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Special Issue "Melatonin and Its Analogues: Experimental and Clinical Aspects"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (31 March 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Russel J. Reiter

Department of Cellular & Structural Biology, The UT Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA
Website | E-Mail
Interests: melatonin; free radicals of disease processes and aging; oxygen derivatives

Special Issue Information

Dear Colleagues,

Melatonin, an ancient molecule that is present throughout the plant and animal kingdoms, has an uncommonly wide variety of receptor-mediated and receptor-independent functions. Discovered in, and initially thought to be only produced by, the pineal gland, melatonin synthesis was found to be produced in a host of vertebrate organs, in invertebrates, in unicells and in plants, none of which has a pineal gland. In vertebrates, melatonin is synthesized in a large number of organs, including but not limited to, the retinas, gastrointestinal tract, ovary including the oocyte, etc. It has been speculated that every cell, plant and animal, may produce melatonin in their mitochondria and, in green plants, in chloroplasts. Melatonin membrane receptors, designated MT1 and MT2, are widely distributed in eukaryotic cells. Additionally, melatonin-binding sites (ROR and RZR orphan nuclear receptors) also exist in the nucleus and in the cytosol, for example quinone reductase and calmodulin. Via its receptors and as a consequence of its receptor-independent actions as a free-radical scavenger, melatonin has an uncommonly large array of functions. While perhaps best known for its effects in circadian rhythms, which includes sleep, melatonin has other actions including cancer inhibition, immune stimulation, oocyte maturation, regulation of seasonal reproduction in photosensitive mammals, limiting neurodegenerative diseases (Alzheimer, Parkinson, amyotrophic lateral sclerosis, etc.), reducing the toxicity of prescription drugs and drugs of abuse, and protecting against heavy metal toxicity and environmental pollutants. In both plants and animals melatonin is a powerful radical scavenger and, in plants, melatonin also modulates seed germination and growth. Melatonin analogues have been developed and are advanced especially for use to overcome sleep disorders and depression. Clinically, melatonin is being tested as a treatment for osteoporosis, poor oocyte quality, pre-eclampsia, heart damage due to ischemia, etc. Papers related to any aspect of melatonin physiology, biochemistry and molecular biology, as well as clinical reports, will be considered for this Special Issue.

Prof. Dr. Russel J. Reiter


Guest Editor

Manuscript Submission Information

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Keywords

  • animal
  • plant
  • neurodegeneration
  • stroke
  • stem cells
  • ischemia/reperfusion
  • chloroplasts; proteomics
  • enzyme regulation
  • photosynthesis
  • apoptosis
  • oxidative stress
  • free radicals

Published Papers (35 papers)

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Open AccessArticle Single Administration of Melatonin Modulates the Nitroxidergic System at the Peripheral Level and Reduces Thermal Nociceptive Hypersensitivity in Neuropathic Rats
Int. J. Mol. Sci. 2017, 18(10), 2143; https://doi.org/10.3390/ijms18102143
Received: 15 September 2017 / Revised: 5 October 2017 / Accepted: 12 October 2017 / Published: 14 October 2017
Cited by 2 | PDF Full-text (2717 KB) | HTML Full-text | XML Full-text
Abstract
Neuropathic pain is a severe condition with unsatisfactory treatments. Melatonin, an indolamine, seems to be a promising molecule suitable for this purpose due to its well-known anti-inflammatory, analgesic, and antioxidant effects, as well as its modulation of the nitroxidergic system. Nevertheless, the data
[...] Read more.
Neuropathic pain is a severe condition with unsatisfactory treatments. Melatonin, an indolamine, seems to be a promising molecule suitable for this purpose due to its well-known anti-inflammatory, analgesic, and antioxidant effects, as well as its modulation of the nitroxidergic system. Nevertheless, the data on its mechanism of action and potentialities are currently insufficient in this pathology, especially at the peripheral level. Thus, this work evaluated the effect of a single administration of melatonin in an established mononeuropathy pain model that monitors the behaviour and the changes in the nitroxidergic system in dorsal root ganglia and skin, which are affected by nervous impairment. Experiments were carried out on Sprague Dawley rats subdivided into the sham operated (control) and the chronic constriction injured animals, a model of peripheral neuropathic pain on sciatic nerve. Single administrations of melatonin (5–10 mg/kg) or vehicle were injected intraperitoneally on the 14th day after surgery, when the mononeuropathy was established. The animals were behaviourally tested for thermal hyperalgesia. The dorsal root ganglia and the plantar skin of the hind-paws were removed and processed for the immunohistochemical detection of neuronal and inducible nitric oxide synthases. The behavioural results showed an increase of withdrawal latency during the plantar test as early as 30 min after melatonin administration. The immunohistochemical results indicated a modulation of the nitroxidergic system both at dorsal root ganglia and skin level, permitting speculate on a possible mechanism of action. We showed that melatonin may be a possible therapeutic strategy in neuropathic pain. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Comparative In Vitro Controlled Release Studies on the Chronobiotic Hormone Melatonin from Cyclodextrins-Containing Matrices and Cyclodextrin: Melatonin Complexes
Int. J. Mol. Sci. 2017, 18(8), 1641; https://doi.org/10.3390/ijms18081641
Received: 29 June 2017 / Revised: 24 July 2017 / Accepted: 25 July 2017 / Published: 28 July 2017
Cited by 4 | PDF Full-text (3112 KB) | HTML Full-text | XML Full-text
Abstract
A series of hydrophilic matrix tablets was prepared and tested with respect to their ability to release the hormone melatonin in a controlled manner, in order to alleviate sleep onset and sleep maintenance dysfunctions. Besides the active ingredient, the tablets were comprised of
[...] Read more.
