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A series of studies have been carried out in animals and cancer patients to delineate the effects of alcohol on T cell function. In one study, the role of ethanol and CD4+ T cells in controlling tumor growth was examined by implanting 201T human lung adenocarcinoma cell line into the lung of ethanol-fed BALB/c mice that also received anti-CD4 antibody . These mice exhibited significantly larger tumors compared with non-ethanol fed control mice. In another study, alcohol consuming mice that were inoculated with B16BL6 melanoma showed marked reduction in the number of CD8+ T cells that specifically recognize a melanoma-specific antigen (i.e., gp100) compared with water-drinking control mice . Also, in these ethanol-fed mice, CD8+CD44hi T memory cells failed to expand. On the other hand, multiple studies in alcohol-consuming mice showed an increase in the percentage of cells known to suppress anti-tumor T cell immune responses, such as T regulatory cells (Tregs) (CD4+CD25+FOXP3+) and invariant natural killer T cells (iNKT) cells (CD3+NK1.1+) [156,157,158].
It was reported that several physiological or pathological conditions indeed alter the morphology of the pineal glands. For example, the pineal gland of obese individuals is usually significantly smaller than that in a lean subject . The pineal volume is also significantly reduced in patients with primary insomnia compared to healthy controls and further studies are needed to clarify whether low pineal volume is the basis or a consequence of a functional sleep disorder . These observations indicate that the phenotype of the pineal gland may be changeable by health status or by environmental factors, even in humans. The largest pineal gland was recorded in new born South Pole seals; it occupies one third of their entire brain [9,10]. The pineal size decreases as they grow. Even in the adult seal, however, the pineal gland is considerably large and its weight can reach up to approximately 4000 mg, 27 times larger than that of a human. This huge pineal gland is attributed to the harsh survival environments these animals experience .
The most widely accepted concept is that melatonin is the recognized major product of the pineal gland. Melatonin is the derivative of tryptophan. It was first isolated from the pineal gland of the cow and it was initially classified as a neuroendocrine-hormone . Subsequently, it was discovered that retina [20,21] and Harderian gland [20,22,23,24] also produced melatonin. Recently, it has been found that almost all organs, tissues and cells tested have the ability to synthesize melatonin using the same pathway and enzymes the pineal uses [25,26]. These include, but not limited to, skin , lens , ciliary body [29,30], gut [31,32], testis , ovary [34,35], uterus , bone marrow [37,38], placenta [39,40], oocytes , red blood cells , plantlets , lymphocytes , astrocytes, glia cells , mast cells  and neurons . Not only melatonin but also the melatonin biosynthetic machinery including mRNA and proteins of arylalkylamine N-acetyltransferase (AANAT) and/or N-acetyl-serotonin methyltransferase (ASMT) [formerly hydroxyindoleO-methyltransferase (HIOMT)] have been identified in these organs, tissues and cells. It was calculated that the amounts of extrapineal derived melatonin is much greater than that produced by the pineal . However, the extra pineal-derived melatonin cannot replace/compensate for the role played by the pineal-derived melatonin in terms of circadian rhythm regulation. As we know pineal melatonin exhibits a circadian rhythm in circulation and in the CSF with a secretory peak at night and low level during the day ; thus, the primary function of the pineal-derived melatonin is as a chemical signal of darkness for vertebrates . This melatonin signal helps the animals to cope with the light/dark circadian changes to synchronize their daily physiological activities (feeding, metabolism, reproduction, sleep, etc.).
For the photoperiod sensitive reproductive animals, the melatonin signal regulates their reproductive activities to guide them to give birth during the right seasons . Interestingly, even low ranking species that lack a pineal gland, for example, marine zooplankton, also exhibit a melatonin circadian rhythm which is responsible for their daily physiological activities . While, the extrapineal melatonin in vertebrates does not contribute to the melatonin circadian rhythm and it does not serve as the chemical signal of darkness since pinealectomy in animals distinguishes this rhythm [52,53,54]. This was further confirmed by the recent discovery that the expressions of AANAT and ASMT are present in mitochondria of both pinealocytes and neuron cells and their mitochondria synthesized melatonin. However, the expressions of AANAT and ASMT exhibit a circadian rhythm that matched the fluctuation in melatonin levels only in the mitochondria of pineal gland while this rhythm was absent in the mitochondria of neuronal cells . Thus, the primary function of extrapineal melatonin (except for the retina; retinas not only possess an internal melatonin rhythm [56,57]; retinal melatonin might participate in melatonin circadian rhythm of the general circulation in some species [58,59,60]) is to serve as an antioxidant, autocoid, paracoid and tissue factor locally [49,61].
