melatonin acts through two G protein-coupled receptors (MT1 and MT2). Melatonin modulates insulin release, such as elevated insulin levels in the evening compared to morning hours, exerts cardioprotective effects through the cGMP pathway and nitric oxide production in endothelial cells, and controls oxidative stress and apoptosis in myocardial tissue. Melatonin through MT2 receptors increases lipolysis and thermogenesis, which have a positive effect on weight reduction in obese individuals. Currently, most drugs that target melatonin receptors are primarily used to treat neurological disorders. A detailed investigation to explore the role of melatonin and its signalling pathway in peripheral organs is essential to develop therapeutic molecules for managing metabolic disorders.

Melatonin induces white-to-beige adipocyte transdifferentiation through melatonin receptor 1-mediated direct browning and indirect M2 polarization.

Previous studies have shown that melatonin induces adipocyte browning in vivo. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. In vivo oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization in vivo. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.

Mitochondria Express Functional Signaling Ligand-Binding Receptors that Regulate their Biological Responses - the Novel Role of Mitochondria as Stress-Response Sentinels.

Evidence accumulated mitochondria, as the "powerplants of the cell," express several functional receptors for external ligands that modify their function and regulate cell biology. This review sheds new light on the role of these organelles in sensing external stimuli to facilitate energy production for cellular needs. This is possible because mitochondria express some receptors on their membranes that are responsible for their autonomous responses. This is not surprising given the widely accepted hypothesis that these intracellular organelles originated from prokaryotic ancestors that fused with eukaryotic cells during early evolution. It has been reported that mitochondria express functional estrogen, androgen, glucocorticoid, 5-hydroxytryptamine, melatonin, and cannabinoid receptors. What is intriguing is recent evidence showing that mitochondria could also be directly regulated by active mediators of intracellular complement (complosome) and intrinsic mediators of purinergic signaling. Accordingly, they express receptors for intracellular complement cleavage fragments (C5a and C3a) as well as for adenosine triphosphate (ATP), which, besides its crucial role in transferring energy in the cells, is also an important signaling molecule interacting with P2X7 receptor expressed not only on the cell surface but also on the mitochondria membrane. Based on this, intrinsic complosome and purinergic signaling mediators emerge as important cooperating regulators of reactive oxygen species (ROS) release from mitochondria and activators of intracellular pattern recognition receptor Nlrp3 inflammasome. This activation within the beneficial "hormetic zone response" regulates cell metabolism, proliferation, migration, and adaptation to the surrounding challenges of the microenvironment in a favorable way.

Exploring melatonin's signalling pathways in the protection against age-related skin deterioration.

Melatonin, renowned for regulating sleep-wake cycles, also exhibits notable anti-aging properties for the skin. Synthesized in the pineal gland and various tissues including the skin, melatonin's efficacy arises from its capacity to combat oxidative stress and shield the skin from ultraviolet (UV)-induced damage. Moreover, it curbs melanin production, thereby potentially ameliorating hyperpigmentation. The presence of melatonin receptors in diverse skin cell types and its documented ability to enhance skin tone, hydration, and texture upon topical administration underscores its promise as an anti-aging agent. Melatonin's protective effects likely emanate from its multifaceted characteristics, encompassing antioxidant, anti-inflammatory, and immunomodulatory functions, as well as its influence on collagen synthesis and mitochondrial activity. Chronic inflammation and oxidative stress initiate a detrimental feedback loop. Reactive oxygen species (ROS), notorious for damaging cellular structures, provoke immune responses by oxidizing vital molecules and activating signaling proteins. This triggers heightened expression of inflammatory genes, perpetuating the cycle. Such dysregulation significantly compromises the body's resilience against infections and other health adversities. This study embarks on an exploration of the fundamental signaling pathways implicated in skin aging. Furthermore, it delves into the therapeutic potential of melatonin and its anti-aging attributes within the realm of skin health.

