224 results on '"Mediavilla, A"'
Search Results
2. Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells
- Author
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Gonzalez, A., Cos, S., Martinez-Campa, C., Alonso-Gonzalez, C., Sanchez-Mateos, S., Mediavilla, M. D., and Sanchez-Barcelo, E. J.
- Published
- 2008
3. Melatonin prevents the estrogenic effects of sub-chronic administration of cadmium on mice mammary glands and uterus
- Author
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Alonso-González, C., González, A., Mazarrasa, O., Güezmes, A., Sánchez-Mateos, S., Martínez-Campa, C., Cos, S., Sánchez-Barceló, E. J., and Mediavilla, M. D.
- Published
- 2007
4. Melatonin prevents oxidative stress and changes in antioxidant enzyme expression and activity in the liver of aging rats
- Author
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Mauriz, José L., Molpeceres, Virginia, García-Mediavilla, María V., González, Paquita, Barrio, Juan P., and González-Gallego, Javier
- Published
- 2007
5. Melatonin inhibits both ERα activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium
- Author
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Martínez-Campa, C., Alonso-González, C., Mediavilla, M. D., Cos, S., González, A., Ramos, S., and Sánchez-Barceló, E. J.
- Published
- 2006
6. Melatonin–estrogen interactions in breast cancer
- Author
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Sánchez-Barceló, Emilio J., Cos, Samuel, Mediavilla, Dolores, Martínez-Campa, Carlos, González, Alicia, and Alonso-González, Carolina
- Published
- 2005
7. Melatonin modulates aromatase activity in MCF-7 human breast cancer cells
- Author
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Cos, Samuel, Martínez-Campa, Carlos, Mediavilla, Maria D., and Sánchez-Barceló, Emilio J.
- Published
- 2005
8. Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro?
- Author
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Cos, Samuel, Mediavilla, Maria Dolores, Fernández, Rosario, González-Lamuño, Domingo, and Sánchez-Barceló, Emilio J.
- Published
- 2002
9. Constitutive photomorphogenesis protein 1 (COP1) and COP9 signalosome, evolutionarily conserved photomorphogenic proteins as possible targets of melatonin
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Emilio J. Sánchez-Barceló, Jerry Vriend, M. D. Mediavilla, and Russel J. Reiter
- Subjects
0301 basic medicine ,Proteasome Endopeptidase Complex ,Ubiquitin-Protein Ligases ,Arabidopsis ,Deubiquitinating enzyme ,Evolution, Molecular ,Mice ,03 medical and health sciences ,Endocrinology ,Ubiquitin ,Cryptochrome ,Animals ,Humans ,COP9 signalosome ,Melatonin ,Genetics ,biology ,Arabidopsis Proteins ,COP9 Signalosome Complex ,Chemistry ,Tumor Suppressor Proteins ,fungi ,biology.organism_classification ,Ubiquitin ligase ,Cell biology ,Cell Transformation, Neoplastic ,030104 developmental biology ,Proteasome ,Multiprotein Complexes ,biology.protein ,Photomorphogenesis ,Peptide Hydrolases - Abstract
The ubiquitin proteasome system has been proposed as a possible mechanism involved in the multiple actions of melatonin. COP1 (constitutive photomorphogenesis protein 1), a RING finger-type ubiquitin E3 ligase formerly identified in Arabidopsis, is a central switch for the transition from plant growth underground in darkness (etiolation) to growth under light exposure (photomorphogenesis). In darkness, COP1 binds to photomorphogenic transcription factors driving its degradation via the 26S proteasome; blue light, detected by cryptochromes, and red and far-red light detected by phytochromes, negatively regulate COP1. Homologues of plant COP1 containing all the structural features present in Arabidopsis as well as E3 ubiquitin ligase activity have been identified in mice and humans. Substrates for mammalian (m) COP1 include p53, AP-1 and c-Jun, p27(Kip1) , ETV1, MVP, 14-3-3σ, C/EBPα, MTA1, PEA3, ACC, TORC2 and FOXO1. This mCOP1 target suggests functions related to tumorigenesis, gluconeogenesis, and lipid metabolism. The role of mCOP1 in tumorigenesis (either as a tumor promoter or tumor suppressor), as well as in glucose metabolism (inhibition of gluconeogenesis) and lipid metabolism (inhibition of fatty acid synthesis), has been previously demonstrated. COP1, along with numerous other ubiquitin ligases, is regulated by the COP9 signalosome; this protein complex is associated with the oxidative stress sensor Keap1 and the deubiquitinase USP15. The objective of this review was to provide new information on the possible role of COP1 and COP9 as melatonin targets. The hypothesis is based on common functional aspects of melatonin and COP1 and COP9, including their dependence on light, regulation of the metabolism, and their control of tumor growth.
