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Table 1 Biological functions and processes that may be affected by MLT and suggested mechanisms of action in various models

From: Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action

Function or process Effects Suggested mechanisms Type of evidence (references)
Cancer Tumour regression; activation of tumour-suppressive signalling network; oncostatic activity; modulation of oestrogen and androgen; immunomodulation or neuroimmunomodulation; cytoskeletal modulation; modulation of water transport; resynchronisation of the intracellular clock network; modulation of cellular redox status; haematopoiesis; reduced cardiotoxicity; enhanced mitochondrial function; anti-oestrogen; epigenetic regulation; radioprotection Reduction of cellular proliferation; free radical scavenging; inhibition of the uptake of linoleic acid; stimulation of glutathione production (γ-glutamylcysteine synthase and reduced reactants such as hydroxyl radical, hydrogen peroxide, hypochlorous acid, singlet oxygen, the peroxynitrite anion and peroxynitrous acid); blocking cell-cycle progression from the G phase to the S phase and by increasing p53, p21 and p27Kip1 gene and protein expression (via increased expression of E-cadherin and β1-integrin proteins); stimulation of lymphocytes, monocytes, granulocytes, macrophages, T-helpers (Th1 and Th2), T and B lymphocytes and thrombocytes; NK cell activity; platelet generation; enhancement of the production of cytokines IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-24, IFN-γ and TNF-α; co-activation of protein kinase C and protein kinase A, and phospholipase C; inhibition of angiogenesis (via inhibition of endothelin-converting enzyme-1 and insulin-like growth factor 1); cell apoptosis; inhibition of 17β-oestradiol; stimulation of biopterins; microfilament modulation; switching microfilament phenotypes; improving oxidative phosphorylation and increasing ATP generation; reduced electron leakage and mPTP opening; decrease in gonadal steroids; downregulation of the expression of oestrogen α receptors; potentiation of cytostatic anti-oestrogen sensitivity of chemotherapeutic agents; inhibition of DNA methyltransferase; inhibition of telomerase; inhibition of metastasis; mutations in the melatonin receptors (MLT1 and MLT2); alterations of arylalkylamine N-acetyltransferase; reduced thrombocytopenia; inhibition of prostaglandin E2; inactivation of calmodulin In vitro, animal and clinical studies, RCTs, epidemiological studies, SRs [31, 37, 44, 63, 68, 69, 72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108]
Metabolic and cardiovascular disorders Anti-oxidative; anti-inflammatory; anti-hypertensive; regulation of lipid and glucose metabolism; reduction of nephrotoxicity Free radical scavenging; inhibition of pro-inflammatory mediator; iNOS/i-mtNOS; optimisation of nNOS/c-mtNOS; reduction of factor 1-α and NF-κB; downregulation of Bcl-2 and activation of p53 and CD95; increase in catalase activity and reduction in thiobarbituric acid reactive substrates; reduction in lipid peroxidation, creatinine, uric acid and blood urea nitrogen levels In vitro, animal studies, placebo-controlled RCTs [80, 90, 92, 106, 109,110,111,112,113,114]
Gastrointestinal conditions Anti-oxidative; anti-inflammatory Free radical scavenging; inhibition of pro-inflammatory cytokines, cell adhesion molecules, NO production, COX-2 expression, NF-κ activation; regulation of macrophage activity Animal studies, RCTs [50, 79,80,81, 92, 114, 115]
Neonatology and paediatrics Anti-inflammatory; anti-oxidative; sedative Reduction of pro-inflammatory cytokines (IL-6, IL-8 and TNF-α) and nitrite/nitrate levels; inflammatory-derived activation of phospholipase A2, lipoxygenase and cyclooxygenases; increased glutathione peroxidase activity; reduction of C-reactive protein Animal and human studies, RCTs, open-label [116,117,118,119]
Neurodegenerative disorders Protection against neurodegeneration caused by mitochondrial dysfunction and oxidative/nitrosative stress; apoptosis; prevention of vasoconstriction of cerebral arteries Activations of mitochondrial cell survival pathways; regulation of apoptosis; silencing of the Rip2/Caspase-1 pathway; reduced mitochondrial inducible NO synthase; increased activity of respiratory complexes I, III and IV; increased activity and expression of antioxidant enzymes; high lipophilicity Animal and human studies, SRs [46, 49, 79, 81, 90, 94, 100, 106, 120,122,123,124]
