Editorial

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3 pages, 183 KiB

Open AccessEditorial

Melatonin: A Myriad of Functions to Discover

by Adrián Santos-Ledo and Marina García-Macia

Antioxidants 2024, 13(3), 360; https://doi.org/10.3390/antiox13030360 - 18 Mar 2024

Viewed by 702

Abstract

Melatonin is an indoleamine that has captured our attention since 1958 [...] Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

Research

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21 pages, 11327 KiB

Open AccessArticle

REDOX Balance in Oligodendrocytes Is Important for Zebrafish Visual System Regeneration

by Cristina Pérez-Montes, Jhoana Paola Jiménez-Cubides, Almudena Velasco, Rosario Arévalo, Adrián Santos-Ledo and Marina García-Macia

Antioxidants 2023, 12(12), 2026; https://doi.org/10.3390/antiox12122026 - 22 Nov 2023

Viewed by 1331

Abstract

Zebrafish (Danio rerio) present continuous growth and regenerate many parts of their body after an injury. Fish oligodendrocytes, microglia and astrocytes support the formation of new connections producing effective regeneration of the central nervous system after a lesion. To understand the [...] Read more.

Zebrafish (Danio rerio) present continuous growth and regenerate many parts of their body after an injury. Fish oligodendrocytes, microglia and astrocytes support the formation of new connections producing effective regeneration of the central nervous system after a lesion. To understand the role of oligodendrocytes and the signals that mediate regeneration, we use the well-established optic nerve (ON) crush model. We also used sox10 fluorescent transgenic lines to label fully differentiated oligodendrocytes. To quench the effect of reactive oxygen species (ROS), we used the endogenous antioxidant melatonin. Using these tools, we measured ROS production by flow cytometry and explored the regeneration of the optic tectum (OT), the response of oligodendrocytes and their mitochondria by confocal microscopy and Western blot. ROS are produced by oligodendrocytes 3 h after injury and JNK activity is triggered. Concomitantly, there is a decrease in the number of fully differentiated oligodendrocytes in the OT and in their mitochondrial population. By 24 h, oligodendrocytes partially recover. Exposure to melatonin blocks the changes observed in these oligodendrocytes at 3 h and increases their number and their mitochondrial populations after 24 h. Melatonin also blocks JNK upregulation and induces aberrant neuronal differentiation in the OT. In conclusion, a proper balance of ROS is necessary during visual system regeneration and exposure to melatonin has a detrimental impact. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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21 pages, 3778 KiB

Open AccessArticle

Agomelatine, a Melatonin-Derived Drug, as a New Strategy for the Treatment of Colorectal Cancer

by Sara Moreno-SanJuan, Jose D. Puentes-Pardo, Jorge Casado, Julia Escudero-Feliu, Huda Khaldy, Javier Arnedo, Ángel Carazo and Josefa León

Antioxidants 2023, 12(4), 926; https://doi.org/10.3390/antiox12040926 - 13 Apr 2023

Cited by 3 | Viewed by 2411

Abstract

The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) [...] Read more.

The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) and an in vivo xenograft model. The inhibitory effects of agomelatine and melatonin were stronger in the cells harboring the wild-type p53, although in both cell lines, the effect of agomelatine was greater than that of the melatonin. In vivo, only agomelatine was able to reduce the volumes of tumors generated by the HCT-116-p53-null cells. Both treatments induced changes in the rhythmicity of the circadian-clock genes in vitro, albeit with some differences. Agomelatine and melatonin regulated the rhythmicity of Per1-3, Cry1, Sirt1, and Prx1 in the HCT-116 cells. In these cells, agomelatine also regulated Bmal1 and Nr1d2, while melatonin changed the rhythmicity of Clock. In the HCT-116-p53-null cells, agomelatine regulated Per1-3, Cry1, Clock, Nr1d2, Sirt1, and Prx1; however, melatonin only induced changes in Clock, Bmal1, and Sirt1. The differences found in the regulation of the clock genes may explain the greater oncostatic effect of agomelatine in CRC. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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14 pages, 5624 KiB

