Higher Melatonin Levels Research Articles

Melatonin inhibits embryonic rat H9c2 cells growth through induction of apoptosis and cell cycle arrest via PI3K‐AKT signaling pathway

Our recent epidemiological study revealed that maternal sleep during the periconceptional period should be involved in the risk of congenital heart disease (CHD) in offspring. Melatonin, a sleep related hormone, has been suggested to play a crucial role in embryonic development based on the emerging evidence. In this study, we set out to assess the effect of melatonin on the embryonic cardiac cell growth and to explore the underlying mechanisms. We observed the effect of different gradient doses of melatonin as 10, 100, or 1,000 μM on cell proliferation in H9c2 embryonic rat cardiac cells. Furthermore, flow cytometry was applied to evaluate the impact on apoptosis and cell cycle. RNA-seq was conducted to screen the changes in expression of mRNA and signaling pathways. Quantitative Real-Time-PCR (qRT-PCR) was then conducted to validate the results. It was observed that melatonin could inhibit H9c2 cell growth, at the doses of 100 and 1,000 μM, but not at 10μM. Moreover, melatonin ranged from 100 to 1,000 μM could instigate cell cycle arrest at G1 phase and simulate apoptosis, in a dose-dependent manner. In addition, melatonin was found to down-regulate the expression of a number of genes, which are related to heart development (SPARC, IFITM3, TNNT2, LOX), and PI3K-Akt signaling pathway activation (FN1, HSP90B1, THBS1, MFGE8, and CLU). Our findings suggested that high level of melatonin could be capable of inhibiting growth through the induction of apoptosis and cell cycle arrest via PI3K-AKT signaling pathway, thereby interfering with embryonic heart development. Considering this study is based on H9c2 embryonic rat cardiac cells, future additional studies using human embryonic cardiac cell are warranted.

Maternal Psychological and Biological Factors Associated to Gestational Complications.

Early detection of gestational complications is a priority in obstetrics. In our social context, this is linked to maternity age. Most studies are focused on biological factors. However, pregnancy is also influenced by social and psychological factors, which have not been deeply explored. We aimed to identify biopsychosocial risk and protective factors associated with the development of maternal and fetal complications. We enrolled 182 healthy pregnant women, and plasma melatonin and cortisol levels were measured in the first trimester by chemiluminescent immunoassays. At different time points along gestation, women answered several questionnaires (positive and negative affect schedule, hospital anxiety and depression scale, pregnancy concerns scale, life orientation test, resilience scale, life satisfaction scale and life–work conflicts scale). They were followed up until delivery and categorized as normal pregnancy, maternal or fetal complications. Maternal complications were associated with low melatonin (OR = 0.99 [0.98; 1.00]; p-value = 0.08) and life satisfaction (OR = 0.64 [0.41; 0.93]; p-value = 0.03) and fetal complications were associated with high cortisol (OR = 1.06 [1.02; 1.13]; p-value = 0.04), anxiety (OR = 2.21 [1.10; 4.55]; p-value = 0.03) and life–work conflicts (OR = 1.92 [1.04; 3.75]; p-value = 0.05). We conclude that psychological factors influence pregnancy outcomes in association with melatonin and cortisol alterations. High maternal melatonin and life satisfaction levels could be potential protective factors against the development of maternal complications during pregnancy. Low anxiety and cortisol levels and reduced work–life conflicts could prevent fetal complications.

