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Cited by 221Circadian rhythm and melatoninmelanin and skin pigmentationParathyroid Disorders and Treatments

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Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland

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Tan, Dun, Xu, Bing, Zhou, Xinjia, Reiter, Russel·2018·Molecules
DOI 10.3390/molecules23020301PMC PMC6017004
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Abstract

The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective antioxidant. An intact and functional pineal gland is necessary for preserving optimal human health. Unfortunately, this gland has the highest calcification rate among all organs and tissues of the human body. Pineal calcification jeopardizes melatonin’s synthetic capacity and is associated with a variety of neuronal diseases. In the current review, we summarized the potential mechanisms of how this process may occur under pathological conditions or during aging. We hypothesized that pineal calcification is an active process and resembles in some respects of bone formation. The mesenchymal stem cells and melatonin participate in this process. Finally, we suggest that preservation of pineal health can be achieved by retarding its premature calcification or even rejuvenating the calcified gland.

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Figures

Figure 1 Illustration of the SCN-melatonin loop. Solid arrows indicate the neuronal connections and the direction of neuronal projections. Dash arrows indicate the input signals. SCN is the master clock which determines the biological rhythms as well as the melatonin circadian rhythm. Its intrinsic circadian interval is longer than 24 h. The natural photoperiod (photos) serves as an input signal to entrain melatonin circadian rhythm to 24 h; in turn, melatonin functions as a signal of photoperiod to re-entrain the biological rhythm of SCN to 24 h. MRGC: melanopsin-containing retinal ganglion cells; RHT: retino-hypothalamic tract; SCN: suprachasmatic nucleus; PVN: paraventricular nucleus; IMCC: Intermediolateral cell column; SCG: sympathetic cervical ganglion; PG: pineal gland. Mel: melatonin.
Figure 1 Illustration of the SCN-melatonin loop. Solid arrows indicate the neuronal connections and the direction of neuronal projections. Dash arrows indicate the input signals. SCN is the master clock which determines the biological rhythms as well as the melatonin circadian rhythm. Its intrinsic circadian interval is longer than 24 h. The natural photoperiod (photos) serves as an input signal to entrain melatonin circadian rhythm to 24 h; in turn, melatonin functions as a signal of photoperiod to re-entrain the biological rhythm of SCN to 24 h. MRGC: melanopsin-containing retinal ganglion cells; RHT: retino-hypothalamic tract; SCN: suprachasmatic nucleus; PVN: paraventricular nucleus; IMCC: Intermediolateral cell column; SCG: sympathetic cervical ganglion; PG: pineal gland. Mel: melatonin.CC BY · PubMed Central
Figure 2 The different levels and shapes of melatonin circadian rhythms in the CSF of the third ventricle and in the peripheral blood. The nightly melatonin levels in CSF of the third ventricle are more robust than those in the peripheral plasma and also exhibit sharp rises and falls (square wave). The pattern of the melatonin circadian rhythm in CSF of the third ventricle is similar to that of the pineal gland rather than in the plasma (see the insert part which illustrates the melatonin synthetic pattern in pineal gland of rat). The data was obtained from the long term (5 days) pineal gland dialysis in a free running rat. Extrapineal-generated melatonin and the diet-derived melatonin may increase peripheral plasma melatonin levels; however, they do not mimic the pattern and reach the high level of the melatonin circadian rhythm in the CSF of the third ventricle to impact the function of bio-clock. From Tan et al. [63].
Figure 2 The different levels and shapes of melatonin circadian rhythms in the CSF of the third ventricle and in the peripheral blood. The nightly melatonin levels in CSF of the third ventricle are more robust than those in the peripheral plasma and also exhibit sharp rises and falls (square wave). The pattern of the melatonin circadian rhythm in CSF of the third ventricle is similar to that of the pineal gland rather than in the plasma (see the insert part which illustrates the melatonin synthetic pattern in pineal gland of rat). The data was obtained from the long term (5 days) pineal gland dialysis in a free running rat. Extrapineal-generated melatonin and the diet-derived melatonin may increase peripheral plasma melatonin levels; however, they do not mimic the pattern and reach the high level of the melatonin circadian rhythm in the CSF of the third ventricle to impact the function of bio-clock. From Tan et al. [63].CC BY · PubMed Central
Figure 3 The laminated pineal gland calcification at different ages and their similarity to the osteons of compact bone. (A) Pineal calcification in 14 year old subject; (B) 47 year old; (C) 62 year old; (D) osteons; (A–C) were modified from Hermann et al. [239].
Figure 3 The laminated pineal gland calcification at different ages and their similarity to the osteons of compact bone. (A) Pineal calcification in 14 year old subject; (B) 47 year old; (C) 62 year old; (D) osteons; (A–C) were modified from Hermann et al. [239].CC BY · PubMed Central
Figure 4 The proposed mechanisms underlying melatonin’s actions on bone formation. (A) melatonin induces MSCs differentiation into osteoblasts via MT2; (B) it promotes osteoprotegerin (OPG) expression in preosteoblasts which would inactive RANKL, leading to a suppression of osteoclastogenesis; and (C) through melatonin’s free-radical scavenging and antioxidant properties, protecting against radical induced loss of osteoblasts and osteoclasts. PTH (parathyroid hormone); Type I col (type I collagen); OSP (osteopontin); BMP-2 (bone morphogenetic protein 2); ALP (alkaline phosphatase); OCN (osteocalcin); TRAP (tartrate-resistant acid phosphatase); RANKL (receptor activator of NFĸB ligand); OPG (osteoprotegerin). From Maria and Witt-Enderby [262].
Figure 4 The proposed mechanisms underlying melatonin’s actions on bone formation. (A) melatonin induces MSCs differentiation into osteoblasts via MT2; (B) it promotes osteoprotegerin (OPG) expression in preosteoblasts which would inactive RANKL, leading to a suppression of osteoclastogenesis; and (C) through melatonin’s free-radical scavenging and antioxidant properties, protecting against radical induced loss of osteoblasts and osteoclasts. PTH (parathyroid hormone); Type I col (type I collagen); OSP (osteopontin); BMP-2 (bone morphogenetic protein 2); ALP (alkaline phosphatase); OCN (osteocalcin); TRAP (tartrate-resistant acid phosphatase); RANKL (receptor activator of NFĸB ligand); OPG (osteoprotegerin). From Maria and Witt-Enderby [262].CC BY · PubMed Central
Figure 5 Histology and ultrastructure of cells located in a concretion of the turkey pineal gland. (A) mature concretions identified with Mallory’s stain. Two types of cells are present in the concretion (semi-thin section stained with toluidine blue); (B) polygonal cells; (C) elongated cells; (D) The presence of calcium in the concretions was demonstrated with Alizarin red S; note the characteristic appearance of cells located in the concretion; (E) ultrastructure of cells located in the calcified area (fixation with the PPA method). 1: the osteocyte-like cell surrounded by mineralized collagen fibrils in the central part of the calcification area. Note the “halo” around the cell and large pyroantimonate precipitate located mainly outside the cell membrane, 2: the junction of processes of osteocyte-like cells, 3: a cell showing a fibrocyte-like appearance in the peripheral part of the calcification area. Note the extra-cellular matrix containing collagen and calcium deposits, 4: numerous calcium precipitates in the intercellular spaces in the peripheral part of the calcification area, 5: The cell process with scattered deposits in the middle part of the concretion. Note the adjacent extra-cellular matrix rich in collagen and pyroantimonate precipitates. Modified from Przybylska-Gornowicz et al. [159].
Figure 5 Histology and ultrastructure of cells located in a concretion of the turkey pineal gland. (A) mature concretions identified with Mallory’s stain. Two types of cells are present in the concretion (semi-thin section stained with toluidine blue); (B) polygonal cells; (C) elongated cells; (D) The presence of calcium in the concretions was demonstrated with Alizarin red S; note the characteristic appearance of cells located in the concretion; (E) ultrastructure of cells located in the calcified area (fixation with the PPA method). 1: the osteocyte-like cell surrounded by mineralized collagen fibrils in the central part of the calcification area. Note the “halo” around the cell and large pyroantimonate precipitate located mainly outside the cell membrane, 2: the junction of processes of osteocyte-like cells, 3: a cell showing a fibrocyte-like appearance in the peripheral part of the calcification area. Note the extra-cellular matrix containing collagen and calcium deposits, 4: numerous calcium precipitates in the intercellular spaces in the peripheral part of the calcification area, 5: The cell process with scattered deposits in the middle part of the concretion. Note the adjacent extra-cellular matrix rich in collagen and pyroantimonate precipitates. Modified from Przybylska-Gornowicz et al. [159].CC BY · PubMed Central

