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In view of the recent revival of interest in circadian biology and circadian epidemiology at the Medical University of Vienna, it seems appropriate to highlight the rich and pioneering history of circadian research in Austria. Among the forefathers of circadian research in Vienna are Otto Marburg (1874-1948), who discovered important elements of the pineal gland physiology, Robert Hofstätter (1883-1970), who used pineal gland extract in obstetrics/gynecology, and Paul Engel (1907-1997), who discovered that the pineal gland was controlled by light. More recently, Vera Lapin (1920-2007) showed that surgical removal of the pineal gland increased tumor growth, while Franz Waldhauser (*1946) investigated melatonin in conjunction with night work. Michael Kundi (*1950) and his team conducted among the first studies demonstrating differences in rhythms of night workers and early evidence for health impairments among them. Furthermore, Vienna-born Erhard Haus (1926-2013) pioneered the discovery of the role and importance of melatonin in relation to numerous diseases. This rich pioneering contribution of scientists in Vienna or with roots in Vienna is continued today by a new generation of chronobiologists, epidemiologists and clinicians in Vienna whose new insights contribute to the rapidly developing field of circadian rhythms research. Current topics and contributions relate to the impact of circadian rhythm disruption on health, and the application of chronotherapeutic approaches in clinical and preventive settings., (© 2023. The Author(s).)

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Aging affects anxiety levels in rats while the pineal gland, via its hormone melatonin, could modulate their inherited life "clock." The present study aimed to explore the impact of plasma melatonin deficiency on anxiety responses and the possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) axis and heat shock proteins (Hsp) 70 and 90 in the frontal cortex (FC) and the hippocampus in young adult, middle-aged and elderly rats with pinealectomy., Results: Melatonin deficiency induced at different life stages did not affect the lifespan of rats. Pinealectomy abolished the circadian rhythm of motor activity, measured for 48 h in the actimeter, in young adult but not in middle-aged rats. Pinealectomy reduced the motor activity of the young adult rats during the dark phase and impaired the diurnal activity variations of old rats. The same generations (3- and 18 month-old rats with pinealectomy) had lower anxiety levels than the matched sham groups, measured in three tests: elevated-plus maze, light-dark test, and novelty-suppressed feeding test. While the activity of the HPA axis remained intact in young adult and middle-aged rats with melatonin deficiency, a high baseline corticosterone level and blunted stress-induced mechanism of its release were detected in the oldest rats. Age-associated reduced Hsp 70 and 90 levels in the FC but not in the hippocampus were detected. Pinealectomy diminished the expression of Hsp 70 in the FC of middle-aged rats compared to the matched sham rats., Conclusions: Our results suggest that while melatonin hormonal dysfunction impaired the motor activity in the actimeter and emotional behavior in young adult and elderly rats, the underlying pathogenic mechanism in these generations might be different and needs further verification., (© 2024. The Author(s).)

Circadian rhythms (CRs) are 24-hour periodic oscillations governed by an endogenous circadian pacemaker located in the suprachiasmatic nucleus (SCN), which organizes the physiology and behavior of organisms. Circadian rhythm disruption (CRD) is also indicative of the aging process. In mammals, melatonin is primarily synthesized in the pineal gland and participates in a variety of multifaceted intracellular signaling networks and has been shown to synchronize CRs. Endogenous melatonin synthesis and its release tend to decrease progressively with advancing age. Older individuals experience frequent CR disruption, which hastens the process of aging. A profound understanding of the relationship between CRs and aging has the potential to improve existing treatments and facilitate development of novel chronotherapies that target age-related disorders. This review article aims to examine the circadian regulatory mechanisms in which melatonin plays a key role in signaling. We describe the basic architecture of the molecular circadian clock and its functional decline with age in detail. Furthermore, we discuss the role of melatonin in regulation of the circadian pacemaker and redox homeostasis during aging. Moreover, we also discuss the protective effect of exogenous melatonin supplementation in age-dependent CR disruption, which sheds light on this pleiotropic molecule and how it can be used as an effective chronotherapeutic medicine.

Objectives: In this study, we investigated the relationship between infantile colic, migraine, and biorhythm regulation, by evaluating biochemical and molecular parameters., Study Design: Healthy infants with and without infantile colic were eligible for this prospective cohort study. A questionnaire was applied. Between the 6th and 8th postnatal weeks, day and night circadian histone gene H3f3b mRNA expression and spot urine excretion of serotonin, cortisol, and 6-sulphatoxymelatonin were analyzed., Results: Among the 95 infants included, 49 were diagnosed with infantile colic. In the colic group, defecation difficulty, sensitivity to light/sound, and maternal migraine frequency increased and sleep disruption was typical. In the melatonin analysis, the difference between day and night levels was significant in the control group, indicating an established circadian rhythm ( P = 0.014). In the colic group, there was no day-night difference ( P = 0.216) in melatonin, but serotonin levels were higher at night. In the cortisol analysis, day-night values were similar in both groups. Day-night variability of H3f3b mRNA levels between the groups was significant, indicating circadian rhythm disturbance in the colic group compared to the control group ( P = 0.003). Fluctuations in circadian genes and hormones expected in healthy rhythm were revealed in the control group, but were missing in the colic group., Conclusion: Due to the gaps in the etipathogenesis in infantile colic, a unique effective agent has not been discovered so far. This study, which demonstrated for the first time that infantile colic is a biorhythm disorder using molecular methods, fills the gap in this regard and points to a completely different perspective in terms of treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The photoperiod is the predominant environmental factor that governs seasonal reproduction in animals; however, the underlying molecular regulatory mechanism has yet to be fully elucidated. Herein, Yangzhou geese ( Anser cygnoides ) were selected at the spring equinox (SE), summer solstice (SS), autumn equinox (AE), and winter solstice (WS), and the regulation of seasonal reproduction via the light-driven cyclical secretion of pineal melatonin was investigated. We show that there were seasonal variations in the laying rate and GSI, while the ovarian area decreased 1.5-fold from the SS to the AE. Moreover, not only did the weight and volume of the pineal gland increase with a shortened photoperiod, but the secretory activity was also enhanced. Notably, tissue distribution further revealed seasonal oscillations in melatonin receptors (Mtnrs ) in the pineal gland and the hypothalamus-pituitary-gonadal (HPG) axis. The immunohistochemical staining indicated higher Mtnr levels due to the shortened photoperiod. Furthermore, the upregulation of aralkylamine N -acetyltransferase ( Aanat ) was observed from the SS to the AE, concurrently resulting in a downregulation of the gonadotrophin-releasing hormone ( GnRH ) and gonadotropins ( GtHs ). This trend was also evident in the secretion of hormones. These data indicate that melatonin secretion during specific seasons is indicative of alterations in the photoperiod, thereby allowing for insight into the neuroendocrine regulation of reproduction via an intrinsic molecular depiction of external photoperiodic variations.