Development and effect analysis of circadian rhythm-assisted LED lighting for reproducing short-wavelength ratio characteristics of natural light

The short-wavelength ratio of natural light that changes a day cycle helps maintain the circadian rhythm. The circadian rhythm is a phenomenon in which the flow of physical activity is repeated every 24 hours and is synchronized mainly by natural light. However, since people's exposure time to artificial lighting has increased recently, the issue of circadian rhythm imbalance has been raised, and lighting techniques for reproducing the color temperature or wavelength characteristics of natural light have been proposed. There has not been any case for the short-wavelength ratio cycle reproduction of natural light close to the circadian rhythm; thus, a circadian rhythm-assisted LED light that reproduces the short-wavelength ratio of natural light for one day is presented in this paper, and its effect is confirmed through animal experiment. After the lighting control standard is derived through the analysis of natural light characteristics, its periodic short-wavelength ratio is realized through the control of each LED lighting channel. Subsequently, rat-based animal experiment is conducted to analyze the amount of melatonin, a major factor in circadian rhythm. The results confirm that the proposed lighting environment has higher melatonin levels by about 17% (day7) and 24% (day14) compared with the general lighting environment.

Increased Expression of Colonic Mucosal Melatonin in Patients with Irritable Bowel Syndrome Correlated with Gut Dysbiosis

Dysregulation of the gut microbiota/gut hormone axis contributes to the pathogenesis of irritable bowel syndrome (IBS). Melatonin plays a beneficial role in gut motility and immunity. However, altered expression of local mucosal melatonin in IBS and its relationship with the gut microbiota remain unclear. Therefore, we aimed to detect the colonic melatonin levels and microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and explore their relationship in germ-free (GF) rats and BON-1 cells. Thirty-two IBS-D patients and twenty-eight healthy controls (HCs) were recruited. Fecal specimens from IBS-D patients and HCs were separately transplanted into GF rats by gavage. The levels of colon mucosal melatonin were assessed by immunohistochemical methods, and fecal microbiota communities were analyzed using 16S rDNA sequencing. The effect of butyrate on melatonin synthesis in BON-1 cells was evaluated by ELISA. Melatonin levels were significantly increased and negatively correlated with visceral hypersensitivity in IBS-D patients. GF rats inoculated with fecal microbiota from IBS-D patients had high colonic melatonin levels. Butyrate-producing Clostridium cluster XIVa species, such as Roseburia species and Lachnospira species, were positively related to colonic mucosal melatonin expression. Butyrate significantly increased melatonin secretion in BON-1 cells. Increased melatonin expression may be an adaptive protective mechanism in the development of IBS-D. Moreover, some Clostridium cluster XIVa species could increase melatonin expression via butyrate production. Modulation of the gut hormone/gut microbiota axis offers a promising target of interest for IBS in the future.

Effect of Exogenous Melatonin Administration in Critically Ill Patients on Delirium and Sleep: A Randomized Controlled Trial.

Introduction Sleep deprivation is a contributor for delirium in intensive care. Melatonin has been proposed as a pharmacological strategy to improve sleep, but studies have shown that the increase in plasma levels of melatonin do not correlate to a beneficial clinical effect; in addition, melatonin's short half-life may be a major limitation to achieving therapeutic levels. This study applies a previously published novel regimen of melatonin with proven sustained levels of melatonin during a 12 h period. In this study, the aim is to determine if such melatonin dosing positively influences on the sleep architecture and the incidence of delirium in intensive care. Methods Single center, randomized control trial with consecutive recruitment over 5 years. Medical and surgical patients were in a recovery phase, all weaning from mechanical ventilation. Randomized allocation to placebo or enteral melatonin, using a previously described regimen (loading dose of 3 mg at 21 h, followed by 0.5 mg hourly maintenance dose until 03am through a nasogastric tube). Sleep recordings were performed using polysomnogram at baseline (prior to intervention) and the third night on melatonin (postintervention recording). Delirium was assessed using the Richmond Agitation and the Confusion Assessment Method Scales. Environmental light and noise levels were recorded using a luxmeter and sound meter. Results 80 patients were screened, but 33 were recruited. Sleep studies showed no statistical differences on arousal index or length of sleep. Baseline delirium scores showed no difference between groups when compared to postintervention scores. RASS scores were 1 in both groups at baseline, compared to zero (drug group) and 0.5 (placebo group) posttreatment. CAM scores were zero (drug group) and 1 (placebo group) at baseline, compared to zero (in both groups) postintervention. Conclusion High levels of plasma melatonin during the overnight period of intensive care cohort patients did not improve sleep nor decreased the prevalence of delirium. This trial is registered with Anzctr.org.au/ACTRN12620000661976.aspx.

