Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense

Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune–pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.

Melatonin’s neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders

Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin’s prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin’s potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin’s ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.

Tryptophan Metabolites and Aryl Hydrocarbon Receptor in Severe Acute Respiratory Syndrome, Coronavirus-2 (SARS-CoV-2) Pathophysiology

The metabolism of tryptophan is intimately associated with the differential regulation of diverse physiological processes, including in the regulation of responses to severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection that underpins the COVID-19 pandemic. Two important products of tryptophan metabolism, viz kynurenine and interleukin (IL)4-inducible1 (IL41)-driven indole 3 pyruvate (I3P), activate the aryl hydrocarbon receptor (AhR), thereby altering the nature of immune responses to SARS-CoV-2 infection. AhR activation dysregulates the initial pro-inflammatory cytokines production driven by neutrophils, macrophages, and mast cells, whilst AhR activation suppresses the endogenous antiviral responses of natural killer cells and CD8+ T cells. Such immune responses become further dysregulated by the increased and prolonged pro-inflammatory cytokine suppression of pineal melatonin production coupled to increased gut dysbiosis and gut permeability. The suppression of pineal melatonin and gut microbiome-derived butyrate, coupled to an increase in circulating lipopolysaccharide (LPS) further dysregulates the immune response. The AhR mediates its effects via alterations in the regulation of mitochondrial function in immune cells. The increased risk of severe/fatal SARS-CoV-2 infection by high risk conditions, such as elderly age, obesity, and diabetes are mediated by these conditions having expression levels of melatonin, AhR, butyrate, and LPS that are closer to those driven by SARS-CoV-2 infection. This has a number of future research and treatment implications, including the utilization of melatonin and nutraceuticals that inhibit the AhR, including the polyphenols, epigallocatechin gallate (EGCG), and resveratrol.

Monosodium glutamate administration early in life alters pineal melatonin nocturnal profile in adulthood

The pineal gland synthesizes melatonin exclusively at night, which gives melatonin the characteristic of a temporal synchronizer of the physiological systems. Melatonin is a regulator of insulin activities centrally and also peripherally and its synthesis is reduced in diabetes. Since monosodium glutamate (MSG) is often used to induce the type 2 diabetic and metabolic syndrome in animal models, the purpose of this work is to evaluate the potential effects of MSG given to neonates on the pineal melatonin synthesis in different aged male and female rats. Wistar rats were subcutaneously injected with MSG (4mg/g/day) or saline solution (0.9%) from the second to eighth post-natal day. The circadian profiles both melatonin levels and AANAT activity were monitored at different ages. Body weight, naso-anal length, adipose tissues weight, GTT, ITT and serum insulin levels were also evaluated. Typical obesity with the neonatal MSG treatment was observed, indicated by a great increase in adipose depots without a concurrent increase in body weight. MSG treatment did not cause hyperglycemia or glucose intolerance, but induced insulin resistance. An increase of melatonin synthesis at ZT 15 with phase advance was observed in in some animals. The AANAT activity was positively parallel to the melatonin circadian profile. It seems that MSG causes hypothalamic obesity which may increase AANAT activity and melatonin production in pineal gland. These effects were not temporally correlated with insulin resistance and hyperinsulinemia indicating the hypothalamic lesions, particularly in arcuate nucleus induced by MSG in early age, as the principal cause of the increase in melatonin production.

Effect of cold and warm white light on selected endocrine and immune parameters of broiler embryos and hatchlings

Lighting conditions during incubation can influence embryonic development, post-hatching ontogeny and production efficiency. Previous studies revealed that different light colours differently affect pineal melatonin biosynthesis in embryos and postembryonic development of broiler chickens, but physiological mechanisms mediating these effects are not known. Cold and warm white light consists of different wavelengths and therefore the aim of the present study was to explore if these two lights can differently influence the development of circadian melatonin biosynthesis, production of thyroid hormones and corticosterone, concentration of metabolites (glucose, cholesterol and triacylglycerols) as well as expression of two important immune genes, presenilin 1 and avian beta-defensin 1 (AvBD-1). We evaluated these traits in embryos before hatching (456, 460, 465, 468 and 472 h of incubation) and in hatchlings. The rhythmic profile of pineal melatonin with higher concentrations during the dark time was determined in both treatment groups. Melatonin levels increased considerably in hatchlings in comparison with embryos, but we found no difference in rhythm characteristics between groups. We did not identify any daily rhythms in plasma corticosterone and thyroid hormone levels in either studied age and no differences were found between light treatments in concentrations of thyroid hormones, corticosterone, metabolites and expression of presenilin and AvBD-1. The expected developmental increase of thyroid hormones was proved. Gene expression of presenilin increased in the duodenum of hatchlings in comparison with embryos, but the expression did not change in the bursa of Fabricius. On the other hand, expression of AvBD-1 decreased in hatchlings compared to embryos in both tissues. Based on these results, we can conclude that the colour temperature of white light did not influence endocrine and immune parameters determined in this study and probably monochromatic rather than polychromatic light should be used to influence embryonic development and postembryonic ontogeny of broiler chickens.

Avoiding room light during night may stimulate immunity in COVID-19 patients by promoting melatonin production

COVID-19 is one of the greatest health issues facing humankind for many decades; it emerged in Wuhan, China, late in December 2019, and rapidly spread over the world within the short period. This report emphasizes the potential hazards of exposure to room light at night which affects the immunity of COVID-19 patients by suppressing their melatonin, which is only released from the pineal gland at night. Exposure to light at night is especially common in the hospital setting. This may make the symptom worse for the hospitalized patients and the light at night should not be ignored. Thus, I suggest that COVID-19 patients should avoid light at night either by wearing eye masks or darkening the room to enhance pineal melatonin synthesis and increase their serum melatonin levels.