Melatonin and human mitochondrial diseases
Reza Sharafati-Chaleshtori1, Hedayatollah Shirzad2, Mahmoud Rafieian-Kopaei2, Amin Soltani2
1 Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
2 Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
|Date of Submission||25-Aug-2015|
|Date of Decision||07-Sep-2016|
|Date of Acceptance||22-Oct-2016|
|Date of Web Publication||27-Jan-2017|
Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord
Source of Support: None, Conflict of Interest: None
Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function.
Keywords: Antioxidant, free radical, melatonin, mitochondrial dysfunction, neurodegenerative disorders, nitric oxide, pineal gland hormone
|How to cite this article:|
Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A. Melatonin and human mitochondrial diseases. J Res Med Sci 2017;22:2
| Introduction|| |
Enhanced generation of reactive oxygen species (ROS) is considered as one of the main contributory factors in a wide variety of diseases and age-related degeneration. Oxidative stress induced by these free radicals has been implicated in etiology of cancer,, diabetes mellitus,, cardiovascular diseases,, neurodegenerative diseases,, neuropsychological disorders,, and infectious disease.,
Mitochondria are considered as the main source of ROS/reactive nitrogen species (RNS) generators which are the predominant target of their actions, resulting in widespread damage to mitochondrial respiratory chain. This process produces further increase in free radical generation, causing a self-induced vicious cycle., This process and some other conditions may cause mitochondrial diseases which are a group of complications caused by mitochondrial dysfunction. Mitochondrial diseases are also caused by mutations in the mitochondria affecting mitochondrial function. Mutations in mitochondria are also facilitated by high level of oxidative stress.
Melatonin has been shown to play a crucial role in regulation of mitochondrial homeostasis. Melatonin, in addition to being a powerful antioxidant, decreases nitric oxide (NO) generation in mitochondria and maintains bioenergetic functions of the cell.,
The purpose of the current study was to identify melatonin production, metabolism, and clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, and diseases related to brain function. Furthermore, the mechanisms through which melatonin can exert neuroprotection against neurodegenerative disorders related to mitochondrial dysfunctions are reviewed.
| Mitochondria and Free Radical Generation in Mitochondria|| |
The main function of mitochondria is production of adenosine triphosphate (ATP) through the electron transport chain (ETC). The primary function of the ETC is conversion of redox energy to an electrochemical gradient which causes synthesis of ATP from adenosine diphosphate and production of phosphate by ATP synthase. The ultimate generation of the respiratory chain is water which is produced in a four-electron reduction of molecular oxygen (O2). During this process, a section of O2 is converted to ROS, including superoxide anion radical (O2•−), reactive hydroxyl radical (• OH), and hydrogen peroxide (H2O2).
Mitochondrial NO synthase (NOS) is responsible for production of NO radical (• NO) from L-arginine. The free radical • NO is produced by several forms of NOS.• NO is able to easily cross membranes and enter mitochondria regardless of its origin.• NO can strongly interfere with the respiratory chain components such as cytochrome C-oxidase.
These free radicals can damage proteins of respiratory complexes. When • NO reaches high levels, it can start free radical-mediated chain reactions which destroy DNA molecules, proteins, and lipids., Damage to the mitochondrial respiratory chain leads to further generation of free radicals and breakdown of proton potential, apoptosis, and cell death.
Free radicals are usually generated in cells during normal activity. Among the mechanisms which control the ROS/RNS production is the enzyme superoxide dismutase function in mitochondrial membrane that removes O2•−. The • OH generated from H2O2 is scavenged by glutathione peroxidase (GPx). These enzymes which are the important parts of antioxidant defense system reduce free radicals within the mitochondria.
Antioxidants such as Vitamins C and E are able to participate in the antioxidant defense system of mitochondria, but they cannot convert O2•− to O2. It is glutathione (GSH) which scavenges O2•−, as well as participating in several redox reactions. In the mitochondria, the redox cycling is very active and prevents significant loss of GSH. This process is very important because the mitochondrial GPx and GSH reductase activities depend only on GSH uptake from the cytoplasm for keeping adequate GSH levels. Melatonin, by stimulating the activity of the enzyme γ-glutamyl-cysteine synthetase, promotes synthesis of GSH. It also plays an important role in mitochondrial physiology through its effects on gene expression of GPx, GSH reductase, catalase, and dismutase, helping in maintaining the GSH/GSSG ratio and in high recycling of GSH.,
| Melatonin and Reduction of Oxidative Stress|| |
Free radicals are atoms or molecules with unpaired electrons which make them highly toward other substances. Free radicals such as H2O2 and • OH which are called ROS can cause oxidative stress and damage to cell components.,, Increased production of ROS and other free radicals or decreased antioxidant enzymes can cause oxidative damages to organs, tissues, and various cells such as brain, heart, and vascular cells.,, Oxidative stress is also the background of many hard curable diseases such as high blood pressure,, atherosclerosis,, and infectious diseases.,,
ROS are mostly produced in the mitochondria as normal cell respiration. The interrelationship between mitochondria and its ROS generation suggests shared pathogenic mechanisms in ROS-related diseases and mitochondria.
In this regard, mitochondria are considered as endogenous producers of ROS and the central executioners of cell death. Increased mitochondrial Ca2 − overload is associated with generation of superoxide which induces the release of pro-apoptotic proteins implicated in pathogenesis of neurodegenerative diseases and several features of cell death.