- Published
- 2016
10. Selective estrogen enzyme modulator actions of melatonin in human breast cancer cells
- Author
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S. Sanchez-Mateos, M. D. Mediavilla, Carolina Alonso-González, Alicia González, Carlos Martínez-Campa, Emilio J. Sánchez-Barceló, and Samuel Cos
- Subjects
medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,17-Hydroxysteroid Dehydrogenases ,medicine.drug_class ,Breast Neoplasms ,Biology ,Melatonin ,Endocrinology ,Breast cancer ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Estrogen Sulfotransferase ,Cancer ,Estrogens ,medicine.disease ,Estrogen ,Cancer cell ,Cancer research ,Steryl-Sulfatase ,Breast disease ,Sulfotransferases ,Breast carcinoma ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Melatonin exerts oncostatic effects on different kinds of neoplasias, especially on estrogen-dependent mammary tumors. Current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways. The intratumoral production of estrogens in breast carcinoma tissue plays a pivotal role in the proliferation of mammary tumoral cells and its blockade is one of the main objectives of the treatment of breast cancer. The aim of the present work is centered on the study of the role of melatonin in the control of some enzymes involved in the formation and transformation of estrogens in human breast cancer cells. The present study demonstrates that melatonin, at physiologic concentrations, modulates the synthesis and transformation of biologically active estrogens in MCF-7 cells, through the inhibition of sulfatase (STS) and 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) activity and expression, enzymes involved in the estradiol formation in breast cancer cells. Physiologic concentrations of melatonin also stimulate the activity and expression of estrogen sulfotransferase (EST), the enzyme responsible for the formation of the biologically inactive estrogen sulfates. The level of EST mRNA steady-state of cells treated with melatonin was three times higher than that in control cells. These findings which document that melatonin has an inhibitory effect on STS and 17beta-HSD1 and a stimulatory effect on EST, in combination with its previously described antiaromatase effect, can open up new and interesting possibilities in clinical applications of melatonin in breast cancer.
- Published
- 2008
11. Melatonin modulates aromatase activity in MCF-7 human breast cancer cells
- Author
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Samuel Cos, Carlos Martínez-Campa, M. D. Mediavilla, and Emilio J. Sánchez-Barceló
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endocrine system ,medicine.medical_specialty ,Antineoplastic Agents ,Breast Neoplasms ,Biology ,Tritium ,Melatonin ,Aromatase ,Endocrinology ,Internal medicine ,medicine ,Humans ,Testosterone ,RNA, Messenger ,skin and connective tissue diseases ,Cell Proliferation ,Cell growth ,Androstenedione ,MCF-7 ,Cancer cell ,Androgens ,biology.protein ,Female ,hormones, hormone substitutes, and hormone antagonists ,Endocrine gland ,Hormone ,medicine.drug - Abstract
Most of the current knowledge about the mechanisms by which melatonin inhibits the growth of breast cancer cells point to an interaction of melatonin with estrogen-responsive pathways, thus behaving as an antiestrogenic hormone. However, a possible effect of melatonin on the local synthesis of estrogens had not been examined. The objective of this work was to study whether melatonin may modify the aromatase activity in MCF-7 breast cancer cells thus modulating the local estrogen biosynthesis. In MCF-7 cells cultured with testosterone in estradiol-free media, melatonin (1 nM) counteracts the testosterone-induced cell proliferation dependent on the local biosynthesis of estrogens from testosterone by the aromatase activity of the cells. We found that melatonin reduces the aromatase activity (measured by the tritiated water release assay) of MCF-7 cells both at basal conditions and when aromatase activity was stimulated by cAMP or cortisol. The greatest inhibition of the aromatase activity was obtained with 1 nm melatonin, the same concentration that gives the highest antiproliferative and anti-invasive effects of MCF-7 cells. Finally, by RT-PCR, we found that melatonin downregulates aromatase expression at the transcriptional level in the MCF-7 cells. We conclude that melatonin, at physiological concentrations, decreases aromatase activity and expression in MCF-7 cells. This aromatase inhibitory effect of melatonin, together with its already known antiestrogenic properties interacting with the estrogen-receptor, makes this indoleamine an interesting tool to be considered in the prevention and treatment of hormone-dependent mammary neoplasias.
