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Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation

Gaia Favero, Lorenzo Franceschetti, Francesca Bonomini and 2 more

International Journal of Endocrinology · 2017 · Review

doi:10.1155/2017/1835195

Abstract

Inflammation may be defined as the innate response to harmful stimuli such as pathogens, injury, and metabolic stress; its ultimate function is to restore the physiological homeostatic state. The exact aetiology leading to the development of inflammation is not known, but a combination of genetic, epigenetic, and environmental factors seems to play an important role in the pathogenesis of many inflammation-related clinical conditions. Recent studies suggest that the pathogenesis of different inflammatory diseases also involves the inflammasomes, intracellular multiprotein complexes that mediate activation of inflammatory caspases thereby inducing the secretion of proinflammatory cytokines. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule with fundamental clinical applications. It is involved in mood modulation, sexual behavior, vasomotor control, and immunomodulation and influences energy metabolism; moreover, it acts as an oncostatic and antiaging molecule. Melatonin is an important antioxidant and also a widespread anti-inflammatory molecule, modulating both pro- and anti-inflammatory cytokines in different pathophysiological conditions. This review, first, gives an overview concerning the growing importance of melatonin in the inflammatory-mediated pathological conditions and, then, focuses on its roles and its protective effects against the activation of the inflammasomes and, in particular, of the NLRP3 inflammasome.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indoleamine widely distributed in plants, unicellular organisms, algae, bacteria, invertebrates, and vertebrates. In vertebrates, circulating melatonin is largely derived from the pineal gland, although there are other organs such as gastrointestinal tract, epithelial hair follicles, skin, retina, salivary glands, platelets, and lymphocytes that produce melatonin. Specialized photoreceptive cells in the retina detect a restricted bandwidth of visible light; this information projects directly to the suprachiasmatic nucleus (SCN), the central circadian pacemaker, that triggers the pineal gland to produce this indoleamine during darkness. The maximal melatonin plasma concentration occurs usually 3–5 hours after darkness onset, and its level during the daily light period is low or even undetectable.

The synthesis of melatonin is a multistep process, which starts from the essential aromatic amino tryptophan that is picked up from the blood circulation and hydroxylated, by tryptophan hydroxylase, in 5-hydroxytryptophan (5-HTP). 5-HTP is converted to serotonin by the aromatic amino acid decarboxylase, and serotonin is subsequently converted into N-acetylserotonin (NAS) by the enzyme arylalkylamine N-acetyltransferase. The final step of melatonin synthesis is the conversion of NAS to melatonin by hydroxyindole-O-methyl transferase. Pineal melatonin is immediately released into the blood stream in a circadian manner in response to the above reported photoperiodic information received via the retinopineal pathway. Interestingly, most of the extrapineal organs, except for the retina, may not produce melatonin in a circadian manner and it is not normally released into the blood stream in any significant amount. In these organs, melatonin presumably functions mainly as an antioxidant to protect cells from oxidative damage.

There are three major known pathways of melatonin degradation: (a) the classical hepatic catabolic pathway that generates 6-hydroxymelatonin that is then excreted via the kidney as a sulphate conjugate; (b) the alternative indolic pathway that produces 5-methoxyindole acetic acid or 5-methoxytryptophol; and (c) the kynuric pathway that produces N1-acetyl-N2-formyl-5-kynuramine (AFMK). In addition to the antioxidant properties of melatonin, AFMK and N1-acetyl-5-methoxykinuramine (AMK) are two important melatonin metabolites that have excellent radical scavenging activity.

The first identified function of melatonin was skin-lightening property observed in fish and amphibian. Subsequently, it has been shown that melatonin is a multitasking molecule with many functions, including the involvement in sleep initiation, mood modulation, sexual behavior, vasomotor control, and immunomodulation. Moreover, melatonin has anti-inflammatory and antioxidant actions influencing energy metabolism and it acts as an oncostatic and antiaging molecule. Thus, melatonin is considered an important multitasking molecule with fundamental clinical applications. Melatonin's actions may be mediated by an interaction with specific membrane-bound receptors or they may be receptor-independent; the latter mainly relates to its direct radical scavenging functions. Melatonin receptors include membrane and nuclear binding sites. As of 2011, two membrane-bound melatonin receptors were identified and characterized (MT1 and MT2), which are G protein-coupled seven transmembrane receptors. MT1 receptors are expressed in the retina, ovary, testis, mammary gland, gallbladder, liver, kidney, immune cells, exocrine pancreas, and cardiovascular system, whereas, MT2 receptors are expressed in the duodenal enterocytes, immune system, hypothalamus, SCN, retina, pituitary, blood vessels, testes, kidney, gastrointestinal tract, mammary glands, adipose tissue, and skin. Furthermore, MT1 melatonin receptors are related mainly to reproductive, metabolic, and vasoconstrictive functions, whereas MT2 receptors are involved in the control of circadian rhythms, dopamine release in the retina, and vasodilatation. Furthermore, melatonin may also bind to the MT3 receptor (quinone reductase II), which, however, does not fulfill the criteria of a classical melatonin membrane receptor; it is thought to be a molecular target for antimalarial drugs and seems involved in regulating intraocular pressure. Although the MT3 receptor has not yet been found in humans, it is highly expressed in the liver and kidneys and, in moderate amounts, in the heart, adipose tissue, and brain of hamster.

Nuclear binding sites have also been identified for melatonin, and in fact, melatonin might function also through orphan receptors from the retinoid orphan receptor (ROR) and retinoid Z receptor family. RORα receptors are ubiquitously expressed in all mammalian tissues, and high levels were detected in lymphocytes, neutrophils, and monocytes, while RORβ subform is expressed in the brain, pineal gland, retina, and spleen. Melatonin may also interact with cytosolic proteins including calmodulin and calreticulin, which are involved in the cytoskeleton regulation and control of nuclear receptors, respectively.

Alterations of the 24-hour melatonin profile may be associated with a large variety of pathologies. In fact, endogenous melatonin was observed significantly lower in breast, lung, and prostate cancer patients. This reduction in melatonin levels was observed also in some psychiatric disorders, like schizophrenia and depression, in which the nighttime melatonin level is lower with respect to healthy person; also in patients suffering from metabolic syndrome, diabetes, or sleep disorders, the melatonin rhythm timing is modified. Furthermore, in recent decades, humans have altered the natural light-dark cycle by increasing light at night and spending most of their time indoors; these lifestyle factors induce the disorganization of the circadian system and cause chronodisruption, including perturbations of the melatonin rhythm. The reduction in melatonin is associated with gradual losses in antioxidant protection and immunological and anti-inflammatory effects. In fact, epidemiological studies showed that chronodisruption is associated with an increased incidence of cardiovascular diseases, diabetes, obesity, cognitive and affective impairments, premature aging, and some types of cancer. Throughout life, melatonin levels are also significantly reduced; in young children, nocturnal melatonin levels are highest. During aging, the amplitude of the melatonin peak and total melatonin production is significantly reduced, although there is a great interindividual variability regarding these mechanisms. It is important to underline also that higher melatonin levels likely have important and positive roles in healthy aging and longevity. In fact, a reduction in endogenous melatonin levels throughout life seems to cause greater organism detriments. It is important to remember also that melatonin is an uncommonly safe molecule when taken as a supplement, and it is readily absorbed when it is administered via any route and it crosses easily all morphophysiological barriers, such as the placenta or blood brain barrier.

Herein, we provide first a brief overview on the growing importance of melatonin in inflammatory-mediated pathological conditions, and thereafter, we identify its protective effects against the activation of inflammasomes, inflammatory intracellular multiprotein complexes. In particular, we focus attention on melatonin interactions with NLRP3 inflammasome, the most widely known and studied inflammasome.