Antioxidants such as Vitamins A, C, and E have a little ability to protect the body against free radicals. In preclinical studies, plants' antioxidants have been effective in most of ROS-related diseases such as gastrointestinal complications,,,, cognitive problems,, cardiovascular diseases,, pain,, and other complications.,, However, their effects have not been confirmed in most of large clinical trials. Melatonin has been shown to possess high level of antioxidant activity and the ability to counteract with oxidative stress-induced diseases, even in most of clinical trials., Melatonin is the stimulator of antioxidant enzymes including superoxide dismutase, GPx, GSH reductase, and catalase. It also acts as inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes.
Administration of melatonin in animals with ischemia can reduce malondialdehyde level and other products obtained from the membrane lipid peroxidation as injury indices. Features that help melatonin to prevent lipid peroxidation include being soluble in fat, hydroxyl free radical clearing, inhibition of lipid peroxidation, and increasing the effectiveness of other antioxidants such as Vitamin E and C, clearing of peroxide radicals, and also individual highly reactive oxygen. Melatonin also increases the level of GSH and GSH S-transferase and the activity of GPx. Melatonin can cross blood–brain barrier and placenta easily and reach all the cellular components without difficulty. Hence, it can protect the cell walls, organs, and nuclei against the damage of free radicals.
| Pharmacologic and Therapeutic Aspects of Melatonin|| |
Melatonin was first considered as a hormone responsible for control of circadian rhythms. However, it has several biological functions which are produced by activation of its receptors or due to melatonin role as a powerful antioxidant. Melatonin has a specific role in the protection of mitochondrial DNA and other biological compounds.
Melatonin is now used for insomnia, especially the insomnia associated with attention-deficit hyperactivity disorder, insomnia caused by beta-blockers, delayed sleep phase syndrome, rapid eye movement sleep behavior disorder, and the sleep difficulties in children associated with developmental disorders such as intellectual disabilities, autism, and cerebral palsy. Melatonin is also used to reduce the side effects of stopping smoking or as a sleep remedy after stopping the consumption of benzodiazepines. It might also be used for mild mental impairment, bipolar disease, depression, seasonal affective disorder, Alzheimer's disease, schizophrenia, epilepsy, dementia, stress, delirium, chronic obstructive pulmonary disease, endometriosis, fibromyalgia, tinnitus, nonalcoholic liver disease, chronic fatigue syndrome, age-related vision loss, restless leg syndrome, jaw pain, nerve pain, weakness, sarcoidosis, migraine and tension headache, benign prostatic hyperplasia, irritable bowel syndrome, osteoporosis, tardive dyskinesia, acid reflux disease, infertility, aging, menopause, metabolic syndrome, inflammatory bowel disease (IBD). Recovery after surgery, agitation due to anesthesia, inability to control urination, various cancers including breast, brain, lung, prostate, head, neck, and gastrointestinal tract cancers. Melatonin is also used to reduce some side effects of cancer chemotherapies such as weight loss, fatigue and thrombocytopenia, too.,,,,,,,,,,,,,,
Regarding the aim of the current study, the effects of melatonin on the most important diseases related to mitochondrial dysfunction including cancer, cardiovascular disease, Alzheimer's disease, obesity, diabetes mellitus, affective disorder, gastrointestinal diseases, attention-deficit, hyperactivity disorder, and autism are discussed below. The melatonin side effects are also presented at the end.
Melatonin and cancer
The removal of the pineal gland leads to an increased tumor growth while taking melatonin reverses this effect and inhibits tumor genesis induced by carcinogen. Melatonin is likely to reduce the growth of the tumor cells through inhibiting mitosis and regulating the activity of the receptors in tumor cells. For example, this hormone inhibits the activity and expression of estrogen receptor genes in breast cancer cells. Adding melatonin to tamoxifen has led to slow down the rate of progression of the disease. Consumption of high dose of melatonin (700 mg daily) caused a transient reduction in the size of some tumor populations. In addition, it is noted that added melatonin to chemotherapy and radiotherapy had the influence to reduce the injuries imposed on blood cells and made the remedy more tolerable.,
Researches results have shown that serum and urine melatonin levels in women with breast cancer are low and melatonin usage could inhibit breast tumor growth. A research finding showed that interrupted sleep at 1:30 A.M. led to increase in the concentration of estradiol in the blood while exposure to light at night reduced the menstrual cycle duration. This was accompanied by increasing the risk of breast cancer. It was also reported that the prostate cancer cells treated with melatonin might significantly reduce the number of prostate cancer cells.
Large intestine tumor is one of the tumors that melatonin can have effect on it. The mammalian intestine is the place of melatonin production, and an impaired circadian rhythm of melatonin secretion has been observed in patients with colorectal cancer. An inhibitory effect of melatonin on colon cancer cell was observed through reduced invasion and increased differentiation of cancer cells. Other epidemiological studies have shown that melatonin in children who have exposed to low frequency magnetic field and its risk is lower and leukemia is higher than normal.
Melatonin and cardiovascular disease
The finding that melatonin receptors are found in human arteries may suggest a direct role of this hormone in locally controlling the blood vessel diameter. According to the performed researches, very high concentrations of melatonin decrease the risk of atherosclerosis disease with inhibiting the oxidation of cholesterol low-density lipoprotein (LDL). Circadian changes in hemodynamic parameters including heart rate, cardiac output, and blood pressure are clear. In addition, the occurrence of some acute cardiovascular events such as myocardial infarction and sudden cardiac death showed a circadian pattern as the occurrence of such cutting off blood flow is greater in the early morning. Further, melatonin levels in patients with stroke, migraine, and cardiovascular disease will be reduced.
