Please cite this paper as:

Mukhopadhyay, M., Majumder, R., Banerjee, A. and Bandyopadhyay, D. 2022. A comparative overview on the role of melatonin and vitamins as potential antioxidants against oxidative stress induced degenerative infirmities: An emerging concept. Melatonin Research. 5, 3 (Sep. 2022), 254-277. DOI:https://doi.org/https://doi.org/10.32794/mr112500131.

Review 

A comparative overview on the role of melatonin and vitamins as potential antioxidants against oxidative stress induced degenerative infirmities: An emerging concept 

Manisha Mukhopadhyay^a, Romit Majumder^ab,  Adrita Banerjee^ab, Debasish Bandyopadhyay^a* 

^aOxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata-700009, India

^bDepartment of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata-700006, India

*Correspondence: debasish63@gmail.com, Tel: +91-9433072066 

Running title: Comparative analysis of antioxidant properties of vitamins and melatonin 

Received: June 13, 2022; Accepted: September 9, 2022.

ABSTRACT

Oxidative stress is a biological phenomenon clarified as the decreased ability of the antioxidative system to neutralize the excessive reactive oxygen species (ROS). At a low concentration, ROS serves as a signal molecule to exert its physiological functions but the persistently excessive ROS predisposes a variety of disorders including coronary heart diseases, atherosclerosis, diabetes mellitus, hemolytic anemia, pulmonary diseases, neurodegenerative disorders, etc. The use of antioxidants to protect against oxidative damage is a well-established practice. In these aspects, melatonin and other classical antioxidant vitamins such as carotenoids, α-tocopherol, vitamin D, and ascorbic acid have gained enormous research attention currently. In this review, we will discuss the comparative as well as the synergistic actions of melatonin and other antioxidant vitamins in the treatment of oxidative stress-associated disorders. Noteworthy, based on the evidences we will discuss, we recommend the combination of melatonin and vitamins to alleviate oxidative damage in the broad spectrum.

Keywords: ROS, antioxidant, vitamin, melatonin, synergistic action, degenerative diseases.

_________________________________________________________________________________________________________________________

​1.      INTRODUCTION

Reactive oxygen species (ROS) or reactive oxygen intermediates (ROI) are produced as the by-products of normal cellular metabolism. At low or moderate concentrations, ROS facilitates several physiological processes including the killing of invading pathogens, wound healing, and tissue repairment (1). ROS also acts as important signaling molecules by modulating several redox-sensitive signaling pathways. A delicate balance exists between ROS production and antioxidant defense capacity in all organisms. This balance maintains the homeostasis of the intracellular environments, otherwise, its imbalance will cause oxidative damage to cells. It has been documented that oxidative stress perturbs the mitochondrial function of energy supply and leads to apoptosis (2). Naturally, cells are equipped with antioxidant machinery including enzymatic components such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) (3) as well as non-enzymatic substances including vitamins such as ascorbic acid, alpha-tocopherol, carotenoids and vitamin D (4). Most of these vitamins, except vitamin D, are acquired from the diet. They are highly crucial for maintaining normal cellular functions and their deficiencies may predispose health issues (4).

     Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan derivative, is well recognized for its antioxidative function. A combination of free radical scavenging, metal chelating, and antioxidative enzyme stimulating properties make melatonin a superior choice over other classical antioxidative molecules (5). Despite the endocrinal properties of melatonin, it can be portrayed as a vitamin from a nutritional point of view since it is also present in foods including vegetables, fruits, seeds, rice, medicinal herbs, meat, fish, eggs, and wine at high concentrations (6, 7). Melatonin possesses several functional similarities with vitamin D and A (6). Numerous studies have confirmed the antioxidant potency of melatonin and the underlying mechanisms through which melatonin counteracts oxidative stress (8-11). However, to our best knowledge, few studies have investigated the preventive potential of vitamins on oxidative stress-associated diseases. Additionally, synergistic effects of melatonin and vitamins toward amelioration of oxidative damage remain less explored yet. This review aims to discuss the potential role of vitamins and melatonin in attenuating tissue or cellular oxidative damage, either synergistically or additively.

2.      ROS PRODUCTION AT A GLANCE

Electron transport chain (ETC), the major energy generating pathway, is the harbor of free radical generation. Leakage of electrons from the respiratory chain generates super-oxide anion (O₂•^-), which further leads to the formation of highly reactive hydroxyl radical (•OH), lipid peroxides, hydrogen peroxide (H₂O₂), hypochlorous acid (HOCl) along with reactive nitrogen species (RNS) such as nitric oxide (NO) and peroxynitrite (ONOO•) (12, 13). The H₂O₂ is mainly generated by superoxide dismutase (SOD). In the presence of transition metals such as Fe²⁺ and Cu⁺, H₂O₂ is catalysed to form the most deleterious •OH via Fenton reaction (13-15) (Figure 1). In addition, other enzymatic reactions also can produce ROS including the NADH oxidase, cycloxidase 2 (COX 2), and, cytochrome P450 system (14-17). The phagocytotic process also involves in free radical generation. The non-enzymatic reactions are another source of ROS generation when oxygen reacts with certain organic compounds, cells are exposed to ionizing radiation, or mitochondria are stressed (16-18). Generally, when heavy metals (Cd, Hg, Pb, Fe, and As), some drugs (cyclosporine, tacrolimus, gentamycin, bleomycin), chemical solvents, oxidized food (smoked meat, used oil and fat), cigarette smoke, alcohol are exposed to cells under certain conditions, all of them can produce free radicals as by-products (1, 18, 19). The excessive ROS oxidizes lipid, protein, DNA, and damages cellular structures (14-17). Especially, the •OH and ONOO• are the most reactive species and are the major culprits of cellular lipid peroxidation and membrane damage (2). ROS can also make proteins and DNA oxidative damage to form carboxyl protein and 8-hydroxyguanosine, respectively (2, 20, 21). Overproduction of free radicals for a prolonged period not only triggers chronic and degenerative diseases including atherosclerosis,  diabetes, neurodegenerative diseases, arthritis, and cancer but also accelerates the aging process and inflammation (22, 23).

Fig. 1. ROS  generation in mitochondria and the potential consequences.

3.      ANTIOXIDANTS AGAINST OXIDATIVE STRESS

Antioxidants are those compounds that inhibit molecular oxidation by interrupting radical chain reactions (24). They can donate electron(s) to neutralize ROS  (25). They are usually low molecular weight molecules and can reduce free radicals to cease their propagation reaction and protect the vital molecules. Glutathione, ubiquinol, and uric acid are antioxidants produced endogenously by normal metabolism. Together with the antioxidant enzymes SOD, CAT and GPx they build the first line of cellular defense against oxidative stress (25, 26). This defense system controls the  ROS at a low level. This low level of ROS serves as the physiological redox signaling and also the stimulator of endogenous antioxidant machinery (27). Mitochondria-targeted antioxidants are considered more potent than others since mitochondria are the main site of ROS generation. To access mitochondria, these antioxidants are required to cross the mitochondrial membrane (28). For example, the triphenylphosphonium cation (TPP+) with a positively charged phosphorous atom surrounded by a lipophilic surface can enter mitochondria with ease. Therefore,  ubiquinone moiety of coenzyme Q and vitamin E conjugated with TPP are considered as mitochondrial-targeted antioxidants (29).

4. VITAMINS AS ANTIOXIDANTS

Several vitamins are the most relevant antioxidants present in our diet and they exhibit a variety of physiological roles in human health (30). Vitamins can be obtained from both endogenous and exogenous sources. Certain vitamins are synthesized endogenously under specific conditions, for instance, niacin is a tryptophan-derived molecule in mammals, and vitamin D is converted from 7-dehydrocholesterol in the skin by UV-B radiation (31). Carotenoids, tocopherol, vitamin D, and ascorbic acid are the most well-known conventional antioxidant vitamins and their roles in maintaining cellular redox status are discussed below. 

4.1. Carotenoids.

Carotenoids or provitamin A are naturally occurring compounds that are only produced in the plastid of plants and algae, along with some bacteria and fungi (32). Based on the structure, carotenoids are divided into two classes namely carotenes and xanthophylls. Carotenes are further classified into α-carotene, β-carotene, and lycopene whereas oxygen-derived carotenoids are known as xanthophylls (lutein, zeaxanthin) (33, 34). Since carotenoids are highly lipophilic molecules, they can easily pass through biological membranes, thus forestalling the bilayer of the membrane from radical attack (35). They are highly capable of quenching singlet oxygen, superoxide anion, hydroxyl radicals, peroxyl radicals, and nitrogen-derived radicals. Carotenoids display their antioxidant properties through electron transfer, hydrogen abstraction, or addition reaction. This lipophilic antioxidant also protects against membrane lipid peroxidation (36, 37). Apart from their antioxidant properties, carotenoids also facilitate the regulation of the cell cycle, apoptosis, cell differentiation (38), improvement of the immune system (39), and promoting growth factors (40). Lutein, an anti-inflammatory carotenoid, exerts its function by inhibiting NF-κB pathways (41). Kishimoto et al. suggest that the antioxidant and anti-inflammatory actions of lutein can suppress coronary artery disease, atherosclerosis, hypertension (42, 43), and cancer (44). Others also confirmed the protective effects of lutein on myocardium injury from oxidative stress and apoptosis (45). 