Melatonin membrane receptors have been identified in the SCN of vertebrates [56,89] and the signal transduction pathways seemed to be involved in both MT1 and MT2 to induce an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2) [89,90,91]. Without the feedback information of melatonin, SCN would not properly interpret the natural photoperiodic changes  and would exhibit a free running internal rhythm in which the cycle is longer than 24 h. In this situation the SCN would also instruct the pineal gland to exhibit an unusual melatonin circadian rhythm which is also longer than 24 h. This phenomenon is apparent in completely blind animals and humans whose eyes, specifically the MRGC, do not appropriately receive environmental photoperiodic information [93,94,95]. Importantly, melatonin administration to blind subjects partially re-entrains their biological rhythms close to normal [94,96,97].
Pineal gland is mainly comprised of pinealocytes, microglia and astrocytes. The lineage of pinealocytes is elusive. Current information suggests that pinealocytes are differentiated from Pax6-expresssing neuroepithelial cells . They are specialized to synthesize and release melatonin (and possible some other substances). This explains why pinealocytes with two special characteristics regarding their mitochondria. First, the pinealocytes contain many more mitochondria than those of neuronal cells. Second, the morphologies of these mitochondria exhibit obvious dynamic alterations related to their fission, fusion and mitophagy activities during a 24 h period . Because of the high density of mitochondria, we speculated the mitochondria are the major sites for melatonin synthesis . Subsequent studies have proven this speculation. Melatonin synthesis was identified in the mitochondria of both animal and plant cells [101,102]. Recently, this was further confirmed by Suofa et al. . They observed that the mitochondria are the exclusive sites of melatonin production in pinelocytes and in neuronal cells. The exact subsite of melatonin synthesis occurred in the matrix of mitochondria. Thus, the numerous mitochondria in pinealocytes relate to their melatonin synthetic function. This does not naturally exclude the extra-mitochondrial melatonin production. In cytosol, melatonin can also be synthesized. For example, red blood cells and platelets which are without mitochondria still produced melatonin [42,43]. Due to the substrate, particularly acetyl coenzyme A availability, melatonin synthesis in the extra-mitochondrial sites would not be as efficient as in the mitochondria since acetyl coenzyme A is concentrated in the mitochondria .
As to the association between the aging and melatonin production, in most vertebrates, melatonin production wanes with aging. The reasons for this may be two-fold. Melatonin synthetic capacity is dampened during aging due to the reduced density of β-adrenergic receptors in the pineal gland [215,216] and the downregulation of gene expression or phosphorylation of AANAT/SNAT . A second reason is the increased consumption of melatonin. This is due to the metabolic alterations. For example, more ROS are generated by the aged cells than in the young cells and melatonin as the endogenous antioxidant is used to neutralize the overproduced ROS in aging organisms. Both of these effects may cause its low levels in the aged vertebrates. Low melatonin level is considered as a biomarker of aging [218,219,220]. When melatonin production was depressed by pinealectomy in rats, accumulation of oxidatively-damaged products accelerated their aging process . In contrast, when young pineal glands were grafted to the old animals or exogenous melatonin was supplemented, both significantly increased the life span of experimental animals .
A great deal of attention has recently been given to the relationship of decreased melatonin levels in neurodegenerative diseases and aging associated pineal calcification. With the increased use of the PET scan, susceptibility-weighted magnetic resonance imaging (SWMR) or other advanced technologies, even very small pineal concretions can be identified in patients or animals, which could not be seen previously. It was found that the rates of pineal calcification have been significantly underestimated previously. For example, in non-specifically targeted patients with the average age of 58.7 ± 17.4 years, 214 out of 346 showed PGC on CT scans (62%) ; the data of 12,000 healthy subjects from Turkey indicated that the highest intracranial calcifications occurred in the pineal gland with an incidence of 71.6% . PGC appears to occur without significant differences among countries, regions and races. For example, in Iran the PGC incidence is around 71%  and in African (Ethiopia), it is roughly 72%  and in black people in the US it is 70% . With such a high incidence of PGC in humans and considering the functions of pineal gland, the PGC should not be considered a normal physiological process. 2b1af7f3a8