Melatonin and Alzheimer's disease
Melatonin serum levels and its daily rhythm are reduced in patients affected with Alzheimer's disease. Therefore, in these patients, melatonin supplementation might reduce distractions and improve their memory. Studies have shown that inflammation causes Alzheimer's disease while taking melatonin orally reduces progression of Alzheimer's disease by decreasing pro-inflammatory cytokines.
The findings of a research have shown that exposure to bright light in the elderly can improve sleep and behavioral disorders, depression, and the memory condition. In addition, it would shorten the time to fall asleep and increase sleep duration for a period of 27 min. It also reduces the time of waking. Both factors (light and melatonin) help improve the quality of sleep and night vision disturbances.
Melatonin and obesity
Melatonin can affect body size, obesity, and energy intake; however, these effects sometimes are different based on the species. The direct effect of melatonin is possibly on brown fat while its indirect effect found to be through sympathetic system. However, this effect is less discernible in the species whose activity and life do not depend on light. Melatonin increases sensitivity to insulin. This increased insulin sensitivity and decreased plasma triglyceride may be due to the effect of weight loss caused by melatonin.
As mentioned earlier, plasma melatonin is decreased with increasing age; however, the level of leptin and visceral fat and nonfasting insulin increases. In a study, daily melatonin supplementation for 10 weeks resulted in decrease in leptin, nonfasting insulin, and visceral fat, which based on the conducted studies, the mentioned reduction was in response to melatonin supplements independent on changes in the regulation of testicular, thyroid, adrenal, and somatotropin.
Melatonin and diabetes mellitus
Administration of melatonin to middle-aged rats reduced visceral fat, plasma insulin, insulin-like growth factor, and leptin levels. In addition, administration of melatonin to women after menopause has been shown to decrease insulin sensitivity and glucose tolerance. Melatonin increases carbohydrate utilization in liver and decreases hepatic lipolysis. Long-term treatment with melatonin led to increase insulin doses, triglycerides, leptin, cholesterol and high-density lipoprotein (HDL), esterified cholesterol, free cholesterol, and total cholesterol. High doses of melatonin inhibited the oxidation of LDL cholesterol.
Melatonin and affective disorder
During pregnancy and after childbirth, some degrees of depression with unknown etiology are common. In pregnant women with severe depression, the plasma melatonin level during night, especially at early morning hours, was found to be lower than that of healthy people. In severe depression, the sensitivity to estradiol or progesterone effects on melatonin receptors will decrease. Therefore, increased sexual hormones during pregnancy and melatonin secretion in healthy pregnant women will increase; however, in patients with severe depression, it does not work. A study showed that decreased tryptophan followed by diminished serotonin will decrease melatonin secretion. Decreased melatonin is also associated with different affective disorders. Low-melatonin syndrome or melatonin deficiency depression has been reported in a subgroup of depressed patients. Administration of melatonin to unresponsive depressed patients to conventional drugs was also effective on their depression and their sleep quality.
Melatonin and gastrointestinal diseases
It has been reported that melatonin supplements can reduce the risk of stomach ulcers. In the case of more severe ulcers, the melatonin concentrations in samples were lower than that of control group.
Administration of melatonin is effective in reduction of damage to the oral cavity tissues through converting free radicals to inactive forms. Furthermore, pharmacological dosages of melatonin with increased expression of endogenous antioxidant enzymes such as GPx, superoxide dismutase, and catalase can be effective in the treatment of inflammatory lesions after the oral cavity surgery including dental extraction. Researchers have shown that the application of exogenous melatonin in an animal model prevented the stress-induced gastric damage and accelerated stomach ulcer healing by increasing blood flow and mucus retention. They also reported the effect of melatonin in prevention of esophageal damages caused by acid, pepsin, and bile solutions.
Melatonin and attention-deficit hyperactivity disorder
Attention-deficit disorder occurs in two forms, with or without hyperactivity. People with attention-deficit disorders have been found with specific behaviors such as lack of attention to the audience, frequent mistakes in homework and career, distraction and forgetting distinguishing them from others.
In a study done in 2006 to determine the association between attention-deficit disorder and sleep disorders, it was observed that in 25% of children with attention-deficit, hyperactivity disorder suffers from sleep disorders. The use of melatonin in such children improved their sleep and resulted in eliminating the symptoms.
Melatonin and autism
The serum melatonin level in autistic children (a neurological disorder that is characterized by abnormalities in social behavior and communication) is lower than healthy children. In a survey conducted in this field reported that plasma melatonin concentration found to be low in healthy parents of patients with autism suggesting a genetic origin. These patients suffer from irregular sleep-wake circadian cycle which can be improved by melatonin supplementation.
Melatonin safety and interactions
Melatonin is an inexpensive and safe medication. Except a couple of studies which reported transient or mild adverse effects in a small number of subjects, other studies did not report any adverse effect for it. The side effects reported for melatonin include dizziness, confusion, daytime sleepiness, headache, irritability, mild anxiety abdominal discomfort, and short-lasting feelings of depression., Drug interactions of melatonin with other medications have been reported for anticoagulants, immunosuppressants, antidiabetes, and birth control pills.