2. Melatonin and Inflammation

Inflammation is defined, for many years, as the response to tissue injury and infection. This concept was recently updated due to the avalanche of reports in which molecules and cells associated with inflammation are involved also in the absence of tissue injury or infection. Thus, inflammation may be defined as the innate response to harmful stimuli such pathogens, injury, and metabolic stress, and its ultimate function is to restore the physiological homeostatic state. However, the exact aetiology leading to the development of inflammation is not known, but a combination of genetic, epigenetic, and environmental factors seems to play an important role. Initial stages of inflammation are mediated by the activation of the immune system and usually persist for only a short time. However, in this stage, the response may continue and progress to chronic inflammation, which predisposes to various chronic pathologies.

Pathological inflammation has been related to several different diseases, and current anti-inflammatory drugs have significant side effects; so, it is important to identify new therapeutic approaches to reduce inflammatory processes without impairing the physiologic inflammatory response. As reported above, melatonin has many actions and numerous experimental studies have shown that melatonin is not only an important antioxidant but also a widespread anti-inflammatory molecule. Thus, melatonin is a molecule of high clinical interest.

During the inflammatory process, the stimulation of inflammation-related genes may occur due to the activation of the nuclear transcription factor-kappa B (NF-κB). NF-κB is a ubiquitous oxidative stress-sensitive transcription factor that plays a critical role in the regulation of a variety of genes important in cellular responses including inflammation, innate immunity, cell growth, and death. NF-κB is primarily a cytoplasmic factor that is expressed virtually in all cells and constitutes the major inducible transcription factor whose modulation triggers a cascade of molecular events, some of which are potential key targets for the treatment of inflammation. After its activation, NF-κB translocates to the nucleus and binds to specific elements modulating transcription of proinflammatory genes. Various studies have shown that melatonin modulates the NF-κB signalling pathway during inflammation, and this modulation can occur during early as well as late stages of pathological processes.

Additionally, cytokines are major mediators of local and intercellular communication required for an integrated response to a variety of stimuli during immune and inflammatory processes. Different cytokines are associated with inflammatory pathological processes; in fact, the clinical outcome is partly determined by the loss of balance between proinflammatory cytokines, like interleukin- (IL-) 1β, IL-2, IL-6, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and anti-inflammatory molecules, such as IL-10 and tumor growth factor-β (TGF-β).

Experimental evidence suggests that melatonin exerts its anti-inflammatory effects by modulating both pro- and anti-inflammatory cytokines in different pathophysiological conditions. Furthermore, Carrillo-Vico et al. showed that the presence of melatonin's receptors in a mast cell line modulate an anti-inflammatory pathway via inhibition of TNF-α release. Other anti-inflammatory actions of melatonin, and its metabolites AFMK and AMK, are inhibition of prostaglandins synthesis, production of adhesion molecules, and downregulation of cyclooxygenase 2 expression in macrophages, of leukocyte-endothelial adhesion, and of leukocyte transendothelial cell migration, together with the reduction of the polymorphonuclear cell recruitment to the inflammatory site. Furthermore, the overproduction of reactive oxygen species (ROS) contributes significantly to inflammation, a process that leads in turn to the further production of ROS and activation of prooxidant enzymes. Melatonin also counteracts inflammatory processes by scavenging free radicals and activating endogenous antioxidant defense due to its important and well-known antioxidant properties.

In general, melatonin is highly effective in protecting cells from damage under severe inflammatory conditions. There are several sites where melatonin may interfere during the inflammatory process. As a result, definition of the role of melatonin in the pathophysiological mechanisms of inflammation is a large and growing research field, in which further studies are necessary to elucidate its complex regulatory mechanisms of action in different cells, tissues, and pathological conditions.

3. Melatonin and Inflammasomes

As reported above, inflammation is a key feature in the pathogenesis of many clinical conditions. It is also a factor now recognized as a component of aging since this is associated with a low level of inflammatory process, so-called inflammaging; this results from the innate immune system deregulation, chronic proinflammatory cytokine production, NF-κB translocation and activation, and oxidative stress. Recent studies suggest also a role of the inflammasome in the pathogenesis of different inflammatory diseases. Inflammasomes, present in a variety of cells, are intracellular multiprotein complexes that mediate activation of inflammatory caspases and in turn induce the secretion of proinflammatory cytokines (IL-1β and IL-18). Inflammasome activation is induced by a variety of endogenous and exogenous signals; in fact, in addition to responding to insults and pathogens, inflammasomes can also be activated by signals stemming from the commensal microbiota.

To date, five different inflammasomes (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing (NLRP) 1–3) have been clearly identified: NLRP1, NLRP2, NLRP3, AIM2, and IPAF/NLRC4; of these, NLRP3 is the best characterized (Figure 1).

The present review focuses on recent insights into the melatonin modulation of the expression of these inflammatory mediators and their effects on cell signalling pathways responsible for melatonin's anti-inflammatory activity. There are relatively few studies about the interaction between melatonin and the inflammasome NLRP3. In detail, NLRP3 inflammasome responds to a variety of signals that are indicative of damage to the host, including environmental irritants, endogenous danger signals, pathogens, mitochondria-derived ROS, and DNA released from damaged mitochondria into the cytosol. Activation of the NLRP3 inflammasome requires two signals: microbial molecules or endogenous cytokines, which upregulate the expression of NLRP3 and pro-IL-1β through the activation of NF-κB pathway. Thus, the activation of NLRP3 inflammasome-related innate immunity pathways amplifies the inflammatory response NF-κB mediated. The second signal is induced by various damage-associated molecular patterns (DAMPs), leading to the assembly of the inflammasome multiprotein complex. Once the inflammasome is activated, caspase-1 advances pro-IL-1β and pro-IL-18 into their mature active process and induces their subsequent secretion. Finally, IL-1β and IL-18 initiate an inflammatory process of regulated cell death known as pyroptosis. The activation of the NLRP3 inflammasome can help the host defense against invading bacteria and pathogens; however, excessive activation of the inflammasome can lead to inflammation-associated tissue injury (Figure 2). The ability of NLRP3 to respond to a variety of signals contributes to its biological importance in several complex diseases, including cancer, atherosclerosis, type 2 diabetes mellitus, gout and metabolic syndrome, cardiovascular diseases, renal disorders, and lung and central nervous diseases.

Infectious aetiologies, such as sepsis and pneumonia, are leading causes of acute lung injury. Extracellular histones are produced during acute lung injury and activate the NLRP3 inflammasome promoting in turn the recruitment of neutrophils and suggesting a positive feedback and a potential mechanism of inflammatory propagation. Recently, Zhang et al. demonstrated that intratracheally administration of melatonin reduced pulmonary inflammation in acute lung injury through inhibiting the assembly of the NLRP3 inflammasome. This inhibition is mediated not only through reduction of the release of extracellular histones in the lung but also through direct blockage of extracellular histone-induced activation of the NLRP3 inflammasome. However, the authors reported no alteration in the levels of TNF-α expression suggesting that melatonin selectively affects the activation of NLRP3 inflammasome. The inhibition mechanism of the NLRP3 inflammasome activation by melatonin in acute lung injury requires further study.

Furthermore, other recent publications report on the effect of melatonin treatment against NLRP3 complex assembly in radiation-induced mucositis, sepsis, and aging. Fernández-Gil et al. reported, during mucositis development following tongue irradiation, the involvement of mitochondrial oxidative stress and of bioenergetic impairment in promoting inflammation through the assembly of the NLRP3 inflammasome that leads in turn to caspase-1 activation and cleavage into the mature forms of pro-IL-1β, which is produced by NF-κB pathway. Furthermore, its significant increase in the tissue levels of IL-1β, TNF-α, and cyclooxygenase-2 expression was observed, supporting the hypothesis that NF-κB and NLRP3 work together to activate inflammatory pathways of the innate immune response. Interestingly, the application of melatonin gel prevented mucosal disruption and ulcer formation, protecting the mitochondria from radiation damage and blunting NF-κB/NLRP3 inflammasome signalling activation in the tongue. Ortiz and colleagues obtained interesting results about the melatonin's antagonist effects on both NF-κB and NLRP3 signalling. The therapeutic benefit of melatonin gel against oral mucositis is related to its inhibitory effects on NF-κB/NLRP3 signalling and also on modulation of a correct balance between pro- and anti-inflammatory cytokines; moreover, it may also be attributed to melatonin's capabilities to protect the mitochondria in epithelial cells, as well as stem cells, from radiation. Ortiz and colleagues also showed, for the first time, that melatonin is synthesized in rat tongue, where it acts in autocrine/paracrine signalling by binding to MT1, MT2, and RORγ receptors, suggesting a role of melatonin also in healthy oral mucosal physiology. However, irradiation drastically decreased basal melatonin levels, probably due to its rapid use as a scavenger of free radicals that were induced by radiation. Interestingly, the induction of MT1/MT2 melatonin membrane receptor expression after high-dose melatonin administration indicates that the therapeutic benefits of melatonin are not restricted to low doses. It is important to underline also that systemic administration of melatonin did not achieve effective concentrations in the oral mucosa, so the above-reported observations suggest that the melatonin gel formulation may have important therapeutic potential in patients with oral mucositis (Figure 3). However, it is important to evaluate in depth the mechanisms of action of melatonin together with the dose and modality of administration.