Seasonal changes in food intake and adiposity in many animal species are triggered by changes in the photoperiod. These latter changes are faithfully transduced into a biochemical signal by melatonin secreted by the pineal gland. Seasonal variations, encoded by melatonin, are integrated by third ventricular tanycytes of the mediobasal hypothalamus through the detection of the thyroid-stimulating hormone (TSH) released from the pars tuberalis. The mediobasal hypothalamus is a critical brain region that maintains energy homeostasis by acting as an interface between the neural networks of the central nervous system and the periphery to control metabolic functions, including ingestive behavior, energy homeostasis, and reproduction. Among the cells involved in the regulation of energy balance and the blood-hypothalamus barrier (BHB) plasticity are tanycytes. Increasing evidence suggests that anterior pituitary hormones, specifically TSH, traditionally considered to have unitary functions in targeting single endocrine sites, display actions on multiple somatic tissues and central neurons. Notably, modulation of tanycytic TSH receptors seems critical for BHB plasticity in relation to energy homeostasis, but this needs to be proven., (© 2023 New York Academy of Sciences.)

Melatonin has profound antioxidant activity and numerous functions in humans as well as in livestock and poultry. Additionally, melatonin plays an important role in regulating the biological rhythms of animals. Combining melatonin with scientific breeding management has considerable potential for optimizing animal physiological functions, but this idea still faces significant challenges. In this review, we summarized the beneficial effects of melatonin supplementation on physiology and reproductive processes in cattle, including granulosa cells, oocytes, circadian rhythm, stress, inflammation, testicular function, spermatogenesis, and semen cryopreservation. There is much emerging evidence that melatonin can profoundly affect cattle. In the future, we hope that melatonin can not only be applied to cattle, but can also be used to safely and effectively improve the efficiency of animal husbandry.

Melatonin (N-acetyl-5-methoxytryptamine) plays an important role in plant growth and development, and in the response to various abiotic stresses. However, its role in the responses of barley to low phosphorus (LP) stress remains largely unknown. In the present study, we investigated the root phenotypes and metabolic patterns of LP-tolerant (GN121) and LP-sensitive (GN42) barley genotypes under normal P, LP, and LP with exogenous melatonin (30 μM) conditions. We found that melatonin improved barley tolerance to LP mainly by increasing root length. Untargeted metabolomic analysis showed that metabolites such as carboxylic acids and derivatives, fatty acyls, organooxygen compounds, benzene and substituted derivatives were involved in the LP stress response of barley roots, while melatonin mainly regulated indoles and derivatives, organooxygen compounds, and glycerophospholipids to alleviate LP stress. Interestingly, exogenous melatonin showed different metabolic patterns in different genotypes of barley in response to LP stress. In GN42, exogenous melatonin mainly promotes hormone-mediated root growth and increases antioxidant capacity to cope with LP damage, while in GN121, it mainly promotes the P remobilization to supplement phosphate in roots. Our study revealed the protective mechanisms of exogenous MT in alleviating LP stress of different genotypes of barley, which can be used in the production of phosphorus-deficient crops.

The circadian system modulates all visceral organ physiological processes including urine storage and voiding. The "master clock" of the circadian system lies within suprachiasmatic nucleus of the hypothalamus while "peripheral clocks" are found in most peripheral tissue and organs, including the urinary bladder. Disruptions of circadian rhythms can cause organ malfunction and disorder or exacerbate pre-existing ones. It has been suggested that nocturia, which develops mostly in the elderly, could be a circadian-related disorder of the bladder. In the bladder, many types of gap junctions and ion channels in the detrusor, urothelium and sensory nerves are likely under strict local peripheral circadian control. The pineal hormone, melatonin, is a circadian rhythm synchroniser capable of controlling a variety of physiological processes in the body. Melatonin predominantly acts via the melatonin 1 and melatonin 2 G-protein coupled receptors expressed in the central nervous system, and many peripheral organs and tissues. Melatonin could be beneficial in the treatment of nocturia and other common bladder disorders. The ameliorating action of melatonin on bladder function is likely due to multiple mechanisms which include central effects on voiding and peripheral effects on the detrusor and bladder afferents. More studies are warranted to determine the precise mechanisms of circadian rhythm coordination of the bladder function and melatonin influences on the bladder in health and diseases., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Circadian clock is an internal mechanism evolved to adapt to cyclic environmental changes, especially diurnal changes. Keeping the internal clock in synchronization with the external clock is essential for health. Mismatch of the clocks due to phase shift or disruption of molecular clocks may lead to circadian disorders, including abnormal sleep-wake cycles, as well as disrupted rhythms in hormone secretion, blood pressure, heart rate, body temperature, etc. Long-term circadian disorders are risk factors for various common critical diseases such as metabolic diseases, cardiovascular diseases, and tumor. To prevent or treat the circadian disorders, scientists have conducted extensive research on the function of circadian clocks and their roles in the development of diseases, and screened hundreds of thousands of compounds to find candidates to regulate circadian rhythms. In addition, melatonin, light therapy, exercise therapy, timing and composition of food also play a certain role in relieving associated symptoms. Here, we summarized the progress of both drug- and non-drug-based approaches to prevent and treat circadian clock disorders.

As people age, their risks of developing degenerative diseases such as cancer, diabetes, Parkinson's Disease (PD), Alzheimer's Disease (AD), rheumatoid arthritis, and osteoporosis are generally increasing. Millions of people worldwide suffer from these diseases as they age. In most countries, neurodegenerative diseases are generally recognized as the number one cause afflicting the elderly. Endoplasmic reticulum (ER) stress has been suggested to be associated with some human neurological diseases, such as PD and AD. Melatonin, a neuroendocrine hormone mainly synthesized in the pineal gland, is involved in pleiotropically biological functions, including the control of the circadian rhythm, immune enhancement, and antioxidant, anti-aging, and anti-tumor effects. Although there are many papers on the prevention or suppression of diseases by melatonin, there are very few papers about the effects of melatonin on ER stress in neurons and neurodegenerative diseases. This paper aims to summarize and present the effects of melatonin reported so far, focusing on its effects on neurons and neurodegenerative diseases related to ER stress. Studies have shown that the primary target molecule of ER stress for melatonin is CHOP, and PERK and GRP78/BiP are the secondary target molecules. Therefore, melatonin is crucial in protecting neurons and treating neurodegeneration against ER stress.