4.2. Vitamin D.

Vitamin D (calciferol) comprises of two major forms, vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). Vitamin D₂ is mainly obtained from dietary sources while vitamin D₃ is synthesized from 7-dehydrocholesterol in human skin upon exposure to sunlight. After cutaneous synthesis and/or dietary intake, it undergoes an activation process in the liver and kidney forming 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ (calcitriol), respectively (46). This prohormone not only maintains calcium homeostasis but is also crucial for numerous other physiological activities (47, 48). For example, vitamin D deficiency is prone to developing certain chronic disorders including insulin resistance and type 2 diabetes (49, 50), cardiovascular complications (51), and progressive chronic kidney diseases (52). It acts as a membrane antioxidant by inhibiting lipid peroxidation (53). Sardar et al. (54) have suggested that the antioxidant efficacy of vitamin D₃ against lipid peroxidation is similar to that of vitamin E. Vitamin D₃ holds a more prominent influence on the enhancement of the activity of antioxidant enzymes such as glutathione peroxidase (GPx) and glucose-6-phosphate dehydrogenase (G6PDH) than vitamin E (54). Evidence has implied that vitamin D₃ administration in diabetic mice reduces their ROS formation by down-regulating NADPH oxidase expression (55, 56). Vitamin D  improves SOD activity in mice (57-59) and enhances the ROS removal process by increasing the intracellular pool of reduced glutathione via upregulation of glutamate-cysteine ligase (GCL) and glutathione reductase (GR) gene expressions (60). A positive correlation between plasma GSH and vitamin D has been reported by Jain et al. (61). Vitamin D₃ exerts its antioxidative action through binding with its nuclear receptor VDR (vitamin D receptor). It regulates intracellular oxidative metabolism by recruiting several nuclear coactivators or corepressors that mediate gene expression. When binding to the receptor, vitamin D₃ induces downstream signaling and controls free radical generation in mice hepatocytes (57, 60, 62). 

4.3. Vitamin E.

The antioxidant vitamin was first identified by Evans and Bishop (1922) as a regulatory component of the murine reproductive system (63). It is made up of eight analogs including α, β, γ, δ tocopherols and four corresponding tocotrienols. Among them, the most common form α-tocopherol is present in human tissues (64). It is well documented that vitamin E acts as a potent peroxyl radical scavenger thus it prevents the propagation of chain reaction of polyunsaturated fatty acids in the cell membrane (65, 66). Another crucial role of this vitamin E is to modulate cell signaling pathways. Cell proliferation and differentiation along with apoptosis are efficiently regulated  by protein kinase C (PKC). The PKC family have 12 isoenzymes which are expressed in a variety of cells, respectively to transduce cell signaling through receptor activation. It has been reported that PKC is inhibited by α-tocopherol. The plausible mechanism of PKC inhibition lies in the activation of protein phosphatase 2A and increase in  PKC- α dephosphorylation (67, 68).  Furthermore, vitamin E reduces superoxide anion formation in neutrophils and macrophages and inhibits platelet aggregation and endothelial nitric oxide production (69). Vitamin E deficiency might also induce the risk of heart attack, cancer, stroke, fibrocystic breast disease, epilepsy, diabetes, Parkinson’s disease, and Alzheimer’s disease (70).

4.4. Vitamin C.

Vitamin C (ascorbic acid) a water-soluble molecule plays a dual role in the redox reaction. Some mammals, other than humans, non-human primates, and guinea pigs, are capable of producing vitamin C from glucose. Humans along with these species have lost gluconolactone oxidase, a key regulatory enzyme for catalyzing the final step of vitamin C biosynthesis, during evolution (71, 72). Vitamin C is a potent reductive agent which is able to donate electrons to neutralize ROS. When ascorbic acid donates one electron, it is transformed into a semi-dehydroascorbic acid or ascorbyl radical. This intermediate is transient and quickly converted into dehydroascorbic acid by losing another electron (73-75). Vitamin C is highly effective to scavenge  H₂O₂, •OH, O₂^-•, and singlet oxygen (¹O₂). This property makes vitamin C an important antioxidant to protect cellular components from oxidative damage. Vitamin C also preserves the antioxidant capacity of vitamin E by reducing tocopheroxyl radicals and protects the cell membrane and other cellular compartments (76). However, vitamin C displays a prooxidant effect via promoting the reduction of redox-active transition metals like Fe³⁺ to Fe²⁺ and Cu²⁺ to Cu⁺, which in turn can reduce H₂O₂, thus, producing the most dangerous •OH  through the Fenton reaction. In the human body, the elimination of free iron via the iron-binding protein transferrin and ferritin is a possible approach to targetting vitamin C-mediated oxidation (77).

5.      MELATONIN AS AN ANTIOXIDANT

Melatonin is  a potent antioxidant due to its ability to initiate a cascade of reactions against free radicals. Melatonin can directly scavenge free radicals (78) while its secondary and tertiary metabolites can also detoxify free radicals. Due to this cascade reactions, one melatonin molecule  can quench up to 10 ROS. This characteristic of melatonin is different from other classical antioxidants which can only scavenge a reactive oxygen moiety per molecule. Melatonin is a amphiphilic molecule and can easily pass through the biological membrane to exert its antioxidative effect (79-81). Several comparative studies  of  melatonin with other endogenous or exogenous antioxidants including  vitamin C, vitamin E, NADH, and glutathione in both in vitro and in vivo conditions have confirmed superiority of melatonin over them (82). Melatonin’s metabolites such as cyclic-3-hydroxymelatonin (C₃HOM) (83) and N-acetyl-5-methoxykynuramine (AMK) (84) are even more efficient hydroxyl radical scavengers than melatonin itself. N¹-acetyl-N²- formyl-5-methoxykynuramine (AFMK), another metabolite of melatonin, is also capable of quenching radicals through three different mechanisms; (a) radical adduct formation, (b) hydrogen transfer, and (c) single electron transfer (84). In addition,  melatonin can stimulates gene expression and activity of several antioxidant enzymes including  SOD, GPx and CAT (85) to produce its indirect antioxidant capacity. Therefore, melatonin effectively preserve cell membrane fluidity and function by preventing lipid peroxidation and protein degradation (86).

6.      MELATONIN: A STRONG DEFENDER OF MITOCHONDRIA

Mitochondria serve multiple important functions including regulation of cellular metabolism, ATP production and apoptosis. Excess of ROS and RNS production during mitochondrial respiration can lead to cell death. The role of melatonin as a mitochondrial protector was first reported by Mansouri et al. (87). When compared to two synthetic mitochondria-targeted antioxidants, MitoQ and MitoE (88, 89) melatonin exhibits similar or even better mitochondrial protective effects than them (90). The implication of these findings supports the fact that melatonin should be considered as an endogenous mitochondria-targeted antioxidant consistent with the proposal that mitochondria might be the intracellular site of melatonin production (91). Many studies have elucidated the ameliorative role of melatonin against mitochondrial injury caused by several threats like ischemia/reperfusion (92, 93), sepsis (94, 95), in vitro fertilization (96, 97), β-amyloid peptide (98, 99), arsenite (100) and lipopolysaccharide (101). Additionally, melatonin administration significantly delays the onset and mortality of animal model of Huntington’s disease (HD) which is an autosomal neurodegenerative disorder where mitochondrial alteration plays an integral role in the pathogenesis (102). Multiple sclerosis, the most common inflammatory disease of the locomotic neurons  with mitochondrial abnormalities, can be alleviated through restoring mitochondrial function followed by melatonin administration (103). Melatonin also preserves the mitochondrial membrane potential which is important for ATP generation and establishing homeostasis in the overall mitochondrial function (104, 105). It stimulates anti-apoptotic mitochondrial protein while suppressing the pro-apoptotic protein expression thus preventing mitochondria associated apoptosis (106, 107). Furthermore, melatonin is also involved in the inhibition of caspase 3 activity as well as the release of cytochrome C from mitochondria (108, 109). Hence, melatonin provides overall protection to mitochondria thus reducing oxidative damage.

7.      CUMULATIVE ACTIONS OF VITAMINS AND MELATONIN

Melatonin and other classical antioxidant vitamins have profound effects on cellular redox metabolism. Some of their synergistic as well as combined functions on various organs are discussed below (Figure 2).

Fig. 2. The action pathways of vitamins and melatonin in amelioration of ROS.

     ROS: Reactive oxygen species, P2A: Protein phosphatase 2A, PKC-α: Protein kinase C-α, NF-κβ: Nuclear factor-kappa B, C₃HOM: Cyclic-3-hydroxy melatonin, AMK:N-acetyl-5-methoxykynuramine, AFMK: N¹-acetyl-N²- formyl-5-methoxykynuramine

7.1.  Cardioprotective action.

Pieces of evidence collected during the last 15 years have shown the crucial effects of melatonin on the cardiovascular system (110, 111). The cardio-protective role of melatonin pertains to its direct free radical scavenging and anti-inflammatory activities. It inhibits the release of inflammatory cytokines including TNF-α, IL-1β, and IL-6 while increasing anti-inflammatory mediators such as IL-10 thus, promoting the overall anti-inflammatory effect (112). Since dyslipidemia is a major contributory factor to coronary heart disease (CHD), studies have demonstrated that melatonin regulates blood lipid and prevents oxidized LDL formation, both of which preserve  cardiomyocytes from oxidative injury (111). Melatonin exhibits beneficial effects on cardiac health via its receptor-mediated action. Melatonin receptors, MT1 and MT2 are both expressed in the cardiovascular system and are responsible for the regulation of the vascular tone. MT1 mediates vasoconstriction while MT2 mediates vascular dilation (113). On the other hand, vitamin E also shows the cardio-protective effects due to its antioxidant and anti-inflammatory actions (114). Vitamin E attenuates myocardial infarction via diminishing ROS generation and lipid peroxidation. Many studies have suggested the antioxidant and anti-atherogenic properties of vitamin E in the animal model (115-117). Several clinical studies also support the evidence (118,119). Endothelial nitric oxide (NO) generated by the action of nitric oxide synthase is found to regulate the vascular tone and endothelial functions. Cardiomyocytes express NOS that regulates myocardial contractility, heart rate and cardiac oxygen consumption (120). Chronic alcohol consumption is attributed to reduce NO synthesis and decreases the bioactive NO which is ameliorated by both of melatonin and vitamin C which indicates the potential of the synergistic action between melatonin and other classic antioxidants (121).