Prenatal Constant Light Exposure Induces Behavioral Deficits in Male and Female Rat Offspring: Effects of Prenatal Melatonin Treatment

Prenatal constant light exposure (CLE) impaired the anxiety response and circadian rhythms of testicular enzymes in adult male rat offspring, while melatonin corrected these deficiencies. However, the mechanism by which CLE induces these long-term behavioral consequences and the impact of melatonin system have not been examined. The aim of the present study was to investigate the effects of prenatal CLE and melatonin treatment on anxiety- and depression-like behaviors, and the melatonin system in male and female adult rat offspring. Six groups of male and female rat offspring (P60) exposed to either light/dark (LD) or CL regimes, and treated with vehicle or melatonin (10 mg/kg, s.c.) were evaluated for anxiety by open field (OF), elevated plus maze (EPM), and light/dark (LD) tests, and depressive-like response by splash test and sucrose preference test. Plasma adrenocorticotropic hormone (ACTH), corticosterone (CORT) and melatonin expression, and hippocampal MT1A and MT1b receptor expression were assessed by ELISA. Prenatal CLE induced behavioral deficits and elevated plasma CORT levels, while melatonin levels, their circadian rhythmicity, and hippocampal MT receptor expression were not altered in male and female offspring in the CLE regime. However, prenatal melatonin treatment corrected behavioral deficits in a sex-specific manner by up-regulating hippocampal MT receptors, even without altering systemic melatonin levels or normalizing CORT in either sex. The results of this study suggest critical insights into how prenatal environmental factors and therapeutic interventions shape physiological and behavioral outcomes.

Melatonin in Male Dromedary Camel (Camelus dromedarius) Seminal Plasma and Its Specific MT1 and MT2 Receptors on Sperm Membranes.

Camels (Camelus dromedarius) are seasonal short-day breeders, regulated by photoperiod and melatonin secretion. However, no studies have explored melatonin levels in camel seminal plasma or their relationship with testosterone, age, or climatic factors, nor is it known whether melatonin receptors exist in camel spermatozoa to respond to seminal melatonin. This study aimed to analyze melatonin levels in camel seminal plasma and its specific receptors in spermatozoa. Semen samples were obtained from November to March (breeding season). Testosterone and melatonin levels were measured in seminal plasma by ELISA. Melatonin receptors were localized in spermatozoa using immunofluorescence, and their presence was confirmed by Western Blot. Melatonin levels were higher from November to January and decreased in February and March. No correlation between testosterone and melatonin levels was found, but both hormones were negatively correlated with daylength (p = 0.0089 and p = 0.0688, respectively). Testosterone, but not melatonin, levels were affected by age. Two melatonin receptors (MT1, MT2) were detected on camel spermatozoa, with several immunotypes labeled mainly in the tail and post-acrosome region, but also in the acrosome and neck. Western Blot analysis confirmed the presence of these receptors, showing a 39 kDa band for MT1 and a 36 kDa band for MT2. Understanding melatonin's effects on sperm could help ejaculates' processing procedures, semen handling, and infertility issues in camels.

Exploring the Analgesic Effect of Acupuncture on Knee Osteoarthritis Based on MLT/cAMP/PKA/CREB Signaling Pathway.

Acupuncture is an effective treatment for knee osteoarthritis (KOA), reducing pain and improving function. While melatonin (MLT) has notable pain relief benefits, the analgesic mechanism of acupuncture in KOA and its relationship with melatonin are still unknown. This study aims to explore this mechanism. In this work, the KOA rabbit model was constructed using the traditional Hulth method, and the therapeutic effect was assessed by the Lequesne MG score and Pain assessment by hot plate test. The pathological alterations of cartilage tissue were observed using hematoxylin and eosin (H&E) staining, Safranin O-fast green and MASSON staining to observe the pathological changes in cartilage tissue, and the efficacy was evaluated according to the principles of Mankin score and Osteoarthritis Research Society International (OARSI) score. Meanwhile, MLT in serum, cyclic adenosine monophosphate (cAMP) in cartilage, and matrix metalloproteinase-3 (MMP-3) in joint fluid were detected by enzyme-linked immunosorbent assay. In addition, the expression of aromatic L-amino acid N-acetyltransferase (AANAT), melatonin receptor 1 (MT1) and 2 (MT2) mRNAs in cartilage was determined by real-time quantitative reverse transcription-polymerase chain reaction, and the levels of proteins related to PKA/CREB signaling pathway were detected by Western blotting. Based on the results of Lequesne MG score and Pain assessment by hot plate test experimental data, the treatment group presented significant improvements in knee pain and overall function relative to OA (Osteoarthritis) group. Besides, according to results of histologic staining, Mankin and OARSI scores, articular cartilage degeneration of treatment group remarkably improved. In addition, acupuncture significantly reduced the expression of the inflammatory factor MMP-3 in knee joint fluid and significantly increased the levels of MLT, AANAT, MT1, MT2, cAMP, PKA and CREB. By regulating sympathetic excitability, acupuncture may activate the MLT/cAMP/PKA/CREB signaling pathway, decrease inflammatory factor expression and slow down degradation of articular cartilage, resulting in the relief of knee pain.