Open AccessArticle

Pro-Apoptotic and Anti-Migration Properties of a Thiazoline-Containing Platinum(II) Complex in MDA-MB-231 Breast Cancer Cells: The Role of Melatonin as a Synergistic Agent

by Samuel Estirado, Elena Fernández-Delgado, Emilio Viñuelas-Zahínos, Francisco Luna-Giles, Ana B. Rodríguez, José A. Pariente and Javier Espino

Antioxidants 2022, 11(10), 1971; https://doi.org/10.3390/antiox11101971 - 01 Oct 2022

Cited by 3 | Viewed by 1892

Abstract

Triple-negative breast cancer (TNBC) is an aggressive cancer insensitive to hormonal and human epidermal growth factor receptor 2 (HER2)-targeted therapies and has a poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies for the management of TNBC. In [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive cancer insensitive to hormonal and human epidermal growth factor receptor 2 (HER2)-targeted therapies and has a poor prognosis. Therefore, there is a need for the development of convenient anticancer strategies for the management of TNBC. In this paper, we evaluate the antitumoral potential of a platinum(II) complex coordinated with the ligand 2-(3,5-diphenylpyrazol-1-yl)-2-thiazoline (DPhPzTn), hereafter PtDPhPzTn, against the TNBC cell line MDA-MB-231, and compared its effect with both cisplatin and its less lipophilic counterpart PtPzTn, the latter containing the ligand 2-(pyrazol-1-yl)-2-thiazoline (PzTn). Then, the putative potentiating actions of melatonin, a naturally occurring antioxidant with renowned antitumor properties, on the tumor-killing ability of PtDPhPzTn were also checked in TNBC cells. Our results show that PtDPhPzTn presented enhanced cytotoxicity compared to both the classical drug cisplatin and PtPzTn. In addition, PtDPhPzTn was able to induce apoptosis, being more selective for MDA-MB-231 cells when compared to non-tumor breast epithelial MCF10A cells. Likewise, PtDPhPzTn produced moderate S phase arrest and greatly impaired the migration ability of MDA-MB-231 cells. Most importantly, the co-stimulation of TNBC cells with PtDPhPzTn and melatonin substantially enhanced apoptosis and markedly improved the anti-migratory action compared to PtDPhPzTn alone. Altogether, our findings provide evidence that PtDPhPzTn and melatonin could be potentially applied to breast cancer treatment as powerful synergistic agents. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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21 pages, 3558 KiB

Open AccessArticle

Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity

by Samira Aouichat, Enrique Raya, Antonio Molina-Carballo, Antonio Munoz-Hoyos, Abdelkarim Saleh Aloweidi, Ehab Kotb Elmahallawy and Ahmad Agil

Antioxidants 2022, 11(9), 1646; https://doi.org/10.3390/antiox11091646 - 25 Aug 2022

Cited by 6 | Viewed by 2314

Abstract

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into [...] Read more.

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg/kg. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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17 pages, 2647 KiB

Open AccessArticle

Melatonin Nuclear Receptors Mediate Green-and-Blue-Monochromatic-Light-Combinations-Inhibited B Lymphocyte Apoptosis in the Bursa of Chickens via Reducing Oxidative Stress and Nfκb Expression

by Yijia Zhang, Zixu Wang, Yulan Dong, Jing Cao and Yaoxing Chen

Antioxidants 2022, 11(4), 748; https://doi.org/10.3390/antiox11040748 - 08 Apr 2022

Cited by 2 | Viewed by 1807

Abstract

Previous studies found that melatonin modulates a combination of green-and-blue-light-induced B-lymphocyte proliferation via its membrane receptors Mel1a and Mel1c. However, in addition to its membrane-bound receptors, melatonin also functions through binding to nuclear receptors RORα/RORβ/RORγ. In this study, we raised 120 chicks under [...] Read more.