Serum Melatonin with Respect to Mental Health (Anxiety & Depression) Status of First Year M.B.B.S Students

Introduction: Melatonin is a pineal hormone secreted in circadian manner, with a peak during evening and night. Night-time light exposure is a powerful suppressor of nocturnal melatonin secretion. Dopamine and serotonin have complex relationship in melatonin synthesis and secretion. Reduced levels of melatonin have been associated with severe depression. Melatonin exhibits GABA-like effects may be responsible to reduce anxiety.
 Objectives: To determine the Serum Melatonin levels with respect to bedtime and its correlation with the severity of anxiety and depression. Also, to find the difference in anxiety score, depression score and serum melatonin level with respect to gender.
 Methods: A cross sectional study was done amongst first year medical students, and anxiety and depression score was calculated using Hamilton’s anxiety and depression scale. Estimation of Serum Melatonin was done on the fasting morning blood samples.
 Results and Conclusion: The present study shows that there is no significant difference in melatonin secretion in the students with late bedtime. With the increasing severity of the anxiety the serum melatonin was found to be lower, but the difference was not statistically significant. Similar results were observed with depression. The results shows non-significant higher anxiety and depression scores in females as compared to males. The study results also shows the significant high levels of melatonin in males as compared to females. Low melatonin levels in females may be attributed to high anxiety and depression in females.

Abstract C046: Racial and ethnic differences in the association of body mass index (BMI) and melatonin levels among men in the Multiethnic Cohort Study

Abstract Purpose Obesity and circadian rhythm disruption are risk factors for various cancers, including advanced prostate cancer. Given the differences in obesity rates by racial groups, the emerging evidence suggesting racial differences in circadian function, and the well-known racial disparities in cancer incidence and mortality, we aimed to explore the association between obesity and melatonin levels within a diverse population and assess how this association differed by racial/ethnic group. Methods This study leveraged 2,786 male controls from a nested case-control study within the Multiethnic Cohort Study. Melatonin was measured by its primary metabolite, 6-sulfatoxymelatonin, in first-morning void and overnight urine samples collected between 2001 and 2006 prior to cancer diagnosis. We categorized men based on body mass index (BMI) as underweight:<18.5 kg/m2; normal: 18.5 kg/m2 to <25 kg/m2; overweight: 25 kg/m2 to <30 kg/m2; and obese: 30 kg/m2. We used linear regression models to evaluate the association between obesity and melatonin levels, adjusted for urinary creatinine levels, age, race/ethnicity, occupation, years of schooling, month of urine collection, sleep duration, physical activity, smoking, and alcohol use. We further examined associations between obesity and melatonin within racial/ethnic groups. Results The prevalence of obesity differed by race/ethnicity, with 34.3% of Native Hawaiian (NH), 25.0% of African American (AA), 22.1% of Latino, 14.8% of White, and 10.6% of Japanese men categorized as obese (chisq p-value < 0.001). Latino and White men had the highest levels of melatonin with a median of 25.1 ng melatonin/mg creatinine; the median levels in Japanese (23.4 ng/mg), AA (23.0 ng/mg), and NH men (22.3 ng/mg) were lower (Kruskal-Wallis p-value=0.03). These differences remained after adjusting for BMI, with AAs having the lowest and Latinos the highest melatonin levels. In multivariable models, men who were obese had melatonin levels that were 16.9% (95% CI: 9.8%, 23.5%) lower than normal weight (NW) men. When stratified by race/ethnicity, we found that obese white men had 16.5% (95% CI: 3.0%, 28.1%) lower levels than NW white men; obese NH men had 23.7% (95% CI: 2.9%, 40.0%) lower levels than NW NH men; and obese Japanese men had 18.4% (95% CI: 7.5%, 28.1%) lower levels than NW Japanese men. Although not statistically significant, obesity was associated with lower melatonin levels among AA (13.9% lower, 95% CI: 29.6% lower, 5.2 % higher) and Latino (8.6% lower, 95% CI: 28.5% lower, 17.0% higher) men. Conclusion To our knowledge, this is the first study looking at the association between obesity and melatonin levels in a diverse population of men. We found that obese men had lower melatonin levels and that melatonin levels and obesity rates differed by racial groups. These findings will be expanded on to investigate the interplay between melatonin, obesity and race/ethnicity on risk of prostate cancer and potentially point to an underlying reason for racial disparities in cancer. Citation Format: Ilkania M Chowdhury-Paulino, Iona Cheng, Unnur A Valdimarsdottir, Loic Le Marchand, Christopher A Haiman, Lynne Wilkens, Lorelei A Mucci, Sarah C Markt. Racial and ethnic differences in the association of body mass index (BMI) and melatonin levels among men in the Multiethnic Cohort Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C046.

