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22 pages, 10339 KiB

Open AccessArticle

Melatonin Orchestrates Lipid Homeostasis through the Hepatointestinal Circadian Clock and Microbiota during Constant Light Exposure

by Fan Hong, Shijia Pan, Pengfei Xu, Tingting Xue, Jialin Wang, Yuan Guo, Li Jia, Xiaoxiao Qiao, Letong Li and Yonggong Zhai

Cells 2020, 9(2), 489; https://doi.org/10.3390/cells9020489 - 20 Feb 2020

Cited by 70 | Viewed by 7533

Abstract

Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining [...] Read more.

Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light–12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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17 pages, 4950 KiB

Open AccessArticle

Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac

by Aroha B. Sánchez, Beatriz Clares, María J. Rodríguez-Lagunas, María J. Fábrega and Ana C. Calpena

Cells 2020, 9(1), 180; https://doi.org/10.3390/cells9010180 - 10 Jan 2020

Cited by 13 | Viewed by 4215

Abstract

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are [...] Read more.

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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18 pages, 4207 KiB

Open AccessEditor’s ChoiceArticle

Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy

by Alessandra Stacchiotti, Ilaria Grossi, Raquel García-Gómez, Gaurangkumar Arvindbhai Patel, Alessandro Salvi, Antonio Lavazza, Giuseppina De Petro, Maria Monsalve and Rita Rezzani

Cells 2019, 8(9), 1053; https://doi.org/10.3390/cells8091053 - 8 Sep 2019

Cited by 66 | Viewed by 8368

Abstract

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but [...] Read more.

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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19 pages, 3437 KiB

Open AccessArticle

Melatonin Improves In Vitro Development of Vitrified-Warmed Mouse Germinal Vesicle Oocytes Potentially via Modulation of Spindle Assembly Checkpoint-Related Genes

by Zhenzheng Wu, Bo Pan, Izhar Hyder Qazi, Haoxuan Yang, Shichao Guo, Jingyu Yang, Yan Zhang, Changjun Zeng, Ming Zhang, Hongbing Han, Qingyong Meng and Guangbin Zhou

Cells 2019, 8(9), 1009; https://doi.org/10.3390/cells8091009 - 30 Aug 2019

Cited by 43 | Viewed by 5484

Abstract

The present study aimed to investigate the effect of melatonin (MT) supplementation on in vitro maturation of vitrified mouse germinal vesicle (GV) oocytes. The fresh oocytes were randomly divided into three groups: untreated (control), or vitrified by open-pulled straw method without (vitrification group) [...] Read more.

The present study aimed to investigate the effect of melatonin (MT) supplementation on in vitro maturation of vitrified mouse germinal vesicle (GV) oocytes. The fresh oocytes were randomly divided into three groups: untreated (control), or vitrified by open-pulled straw method without (vitrification group) or with MT supplementation (vitrification + MT group). After warming, oocytes were cultured in vitro, then the reactive oxygen species (ROS) and glutathione (GSH) levels, mitochondrial membrane potential, ATP levels, spindle morphology, mRNA expression of spindle assembly checkpoint (SAC)-related genes (Mps1, BubR1, Mad1, Mad2), and their subsequent developmental potential in vitro were evaluated. The results showed that vitrification/warming procedures significantly decreased the percentage of GV oocytes developed to metaphase II (MII) stage, the mitochondrial membrane potential, ATP content, and GSH levels, remarkably increased the ROS levels, and significantly impaired the spindle morphology. The expressions of SAC-related genes were also altered in vitrified oocytes. However, when 10⁻⁷ mol/L MT was administered during the whole length of the experiment, the percentage of GV oocytes matured to MII stage was significantly increased, and the other indicators were also significantly improved and almost recovered to the normal levels relative to the control. Thus, we speculate that MT might regulate the mitochondrial membrane potential, ATP content, ROS, GSH, and expression of SAC-related genes, potentially increasing the in vitro maturation of vitrified-warmed mouse GV oocytes. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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18 pages, 3815 KiB

Open AccessArticle

Antioxidant and Pro-Oxidant Activities of Melatonin in the Presence of Copper and Polyphenols In Vitro and In Vivo

by Jiajia Wang, Xiaoxiao Wang, Yufeng He, Lijie Jia, Chung S. Yang, Russel J. Reiter and Jinsong Zhang

Cells 2019, 8(8), 903; https://doi.org/10.3390/cells8080903 - 15 Aug 2019

Cited by 45 | Viewed by 6519

Abstract

Melatonin is a well-documented antioxidant. Physicochemical analysis using the density functional theory suggests that melatonin is a copper chelating agent; however, experimental evidence is still in demand. The present study investigated the influence of melatonin on reactive oxygen species (ROS) generated from polyphenol [...] Read more.