A series of hydrophilic matrix tablets was prepared and tested with respect to their ability to release the hormone melatonin in a controlled manner, in order to alleviate sleep onset and sleep maintenance dysfunctions. Besides the active ingredient, the tablets were comprised of combinations of the following: HPMC K 15M, low viscosity sodium alginate, microcrystalline cellulose (Avicel PH 102), magnesium stearate, and the cyclodextrins, α-CD, β-CD, γ-CD, HP-β-CD, sulfated β-CD, HP-α-CD and HP-γ-CD, and MLT (guest):CD (host) complexes of the above cyclodextrins, in 1:1 ratio. The controlled release studies were conducted in two aqueous dissolution media at pH 1.2 and 7.4. The stoichiometry of the formed complexes was examined by applying the continuous variation method (Job plot), while the stability constants were calculated by monitoring the spectrophotometric properties of free and CD-encapsulated melatonin (UV-Vis). Host-guest interactions were studied by Nuclear Magnetic Resonance (NMR) spectroscopy. The dissolution data suggest that melatonin is released faster from the MLT:CD complexes than from the rest matrix systems. This enhancement in the dissolution rate and the % release of melatonin from the complexes is due to the increased solubility of the MLT:CD complexes. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Effects of Melatonin on Early Pregnancy in Mouse: Involving the Regulation of StAR, Cyp11a1, and Ihh Expression
Int. J. Mol. Sci. 2017, 18(8), 1637; https://doi.org/10.3390/ijms18081637
Received: 3 April 2017 / Revised: 18 July 2017 / Accepted: 21 July 2017 / Published: 27 July 2017
Cited by 1 | PDF Full-text (5916 KB) | HTML Full-text | XML Full-text
Abstract
To test whether melatonin plays an important role in the process of early pregnancy, melatonin was given in drinking water to pregnant mice at different gestation stages. These included mice who were given melatonin 14 days prior to their successful mating (confirmed by
[...] Read more.
To test whether melatonin plays an important role in the process of early pregnancy, melatonin was given in drinking water to pregnant mice at different gestation stages. These included mice who were given melatonin 14 days prior to their successful mating (confirmed by vaginal plug) (Group A), after successful mating (Group B), and 14 days prior to and until after successful mating (Group C). Melatonin administration significantly enhanced serum as well as ovarian melatonin levels in the mice. It was observed that melatonin did not affect the natural estrous of mice. On day 0.5 of gestation (D0.5), melatonin not only elevated progesterone (P) secretion, but also upregulated expressions of StAR and Cyp11a1, the two marker genes of corpus luteum in ovaries (p < 0.05). Group A had a significantly lower estradiol (E2) secretion and a higher number of implantation sites as well as litter size than controls (p < 0.05) and also had an increased Ihh expression in endometrium of D7.5 gestation. Melatonin treatment after successful mating improved the progesterone (P) secretion at D7.5 of gestation (p < 0.05) and significantly induced leukaemia inhibitory factor (LIF) expression (p < 0.05). Our study indicates that melatonin treatment up-regulated the genes involved in pregnenolone synthesis in ovary and Ihh expression in uterine endometrium. The mechanisms of melatonin to improve embryo implantation related to their actions on promoting the development of corpus luteum before gestation and helping to specify uterine receptivity in early pregnant mice. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Decreases Glucose Metabolism in Prostate Cancer Cells: A 13C Stable Isotope-Resolved Metabolomic Study
Int. J. Mol. Sci. 2017, 18(8), 1620; https://doi.org/10.3390/ijms18081620
Received: 2 July 2017 / Revised: 18 July 2017 / Accepted: 20 July 2017 / Published: 26 July 2017
Cited by 1 | PDF Full-text (4769 KB) | HTML Full-text | XML Full-text
Abstract
The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative
[...] Read more.
The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative glucose transporters (GLUT/SLC2A) was proposed in prostate cancer cells. The prostate cells have a particular metabolism that changes during tumor progression. During the first steps of carcinogenesis, oxidative phosphorylation is reactivated while the switch to the “Warburg effect” only occurs in advanced tumors and in the metastatic stage. Here, we investigated whether melatonin might change prostate cancer cell metabolism. To do so, 13C stable isotope-resolved metabolomics in androgen sensitive LNCaP and insensitive PC-3 prostate cancer cells were employed. In addition to metabolite 13C-labeling, ATP/AMP levels, and lactate dehydrogenase or pentose phosphate pathway activity were measured. Melatonin reduces lactate labeling in androgen-sensitive cells and it also lowers 13C-labeling of tricarboxylic acid cycle metabolites and ATP production. In addition, melatonin reduces lactate 13C-labeling in androgen insensitive prostate cancer cells. Results demonstrated that melatonin limits glycolysis as well as the tricarboxylic acid cycle and pentose phosphate pathway in prostate cancer cells, suggesting that the reduction of glucose uptake is a major target of the indole in this tumor type. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril
Int. J. Mol. Sci. 2017, 18(8), 1612; https://doi.org/10.3390/ijms18081612
Received: 26 May 2017 / Revised: 10 July 2017 / Accepted: 13 July 2017 / Published: 25 July 2017
Cited by 2 | PDF Full-text (2451 KB) | HTML Full-text | XML Full-text
Abstract
Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or
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Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle The Impact of Melatonin on Colon Cancer Cells’ Resistance to Doxorubicin in an in Vitro Study
Int. J. Mol. Sci. 2017, 18(7), 1396; https://doi.org/10.3390/ijms18071396
Received: 31 March 2017 / Revised: 18 May 2017 / Accepted: 23 June 2017 / Published: 29 June 2017
Cited by 4 | PDF Full-text (4499 KB) | HTML Full-text | XML Full-text
Abstract
Multi-drug resistance (MDR) is the main cause of low effectiveness of cancer chemotherapy. P-glycoprotein (P-gp) is one of the main factors determining MDR. Some studies indicate the potential role of melatonin (MLT) in MDR. In this study, we examined the effect of MLT
[...] Read more.
Multi-drug resistance (MDR) is the main cause of low effectiveness of cancer chemotherapy. P-glycoprotein (P-gp) is one of the main factors determining MDR. Some studies indicate the potential role of melatonin (MLT) in MDR. In this study, we examined the effect of MLT on colon cancer cell’s resistance to doxorubicin (DOX). Using the sulforhodamine B (SRB), method the effect of tested substances on the survival of LoVo (colon cancer cells sensitive to DOX) and LoVoDX (colon cancer cells resistant to DOX) was rated. Using immunocytochemistry (ICC), the expression of P-gp in the LoVo and LoVoDX was determined. With the real-time PCR (RT-PCR) technique, the ABCB1 expression in LoVoDX was evaluated. Based on the results, it was found that MLT in some concentrations intensified the cytotoxicity effect of DOX in the LoVoDX cells. In the ICC studies, it was demonstrated that certain concentrations of MLT and DOX cause an increase in the percentage of cells expressing P-gp, which correlates positively with ABCB1 expression (RT-PCR). The mechanism of overcoming resistance by MLT is probably not only associated with the expression of P-gp. It seems appropriate to carry out further research on the use of MLT as the substance supporting cancer chemotherapy. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Oral Supplementation of Melatonin Protects against Fibromyalgia-Related Skeletal Muscle Alterations in Reserpine-Induced Myalgia Rats
Int. J. Mol. Sci. 2017, 18(7), 1389; https://doi.org/10.3390/ijms18071389
Received: 26 May 2017 / Revised: 19 June 2017 / Accepted: 27 June 2017 / Published: 29 June 2017
Cited by 6 | PDF Full-text (4996 KB) | HTML Full-text | XML Full-text
Abstract
Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain and an extensive array of other symptoms including disordered sleep, fatigue, depression and anxiety. Important factors involved in the pathogenic process of fibromyalgia are inflammation and oxidative stress, suggesting that ant-inflammatory and/or antioxidant
[...] Read more.