Melatonin is one of the normal components of breast milk and is synthesized from tryptophan. Although the maternal use of melatonin during breastfeeding seems to be safe, there are no enough data to make its usage sure. The safety usage of melatonin during pregnancy is the same.
| Discussion|| |
Mitochondrial dysfunction is one of the main causative complications of a lot of diseases, especially the neurodegenerative diseases. The main cause of these diseases is free radical-induced oxidative stress.,
Fee radical theory of aging and degenerative diseases attributes the damage to cellular components through ROS imbalance as a major determinant of life span and disease. Among the possible affecting organs, the brain and cell membranes possess high proportion of easily peroxidizable fatty acids; hence, they are the main targets for oxidative stress. Phospholipids including phosphatidylinositol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and sphingomyelin make the most abundant content of cellular membrane. Therefore, extensive and persistent oxidative damage in the brain and cell membranes may easily cause the death of these cells.
Antioxidant therapy is a way for slowing the oxidative damage that is responsible for functional decline or death of the cells or organs. Endogenous antioxidant defense system reduces free radicals within the mitochondria. However, in extensive oxidative stresses, the endogenous antioxidants should be restored. Various antioxidants have been extensively examined against oxidative-induced damage., Antioxidants such as Vitamins C and E are able to participate in the antioxidant defense system of mitochondrial; however, in most cases, they are not effective. For example, they cannot convert O2•− to O2, and for this process, GSH is needed. The mitochondrial GPx and GSH reductase activities depend only on GSH uptake from the cytoplasm to keep adequate GSH levels. Melatonin by stimulating the activity of the enzyme γ-glutamyl-cysteine synthetase promotes synthesis of GSH. It also plays an important role in mitochondrial physiology through its effects on gene expression of GPx, GSH reductase, catalase, and dismutase, helping in maintaining the GSH/GSSG ratio and in high recycling of GSH.,
More importantly, melatonin is selectively taken up by mitochondria and acts as a powerful antioxidant. Furthermore, melatonin increases the permeability of membranes and acts as inhibitor of lipoxygenase. Melatonin also acts as stimulator of antioxidant enzymes including superoxide dismutase, GPx, GSH reductase, and catalase. Melatonin has been effective against a wide variety of pathological conditions. It is also effective on the activity of fibroblasts and stimulates the synthesis of Type I collagen fibers  as well as puberty timing. Activation of melatonin receptors prevents from many fatal diseases by increasing the release of some immune system inhibitor cytokines due to stress. Melatonin can cause to resistance against oxidative damages by stimulating the antioxidant enzymes and microsomal membranes stabilization. Melatonin is considered to have protective effects against the damage caused by ultraviolet radiation.
Based on the performed examinations, melatonin reduces the risk of atherosclerosis. In patients with Alzheimer's disease, the use of melatonin supplements could reduce the distraction and improve memory in such patients. It was revealed that melatonin could influence the body size, obesity, and energy intake as well. According to the previous studies, received melatonin led to decrease enhanced insulin doses, triglycerides, and leptin, while increased HDL cholesterol, esterified cholesterol, free cholesterol, and total cholesterol, and inhibited the oxidation of LDL cholesterol. The use of melatonin could improve sleep and remove attention-deficit hyperactivity disorder symptoms, as well as irregular circadian sleep-wake circle in patients with autism. More importantly, melatonin is relatively an inexpensive and safe medication, and although it is not sure, it seems to be safe to use during pregnancy and lactation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Authors' Contributions|| |
- MRK contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.
- RShC contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.
- HSh contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.
- AS contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.
| References|| |
Shirzad H, Taji F, Rafieian-Kopaei M. Correlation between antioxidant activity of garlic extracts and WEHI-164 fibrosarcoma tumor growth in BALB/c mice. J Med Food 2011;14:969-74.
Azadmehr A, Hajiaghaee R, Afshari A, Amirghofran Z, Refieian-Kopaei M, Darani YH, et al
. Evaluation of in vivo
immune response activity and in vitro
anti-cancer effect by Scrophularia megalantha
. J Med Plants Res 2011;5:2365-8.
Asgary S, Rafieian-Kopaei M, Shamsi F, Najafi S, Sahebkar A. Biochemical and histopathological study of the anti-hyperglycemic and anti-hyperlipidemic effects of cornelian cherry (Cornus mas
L.) in alloxan-induced diabetic rats. J Complement Integr Med 2014;11:63-9.
Baharvand-Ahmadi B, Bahmani M, Tajeddini P, Naghdi N, Rafieian-Kopaei M. An ethno-medicinal study of medicinal plants used for the treatment of diabetes. J Nephropathol 2016;5:44-50.
Khosravi-Boroujeni H, Sarrafzadegan N, Mohammadifard N, Sajjadi F, Maghroun M, Asgari S, et al.
White rice consumption and CVD risk factors among Iranian population. J Health Popul Nutr 2013;31:252-61.
Sadeghi M, Khosravi-Boroujeni H, Sarrafzadegan N, Asgary S, Roohafza H, Gharipour M, et al.
Cheese consumption in relation to cardiovascular risk factors among Iranian adults-IHHP Study. Nutr Res Pract 2014;8:336-41.
Rabiei Z, Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects of Ziziphus jujuba
extract on memory and learning impairment induced by bilateral electric lesions of the nucleus basalis of Meynert in rat. Neurochem Res 2014;39:353-60.