Melatonin is a well-documented antioxidant. Physicochemical analysis using the density functional theory suggests that melatonin is a copper chelating agent; however, experimental evidence is still in demand. The present study investigated the influence of melatonin on reactive oxygen species (ROS) generated from polyphenol autoxidation in the presence of copper. Surprisingly, we found that melatonin paradoxically enhanced ROS formation in a redox system containing low concentrations of copper and quercetin (Que) or (−)-epigallocatechin-3-gallate (EGCG), due to reduction of cupric to cuprous ion by melatonin. Addition of DNA to this system inhibited ROS production, because DNA bound to copper and inhibited copper reduction by melatonin. When melatonin was added to a system containing high concentrations of copper and Que or EGCG, it diminished hydroxyl radical formation as expected. Upon addition of DNA to high concentrations of copper and Que, this pro-oxidative system generated ROS and caused DNA damage. The DNA damage was not prevented by typical scavengers of hydroxyl radical DMSO or mannitol. Under these conditions, melatonin or bathocuproine disulfonate (a copper chelator) protected the DNA from damage by chelating copper. When melatonin was administered intraperitoneally to mice, it inhibited hepatotoxicity and DNA damage evoked by EGCG plus diethyldithiocarbamate (a copper ionophore). Overall, the present study demonstrates the pro-oxidant and antioxidant activities of melatonin in the redox system of copper and polyphenols. The pro-oxidant effect is inhibited by the presence of DNA, which prevents copper reduction by melatonin. Interestingly, in-vivo melatonin protects against copper/polyphenol-induced DNA damage probably via acting as a copper-chelating agent rather than a hydroxyl radical scavenger. Melatonin with a dual function of scavenging hydroxyl radical and chelating copper is a more reliable DNA guardian than antioxidants that only have a single function of scavenging hydroxyl radical. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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23 pages, 6926 KiB

Open AccessEditor’s ChoiceArticle

Neurological Enhancement Effects of Melatonin against Brain Injury-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration via AMPK/CREB Signaling

by Shafiq Ur Rehman, Muhammad Ikram, Najeeb Ullah, Sayed Ibrar Alam, Hyun Young Park, Haroon Badshah, Kyonghwan Choe and Myeong Ok Kim

Cells 2019, 8(7), 760; https://doi.org/10.3390/cells8070760 - 21 Jul 2019

Cited by 136 | Viewed by 11986

Abstract

Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) [...] Read more.

Oxidative stress and energy imbalance strongly correlate in neurodegenerative diseases. Repeated concussion is becoming a serious public health issue with uncontrollable adverse effects in the human population, which involve cognitive dysfunction and even permanent disability. Here, we demonstrate that traumatic brain injury (TBI) evokes oxidative stress, disrupts brain energy homeostasis, and boosts neuroinflammation, which further contributes to neuronal degeneration and cognitive dysfunction in the mouse brain. We also demonstrate that melatonin (an anti-oxidant agent) treatment exerts neuroprotective effects, while overcoming oxidative stress and energy depletion and reducing neuroinflammation and neurodegeneration. Male C57BL/6N mice were used as a model for repetitive mild traumatic brain injury (rmTBI) and were treated with melatonin. Protein expressions were examined via Western blot analysis, immunofluorescence, and ELISA; meanwhile, behavior analysis was performed through a Morris water maze test, and Y-maze and beam-walking tests. We found elevated oxidative stress, depressed phospho-5′AMP-activated protein kinase (p-AMPK) and phospho- CAMP-response element-binding (p-CREB) levels, and elevated p-NF-κB in rmTBI mouse brains, while melatonin treatment significantly regulated p-AMPK, p-CREB, and p-NF-κB in the rmTBI mouse brain. Furthermore, rmTBI mouse brains showed a deregulated mitochondrial system, abnormal amyloidogenic pathway activation, and cognitive functions which were significantly regulated by melatonin treatment in the mice. These findings provide evidence, for the first time, that rmTBI induces brain energy imbalance and reduces neuronal cell survival, and that melatonin treatment overcomes energy depletion and protects against brain damage via the regulation of p-AMPK/p-CREB signaling pathways in the mouse brain. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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18 pages, 6839 KiB

Open AccessArticle

Melatonin and (−)-Epigallocatechin-3-Gallate: Partners in Fighting Cancer

by Lingyun Zhang, Yufeng He, Ximing Wu, Guangshan Zhao, Ke Zhang, Chung S. Yang, Russel J. Reiter and Jinsong Zhang

Cells 2019, 8(7), 745; https://doi.org/10.3390/cells8070745 - 19 Jul 2019

Cited by 27 | Viewed by 5111

Abstract

We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (−)-epigallocatechin-3-gallate (EGCG) in mice. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of [...] Read more.