From spermatogenesis to fertilisation: the role of melatonin on ram spermatozoa.

This review presents recent findings on the effect of melatonin on ram spermatozoa. This hormone regulates seasonal reproduction in the ovine species through the hypothalamic-pituitary-gonadal axis, but it also exerts direct effects on spermatogenesis, seminal quality and fertility. In the testis, melatonin stimulates blood flow to this organ, but it also appears to be involved in the differentiation of spermatogonial stem cells and the secretion of testosterone through the MT1 and MT2 receptors. In the epididymis, this hormone modulates sperm maturation and the secretory activity of epidydimal epithelial cells. In addition, the antioxidant activity of melatonin may protect spermatozoa from oxidative damage during their formation in the testis and their maturation in the epididymis. After ejaculation, the melatonin present in seminal plasma may also protect sperm from oxidative damage and premature capacitation and may improve seminal quality. Finally, once the sperm begins its transit through the female genital tract, melatonin may modulate sperm capacitation. Thus, melatonin could have a bimodal activity in ram sperm capacitation, so high concentrations, such as those in seminal plasma, have a decapacitating effect. In contrast, low concentrations, such as those present in the female reproductive tract, may promote it, likely through interaction with MT2 receptors. In addition, melatonin could also be involved in chemotaxis and fertilisation, although further studies are needed to elucidate the specific role of melatonin in these processes. Finally, the effect of latitude and melatonin receptor gene polymorphisms in ram reproduction is also discussed.

Cytoprotective effect of melatonin against MPP+ toxicity in SH-SY5Y cells: Role sharing of two types of antioxidative activities of melatonin

Melatonin is a neurohormone that is not only a regulator of circadian cycles, but also a potent antioxidant. Parkinson’s disease (PD) is a major neurodegenerative disease that may result from oxidative stress as a part of its pathogenic cascade. Therefore, antioxidants, including melatonin, have attracted attention as potential candidates for neuroprotection against PD-related neurotoxicity. In this study, we report that melatonin has 2 types of antioxidant mechanisms of neuroprotection in an experimental cellular PD model using 1-Methyl-4-phenylpyridinium ion (MPP+) in human neuroblastoma SH-SY5Y cells. The first mechanism is a classical antioxidative mechanism through the direct action of melatonin, which reduces lipid hydroperoxide and 8-OHdG. The second mechanism is an indirect antioxidative effect via the melatonin receptor (Mel-R)/PI3K/Akt/Nrf2 cascade. Melatonin and Mel-R agonist activated PI3K/Akt signaling and Nrf2. Both Mel-R antagonist and the PI3K inhibitor blocked transcription induced by Nrf2 and the cytoprotective effect of melatonin. Interestingly, the antioxidative effect due to the Nrf2-related mechanism contributed mainly to a decrease of protein carbonyl, but not to lipid hydroperoxide and 8-OHdG. Mel-R agonist also showed a similar effect. Our results elucidate the mechanism of melatonin's powerful antioxidative effect and suggest the application of melatonin therapy to PD-related cytotoxicity.

Cross-species comparison of AlphaFold-derived G protein-coupled receptor structures reveals novel melatonin-related receptor in Neurospora crassa.

Melatonin, a molecule with diverse biological functions, is ubiquitously present in living organisms. There is significant interest in understanding melatonin signal transduction pathways in humans, particularly due to its critical role in regulating the sleep-wake cycle. However, a knowledge gap remains in fully elucidating the mechanisms by which melatonin influences circadian regulation. To bridge this gap, there is a growing need for a model system to study the role of melatonin in circadian clocks, with Neurospora crassa being a promising candidate. As a first step in this investigation, we focused on identifying melatonin receptors in N. crassa. Given the lack of sequence similarity between potential receptors in this fungus and known human melatonin receptors, we utilized structural similarity analysis through AlphaFold2. This approach led to the identification of a strong candidate gene, gpr-3, which shares structural similarities with human melatonin receptors. Experimental validation confirmed that the removal of GPR-3 from cells results in the absence of melatonin signaling. This proof-of-concept study underscores the potential of N. crassa as a model organism for circadian research and demonstrates the broader applicability of using AlphaFold2, especially when sequence similarity does not lead to candidate genes, for identifying novel receptors across different species.