In addition to NLRP3 functions in epithelial cells of the mucosal surface, the inflammasome is also related to the secretion of proinflammatory cytokines that contribute to obesity-associated chronic inflammatory conditions. Obesity may induce NLRP3-dependent caspase-1 activation and thus pyroptosis and the proinflammatory response in hypertrophic adipocytes. Recently, Liu et al. demonstrated that exogenous melatonin ameliorates inflammation of adipose tissue by inhibiting the expression of inflammasome genes including NLRP3, apoptotic-associated speck-like protein containing a caspase recruitment domain (ASC), and thereby caspase-1 and IL-1β. Furthermore, melatonin in the adipose tissue reduces the phosphorylation of NF-κB and inhibits the NLRP3 pathway in downstream. These findings, with others in which NF-κB signal is central for performing the melatonin's anti-inflammatory functions, indicate that melatonin is a potential antiobesity agent that may also reverse obesity-related systemic inflammation.

The anti-inflammatory properties of melatonin have been extensively studied also in models of sepsis in which melatonin inhibits the NF-κB pathway activation, induces the conservation of the mitochondrial homeostasis, and reduces ROS and proinflammatory cytokine production. García et al., Rahim et al., and Volt et al. recently showed that melatonin blunts the NF-κB/NLRP3 connection and activation during cardiac sepsis and aging. These studies provide the basis for further investigations on the efficacy of melatonin in protecting against myocardial damage and in enhancing the survival of septic mice. Thus, the NLRP3 inflammasome could be considered as a target of melatonin, which transforms a severe myocardial septic condition into a moderate inflammatory state, thus preventing cardiac failure. However, the specific interaction of melatonin with the NLRP3 inflammasome during sepsis in cardiac tissue remains to be clearly identified. Furthermore, to test the anti-inflammatory beneficial effects of melatonin, Rahim and colleagues carried out a phase II clinical trial in septic patients (Eudract number 2008-006782-83) who were treated with a new-patented injectable formulation of melatonin (PCT/ES2015070236) and the preliminary data related to this clinical trial suggested the same beneficial effects of melatonin in humans as observed in experimental animal models.

Chronic melatonin treatment absolutely prevented age-dependent oxidative stress and mitochondrial impairment in multiple organs including the heart. Moreover, Volt et al. showed that melatonin administration in aged mice counteracted the septic response, reducing inflammation, oxidative stress, and mitochondrial alterations and inhibiting the intrinsic apoptotic pathway; however, melatonin did not counteract the inflammaging response. These results account for an important duality of melatonin effects: chronic, low doses of melatonin prevent the age-dependent increase in inflammation, ROS, and mitochondrial impairment characteristic of inflammaging; by comparison, acute, high doses of melatonin counteract septic inflammation without influencing the basal inflammatory status of aged mice. According to Volt et al., melatonin should be administered in a chronic schedule in order to prevent inflammaging and in acute schedule to counteract severe inflammatory responses. Eventually, further investigations are necessary to clarify whether the decreased melatonin production promotes the chronoinflammaging process. Also, Garcia et al. evaluated the melatonin effect against NF-κB/NLRP3 inflammatory pathway in mouse heart during sepsis, demonstrating for the first time that melatonin requires the RORα receptors to blunt the NF-κB/NLRP3 connection during sepsis. The multiple molecular targets of melatonin observed in the reported studies explain and justify its potent anti-inflammatory efficacy against systemic innate immune activation and underline a promising melatonin therapeutic application in the treatment of sepsis.

The beneficial effects of melatonin due to the inhibition of the NLRP3 inflammasome have received increased attention since it is related to the improvement of many inflammatory diseases. In this regard, Cao et al. showed that cadmium exposure significantly increased the expression of NLRP3 and active caspase-1 (p20) in the liver, suggesting that NLRP3 is involved in cadmium-induced hepatocyte death and that this type of hepatocyte death is caspase-1 dependent. Interestingly, the authors found that melatonin treatment significantly alleviated cadmium-induced liver injury by decreasing serum alanine aminotransferase/aspartate aminotransferase levels, suppressing the production of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and the induction of NLRP3 mRNA and protein expression. Cao et al. documented that the protective effect of melatonin is mediated by the thioredoxin-interacting protein- (TXNIP-) NLRP3 inflammasome pathway. Thus, TXNIP is a key endogenous regulator of the cellular redox balance that plays an important role in the pathogenesis of acute liver failure and directly activates the NLRP3 inflammasome under oxidative stress conditions. Targeting TXNIP-NLRP3 pathway may represent a therapeutic approach for treating liver disease.

NLRP3 inflammasome is associated also with the incidence and progression of central nervous system diseases including cerebral hemorrhage, ischemic stroke, meningitis, Parkinson disease, glutamate-associated brain damage, and subarachnoid hemorrhage. Recently Dong and collaborators demonstrated that melatonin exerts neuroprotective actions via its antiapoptotic effects, which are NLRP3 inflammasome-associated. To summarize, Dong et al. observed that melatonin has neuroprotective properties against subarachnoid haemorrhage, inducing increased survival rate, as well as elevated neurological scores and brain antioxidant content and reduced brain oedema, apoptotic ratio, and blood brain barrier disruption. These actions involve inhibition of NLRP3 inflammasome activation and the subsequent production of IL-1β and IL-18.

A novel melatonin derivative, 5-hydroxy-2′-isobutyl-strepchlorin (HIS) was recently synthesized from deacetylmelatonin. In their observations, Shim and collaborators stated that low concentrations of HIS significantly inhibited the NLRP3 inflammasome activation by interference with formation of NLRP3 inflammasome complex without mitochondrial ROS inhibition.

4. Conclusion

Actually, NLRP3 inflammasome and/or mitochondria are known to be major targets of interest for the pharmacological management of inflammatory diseases. Recent years have seen significant progress in understanding how inflammasomes contribute to the pathology of multiple inflammatory and immune diseases. However, many important questions remain to be answered, including how host cells determine which inflammasome activates under specific conditions and how inflammasome signalling is interwoven with other innate and adaptive immune pathways. In summary, the multiple molecular targets of melatonin observed in the reported studies explain its potent anti-inflammatory efficacy against systemic innate immune activation and underline a promising therapeutic application for melatonin in the treatment of different inflammatory-mediated pathological conditions.

References 181

  1. 1.

    Hardeland R., Poeggeler B. Non-vertebrate melatonin. Journal of Pineal Research. 2003;34:233-241.

    Not in our library10.1034/j.1600-079x.2003.00040.x

  2. 2.

    Iriti M., Varoni E. M., Vitalini S. Melatonin in traditional Mediterranean diets. Journal of Pineal Research. 2010;49:101-105.

    Not in our library10.1111/j.1600-079x.2010.00777.x

  3. 3.

    Slominski R. M., Reiter R. J., Schlabritz-Loutsevitch N., Ostrom R. S., Slominski A. T. Melatonin membrane receptors in peripheral tissues: distribution and functions. Molecular and Cellular Endocrinology. 2012;351:152-166.

    Not in our library10.1016/j.mce.2012.01.004

  4. 4.