Exposure to the space environment induces a number of pathophysiological outcomes in astronauts, including bone demineralization, sleep disorders, circadian clock dysregulation, cardiovascular and metabolic dysfunction, and reduced immune system function. A recent report describing experiments aboard the Space Shuttle mission, STS-132, showed that the level of melatonin, a hormone that provides the biochemical signal of darkness, was decreased during microgravity in an in vitro culture model. Additionally, abnormal lighting conditions in outer space, such as low light intensity in orbital spacecraft and the altered 24-h light-dark cycles, may result in the dysregulation of melatonin rhythms and the misalignment of the circadian clock from sleep and work schedules in astronauts. Studies on Earth have demonstrated that melatonin regulates various physiological functions including bone metabolism. These data suggest that the abnormal regulation of melatonin in outer space may contribute to pathophysiological conditions of astronauts. In addition, experiments with high-linear energy transfer radiation, a ground-based model of space radiation, showed that melatonin may serve as a protectant against space radiation. Gene expression profiling using an in vitro culture model exposed to space flight during the STS-132 mission, showed that space radiation alters the expression of DNA repair and oxidative stress response genes, indicating that melatonin counteracts the expression of these genes responsive to space radiation to promote cell survival. These findings implicate the use of exogenous melatonin and the regulation of endogenous melatonin as countermeasures for the physiological consequences of space flight., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oral cancer (OC) has emerged as a major medical and social issue in many industrialized nations due to the high death rate. It is becoming increasingly common in people under the age of 45, although the underlying causes and mechanisms of this increase remain unclear. Melatonin, as a pleiotropic hormone, plays a pivotal role in a wide variety of cellular and physiological functions. Mounting evidence supports melatonin's ability to modify/influence oral carcinogenesis, help in the reduction of the incidence of OC, and increase chemo- and radiosensitivity. Despite its potential anti-carcinogenic effects, the precise function of melatonin in the management of OC is not well understood. This review summarizes the current knowledge regarding melatonin function in anti-carcinogenesis mechanisms for OC. In addition, clinical assessment and the potential therapeutic utility of melatonin in OC are discussed. This review will provide a basis for researchers to create new melatonin-based personalized medicines for treating and preventing OC.

Melatonin, mainly released from the pineal gland, also produced in the reproductive organs and cells, plays important roles in rhythms of the sleep-wake cycle, retardation of ageing processes, and antioxidant/anti-inflammatory functions. As a key mediator in reproductive systems, melatonin is participated in the reproductive process via regulating gamete and embryo development and influences reproductive diseases and pregnancy outcomes. The underlying mechanisms include epigenetic and other regulations, which are interesting for exploring new targets in the prevention and treatment of reproductive diseases. This review discusses the relationship between melatonin and reproductive functions and dysfunction, as well as potential clinical applications of melatonin in reproductive medicine. Notably, Developmental Origins of Health and Diseases (DOHaD) is closely linked to reproduction, this article is the first to review the new progress in studies on the possible relationship between melatonin and DOHaD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The hypotensive effects of melatonin are based on a negative correlation between melatonin levels and blood pressure in humans. However, there is a positive correlation in nocturnal animals that are often used as experimental models in cardiovascular research, and the hypotensive effects and mechanism of melatonin action are often investigated in rats and mice. In rats, the hypotensive effects of melatonin have been studied in normotensive and spontaneously or experimentally induced hypertensive strains. In experimental animals, blood pressure is often measured indirectly during the light (passive) phase of the day by tail-cuff plethysmography, which has limitations regarding data quality and animal well-being compared to telemetry. Melatonin is administered to rats in drinking water, subcutaneously, intraperitoneally, or microinjected into specific brain areas at different times. Experimental data show that the hypotensive effects of melatonin depend on the experimental animal model, blood pressure measurement technique, and the route, time and duration of melatonin administration. The hypotensive effects of melatonin may be mediated through specific membrane G-coupled receptors located in the heart and arteries. Due to melatonin's lipophilic nature, its potential hypotensive effects can interfere with various regulatory mechanisms, such as nitric oxide and reactive oxygen species production and activation of the autonomic nervous and circadian systems. Based on the research conducted on rats, the cardiovascular effects of melatonin are modulatory, delayed, and indirect., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Multi drug resistance (MDR) generally limits the efficacy of chemotherapy in cancer patients and can be categorized into primary or acquired resistance. Melatonin (MLT), a lipophilic hormone released from pineal gland, is a molecule with oncostatic effects. Here, we will briefly review the contribution of different microenvironmental components including fibroblasts, immune and inflammatory cells, stem cells and vascular endothelial cells in tumor initiation, progression and development. Then, the mechanisms by which MLT can potentially affect these elements and regulate drug resistance will be presented. Finally, we will explain how different studies have used novel strategies incorporating MLT to suppress cancer resistance against therapeutics., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier B.V.)

The MT1/2 receptors, members of the melatonin receptor, belong to G protein-coupled receptors and mainly regulate circadian rhythms and sleep in the brain. Previous studies have shown that in many other cells and tissues, such as HEK293T cells and the retina, MT1/2 receptors can be involved in mitochondrial homeostasis, antioxidant, and anti-inflammatory responses. In our study, we aimed to investigate the effects of blue light (BL) exposure on the expression of melatonin and its receptors in the mouse cornea and to evaluate their functional role in corneal epithelial damage. After exposing 8-week-old C57BL/6 mice to BL at 25 and 100 J/cm 2 twice a day for 14 days, a significant increase in the expression of 4-HNE and MT2 was observed in the cornea. MT2 antagonist-treated mice exposed to BL showed an increased expression of p62 and decreased expression of BAX and cleaved caspase 3 compared with mice exposed only to BL. In addition, MT2 antagonist-treated mice showed more enhanced MDA and corneal damage. In conclusion, BL exposure can induce MT2 expression in the mouse cornea. MT2 activation can modulate impaired autophagy and apoptosis by increasing the expression of BAX, an apoptosis activator, thereby regulating the progression of corneal epithelial damage induced by BL exposure.

Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness., (Copyright © 2018 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Melatonin, the primary hormone involved in circadian entrainment, plays a significant role in bone physiology. This study aimed to assess the role of MEK1/2 and MEK5 in melatonin-mediated actions in mouse and human mesenchymal stem cells (MSCs) and on bone using small-molecule inhibitors and CRISPR/Cas9 knockout approaches. Consistent with in vitro studies performed in mMSCs and hMSCs, nightly (25 mg/kg, i.p., 45 days) injections with PD184352 (MEK1/2 inhibitor) or Bix02189 (MEK5 inhibitor) or SC-1-151 (MEK1/2/5 inhibitor) demonstrated that MEK1/2 and MEK5 were the primary drivers underlying melatonin's actions on bone density, microarchitecture (i.e., trabecular number, separation, and connectivity density), and bone mechanical properties (i.e., ultimate stress) through increases in osteogenic (RUNX2, BMP-2, FRA-1, OPG) expression and decreases in PPARγ. Furthermore, CRISPR/Cas9 knockout of MEK1 or MEK5 in mMSCs seeded on PLGA scaffolds and placed into critical-size calvarial defects in Balb(c) mice (male and female) revealed that treatment with melatonin (15 mg/L; p.o., nightly, 90 days) mediates sex-specific actions of MEK1 and MEK5 in new bone formation. This study is the first to demonstrate a role for MEK1/2 and MEK5 in modulating melatonin-mediated actions on bone formation in vivo and in a sex-specific manner., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Migraine is a chronic disease of global concern, regardless of socio-economic and cultural background. It most often and intensely affects young adults, especially women. Numerous mechanisms of a migraine attack have been identified (disturbances in the reaction of vessels, functions of neurotransmitters, cortical neurons, ion channels, receptors, the process of neurogenic inflammation), and many of its symptoms can be explained by activation of the hypothalamus and disturbances in its communication with other brain regions (including the brainstem). Numerous neuropeptides and neurochemical systems also play a role in migraine. One of them is melatonin, a hormone that allows the body to adapt to cyclically changing environmental and food conditions. In this article, we present the pathophysiological basis of melatonin release from the pineal gland and other tissues (including the intestines) under the influence of various stimuli (including light and food), and its role in stimulating the brain structures responsible for triggering a migraine attack. We analyze publications concerning research on the role of melatonin in various headaches, in various stages of migraine, and in various phases of the menstrual cycle in women with migraine, and its impact on the occurrence and severity of migraine attacks. Melatonin as an internally secreted substance, but also present naturally in many foods. It is possible to supplement melatonin in the form of pharmaceutical preparations, and it seems, to be a good complementary therapy (due to the lack of significant side effects and pharmacological interactions) in the treatment of migraine, especially: in women of childbearing age, in people taking multiple medications for other diseases, as well as those sensitive to pharmacotherapy.

In humans, an adaptable internal biological system generates circadian rhythms that maintain synchronicity of behavior and physiology with the changing demands of the 24-h environment. Development of the circadian system begins in utero and continues throughout the first few years of life. Maturation of the clock can be measured through sleep/wake patterns and hormone secretion. Circadian rhythms, by definition, can persist in the absence of environmental input; however, their ability to adjust to external time cues is vital for adaptation and entrainment to the environment. The significance of these external factors that influence the emergence of a stable circadian clock in the first years of life remain poorly understood. Infants raised in our post-modern world face adverse external circadian signals, such as artificial light and mistimed hormonal cues via breast milk, which may increase interference with the physiological mechanisms that promote circadian synchronization. This review describes the very early developmental stages of the clock and common circadian misalignment scenarios that make the developing circadian system more susceptible to conflicting time cues and temporal disorder between the maternal, fetal, infant, and peripheral clocks., (© 2022. The Author(s).)

LIGHT POLLUTION Artificial light can be a polluting agent deleterious for the retina, in relation to the toxicity of the blue band (380-500 nm) of the visible spectrum (380-700nm) specifically used in light-emitting diodes (LEDs). Photo-toxicity results from photochemical damage to the pigmented epithelium and retinal photoreceptors responsible for the visual function of the retina. Their photosensitive pigments, opsins for the cones and rhodopsin for the sticks, are consumed during the day and regenerated at night. Exposure to light at night seriously disrupts their metabolism. Photo-toxicity, along with heredity, is a major factor in degenerative diseases of the retina with, in addition to, the impact of age and tobacco for the most common of them, age-related macular degeneration: ARMD.Exposure to artificial light at night (LAN) has a deleterious effect on the internal clock. Intrinsically photosensitive ganglion cells (ipRGSs) are responsible for the non-visual functions of the retina, and perceive the light signal that is transmitted to the internal clock to reach the pineal gland. Light inhibits the secretion of melatonin and is able to advance or delay the clock depending on the time of exposure, causing desynchronization. Shift and night workers, like teenagers, are exposed to LAN. The incidence of breast cancer, higher in nurses exposed to LAN, is related to melatonin inhibition, sleep deprivation and desynchronization. The exposure of adolescents to screens is also questionable because the LEDs of the devices emit a blue light, the impact of which on the clock is considerable. The chronic desynchronizations of both shiftworkers and adolescents should be considered a major public health concern., Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