Fibromyalgia is a chronic syndrome characterized by widespread musculoskeletal pain and an extensive array of other symptoms including disordered sleep, fatigue, depression and anxiety. Important factors involved in the pathogenic process of fibromyalgia are inflammation and oxidative stress, suggesting that ant-inflammatory and/or antioxidant supplementation might be effective in the management and modulation of this syndrome. Recent evidence suggests that melatonin may be suitable for this purpose due to its well known ant-inflammatory, antioxidant and analgesic effects. Thus, in the current study, the effects of the oral supplementation of melatonin against fibromyalgia-related skeletal muscle alterations were evaluated. In detail, 90 Sprague Dawley rats were randomly treated with reserpine, to reproduce the pathogenic process of fibromyalgia and thereafter they received melatonin. The animals treated with reserpine showed moderate alterations at hind limb skeletal muscles level and had difficulty in moving, together with significant morphological and ultrastructural alterations and expression of inflammatory and oxidative stress markers in the gastrocnemius muscle. Interestingly, melatonin, dose and/or time dependently, reduced the difficulties in spontaneous motor activity and the musculoskeletal morphostructural, inflammatory, and oxidative stress alterations. This study suggests that melatonin in vivo may be an effective tool in the management of fibromyalgia-related musculoskeletal morphofunctional damage. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle New MT2 Melatonin Receptor-Selective Ligands: Agonists and Partial Agonists
Int. J. Mol. Sci. 2017, 18(7), 1347; https://doi.org/10.3390/ijms18071347
Received: 26 March 2017 / Revised: 2 June 2017 / Accepted: 20 June 2017 / Published: 23 June 2017
Cited by 4 | PDF Full-text (2303 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The search for melatonin receptor agonists and antagonists specific towards one of the receptor subtypes will extend our understanding of the role of this system in relaying circadian information to the body. A series of compounds derived from a hit compound discovered in
[...] Read more.
The search for melatonin receptor agonists and antagonists specific towards one of the receptor subtypes will extend our understanding of the role of this system in relaying circadian information to the body. A series of compounds derived from a hit compound discovered in a screening process led to powerful agonists specific for one of the isoform of the melatonin receptor namely, MT2. The compounds are based on a poorly explored skeleton in the molecular pharmacology of melatonin. By changing the steric hindrance of one substituent (i.e., from a hydrogen atom to a tributylstannyl group), we identified a possible partial agonist that could lead to antagonist analogues. The functionalities of these compounds were measured with a series of assays, including the binding of GTPγS, the inhibition of the cyclic AMP production, the β-arrestin recruitment, and the cell shape changes as determined by cellular dielectric spectroscopy (CellKey®). The variations between the compounds are discussed. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle AA-NAT, MT1 and MT2 Correlates with Cancer Stem-Like Cell Markers in Colorectal Cancer: Study of the Influence of Stage and p53 Status of Tumors
Int. J. Mol. Sci. 2017, 18(6), 1251; https://doi.org/10.3390/ijms18061251
Received: 17 March 2017 / Revised: 5 June 2017 / Accepted: 7 June 2017 / Published: 11 June 2017
PDF Full-text (2420 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability
[...] Read more.
The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability to kill CSCs. Although there are no data linking the loss of p53 function and melatonin synthesis or signaling in cancer, melatonin does activate the p53 tumor-suppressor pathway in this disease. In this work, we analyze whether the expression of melatonin synthesis and signaling genes are related to the expression of CSC markers and the implication of p53 status in samples from patients with CRC. Arylalkylamine N-acetyltransferase (AA-NAT), MT1, and MT2 expression decreased in tumor samples versus normal mucosa samples in mutated p53 (mtp53) tumors versus those with wild-type p53 (wtp53). Further, AA-NAT and MT2 expression were lower in advanced stages of the disease in wtp53 tumors. On the contrary, CD44 and CD66c expression was higher in tumor versus normal mucosa in wtp53 tumors. Additionally, CD44 expression was higher in advanced stages of the disease regardless of the p53 status. Patients with CD44highCD66chigh and wtp53 tumors in advanced stages showed low expression of AA-NAT and MT2 in wtp53 tumors. These results could indicate a possible interaction of these pathways in CRC. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy
Int. J. Mol. Sci. 2017, 18(6), 1130; https://doi.org/10.3390/ijms18061130
Received: 28 March 2017 / Revised: 9 May 2017 / Accepted: 17 May 2017 / Published: 31 May 2017
Cited by 2 | PDF Full-text (3737 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we
[...] Read more.
A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Suppression of Osteoclastogenesis by Melatonin: A Melatonin Receptor-Independent Action
Int. J. Mol. Sci. 2017, 18(6), 1142; https://doi.org/10.3390/ijms18061142
Received: 24 March 2017 / Revised: 15 May 2017 / Accepted: 23 May 2017 / Published: 26 May 2017
Cited by 4 | PDF Full-text (1969 KB) | HTML Full-text | XML Full-text
Abstract
In vertebrates, melatonin is primarily secreted from the pineal gland but it affects various biological processes including the sleep-wake cycle, vasomotor control, immune system and bone homeostasis. Melatonin has been known to promote osteoblast differentiation and bone maturation, but a direct role of
[...] Read more.