7.2.  Protection of neurodegenerative disorders.

The complexed chemical constituents of membrane and high energy requirement make neurons more vulnerable to oxidative stress. Neuronal loss will negatively affects the behavior and physiological functions of the individuals. Many acute factors including  hypoxia, stroke, physical trauma, hypoglycemia, drug neurotoxicity, viruses, and radiation can cause  neuronal damage (122). The glutamate excitotoxicity, oxidative injury and mitochondrial malfunction are three major causative factors related to the neuronal loss (123). Glutamate is an important neurotransmitter in CNS which plays a pivotal role in learning and memory formation. Excessive production of glutamate induces  neuronal  excitatory effects through activation of glutamate-N-methyl-D-aspartate (NMDA) receptor leading to Ca²⁺ overload and cell death. Amyloid-β protein, a biomarker of Alzheimer’s disease (AD), is also a stimulator of glutamate accumulation and an activator of NMDA receptor . NMDA receptor activation further promotes phosphorylation of tau protein and leads to the disintegration of microtubules, loss of synapse and gradually neuronal death (124). Additionally, increased prostaglandin secretion and free radical formation in microglia trigger cytokine production including IL-6, IL-1β, TNF-α that contribute to neuronal damage (125). It is well known that mitochondria play a pivotal role in energy metabolism and apoptosis in brain cells (126). Mitochondrial dysfunction results in decreased ATP formation and ROS generation leading to apoptosis (127). Impaired mitochondrial proteins related to  electron transport chain are associated with pathophysiology of AD, Parkinson’s disease (PD), and amylotrophic lateral sclerosis (ALS) (128, 129). Melatonin is considered as a neuroprotective agent as it shows anti excitatory and sedative effects (130-132). The protective mechanism of melatonin is partially mediated by the GABAergic system indicating that melatonin inhibits the β-amyloid peptide toxicity through the activation of GABA receptors (133). Melatonin also can promote gene transcription of antioxidant enzymes of SOD-1, CAT and GPx in the cortex of transgenic AD mice (134). Melatonin controls ROS production by inhibiting NADPH oxidase which is the main source of oxidative stress in AD brain (135).  Furthermore, the protective action of this ubiquitous indole against AD and PD may contribute to its role in maintaining mitochondrial homeostasis (136). Moreover, vitamin E is also a neuroprotective agent. For example,  vitamin E deficiency is mostly related to neurological complications (137-139). Many other studies have  demonstrated that α-tocopherol protects neurons from oxidative stress in  both the in vivo and in vitro conditions (140-142). The anti-inflammatory as well as antioxidative actions of this vitamin are attributed to its neuroprotective function. It has been found that α-tocopherol supplementation can reduce the synthesis of inflammatory mediator prostaglandin E2 by inhibiting the activity of cyclooxygenase 2 (COX-2) (143). Furthermore, vitamin E inhibits p38 MAPK (mitogen-activated protein kinase) thus, hindering phosphorylation of tau protein since phosphorylated aggregation of tau causes neurofibrillary tangles which is an important biomarker in AD brain (144). Montilla Lopez P et al. (145) have demonstrated that the toxicity of ocadeic acid in neuroblastoma cells is mitigated by administration of both melatonin and vitamin C. However, melatonin is more efficacious than vitamin C. (Table 1). 

Table 1: Comparative studies of melatonin and vitamins.

Since oxidative stress is a major factor in the pathogenesis of diabetes mellitus; antioxidant therapy could be a suitable strategy to alleviate the symptoms. Being a potent antioxidant, melatonin reduces lipid peroxidation and enhances GPx activity in Type 1 diabetic rats in comparable to vitamin E (146). Melatonin administration maintains normal blood glucose level and preserves the healthy pancreatic β-cells to prevent insulin leakage in diabetic animal model (147, 148). This indicates melatonin’s role in glucose metabolism. Elevated glucose level has been observed in pinealectomized rats even in the presence of high insulin levels. This is probably due to the increased gluconeogenesis in these rats (149). The potential mechanism is that melatonin inhibits phosphoenolpyruvate carboxykinase (PEPCK), the major enzyme in the gluconeogenic pathway, by up-regulating the rate of AKT phosphorylation, required for lowering PEPCK gene expression (149). In addition, melatonin also promotes glucose utilization via the pentose phosphate pathway by increasing  glucose-6-phosphate dehydrogenase activity hence, restricting glucose accumulation as well as enhancing NADPH formation required for glutathione metabolism (150, 151). Furthermore, the strong anti-inflammatory action of melatonin confers it more powerful against inflammation-induced metabolic disorders. The inflammation induced by pro-inflammatory cytokines including TNF-α, IL-6, IL-1β, and CRP (C reactive Protein) is a important risk factor of  both type 1 and type 2 diabetes (152). In this context, melatonin modulates the pro-inflammatory transcriptional factor NFκB signaling pathway and deactivates NLRP3 (153,154). In diabetic rats, melatonin was found to restore the activity of pancreatic β-cells by improving anti-inflammatory cytokine IL10 level along with lowering the pro-inflammatory cytokines (155). As to other classic antioxidants, since oxidative stress-induced cardiac dysfunction is directly linked to diabetes, thus, vitamin C has been used in diabetic patients in preventing microangiopathy (156), decreasing atherosclerotic plaque and strengthening the vascular integrity (157). An elevated plasma level of vitamin E was observed in diabetes. This could be either the outcome of defective utilization or a compensatory effect to combat stress-mediated diabetes (156). Vitamin D also provides some beneficial effects against diabetes (158). The presence of VDR in pancreatic β-cells indicates its involvement in insulin secretion (158). Vitamin D regulates calbindin, the calcium-binding protein in β-cell which modulates insulin secretion via regulating intracellular calcium (158). An in vitro study by Norman et al. (159) have showed that insulin secretion is reduced by almost 48% in vitamin D deficient perfused rat pancreas compared with that of vitamin D replenished group  The in vivo experiments also support the same evidence (160). This antioxidant vitamin indirectly inhibits cytokine-induced pancreatic cell apoptosis via down-regulating NFκB (161). Based on evidences mentioned above,  melatonin and antioxidant vitamins have the capacity to protect against hyperglycemia. 

7.4. Protection against hemolytic anemia.

Oxidative stress is a major factor to impact functions of erythrocytes. Thalassemia, is a hereditary haemolytic anaemia with absent or reduced production of either α globin chain (α-thalassemia) or β globin chain (β-thalassemia). Both these types are characterized by abnormal erythropoiesis and short red blood cells (RBC) life span with associated symptoms of anaemia, hepato-splenomegaly and iron overload in RBC (162). The haemoglobin oxidation and superoxide anion formation in RBC are the other characteristic features in thalassaemic patients (163). Structural deformities of protein binding in RBC cause hemolysis leading to leakage of free iron in circulation.  In addition to endogenous iron release in thalassaemic patients, iron overload occurs due to blood transfusion and oral iron intake (164, 165). In contrast to free iron accumulation, iron deficiency also leads to haemolytic anaemia. Decreased rate of RBC formation with subsequent loss of haemoglobin synthesis is the main outcome of iron deficiency anaemia (166). On the other hand, individuals with G6PDH deficient are also subjected to haemolysis. G6PDH is the key enzyme in the hexose monophosphate (HMP) shunt pathway which generates reducing metabolites like NADPH in RBC. HMP shunt pathway is the sole source of NADPH formation in RBCs as they are devoid of mitochondria (167). NADPH enhances reduced glutathione (GSH)  levels when the erythrocytes are subjected to oxidative stress. G6PDH deficiency in X-linked recessive disorder results in NADPH depletion and diminished GSH regeneration (168, 169). The most common clinical consequences in G6PDH deficient subjects are neonatal jaundice and chronic haemolytic anaemia (170). As oxidative stress seems to be a major etiology in haemolytic anaemia, the application of antioxidants appears effective in combating erythrocytic deformities. In this respect, melatonin seems as a suitable choice  (171). Allegra et al. have tested the protective effects of melatonin on human erythrocytes from MDA-induced oxidative stress and they observed that melatonin inhibits the vitamin E oxidation (172). The protective mechanisms of melatonin are not only confined by its free radical scavenging activity but also the iron-chelating property. Melatonin chelates iron to prevent hydroxyl radical formation and consequent eryptosis (170, 173). Comparably, vitamin C (174) and vitamin E (175) also have a stimulatory role in erythropoiesis. For example, rats with vitamin A deficiency suffer haematological disturbances including losses of haematopoietic tissue in bone marrow, hypochromia, reduced haemoglobin concentration and splenic accumulation of haemosiderin (176, 177). β-carotene and resveratrol have been reported to directly scavenge ROS in human erythrocyte by improving antioxidant enzyme activity (178). Vitamin C as a reducing agent, facilitates iron absorption as well as iron mobilization. The formation of iron-ascorbate chelate is more soluble in the alkaline medium of the intestine and hence increases its  absorption rate  (179,  180). The combination of vitamin C and melatonin has been used in preventing phenylhydrazine-induced haemolytic anaemia and associated cardiovascular disorders (181).