    Reiter R. J., Tan D. X., Korkmaz A. The circadian melatonin rhythm and its modulation: possible impact on hypertension. Journal of Hypertension Supplement. 2009;27:S17-S20.

    Not in our library10.1097/http://01.hjh.0000358832.41181.bf

  5. 5.

    Singh M., Jadhav H. R. Melatonin: functions and ligands. Drug Discovery Today. 2014;19:1410-1418.

    Not in our library10.1016/j.drudis.2014.04.014

  6. 6.

    Stehle J. H., Saade A., Rawashdeh O., et al. A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. Journal of Pineal Research. 2011;51:17-43.

    Not in our library10.1111/j.1600-079x.2011.00856.x

  7. 7.

    Acuña-Castroviejo D., Escames G., Venegas C., et al. Extrapineal melatonin: sources, regulation, and potential functions. Cellular and Molecular Life Sciences. 2014;71:2997-3025.

    Not in our library10.1007/s00018-014-1579-2

  8. 8.

    Esteban-Zubero E., Alatorre-Jiménez M. A., López-Pingarrón L., et al. Melatonin’s role in preventing toxin-related and sepsis-mediated hepatic damage: a review. Pharmacological Research. 2016;105:108-120.

    Not in our library10.1016/j.phrs.2016.01.018

  9. 9.

    Manchester L. C., Coto-Montes A., Boga J. A., et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. Journal of Pineal Research. 2015;59:403-419.

    Not in our library10.1111/jpi.12267

  10. 10.

    Zagajewski J., Drozdowicz D., Brzozowska I., et al. Conversion L-tryptophan to melatonin in the gastrointestinal tract: the new high performance liquid chromatography method enabling simultaneous determination of six metabolites of L-tryptophan by native fluorescence and UV-VIS detection. Journal of Physiology and Pharmacology. 2012;63:613-621.

    Not in our library

  11. 11.

    Zhang H. M., Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. Journal of Pineal Research. 2014;57:131-146.

    Not in our library10.1111/jpi.12162

  12. 12.

    Bravo R., Matito S., Cubero J., et al. Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Age (Dordrecht, Netherlands). 2013;35:1277-1285.

    Not in our library10.1007/s11357-012-9419-5

  13. 13.

    Reiter R. J. Melatonin: that ubiquitously-acting pineal hormone. News in Physiological Sciences. 1991;6:223-227.

    Not in our library

  14. 14.

    Reiter R. J., Tan D. X., Galano A. Melatonin: exceeding expectations. Physiology (Bethesda, Md.). 2014;29:325-333.

    Not in our library10.1152/physiol.00011.2014

  15. 15.

    Dominguez-Rodriguez A., Abreu-Gonzalez P., Reiter R. J. Clinical aspects of melatonin in the acute coronary syndrome. Current Vascular Pharmacology. 2009;7:367-373.

    Not in our library10.2174/157016109788340749

  16. 16.

    Reiter R. J. The melatonin rhythm: both a clock and a calendar. Experientia. 1993;49:654-664.

    Not in our library10.1007/bf01923947

  17. 17.

    Axelrod J., Wurtman R. J., Snyder S. H. Control of hydroxyindole-O-methyltransferase activity in the rat pineal gland by environmental lightening. Nature. 1985;201:p. 1134.

    Not in our library

  18. 18.

    Claustrat B., Leston J. Melatonin: physiological effects in humans. Neuro-Chirurgie. 2015;61:77-84.

    Not in our library10.1016/j.neuchi.2015.03.002

  19. 19.

    Weissbach A. A novel system for the incorporation of amino acids by extracts of E. coli B. Biochimica et Biophysica Acta. 1960;41:498-509.

    Not in our library10.1016/0006-3002(60)90048-2

  20. 20.

    Claustrat B., Brun J., Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Medicine Reviews. 2005;9:11-24.

    Not in our library10.1016/j.smrv.2004.08.001

  21. 21.

    Favero G., Franceschetti L., Buffoli B., et al. Melatonin: protection against age-related cardiac pathology. Ageing Research Reviews. 2017;35:336-349.

    Not in our library10.1016/j.arr.2016.11.007

  22. 22.

    Pandi-Perumal S. R., Srinivasan V., Maestroni G. J., Cardinali D. P., Poeggeler B., Hardeland R. Melatonin: nature’s most versatile biological signal? The FEBS Journal. 2006;273:2813-2838.

    Not in our library10.1111/j.1742-4658.2006.05322.x

  23. 23.

    Venegas C., García J. A., Escames G., et al. Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. Journal of Pineal Research. 2012;52:217-227.

    Not in our library10.1111/j.1600-079x.2011.00931.x

  24. 24.

    Gonzalez-Arto M., Hamilton T. R., Gallego M., et al. Evidence of melatonin synthesis in the ram reproductive tract. Andrology. 2016;4:163-171.

    Not in our library10.1111/andr.12117

  25. 25.

    Facciola G., Hidestrand M., von Bahr C., Tybring G. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. European Journal of Clinical Pharmacology. 2001;56:881-888.

    Not in our library10.1007/s002280000245

  26. 26.

    Reiter R. J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocrine Reviews. 1991;12:151-180.

    Not in our library10.1210/edrv-12-2-151

  27. 27.

    Grace M. S., Cahill G. M., Besharse J. C. Melatonin deacetylation: retinal vertebrate class distribution and Xenopus laevis tissue distribution. Brain Research. 1991;559:56-63.

    Not in our library10.1016/0006-8993(91)90286-5

  28. 28.

    Rogawski M. A., Roth R. H., Aghajanian G. K. Melatonin: deacetylation to 5-methoxytryptamine by liver but not brain aryl acylamidase. Journal of Neurochemistry. 1979;32:1219-1226.

    Not in our library10.1111/j.1471-4159.1979.tb11049.x

  29. 29.

    Hardeland R., Reiter R. J., Poeggeler B., Tan D. X. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neuroscience and Biobehavioral Reviews. 1993;17:347-357.

    Not in our library10.1016/s0149-7634(05)80016-8

  30. 30.

    Slominski A., Tobin D. J., Zmijewski M. A., Wortsman J., Paus R. Melatonin in the skin: synthesis, metabolism and functions. Trends in Endocrinology and Metabolism. 2008;19:17-24.

    Not in our library10.1016/j.tem.2007.10.007

  31. 31.

    Tan D. X., Manchester L. C., Terron M. P., Flores L. J., Reiter R. J. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? Journal of Pineal Research. 2007;42:28-42.

    Not in our library10.1111/j.1600-079x.2006.00407.x

  32. 32.

    Jeon H. L., Yoo J. M., Lee B. D., Lee S. J., Sohn E. J., Kim M. R. Anti-inflammatory and antioxidant actions of N-arachidonoyl serotonin in RAW264.7 cells. Pharmacology. 2016;97:195-206.

    Not in our library10.1159/000443739

  33. 33.

    Kalogiannis M., Delikatny E. J., Jeitner T. M. Serotonin as a putative scavenger of hypohalous acid in the brain. Biochimica et Biophysica Acta. 2016;1862:651-661.

    Not in our library10.1016/j.bbadis.2015.12.012

  34. 34.

    Lerner A. B., Case J. D., Takahashi Y., Lee T. H., Mori N. Isolation of melatonin, the pineal gland factor that lightens melanocytes. Journal of the American Chemical Society. 1958;80:2587-2592.

    Not in our library10.1021/ja01543a060

  35. 35.

    Lerner A. B., Case J. D., Heinzelmann R. V. Structure of melatonin. Journal of the American Chemical Society. 1959;81:6085.

    Not in our library10.1021/ja01531a060

  36. 36.

    Agabiti-Rosei C., Favero G., De Ciuceis C., et al. Effect of long-term treatment with melatonin on vascular markers of oxidative stress/inflammation and on the anticontractile activity of perivascular fat in aging mice. Hypertension Research. 2017;40:41-50.

    Not in our library10.1038/hr.2016.103

  37. 37.

    Hardeland R., Cardinali D. P., Srinivasan V., Spence D. W., Brown G. M., Pandi-Perumal S. R. Melatonin—a pleiotropic, orchestrating regulator molecule. Progress in Neurobiology. 2011;93:350-384.