In vertebrates, melatonin is primarily secreted from the pineal gland but it affects various biological processes including the sleep-wake cycle, vasomotor control, immune system and bone homeostasis. Melatonin has been known to promote osteoblast differentiation and bone maturation, but a direct role of melatonin on osteoclast differentiation is still elusive. The present study investigated the effect of melatonin on the differentiation of macrophages to osteoclasts. The presence of melatonin significantly reduced receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and the siRNA-mediated knockdown of the melatonin receptor failed to overcome the anti-osteoclastogenic effect of melatonin. Although melatonin treatment did not affect the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), it markedly inhibited the activation of NF-κB and subsequent induction of nuclear factor of activated T cell cytoplasmic 1(NFATc1). Thus, our results suggest that melatonin could suppress osteoclast differentiation through downregulation of NF-κB pathway with concomitant decrease in the NFATc1 transcription factor induction. Furthermore, melatonin seems to have an anti-osteoclastogenic effect independent of plasma membrane melatonin receptors. In addition to previously reported properties of melatonin, our study proposes another aspect of melatonin and bone homeostasis. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Attenuates Pulmonary Hypertension in Chronically Hypoxic Rats
Int. J. Mol. Sci. 2017, 18(6), 1125; https://doi.org/10.3390/ijms18061125
Received: 29 March 2017 / Revised: 19 May 2017 / Accepted: 19 May 2017 / Published: 24 May 2017
Cited by 4 | PDF Full-text (5680 KB) | HTML Full-text | XML Full-text
Abstract
Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We
[...] Read more.
Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We examined the hypothesis that daily administration of melatonin (10 mg/kg) mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. The right ventricular systolic pressure (RVSP) and the thickness of pulmonary arteriolar wall were measured from normoxic control, vehicle- and melatonin-treated hypoxic rats exposed to 10% O2 for 14 days. Levels of markers for oxidative stress (malondialdhyde) and inflammation (tumor necrosis factor-α (TNFα), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2)) and the expressions of total endothelial NO synthase (eNOS) and phosphorylated eNOS at serine1177 (ser1177) were determined in the lung tissue. We found that the RVSP and the thickness of the arteriolar wall were significantly increased in the vehicle-treated hypoxic animals with elevated levels of malondialdhyde and mRNA expressions of the inflammatory mediators, when compared with the normoxic control. In addition, the phosphorylated eNOS (ser1177) level was significantly decreased, despite an increased eNOS expression in the vehicle-treated hypoxic group. Melatonin treatment significantly attenuated the levels of RVSP, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the eNOS phosphorylation in the lung. These results suggest that melatonin attenuates pulmonary hypertension by antagonizing the oxidative injury and restoration of NO production. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Secretion Is Increased in Children with Severe Traumatic Brain Injury
Int. J. Mol. Sci. 2017, 18(5), 1053; https://doi.org/10.3390/ijms18051053
Received: 7 April 2017 / Revised: 9 May 2017 / Accepted: 11 May 2017 / Published: 13 May 2017
Cited by 2 | PDF Full-text (744 KB) | HTML Full-text | XML Full-text
Abstract
Background: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Oxidative stress plays a significant role in brain damage and melatonin exhibits both direct and indirect antioxidant effects. The primary aim of the present study was to evaluate
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Background: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Oxidative stress plays a significant role in brain damage and melatonin exhibits both direct and indirect antioxidant effects. The primary aim of the present study was to evaluate serum melatonin levels in children with severe TBI in comparison to critically ill children admitted to the Pediatric Intensive Care Unit for conditions other than TBI. Methods: Twenty-four children were evaluated, equally divided into severe TBI and no-TBI. Blood samples for serum melatonin analysis were collected at 22:00, 01:00, 03:00, 05:00, 08:00, and 12:00. Results: Mean serum melatonin peaks in children of the TBI group were higher compared to the values of no-TBI critically ill children (495 ± 102 vs. 294 ± 119 pg/mL, p = 0.0002). Furthermore, the difference was even more significant in comparison to values reported in literature for healthy age-matched children (495 ± 102 vs. 197 ± 71 pg/mL, p < 0.0001). Conclusion: This study has shown that endogenous serum melatonin levels dramatically increase in children after severe TBI. This elevation is likely to represent a response to oxidative stress and/or inflammation due to severe head injury. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle High Concentration of Melatonin Regulates Leaf Development by Suppressing Cell Proliferation and Endoreduplication in Arabidopsis
Int. J. Mol. Sci. 2017, 18(5), 991; https://doi.org/10.3390/ijms18050991
Received: 27 March 2017 / Revised: 22 April 2017 / Accepted: 2 May 2017 / Published: 5 May 2017
Cited by 3 | PDF Full-text (3994 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
N-acetyl-5-methoxytryptamine (Melatonin), as a crucial messenger in plants, functions in adjusting biological rhythms, stress tolerance, plant growth and development. Several studies have shown the retardation effect of exogenous melatonin treatment on plant growth and development. However, the in vivo role of melatonin
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N-acetyl-5-methoxytryptamine (Melatonin), as a crucial messenger in plants, functions in adjusting biological rhythms, stress tolerance, plant growth and development. Several studies have shown the retardation effect of exogenous melatonin treatment on plant growth and development. However, the in vivo role of melatonin in regulating plant leaf growth and the underlying mechanism are still unclear. In this study, we found that high concentration of melatonin suppressed leaf growth in Arabidopsis by reducing both cell size and cell number. Further kinetic analysis of the fifth leaves showed that melatonin remarkably inhibited cell division rate. Additionally, flow cytometic analysis indicated that melatonin negatively regulated endoreduplication during leaf development. Consistently, the expression analysis revealed that melatonin regulated the transcriptional levels of key genes of cell cycle and ribosome. Taken together, this study suggests that high concentration of melatonin negatively regulated the leaf growth and development in Arabidopsis, through modulation of endoreduplication and the transcripts of cell cycle and ribosomal key genes. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Promotes the In Vitro Development of Microinjected Pronuclear Mouse Embryos via Its Anti-Oxidative and Anti-Apoptotic Effects
Int. J. Mol. Sci. 2017, 18(5), 988; https://doi.org/10.3390/ijms18050988
Received: 31 March 2017 / Revised: 27 April 2017 / Accepted: 2 May 2017 / Published: 5 May 2017
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Abstract
CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats) combined with pronuclear microinjection has become the most effective method for producing transgenic animals. However, the relatively low embryo developmental rate limits its application. In the current study, it was observed that 10−7 M melatonin