We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (−)-epigallocatechin-3-gallate (EGCG) in mice. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of p21. In human tongue cancer TCA8113 cells, melatonin-induced p21 and EGCG-mediated formation of quinoproteins were positively associated with the oncostatic effects of melatonin and EGCG. Melatonin-stimulated an increase in p21 which was correlated with a pronounced nuclear translocation of thioredoxin 1 and thioredoxin reductase 1, both of which are known to induce p21 via promoting p53 trans-activation. Melatonin did not influence the EGCG-mediated increase of quinoprotein formation nor did EGCG impair melatonin-induced p21 up-regulation. Co-treatment with both agents enhanced the cell-killing effect as well as the inhibitory activities against cell migration and colony formation. It is known that p21 also plays a powerful anti-apoptotic role in some cancer cells and confers these cells with a survival advantage, making it a target for therapeutic suppression. In human hepatocellular carcinoma HepG2 cells, melatonin suppressed p21 along with the induction of pro-survival proteins, PI3K and COX-2. However, EGCG prevented against melatonin-induced PI3K and COX-2, and melatonin probably sensitized HepG2 cells to EGCG cytotoxicity via down-regulating p21, Moreover, COX-2 and HO-1 were significantly reduced only by the co-treatment, and melatonin aided EGCG to achieve an increased inhibition on Bcl2 and NFκB. These events occurring in the co-treatment collectively resulted in an enhanced cytotoxicity. In addition, the co-treatment also enhanced the inhibitory activities against cell migration and colony formation. Overall, the results gathered from these two cancer cell lines with a divergent p21 response to melatonin show that the various oncostatic activities of melatonin and EGCG together are more robust than each agent alone, suggesting that they may be useful partners in fighting cancer. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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Review

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16 pages, 1145 KiB

Open AccessReview

Melatonin’s Antineoplastic Potential Against Glioblastoma

by Enrico Moretti, Gaia Favero, Luigi Fabrizio Rodella and Rita Rezzani

Cells 2020, 9(3), 599; https://doi.org/10.3390/cells9030599 - 3 Mar 2020

Cited by 23 | Viewed by 5366

Abstract

Glioblastoma (GBM) is one of the most intransigent and aggressive brain tumors, and its treatment is extremely challenging and ineffective. To improve patients’ expectancy and quality of life, new therapeutic approaches were investigated. Melatonin is an endogenous indoleamine with an incredible variety of [...] Read more.

Glioblastoma (GBM) is one of the most intransigent and aggressive brain tumors, and its treatment is extremely challenging and ineffective. To improve patients’ expectancy and quality of life, new therapeutic approaches were investigated. Melatonin is an endogenous indoleamine with an incredible variety of properties. Due to evidence demonstrating melatonin’s activity against several cancer hallmarks, there is growing interest in its use for preventing and treating cancer. In this review, we report on the potential effects of melatonin, alone or in combination with anticancer drugs, against GBM. We also summarize melatonin targets and/or the intracellular pathways involved. Moreover, we describe melatonin’s epigenetic activity responsible for its antineoplastic effects. To date, there are too few clinical studies (involving a small number of patients) investigating the antineoplastic effects of melatonin against GBM. Nevertheless, these studies described improvement of GBM patients’ quality of life and did not show significant adverse effects. In this review, we also report on studies regarding melatonin-like molecules with the tumor-suppressive properties of melatonin together with implemented pharmacokinetics. Melatonin effects and mechanisms of action against GBM require more research attention due to the unquestionably high potential of this multitasking indoleamine in clinical practice. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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23 pages, 1259 KiB

Open AccessFeature PaperReview

Impact of Melatonin on Skeletal Muscle and Exercise

by Alessandra Stacchiotti, Gaia Favero and Luigi Fabrizio Rodella

Cells 2020, 9(2), 288; https://doi.org/10.3390/cells9020288 - 24 Jan 2020

Cited by 53 | Viewed by 14698

Abstract

Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime [...] Read more.

Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut–muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of melatonin as a safe nutraceutical that limits skeletal muscle frailty and prolongs physical performance. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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14 pages, 1184 KiB

Open AccessReview

Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma

by Ko-Hsiu Lu, Renn-Chia Lin, Jia-Sin Yang, Wei-En Yang, Russel J. Reiter and Shun-Fa Yang

Cells 2019, 8(12), 1618; https://doi.org/10.3390/cells8121618 - 12 Dec 2019

Cited by 43 | Viewed by 6340

Abstract

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11–15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in [...] Read more.

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11–15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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23 pages, 1737 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans

by Bahare Salehi, Farukh Sharopov, Patrick Valere Tsouh Fokou, Agnieszka Kobylinska, Lilian de Jonge, Kathryn Tadio, Javad Sharifi-Rad, Malgorzata M. Posmyk, Miquel Martorell, Natália Martins and Marcello Iriti

Cells 2019, 8(7), 681; https://doi.org/10.3390/cells8070681 - 5 Jul 2019

Cited by 125 | Viewed by 17310

Abstract

Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood–brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, [...] Read more.

Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood–brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, up-regulating antioxidant enzymes, reducing mitochondrial electron leakage, and interfering with proinflammatory signaling pathways. Detected in various medicinal and food plants, its concentration is widely variable. Plant generative organs (e.g., flowers, fruits), and especially seeds, have been proposed as having the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. In addition, seeds are also rich in other substances (lipids, sugars, and proteins), constituting the energetic reserve for a potentially growing seedling and beneficial for the human diet. Thus, given that dietary melatonin is absorbed in the gastrointestinal tract and transported into the bloodstream, the ingestion of medicinal and plant foods by mammals as a source of melatonin may be conceived as a key step in serum melatonin modulation and, consequently, health promotion. Full article

(This article belongs to the Special Issue Melatonin in Human Health and Diseases)

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