- Published
- 2005
12. Melatonin inhibits mammary gland development in female mice.
- Author
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Mediavilla, M.D., Martín, M., and Sánchez-Barceló, E.J.
- Published
- 1992
- Full Text
- View/download PDF
13. Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro?
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M. D. Mediavilla, Rosario Fernandez, Emilio J. Sánchez-Barceló, Domingo González-Lamuño, and Samuel Cos
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education.field_of_study ,medicine.medical_specialty ,TUNEL assay ,Cell growth ,Population ,Biology ,Andrology ,Melatonin ,Endocrinology ,MCF-7 ,Apoptosis ,Internal medicine ,Cancer cell ,medicine ,Viability assay ,education ,medicine.drug - Abstract
Melatonin inhibits proliferation of the estrogen-responsive MCF-7 human breast cancer cells. The objective of this work was to assess whether melatonin not only regulates MCF-7 cell proliferation but also induces apoptosis. In this experiment we used 1,25-dihydroxycholecalciferol (D 3 ) as a positive control because it inhibits MCF-7 cell proliferation and induces apoptosis. MCF-7 cells were cultured with either 1 nM melatonin, 100 nM D 3 or its diluent to determine their effects on cell proliferation, cell viability, cell-cycle phase distribution, population of apoptotic cells, and expression of p53. p21WAF1, bcl-2, bcl-X L and bax proteins. After 24 or 48 hr of incubation, both melatonin and D 3 -treatment significantly decreased the number of viable cells in relation to the controls, although no differences in cell viability were observed between the treatments. The incidence of apoptosis, measured as the population of cells falling in the sub-G 1 region of the DNA histogram, or by the TUNEL reaction, was similar in melatonin-treated and control cells whereas, as expected, apoptosis was higher among cells treated with D 3 than in controls. The expression of p53 and p21WAF1 proteins significantly increased after 24 or 48 hr of incubation with either melatonin or D 3 , No significant changes in bcl-2, bcl-X L and bax mRNAs were detected after treatment with melatonin whereas in D 3 -treated cells, a significant drop in bcl-X L was observed. These data support the hypothesis that melatonin reduces MCF-7 cell proliferation by modulating cell-cycle length through the control of the p53-p21 pathway, but without clearly inducing apoptosis.
- Published
- 2002
14. Diurnal changes in cyclic nucleotide response to pineal indoles in murine mammary glands
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M. Dolores Mediavilla, Roberto A. Bonanni Rey, Daniel P. Cardinali, and Emilio J. Sánchez-Barceló
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medicine.medical_specialty ,Indoles ,Mammary gland ,Radioimmunoassay ,Biology ,Pineal Gland ,Melatonin ,Mice ,Cyclic nucleotide ,chemistry.chemical_compound ,Pineal gland ,Mammary Glands, Animal ,Endocrinology ,Internal medicine ,Cyclic AMP ,medicine ,Animals ,Phosphodiesterase inhibitor ,Cyclic GMP ,Mice, Inbred BALB C ,Circadian Rhythm ,medicine.anatomical_structure ,chemistry ,5-Methoxytryptamine ,Female ,Serotonin ,medicine.drug - Abstract
The aim of this study was to determine whether pineal indoles affect cyclic nucleotide levels in mammary gland slices of BALB/c adult mice. Melatonin at 0.1 nM-10 microM concentrations decreased cAMP and augmented cGMP concentration in murine mammary gland slices in the presence of a phosphodiesterase inhibitor (1 mM theophylline), an index of cyclic nucleotide synthesis. Melatonin-induced changes in cyclic nucleotide levels were significantly larger at the end of the light period (2000) than in the morning (at 1000). Indole-induced inhibition of cyclic AMP levels by mammary slices exhibited the following order of potency: 5-methoxytryptamine > melatonin > or = 6-hydroxymelatonin > serotonin, N-acetylserotonin > 5-hydroxytryptophol. The order of potency for indole-induced augmentation of cyclic GMP levels was: 5-methoxytryptamine > melatonin > 6-hydroxymelatonin > serotonin, N-acetylserotonin, 5-hydroxytryptophol. When melatonin or 5-methoxytryptamine (10 nM) were examined for their effects on cAMP and cGMP levels in mammary glands of mice killed at six different time intervals during the 24-hr cycle, the activity was maximal during night. The data demonstrate that 5-methoxytryptamine and melatonin decreased cAMP and increased cGMP levels in mammary gland slices. Methoxyindole-induced changes in cyclic nucleotide synthesis in murine mammary glands exhibit the time-dependency known to occur in several other melatonin-influenced responses.