An animal's ability to respond optimally to changing environmental conditions is paramount to successfully reproducing and thus maximizing fitness. Studies on photoperiod-induced changes in neural thyroid hormone metabolism have conclusively linked environmental cues to the neuroendocrine reproductive axis of birds and mammals. Whether this conserved mechanism also transduces changes in environmental temperature, however, has not been fully addressed. We investigated whether the hormone melatonin mediates the effects of low-temperature dormancy on thyroid hormone metabolism within the hypothalamus of red-sided garter snakes (Thamnophis sirtalis parietalis). To address this question, we used immunohistochemistry to assess changes in thyroid-stimulating hormone (TSH) in the infundibulum of the pituitary and deiodinase 3 (Dio3) and gonadotropin-releasing hormone (GnRH) in the hypothalamus. We also asked if changes in TSH, Dio3, and/or GnRH immunoreactivity are associated with changes in male courtship behavior. In contrast to our predictions, 6 weeks of dormancy at 4°C significantly decreased the number of TSH-labeled cells in the infundibulum. It is possible that the observed decrease in TSH is related to the release of snakes from temperature refractoriness, but this idea needs further testing. Treatment of snakes with the melatonin precursor 5-hydroxytryptophan during dormancy at 4°C both reversed the temperature-induced change in TSH immunoreactivity and disrupted the temporal pattern of male courtship behavior. These results suggest that TSH cells within the infundibulum are both modulated by temperature and sensitive to changes in melatonin. As predicted, male snakes hibernated at an elevated temperature of 12°C for 6 weeks and treated with vehicle showed no change in TSH-, Dio3-, or GnRH-immunoreactive cell number. Treatment of snakes with the melatonin receptor antagonist luzindole was not sufficient in rescuing the effects of dormancy at 12°C on TSH immunoreactivity or courtship behavior. However, luzindole-treated snakes showed a significant increase in GnRH-immunoreactive cell number, suggesting that melatonin exerts an inhibitory effect on GnRH in garter snakes. In summary, our results provide critical insights into the mechanisms that mediate the effects of temperature on reproductive physiology and behavior., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: The internal clock is driven by circadian genes [e.g., Clock, Bmal1, Per1-3, Cry1-2], hormones [e.g., melatonin, cortisol], as well as zeitgeber ['synchronisers']. Chronic disturbances in the circadian rhythm in Objectives: The aim of this review is to summarise the current knowledge and literature regarding circadian rhythms in the context of mood disorders, focussing on the role of circadian genes, hormones, and neurotransmitters., Methods: The review presents the current knowledge and literature regarding circadian rhythms in mood disorders using the Pubmed database. Articles with a focus on circadian rhythms and mood disorders [n=123], particularly from 1973 to 2020, were included., Results: The article suggests a molecular link between disruptions in the circadian rhythm and mood disorders. Circadian disturbances, caused by the dysregulation of circadian genes, hormones, and neurotransmitters, often result in a clinical picture resembling depression., Conclusion: The article suggests a molecular link between disruptions in the circadian rhythm and mood disorders. Circadian disturbances, caused by the dysregulation of circadian genes, hormones, and neurotransmitters, often result in a clinical picture resembling depression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Melatonin is a naturally occurring molecule derived from tryptophan. Melatonin is a key player in relaying the circadian rhythm between our environment and our body. It has also a key role in rhythming the seasons (more production during long nights and less during short ones) as well as in the reproduction cycles of the mammals. Melatonin is often and surprisingly presented as a molecule with multiple therapeutic properties that can fix (or help to fix) many health issues, such as diseases (cancer, ageing, virus-induced affections including COVID-19, etc…) or toxicological situations (metals, venoms, chemical such as adriamycin [doxorubicin], methotrexate or paclitaxel). The mechanistics behind those wonders is still missing and this is puzzling. In the present commentary, the main well-established biological properties are presented and briefly discussed with the aim of delineating the borders between facts and wishful thinking., (© 2022 médecine/sciences – Inserm.)

Background: The increasing incidence of chronic kidney disease (CKD), as a consequence of the high prevalence of arterial hypertension and type 2 diabetes mellitus (T2DM), warrants the need for developing effective treatment approaches. In this regard, the pineal gland-derived hormone melatonin may represent an appealing treatment approach of CKD and its associated risk factors., Summary: Targeting the adverse pathophysiology surrounding CKD and its associated risk factors has been the concept of pharmacologic treatment developed for its management. This review article aimed to present the role of melatonin in this direction, by providing an overview of melatonin's physiology followed by its effect as a therapeutic agent in arterial hypertension and T2DM., Key Messages: Melatonin, the primary darkness hormone, possesses pleiotropic mechanisms of action which may have important implications in various pathologic states since its receptors are situated across various organ systems. As a treatment tool in arterial hypertension, melatonin may be efficacious in reducing both daytime and nocturnal blood pressure by influencing endothelial function, oxidative stress, the autonomic nervous system, and the renin-angiotensin system. Melatonin may also increase insulin sensitivity and β-cell function. However, late meal intake may be detrimental in glucose regulation, as consumption close to melatonin peak concentrations may induce hyperglycemia and insulin resistance. This finding may explain the inconsistent glycose regulation achieved with melatonin in clinical trials and meta-analyses. Additionally, the presence of genetic variants to melatonin receptor 2 may predispose to T2DM development. Finally, we present the available preclinical evidence supporting melatonin's efficacy in ameliorating CKD's pathophysiology since melatonin supplementation has not been adequately explored in patients with CKD. The combined use of stem cells with melatonin is an appealing therapeutic approach which ought to be assessed further., (© 2022 S. Karger AG, Basel.)

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology-for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.

Epilepsy is a chronic neurological disease with recurrent seizures. Its incidence, the social and psychological aspects of epilepsy-associated stigmatization in society, the medical risk of severe seizures, and the challenges in treatment confirm its medical and social significance. The pathogenesis of the diseases is associated with abnormal activity of a population of neurons due to various mechanisms, the most frequent being oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction. In the last 3-4 decades, the possible connection between epilepsy and melatonin - a neurohormone secreted by the pineal gland - has been sought and studied. Various physiological functions of melatonin in humans have been proven - regulation of circadian rhythms (diurnal, seasonal), sleep and wakefulness, participation in the processes of thermoregulation, tumour growth and aging, sexual activity and reproductive functions. It also has immunomodulatory, cytoprotective and antioxidant activity. The results from the studies with experimental models with animals conducted so far in search of a correlation between melatonin and epileptogenesis are mainly in support of the hypothesis of its anticonvulsant effect. The studies with humans are diverse in design, with a smaller number of participants, and the results are not always in explicit support of this hypothesis. The correlation between melatonin concentration and the course of the disease in patients with epilepsy has been discussed. The possibility of adding melatonin to anti-epileptic therapy has also been studied recently., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic obstructive pulmonary disease (COPD), a progressive respiratory disease, is characterized by the alveolar epithelium injury and persistent airway inflammation. It is documented that oscillation and dysregulated expression of circadian clock genes, like Bmal1, Per1, and Per2, involved in COPD pathogenies, including chronic inflammation and imbalanced autophagy level, and targeting the associations of circadian rhythm and autophagy is promising strategies in the management and treatment of COPD. Herein, we reviewed the mechanisms of the circadian clock and the unbalance of the autophagic level in COPD, as well as the link between the two, so as to provide further theoretical bases for the study on the pathogenesis of COPD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Yuedi Hu et al.)