8.      CONCLUDING REMARKS AND FUTURE PERSPECTIVE

     Melatonin as a broad-spectrum antioxidant scavenges free radicals under a variety of physiopathological conditions. The cascade reactions of melatonin with its metabolites make it more potent  than other classical antioxidant vitamins. Most of the vitamins only have the capacity to scavenge one ROS per molecule, whereas melatonin having the ability to interact with several  ROS and RNS due to its metabolites retaining the capability to further detoxify the radical. For this reason, melatonin scavenges multiple times of more toxic ROS than any other classic antioxidants (186). Hence, from this review we conclude that melatonin is superior than other classical antioxidant vitamins as to its protective effect on oxidative tissue damage. Moreover, melatonin can be an option combined with vitamins and this combination  can bring more assertive outcomes toward offering protection against oxidative stress in organisms.

ACKNOWLEDGEMENTS                                           

     Manisha Mukhopadhyay   gratefully   acknowledges  the receipt   of  the   UGC  Junior   Research Fellowship  (ref  no.1558/(NET-JULY 2018),  Govt.  of  India. Romit Majumder is supported by SVMCM Schlorship (WBP211631173194) provided by the Government of West Bengal. A  Junior  Research  Fellowship  (JRF) under  WBDST  [304(Sanc.)/STP/S&T/1G-67/2017 DATED 29.03.2018] is greatly acknowledged by AB. Prof. DB  is  supported from  the departmental  BI  grant  of  University  of  Calcutta.  DB  also  gratefully  acknowledges  the support he  has received  from  DST-PURSE  Program  awarded  to  the  University  of  Calcutta.

AUTHORSHIP

     Prof. DB contributed to the conception, critical correction of the manuscript and finally approved  it. MM prepared the first version of manuscript and figures. RM drafted the figures and tables and edited the manuscript. AB has contributed tofinal formatting and editing the manuscript.

CONFLICT OF INTEREST

     Authors declare no conflict of interest.

REFERENCES

1. Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE (2014) Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Phys. Rev. 94 (2): 329-354. DOI: 10.1152/physrev.00040.2012.

2. Pizzino G, Irrera N, Cucinotta M, Pallio G,Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A (2017) Oxidative Stress: Harms and benefits for human health. Oxid. Med. Cell Longev. 2017: 8416763. DOI:10.1155/2017/8416763.

3. Khansari N, Shakiba Y, Mahmoudi M (2009) Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat. Inflamm. Allergy Drug Discov. 3 (1): 73-80. DOI: 10.2174/187221309787158371.

4. Sinbad OO, FolorunshoAA, Olabisi OL, Ayoola OA,  Temitope EJ (2019) Vitamins as antioxidants. J. Food Sci.Nutr. Res. 2 (3): 214-235.DOI:10.26502/jfsnr.2642-11000021.

5.  Gulcin I, Buyukokuroglu ME, Kufrevioglu OI (2003) Metal chelating and hydrogen peroxide scavenging effects of melatonin. J. Pineal Res. 34 (4): 278–281. DOI:10.1034/j.1600-079x.2003.00042.x.

6. Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM,  Reiter RJ (2003) Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J. Pineal Res. 34 (1): 75–78. DOI:10.1034/j.1600-079x.2003.02111.x.

7.  Ziegler E, Filer LJ Jr (1996) Present knowledge in nutrition, 7th edn. International Life Science Institute, Washington.

8. Mukherjee D, Ghosh AK, Dutta M, MitraE, Mallick S, Saha B, Reiter RJ,  Bandyopadhyay D (2015) Mechanisms of isoproterenol-induced cardiac mitochondrial damage: protective actions of melatonin. J. Pineal Res. 58 (3): 275–290. DOI: 10.1111/jpi.12213.

9. Bose G, Ghosh A, Chattopadhyay A, Pal PK, Bandyopadhyay D (2019) Melatonin as a potential therapeutic molecule against myocardial damage caused by high fat diet (HFD). Melatonin Res. 2 (3): 37-56. DOI: 10.32794/mr11250030.

10. 10.  Ghosh A, Bose G, Dey T, Pal PK, Mishra S, Ghosh AK,  Bandyopadhyay D (2019) Melatonin protects against cardiac damage induced by a combination of high fat diet and isoproterenol exacerbated oxidative stress in male Wistar rats. Melatonin Res. 2 (1): 9-31. DOI:10.32794/mr11250009.

11. Pal PK, Sarkar S, MishraS, Chattopadhyay S, Chattopadhyay A,  Bandyopadhyay D (2020) Amelioration of adrenaline induced oxidative gastrointestinal damages in rat by melatonin through SIRT1-NFκB and PGC1α-AMPKα cascades. Melatonin Res. 3 (4): 482-502. DOI: 10.32794/mr11250074.

12. Halliwell B (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol. 141 (2): 312-322. DOI: 10.1104/pp.106.077073.

13. Bahorun T, Soobrattee MA, Luximon-Ramma V, Aruoma OI (2006). Free radicals and antioxidants in cardiovascular health and disease. Int. J. Medic. Update 1 (2): 25-41. DOI:10.4314/ijmu.v1i2.39839.

14. Kumar S, Pandey AK (2015) Free radicals: health implications and their mitigation by herbals. J. Adv. Med.Medic. Res. 7 (6): 438-457. DOI: 10.9734/BJMMR/2015/16284.

15. Valko M, Izakovic M, Mazur M, RhodesCJ, Telser J(2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell Biochem. 266 (1): 37-56. DOI: 10.1023/b:mcbi.0000049134.69131.89.

16. ValkoM, LeibfritzD, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39 (1): 44-84.DOI: 10.1016/j.biocel.2006.07.001.

17. Dröge W (2002) Free radicals in the physiological control of cell function. Physiol. Rev. 82 (1): 47–95. DOI: 10.1152/physrev.00018.2001.

18. Willcox JK, Ash SL,Catignani GL (2004) Antioxidants and prevention of chronic disease. Crit. Rev. Food Sci. Nutr. 44 (4): 275-295. DOI:10.1080/10408690490468489.

19. Halliwell B (2007) Biochemistry of oxidative stress. Biochem. Soc. trans. 35 (Pt 5): 1147–1150. DOI: 10.1042/BST0351147.

20. Valko M, Rhodes CJB, Moncol J, Izakovic MM, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 160 (1): 1-40. DOI:10.1016/j.cbi.2005.12.009.

21. Nishida N, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, Inoue T, Minami Y, Ueshima K, Sakurai T, KudoM (2013) Reactive oxygen species induce epigenetic instability through the formation of 8-hydroxydeoxyguanosine in human hepatocarcinogenesis. Dig. Dis. 31 (5-6): 459–466. DOI:10.1159/000355245.

22. 22.  Khansari N, Shakiba Y, Mahmoudi M (2009) Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat. Inflamm. Allergy Drug Discov. 3 (1): 73–80. DOI:10.2174/187221309787158371.

23. Liu Z, Zhou T, Ziegler, AC, Dimitrion P,  Zuo L (2017) Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications. Oxid. Med. Cell Longev. 2017: 2525967. DOI:10.1155/2017/2525967.

24. 24.  Wojtunik-Kulesza KA, Oniszczuk A, Oniszczuk T, Waksmundzka-Hajnos M (2016) The influence of common free radicals and antioxidants on development of Alzheimer's disease. Biomed. Pharmacother. 78: 39–49. DOI:10.1016/j.biopha.2015.12.024.

25. 25.  Shi H, Noguchi N,  Niki E (1999) Comparative study on dynamics of antioxidative action of alpha-tocopheryl hydroquinone, ubiquinol, and alpha-tocopherol against lipid peroxidation. Free Radic.Biol. Med. 27 (3-4): 334–346. DOI:10.1016/s0891-5849(99)000532.

26. Sies H (1997) Oxidative stress: Oxidants and antioxidants. Exp. Physiol. 82 (2): 291–295. DOI:10.1113/expphysiol.1997.sp004024.

27. Moldogazieva NT, Mokhosoev IM, Feldman NB, Lutsenko SV (2018) ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications. Free Radic .Res. 52 (5): 507–543. DOI:10.1080/10715762.2018.1457217.

28. Oyewole AO, Birch-Machin MA (2015) Mitochondria-targeted antioxidants. FASEB J. 29 (12): 4766–4771. DOI: 10.1096/fj.15-275404.

29. Galley H. F (2010). Bench-to-bedside review: Targeting antioxidants to mitochondria in sepsis. Crit. Care 14 (4): 230. DOI:10.1186/cc9098.

30.  Maqbool MA, Aslam M, Akbar W, Iqbal Z (2017) Biological importance of vitamins for human health: A review. J. Agric. Basic Sci. 2 (3): 50-58.

31. McDowell LR (2000). Vitamins in animal and human nutrition. John Wiley & Sons. DOI: 10.1002/9780470376911.

32. 32.  Alós E, Rodrigo, MJ, Zacarias L (2016) Manipulation of carotenoid content in plants to improve human health. Subcell. Biochem.79: 311–343. DOI:10.1007/978-3-319-39126-7_12.

33. Yaroshevich IA, Krasilnikov PM,  Rubin AB (2015) Functional interpretation of the role of cyclic carotenoids in photosynthetic antennas via quantum chemical calculations. Comput. Theor. Chem. 1070: 27-32. DOI:10.1016/j.comptc.2015.07.016.