- Published
- 1992
15. Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene
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M. D. Mediavilla, S. Ramos, L. Kothari, A. Giiezmez, E. J. Sánchez Barceló, and F. Garijo
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Genetically modified mouse ,Gene Expression Regulation, Viral ,Pathology ,medicine.medical_specialty ,Mammary gland ,Mice, Transgenic ,Biology ,Melatonin ,Mice ,Endocrinology ,Mammary Glands, Animal ,Parenchyma ,medicine ,Animals ,Repetitive Sequences, Nucleic Acid ,Histology ,Hyperplasia ,medicine.disease ,Epithelium ,medicine.anatomical_structure ,Genes, ras ,Mammary Tumor Virus, Mouse ,Female ,Immunostaining ,medicine.drug - Abstract
Mediavilla MD, Guezmez A, Ramos S, Kothari L, Garijo F, Sanchez Barcelo EJ. Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-ras proto-oncogene. J. Pineal Res. 1997; 22:86–94. © Munksgaard, Copenhagen. Abstract The oncostatic effects of melatonin on the mammary gland have been studied in transgenic mice carrying the N-ras proto-oncogene under the control of the MMTV-LTR. Female (4-week-old) virgin mice with positive transgenic pedigrees were injected with melatonin (200 μg/mouse/ day, five times a week) or vehicle late in the evening. After 5 months of treatment, animals were sacrificed and the mammary glands were dissected for whole mounts, histology, and immunohistochemical analysis with a mouse monoclonal antibody specific for N-ras protein. Mammary glands of control transgenic mice showed different densities of hyperplastic alveolar nodules (HANs) consisting primarily of dysplastic epithelial cells with nuclear atypia and prominent nucleoli. The epithelial cells of HANs showed a high expression of N-ras while no immunostaining was detected in the unaffected mammary parenchyma. Only one (10%) of the control transgenic mice presented an infiltrating ductal carcinoma with the neoplastic cells overexpressing N-ras protein. The mammary glands of melatonin treated mice had a lower density of HANs, absence of epithelial dysplastic cells, and weak immunostaining of N-ras protein in comparison to the vehicle-treated group. None of the melatonin treated animals developed mammary carcinomas during the observation period. The lymph nodes of the inguinal mammary glands of all the vehicle-treated transgenic mice presented hyperplasia and two animals even had lymphomas, whereas in melatonin-treated animals there was less hyperplasia (two cases were atrophic) and a lack of lymphomas. We conclude that in the mammary glands of MMTV-LTR/N-ras transgenic female virgin mice, melatonin a) reduces the incidence of HANs and the expression of N-ras protein in focal hyperplastic lesions, b) completely prevents the development of epithelial cell atypia and mammary adenocarcinomas, and c) also reduces the hyperplasia of the mammary lymphoid tissue and prevents the development of lymphomas.