Rabiei Z, Rafieian M. Effects of Zizyphus jujuba
extract on motor coordination impairment induced by bilateral electric lesions of the nucleus basalis of Meynert in rat. Physiol Pharmacol 2014;17:469-77.
Bahmani M, Shirzad H, Majlesi M, Shahinfard N, Rafieian-Kopaei M. A review study on analgesic applications of Iranian medicinal plants. Asian Pac J Trop Med 2014;7S1:S43-53.
Delfan B, Bahmani M, Hassanzadazar H, Saki K, Rafieian-Kopaei M. Identification of medicinal plants affecting on headaches and migraines in Lorestan Province, West of Iran. Asian Pac J Trop Med 2014;7S1:S376-9.
Bagheri N, Taghikhani A, Rahimian G, Salimzadeh L, Azadegan Dehkordi F, Zandi F, et al.
Association between virulence factors of Helicobacter pylori
and gastric mucosal interleukin-18 mRNA expression in dyspeptic patients. Microb Pathog 2013;65:7-13.
Rahimian G, Sanei MH, Shirzad H, Azadegan-Dehkordi F, Taghikhani A, Salimzadeh L, et al.
Virulence factors of Helicobacter pylori
vacA increase markedly gastric mucosal TGF-ß1 mRNA expression in gastritis patients. Microb Pathog 2014;67-68:1-7.
Czesnikiewicz-Guzik M, Konturek SJ, Loster B, Wisniewska G, Majewski S. Melatonin and its role in oxidative stress related diseases of oral cavity. J Physiol Pharmacol 2007;58 Suppl 3:5-19.
Col C, Dinler K, Hasdemir O, Buyukasik O, Bugdayci G. Oxidative stress and lipid peroxidation products: Effect of pinealectomy or exogenous melatonin injections on biomarkers of tissue damage during acute pancreatitis. Hepatobiliary Pancreat Dis Int 2010;9:78-82.
Dimauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med 2005;37:222-32.
Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Ageing 2005;2:17.
Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, et al.
Regulation of antioxidant enzymes: A significant role for melatonin. J Pineal Res 2004;36:1-9.
Yang Q, Scalbert E, Delagrange P, Vanhoutte PM, O'Rourke ST. Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries. Am J Physiol Heart Circ Physiol 2001;280:H76-82.
Galano A. On the direct scavenging activity of melatonin towards hydroxyl and a series of peroxyl radicals. Phys Chem Chem Phys 2011;13:7178-88.
Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res 2013;54:245-57.
Lenaz G, Genova ML. Structure and organization of mitochondrial respiratory complexes: A new understanding of an old subject. Antioxid Redox Signal 2010;12:961-1008.
Liochev SI, Fridovich I. Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase. Free Radic Biol Med 2010;48:1565-9.
Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, et al.
Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med 1999;27:838-47.
Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S. Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N
Y Acad Sci 2001;939:200-15.
Rafieian-Kopaei M, Baradaran A, Rafieian M. Plants antioxidants: From laboratory to clinic. J Nephropathol 2013;2:152-3.
Rafieian-Kopaei M, Baradaran A, Rafieian M. Oxidative stress and the paradoxical effects of antioxidants. J Res Med Sci 2013;18:629.
Sharafati Chaleshtori R, Sharafati Chaleshtori F, Rafieian M. Biological characterization of Iranian walnut (Juglans regia
) leaves. Turk J Biol 2011;35:635-9.
Alibabaei Z, Rabiei Z, Rahnama S, Mokhtari S, Rafieian-Kopaei M. Matricaria chamomilla
extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine. Biomed Aging Pathol 2014;4:355-60.
Sarrafchi A, Bahmani M, Shirzad H, Rafieian-Kopaei M. Oxidative stress and Parkinson's disease: New hopes in treatment with herbal antioxidants. Curr Pharm Des 2016;22:238-46.
Sharafati-Chaleshtori R, Rokni N, Rafieian-Kopaei M, Drees F, Sharafati-Chaleshtori, A, Salehi E. Use of tarragon (Artemisia dracunculus
) essential oil as a natural preservative in beef burger. Ital J Food Sci 2014;26:427-32.
Asgary S, Sahebkar A, Afshani MR, Keshvari M, Haghjooyjavanmard S, Rafieian-Kopaei M. Clinical evaluation of blood pressure lowering, endothelial function improving, hypolipidemic and anti-inflammatory effects of pomegranate juice in hypertensive subjects. Phytother Res 2014;28:193-9.
Khosravi-Boroujeni H, Mohammadifard N, Sarrafzadegan N, Sajjadi F, Maghroun M, Khosravi A, et al.
Potato consumption and cardiovascular disease risk factors among Iranian population. Int J Food Sci Nutr 2012;63:913-20.
Rafieian-Kopaei M, Shahinfard N, Rouhi-Boroujeni H, Gharipour M, Darvishzadeh-Boroujeni P. Effects of Ferulago angulata
extract on serum lipids and lipid peroxidation. Evid Based Complement Alternat Med 2014;2014:680856.
Bagheri N, Rahimian G, Salimzadeh L, Azadegan F, Rafieian-Kopaei M, Taghikhani A, et al.
Association of the virulence factors of Helicobacter pylori
and gastric mucosal interleukin-17/23 mRNA expression in dyspeptic patients. EXCLI J 2013;12:5-14.