Plant Perception of Light: The role of indoleamines in Scutellaria species

Light mediates plant growth through diverse mechanisms and signaling networks including plant growth regulators (PGRs). We hypothesized that a novel class of PGRs, the indoleamines, are plant signaling molecules that perceive changes in light composition and initiate a cascade of metabolic responses. We used three Scutellaria model species (skullcap): S. lateriflora, S. galericulata and S. racemosa that produce high levels of melatonin and serotonin to investigate this hypothesis. Axenic Scutellaria cultures were exposed to red, blue, green or full spectrum white light spectra provided by light emitting diode (LED) lighting systems, or daylight fluorescent bulbs. Melatonin (MEL), serotonin (5HT), abscisic acid (ABA), auxin (IAA), and jasmonic acid (JA), were quantified by liquid chromatography with tandem mass spectrometry. Melatonin was detected consistently in plants grown under blue light in all species of Scutellaria. In S. galericulata, significant quantities of ABA were detected in plants grown under white light but not detected in plants grown under other light spectra. In timeline studies of S. racemosa plants exposed to limited red or blue light spectra had significantly reduced levels of tryptamine (TRM), 5HT and MEL in the shoots initially but melatonin was detected after 12 hours and quantifiable amounts of 5HT were detected after 7 days. Supplementation of the culture medium with MEL or 5HT did not change the pattern of MEL in blue light grown cultures but did change patterns of 5HT accumulation. 5HT was highest in plants grown under red light immediately after culture and decreased over 7 days. These data indicate that the relative amounts of MEL and 5HT are responsive to light spectra and redirect metabolic resources to enable plant adaptations to changing environments.

Measuring melatonin by immunoassay.

The pineal gland hormone melatonin continues to be of considerable interest to biomedical researchers. Of particular interest is the pattern of secretion of melatonin in relation to sleep timing as well as its potential role in certain diseases. Measuring melatonin in biological fluids such as blood and saliva presents particular methodological challenges since the production and secretion of the hormone are known to be extremely low during the light phase in almost all situations. Active secretion only occurs around the time of lights out in a wide range of species. The challenge then is to develop practical high-throughput assays that are sufficiently sensitive and accurate enough to detect levels of melatonin less than 1pg/mL in biological fluids. Mass spectrometry assays have been developed that achieve the required sensitivity, but are really not practical or even widely available to most researchers. Melatonin radioimmunoassays and ELISA have been developed and are commercially available. But the quality of the results that are being published is very variable, partly not only because of poor experimental designs, but also because of poor assays. In this review, I discuss issues around the design of studies involving melatonin measurement. I then provide a critical assessment of 21 immunoassay kits marketed by 11 different companies with respect to validation, specificity and sensitivity. Technical managers of the companies were contacted in an attempt to obtain information not available online or in kit inserts. A search of the literature was also conducted to uncover papers that have reported the use of these assays, and where possible, both daytime and night-time plasma or saliva melatonin concentrations were extracted and tabulated. The results of the evaluations are disturbing, with many kits lacking any validation studies or using inadequate validation methods. Few assays have been properly assessed for specificity, while others report cross-reaction profiles that can be expected to result in over estimation of the melatonin levels. Some assays are not fit for purpose because they are not sensitive enough to determine plasma or saliva DLMO of 10 and 3pg/mL, respectively. Finally, some assays produce unrealistically high daytime melatonin levels in humans and laboratory animals in the order of hundreds of pg/mL. In summary, this review provides a comprehensive and unique assessment of the current commercial melatonin immunoassays and their use in publications. It provides researchers new to the field with the information they need to design valid melatonin studies from both the perspective of experimental/clinical trial design and the best assay methodologies. It will also hopefully help journal editors and reviewers who may not be fully aware of the pitfalls of melatonin measurement make better informed decisions on publication acceptability.