Plausible therapeutic effects of melatonin and analogs in the dopamine-associated pathophysiology of bipolar disorder.

Bipolar disorder (BD) is a significant neuropsychiatric condition characterized by marked psychological mood disturbances. Despite extensive research on the symptomatology of BD, the mechanisms underlying its development and presentation remain unknown. Consequently, potential treatments are limited, and existing medications often cause significant side effects, leading to treatment discontinuation. Dopamine (DA) has been implicated in behavioral regulation, reward systems, and mood, highlighting the importance of the dopaminergic system in BD. Elevated levels of DA and tyrosine hydroxylase are associated with the onset of manic episodes, whereas reduced levels are linked to the depressive phase. Additionally, endogenous melatonin (MEL) levels are considerably lower in patients with BD. When administered as a treatment, exogenous MEL and MEL agonists improve behavioral characteristics and significantly modulate DA-related pathophysiological pathways in BD, with minimal adverse effects achieved through MEL receptor activation. Moreover, MEL and MEL agonists offer neuroprotection by promoting physiological homeostasis during disruption. The aim of this review is to investigate and propose MEL receptors as potential novel therapeutic targets for BD. This review seeks to analyze the role of MEL and its agonists in modulating dopamine-related pathophysiological pathways, improving behavioral outcomes, and providing neuroprotection with minimal side effects.

Testicular characteristics and artificial vagina-mediated semen collection training in young rams according to melatonin receptor MT1 gene polymorphisms

Testicular characteristics and artificial vagina-mediated semen collection training in young rams according to melatonin receptor MT1 gene polymorphisms

Relationship between the RsaI polymorphism of the melatonin receptor MT1 gene (MTNR1A) and the gene expression of the nuclear receptor RORA in the ram testis

Relationship between the RsaI polymorphism of the melatonin receptor MT1 gene (MTNR1A) and the gene expression of the nuclear receptor RORA in the ram testis

Melatonin Ameliorates Organellar Calcium Homeostasis, Improving Endoplasmic Reticulum Stress-Mediated Apoptosis in the Vastus Lateralis Muscle of Both Sexes of Obese Diabetic Rats.

Endoplasmic reticulum (ER) stress is a crucial factor in the progression of obesity-related type 2 diabetes (diabesity), contributing to skeletal muscle (SKM) dysfunction, calcium imbalance, metabolic inflexibility, and muscle atrophy. The ER and mitochondria together regulate intracellular calcium levels, and melatonin, a natural compound with antioxidant properties, may alleviate these challenges. Our previous research showed that melatonin raises intracellular calcium and preserves muscle structure by enhancing mitochondrial function in obese diabetic rats. This study further explores melatonin's potential to reduce ER stress in the vastus lateralis (VL) muscle by modulating the unfolded protein response (UPR) and restoring calcium levels disrupted by diabesity. Five-week-old Zücker diabetic fatty (ZDF) rats and lean littermates of both sexes were divided into control and melatonin-treated groups (10 mg/kg/day for 12 weeks). Flame atomic absorption spectrometry results showed that melatonin restored VL intraorganellar calcium homeostasis, increasing calcium levels in mitochondria and reducing them in the ER by raising the activity and expression of calcium transporters in both sexes of ZDF rats. Melatonin also decreased ER stress markers (GRP78, ATF6, IRE1α, and PERK) and reduced pro-apoptosis markers (Bax, Bak, P-JNK, cleaved caspase 3 and 9) while increasing Bcl2 levels and melatonin receptor 2 (MT2) expression. These findings suggest that melatonin may protect against muscle atrophy in obese and diabetic conditions by mitigating ER stress and calcium imbalance, highlighting its therapeutic potential.