Bahmani M, Rafieian-Kopaei M, Hassanzadazar H, Saki K, Karamati SA, Delfan B. A review on most important herbal and synthetic antihelmintic drugs. Asian Pac J Trop Med 2014;7S1:S29-33.
Sharafati Chaleshtori R, Rokni N, Razavilar V, Rafieian Kopaei M. The Evaluation of the antibacterial and antioxidant activity of tarragon (Artemisia dracunculus
L.) essential oil and its chemical composition. Jundishapur J Microbiol 2013;6:1-5. [Doi: 10.5812/jjm. 7877].
Kirkinezos IG, Moraes CT. Reactive oxygen species and mitochondrial diseases. Semin Cell Dev Biol 2001;12:449-57.
Rego AC, Oliveira CR. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: Implications for the pathogenesis of neurodegenerative diseases. Neurochem Res 2003;28:1563-74.
Bahmani M, Zargaran A, Rafieian-Kopaei M. Identification of medicinal plants of Urmia for treatment of gastrointestinal disorders. Rev Bras Farmacogn 2014;24:468-80.
Hosseini-asl K, Rafieian-kopaei M. Can patients with active duodenal ulcer fast Ramadan? Am J Gastroenterol 2002;97:2471-2.
Sharafati Chaleshtori R, Rafieian-Kopaei M, Salehi E. Bioactivity of Apium petroselinum
and Portulaca oleracea
essential oils as natural preservatives. Jundishapur J Microbiol 2015;8:1-2. [Doi: 10.5812/jjm. 20128].
Sharafati Chaleshtori R, Rokni N, Rafieian-Kopaei M, Drees F, Salehi E. Antioxidant and antibacterial activity of basil (Ocimum basilicum
L.) essential oil in beef burger. J Agric Sci Technol 2015;17:817-26.
Rabiei Z, Hojjati M, Rafieian-Kopaeia M, Alibabaei Z. Effect of Cyperus rotundus
tubers ethanolic extract on learning and memory in animal model of Alzheimer. Biomed Aging Pathol 2013;3:185-91.
Rabiei Z, Rafieian-Kopaei M. Neuroprotective effect of pretreatment with Lavandula officinalis
ethanolic extract on blood-brain barrier permeability in a rat stroke model. Asian Pac J Trop Med 2014;7S1:S421-6.
Mirhosseini M, Baradaran A, Rafieian-Kopaei M. Anethum graveolens
and hyperlipidemia: A randomized clinical trial. J Res Med Sci 2014;19:758-61.
Bahmani M, Zargaran A, Rafieian-Kopaei M, Saki K. Ethnobotanical study of medicinal plants used in the management of diabetes mellitus in the Urmia, Northwest Iran. Asian Pac J Trop Med 2014;7S1:S348-54.
Asadi-Samani M, Bahmani M, Rafieian-Kopaei M. The chemical composition, botanical characteristic and biological activities of Borago officinalis
: A review. Asian Pac J Trop Med 2014;7S1:S22-8.
Bahmani M, Sarrafchi A, Shirzad H, Rafieian-Kopaei M. Autism: Pathophysiology and promising herbal remedies. Curr Pharm Des 2016;22:277-85.
Rahnama S, Rabiei Z, Alibabaei Z, Mokhtari S, Rafieian-Kopaei M, Deris F. Anti-amnesic activity of Citrus aurantium
flowers extract against scopolamine-induced memory impairments in rats. Neurol Sci 2015;36:553-60.
Shayganni E, Bahmani M, Asgary S, Rafieian-Kopaei M. Inflammaging and cardiovascular disease: Management by medicinal plants. Phytomedicine 2016;23:1119-26.
Anisimov VN. Effects of exogenous melatonin – A review. Toxicol Pathol 2003;31:589-603.
Ravindra T, Lakshmi NK, Ahuja YR. Melatonin in pathogenesis and therapy of cancer. Indian J Med Sci 2006;60:523-35.
Fournier I, Ploye F, Cottet-Emard JM, Brun J, Claustrat B. Folate deficiency alters melatonin secretion in rats. J Nutr 2002;132:2781-4.
Altun A, Ugur-Altun B. Melatonin: Therapeutic and clinical utilization. Int J Clin Pract 2007;61:835-45.
Ozben T. Antioxidant supplementation on cancer risk and concurrent use of antioxidants during cancer therapy: An update. Curr Top Med Chem 2015;15:170-8.
Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186-95.
Farhud D, Asghari M, Sadighi H. Gene and aging. Iran J Public Health 2008;37:1-8.
Mirick DK, Davis S. Melatonin as a biomarker of circadian dysregulation. Cancer Epidemiol Biomarkers Prev 2008;17:3306-13.
Anisimov VN, Popovich IG, Zabezhinski MA. Melatonin and colon carcinogenesis: I. Inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats. Carcinogenesis 1997;18:1549-53.
Stevens RG, Blask DE, Brainard GC, Hansen J, Lockley SW, Provencio I, et al.
Meeting report: The role of environmental lighting and circadian disruption in cancer and other diseases. Environ Health Perspect 2007;115:1357-62.
Duell PB, Wheaton DL, Shultz A, Nguyen H. Inhibition of LDL oxidation by melatonin requires supraphysiologic concentrations. Clin Chem 1998;44:1931-6.
Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 2006;27:41-9.
Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: A randomized controlled trial. JAMA 2008;299:2642-55.
Prunet-Marcassus B, Desbazeille M, Bros A, Louche K, Delagrange P, Renard P, et al.
Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology 2003;144:5347-52.
Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology 1999;140:1009-12.
Parry BL, Berga SL, Mostofi N, Klauber MR, Resnick A. Plasma melatonin circadian rhythms during the menstrual cycle and after light therapy in premenstrual dysphoric disorder and normal control subjects. J Biol Rhythms 1997;12:47-64.
Bubenik GA. Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol 2008;59 Suppl 2:33-51.
Dalton EJ, Rotondi D, Levitan RD, Kennedy SH, Brown GM. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci 2000;25:48-52.
Ardalan G, Farhoud D. Hyperactivity, attention and concentration deficit in preschool children. Iran J Pediatr 2002;12:53-6.
Betancourt-Fursow DJ, Jimenez-Leon J, Jimenez-Betancourt C. Attention deficit hyperactivity disorder and sleep disorders. Rev Neurol 2006;42:S37-51.
Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsäter H, et al.
Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 2008;13:90-8.
Arendt J. Safety of melatonin in long-term use. J Biol Rhythms 1997;12:673-81.
Asadi SY, Parsaei P, Karimi M, Ezzati S, Zamiri A, Mohammadizadeh F, et al.
Effect of green tea (Camellia sinensis
) extract on healing process of surgical wounds in rat. Int J Surg 2013;11:332-7.
Asadbeigi M, Mohammadi T, Rafieian-Kopaei M, Saki K, Bahmani M, Delfan M. Traditional effects of medicinal plants in the treatment of respiratory diseases and disorders: An ethnobotanical study in the Urmia. Asian Pac J Trop Med 2014;7S1:S364-8.
Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;222:236-45.
|This article has been cited by|
||Pathogenesis and Management of COVID-19
| ||Khalid O. Alfarouk,Sari T. S. AlHoufie,Samrein B. M. Ahmed,Mona Shabana,Ahmed Ahmed,Saad S. Alqahtani,Ali S. Alqahtani,Ali M. Alqahtani,AbdelRahman M. Ramadan,Mohamed E. Ahmed,Heyam S. Ali,Adil Bashir,Jesus Devesa,Rosa A. Cardone,Muntaser E. Ibrahim,Laurent Schwartz,Stephan J. Reshkin |
| ||Journal of Xenobiotics. 2021; 11(2): 77 |
|[Pubmed] | [DOI]|
||The roles of melatonin on kidney injury in obese and diabetic conditions
| ||Sasivimon Promsan,Anusorn Lungkaphin |
| ||BioFactors. 2020; |
|[Pubmed] | [DOI]|
||Time-dependent melatonin secretion is associated with mitochondrial function in peripheral blood mononuclear cells (PBMC) of male volunteers
| ||C. Silaidos,J. Grube,C. Muley,G.P. Eckert |
| ||Mitochondrion. 2020; |
|[Pubmed] | [DOI]|
||DAILY AND SEASONAL MITOCHONDRIAL PROTECTION: UNRAVELING COMMON POSSIBLE MECHANISMS INVOLVING VITAMIN D AND MELATONIN
| ||Feres José Mocayar Marón,León Ferder,Russel J. Reiter,Walter Manucha |
| ||The Journal of Steroid Biochemistry and Molecular Biology. 2020; : 105595 |
|[Pubmed] | [DOI]|
||Melatonin, an ubiquitous metabolic regulator: functions, mechanisms and effects on circadian disruption and degenerative diseases
| ||Andreea Iulia Socaciu,Razvan Ionut,Mihai Adrian Socaciu,Andreea Petra Ungur,Maria Bârsan,Angelica Chiorean,Carmen Socaciu,Armand Gabriel Râjnoveanu |
| ||Reviews in Endocrine and Metabolic Disorders. 2020; |
|[Pubmed] | [DOI]|
||Both objective and paradoxical insomnia elicit a stress response involving mitokine production
| ||Morena Martucci,Maria Conte,Rita Ostan,Antonio Chiariello,Filomena Miele,Claudio Franceschi,Stefano Salvioli,Aurelia Santoro,Federica Provini |
| ||Aging. 2020; 12(11): 10497 |
|[Pubmed] | [DOI]|
||Streptozotosin ile Indüklenmis Diyabetik Siçanlarda Melatoninin Antioksidan Aktivitesi; Kan ve Karaciger Dokusunda
| ||Songül DOGANAY,Seyma TRABZON,Nurten BAHTIYAR,Derya GÜZEL,Ayla EREN ÖZDEMIR,Arzu SAHIN |
| ||Sakarya Medical Journal. 2020; |
|[Pubmed] | [DOI]|
Falls Risk, Circadian Rhythms and Melatonin: Current Perspectives
| ||Nandu Goswami,Carolina Abulafia,Daniel Vigo,Maximilian Moser,Germaine Cornelissen,Daniel Cardinali |
| ||Clinical Interventions in Aging. 2020; Volume 15: 2165 |
|[Pubmed] | [DOI]|