34. Berman J, Zorrilla-López U, Sandmann G, Capell T, Christou P, Zhu C (2017) The silencing of carotenoid β-Hydroxylases by RNA interference in different maize genetic backgrounds increases the β-Carotene content of the endosperm. Int. J. Mol. Sci. 18 (12): 2515. DOI:10.3390/ijms18122515.

35. Fiedor J,  Burda K (2014) Potential role of carotenoids as antioxidants in human health and disease. Nutrients 6 (2): 466-488. DOI:  10.3390/nu6020466.

36. Xavier AA, Pérez-Gálvez A (2016) Carotenoids as a source of antioxidants in the diet. Subcell. biochem. 79: 359–375. DOI:10.1007/978-3-319-39126-7_14.

37. 37.  Mazur M, Valko M (2009) low oxygen pressure (an EPR spectroscopy and computational study). Chem. Phys. Lett. 478 (4–6): 266–270. DOI: 10.1016/j.cplett.2009.07.088.

38. 38.  Gloria NF, Soares N, Brand C, Oliveira FL, Borojevic R, Teodoro A J (2014) Lycopene and beta-carotene induce cell-cycle arrest and apoptosis in human breast cancer cell lines. Anticancer Res. 34 (3): 1377–1386.

39. Karadas F, Erdoğan S, Kor D, Oto G, Uluman M (2016) The effects of different types of antioxidants (Se, vitamin E and carotenoids) in broiler diets on the growth performance, skin pigmentation and liver and plasma antioxidant concentrations. Rev. Bras. Cienc. Avic. 18: 101-116. DOI:10.1590/18069061-2015-0155.

40. Diener A, Rohrmann S (2016) Associations of serum carotenoid concentrations and fruit or vegetable consumption with serum insulin-like growth factor (IGF)-1 and IGF binding protein-3 concentrations in the Third National Health and Nutrition Examination Survey (NHANES III). J. Nutr. Sci. 5: e13. DOI:10.1017/jns.2016.1.

41. Serasanambati M, Chilakapati SR (2016) Function of nuclear factor kappa B (NF-kB) in human diseases-a review. South Ind. J. Biol. Sci. 2: 368–387. DOI: 10.22205/sijbs/2016/v2/i4/103443.

42. Kishimoto Y, Taguchi C, Saita E, Suzuki-Sugihara N, Nishiyama H, Wang W, Masuda Y, Kondo K. (2017) Additional consumption of one egg per day increases serum lutein plus zeaxanthin concentration and lowers oxidized low-density lipoprotein in moderately hypercholesterolemic males.  Food Res. Int. 99 (Pt 2): 944–949. DOI:10.1016/j.foodres.2017.03.003.

43. Perrone S, Tei M, Longini M, Buonocore G (2016) The multiple facets of lutein: A call for further investigation in the perinatal period. Oxid. Med. Cell Longev. 2016: 5381540. DOI:10.1155/2016/5381540.

44. Rafi MM, Kanakasabai S, Gokarn SV, Krueger EG,  BrightJJ (2015) Dietary lutein modulates growth and survival genes in prostate cancer cells.  J. Med. Food. 18 (2): 173–181. DOI:10.1089/jmf.2014.0003.

45. Gammone MA, Riccioni G, D'Orazio N (2015) Carotenoids: potential allies of cardiovascular health?. Food Nutr. Res. 59: 26762. DOI:10.3402/fnr.v59.26762.

46. Holick MF (1996) Vitamin D and bone health. J. Nutr. 126 (4 Suppl): 1159S–64S. DOI:10.1093/jn/126.suppl_4.1159S.

47. Norman AW (2008) From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 88 (2): 491S–499S. DOI: 10.1093/ajcn/88.2.491S.

48. Giovannucci E (2009) Expanding roles of vitamin D. J. Clin. Endocrinol. Metab. 94 (2): 418–420. DOI:10.1210/jc.2008-2695.

49. Chiu KC, Chu A, Go VL, Saad MF (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am. J. Clin. Nutr. 79 (5): 820–825. DOI:10.1093/ajcn/79.5.820.

50. Mitri J, Muraru MD, Pittas AG (2011) Vitamin D and type 2 diabetes: a systematic review. Eur. J. Clin. Nutr. 65 (9): 1005–1015. DOI: 10.1038/ejcn.2011.118.

51. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, BenjaminEJ, D'Agostino, RB, Wolf M, Vasan RS (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117 (4): 503–511. DOI:10.1161/CIRCULATIONAHA.107.706127.

52. Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, Mallamaci F, & Zoccali C (2009) Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 75 (1): 88–95. DOI:10.1038/ki.2008.501.

53. Wiseman H (1993) Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS lett. 326 (1-3): 285–288. DOI:10.1016/0014-5793(93)81809-e.

54. Sardar S, Chakraborty A, Chatterjee M (1996) Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague--Dawley rats. Int. J. Vitam. Nutr. Res. 66 (1): 39–45. DOI: 10.1080/01635589809514725.

55. Labudzynskyi DO, Zaitseva OV, Latyshko NV, Gudkova OO, VelikyMM (2015) Vitamin D3 contribution to the regulation of oxidative metabolism in the liver of diabetic mice. Ukr. Biochem. J. 87 (3): 75–90.

56. Kono K, Fujii H, Nakai K, Goto S, Kitazawa R, Kitazawa S, Shinohara M, Hirata M, Fukagawa M, Nishi S (2013) Anti-oxidative effect of vitamin D analog on incipient vascular lesion in non-obese type 2 diabetic rats. Am. J. Nephrol. 37 (2): 167–174. DOI:10.1159/000346808.

57. Zhong W, Gu B, Gu Y, Groome LJ, Sun J,  Wang Y (2014) Activation of vitamin D receptor promotes VEGF and CuZn-SOD expression in endothelial cells. J. Steroid Biochem.Mol. Biol. 140: 56–62. DOI: 10.1016/j.jsbmb.2013.11.017.

58. Greń A (2013) Effects of vitamin E, C and D supplementation on inflammation and oxidative stress in streptozotocin-induced diabetic mice. Int. J. Vitam. Nutr. Res. 83 (3): 168–175.DOI:10.1024/0300-9831/a000156.

59. Hamden K, Carreau S, Jamoussi K, Ayadi F, Garmazi F, Mezgenni N, Elfeki A (2008) Inhibitory effects of 1alpha, 25dihydroxyvitamin D3 and Ajuga iva extract on oxidative stress, toxicity and hypo-fertility in diabetic rat testes. J. Physiol. Biochem. 64 (3): 231–239. DOI: 10.1007/BF03216108.

60. Kanikarla-Marie P, Jain SK (2016) 1,25(OH)2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). J. Steroid Biochem. Mol. Biol. 159: 94–101. DOI: 10.1016/j.jsbmb.2016.03.002.

61. Jain S K, Micinski D, Huning L, Kahlon G, Bass PF, Levine, SN (2014) Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. Eur. J. Clin. Nutr. 68 (10): 1148–1153. DOI:10.1038/ejcn.2014.114.

62. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C,  Demay M (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29 (6): 726–776. DOI:10.1210/er.2008-0004.

63. Evans, HM, Bishop KS (1922) On the existence of a hitherto unrecognized dietary factor essential forreproduction. Science 56 (1458): 650–651. DOI:10.1126/science.56.1458.650.

64. Mustacich DJ, Bruno RS,  Traber MG (2007) Vitamin E. Vitam. Horm. 76: 1–21. DOI:10.1016/S0083-6729(07)76001-6.

65. Burton GW, Cheeseman KH, Doba T, Ingold, KU,  Slater TF (1983) Vitamin E as an antioxidant in vitro and in vivo.  Ciba Found. Symp. 101: 4–18. DOI:10.1002/9780470720820.ch2.

66. Howard AC, McNeil, AK, McNeil PL (2011) Promotion of plasma membrane repair by vitamin E. Nat. Commun. 2: 597. DOI:https://doi.org/10.1038/ncomms1594.

67. Ventura C,  Maioli M (2001) Protein kinase C control of gene expression. Crit. Rev. Eukaryot. Gene Expr. 11 (1-3): 243–267. PMID: 11693964.

68. Buchner K (2000) The role of protein kinase C in the regulation of cell growth and in signalling to the cell nucleus. J. Cancer Res. Clin. Oncol. 126 (1): 1–11. DOI:10.1007/pl00008458.

69. Azzi A, Boscoboinik D, Clément S, Marilley D, Ozer N K, Ricciarelli R,  Tasinato A (1997) Alpha-tocopherol as a modulator of smooth muscle cell proliferation. Prostaglandins Leukot. Essent. Fatty Acids  57 (4-5): 507–514. DOI:10.1016/s0952-3278(97)90436-1.

70. Azzi A, Ricciarelli R,  Zingg JM (2002) Non-antioxidant molecular functions of alpha-tocopherol (vitamin E). FEBS Lett. 519 (1-3): 8–10. DOI:10.1016/s0014-5793(02)02706-0.

71. Nishikimi M, Fukuyama R, Minoshima S, Shimizu N,  Yagi K (1994) Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J. Biol.Chem. 269 (18): 13685–13688.DOI:10.1016/S0021-9258(17)36884-9.

72. Nishikimi M,  Yagi K (1996) Biochemistry and molecular biology of ascorbic acid biosynthesis. Subcell. Biochem. 25: 17–39. DOI:10.1007/978-1-4613-0325-1_2.

73. Buettner GR, Moseley PL (1993) EPR spin trapping of free radicals produced by bleomycin and ascorbate. Free Radic. Res. Commun. 19 Suppl1: S89–S93. DOI:10.3109/10715769309056s89.