Previous studies found that melatonin modulates a combination of green-and-blue-light-induced B-lymphocyte proliferation via its membrane receptors Mel1a and Mel1c. However, in addition to its membrane-bound receptors, melatonin also functions through binding to nuclear receptors RORα/RORβ/RORγ. In this study, we raised 120 chicks under 400–700 nm white (WW), 660 nm red (RR), 560 nm green (GG) and 480 nm blue light (BB) from P0 to P26. From P27 to P42, half of the chickens in green, blue and red were switched to blue (G→B), green (B→G) and red (R→B), respectively. We used immunohistochemistry, Western blotting, qRT-PCR, Elisa and MTT to investigate the influence of various monochromatic light combinations on the bursal B lymphocyte apoptosis and oxidative stress levels as well as estimate whether melatonin and its nuclear receptors were involved in this process. Consistent with the increase in the plasma melatonin concentration and antioxidant enzyme activity, we observed that G→B significantly decreased the RORα, RORγ mRNA level, inhibited Bax, Caspase-3 and p-iκb, p-p65 protein expression, increased the IL-10 level and Nrf2, HO-1 protein expression, down-regulated the MDA and pro-inflammatory IL-6, TNF-α and IFN-γ levels in the bursa compared with WW, RR, GG, BB and R→B, respectively. Our in vitro results showed exogenous melatonin supplementation inhibited B-lymphocyte apoptosis, decreased IL-6, TNF-α, IFN-γ and ROS production, down-regulated RORα, RORγ mRNA level and p-iκb and p-p65 protein expression, whereas it improved the IL-10 level and Nrf2 and the HO-1 protein expression in bursal B lymphocyte. Moreover, these responses were abrogated by RORα agonist SR1078 but were mimicked by RORα antagonist SR3335 or RORγ antagonist GSK2981278. In addition, p65 antagonist BAY reversed RORα/RORγ-mediated G→B-inhibited bursal B lymphocyte apoptosis. Overall, we concluded that melatonin nuclear RORα/RORγ mediates G→B-inhibited bursal B lymphocyte apoptosis via reducing oxidative stress and Nfκb expression. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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13 pages, 1948 KiB

Open AccessArticle

Functional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium

by Kyungjin Lee, Geun-Hee Choi and Kyoungwhan Back

Antioxidants 2022, 11(3), 596; https://doi.org/10.3390/antiox11030596 - 21 Mar 2022

Cited by 11 | Viewed by 2539

Abstract

Serotonin N-acetyltransferase is the penultimate enzyme in the melatonin biosynthetic pathway that catalyzes serotonin into N-acetylserotonin. Many SNAT genes have been cloned and characterized from organisms ranging from bacteria to plants and mammals. However, to date, no SNAT gene has been [...] Read more.

Serotonin N-acetyltransferase is the penultimate enzyme in the melatonin biosynthetic pathway that catalyzes serotonin into N-acetylserotonin. Many SNAT genes have been cloned and characterized from organisms ranging from bacteria to plants and mammals. However, to date, no SNAT gene has been identified from Archaea. In this study, three archaeal SNAT candidate genes were synthesized and expressed in Escherichia coli, and SNAT enzyme activity was measured using their purified recombinant proteins. Two SNAT candidate genes, from Methanoregulaceae (Archaea) and Pyrococcus furiosus, showed no SNAT enzyme activity, whereas a SNAT candidate gene from Thermoplasma volcanium previously named TvArd1 exhibited SNAT enzyme activity. The substrate affinity and the maximum reaction rate of TvSNAT toward serotonin were 621 μM and 416 pmol/min/mg protein, respectively. The highest amine substrate was tyramine, followed by tryptamine, serotonin, and 5-methoxytryptamine, which were similar to those of plant SNAT enzymes. Homologs of TvSNAT were found in many Archaea families. Ectopic overexpression of TvSNAT in rice resulted in increased melatonin content, antioxidant activity, and seed size in conjunction with the enhanced expression of seed size-related gene. This study is the first to report the discovery of SNAT gene in Archaea. Future research avenues include the cloning of TvSNAT orthologs in different phyla, and identification of their regulation and functions related to melatonin biosynthesis in living organisms. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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Review

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18 pages, 880 KiB

Open AccessReview

Melatonin in Neurodevelopmental Disorders: A Critical Literature Review

by Cyrille Feybesse, Sylvie Chokron and Sylvie Tordjman

Antioxidants 2023, 12(11), 2017; https://doi.org/10.3390/antiox12112017 - 20 Nov 2023

Cited by 1 | Viewed by 1579

Abstract

The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its physiological effects are considered to understand better the role of melatonin in typical and atypical neurodevelopment. Then, several neurodevelopmental disorders occurring during [...] Read more.