- Published
- 1997
16. Melatonin prevents the estrogenic effects of sub-chronic administration of cadmium on mice mammary glands and uterus
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Andrés Güezmes, M. D. Mediavilla, Carolina Alonso-González, S. Sanchez-Mateos, O. Mazarrasa, Samuel Cos, Emilio J. Sánchez-Barceló, Alicia González, and Carlos Martínez-Campa
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medicine.medical_specialty ,Ratón ,medicine.drug_class ,Mammary gland ,Uterus ,Biology ,Melatonin ,Mice ,Endocrinology ,Mammary Glands, Animal ,Internal medicine ,medicine ,Animals ,Humans ,Estrogens, Non-Steroidal ,Carcinogen ,medicine.anatomical_structure ,Estrogen ,Ovariectomized rat ,Environmental Pollutants ,Female ,Metalloestrogen ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Cadmium - Abstract
Cadmium (Cd) is a heavy metal classified as a human carcinogen. Occupational exposure, dietary consumption and cigarette smoking are sources of Cd contamination. Cd-induced carcinogenicity depends on its oxidative and estrogenic actions. A possible role of Cd in breast cancer etiology has been recently suggested. Melatonin, because of its antioxidant and antiestrogenic properties could counteract the toxic effects of this metalloestrogen. Our aim was both to determine the effects of relevant doses of Cd on mice mammary glands and uterus and to test whether melatonin would counteract its effects. Female mice of different ages and estrogenic status (prepuberal, adult intact, adult ovariectomized) were treated with CdCl(2) (2-3 mg/kg, i.p.), melatonin (10 microg/mL in drinking water), CdCl(2) + melatonin, or diluents. Whereas in prepuberal animals Cd disturbs mammary ductal growth and reduces the number of terminal end buds, in adults, regardless of the steroidal milieu, Cd exerts estrogenic effects on mammary glands, increasing lobuloalveolar development and ductal branching. Uterine weight also increased as a result of Cd treatment. The effects of Cd are partially inhibited by melatonin. In adult ovariectomized mice, Cd concentration in blood of animals treated with CdCl(2) + melatonin was lower than in mice receiving only Cd; the opposite effects were found in non-castrated animals. As Cd mimics the effect of estrogens, the high incidence of breast cancer in tobacco smokers and women working in industries related with Cd could be explained because of the properties of this metal. The effects of melatonin point to a possible role of this indoleamine as a preventive agent for environmental or occupational Cd contamination.
- Published
- 2007
17. Melatonin inhibits both ER alpha activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium
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Carolina Alonso-González, M. D. Mediavilla, Emilio J. Sánchez-Barceló, Carlos Martínez-Campa, Alicia González, Samuel Cos, and S. Ramos
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Transcriptional Activation ,medicine.medical_specialty ,medicine.drug_class ,Estrogen receptor ,Breast Neoplasms ,Biology ,Melatonin ,Transactivation ,Endocrinology ,Estrogen Receptor Modulators ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Cell Proliferation ,Cell growth ,Estrogen Receptor alpha ,Cell biology ,AP-1 transcription factor ,Estrogen ,Metalloestrogen ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Cadmium - Abstract
Cadmium (Cd) is a heavy metal affecting human health both through environmental and occupational exposure. There is evidence that Cd accumulates in several organs and is carcinogenic to humans. In vivo, Cd mimics the effect of estrogens in the uterus and mammary gland. In estrogen-responsive breast cancer cell lines, Cd stimulates proliferation and can also activate the estrogen receptor independent of estradiol. The ability of this metalloestrogen to increase gene expression in MCF7 cells is blocked by anti-estrogens suggesting that the activity of these compounds is mediated by ER alpha. The aims of this work were to test whether melatonin inhibits Cd-induced proliferation in MCF7 cells, and also to study whether melatonin specifically inhibits Cd-induced ER alpha transactivation. We show that melatonin prevents the Cd-induced growth of synchronized MCF7 breast cancer cells. In transient transfection experiments, we prove that both ER alpha- and ER beta-mediated transcription are stimulated by Cd. Melatonin is a specific inhibitor of Cd-induced ER alpha-mediated transcription in both estrogen response elements (ERE)- and AP1-containing promoters, whereas ER beta-mediated transcription is not inhibited by the pineal indole. Moreover, the mutant ER alpha-(K302G, K303G), unable to bind calmodulin, is activated by Cd but becomes insensitive to melatonin treatment. These results proved that melatonin inhibits MCF7 cell growth induced by Cd and abolishes the stimulatory effect of the heavy metal in cells expressing ER alpha at both ERE-luc and AP1-luc sites. We can infer from these experiments that melatonin regulates Cd-induced transcription in both ERE- and AP1 pathways. These results also reinforce the hypothesis of the anti-estrogenic properties of melatonin as a valuable tool in breast cancer therapies.