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CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats) combined with pronuclear microinjection has become the most effective method for producing transgenic animals. However, the relatively low embryo developmental rate limits its application. In the current study, it was observed that 10−7 M melatonin is considered an optimum concentration and significantly promoted the in vitro development of murine microinjected pronuclear embryos, as indicated by the increased blastocyst rate, hatching blastocyst rate and blastocyst cell number. When these blastocysts were implanted into recipient mice, the pregnancy rate and birth rate were significantly higher than those of the microinjected control, respectively. Mechanistic studies revealed that melatonin treatment reduced reactive oxygen species (ROS) production and cellular apoptosis during in vitro embryo development and improved the quality of the blastocysts. The implantation of quality-improved blastocysts led to elevated pregnancy and birth rates. In conclusion, the results revealed that the anti-oxidative and anti-apoptotic activities of melatonin improved the quality of microinjected pronuclear embryos and subsequently increased both the efficiency of embryo implantation and the birth rate of the pups. Therefore, the melatonin supplementation may provide a novel alternative method for generating large numbers of transgenic mice and this method can probably be used in human-assisted reproduction and genome editing. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin and Vitamin D Interfere with the Adipogenic Fate of Adipose-Derived Stem Cells
Int. J. Mol. Sci. 2017, 18(5), 981; https://doi.org/10.3390/ijms18050981
Received: 7 April 2017 / Revised: 28 April 2017 / Accepted: 2 May 2017 / Published: 5 May 2017
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Abstract
Adipose-derived stem cells (ADSCs) represent one of the cellular populations resident in adipose tissue. They can be recruited under certain stimuli and committed to become preadipocytes, and then mature adipocytes. Controlling stem cell differentiation towards the adipogenic phenotype could have a great impact
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Adipose-derived stem cells (ADSCs) represent one of the cellular populations resident in adipose tissue. They can be recruited under certain stimuli and committed to become preadipocytes, and then mature adipocytes. Controlling stem cell differentiation towards the adipogenic phenotype could have a great impact on future drug development aimed at counteracting fat depots. Stem cell commitment can be influenced by different molecules, such as melatonin, which we have previously shown to be an osteogenic inducer. Here, we aimed at evaluating the effects elicited by melatonin, even in the presence of vitamin D, on ADSC adipogenesis assessed in a specific medium. The transcription of specific adipogenesis orchestrating genes, such as aP2, peroxisome proliferator-activated receptor γ (PPAR-γ), and that of adipocyte-specific genes, including lipoprotein lipase (LPL) and acyl-CoA thioesterase 2 (ACOT2), was significantly inhibited in cells that had been treated in the presence of melatonin and vitamin D, alone or in combination. Protein content and lipid accumulation confirmed a reduction in adipogenesis in ADSCs that had been grown in adipogenic conditions, but in the presence of melatonin and/or vitamin D. Our findings indicate the role of melatonin and vitamin D in deciding stem cell fate, and disclose novel therapeutic approaches against fat depots. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Beneficial Effects of Melatonin on the In Vitro Maturation of Sheep Oocytes and Its Relation to Melatonin Receptors
Int. J. Mol. Sci. 2017, 18(4), 834; https://doi.org/10.3390/ijms18040834
Received: 6 March 2017 / Revised: 31 March 2017 / Accepted: 7 April 2017 / Published: 17 April 2017
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Abstract
(1) Background: The binding sites of melatonin, as a multifunctional molecule, have been identified in human, porcine, and bovine samples. However, the binding sites and mechanisms of melatonin have not been reported in sheep; (2) Methods: Cumulus–oocyte complexes (COCs) were cultured in TCM-199
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(1) Background: The binding sites of melatonin, as a multifunctional molecule, have been identified in human, porcine, and bovine samples. However, the binding sites and mechanisms of melatonin have not been reported in sheep; (2) Methods: Cumulus–oocyte complexes (COCs) were cultured in TCM-199 supplemented with melatonin at concentrations of 0, 10−3, 10−5, 10−7, 10−9, and 10−11 M. Melatonin receptors (MT1 and MT2) were evaluated via immunofluorescence and Western blot. The effects of melatonin on cumulus cell expansion, nuclear maturation, embryo development, and related gene (GDF9, DNMT1, PTX3, HAS2, and EGFR) expression were investigated. The level of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were evaluated in oocytes and cumulus, respectively; (3) Results: Both MT1 and MT2 were expressed in oocytes, cumulus cells, and granulosa cells. Melatonin with a concentration of 10−7 M significantly enhanced the rates of nuclear maturation, cumulus cells expansion, cleavage, and blastocyst. Melatonin enhanced the expression of BMP15 in oocytes and of PTX3, HAS2, and EGFR in cumulus cells. Melatonin decreased the cAMP level of oocytes but enhanced the cGMP level in oocytes and cumulus cells; (4) Conclusion: The higher presence of MT1 in GV cumulus cells and the beneficial effects of melatonin indicated that its roles in regulating sheep oocyte maturation may be mediated mainly by the MT1 receptor. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Behavior of Human Osteoblast Cells Cultured on Titanium Discs in Relation to Surface Roughness and Presence of Melatonin
Int. J. Mol. Sci. 2017, 18(4), 823; https://doi.org/10.3390/ijms18040823
Received: 5 March 2017 / Revised: 4 April 2017 / Accepted: 8 April 2017 / Published: 13 April 2017
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Abstract
The aim of this work was to observe the behavior of osteoblast cells cultured in vitro on titanium discs in relation to disc surface roughness and the addition of melatonin to the culture medium. MG63 osteoblast cells were cultivated on 120 Grade 5
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The aim of this work was to observe the behavior of osteoblast cells cultured in vitro on titanium discs in relation to disc surface roughness and the addition of melatonin to the culture medium. MG63 osteoblast cells were cultivated on 120 Grade 5 Ti divided into three groups: Group E, treated with dual acid etch; Group EP, treated with dual acid etch and calcium phosphate; and Group M, machined. Surface roughness was examined under a laser scanning confocal microscope (CLSM) and scanning electron microscopy (SEM). The proliferation and morphology of cells were determined under fluorescence microscopy and SEM. Messenger ribonucleic acid (mRNA) of different genes related to osteoblastic differentiation was quantified by means of real-time quantitative polymerase chain reaction (RT-PCR) assay. The greatest surface roughness was found in Group EP (Ra 0.354 µm), followed by Group E (Ra 0.266 µm), and Group M (Ra 0.131 µm), with statistically significant differences between the groups (p < 0.001). In the presence of melatonin a trend to a higher cell proliferation was observed in all groups although significant differences were only found in Group M (p = 0.0079). Among the genes studied, a significant increase in phosphate-regulating neutral endopeptidase, X-linked (PHEX) expression was observed in cells cultured on EP discs. The addition of melatonin increased osteoblast cell proliferation and differentiation, and may favor the osseointegration of dental implants. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats
Int. J. Mol. Sci. 2017, 18(4), 763; https://doi.org/10.3390/ijms18040763
Received: 3 March 2017 / Revised: 24 March 2017 / Accepted: 30 March 2017 / Published: 11 April 2017
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Abstract
Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role
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Angiogenesis is a hallmark of ovarian cancer (OC); the ingrowth of blood vessels promotes rapid cell growth and the associated metastasis. Melatonin is a well-characterized indoleamine that possesses important anti-angiogenic properties in a set of aggressive solid tumors. Herein, we evaluated the role of melatonin therapy on the angiogenic signaling pathway in OC of an ethanol-preferring rat model that mimics the same pathophysiological conditions occurring in women. OC was chemically induced with a single injection of 7,12-dimethylbenz(a)anthracene (DMBA) under the ovarian bursa. After the rats developed serous papillary OC, half of the animals received intraperitoneal injections of melatonin (200 µg/100 g body weight/day) for 60 days. Melatonin-treated animals showed a significant reduction in OC size and microvessel density. Serum levels of melatonin were higher following therapy, and the expression of its receptor MT1 was significantly increased in OC-bearing rats, regardless of ethanol intake. TGFβ1, a transforming growth factor-beta1, was reduced only after melatonin treatment. Importantly, vascular endothelial growth factor (VEGF) was severely reduced after melatonin therapy in animals given or not given ethanol. Conversely, the levels of VEGF receptor 1 (VEGFR1) was diminished after ethanol consumption, regardless of melatonin therapy, and VEGFR2 was only reduced following melatonin. Hypoxia-inducible factor (HIF)-1α was augmented with ethanol consumption, and, notably, melatonin significantly reduced their levels. Collectively, our results suggest that melatonin attenuates angiogenesis in OC in an animal model of ethanol consumption; this provides a possible complementary therapeutic opportunity for concurrent OC chemotherapy. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin Pharmacological Blood Levels Increase Total Antioxidant Capacity in Critically Ill Patients
Int. J. Mol. Sci. 2017, 18(4), 759; https://doi.org/10.3390/ijms18040759
Received: 21 February 2017 / Revised: 22 March 2017 / Accepted: 30 March 2017 / Published: 3 April 2017
Cited by 5 | PDF Full-text (3839 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this study, the aim was to test the biochemical effects of melatonin supplementation in Intensive Care Unit (ICU) patients, since their blood levels are decreased. Sixty-four patients were enrolled in the study. From the evening of the 3rd ICU day, patients were
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In this study, the aim was to test the biochemical effects of melatonin supplementation in Intensive Care Unit (ICU) patients, since their blood levels are decreased. Sixty-four patients were enrolled in the study. From the evening of the 3rd ICU day, patients were randomized to receive oral melatonin (3 mg, group M) or placebo (group P) twice daily, at 20:00 and 24:00, until discharged. Blood was taken (at 00:00 and 14:00), on the 3rd ICU day to assess basal nocturnal melatonin values, and then during the treatment period on the 4th and 8th ICU days. Melatonin, total antioxidant capacity, and oxidative stress were evaluated in serum. Melatonin circadian rhythm before treatment was similar in the two groups, with a partial preservation of the cycle. Four hours from the 1st administration (4th ICU day, 00:00), melatonin levels increased to 2514 (982.3; 7148) pg·mL−1 in group M vs. 20.3 (14.7; 62.3) pg·mL−1 in group P (p < 0.001). After five treatment days (8th ICU day), melatonin absorption showed a repetitive trend in group M, while in group P nocturnal secretion (00:00) was impaired: 20 (11.5; 34.5) pg·mL−1 vs. 33.8 (25.0; 62.2) on the 3rd day (p = 0.029). Immediately from the beginning of treatment, the total antioxidant capacity was significantly higher in melatonin treated subjects at 00:00; a significant correlation was found between total antioxidant capacity and blood melatonin values (ρ = 0.328; p < 0.001). The proposed enteral administration protocol was adequate, even in the early phase, to enhance melatonin blood levels and to protect the patients from oxidative stress. The antioxidant effect of melatonin could play a meaningful role in the care and well-being of these patients. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle TRPV4 Stimulation Induced Melatonin Secretion by Increasing Arylalkymine N-acetyltransferase (AANAT) Protein Level
Int. J. Mol. Sci. 2017, 18(4), 746; https://doi.org/10.3390/ijms18040746
Received: 5 March 2017 / Revised: 21 March 2017 / Accepted: 27 March 2017 / Published: 1 April 2017
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Abstract
Melatonin is a molecule which has gained a great deal of interest in many areas of science; its synthesis was classically known to be in the pineal gland. However, many organs synthesize melatonin, such as several ocular structures. Melatonin is known to participate
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Melatonin is a molecule which has gained a great deal of interest in many areas of science; its synthesis was classically known to be in the pineal gland. However, many organs synthesize melatonin, such as several ocular structures. Melatonin is known to participate in many functions apart from its main action regulating the circadian rhythm. It is synthesized from serotonin in two steps, with a rate-limiting step carried out by arylalkymine N-acetyltransferase (AANAT). In this report, the role of TRPV4 channel present in human ciliary body epithelial cells in AANAT production was studied. Several experiments were undertaken to verify the adequate time to reach the maximal effect by using the TRPV4 agonist GSK1016790A, together with a dose–response study. An increase of 2.4 folds in AANAT was seen after 18 h of incubation with 10 nM of GSK1016790A (p < 0.001, n = 6). This increment was verified by antagonist assays. In summary, AANAT levels and therefore melatonin synthesis change after TRPV4 channel stimulation. Using this cell model together with human ciliary body tissue it is possible to suggest that AANAT plays an important role in pathologies related to intraocular pressure. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle Melatonin MT1 and MT2 Receptors in the Ram Reproductive Tract
Int. J. Mol. Sci. 2017, 18(3), 662; https://doi.org/10.3390/ijms18030662
Received: 21 February 2017 / Revised: 10 March 2017 / Accepted: 15 March 2017 / Published: 19 March 2017
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Abstract
Some melatonin functions in mammals are exerted through MT1 and MT2 receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis,