Heavy metal toxicity is one of the most devastating abiotic stresses. Heavy metals cause serious damage to plant growth and productivity, which is a major problem for sustainable agriculture. It adversely affects plant molecular physiology and biochemistry by generating osmotic stress, ionic imbalance, oxidative stress, membrane disorganization, cellular toxicity, and metabolic homeostasis. To improve and stimulate plant tolerance to heavy metal stress, the application of biostimulants can be an effective approach without threatening the ecosystem. Melatonin ( N -acetyl-5-methoxytryptamine), a biostimulator, plant growth regulator, and antioxidant, promotes plant tolerance to heavy metal stress by improving redox and nutrient homeostasis, osmotic balance, and primary and secondary metabolism. It is important to perceive the complete and detailed regulatory mechanisms of exogenous and endogenous melatonin-mediated heavy metal-toxicity mitigation in plants to identify potential research gaps that should be addressed in the future. This review provides a novel insight to understand the multifunctional role of melatonin in reducing heavy metal stress and the underlying molecular mechanisms.

Bone‑related diseases comprise a large group of common diseases, including fractures, osteoporosis and osteoarthritis (OA), which affect a large number of individuals, particularly the elderly. The progressive destruction and loss of alveolar bone caused by periodontitis is a specific type of bone loss, which has a high incidence and markedly reduces the quality of life of patients. With the existing methods of prevention and treatment, the incidence and mortality of bone‑related diseases are still gradually increasing, creating a significant financial burden to societies worldwide. To prevent the occurrence of bone‑related diseases, delay their progression or reverse the injuries they cause, new alternative or complementary treatments need to be developed. Melatonin exerts numerous physiological effects, including inducing anti‑inflammatory and antioxidative functions, resetting circadian rhythms and promoting wound healing and tissue regeneration. Melatonin also participates in the health management of bone and cartilage. In the present review, the potential roles of melatonin in the pathogenesis and progression of bone injury, osteoporosis, OA and periodontitis are summarized. Furthermore, the high efficiency and diversity of the physiological regulatory effects of melatonin are highlighted and the potential benefits of the use of melatonin for the clinical prevention and treatment of bone‑related diseases are discussed.

Melatonin is a key intracellular neuroimmune-endocrine regulator and coordinator of multiple complex and interrelated biological processes. The main functions of melatonin include the regulation of neuroendocrine and antioxidant system activity, blood pressure, rhythms of the sleep-wake cycle, the retardation of ageing processes, as well as reseting and optimizing mitochondria and thereby the cells of the immune system. Melatonin and its agonists have therefore been mooted as a treatment option across a wide array of medical disorders. This article reviews the role of melatonin in the regulation of respiratory system functions under normal and pathological conditions. Melatonin can normalize the structural and functional organization of damaged lung tissues, by a number of mechanisms, including the regulation of signaling molecules, oxidant status, lipid raft function, optimized mitochondrial function and reseting of the immune response over the circadian rhythm. Consequently, melatonin has potential clinical utility for bronchial asthma, chronic obstructive pulmonary disease, lung cancer, lung vascular diseases, as well as pulmonary and viral infections. The integration of melatonin's effects with the alpha 7 nicotinic receptor and the aryl hydrocarbon receptor in the regulation of mitochondrial function are proposed as a wider framework for understanding the role of melatonin across a wide array of diverse pulmonary disorders., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In recent years, people have become increasingly interested in bioactive ingredients from plants, especially antioxidant molecules such as melatonin, which are beneficial to human health. The purpose of this article is to provide new information on plant-derived foods with a high content of melatonin. We comprehensively summarize the content of melatonin in plant-derived foods and discuss the factors that influence melatonin levels to provide new ideas on enhancement. Additionally, we describe the biosynthetic pathway of melatonin and identify its major functions. Medicinal herbs are often rich in melatonin while many vegetables and fruits exhibit somewhat lower levels with wide variations among species. The genetic traits of plants, the phenological stage of the cultivar, the photoperiod, the level of stress to which the plants are exposed at the time of harvest, exposure to agrochemicals and determination methods are the main factors affecting the melatonin content. To date, standardization of uniform sampling times and the use of suitable pretreatments as well as determination methods have not been achieved. The results of the studies reviewed highlight the potentially important role of plant melatonin in influencing the progression of human diseases. Based on the health promotional aspects of melatonin, consuming foods containing higher concentrations of tryptophan and melatonin is suggested.

Melatonin, the neurohormone mainly synthesized in and secreted from the pineal gland of vertebrates following a circadian rhythm, is an important factor regulating various physiological processes, including reproduction. Recent data indicate that melatonin is also synthesized in the ovary and that it acts directly at the level of the ovary to modulate ovarian physiology. In some teleosts, melatonin is reported to affect ovarian steroidogenesis. The direct action of melatonin on the ovary could be a possible factor promoting oocyte maturation in teleosts. A role for melatonin in follicle rupture during ovulation in the teleost medaka has recently emerged. In addition, melatonin is suggested to affect oocyte maturation by its antioxidant activity. However, the molecular mechanisms underlying these direct effects of melatonin are largely unknown., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Part of the life cycle of several fish species includes important salinity changes, as is the case for the sea bass (Dicentrarchus labrax) or the Atlantic salmon (Salmo salar). Salmo salar juveniles migrate downstream from their spawning sites to reach seawater, where they grow and become sexually mature. The process of preparation enabling juveniles to migrate downstream and physiologically adapt to seawater is called smoltification. Daily and seasonal variations of photoperiod and temperature play a role in defining the timing of smoltification, which may take weeks to months, depending on the river length and latitude. Smoltification is characterised by a series of biochemical, physiological and behavioural changes within the neuroendocrine axis. This review discusses the current knowledge and gaps related to the neuroendocrine mechanisms that mediate the effects of light and temperature on smoltification. Studies performed in S. salar and other salmonids, as well as in other species undergoing important salinity changes, are reviewed, and a particular emphasis is given to the pineal hormone melatonin and its possible role in osmoregulation. The daily and annual variations of plasma melatonin levels reflect corresponding changes in external photoperiod and temperature, which suggests that the hormonal time-keeper melatonin might contribute to controlling smoltification. Here, we review studies on (i) the impact of pinealectomy and/or melatonin administration on smoltification; (ii) melatonin interactions with hormones involved in osmoregulation (e.g., prolactin, growth hormone and cortisol); (iii) the presence of melatonin receptors in tissues involved in osmoregulation; and (iv) the impacts of salinity changes on melatonin receptors and circulating melatonin levels. Altogether, these studies show evidence indicating that melatonin interacts with the neuroendocrine pathways controlling smoltification, although more information is needed to clearly decipher its mechanisms of action., (© 2021 British Society for Neuroendocrinology.)