Melatoninin kaynağı triptofanın IVF hastalarının sonuçlarına ve Doppler parametrelerine etkisi

Aims: Melatonin is the most powerful antioxidant and protects sperm, oocyte and embryo against oxidative stress. The effect of tryptophan, which is the building block of melatonin, on follicular melatonin levels and IVF outcomes is unknown. The objective of this study was to investigate the effect of tryptophan administration, a precursor for melatonin, on the levels of intrafollicular melatonin with the aim to reveal the correlation between tryptophan and the total number and quality of oocytes as well as clinical pregnancy rates. In addition, we aimed to examine the effect of melatonin increased by tryptophan on uterine and ovarian blood flow. Methods: Out of 103 patients who applied to Ondokuzmayis University IVF clinic for IVF treatment, 51 patients were administered a 100 mg dose of tryptophan orally (Group A) and 50 control patients who were randomly selected did not receive tryptophan (Group B). Firstly, follicular melatonin levels were compared between Group A receiving tryptophan and Group B without tryptophan. Both groups were also compared according to the oocyte count, oocyte count, fertilized oocyte count, embryo count and pregnancy rates, ultimately. In addition, all patients were measured for uterine and ovarian artery blood flow by vaginal ultrasound on the day of OPU.. Results: There were no differences in age (32.16 ± 3.82 years vs 33.06 ± 4.44 years) (p = 0.276), BMI (28.45 ± 2.82 kg/m)2 vs 28.15 ± 3.03kg/m2 (p = 0.602) and peak estradiol levels (2451.69 ± 469.75 pg/ml vs 2420.26 ± 443.71 pg / ml) (p = 0.73) between the groups. Group A exhibited high levels of melatonin in the follicular fluid with a mean value of 259.8 pg/ml, whereas Group B had 91.3 pg/ml (p <0.001). There were found significant differences in the oocyte count (9.08 ± 3.22 vs 7.66 ± 1.89) (p = 0,008), mature oocyte count (7.2 ± 2.8 vs 6.1 ± 1.8) (p = 0,021) and fertilized oocyte count (6.35 ± 2.44 vs 5.28 ± 1.69) between group A and group B. Pregnancy rates were higher in group A (35.3%). The pregnancy rate (30%) was lower in Group B, which did not receive tryptophan and had low melatonin levels in follicular fluid. However, there was no statistically significant difference. Uterine, ovarian artery systolic and diastolic blood flows of Group A were significantly lower than Group B (P <0.001). Conclusions: Administration of tryptophan to IVF patients significantly increases the level of melatonin in follicular fluid. The results demonstrate that high levels of melatonin in follicular fluid may increase oocyte count and quality although they do not significantly improve clinical pregnancy rates.

Injectable melatonin: an anti-cancer and anti-viral treatment option

Intravenous infusion of high doses of melatonin would represent the most eligible route to treat conveniently patients hospitalized in critical care units or with undergoing oncologic therapies, wherein adequate, accurate and constant dosages and high levels of melatonin would be required. After several attempts, a stable concentrate bulk solution of 10% melatonin (Survivis®) has been successfully achieved. The injectable route is also referred for lifethreatening injuries.