    Not in our library10.1016/j.pneurobio.2010.12.004

  38. 38.

    Hardeland R., Poeggeler B. Melatonin beyond its classical functions. Open Physiology Journal. 2008;1:1-23.

    Not in our library10.2174/1874360900801010001

  39. 39.

    Celinski K., Konturek S. J., Konturek P. C., et al. Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. Journal of Pineal Research. 2011;50:389-394.

    Not in our library10.1111/j.1600-079x.2011.00855.x

  40. 40.

    Leja-Szpak A., Jaworek J., Pierzchalski P., Reiter R. J. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). Journal of Pineal Research. 2010;49:248-255.

    Not in our library10.1111/j.1600-079x.2010.00789.x

  41. 41.

    Pandi-Perumal S. R., Trakht I., Srinivasan V., et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Progress in Neurobiology. 2008;85:335-353.

    Not in our library10.1016/j.pneurobio.2008.04.001

  42. 42.

    Yu H. S., Hernandez V., Haywood M., Wong C. G. Melatonin inhibits the proliferation of retinal pigment epithelial (RPE) cells in vitro. In Vitro Cellular & Developmental Biology. Animal. 1993;29A:415-418.

    Not in our library10.1007/bf02633991

  43. 43.

    Emet M., Ozcan H., Ozel L., Yayla M., Halici Z., Hacimuftuoglu A. A review of melatonin, its receptors and drugs. The Eurasian Journal of Medicine. 2016;48:135-141.

    Not in our library10.5152/eurasianjmed.2015.0267

  44. 44.

    Erren T. C., Reiter R. J. Melatonin: a universal time messenger. Neuro Endocrinology Letters. 2015;36:187-192.

    Not in our library

  45. 45.

    Mauriz J. L., Collado P. S., Veneroso C., Reiter R. J., González-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. Journal of Pineal Research. 2013;54:1-14.

    Not in our library10.1111/j.1600-079x.2012.01014.x

  46. 46.

    Dubocovich M. L., Rivera-Bermudez M. A., Gerdin M. J., Masana M. I. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Frontiers in Bioscience. 2003;8:d1093-d1108.

    Not in our library10.2741/1089

  47. 47.

    Dubocovich M. L., Delagrange P., Krause D. N., Sugden D., Cardinali D. P., Olcese J. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacological Reviews. 2010;62:343-380.

    Not in our library10.1124/pr.110.002832

  48. 48.

    Witt-Enderby P. A., Bennett J., Jarzynka M. J., Firestine S., Melan M. A. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sciences. 2003;72:2183-2198.

    Not in our library10.1016/s0024-3205(03)00098-5

  49. 49.

    Dubocovich M. L., Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27:101-110.

    Not in our library10.1385/endo:27:2:101

  50. 50.

    Dubocovich M. L., Hudson R. L., Sumaya I. C., Masana M. I., Manna E. Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57BL/6 mouse. Journal of Pineal Research. 2005;39:113-120.

    Not in our library10.1111/j.1600-079x.2005.00230.x

  51. 51.

    Flemström G., Bengtsson M. W., Mäkelä K., Herzig K. H. Effects of short-term food deprivation on orexin-A-induced intestinal bicarbonate secretion in comparison with related secretagogues. Acta Physiologica (Oxford, England). 2010;198:373-380.

    Not in our library10.1111/j.1748-1716.2009.02067.x

  52. 52.

    Lardone P. J., Carrillo-Vico A., Molinero P., Rubio A., Guerrero J. M. A novel interplay between membrane and nuclear melatonin receptors in human lymphocytes: significance in IL-2 production. Cellular and Molecular Life Sciences. 2009;66:516-525.

    Not in our library10.1007/s00018-008-8601-5

  53. 53.

    Srinivasan V., Pandi-Perumal S. R., Spence D. W., Kato H., Cardinali D. P. Melatonin in septic shock: some recent concepts. Journal of Critical Care. 2010;25:p. 656.e1-6.

    Not in our library10.1016/j.jcrc.2010.03.006

  54. 54.

    Vella F., Ferry G., Delagrange P., Boutin J. A. NRH:quinone reductase 2: an enzyme of surprises and mysteries. Biochemical Pharmacology. 2005;71:1-12.

    Not in our library10.1016/j.bcp.2005.09.019

  55. 55.

    Ekmekcioglu C. Melatonin receptors in humans: biological role and clinical relevance. Biomedicine & Pharmacotherapy. 2006;60:97-108.

    Not in our library10.1016/j.biopha.2006.01.002

  56. 56.

    Hardeland R. Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. Journal of Pineal Research. 2013;55:325-356.

    Not in our library10.1111/jpi.12090

  57. 57.

    Yonei Y., Hattori A., Tsutsui K., Okawa M., Ishizuka B. Effects of melatonin: basic studies and clinical applications. Anti-Ageing Medicine. 2003;7:85-91.

    Not in our library

  58. 58.

    Nosjean O., Nicolas J. P., Klupsch F., Delagrange P., Canet E., Boutin J. A. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochemical Pharmacology. 2001;61:1369-1379.

    Not in our library10.1016/s0006-2952(01)00615-3

  59. 59.

    Carlberg C. Gene regulation by melatonin. Annals of the New York Academy of Sciences. 2000;917:387-396.

    Not in our library10.1111/j.1749-6632.2000.tb05403.x

  60. 60.

    Carrillo-Vico A., Lardone P. J., Fernandez-Santos J. M., et al. Human lymphocyte-synthesized melatonin is involved in the regulation of the interleukin-2/interleukin-2 receptor system. The Journal of Clinical Endocrinology and Metabolism. 2005;90:992-1000.

    Not in our library10.1210/jc.2004-1429

  61. 61.

    Roy D., Angelini N. L., Fujieda H., Brown G. M., Belsham D. D. Cyclical regulation of GnRH gene expression in GT1-7 GnRH-secreting neurons by melatonin. Endocrinology. 2001;142:4711-4720.

    Not in our library10.1210/endo.142.11.8464

  62. 62.

    Benitez-King G., Huerto-Delgadillo L., Anton-Tay F. Binding of 3H-melatonin to calmodulin. Life Sciences. 1993;53:201-207.

    Not in our library10.1016/0024-3205(93)90670-x

  63. 63.

    Macias M., Escames G., León J., et al. Calreticulin-melatonin. An unexpected relationship. European Journal of Biochemistry. 2003;270:832-840.

    Not in our library10.1046/j.1432-1033.2003.03430.x

  64. 64.

    Lissoni P., Pittalis S., Rovelli F., et al. Immunomodulatory properties of a pineal indole hormone other than melatonin, the 5-methoxytryptophol. Journal of Biological Regulators and Homeostatic Agents. 1996;10:27-30.

    Not in our library

  65. 65.

    Mazzoccoli G., Carughi S., De C. A., La V. M., Vendemiale G. Melatonin and cortisol serum levels in lung cancer patients at different stages of disease. Medical Science Monitor. 2005;11:CR284-CR288.

    Not in our library

  66. 66.

    Scholtens R. M., van Munster B. C., van Kempen M. F., de Rooij S. E. Physiological melatonin levels in healthy older people: a systematic review. Journal of Psychosomatic Research. 2016;86:20-27.

    Not in our library10.1016/j.jpsychores.2016.05.005

  67. 67.

    Lanfumey L., Mongeau R., Hamon M. Biological rhythms and melatonin in mood disorders and their treatments. Pharmacology & Therapeutics. 2013;138:176-184.

    Not in our library10.1016/j.pharmthera.2013.01.005

  68. 68.

    Srinivasan V., Smits M., Spence W., et al. Melatonin in mood disorders. The World Journal of Biological Psychiatry. 2006;7:138-151.

    Not in our library10.1080/15622970600571822

  69. 69.

    Karasek M. Melatonin, human aging, and age-related diseases. Experimental Gerontology. 2004;39:1723-1729.

    Not in our library10.1016/j.exger.2004.04.012

  70. 70.