Mental disorders Anti-inflammatory; anti-nociceptive; anxiolytic; drug detoxification Regulating cytokine production of immunocompetent cells; reducing adhesion molecules and pro-inflammatory cytokines including IL-6, IL-8 and TNF; modifying serum inflammatory parameters; neutralising free radicals and non-radical oxygen-based reactants Animal and human studies [34, 66, 123, 125,126,127,128,129,130]
Pain syndromes Anti-nociceptive, antiallodynic and analgesic effects; synchronisation of biological rhythms Activation of melatoninergic MLT1/MLT2 receptors; release of opioid peptides (β-endorphins); interaction with opioid, γ-aminobutyric acid or N-methyl-daspartate receptors; NO-arginine pathway; antioxidant and anti-inflammatory effect; regulation of endoplasmic reticulum and mitochondrial activity Animal and human studies [33, 117, 131, 132]
Reproductive functions Antioxidant, anti-inflammatory, anti-apoptotic, cytoprotective and neuroprotective effects; reduced risk of complications; increased homeostasis; gonadotropin secretion; higher rate of mature oocytes and quality embryos Activation of melatoninergic MLT1/MLT2 receptors; inhibition of adenyl cyclase activity; forskolin-induced cAMP formation with subsequent reduction in activated protein kinase; alteration of granulosa cell steroidogenesis and folliculogenesis; corpus luteum function; inhibition of prostaglandins, oxytocin, cortisol production and LDL peroxidation; activation of prolactin secretion; free hydroxyl radicals scavenging; prevention against DNA damage; activation of superoxide dismutase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase; inhibition of NO synthase; deferred apoptosis of villous cytotrophoblasts and protection of syncytiotrophoblasts; improved haemodynamics and nutrient transfer at the placental-uterine interface In vitro, animal and human studies [62, 95, 115, 119, 133,134,135,136,137,138,139]
Sleep disorders Sleep enhancer; shifted circadian rhythms; reduced duration of jet lag Activation of alpha-2 noradrenergic receptor agonist clonidine; lowered core body temperature; opening of the sleep gate and facilitation of re-entrainment to suprachiasmatic nuclei; potentiation of GABA on GABAA receptors; inactivation of calmodulin RCTs [26, 29, 39, 42, 64, 67, 70, 80, 81, 90, 92, 94, 103, 105,106,107, 124, 140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161]
Traumatic CNS injury Attenuation of neural damage; neuroprotective effects; inhibition of necrosis, apoptosis; immunomodulation; protection of nuclear and mitochondrial DNA; anti-oxidative effects Free radical scavenging (including the hydroxyl radical, hydrogen peroxide, singlet oxygen, NO, peroxynitrite anion and peroxynitrous acid); inhibition of pro-inflammatory cytokines or quinone reductase 2, calcium ion-mediated toxicity, proxidative enzymes NO synthase, lipoxygenase and phospholipase A2; activation of the tumour necrosis factor receptors; increased efficiency of oxidative phosphorylation; reduction of NF-κB or TNF expression; modulation of angiogenesis; stimulation of superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase and glutathione; induction of γ-glutamylcysteine synthetase; activation of glucose-6-phosphate dehydrogenase In vitro, animal and human studies [27, 32, 46, 61, 94, 106, 162,163,164,165,166,167,168]
  1. ATP adenosine triphosphate, cANP cyclic adenosine monophosphate, c-mtNOS constitutive mitochondrial nitric oxide synthase, CNS central nervous system, COX-2 cyclooxygenase 2, GABA gamma-aminobutyric acid, iNOS inducible nitric oxide synthase, i-mtNOS inducible mitochondrial nitric oxide synthase, LDL low-density lipoproteins, MLT melatonin, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NK natural killer, nNOS neuronal nitric oxide synthase, NO nitric oxide, mPTP mitochondrial permeability transition pore, RCT randomised controlled trial, SR systematic review, TNFα tumour necrosis factor α