74. Bielski BH, Richter HW, Chan PC (1975) Some properties of the ascorbate free radical. Ann. N. Y. Acad. Sci. 258: 231–237. DOI:10.1111/j.1749-6632.1975.tb29283.x.

75. Padayatty SJ, Katz A, WangY, EckP, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK,  Levine M (2003) Vitamin C as an antioxidant: evaluation of its role in disease prevention. J. Am. Coll. Nutr. 22 (1): 18–35. DOI:10.1080/07315724.2003.10719272.

76. Neužil J, Thomas SR,  Stocker R (1997) Requirement for, promotion, or inhibition by α-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation. Free Radic. Biol. Med. 22 (1-2): 57-71. DOI:10.1016/s0891-5849(96)00224-9.

77. Carr A, Frei B (1999) Does vitamin C act as a pro-oxidant under physiological conditions?. FASEB J. 13 (9): 1007–1024. DOI:10.1096/fasebj.13.9.1007.

78. Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR (1994) Melatonin a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann. N. Y Acad.  Sci. 738: 419–420. DOI:10.1111/j.1749-6632.1994.tb21831.x.

79. García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J. 29 (9): 3863–3875. DOI:10.1096/fj.15-273656.

80. Tan DX, Hardeland R, Manchester LC, Poeggeler B, Lopez-Burillo S, Mayo JC, Sainz RM,  Reiter, RJ (2003) Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical J. Pineal Res. 34 (4): 249–259. DOI:10.1034/j.1600-079x.2003.00037.x.

81. Lowes DA, Webster NR, Murphy MP,  Galley HF (2013) Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth. 110 (3): 472–480. DOI:10.1093/bja/aes577.

82. Gitto E, Tan DX, Reiter RJ, Karbownik M, Manchester LC, Cuzzocrea S, Fulia F, Barberi I (2001) Individual and synergistic antioxidative actions of melatonin: studies with vitamin E, vitamin C, glutathione and desferrioxamine (desferoxamine) in rat liver homogenates. J. Pharm. Pharmacol. 53 (10):1393–1401. DOI: 10.1211/0022357011777747.

83. Tan DX, Hardeland R, Manchester LC, Galano A, Reiter RJ (2014) Cyclic-3-hydroxymelatonin (C3HOM), a potent antioxidant, scavenges free radicals and suppresses oxidative reactions. Curr. Med. Chem. 21 (13): 1557–1565. DOI: 10.2174/0929867321666131129113146.

84. Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J. Pineal Res. 54 (3): 245–257. DOI: 10.1111/jpi.12010.

85. Dziegiel P, Murawska-Ciałowicz E, Jethon Z, Januszewska L, Podhorska-Okołów M, Surowiak P, Zawadzki M, Rabczyński J, Zabel M (2003) Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication. J. Pineal Res. 35 (3): 183–187. DOI: 10.1034/j.1600-079x.2003.00079.x.

86. García JJ, Reiter RJ, Guerrero JM, Escames G, Yu BP, Oh CS, Muñoz-Hoyos A (1997) Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett. 408 (3): 297–300. DOI: 10.1016/s0014-5793(97)00447-x.

87. Mansouri A, Gaou I, De Kerguenec C, Amsellem S, Haouzi D, Berson A, Moreau A, Feldmann G, Lettéron P, Pessayre D, Fromenty B (1999) An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice. Gastroenterol. 117 (1): 181–190. DOI: 10.1016/s0016-5085(99)70566-4.

88. Smith RA, Porteous CM, Coulter CV, Murphy MP (1999) Selective targeting of an antioxidant to mitochondria. Eur. J. Biochem. 263 (3): 709-716. DOI: 10.1046/j.1432-1327.1999.00543.x.

89. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276 (7): 4588-4596. DOI: 10.1074/jbc.M009093200.

90. Lowes DA, Webster NR, Murphy MP, Galley HF (2013) Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth. 110 (3): 472-480. DOI: 10.1093/bja/aes577.

91. Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ (2010) Changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol. Rev. Camb. Philos. Soc .85: 607 -623. DOI: 10.1111/j.1469-185X.2009.00118.x.

92. Yang Y, Duan W, Jin Z, Yi W, Yan J, Zhang S, Wang N, Liang Z, Li Y, Chen W, Yi D, Yu S (2013) JAK 2/STAT 3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. J. Pineal Res. 55 (3): 275-286. DOI: 10.1111/jpi.12070.

93. Huang WY, Jou MJ, Peng TI (2013) mtDNA T8993G mutation-induced F1F0-ATP synthase defect augments mitochondrial dysfunction associated with hypoxia/reoxygenation: the protective role of melatonin. PloS one 8 (11): e81546. DOI: 10.1371/journal.pone.0081546.

94. Doerrier C, García JA, Volt H, Díaz-Casado ME, Lima-Cabello E, Ortiz F, Luna-Sanchez M, Escames G, Lopez LC, Acuña-Castroviejo D (2015) Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry. Life Sci. 121: 158-165. DOI: 10.1016/j.lfs.2014.11.031.

95. Zhang H, Liu D, Wang X, Chen X, Long Y, Chai W, Zhou X, Rui X, Zhang Q, Wang H, Yang Q (2013) Melatonin improved rat cardiac mitochondria and survival rate in septic heart injury. J. Pineal Res. 55 (1):1-6.DOI: 10.1111/jpi.12033.

96. Ren L, Wang Z, An L, Zhang Z, Tan K, Miao K,Tao Li, Cheng L, Zhang Z, Yang M, Wu Z, Tian J (2015) Dynamic comparisons of high-resolution expression profiles highlighting mitochondria-related genes between in vivo and in vitro fertilized early mouse embryos. Hum. Reprod. 30 (12): 2892-2911. DOI: 10.1093/humrep/dev228.

97. Zhao XM, Min JT, Du WH, Hao HS, Liu Y, Qin T, Wang D, Zhu HB (2015) Melatonin enhances the in vitro maturation and developmental potential of bovine oocytes denuded of the cumulus oophorus. Zygote 23 (4): 525-536. DOI: 10.1017/S0967199414000161.

98. Ionov M, Burchell V, Klajnert B, Bryszewska M, Abramov AY (2011) Mechanism of neuroprotection of melatonin against beta-amyloid neurotoxicity. Neurosci. 180: 229–237. DOI: 10.1016/j.neuroscience.2011.02.045.

99. Dragicevic N, Copes N, O’Neal‐Moffitt G, Jin J, Buzzeo R, Mamcarz M, Tan J, Cao C, Olcese JM, Arendash GW, Bradshaw PC (2011) Melatonin treatment restores mitochondrial function in Alzheimer’s mice: A mitochondrial protective role of melatonin membrane receptor signaling. J. Pineal Res. 51 (1): 75-86. DOI: 10.1111/j.1600-079X.2011.00864.x.

100. Teng YC, Tai YI, Huang HJ, Lin AM (2015) Melatonin ameliorates arsenite-induced neurotoxicity: Involvement of autophagy and mitochondria. Mol. Neurobiol. 52: 1015–1022. DOI: 10.1007/s12035-015-9250-y.

101. Escames G, León J, Macías M, Khaldy H, Acuña-Castroviejo D (2003) Melatonin counteracts lipopolysaccharide‐induced expression and activity of mitochondrial nitric oxide synthase in rats.  FASEB J. 17 (8): 1-22. DOI: 10.1096/fj.02-0692fje.

102. Wang, X., Sirianni, A., Pei, Z., Cormier, K., Smith, K., Jiang, J., Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J. Neurosci. 31 (41): 14496-14507. DOI: 10.1523/JNEUROSCI.3059-11.2011.

103. Kashani IR, Rajabi Z, Akbari M, Hassanzadeh G, Mohseni A, Eramsadati MK, Rafiee K, Beyer C, Kipp M, Zendedel A (2014) Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp. Brain Res. 232 (9): 2835–2846. DOI: 10.1007/s00221-014-3946-5.

104. .Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, Zhu WP (2015) Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet. Mol. Res. 14 (3): 7481-7489. DOI: 10.4238/2015.July.3.24.

105. Waseem M, Tabassum H, Parvez S (2016) Melatonin modulates permeability transition pore and 5-hydroxydecanoate induced KATP channel inhibition in isolated brain mitochondria. Mitochondrion 31: 1-8. DOI: 10.1016/j.mito.2016.08.005.

106. Zhao XM, Hao HS, Du WH, Zhao SJ, Wang HY, Wang N, Wang D, Liu Y, Qin T, Zhu HB (2016) Melatonin inhibits apoptosis and improves the developmental potential of vitrified bovine oocytes. J. Pineal Res. 60 (2): 132-141. DOI: 10.1111/jpi.12290.

107. Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, Li J, Di S, Yue L, Liang G, Reiter RJ, Qu Y (2015) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT 1‐dependent mechanism during ischemic‐stroke in mice. J. Pineal Res. 58 (1): 61-70. DOI: 10.1111/jpi.12193.

108. Jumnongprakhon P, Govitrapong P, Tocharus C, Tungkum W, Tocharus J (2014) Protective effect of melatonin on methamphetamine-induced apoptosis in glioma cell line. Neurotoxic. Res. 25 (3): 286-294. DOI: 10.1007/s12640-013-9419-y.

109. Chen J, Wang L, Wu C, Hu Q, Gu C, Yan F, Li J, Yan W, Chen G (2014) Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J. Pineal Res. 56 (1): 12-19. DOI: 10.1111/jpi.12086.

110. Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L (2010) Beneficial effects of melatonin in cardiovascular disease. Ann. Med. 42 (4): 276-285. DOI: 10.3109/07853890903485748.