- Published
- 2006
18. Melatonin-estrogen interactions in breast cancer
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Carlos Martínez-Campa, Alicia González, Emilio J. Sánchez-Barceló, Carolina Alonso-González, Samuel Cos, and Dolores Mediavilla
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Selective Estrogen Receptor Modulators ,medicine.medical_specialty ,medicine.drug_class ,Estrogen receptor ,Breast Neoplasms ,Pharmacology ,Melatonin ,Endocrinology ,Breast cancer ,Internal medicine ,medicine ,Humans ,Aromatase ,Mammary tumor ,biology ,Cancer ,Estrogens ,medicine.disease ,Selective estrogen receptor modulator ,Estrogen ,biology.protein ,Female ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
In this article, we review the experimental data supporting an oncostatic role of melatonin on hormone-dependent mammary tumors. Beginning with the evidence on the role of estrogens in breast cancer etiology and mammary tumor growth, we summarize the actual therapeutic strategies with estrogens as a target. Additionally, we demonstrate that melatonin fulfills all the requirements to be considered as an antiestrogenic drug which shares properties with drugs of the two main pharmacological groups of substances which interact with the estrogen-signaling pathways such as: (i) drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens; and (ii) drugs that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors. Furthermore, melatonin decreases circulating levels of estradiol. These three antiestrogenic mechanisms suggest that melatonin may have an important role in the prevention and treatment of hormone-dependent mammary cancer.
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- 2005
19. Effects of melatonin on mammary gland lesions in transgenic mice overexpressing N-rasproto-oncogene.
- Author
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Mediavilla, M.D., Giiezmez, A., Ramos, S., Kothari, L., Garijo, F., and Barceló, E.J. Sanchez
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- 1997
- Full Text
- View/download PDF
20. Pharmacological profile and diurnal rhythmicity of 2-[125I]-iodomelatonin binding sites in murine mammary tissue.
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Recio, J., Mediavilla, M. D., Cardinali, D. P., and Sánchez-Barceló, E. J.
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- 1994
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21. Histopathologic Features of DMBA-Induced Mammary Tumors in Blind-Underfed, Blind-Anosmic, and Blind Cold-Exposed Rats: Influence of the Pineal Gland.
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Cos, S., Garijo, F., Corral, J., Mediavilla, M.D., and Sánchez-Barcelo, E J.
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- 1989
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22. Antigonadal Actions of Olfactory and Light Deprivation. II. Effects of Pinealectomy or Melatonin Injections in Olfactory Bulb Deafferented or Bulbectomized Male Rats.
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Mediavilla, M. D., Sánchez-Barceló, E. J., Sánchez-Criado, J. E., Cos, S., and Cortines, M. D. G.