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Some melatonin functions in mammals are exerted through MT1 and MT2 receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, accessory glands and ductus deferens. Real-time polymerase chain reaction (qPCR) revealed higher levels of m-RNA for both receptors in the testis, ampulla, seminal vesicles, and vas deferens, than in the other organs of the reproductive tract (p < 0.05). Western blot analyses showed protein bands compatible with the MT1 in the testis and cauda epididymis, and for the MT2 in the cauda epididymis and deferent duct. Immunohistochemistry analyses revealed the presence of MT1 receptors in spermatogonias, spermatocytes, and spermatids, and MT2 receptors in the newly-formed spermatozoa in the testis, whereas both receptors were located in the epithelial cells of the ampulla, seminal vesicles, and ductus deferens. Indirect immunofluorescence showed significant differences in the immunolocation of both receptors in spermatozoa during their transit in the epididymis. In conclusion, it was demonstrated that melatonin receptors are present in the ram reproductive tract. These results open the way for new studies on the molecular mechanism of melatonin and the biological significance of its receptors. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessArticle The Role of the Melatoninergic System in Light-Entrained Behavior of Mice
Int. J. Mol. Sci. 2017, 18(3), 530; https://doi.org/10.3390/ijms18030530
Received: 20 January 2017 / Revised: 16 February 2017 / Accepted: 26 February 2017 / Published: 1 March 2017
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Abstract
The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do
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The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans
Int. J. Mol. Sci. 2017, 18(6), 1314; https://doi.org/10.3390/ijms18061314
Received: 12 March 2017 / Revised: 20 May 2017 / Accepted: 5 June 2017 / Published: 20 June 2017
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Abstract
Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety
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Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin Scavenger Properties against Oxidative and Nitrosative Stress: Impact on Gamete Handling and In Vitro Embryo Production in Humans and Other Mammals
Int. J. Mol. Sci. 2017, 18(6), 1119; https://doi.org/10.3390/ijms18061119
Received: 24 March 2017 / Revised: 19 May 2017 / Accepted: 21 May 2017 / Published: 14 June 2017
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Abstract
Oxidative and nitrosative stress are common problems when handling gametes in vitro. In vitro development in mammalian embryos is highly affected by culture conditions, especially by reactive oxygen species (ROS) and reactive nitrogen species (RNS), because their absence or overproduction causes embryo arrest
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Oxidative and nitrosative stress are common problems when handling gametes in vitro. In vitro development in mammalian embryos is highly affected by culture conditions, especially by reactive oxygen species (ROS) and reactive nitrogen species (RNS), because their absence or overproduction causes embryo arrest and changes in gene expression. Melatonin in gamete co-incubation during in vitro fertilization (IVF) has deleterious or positive effects, depending on the concentration used in the culture medium, demonstrating the delicate balance between antioxidant and pro-oxidant activity. Further research is needed to better understand the possible impact of melatonin on the different IVP steps in humans and other mammals, especially in seasonal breeds where this neuro-hormone system highly regulates its reproduction physiology. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy
Int. J. Mol. Sci. 2017, 18(6), 1221; https://doi.org/10.3390/ijms18061221
Received: 29 March 2017 / Revised: 2 June 2017 / Accepted: 5 June 2017 / Published: 7 June 2017
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Abstract
Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian
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Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Local Actions of Melatonin in Somatic Cells of the Testis
Int. J. Mol. Sci. 2017, 18(6), 1170; https://doi.org/10.3390/ijms18061170
Received: 23 February 2017 / Revised: 18 May 2017 / Accepted: 18 May 2017 / Published: 31 May 2017
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Abstract
The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin
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The pineal hormone melatonin regulates testicular function through the hypothalamic-adenohypophyseal axis. In addition, direct actions of melatonin in somatic cells of the testis have been described. Melatonin acts as a local modulator of the endocrine activity in Leydig cells. In Sertoli cells, melatonin influences cellular growth, proliferation, energy metabolism and the oxidation state, and consequently may regulate spermatogenesis. These data pinpoint melatonin as a key player in the regulation of testicular physiology (i.e., steroidogenesis, spermatogenesis) mostly in seasonal breeders. In patients with idiopathic infertility, melatonin exerts anti-proliferative and anti-inflammatory effects on testicular macrophages, and provides protective effects against oxidative stress in testicular mast cells. Consequently, melatonin is also involved in the modulation of inflammatory and oxidant/anti-oxidant states in testicular pathology. Overall, the literature data indicate that melatonin has important effects on testicular function and male reproduction. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis
Int. J. Mol. Sci. 2017, 18(5), 1014; https://doi.org/10.3390/ijms18051014
Received: 30 March 2017 / Revised: 26 April 2017 / Accepted: 2 May 2017 / Published: 8 May 2017
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Abstract
Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK). Melatonin has attracted scientific attention as a potent antioxidant and protector
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Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK). Melatonin has attracted scientific attention as a potent antioxidant and protector of tissue against oxidative stress. l-Tryptophan and kynuramines share common beneficial features with melatonin. Melatonin was originally discovered as a pineal product, has been detected in the gastrointestinal tract, and its receptors have been identified in the pancreas. The role of melatonin in the pancreatic gland is not explained, however several arguments support the opinion that melatonin is probably implicated in the physiology and pathophysiology of the pancreas. (1) Melatonin stimulates pancreatic enzyme secretion through the activation of entero-pancreatic reflex and cholecystokinin (CCK) release. l-Tryptophan and AFMK are less effective than melatonin in the stimulation of pancreatic exocrine function; (2) Melatonin is a successful pancreatic protector, which prevents the pancreas from developing of acute pancreatitis and reduces pancreatic damage. This effect is related to its direct and indirect antioxidant action, to the strengthening of immune defense, and to the modulation of apoptosis. Like melatonin, its precursor and AFMK are able to mimic its protective effect, and it is commonly accepted that all these substances create an antioxidant cascade to intensify the pancreatic protection and acinar cells viability; (3) In pancreatic cancer cells, melatonin and AFMK activated a signal transduction pathway for apoptosis and stimulated heat shock proteins. The role of melatonin and AFMK in pancreatic tumorigenesis remains to be elucidated. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Oral Mucositis: Melatonin Gel an Effective New Treatment
Int. J. Mol. Sci. 2017, 18(5), 1003; https://doi.org/10.3390/ijms18051003