Ramelteon exposure and survival of critically Ill sepsis patients: a retrospective study from MIMIC-IV

BackgroundThe effect of ramelteon, a melatonin receptor agonist, on survival in septic patients remains unknown. The purpose of this retrospective cohort study was to explore the relationship between ramelteon exposure and survival outcomes in septic patients.MethodsData from septic patients admitted to the intensive care unit (ICU) were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, with patients categorized into ramelteon exposure and non-exposure groups based on the use of ramelteon. The primary outcome was 30-day mortality, and secondary outcomes included 90-day mortality, in-hospital mortality, length of ICU stay, and hospital stay. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were employed to address confounding variables. Kaplan–Meier (K-M) analysis and Cox proportional hazards regression models for stepwise regression were utilized to assess the impact of ramelteon exposure on survival.ResultsThis study included 22,152 unexposed patients and 2,708 exposed patients, resulting in 2,607 matched pairs after PSM. Following PSM, ramelteon exposure was associated with significantly lower in-hospital mortality (11.6% vs.19.7%, p < 0.001), 30-day mortality (13.4% vs. 23.2%, p < 0.001), and 90-day mortality (22.1% vs. 30%, p < 0.001).K-M curves demonstrated a significant difference in 30-day and 90-day mortality between the two groups (P < 0.001), irrespective of PSM application. Both PSM (hazard ratio [HR] = 0.53, 95% confidence intervals [CIs] 0.47–0.61, p < 0.001) and IPTW models (HR = 0.59, 95% CI 0.50–0.70, p < 0.001) indicated a significant positive effect of ramelteon usage on 30-day mortality among septic patients compared to the non-exposure group.ConclusionsThis exploratory, retrospective study suggests an association between ramelteon exposure and reduced 30-day and 90-day mortality in septic patients compared with the non-exposure group. Considering the limitations of the retrospective design and the potential for unmeasured confounding, well-designed prospective studies and randomized controlled trials will be needed to confirm these findings.

Circadian Effects of Melatonin Receptor-Targeting Molecules In Vitro.

Circadian rhythms are important for maintaining homeostasis, from regulating physiological activities (e.g., sleep-wake cycle and cognitive performance) to cellular processes (e.g., cell cycle and DNA damage repair). Melatonin is a key regulator of circadian rhythms and exerts control by binding to melatonin receptor 1 (MT1), decreasing neuronal firing in the suprachiasmatic nucleus (SCN). Previous work studying effects of melatonin on circadian rhythms utilized in vivo models. Since MT1 is also expressed outside of the brain, it is important to study impacts of melatonin on circadian gene oscillations in vitro. We evaluated the effects of melatonin and an MT1 inverse agonist, UCSF7447, in U2OS circadian reporter cell lines, which facilitate detailed assessments of oscillatory changes. We report that cellular circadian rhythms are responsive to treatment with MT1-targeting molecules; their activities are not dependent upon the SCN. Corroborating in vivo data, both melatonin and UCSF7447 lengthened the periods of BMAL1 and PER2, and while melatonin delayed circadian phases, UCSF7447 advanced them. Compounds were also dosed at two different times, however this did not yield changes. Our findings indicate the importance of utilizing in vitro models and that the direct effects of melatonin likely go beyond the SCN and should be explored further.

An Experimental Insight Into the Role of Agomelatine in Renal Ischemia/Reperfusion Injury.

Acute kidney injury (AKI) is one of the leading causes of chronic kidney disease and accounts for 50%-75% of mortality following renal pathologies or organ transplantation. Ischemia‒reperfusion injury (IRI) involves an interrupted blood supply to organs and the kidney; IRI exacerbates AKI development. Owing to several pharmacological treatment methods, AKI still has a poor prognosis, and novel therapeutic options are needed. Agomelatine (AGM) is a melatonin receptor agonist (MT1 and MT2) with increased bioavailability and lipophilicity. In this study, we aimed to investigate the antioxidant and anti-inflammatory effects of AGM in experimental renal IRI via long-term and short-term applications. Sixty male Sprague-Dawley rats were randomly divided into six groups (n = 10): the control, I/R, AGM20S, AGM40S, AGM20L, and AGM40L groups. Following the establishment of the renal IRI model, the rats received agomelatine at 20 and 40 mg/kg orally, and agomelatine solvent (hydroxyethylcellulose) was used as a vehicle. At the end of the experiment, blood samples and renal tissues were harvested for histopathological and biochemical analysis. Urea, creatinine, tumor necrosis factor (TNF-α), and interleukin-1 beta (IL-1β) levels were measured in blood serum samples. Malondialdehyde (MDA) levels and increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), and total glutathione (GSH) levels were measured in renal tissue supernatants. Our biochemical results indicated that AGM reduced creatinine, TNF-α, IL-1β, and malondialdehyde levels and increased SOD, CAT, GSHPx, and total GSH levels. Agolematine reduced infiltration, intratubular hemorrhage, and intratubular cast formation histopathologically. Our results suggest that AGM could be a potential therapeutic adjuvant agent for ischemia‒reperfusion injury in the kidney and several other organs.