The biological functions of melatonin range beyond the regulation of the circadian rhythm. With regard to cancer, melatonin's potential to suppress cancer initiation, progression, angiogenesis and metastasis as well as sensitizing malignant cells to conventional chemo- and radiotherapy are among its most interesting effects. The targets at which melatonin initiates its anti-cancer effects are in common with those of a majority of existing anti-cancer agents, giving rise to the notion that this molecule is a pleiotropic agent sharing many features with other antineoplastic drugs in terms of their mechanisms of action. Among these common mechanisms of action are the regulation of several major intracellular pathways including mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) and protein kinase B (AKT/PKB) signaling. The important mediators affected by melatonin include cyclins, nuclear factor-κB (NF-κB), heat shock proteins (HSPs) and c-Myc, all of which can serve as potential targets for cancer drugs. Melatonin also exerts some of its anti-cancer effects via inducing epigenetic modifications, DNA damage and mitochondrial disruption in malignant cells. The regulation of these mediators by melatonin mitigates tumor growth and invasiveness via modulating their downstream responsive genes, housekeeping enzymes, telomerase reverse transcriptase, apoptotic gene expression, angiogenic factors and structural proteins involved in metastasis. Increasing our knowledge on how melatonin affects its target sites will help find ways of exploiting the beneficial effects of this ubiquitously-acting molecule in cancer therapy. Acknowledging this, here we reviewed the most studied target pathways attributed to the anti-cancer effects of melatonin, highlighting their therapeutic potential., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Seed germination is a vital stage in the plant life-cycle that greatly contributes to plant establishment. Melatonin has been shown to promote seed germination under various environmental stresses; however, the mechanism remains largely underexplored. Here, we reported that melatonin antagonized abscisic acid (ABA) to promote seed germination by regulating ABA and gibberellic acid (GA 3 ) balance. Transcriptomic analysis revealed that such a role of melatonin was associated with Ca 2+ and redox signaling. Melatonin pretreatment induced Ca 2+ efflux accompanied by an up-regulation of vacuolar H+/Ca 2+ antiporter 3 (CAX3). AtCAX3 deletion in Arabidopsis exhibited reduced Ca 2+ efflux. Inhibition of Ca 2+ efflux in the seeds of melon and Arabidopsis mutant AtCAX3 compromised melatonin-induced germination under ABA stress. Melatonin increased H 2 O 2 accumulation, and H 2 O 2 pretreatment decreased ABA/GA 3 ratio and promoted seed germination under ABA stress. However, complete inhibition of H 2 O 2 accumulation abolished melatonin-induced ABA and GA 3 balance and seed germination. Our study reveals a novel regulatory mechanism in which melatonin counteracts ABA to induce seed germination that essentially involves CAX3-mediated Ca 2+ efflux and H 2 O 2 accumulation, which, in turn, regulate ABA and GA 3 balance by promoting ABA catabolism and/or GA 3 biosynthesis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Melatonin is a multifunctional biomolecule found in both animals and plants. In this review, the biosynthesis, levels, signaling, and possible roles of melatonin and its metabolites in plants is summarized. Tryptamine 5-hydroxylase (T5H), which catalyzes the conversion of tryptamine into serotonin, has been proposed as a target to create a melatonin knockout mutant presenting a lesion-mimic phenotype in rice. With a reduced anabolic capacity for melatonin biosynthesis and an increased catabolic capacity for melatonin metabolism, all plants generally maintain low melatonin levels. Some plants, including Arabidopsis and Nicotiana tabacum (tobacco), do not possess tryptophan decarboxylase (TDC), the first committed step enzyme required for melatonin biosynthesis. Major melatonin metabolites include cyclic 3-hydroxymelatonin (3-OHM) and 2-hydroxymelatonin (2-OHM). Other melatonin metabolites such as N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK), N-acetyl-5-methoxykynuramine (AMK) and 5-methoxytryptamine (5-MT) are also produced when melatonin is applied to Oryza sativa (rice). The signaling pathways of melatonin and its metabolites act via the mitogen-activated protein kinase (MAPK) cascade, possibly with Cand2 acting as a melatonin receptor, although the integrity of Cand2 remains controversial. Melatonin mediates many important functions in growth stimulation and stress tolerance through its potent antioxidant activity and function in activating the MAPK cascade. The concentration distribution of melatonin metabolites appears to be species specific because corresponding enzymes such as M2H, M3H, catalases, indoleamine 2,3-dioxygenase (IDO) and N-acetylserotonin deacetylase (ASDAC) are differentially expressed among plant species and even among different tissues within species. Differential levels of melatonin and its metabolites can lead to differential physiological effects among plants when melatonin is either applied exogenously or overproduced through ectopic overexpression., (© 2020 Society for Experimental Biology and John Wiley & Sons Ltd.)

Obesity is a predominant risk factor in ischemic stroke and is commonly comorbid with it. Pathologies following these conditions are associated with systemic and local inflammation. Moreover, there is increasing evidence that the susceptibility for ischemic brain damage increases substantially in experimental models of ischemic stroke with concomitant obesity. Herein, we explore the proinflammatory events that occur during ischemic stroke and obesity, and we discuss the influence of obesity on the inflammatory response and cerebral damage outcomes in experimental models of brain ischemia. In addition, because melatonin is a neurohormone widely reported to exhibit protective effects in various diseases, this study also demonstrates the anti-inflammatory role and possible mechanistic actions of melatonin in both epidemic diseases. A summary of research findings suggests that melatonin administration has great potential to exert an anti-inflammatory role and provide protection against obesity and ischemic stroke conditions. However, the efficacy of this hormonal treatment on ischemic stroke with concomitant obesity, when more serious inflammation is generated, is still lacking., (© 2020 International Union of Biochemistry and Molecular Biology.)

The last four decades, we assist to an increasing scientific interest on melatonin, a circadian hormone, a metabolic regulator which influences not only plants' metabolism and their defense against pathogens but mostly the animals and humans' metabolic pathways, their response to circadian disruption, stress and burnout syndrome. In humans, as a hormonal regulator, produced in the pineal grand as well in mitochondria, melatonin is involved in different, complex intracellular signaling pathways, with antioxidant and immune stimulating effects, proving to act as a circadian synchronizer, as a preventive and therapeutic agent in many degenerative diseases, and especially in hormone-dependent cancers. Preclinical or clinical studies showed recently the mechanisms involved in regulating the cellular activity, its role in aging and circadian disturbances and impact on degenerative diseases. Melatonin proved to have an anti-inflammatory, antiapoptotic and powerful antioxidant effect by subtle mechanisms in mitochondrial metabolic pathways. This overview includes recent and relevant literature data related to the impact of endogenous and exogeneous melatonin on the prevention of cancer progression and treatment of various degenerative diseases. Metabolomics, an emerging new omics' technology, based on high performance liquid chromatography coupled with mass spectrometry is presented as an encouraging technique to fingerprint and realize a precise evaluation and monitoring of the turnover of melatonin and its metabolites in different pathological circumstances.

