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Melatonin's Impact on Antioxidative and Anti-Inflammatory

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Melatonin's Impact on Antioxidative and Anti-Inflammatory biomolecules Review Melatonin’s Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease 1, 2, 1 Diana Maria Chitimus y, Mihaela Roxana Popescu y , Suzana Elena Voiculescu , Anca Maria Panaitescu 3, Bogdan Pavel 1, Leon Zagrean 1 and Ana-Maria Zagrean 1,* 1 Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; [email protected] (D.M.C.); [email protected] (S.E.V.); [email protected] (B.P.); [email protected] (L.Z.) 2 Department of Cardiology, “Carol Davila” University of Medicine and Pharmacy, Elias University Hospital, 010164 Bucharest, Romania; [email protected] 3 Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, Filantropia Clinical Hospital, 010164 Bucharest, Romania; [email protected] * Correspondence: [email protected] These authors contributed equally to the work. y Received: 1 July 2020; Accepted: 18 August 2020; Published: 20 August 2020 Abstract: There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies. Keywords: melatonin; antioxidant; homeostasis; allostasis; maternal-fetal signaling; COVID 19; cardiovascular; neurodegenerative 1. Introduction Melatonin is a pineal hormone produced and released in relation to the circadian rhythm, while also synthesized in extrapineal tissues, like heart, liver, placenta, skin, kidney, gut, etc. [1–4]. Melatonin is an important regulator of physiologic processes and a guardian of body homeostatic balance. Its level varies during the day from 5 to 200 pg/mL [5]. Melatonin has antioxidant effects exerted through direct and indirect mechanisms that make this unrivaled multitasking molecule an endogenous protector against highly toxic oxygen- and nitrogen-derived free radicals. The main mechanisms of action attributed to melatonin are free radical Biomolecules 2020, 10, 1211; doi:10.3390/biom10091211 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 30 Biomolecules 2020, 10, 1211 2 of 28 derived free radicals. The main mechanisms of action attributed to melatonin are free radical scavenging, endogenous antioxidative enzymes stimulation, and improving the efficiency of other scavenging,antioxidants. endogenous Melatonin’s antioxidative particularity is enzymes that together stimulation, with its andmetabolites, improving which the eactffi ciencyas antioxidants of other antioxidants.themselves, creates Melatonin’s an antioxidant particularity cascade is that that together yields with radical its metabolites, scavenger products which act [6] as,antioxidants limiting the themselves,oxidative damage creates through an antioxidant a variety cascade of mechanisms that yields [7,8] radical. Thus, scavenger the radical products quencher [6], limitingproperty the of oxidativemelatonin damage against the through hydroxyl a variety radical of (OH) mechanisms is superior [7 ,to8]. that Thus, of glutathione the radical, while quencher its action property against of melatoninthe peroxyl against radical the (ROO hydroxyl) involves radical single (OH) electron is superior transfer, to that hydrogen of glutathione, atom transfer, while itsor radical action against adduct theformation peroxyl [8,9] radical. Besides (ROO) lowering involves the single amount electron of free transfer, radicals, hydrogen melatonin atom can transfer, also interact or radical with adduct non- formation [8,9]. Besides lowering the amount of free radicals, melatonin can also interact with radical oxidants such as hydrogen peroxide (H2O2), singlet oxygen (1O2), and peroxynitrite (HNOO) 1 non-radical[6,10]. Melatonin oxidants is effective such as in hydrogen inhibiting peroxide metal-induced (H2O2), oxidation, singlet oxygen as it was ( O reported2), and peroxynitrite for copper, a (HNOO)redox generating [6,10]. Melatonin metal, but is it e alsoffective chelates in inhibiting iron, lead, metal-induced zinc, and aluminum oxidation, [8]. as it was reported for copper,Along a redox with generating its free radical metal, scavenging but