Melatonin Sources in Sheep Rumen and Its Role in Reproductive Physiology.

In mammals, the melatonin (Mel) concentration in the gastrointestinal tract is 400 times greater than in the pineal gland. However, the origin of Mel in the gastrointestinal tract and its role in reproductive regulation remains unclear. Therefore, we analyzed three potential Mel sources (feed, microorganisms, and the rumen wall) for their contribution to high Mel levels in the rumen and their biological effects. The feed contained high Mel concentrations, and Mel in rumen fluid and blood peaked two hours after feeding. Rumen microbial analysis showed a strong positive correlation between Mel and specific microbes, including Megasphaera, Butyrivibrio, Acetobacter, and Olsenella. In vitro experiments indicated that rumen microorganisms synthesized Mel from tryptophan. The rumen wall also contains key enzymes, AANAT and HIOMT, which catalyze Mel synthesis and membrane receptors MT1 and MT2 that mediate the function of Mel, suggesting that the rumen wall synthesizes Mel. Mel peaked in both rumen fluid and blood two hours after feeding. Feeding also altered blood levels of Mel, Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), progesterone (P4), and Estradiol (E2), with a correlation between Mel and fluctuations in GnRH, LH, P4, and E2 levels. Our findings suggest that feed is the primary source of high Mel levels in the rumen and impacts reproductive hormone fluctuations. This study elucidates the origin of high rumen Mel concentrations and reveals that food intake affects the natural secretion of various hormones, offering a new perspective on food sources for regulating reproductive physiology.

Practical application of melatonin for pancreas disorders: protective roles against inflammation, malignancy, and dysfunctions.

Melatonin, a hormone primarily produced by the pineal gland, exhibits a range of physiological functions that extend beyond its well-known role in regulating circadian rhythms. This hormone influences energy metabolism, modulates insulin sensitivity, and plays a significant role in controlling sleep patterns and food intake. Notably, melatonin is also synthesized in various peripheral organs, including the gastrointestinal system and pancreas, suggesting its function as a local hormone. The presence of melatonin receptors in the pancreas underscores its relevance in pancreatic physiology. Pancreatic disorders, such as diabetes mellitus (DM), pancreatitis, and pancreatic cancer, often stem from inflammatory processes. The majority of these conditions are characterized by dysregulated immune responses and oxidative stress. Melatonin's anti-inflammatory properties are mediated through the inhibition of pro-inflammatory cytokines and the activation of antioxidant enzymes, which help to mitigate cellular damage. Furthermore, melatonin has demonstrated pro-apoptotic effects on cancer cells, promoting cell death in malignant tissues while preserving healthy cells. Thus, melatonin emerges as a multifaceted agent with significant therapeutic potential for pancreatic disorders. Its ability to reduce inflammation and oxidative stress positions it as a promising adjunct therapy for conditions such as diabetes mellitus, pancreatitis, and pancreatic cancer. By modulating immune responses and enhancing cellular resilience through antioxidant mechanisms, melatonin not only addresses the symptoms but also targets the underlying pathophysiological processes associated with these disorders. This review aims to categorize and summarize the impacts of melatonin on pancreatic functions and disorders, emphasizing its potential as a therapeutic agent for managing pancreatic dysfunctions. Future research should focus on elucidating the precise mechanisms by which melatonin exerts its protective effects on pancreatic tissues and exploring optimal dosing strategies for clinical applications. The integration of melatonin into treatment regimens may enhance existing therapies and offer new hope for individuals suffering from pancreatic dysfunctions.