||Irisin Attenuates Myocardial Ischemia/Reperfusion Injury and Improves Mitochondrial Function Through AMPK Pathway in Diabetic Mice
| ||Chao Xin,Zheng Zhang,Guojie Gao,Liping Ding,Chao Yang,Chengzhu Wang,Yanjun Liu,Yufei Guo,Xueqing Yang,Lijuan Zhang,Lina Zhang,Yi Liu,Zhitao Jin,Ling Tao |
| ||Frontiers in Pharmacology. 2020; 11 |
|[Pubmed] | [DOI]|
||Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities
| ||Gerwyn Morris,Basant K. Puri,Adam J. Walker,Michael Maes,Andre F. Carvalho,Ken Walder,Catherine Mazza,Michael Berk |
| ||Pharmacological Research. 2019; : 104450 |
|[Pubmed] | [DOI]|
||The protective effect of melatonin on the in vitro development of yak embryos against hydrogen peroxide-induced oxidative injury
| ||Wei Peng,Mengtong Lei,Jun Zhang,Yong Zhang |
| ||Zygote. 2019; : 1 |
|[Pubmed] | [DOI]|
||Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications
| ||Javier Espino,Ana B. Rodríguez,José A. Pariente |
| ||Current Medicinal Chemistry. 2019; 26(22): 4178 |
|[Pubmed] | [DOI]|
||Chronic Progressive External Ophthalmoplegia and Bilateral Vestibular Hypofunction: Balance, Gait, and Eye Movement Before and After Multimodal Chiropractic Care: A Case Study
| ||Brent S. Russell,Ronald S. Hosek,Kathryn T. Hoiriis,Emily D. Drake |
| ||Journal of Chiropractic Medicine. 2019; 18(2): 144 |
|[Pubmed] | [DOI]|
||Melatonin Supplementation Decreases Hypertrophic Obesity and Inflammation Induced by High-Fat Diet in Mice
| ||Talita da Silva Mendes de Farias,Maysa Mariana Cruz,Roberta Cavalcante da Cunha de Sa,Ilenia Severi,Jessica Perugini,Martina Senzacqua,Suzete Maria Cerutti,Antonio Giordano,Saverio Cinti,Maria Isabel Cardoso Alonso-Vale |
| ||Frontiers in Endocrinology. 2019; 10 |
|[Pubmed] | [DOI]|
||Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep
| ||Alejandro Gonzalez-Candia,Marcelino Veliz,Catalina Carrasco-Pozo,Rodrigo L. Castillo,J. Cesar Cárdenas,Germán Ebensperger,Roberto V. Reyes,Aníbal J. Llanos,Emilio A. Herrera |
| ||Redox Biology. 2019; : 101128 |
|[Pubmed] | [DOI]|
||Melatonin prevents early pituitary dysfunction induced by sucrose-rich diets
| ||María Elisa Mercau,Juan Salvador Calanni,Marcos Luis Aranda,Lilian Julia Caldareri,Ruth Estela Rosenstein,Esteban Martin Repetto,Cora Beatriz Cymeryng |
| ||Journal of Pineal Research. 2019; : e12545 |
|[Pubmed] | [DOI]|
||Obtusifolin inhibits high glucose-induced mitochondrial apoptosis in human umbilical vein endothelial cells
| ||Yu Tang,Zhi-Ying Zhong,Yan-Feng Liu,Gou-Tai Sheng |
| ||Molecular Medicine Reports. 2018; |
|[Pubmed] | [DOI]|
||Anti-Inflammatory Effects of Melatonin in Obesity and Hypertension
| ||Natalia Jorgelina Prado,León Ferder,Walter Manucha,Emiliano Raúl Diez |
| ||Current Hypertension Reports. 2018; 20(5) |
|[Pubmed] | [DOI]|
||Mitochondrial functions and melatonin: a tour of the reproductive cancers
| ||Luiz Gustavo de Almeida Chuffa,Fábio Rodrigues Ferreira Seiva,Maira Smaniotto Cucielo,Henrique Spaulonci Silveira,Russel J. Reiter,Luiz Antonio Lupi |
| ||Cellular and Molecular Life Sciences. 2018; |
|[Pubmed] | [DOI]|
||Leaky brain in neurological and psychiatric disorders: Drivers and consequences
| ||Gerwyn Morris,Brisa S Fernandes,Basant K Puri,Adam J Walker,Andre F Carvalho,Michael Berk |
| ||Australian & New Zealand Journal of Psychiatry. 2018; 52(10): 924 |
|[Pubmed] | [DOI]|
||The role of melatonin in development of gestational diabetes mellitus
| ||Edvard K. Aulamazyan,Inna I. Evsyukova,Maria I. Yarmolinskaya |
| ||Journal of obstetrics and woman disease. 2018; 67(1): 85 |
|[Pubmed] | [DOI]|
||Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies
| ||Pierpaola Davalli,Gaetano Marverti,Angela Lauriola,Domenico D’Arca |
| ||Oxidative Medicine and Cellular Longevity. 2018; 2018: 1 |
|[Pubmed] | [DOI]|
||Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway
| ||Yang Liu,Jiawei Yan,Cao Sun,Guo Li,Sirui Li,Luwei Zhang,Cuixia Di,Lu Gan,Yupei Wang,Rong Zhou,Jing Si,Hong Zhang |
| ||Redox Biology. 2018; 17: 143 |
|[Pubmed] | [DOI]|
||Melatonin, mitochondria, and the metabolic syndrome
| ||Daniel P. Cardinali,Daniel E. Vigo |
| ||Cellular and Molecular Life Sciences. 2017; |
|[Pubmed] | [DOI]|