111. Tengattini S, Reiter RJ, Tan DX, Terron MP, Rodella LF, Rezzani R (2008) Cardiovascular diseases: protective effects of melatonin. J. Pineal Res. 44 (1): 16-25. DOI: 10.1111/j.1600-079X.2007.00518.x.

112. Fu Z, Jiao Y, Wang J, Zhang Y, Shen M, Reiter RJ, Xi Q, Chen Y (2020) Cardioprotective role of melatonin in acute myocardial infarction. Front. Physiol. 11: 366. DOI: 10.3389/fphys.2020.00366.

113. Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, Krause DN (2002) MT(2) melatonin receptors are present and functional in rat caudal artery.  J. Pharmacol. Exp. Ther. 302 (3): 1295–1302. DOI: 10.1124/jpet.302.3.1295.

114. Saremi A, Arora R (2010) Vitamin E and cardiovascular disease. Am. J. Ther. 17 (3): e56-e65. DOI: 10.1097/MJT.0b013e31819cdc9a.

115. Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G (1991) Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am. J. Clin. Nutr. 53 (1): 314S-321S.

116. Reaven PD, Khouw A, Beltz WF, Parthasarathy S, Witztum JL (1993) Effect of dietary antioxidant combinations in humans. Protection of LDL by vitamin E but not by beta-carotene. Arterioscler. Thromb. 13 (4): 590-600. DOI: 10.1161/01.atv.13.4.590.

117. Ferré N, Camps J, Paul A, Cabré M, Calleja L, Osada J, Joven J (2001) Effects of high-fat, low-cholesterol diets on hepatic lipid peroxidation and antioxidants in apolipoprotein E-deficient mice. Mol. Cell. Biochem. 218 (1-2): 165–169. DOI: 10.1023/a:1007296919243.

118. Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R (2001) Dietary cosupplementation with vitamin E and coenzyme Q10 inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler. Thromb. Vasc. Biol. 21 (4): 585-593. DOI: 10.1161/01.atv.21.4.585.

119. Stephens NG, Parsons A, Brown MJ, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347 (9004): 781-786. DOI: 10.1016/s0140-6736(96)90866-1.

120. Kojda G, Kottenberg K (1999) Regulation of basal myocardial function by NO. Cardiovasc. Res. 41 (3): 514-523. DOI: 10.1016/s0008-6363(99)00208-4.

121. Sönmez MF, Narin F, Akkuş D, Ozdamar S (2009) Effect of melatonin and vitamin C on expression of endothelial NOS in heart of chronic alcoholic rats. Toxicol. Ind. Health 25 (6): 385–393. DOI: 10.1177/0748233709106444.

122. Srinivasan V (1997) Melatonin, biological rhythm disorders and phototherapy. Ind. J. Physiol. Pharmacol. 41 (4): 309-328. PMID: 10235654.

123. Reiter RJ (1998) Oxidative damage in the central nervous system: protection by melatonin. Prog. Neurobiol. 56 (3): 359–384. DOI: 10.1016/s0301-0082(98)00052-5.

124. Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A (2013) Amyloid β, glutamate, excitotoxicity in Alzheimer's disease: are we on the right track?. CNS Neurosci.Ther. 19 (8): 549–555. DOI: 10.1111/cns.12095.

125. IcerMA, ArslanN, Gezmen-Karadag M (2021) Effects of vitamin E on neurodegenerative diseases: an update. Acta  Neurobiol. Exp. 81 (1): 21–33. DOI: 10.21307/ane-2021-003.

126. Moreira PI, Cardoso SM, Santos MS, Oliveira CR (2006) The key role of mitochondria in Alzheimer's disease. J. Alzheimers Dis. 9 (2): 101–110. DOI: 10.3233/jad-2006-9202.

127. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim. Biophys. Acta. 1802 (1): 2–10. DOI: 10.1016/j.bbadis.2009.10.006.

128. Blass JP, Baker AC, Ko L, Black RS (1990) Induction of Alzheimer antigens by an uncoupler of oxidative phosphorylation. Arch. Neurol. 47 (8): 864–869. DOI: 10.1001/archneur.1990.00530080046009.

129. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, VintersHV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, PetersenRB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21 (9): 3017–3023. DOI: 10.1523/JNEUROSCI.21-09-03017.2001.

130. Golombek DA, Pévet P, Cardinali DP (1996) Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci. Biobehav. Rev. 20 (3): 403–412. DOI: 10.1016/0149-7634(95)00052-6.

131. Naguib M, Samarkandi AH (2000) The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth. Analg. 91 (2): 473–479. DOI: 10.1097/00000539-200008000-00046.

132. Johnson K, Page A, Williams H, Wassemer E, Whitehouse W (2002) The use of melatonin as an alternative to sedation in uncooperative children undergoing an MRI examination. Clin. Radiol. 57 (6): 502–506. DOI: 10.1053/crad.2001.0923.

133. Paula-Lima AC, Louzada PR, De Mello FG, Ferreira ST (2003) Neuroprotection against Abeta and glutamate toxicity by melatonin: are GABA receptors involved?. Neurotoxic. Res. 5 (5): 323–327. DOI: 10.1007/BF03033152.

134. Olcese J M, Cao C, Mori T, Mamcarz MB, Maxwell A, Runfeldt MJ, Wang L, Zhang C, Lin X, Zhang G, Arendash, GW (2009) Protection against cognitive deficits and markers of neurodegeneration by long‐term oral administration of melatonin in a transgenic model of Alzheimer disease. J. Pineal Res. 47 (1): 82-96. DOI: 10.1111/j.1600-079X.2009.00692.x 

135. Zhou J, Zhang S, Zhao X, Wei T (2008) Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid‐β1–42. J. Pineal Res. 45 (2): 157-165. DOI: 10.1111/j.1600-079X.2008.00570.x.

136. Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP (2011) Melatonin in mitochondrial dysfunction and related disorders. Int. J. Alzheimers Dis. 2011: (326320). DOI: 10.4061/2011/326320.

137. Harding AE, Matthews S, Jones S, Ellis CJK, Booth IW, Muller DPR (1985) Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. New Engl. J. Med. 313 (1): 32-35. DOI: 10.1056/NEJM198507043130107.

138. Ouahchi K, Arita M, Kayden H, Hentati F, Ben Hamida M, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M (1995) Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat. Genet. 9 (2): 141–145. DOI: 10.1038/ng0295-141.

139. Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M (1998) Ataxia with isolated vitamin E deficiency: Heterogeneity of mutations and phenotypic variability in a large number of families. Am. J. Hum. Genet. 62 (2): 301–310. DOI: 10.1086/301699.

140. Behl C, Davis J, Cole GM, Schubert D (1992) Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem. Biophys. Res. Commun. 186 (2): 944–950. DOI: 10.1016/0006-291x(92)90837-b.

141. Behl C (2000) Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB. J. Neural. Transm. 107 (4): 393–407. DOI: 10.1007/s007020070082.

142. Magalhães J, Ascensão A, Marques F, Soares JM, Ferreira R, Neuparth MJ, Duarte JA (2005) Effect of a high-altitude expedition to a Himalayan peak (Pumori, 7,161 m) on plasma and erythrocyte antioxidant profile. Eur. J. Appl. Physiol. 93 (5-6): 726–732. DOI: 10.1007/s00421-004-1222-2.

143. Saito Y, Nishio K, Akazawa YO, Yamanaka K, Miyama A, Yoshida Y, Noguchi N, Niki E (2010) Cytoprotective effects of vitamin E homologues against glutamate-induced cell death in immature primary cortical neuron cultures: Tocopherols and tocotrienols exert similar effects by antioxidant function. Free Radic. Biol. Med. 49 (10): 1542–1549. DOI: 10.1016/j.freeradbiomed.2010.08.016.

144. Giraldo E, Lloret A, Fuchsberger T, Viña J (2014) Aβ and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E. Redox Biol. 2: 873–877. DOI:10.1016/j.redox.2014.03.002.

145. Montilla-López P, Muñoz-Agueda MC, Feijóo López M, Muñoz-Castañeda JR, Bujalance-Arenas I, Túnez-Fiñana I (2002) Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer's disease induced by okadaic acid in neuroblastoma cells. Eur. J. Pharmacol. 451 (3): 237–243. DOI: 10.1016/s0014-2999(02)02151-9.

146. Baydas G, Canatan H, Turkoglu A (2002) Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. J. Pineal Res. 32 (4): 225–230.DOI: 10.1034/j.1600-079x.2002.01856.x.

147. Brömme HJ, Mörke W, Peschke D, Ebelt H, Peschke D (2000) Scavenging effect of melatonin on hydroxyl radicals generated by alloxan. J. Pineal Res. 29 (4): 201–208. DOI: 10.1034/j.1600-0633.2002.290402.x.

148. Ebelt H, Peschke D, Brömme HJ, Mörke W, BlumeR, Peschke E (2000) Influence of melatonin on free radical-induced changes in rat pancreatic beta-cells in vitro. J. Pineal Res. 28 (2): 65–72. DOI: 10.1034/j.1600-079x.2001.280201.x.

149. Nogueira TC, Lellis-Santos C, Jesus DS, Taneda M, Rodrigues SC, Amaral FG, Lopes AM, Cipolla-Neto J, Bordin S, Anhê GF (2011) Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response. Endocrinol. 152 (4): 1253–1263. DOI: 10.1210/en.2010-1088.

150. Sudnikovich EJ, Maksimchik YZ, Zabrodskaya SV, Kubyshin VL, Lapshina EA, Bryszewska M, Reiter RJ, Zavodnik IB (2007) Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur. J. Pharmacol. 569 (3): 180–187. DOI: 10.1016/j.ejphar.2007.05.018.