FACTORS AFFECTING BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS IN OLDER ADULTS WITH DEMENTIA

The purpose of this study was to identify factors predicting behavioral and psychological symptoms of dementia(BPSD) in older adults with Dementia. This is a cross-sectional study, recruiting 157 participants from neurology general hospital as study subjects. Data collection was performed from June 2018 to May 2019. BPSD were classified using a modified version of the Cohen‐Mansfield agitation inventory(CMAI), which are physically non-aggressive behaviors(PNAB), physically aggressive behaviors(PGAB), verbally non-aggressive behaviors(VNAB), verbally aggressive behaviors(VAGB). The Cornell scale for depression in dementia(CSDD), korea activity of daily living scale(K-ADL), korean mini-mental state examination(K-MMSE), activity and sleep time through using actigraphy for 2weeks, salivary melatonin and cortisol level at 4 times a day done after waking up, after breakfast, before and after dinner, and medication were measured as influencing factors. The generalized linear mixed model analyses indicated that VNAB and VAGB were associated with severe depression(p<0.01, respectively), low melatonin level at the after waking up (p<0.05, respectively), and high melatonin level before dinner(p<0.05, respectively). On the PNAB and PGAB, severe depression(p<0.05, respectively) and high activity(p<0.05, respectively) showed great influences. These findings suggest that developing of intervention of BPSD must be started with detecting depression, ADL. Considering the factors of each type of symptom, tailoring an individual approach is recommended. In addition, this study identified that the activity through actigraphy and salivary melatonin measurement are useful tools to examine BPSD. It can be helpful in the objective evaluation of BPSD.

Melatonin application reduces fluoride uptake and toxicity in rice seedlings by altering abscisic acid, gibberellin, auxin and antioxidant homeostasis

The manuscript presents an elaborate report on the ameliorative effects of exogenous melatonin in soil-grown seedlings of the rice variety, IR-64 subjected to prolonged fluoride stress. Exogenous melatonin stimulated the physiological growth of the stressed seedlings by triggering high accumulation of gibberellic acid (GA) and melatonin via up regulation of the biosynthetic genes like GA3ox, TDC, SNAT and ASMT. The endogenous abscisic acid (ABA) content increased via induction of NCED3 and suppression of ABA8ox1. However, the ABA-dependent genes like TRAB1, WRKY71 and OSBZ8 were down regulated in presence of high endogenous GA and melatonin. High melatonin level led to low indole-3-acetic acid accumulation in the treated seedlings during fluoride stress. Melatonin significantly decreased fluoride bioaccumulation by suppressing its uptake via CLC1 and CLC2, and also restored P–H+/ATPase expression. The damage indices like chlorosis (accompanied by low RuBisCo), malondialdehyde, electrolyte leakage, methylglyoxal (detoxified by glyoxalase II) and protein carbonylation were greatly reduced. Increased proline synthesis, activation of the ascorbate-glutathione cycle and enhanced activity of glutathione peroxidase, catalase and guaiacol peroxidase led to low ROS accumulation and localization in the melatonin-treated plants exposed to stress. Overall, melatonin treatment alleviated fluoride-mediated injuries by restricting fluoride uptake, refining the defence machinery and altering the phytohormone homeostasis.

Influence of Daytime LED Light Exposure on Circadian Regulatory Dynamics of Metabolism and Physiology in Mice.