Received: 8 March 2017 / Revised: 19 April 2017 / Accepted: 3 May 2017 / Published: 7 May 2017
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Abstract
The current treatment for cervico-facial cancer involves radio and/or chemotherapy. Unfortunately, cancer therapies can lead to local and systemic complications such as mucositis, which is the most common dose-dependent complication in the oral cavity and gastrointestinal tract. Mucositis can cause a considerably reduced
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The current treatment for cervico-facial cancer involves radio and/or chemotherapy. Unfortunately, cancer therapies can lead to local and systemic complications such as mucositis, which is the most common dose-dependent complication in the oral cavity and gastrointestinal tract. Mucositis can cause a considerably reduced quality of life in cancer patients already suffering from physical and psychological exhaustion. However, the role of melatonin in the treatment of mucositis has recently been investigated, and offers an effective alternative therapy in the prevention and/or management of radio and/or chemotherapy-induced mucositis. This review focuses on the pathobiology and management of mucositis in order to improve the quality of cancer patients’ lives. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin: A Review of Its Potential Functions and Effects on Dental Diseases
Int. J. Mol. Sci. 2017, 18(4), 865; https://doi.org/10.3390/ijms18040865
Received: 17 March 2017 / Revised: 10 April 2017 / Accepted: 13 April 2017 / Published: 19 April 2017
Cited by 3 | PDF Full-text (464 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is a hormone synthesised and secreted by the pineal gland and other organs. Its secretion, controlled by an endogenous circadian cycle, has been proven to exert immunological, anti-oxidant, and anti-inflammatory effects that can be beneficial in the treatment of certain dental diseases.
[...] Read more.
Melatonin is a hormone synthesised and secreted by the pineal gland and other organs. Its secretion, controlled by an endogenous circadian cycle, has been proven to exert immunological, anti-oxidant, and anti-inflammatory effects that can be beneficial in the treatment of certain dental diseases. This article is aimed at carrying out a review of the literature published about the use of melatonin in the dental field and summarising its potential effects. In this review article, an extensive search in different databases of scientific journals was performed with the objective of summarising all of the information published on melatonin use in dental diseases, focussing on periodontal diseases and dental implantology. Melatonin released in a natural way into the saliva, or added as an external treatment, may have important implications for dental disorders, such as periodontal disease, as well as in the osseointegration of dental implants, due to its anti-inflammatory and osseoconductive effects. Melatonin has demonstrated to have beneficial effects on dental pathologies, although further research is needed to understand the exact mechanisms of this molecule. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis
Int. J. Mol. Sci. 2017, 18(4), 843; https://doi.org/10.3390/ijms18040843
Received: 15 March 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 17 April 2017
Cited by 34 | PDF Full-text (5855 KB) | HTML Full-text | XML Full-text
Abstract
There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin
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There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Developmental Programming of Adult Disease: Reprogramming by Melatonin?
Int. J. Mol. Sci. 2017, 18(2), 426; https://doi.org/10.3390/ijms18020426
Received: 9 January 2017 / Revised: 26 January 2017 / Accepted: 13 February 2017 / Published: 16 February 2017
Cited by 7 | PDF Full-text (534 KB) | HTML Full-text | XML Full-text
Abstract
Adult-onset chronic non-communicable diseases (NCDs) can originate from early life through so-called the “developmental origins of health and disease” (DOHaD) or “developmental programming”. The DOHaD concept offers the “reprogramming” strategy to shift the treatment from adulthood to early life, before clinical disease is
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Adult-onset chronic non-communicable diseases (NCDs) can originate from early life through so-called the “developmental origins of health and disease” (DOHaD) or “developmental programming”. The DOHaD concept offers the “reprogramming” strategy to shift the treatment from adulthood to early life, before clinical disease is apparent. Melatonin, an endogenous indoleamine produced by the pineal gland, has pleiotropic bioactivities those are beneficial in a variety of human diseases. Emerging evidence support that melatonin is closely inter-related to other proposed mechanisms contributing to the developmental programming of a variety of chronic NCDs. Recent animal studies have begun to unravel the multifunctional roles of melatonin in many experimental models of developmental programming. Even though some progress has been made in research on melatonin as a reprogramming strategy to prevent DOHaD-related NCDs, future human studies should aim at filling the translational gap between animal models and clinical trials. Here, we review several key themes on the reprogramming effects of melatonin in DOHaD research. We have particularly focused on the following areas: mechanisms of developmental programming; the interrelationship between melatonin and mechanisms underlying developmental programming; pathophysiological roles of melatonin in pregnancy and fetal development; and insight provided by animal models to support melatonin as a reprogramming therapy. Rates of NCDs are increasing faster than anticipated all over the world. Hence, there is an urgent need to understand reprogramming mechanisms of melatonin and to translate experimental research into clinical practice for halting a growing list of DOHaD-related NCDs. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics
Int. J. Mol. Sci. 2016, 17(12), 2124; https://doi.org/10.3390/ijms17122124
Received: 19 October 2016 / Revised: 28 November 2016 / Accepted: 7 December 2016 / Published: 16 December 2016
Cited by 47 | PDF Full-text (1536 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin
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Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessReview Melatonin as a Potential Agent in the Treatment of Sarcopenia
Int. J. Mol. Sci. 2016, 17(10), 1771; https://doi.org/10.3390/ijms17101771
Received: 15 September 2016 / Revised: 17 October 2016 / Accepted: 17 October 2016 / Published: 24 October 2016
Cited by 10 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that
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Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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Open AccessHypothesis Melatonin and Hippo Pathway: Is There Existing Cross-Talk?
Int. J. Mol. Sci. 2017, 18(9), 1913; https://doi.org/10.3390/ijms18091913
Received: 3 August 2017 / Revised: 30 August 2017 / Accepted: 1 September 2017 / Published: 6 September 2017
Cited by 3 | PDF Full-text (1824 KB) | HTML Full-text | XML Full-text
Abstract
Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading
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Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy. Full article
(This article belongs to the Special Issue Melatonin and Its Analogues: Experimental and Clinical Aspects)
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