    Olbrich D., Dittmar M. Older poor-sleeping women display a smaller evening increase in melatonin secretion and lower values of melatonin and core body temperature than good sleepers. Chronobiology International. 2011;28:681-689.

    Not in our library10.3109/07420528.2011.599904

  71. 71.

    Pandi-Perumal S. R., Zisapel N., Srinivasan V., Cardinali D. P. Melatonin and sleep in aging population. Experimental Gerontology. 2005;40:911-925.

    Not in our library10.1016/j.exger.2005.08.009

  72. 72.

    Xie Z., Chen F., Li W. A., et al. A review of sleep disorders and melatonin. Neurological Research. 2017;39:559-565.

    Not in our library10.1080/01616412.2017.1315864

  73. 73.

    Erren T. C., Reiter R. J. Defining chronodisruption. Journal of Pineal Research. 2009;46:245-247.

    Not in our library10.1111/j.1600-079x.2009.00665.x

  74. 74.
    Protecting the Melatonin Rhythm through Circadian Healthy Light Exposure · 2014
    No notice
  75. 75.

    Pines A. Circadian rhythm and menopause. Climacteric. 2016;19:551-552.

    Not in our library10.1080/13697137.2016.1226608

  76. 76.

    Karasek M., Reiter R. J. Melatonin and aging. Neuro Endocrinology Letters. 2002;23:14-16.

    Not in our library

  77. 77.

    Zhao Z. Y., Xie Y., Fu Y. R., Bogdan A., Touitou Y. Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30–110 yr of age. Chronobiology International. 2002;19:1171-1182.

    Not in our library10.1081/cbi-120015958

  78. 78.

    Reiter R. J., Tan D., Kim S. J., et al. Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mechanisms of Ageing and Development. 1999;110:157-173.

    Not in our library10.1016/s0047-6374(99)00058-5

  79. 79.

    Andersen L. P., Gögenur I., Rosenberg J., Reiter R. J. The safety of melatonin in humans. Clinical Drug Investigation. 2016;36:169-175.

    Not in our library10.1007/s40261-015-0368-5

  80. 80.

    Cheung R. T., Tipoe G. L., Tam S., Ma E. S., Zou L. Y., Chan P. S. Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration. Journal of Pineal Research. 2006;41:337-343.

    Not in our library10.1111/j.1600-079x.2006.00372.x

  81. 81.

    Chen J., Chen G., Li J., et al. Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro-inflammatory cytokines. Journal of Pineal Research. 2014;57:340-347.

    Not in our library10.1111/jpi.12173

  82. 82.

    Dong Y., Fan C., Hu W., et al. Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. Journal of Pineal Research. 2016;60:253-262.

    Not in our library10.1111/jpi.12300

  83. 83.

    Antonelli M., Kushner I. It’s time to redefine inflammation. The FASEB Journal. 2017;31:1787-1791.

    Not in our library10.1096/fj.201601326r

  84. 84.
    An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis · 2015
    No notice
  85. 85.

    Kaunzner U. W., Al-Kawaz M., Gauthier S. A. Defining disease activity and response to therapy in MS. Current Treatment Options in Neurology. 2017;19:p. 20.

    Not in our library10.1007/s11940-017-0454-5

  86. 86.

    Yadav S. K., Mindur J. E., Ito K., Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Current Opinion in Neurology. 2015;28:206-219.

    Not in our library10.1097/wco.0000000000000205

  87. 87.

    Chuffa L. G. A., Reiter R. J., Lupi Júnior L. A. Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. Carcinogenesis. 2017.

    Not in our library10.1093/carcin/bgx054

  88. 88.

    Galano A., Tan D. X., Reiter R. J. Melatonin as a natural ally against oxidative stress: a physicochemical examination. Journal of Pineal Research. 2011;51:1-16.

    Not in our library10.1111/j.1600-079x.2011.00916.x

  89. 89.

    Mistraletti G., Paroni R., Umbrello M., et al. Melatonin pharmacological blood levels increase total antioxidant capacity in critically ill patients. International Journal of Molecular Sciences. 2017;18.

    Not in our library10.3390/ijms18040759

  90. 90.

    Agil A., Reiter R. J., Jiménez-Aranda A., et al. Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats. Journal of Pineal Research. 2013;54:381-388.

    Not in our library10.1111/jpi.12012

  91. 91.

    Bonnefont-Rousselot D., Collin F., Jore D., Gardès-Albert M. Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. Journal of Pineal Research. 2011;50:328-335.

    Not in our library10.1111/j.1600-079x.2010.00847.x

  92. 92.
    Melatonin: Buffering the Immune System · 2013
    No notice
  93. 93.

    Reiter R. J., Calvo J. R., Karbownik M., Qi W., Tan D. X. Melatonin and its relation to the immune system and inflammation. Annals of the New York Academy of Sciences. 2000;917:376-386.

    Not in our library10.1111/j.1749-6632.2000.tb05402.x

  94. 94.

    Baeuerle P. A., Baltimore D. NF-kappa B: ten years after. Cell. 1996;87:13-20.

    Not in our library10.1016/s0092-8674(00)81318-5

  95. 95.

    Cuzzocrea S., Reiter R. J. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. European Journal of Pharmacology. 2001;426:1-10.

    Not in our library10.1016/s0014-2999(01)01175-x

  96. 96.

    Korkmaz A., Rosales-Corral S., Reiter R. J. Gene regulation by melatonin linked to epigenetic phenomena. Gene. 2012;503(1):1-11.

    Not in our library10.1016/j.gene.2012.04.040

  97. 97.

    Lezovalch F., Sparapani M., Behl C. N-Acetyl-serotonin (normelatonin) and melatonin in protect neurons against oxidative challenges and suppresses the activity of the transcription factor NF-kB. Journal of Pineal Research. 1998;24:168-178.

    Not in our library10.1111/j.1600-079x.1998.tb00530.x

  98. 98.

    Vriend J., Reiter R. J. Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sciences. 2014;115:8-14.

    Not in our library10.1016/j.lfs.2014.08.024

  99. 99.

    Brzezinski A. Melatonin in humans. The New England Journal of Medicine. 1997;336:186-195.

    Not in our library10.1056/nejm199701163360306

  100. 100.

    Lissoni P., Rovelli F., Meregalli S., et al. Melatonin as a new possible anti-inflammatory agent. Journal of Biological Regulators and Homeostatic Agents. 1997;11:157-159.

    Not in our library

  101. 101.

    Santangelo C., Varì R., Scazzocchio B., Di Benedetto R., Filesi C., Masella R. Polyphenols, intracellular signalling and inflammation. Annali dell'Istituto Superiore di Sanità. 2007;43:394-405.

    Not in our library

  102. 102.

    Habtemariam S., Daglia M., Sureda A., Selamoglu Z., Gulhan M. F., Nabavi S. M. Melatonin and respiratory diseases: a review. Current Topics in Medicinal Chemistry. 2017;17:467-488.

    Not in our library10.2174/1568026616666160824120338

  103. 103.

    Park H. J., Kim H. J., Ra J., et al. Melatonin inhibits lipopolysaccharide-induced CC chemokine subfamily gene expression in human peripheral blood mononuclear cells in a microarray analysis. Journal of Pineal Research. 2007;43:121-129.

    Not in our library10.1111/j.1600-079x.2007.00452.x

  104. 104.

    Yu G. M., Kubota H., Okita M., Maeda T. The anti-inflammatory and antioxidant effects of melatonin on LPS-stimulated bovine mammary epithelial cells. PLoS One. 2017;12(5, article e0178525).

    Not in our library10.1371/journal.pone.0178525

  105. 105.

    Carrillo-Vico A., García-Mauriño S., Calvo J. R., Guerrero J. M. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. The FASEB Journal. 2003;17:755-757.

    Not in our library10.1096/fj.02-0501fje

  106. 106.

    Cuzzocrea S., Misko T. P., Costantino G., et al. Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. The FASEB Journal. 2000;14:1061-1072.

    Not in our library10.1096/fasebj.14.9.1061

  107. 107.