Light is a potent biologic force that profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in animals. Previously we examined the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit more light in the blue-appearing portion of the visible spectrum (465 to 485 nm) than do broad-spectrum cool white fluorescent (CWF) light, on the nighttime melatonin amplitude and circadian regulation of metabolism and physiology. In the current studies, we tested the hypothesis that exposure to blue-enriched LED light at day (bLAD), compared with CWF, promotes the circadian regulation of neuroendocrine, metabolic, and physiologic parameters that are associated with optimizing homeostatic regulation of health and wellbeing in 3 mouse strains commonly used in biomedical research (C3H [melatonin-producing], C57BL/6, and BALB/c [melatonin-non-producing]). Compared with male and female mice housed for 12 wk under 12:12-h light:dark (LD) cycles in CWF light, C3H mice in bLAD evinced 6-fold higher peak plasma melatonin levels at the middark phase; in addition, high melatonin levels were prolonged 2 to 3 h into the light phase. C57BL/6 and BALB/c strains did not produce nighttime pineal melatonin. Body growth rates; dietary and water intakes; circadian rhythms of arterial blood corticosterone, insulin, leptin, glucose, and lactic acid; pO₂ and pCO₂; fatty acids; and metabolic indicators (cAMP, DNA, tissue DNA 3H-thymidine incorporation, fat content) in major organ systems were significantly lower and activation of major metabolic signaling pathways (mTOR, GSK3β, and SIRT1) in skeletal muscle and liver were higher only in C3H mice in bLAD compared with CWF. These data show that exposure of C3H mice to bLAD compared with CWF has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing that may influence scientific outcomes. The absence of enhancement in amelatonic strains suggests hyperproduction of nighttime melatonin may be a key component of the physiology.

Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy

This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.

Exogenous melatonin improves seed germination in Limonium bicolor under salt stress

ABSTRACTMelatonin involves in improving tolerance to abiotic and biotic stresses by regulating various biological processes. However, little is known about the underlying mechanism. Here, we investigated the effects of exogenous melatonin on seed germination in the halophyte Limonium bicolor under salt stress. Specifically, we examined the effect of salt stress on seed germination, melatonin concentration, and changes in the concentrations of nutrients, amylase activity, and hormones in L. bicolor seeds with and without pre-treatment with melatonin. Seed germination was significantly suppressed under a 200 mM NaCl treatment, but pre-treatment with melatonin significantly improved seed germination under salt stress. During seed germination, seeds pre-treated with melatonin contained high levels of melatonin and gibberellic acid (GA), low levels of abscisic acid (ABA), and high levels of amylase and alpha-amylase activity. Melatonin treatment upregulated the expression of key genes involved in GA biosynthesis (GA20ox and GA3ox), downregulated key genes involved in ABA biosynthesis (LbNCED1 and LbNCED3), and upregulated ABA 8ʹ-hydroxylase genes (LbCYP707A1 and LbCYP707A2), which mediate the changes in GA and ABA levels in seeds during germination. A high melatonin concentration in seeds promotes the utilization of nutrients and the synthesis of new proteins to enhance seed germination.

Exogenous melatonin delays postharvest fruit senescence and maintains the quality of sweet cherries

We assessed the effects of postharvest exogenous melatonin (50,100 and 150 µmol L−1) on the senescence and quality of sweet cherries during storage at 0 ± 0.5 °C. Melatonin treatment decreased decay incidence, respiration rate, and weight loss. It delayed the degradation of firmness, lightness, saturation, hue angle, titratable acidity, and total soluble solids content, thus maintaining better fruit quality. Melatonin treatment inhibited increases in O2−, H2O2, malondialdehyde content, and relative membrane permeability, while maintaining higher endogenous melatonin levels and increasing superoxide dismutase and catalase activity. Additionally, melatonin treatment enhanced the activity of antioxidant enzymes, increased the levels of ascorbic acid, and reduced glutathione levels, which are related to the ascorbate–glutathione cycle, as well as increasing the AsA:DHA and GSH:GSSG ratios. Delayed senescence in sweet cherries after exogenous melatonin treatment may be associated with high endogenous melatonin levels and increased antioxidant activity and content.