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Citations

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3 retracted

Show all 305 references

Research works printed but not linked: 4

  1. Commentz, 1986, Pineal calcification does not affect melatonin production, J. Neural Transm. Suppl., 21, 481
  2. Welsh, 1985, Pineal calcification: Structural and functional aspects, Pineal Res. Rev., 3, 41
  3. Welsh, 1977, Effects of superior cervical gangalinectomy, constant light and bliding on the gerbil pineal gland: An ultrastructural analysis, Anat. Rec., 187, 746
  4. Krstic, 1976, Human pineal acervuli: Ultrastructural and X-ray energy dispensive microprobe analysis, Experientia, 32, 800

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Metadata

Authors
Tan, D., Xu, B., Zhou, X., & Reiter, R.
Affiliations
The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Tan, Dun
  • Reiter, Russel
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2018-01-31
Volume
23
Issue
2
Pages
301
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules23020301
PMC
PMC6017004
OpenAlex
W2790796192
Cited by
220
References
305
Citations by year
2026: 17 · 2025: 30 · 2024: 30 · 2023: 33 · 2022: 30 · 2021: 32 · 2020: 24 · 2019: 19 · 2018: 5
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Keywords
pineal gland calcification, melatonin, pineal gland, aging, neuroprotection, antioxidant signaling, photoperiod, mesenchymal stem cells, neuronal diseases
MeSH terms
Aging, Animals, Calcinosis, Humans, Melatonin, Pineal Gland, Rejuvenation

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