The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its physiological effects are considered to understand better the role of melatonin in typical and atypical neurodevelopment. Then, several neurodevelopmental disorders occurring during infancy, such as autism spectrum disorder or neurogenetic disorders associated with autism (including Smith–Magenis syndrome, Angelman syndrome, Rett’s syndrome, Tuberous sclerosis, or Williams–Beuren syndrome) and neurodevelopmental disorders occurring later in adulthood like bipolar disorder and schizophrenia, are discussed with regard to impaired melatonin production and circadian rhythms, in particular, sleep–wake rhythms. This article addresses the issue of overlapping symptoms that are commonly observed within these different mental conditions and debates the role of abnormal melatonin production and altered circadian rhythms in the pathophysiology and behavioral expression of these neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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17 pages, 742 KiB

Open AccessReview

Potential Neuroprotective Role of Melatonin in Sepsis-Associated Encephalopathy Due to Its Scavenging and Anti-Oxidative Properties

by Mariusz Sieminski, Karolina Szaruta-Raflesz, Jacek Szypenbejl and Klaudia Krzyzaniak

Antioxidants 2023, 12(9), 1786; https://doi.org/10.3390/antiox12091786 - 21 Sep 2023

Cited by 1 | Viewed by 1276

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of [...] Read more.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The brain is one of the organs involved in sepsis, and sepsis-induced brain injury manifests as sepsis-associated encephalopathy (SAE). SAE may be present in up to 70% of septic patients. SAE has a very wide spectrum of clinical symptoms, ranging from mild behavioral changes through cognitive disorders to disorders of consciousness and coma. The presence of SAE increases mortality in the population of septic patients and may lead to chronic cognitive dysfunction in sepsis survivors. Therefore, therapeutic interventions with neuroprotective effects in sepsis are needed. Melatonin, a neurohormone responsible for the control of circadian rhythms, exerts many beneficial physiological effects. Its anti-inflammatory and antioxidant properties are well described. It is considered a potential therapeutic factor in sepsis, with positive results from studies on animal models and with encouraging results from the first human clinical trials. With its antioxidant and anti-inflammatory potential, it may also exert a neuroprotective effect in sepsis-associated encephalopathy. The review presents data on melatonin as a potential drug in SAE in the wider context of the pathophysiology of SAE and the specific actions of the pineal neurohormone. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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20 pages, 1287 KiB

Open AccessReview

Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics

by Eva Ramos, Emilio Gil-Martín, Cristóbal De Los Ríos, Javier Egea, Francisco López-Muñoz, René Pita, Antonio Juberías, Juan J. Torrado, Dolores R. Serrano, Russel J. Reiter and Alejandro Romero

Antioxidants 2023, 12(2), 397; https://doi.org/10.3390/antiox12020397 - 06 Feb 2023

Cited by 6 | Viewed by 2378

Abstract

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that [...] Read more.

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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13 pages, 1219 KiB

Open AccessReview

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

by Javier Florido, César Rodriguez-Santana, Laura Martinez-Ruiz, Alba López-Rodríguez, Darío Acuña-Castroviejo, Iryna Rusanova and Germaine Escames

Antioxidants 2022, 11(8), 1621; https://doi.org/10.3390/antiox11081621 - 20 Aug 2022

Cited by 22 | Viewed by 6030

Abstract

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by [...] Read more.

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications. Full article

(This article belongs to the Special Issue Free-Radical Scavenging and Antioxidant Properties of Melatonin)

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