Gastrointestinal (GI) cancers, leading causes of cancer-related deaths, have been serious challenging human diseases up to now. Because of high rates of mortality, late-stage diagnosis, metastasis to distant locations, and low effectiveness and adverse events of routine standard therapies, the quality of life and survival time are low in patients with GI cancers. Hence, many efforts need to be done to explore and find novel efficient treatments. Beneficial effects of melatonin have been reported in a wide variety of human diseases. Melatonin has antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. Various studies have showed the regulatory effects of melatonin on apoptotsis, autophagy and angiogenesis; these properties result in the inhibition of invasion, migration, and proliferation of GI cancer cells in vivo and in vitro. Together, this review suggests that melatonin in combination with anticancer agents may improve the efficacy of routine medicine and survival rate of patients with cancer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Apart from its metabolic or physiological functions, melatonin has a potent cytoprotective activity in the physiological and pathological conditions. It is synthetized by the pineal gland and released into the blood circulation but particularly cerebrospinal fluid in a circadian manner. It can also easily diffuse through cellular membranes due its small size and lipophilic structure. Its cytoprotective activity has been linked to its potent free radical scavenger activity with the desirable characteristics of a clinically- reliable antioxidant. Melatonin detoxifies oxygen and nitrogen-based free radicals and oxidizing agents, including the highly toxic hydroxyl-and peroxynitrite radicals, initiating cellular damage. However, the cytoprotective activity of melatonin is complex and cannot be solely limited to its free radical scavenger activity. It regulates cellular signaling pathways through receptor– dependent and independent mechanisms. Most of these downstream molecules, such as PI3K/AKT pathway components, also contribute to the cytoprotective effects of melatonin. In this term, melatonin is a promising molecule for the treatment of neurodegenerative disorders, such as ischemic stroke, which melatonin reduces ischemic brain injury in animal models of ischemic stroke. It regulates also circadian rhythm proteins after ischemic stroke, playing roles in cellular survival. In this context, present article summarizes the possible role of melatonin in the pathophysiological events after ischemic stroke., Competing Interests: The authors declare no conflict of interest related to this paper., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

This study aimed to reveal the mechanistic basis of the melatonin-mediated amelioration of salinity stress in plants. Electrophysiological experiments revealed that melatonin decreased salt-induced K + efflux (a critical determinant of plant salt tolerance) in a dose- and time-dependent manner and reduced sensitivity of the plasma membrane K + -permeable channels to hydroxyl radicals. These beneficial effects of melatonin were abolished by NADPH oxidase blocker DPI. Transcriptome analyses revealed that melatonin induced 585 (448 up- and 137 down-regulated) and 59 (54 up- and 5 down-regulated) differentially expressed genes (DEGs) in the root tip and mature zone, respectively. The most noticeable changes in the root tip were melatonin-induced increase in the expression of several DEGs encoding respiratory burst NADPH oxidases (OsRBOHA and OsRBOHF), calcineurin B-like/calcineurin B-like-interacting protein kinase (OsCBL/OsCIPK), and calcium-dependent protein kinase (OsCDPK) under salt stress. Melatonin also enhanced the expression of potassium transporter genes (OsAKT1, OsHAK1, and OsHAK5). Taken together, these results indicate that melatonin improves salt tolerance in rice by enabling K + retention in roots, and that the latter process is conferred by melatonin scavenging of hydroxyl radicals and a concurrent OsRBOHF-dependent ROS signalling required to activate stress-responsive genes and increase the expression of K + uptake transporters in the root tip., (© 2020 John Wiley & Sons Ltd.)

Background: Fusarium oxysporum f. sp. niveum (FON) causes Fusarium wilt in watermelon. Several disease-resistant watermelon varieties have been developed to combat Fusarium wilt. However, the key metabolites that mount defense responses in these watermelon varieties are unknown. Herein, we analyzed hormones, melatonin, phenolic acids, and amino acid profiles in the leaf tissue of FON zero (0)-resistant (PI-296341, Calhoun Grey, and Charleston Grey) and -susceptible (Sugar Baby) watermelon varieties before and after infection., Results: We found that jasmonic acid-isoleucine (JA-Ile) and methyl jasmonate (MeJA) were selectively accumulated in one or more studied resistant varieties upon infection. However, indole-3-acetic acid (IAA) was only observed in the FON 0 inoculated plants of all varieties on the 16th day of post-inoculation. The melatonin content of PI-296341 decreased upon infection. Conversely, melatonin was only detected in the FON 0 inoculated plants of Sugar Baby and Charleston Grey varieties. On the 16th day of post-inoculation, the lysine content in resistant varieties was significantly reduced, whereas it was found to be elevated in the susceptible variety., Conclusions: Taken together, Me-JA, JA-Ile, melatonin, and lysine may have crucial roles in developing defense responses against the FON 0 pathogen, and IAA can be a biomarker of FON 0 infection in watermelon plants.

The origin of the coronavirus disease 2019 (COVID-19) pandemic is zoonotic. The circadian day-night is the rhythmic clue to organisms for their synchronized body functions. The "development for mankind" escalated the use of artificial light at night (ALAN). In this article, we tried to focus on the possible influence of this anthropogenic factor in human coronavirus (HCoV) outbreak. The relationship between the occurrences of coronavirus and the ascending curve of the night-light has also been delivered. The ALAN influences the physiology and behavior of bat, a known nocturnal natural reservoir of many Coronaviridae . The "threatened" and "endangered" status of the majority of bat species is mainly because of the destruction of their proper habit and habitat predominantly through artificial illumination. The stress exerted by ALAN leads to the impaired body functions, especially endocrine, immune, genomic integration, and overall rhythm features of different physiological variables and behaviors in nocturnal animals. Night-light disturbs "virus-host" synchronization and may lead to mutation in the genomic part of the virus and excessive virus shedding. We also proposed some future strategies to mitigate the repercussions of ALAN and for the protection of the living system in the earth as well., (Copyright © 2020 Khan, Yumnamcha, Mondal, Devi, Rajiv, Labala, Sanjita Devi and Chattoraj.)