151. Pierrefiche G, Laborit H. (1995) Oxygen free radicals, melatonin, and aging. Exp. Gerontol. 30 (3-4): 213–227. DOI: 10.1016/0531-5565(94)00036-3.

152. Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D (2019) The role of inflammation in diabetes: Current concepts and future perspectives. Eur. Cardiol. 14 (1): 50–59. DOI: 10.15420/ecr.2018.33.1.

153. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX (2000) Melatonin and its relation to the immune system and inflammation. Ann. N. Y. Acad. Sci. 917: 376–386. DOI: 10.1111/j.1749-6632.2000.tb05402.x.

154. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R (2017) Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int. J. Endocrinol. 2017: (1835195). DOI: 10.1155/2017/1835195.

155. Abdulwahab DA, El-Missiry MA, Shabana S, Othman AI, Amer ME (2021) Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon 7 (3): e06474. DOI: 10.1016/j.heliyon.2021.e06474.

156. MooradianAD, Morley JE (1987) Micronutrient status in diabetes mellitus. Am. J. Clin. Nutr. 45 (5): 877–895. DOI: 10.1093/ajcn/45.5.877.

157. Weber P, BendichA, Schalch W (1996) Vitamin C and human health--a review of recent data relevant to human requirements. Int. J. Vitam. Nutr. Res. 66 (1): 19–30. PMID: 8698541.

158. Kadowaki S, Norman AW (1984) Pancreatic vitamin D-dependent calcium binding protein: biochemical properties and response to vitamin D. Arch. Biochem. Biophys. 233 (1): 228-236. DOI: 10.1016/0003-9861(84)90621-0.

159. Norman AW, Frankel BJ, Heldt AM, Grodsky GM (1980) Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 209 (4458): 823-825. DOI: 10.1126/science.6250216.

160. Cade C, Norman AW (1986) Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinol. 119 (1): 84-90. DOI: 10.1210/endo-119-1-84.

161. RiachyR, Vandewalle B, Moerman E, Belaich S, Lukowiak B, Gmyr V, Muharram G, Kerr Conte J, Pattou F (2006) 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis 11 (2): 151–159. DOI: 10.1007/s10495-006-3558-z.

162. Higgs DR, Engel JD, Stamatoyannopoulos G (2012) Thalassaemia. Lancet 379 (9813): 373–383. DOI: 10.1016/S0140-6736(11)60283-3.

163. Korkina L, De Luca C, Deeva I, Perrotta S, Nobili B, Passi S, Puddu P (2000) L1 effects on reactive oxygen (ROS) and nitrogen species (RNS) release, hemoglobin oxidation, low molecular weight antioxidants, and antioxidant enzyme activities in red and white blood cells of thalassemic patients. Transfus. Sci. 23 (3): 253–254. DOI: 10.1016/s0955-3886(00)000990.

164. Yuan J, Bunyaratvej A, Fucharoen S, Fung C, Shinar E, Schrier SL (1995) The instability of the membrane skeleton in thalassemic red blood cells. Blood 86 (10): 3945–3950. PMID: 7579365.

165. Ozment CP, Turi JL (2009) Iron overload following red blood cell transfusion and its impact on disease severity. Biochim. Biophys. Acta. 1790 (7): 694–701. DOI: 10.1016/j.bbagen.2008.09.010.

166. Huser HJ, Rieber EE, Berman AR (1967) Experimental evidence of excess hemolysis in the course of chronic iron deficiency anemia. J. Lab. Clin. Med. 69 (3): 405–414. PMID: 6019402.

167. Efferth T, Schwarzl SM, Smith J, Osieka R (2006) Role of glucose-6-phosphate dehydrogenase for oxidative stress and apoptosis. Cell Death Differ. 13 (3): 527–530. DOI: 10.1038/sj.cdd.4401807.

168. Vanella A, Campisi A, Castorina C, Sorrenti V, Attaguile G, Samperi P, Azzia N, Di Giacomo C, Schilirò G (1991) Antioxidant enzymatic systems and oxidative stress in erythrocytes with G6PD deficiency: effect of deferoxamine. Pharmacol. Res. 24 (1): 25–31. DOI: 10.1016/1043-6618(91)90061-2.

169. Beutler E, Grabowski G (1983) The metabolic basis of inherited disease, eds. JB Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (McGraw-Hill, New York), pp1629-1953. PMID: 7579365.

170. Abdul-Razzak KK, Almomany EM, NusierMK, Obediat AD, Salim AM (2008) Antioxidant vitamins and glucose-6-phosphate dehydrogenase deficiency in full-term neonates. Ger. Med. sci. 24 (6): Doc 10. PMID: 19675737.

171. Paul S, Naaz S, Ghosh AK, Mishra S, Chattopadhyay A, Bandyopadhyay D (2018) Melatonin chelates iron and binds directly with phenylhydrazine to provide protection against phenylhydrazine induced oxidative damage in red blood cells along with its antioxidant mechanisms: an in vitro study. Melatonin Res. 1 (1): 1-20. DOI: 10.32794/mr11250001.

172. Allegra M, Gentile C, Tesoriere L, Livrea MA (2002) Protective effect of melatonin against cytotoxic actions of malondialdehyde: an in vitro study on human erythrocytes J. Pineal Res. 32 (3): 187–193. DOI: 10.1034/j.1600-079x.2002.1o852.x.

173. Nogués MR, Giralt M, Romeu M, Mulero M, Sánchez-Martos V, Rodríguez E, Acuña-Castroviejo D, Mallol J (2006) Melatonin reduces oxidative stress in erythrocytes and plasma of senescence-accelerated mice. J. Pineal Res. 41 (2): 142–149. DOI: 10.1111/j.1600-079X.2006.00344.x.

174. Sultana T, DeVita MV, Michelis MF (2016) Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency. Int.Urol. Nephrol. 48 (9): 1519–1524. DOI: 10.1007/s11255-016-1309-9.

175. Chou AC, Broun GO Jr, Fitch CD (1978) Abnormalities of iron metabolism and erythropoiesis in vitamin E-deficient rabbits. Blood 52 (1): 187–195. PMID: 656627.

176. Wolbach SB, Howe PR (1925) Tissue changes following deprivation of fat-soluble a vitamin. J. Exp. Med. 42 (6): 753–777. DOI: 10.1084/jem.42.6.753.

177. Hodges RE, Sauberlich HE, Canham JE, Wallace DL, Rucker RB, Mejia LA, Mohanram M (1978) Hematopoietic studies in vitamin A deficiency. Am. J .Clin. Nutr. 31 (5): 876–885. DOI:10.1093/ajcn/31.5.876.

178. Revin VV, Gromova NV, Revina ES, Samonova AY, Tychkov AY, Bochkareva SS, Moskovkin AA, Kuzmenko TP (2019) The influence of oxidative stress and natural antioxidants on morphometric parameters of red blood cells, the hemoglobin oxygen binding capacity, and the activity of antioxidant enzymes. BioMed Res. Int. 2019: 2109269. DOI: 10.1155/2019/2109269.

179. Bothwell TH, Bradlow BA, Jacobs P, Keeley K, Kramer S, Seftel H, Zail S (1964) Iron metabolism in scurvy with special reference to erythropoiesis. Br. J. Haematol. 10: 50–58. DOI: 10.1111/j.1365-2141.1964.tb00677.x

180. Lynch SR,  Cook JD (1980) Interaction of vitamin C and iron. Ann. N. Y. Acad. Sci. 355: 32–44. DOI: 10.1111/j.1749-6632.1980.tb21325.x.

181. Ajibade TO, Oyagbemi AA, Durotoye LA, Omóbòwálé TO, Asenuga ER, Olayemi FO (2017) Modulatory effects of melatonin and vitamin  C on oxidative stress-mediated haemolyticanaemia and associated cardiovascular dysfunctions in rats. J. Complement Integr. Med. 14 (1): 20150082. DOI: 10.1515/jcim-2015-0082.

182. Montilla P, Cruz A, PadilloFJ, Tunez I, Gascon F, Munoz MC, Gomez M, Pera C (2001) Melatonin versus vitamin E as protective treatment against oxidative stress after extra‐hepatic bile duct ligation in rats. J. Pineal Res. 31 (2): 138-144. DOI: 10.1034/j.1600-079x.2001.310207.x.

183. Karaoz E, Gultekin F, Akdogan M, Oncu M, Gokcimen A (2002) Protective role of melatonin and a combination of vitamin C and vitamin E on lung toxicity induced by chlorpyrifos-ethyl in rats. Exp. Toxicol. Pathol. 54 (2): 97–108. DOI: 10.1078/0940-2993-00236.

184. El-Sokkary GH (2008) Melatonin and vitamin C administration ameliorate diazepam-induced oxidative stress and cell proliferation in the liver of rats. Cell Prolif. 41 (1): 168–176. DOI: 10.1111/j.1365-2184.2007.00503.x.

185. Akinci A, Esrefoglu M, Cetin A, Ates B (2015) Melatonin is more effective than ascorbic acid and β-carotene in improvement of gastric mucosal damage induced by intensive stress. Arch. Med. Sci. 11 (5): 1129–1136. DOI: 10.5114/aoms.2015.54870.

186. Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ (2015) Melatonin as a     potent  and inducible endogenous antioxidant: synthesis and metabolism. Molecules 20 (10): 18886-18906. DOI: 10.3390/molecules201018886.

This work is licensed under a Creative Commons Attribution 4.0 International License