White LED Light Exposure Inhibits the Development and Xanthophore Pigmentation of Zebrafish Embryo

Circadian rhythm in all living organisms is disturbed continuously by artificial light sources and artificial lighting has become a hazard for public health. Circadian rhythm of melatonin maintains high levels of melatonin during the night and low levels during the day. N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is one of the four enzymes required for melatonin synthesis and mtnr1ba is a melatonin receptor-encoding mRNA that is expressed widely in the embryonic brain. Pax7 has important roles during neural crest development and especially xanthophore pigmentation. Due to its diurnal nature, zebrafish provide a special opportunity for research on circadian rhythms that are regulated by melatonin. Here in this study, we showed that when compared with the white light control group, white LED light exposure resulted in loss of yellow pigmentation, decreased body length and locomotor activity, oxidant-antioxidant imbalance and decreased expressions of aanat2, mtnr1ba, and pax7 in zebrafish embryos. Histological analysis of this group revealed disorganization of the spaces among photoreceptor cells, decreased total retinal thickness and photoreceptor cell layer thickness compared with the control group. Artificial lighting pollution has the potential to become an important risk factor for different diseases including cancer especially for industrialized countries, therefore, more studies should be performed and necessary regulations should be made regarding this risk factor.

Temporal expression patterns of the melatoninergic system in the human thymus of children

ObjectivesTo obtain greater knowledge of the extra-pineal sources of melatonin during development, the amount of indolamine and the expression levels of the last two enzymes involved in its biosynthesis, Arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT), were analyzed in the human thymus from children from three different age groups (from days to years). The melatonin membrane and nuclear receptor expression levels also were studied. MethodsQuantitative reverse transcriptase PCR and western blot were performed to investigate the receptor and enzyme expression levels. The results were examined and correlated with the ages of the thymuses. ResultsWe found high levels of indolamine in the thymuses of newborns (younger than 1 month), which decreased during development; thymuses from the months (from 2 to 11 months) and years (from 1 to 12 years) groups showed lower levels. A similar decline was also observed in the mRNA of the AANAT enzyme and the expression levels of melatonin receptors. However, ASMT expression was exactly the opposite, with low levels in the newborn group and higher levels in the years group. Our results show that the thymic synthesis of melatonin occurs very early in childhood. Additionally, this is the first report that is focused on melatonin receptors expression in the human thymus. ConclusionConsidering the limited melatonin synthesis performed by the newborn pineal gland, we suggest that the high levels of melatonin found in human thymus in this experimental group arise from synthesis in the tissue itself, which could be contributing to the immune efficiency at the thymic level.

Melatonin concentration in the milk of cows supplemented with vitamins and milked twice daily

Melatonin, a hormone secreted in cow milk, has beneficial effects on human health. This study aimed to evaluate the effects of dietary vitamin supplementation and nocturnal milking on the concentration of melatonin in cow milk. Twenty-one confined cows in the final period of lactation were used for the study and the supplemented vitamins were: rumen-protected B vitamins, A, D3, E, and niacin (B3) not protected from rumen degradation. The experimental period had a duration of 10 days. Milk samples were collected during the first two days, without supplementation of vitamins (WITHOUT), and during the final two days, eight days after the beginning of supplementation (WITH). Samples of milk produced without and with supplementation, milked at 05:00 h (NIGHT) or from the total milk produced in the two daily milkings (TOTAL), were analyzed. The concentration of melatonin was determined by enzyme immunoassay using the ELISA kit, and the results were analyzed by ANOVA and Tukey´s test with 5% significance. Supplementation of the diet with vitamins (WITH) did not affect melatonin concentration in TOTAL milk, but it resulted in a concentration 40.55% lower in the NIGHT milk than in the milk from cows without (WITHOUT) supplementation (6.57 vs. 11.06 pg mL-1). Milk milked at night showed melatonin concentrations 1.43 to 2.38 times higher than daily TOTAL milk. The total milk of the herd showed a concentration of 2.13 pg mL-1. The differentiated collection of milk produced during the night period makes it possible to obtain milk with high levels of melatonin.