    Cuzzocrea S., Reiter R. J. Pharmacological actions of melatonin in acute and chronic inflammation. Current Topics in Medicinal Chemistry. 2002;2:153-165.

    Not in our library10.2174/1568026023394425

  108. 108.

    Bertuglia S., Marchiafa P. L., Colantuoni A. Melatonin prevents ischemia reperfusion injury in the hamster cheek pouch. Cardiovascular Research. 1996;31:947-952.

    Not in our library10.1016/s0008-6363(96)00030-2

  109. 109.

    Lloyd J. K. The importance of vitamin E in human nutrition. Acta Paediatrica Scandinavica. 1990;79:6-11.

    Not in our library10.1111/j.1651-2227.1990.tb11322.x

  110. 110.

    Espino J., Pariente J. A., Rodríguez A. B. Oxidative stress and immunosenescence: therapeutic effects of melatonin. Oxidative Medicine and Cellular Longevity. 2012;2012:9.

    Not in our library10.1155/2012/670294

  111. 111.

    Ghosh A. K., Naaz S., Bhattacharjee B., et al. Mechanism of melatonin protection against copper-ascorbate-induced oxidative damage in vitro through isothermal titration calorimetry. Life Sciences. 2017;180:123-136.

    Not in our library10.1016/j.lfs.2017.05.022

  112. 112.

    Reiter R. J., Mayo J. C., Tan D. X., Sainz R. M., Alatorre-Jimenez M., Qin L. Melatonin as an antioxidant: under promises but over delivers. Journal of Pineal Research. 2016;61:253-278.

    Not in our library10.1111/jpi.12360

  113. 113.
    Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism · 2015
    No notice
  114. 114.

    Zhou J., Zhang S., Zhao X., Wei T. Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-β1-42. Journal of Pineal Research. 2008;45:157-165.

    Not in our library10.1111/j.1600-079x.2008.00570.x

  115. 115.

    Maldonado M. D., Mora-Santos M., Naji L., Carrascosa-Salmoral M. P., Naranjo M. C., Calvo J. R. Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacological Research. 2010;62:282-287.

    Not in our library10.1016/j.phrs.2009.11.014

  116. 116.
    Antiinflammatory Activity of Melatonin in Central Nervous System · 2010
    No notice
  117. 117.

    De Ciuceis C., Amiri F., Brassard P., Endemann D. H., Touyz R. M., Schiffrin E. L. Reduced vascular remodeling, endothelial dysfunction, and oxidative stress in resistance arteries of angiotensin II-infused macrophage colony-stimulating factor-deficient mice: evidence for a role in inflammation in angiotensin-induced vascular injury. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2106-2113.

    Not in our library10.1161/01.atv.0000181743.28028.57

  118. 118.

    Franceschi C., Bonafe M., Valensin S., et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Annals of the New York Academy of Sciences. 2000;908:244-254.

    Not in our library10.1111/j.1749-6632.2000.tb06651.x

  119. 119.
    Understanding how we age: insights into inflammaging · 2013
    No notice
  120. 120.

    Volt H., García J. A., Doerrier C., et al. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. Journal of Pineal Research. 2016;60:193-205.

    Not in our library10.1111/jpi.12303

  121. 121.

    Cannizzo E. S., Clement C. C., Sahu R., Follo C., Santambrogio L. Oxidative stress, inflammaging and immunosenescence. Journal of Proteomics. 2011;74:2313-2323.

    Not in our library10.1016/j.jprot.2011.06.005

  122. 122.

    Alegre F., Pelegrin P., Feldstein A. E. Inflammasomes in liver fibrosis. Seminars in Liver Disease. 2017;37:119-127.

    Not in our library10.1055/s-0037-1601350

  123. 123.

    Fenini G., Contassot E., French L. E. Potential of IL-1, IL-18 and inflammasome inhibition for the treatment of inflammatory skin diseases. Frontiers in Pharmacology. 2017;8:p. 278.

    Not in our library10.3389/fphar.2017.00278

  124. 124.

    Lamkanfi M., Dixit V. M. Inflammasomes and their roles in health and disease. Annual Review of Cell and Developmental Biology. 2012;28:137-161.

    Not in our library10.1146/annurev-cellbio-101011-155745

  125. 125.

    Vandanmagsar B., Youm Y. H., Ravussin A., et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Medicine. 2011;17:179-188.

    Not in our library10.1038/nm.2279

  126. 126.

    Conforti-Andreoni C., Ricciardi-Castagnoli P., Mortellaro A. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cellular & Molecular Immunology. 2011;8:135-145.

    Not in our library10.1038/cmi.2010.81

  127. 127.

    Kayagaki N., Warming S., Lamkanfi M., et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117-121.

    Not in our library10.1038/nature10558

  128. 128.

    Martinon F., Burns K., Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Molecular Cell. 2002;10:417-426.

    Not in our library10.1016/s1097-2765(02)00599-3

  129. 129.

    Dinarello C. A. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology. 2009;27:519-550.

    Not in our library10.1146/annurev.immunol.021908.132612

  130. 130.

    Sims J. E., Smith D. E. The IL-1 family: regulators of immunity. Nature Reviews Immunology. 2010;10:89-102.

    Not in our library10.1038/nri2691

  131. 131.

    Man S. M., Karki R., Kanneganti T. D. DNA-sensing inflammasomes: regulation of bacterial host defense and the gut microbiota. Pathogens and Disease. 2016;74, article ftw028.

    Not in our library10.1093/femspd/ftw028

  132. 132.

    Bracey N. A., Duff H. J., Muruve D. A. Hierarchical regulation of wound healing by NOD-like receptors in cardiovascular disease. Antioxidants & Redox Signaling. 2015;22:1176-1187.

    Not in our library10.1089/ars.2014.6125

  133. 133.

    Liu P., Xie Q., Wei T., Chen Y., Chen H., Shen W. Activation of the NLRP3 inflammasome induces vascular dysfunction in obese OLETF rats. Biochemical and Biophysical Research Communications. 2015;468:319-325.

    Not in our library10.1016/j.bbrc.2015.10.105

  134. 134.

    Martinon F., Mayor A., Tschopp J. The inflammasomes: guardians of the body. Annual Review of Immunology. 2009;27:229-265.

    Not in our library10.1146/annurev.immunol.021908.132715

  135. 135.

    Zhou R., Yazdi A. S., Menu P., Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221-225.

    Not in our library10.1038/nature09663

  136. 136.

    Latz E., Xiao T. S., Stutz A. Activation and regulation of the inflammasomes. Nature Reviews Immunology. 2013;13:397-411.

    Not in our library10.1038/nri3452

  137. 137.

    Man S. M., Kanneganti T. D. Regulation of inflammasome activation. Immunological Reviews. 2015;265:6-21.

    Not in our library10.1111/imr.12296

  138. 138.

    Lee S., Suh G. Y., Ryter S. W., Choi A. M. Regulation and function of the nucleotide binding domain Leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease. American Journal of Respiratory Cell and Molecular Biology. 2016;54:151-160.

    Not in our library10.1165/rcmb.2015-0231tr

  139. 139.

    Hirota S. A., Ng J., Lueng A., et al. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflammatory Bowel Diseases. 2011;17:1359-1372.

    Not in our library10.1002/ibd.21478

  140. 140.

    Tschopp J., Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Reviews Immunology. 2010;10:210-215.

    Not in our library10.1038/nri2725

  141. 141.

    Wen H., Ting J. P., O’Neill L. A. A role for the NLRP3 inflammasome in metabolic diseases: did Warburg miss inflammation? Nature Immunology. 2012;13:352-357.

    Not in our library10.1038/ni.2228

  142. 142.

    Kim S., Joe Y., Jeong S. O., et al. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate Immunity. 2014;20:799-815.

    Not in our library10.1177/1753425913508593

  143. 143.

    Krishnan S. M., Dowling J. K., Ling Y. H., et al. Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. British Journal of Pharmacology. 2016;173:752-765.

    Not in our library10.1111/bph.13230

  144. 144.