it also chelatesproperties, iron, melatonin lead, zinc, protects and aluminum the mitochondria [8]. against oxidativeAlong stress with itsby free influencing radical scavenging the mitochondrial properties, membrane melatonin potential protects, thethus mitochondria facilitating electron against oxidativetransfer antioxidant stress by influencing processes the within mitochondrial the cell [11] membrane. The roles potential, of melatonin thus facilitating within mitochondria electron transfer are antioxidantexemplified processes in Figure within 1. the cell [11]. The roles of melatonin within mitochondria are exemplified in Figure1. Glut/SLC2A Figure 1. The roles of melatonin within the mitochondria. Melatonin is transported into mitochondria throughFigure 1. PEPT1The roles/2 oligopeptideof melatonin within and Glut the/ SLC2Amitochondria. transporters, Melatonin but is ittransported is also synthesized into mitochondria within mitochondriathrough PEPT1/2 [12,13 ].oligopeptide Melatonin lowers and Glut/SLC2A the formation transporters, of free radicals but and it protectsis also ATPsynthesized synthesis within at the mitochondrialmitochondria level.[12,13] It. scavengesMelatoninfree lowers oxygen the (ROS)formation and nitrogenof free radicals (RNS) reactiveand protects species, ATP by synthesis preventing at mitochondrialthe mitochondrial apoptosis level. andIt scavenges disruption free of oxygen the electron (ROS) transport and nitrogen chain. (RNS) Melatonin reactive interacts species, with by MT1preventing and MT2 mitochondrial melatonin receptors, apoptosis inhibits and disruption pro-apoptosis of the protein electron synthesis, transport and thechai subsequentlyn. Melatonin cytochromeinteracts with Cleakage MT1 and at theMT2 level melatonin of the membrane. receptors, inhibits It also protects pro-apoptosis mitochondrial protein DNA synthesis, and prevents and the thesubsequently opening of cytochrome the mitochondrial C leakage permeability at the level transition of the membrane. pore (mPTP) It also [13 protects]. mitochondrial DNA and prevents the opening of the mitochondrial permeability transition pore (mPTP) [13]. Melatonin works through both receptor-independent and receptor-dependent antioxidant processes.Melatonin Through works its receptor-mediated through both receptor actions,- melatoninindependent either and inhibits receptor pro-oxidative-dependent enzymes antioxidant such asprocesses. xanthine Through oxidase orits enhances receptor- themediated activity actions, of superoxide melatonin dismutase either inhibits (SOD), glutathionepro-oxidative peroxidase, enzymes andsuch catalase as xanthine [12,13 ].oxidase or enhances the activity of superoxide dismutase (SOD), glutathione peroxidaseGrowing, and evidence catalase supports [12,13]. the anti-inflammatory role of melatonin, both in acute and chronic inflammationGrowing processes. evidence However,supports mostthe anti of- theinflammatory data are obtained role of frommelatonin,in vitro bothand in vivoacuteexperimental and chronic studies,inflammation while clinicalprocesses. studies However, have proven most inconsistentof the data resultsare obtained [14]. Administration from in vitro ofand exogenous in vivo melatoninexperimental in animal studies, studies, while clinical prior to studies acute conditions,have proven have inconsistent shown a results decrease [14] in. theAdministration inflammatory of response,exogenous a reductionmelatonin ofin pro-inflammatoryanimal studies, prior cytokines, to acute interleukine-1 conditions, βhave(IL-1 shownβ), and a tumordecrease necrosis in the factor-inflammatoryα (TNF-α response,), and an increase a reduction in anti-inflammatory of pro-inflammatory cytokine cytokines, IL-4 levels interleukine in serum [15-,161β]. ( InIL- addition,1β), and melatonintumor necrosis inhibits factor the- expressionα (TNF-α), of and cyclooxygenase an increase in (COX) anti-inflammatory and inducible cytokine nitric oxide IL-4 synthase levels in (iNOS), serum Biomolecules 2020, 10, x FOR PEER REVIEW 3 of 30 Biomolecules 2020
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