    Afrasyab A., Qu P., Zhao Y., et al. Correlation of NLRP3 with severity and prognosis of coronary atherosclerosis in acute coronary syndrome patients. Heart and Vessels. 2016;31:1218-1229.

    Not in our library10.1007/s00380-015-0723-8

  145. 145.

    Zhang Y., Li X., Grailer J. J., et al. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. Journal of Pineal Research. 2016;60:405-414.

    Not in our library10.1111/jpi.12322

  146. 146.

    Coll R. C., Robertson A. A., Chae J. J., et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Medicine. 2015;21:248-255.

    Not in our library10.1038/nm.3806

  147. 147.
    Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin 1 · 2007
    No notice
  148. 148.

    Grailer J. J., Canning B. A., Kalbitz M., et al. Critical role for the NLRP3 inflammasome during acute lung injury. Journal of Immunology. 2014;192:5974-5983.

    Not in our library10.4049/jimmunol.1400368

  149. 149.

    Fernández-Gil B., Moneim A. E., Ortiz F., et al. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One. 2017;12(4, article e0174474).

    Not in our library10.1371/journal.pone.0174474

  150. 150.

    Ortiz F., Acuña-Castroviejo D., Doerrier C., et al. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. Journal of Pineal Research. 2015;58:34-49.

    Not in our library10.1111/jpi.12191

  151. 151.

    Henao-Mejia J., Elinav E., Thaiss C. A., Flavell R. A. Inflammasomes and metabolic disease. Annual Review of Physiology. 2014;76:57-78.

    Not in our library10.1146/annurev-physiol-021113-170324

  152. 152.

    Horng T., Hotamisligil G. S. Linking the inflammasome to obesity-related disease. Nature Medicine. 2011;17:164-165.

    Not in our library10.1038/nm0211-164

  153. 153.

    Liu Z., Gan L., Xu Y., et al. Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-κB/GSDMD signal in mice adipose tissue. Journal of Pineal Research. 2017;63(1).

    Not in our library10.1111/jpi.12414

  154. 154.

    Murphy A. J., Kraakman M. J., Kammoun H. L., et al. IL-18 production from the NLRP1 inflammasome prevents obesity and metabolic syndrome. Cell Metabolism. 2016;23:155-164.

    Not in our library10.1016/j.cmet.2015.09.024

  155. 155.

    Giordano A., Murano I., Mondini E., et al. Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. Journal of Lipid Research. 2013;54:2423-2436.

    Not in our library10.1194/jlr.m038638

  156. 156.

    García J. A., Volt H., Venegas C., et al. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. The FASEB Journal. 2015;29:3863-3875.

    Not in our library10.1096/fj.15-273656

  157. 157.

    Escames G., Acuña-Castroviejo D., López L. C., et al. Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. The Journal of Pharmacy and Pharmacology. 2006;58:1153-1165.

    Not in our library10.1211/jpp.58.9.0001

  158. 158.

    Radogna F., Diederich M., Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochemical Pharmacology. 2010;80:1844-1852.

    Not in our library10.1016/j.bcp.2010.07.041

  159. 159.

    Rahim I., Djerdjouri B., Sayed R. K., et al. Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis. Journal of Pineal Research. 2017;62(1).

    Not in our library10.1111/jpi.12410

  160. 160.

    López A., García J. A., Escames G., et al. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. Journal of Pineal Research. 2009;46:188-198.

    Not in our library10.1111/j.1600-079x.2008.00647.x

  161. 161.

    Martín M., Macías M., Escames G., León J., Acuña-Castroviejo D. Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl-hydroperoxide-induced mitochondrial oxidative stress. The FASEB Journal. 2000;14:1677-1679.

    Not in our library10.1096/fj.99-0865fje

  162. 162.

    Wree A., McGeough M. D., Peña C. A., et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. Journal of Molecular Medicine (Berlin, Germany). 2014;92:1069-1082.

    Not in our library10.1007/s00109-014-1170-1

  163. 163.

    An R., Zhao L., Xi C., et al. Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism. Basic Research in Cardiology. 2016;111:p. 8.

    Not in our library10.1007/s00395-015-0526-1

  164. 164.

    Escames G., López L. C., Ortiz F., et al. Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. The FEBS Journal. 2007;274:2135-2147.

    Not in our library10.1111/j.1742-4658.2007.05755.x

  165. 165.

    Acuña-Castroviejo D., Carretero M., Doerrier C., et al. Melatonin protects lung mitochondria from aging. Age (Dordrecht, Netherlands). 2012;34:681-692.

    Not in our library10.1007/s11357-011-9267-8

  166. 166.

    Carretero M., Escames G., López L. C., et al. Long-term melatonin administration protects brain mitochondria from aging. Journal of Pineal Research. 2009;47:192-200.

    Not in our library10.1111/j.1600-079x.2009.00700.x

  167. 167.

    Rodríguez M. I., Carretero M., Escames G., et al. Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice. Free Radical Research. 2007;41:15-24.

    Not in our library10.1080/10715760600936359

  168. 168.

    Rodriguez M. I., Escames G., López L. C., et al. Melatonin administration prevents cardiac and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice. The Journal of Endocrinology. 2007;194:637-643.

    Not in our library10.1677/joe-07-0260

  169. 169.

    Rodríguez M. I., Escames G., López L. C., et al. Chronic melatonin treatment reduces the age-dependent inflammatory process in senescence-accelerated mice. Journal of Pineal Research. 2007;42:272-279.

    Not in our library10.1111/j.1600-079x.2006.00416.x

  170. 170.

    Bubenik G. A., Konturek S. J. Melatonin and aging: prospects for human treatment. Journal of Physiology and Pharmacology. 2011;62:13-19.

    Not in our library

  171. 171.

    Cao Z., Fang Y., Lu Y., et al. Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. Journal of Pineal Research. 2017;62.

    Not in our library10.1111/jpi.12389

  172. 172.

    Jarup L., Akesson A. Current status of cadmium as an environmental health problem. Toxicology and Applied Pharmacology. 2009;238:201-208.

    Not in our library10.1016/j.taap.2009.04.020

  173. 173.

    Park M. J., Kim D. I., Lim S. K., et al. Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1α regulation in vitro and in vivo. Journal of Hepatology. 2014;61:1151-1157.

    Not in our library10.1016/j.jhep.2014.06.032

  174. 174.

    Yang Z., Zhong L., Xian R., Yuan B. MicroRNA-223 regulates inflammation and brain injury via feedback to NLRP3 inflammasome after intracerebral hemorrhage. Molecular Immunology. 2015;65:267-276.

    Not in our library10.1016/j.molimm.2014.12.018

  175. 175.

    Yang F., Wang Z., Wei X., et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. Journal of Cerebral Blood Flow and Metabolism. 2014;34:660-667.

    Not in our library10.1038/jcbfm.2013.242

  176. 176.

    Geldhoff M., Mook-Kanamori B. B., Brouwer M. C., et al. Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis. BMC Infectious Diseases. 2013;13:p. 358.

    Not in our library10.1186/1471-2334-13-358

  177. 177.

    Wang L., Zhai Y. Q., Xu L. L., et al. Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice. Experimental Neurology. 2014;251:22-29.

    Not in our library10.1016/j.expneurol.2013.11.001

  178. 178.
    ER stress induces NLRP3 inflammasome activation and hepatocyte death · 2015
    No notice
  179. 179.

    Li Y., Yang Y., Feng Y., et al. A review of melatonin in hepatic ischemia/reperfusion injury and clinical liver disease. Annals of Medicine. 2014;46:503-511.

    Not in our library10.3109/07853890.2014.934275

  180. 180.

    Yang Y., Sun Y., Yi W., et al. A review of melatonin as a suitable antioxidant against myocardial ischemia-reperfusion injury and clinical heart diseases. Journal of Pineal Research. 2014;57:357-366.

    Not in our library10.1111/jpi.12175

  181. 181.

    Shim D. W., Shin H. J., Han J. W., et al. A novel synthetic derivative of melatonin, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation. Toxicology and Applied Pharmacology. 2015;284:227-235.

    Not in our library10.1016/j.taap.2015.02.006

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