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- 1985
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23. Pharmacological profile and diurnal rhythmicity of 2-[125I]-iodomelatonin binding sites in murine mammary tissue
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M. D. Mediavilla, J. Recio, Emilio J. Sánchez-Barceló, and Daniel P. Cardinali
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medicine.medical_specialty ,Ratón ,Mammary gland ,Receptors, Melatonin ,Receptors, Cell Surface ,Biology ,Binding, Competitive ,Melatonin ,Iodine Radioisotopes ,Mice ,Endocrinology ,Mammary Glands, Animal ,Dopamine ,Internal medicine ,medicine ,Animals ,Biogenic Monoamines ,Binding site ,Receptor ,Mice, Inbred BALB C ,Binding Sites ,Cell Membrane ,In vitro ,Circadian Rhythm ,medicine.anatomical_structure ,Female ,Serotonin ,medicine.drug - Abstract
Recio J, Mediavilla MD, Cardinali DP, Sanchez-Barcelo EJ. Pharmacological profile and diurnal rhythmicity of 2-[125I]-iodomelatonin binding sites in murine mammary tissue. J. Pineal Res. 1994: 16: 10–17. Abstract Recent studies demonstrated that melatonin treatment decreased the growth of mammary glands in pubertal and pregnant mice. In vitro, melatonin inhibited murine mammary gland growth at μM concentrations and increased it at pM concentrations. Melatonin-induced changes of cyclic nucleotide synthesis was also demonstrated in mammary gland slices in vitro. The objective of the present study was to assess the possible existence of specific binding sites for melatonin in murine mammary gland by using 2-[125I]-iodomelatonin as a probe. The specific binding of 2-[125I]-iodomelatonin to murine mammary gland membranes was rapid, saturable, and reversible, showed an affinity in the low nM range, and displayed time, temperature, and pH dependence. Scatchard analysis indicated the existence of a single class of binding sites that exhibited a diurnal rhythmicity in affinity (Kd) and receptor density (Bmax). A maximum in Bmax (267 ± 42 fmol/mg protein) was found at the light period, while affinity was maximal during darkness (Kd= 1.33 ± 0.22 nM). In competition studies dopamine and dopamine-related agents, as well as 6-hydroxymelatonin and serotonin, but not melatonin, effectively displaced 2-[125I]-iodomelatonin from mammary binding sites. The results demonstrated a specific binding of 2-[125I]-iodomelatonin to murine mammary glands, with affinity in the low nM range, and a pharmacological profile that differed from that reported for 2-[125I]-iodomelatonin acceptor sites in other tissues.
- Published
- 1994
24. Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro?
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Samuel, Cos, Maria Dolores, Mediavilla, Rosario, Fernández, Domingo, González-Lamuño, and Emilio J, Sánchez-Barceló
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Cyclin-Dependent Kinase Inhibitor p21 ,Cell Cycle ,bcl-X Protein ,Apoptosis ,Breast Neoplasms ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-bcl-2 ,Cyclins ,Proto-Oncogene Proteins ,Tumor Cells, Cultured ,Humans ,Female ,Tumor Suppressor Protein p53 ,Cell Division ,Cholecalciferol ,Melatonin ,bcl-2-Associated X Protein - Abstract
Melatonin inhibits proliferation of the estrogen-responsive MCF-7 human breast cancer cells. The objective of this work was to assess whether melatonin not only regulates MCF-7 cell proliferation but also induces apoptosis. In this experiment we used 1,25-dihydroxycholecalciferol (D3) as a positive control because it inhibits MCF-7 cell proliferation and induces apoptosis. MCF-7 cells were cultured with either I nM melatonin, 100 nM D3 or its diluent to determine their effects on cell proliferation, cell viability, cell-cycle phase distribution, population of apoptotic cells, and expression of p53, p21WAF1, bcl-2, bcl-X(L) and bax proteins. After 24 or 48 hr of incubation, both melatonin and D3-treatment significantly decreased the number of viable cells in relation to the controls, although no differences in cell viability were observed between the treatments. The incidence of apoptosis, measured as the population of cells falling in the sub-G1 region of the DNA histogram, or by the TUNEL reaction, was similar in melatonin-treated and control cells whereas, as expected, apoptosis was higher among cells treated with D3 than in controls. The expression of p53 and p21WAF1 proteins significantly increased after 24 or 48 hr of incubation with either melatonin or D3. No significant changes in bcl-2, bcl-XL and bax mRNAs were detected after treatment with melatonin whereas in D3-treated cells, a significant drop in bcl-XL was observed. These data support the hypothesis that melatonin reduces MCF-7 cell proliferation by modulating cell-cycle length through the control of the p53-p21 pathway, but without clearly inducing apoptosis.
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- 2002
25. Melatonin inhibits mammary gland development in female mice
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Emilio J. Sánchez-Barceló, M. D. Mediavilla, and M. San Martin
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photoperiodism ,medicine.medical_specialty ,Mice, Inbred BALB C ,Ratón ,Mammary gland ,Body Weight ,DNA ,Biology ,Mammary gland development ,Melatonin ,Mice ,Endocrinology ,medicine.anatomical_structure ,Mammary Glands, Animal ,Internal medicine ,Darkness ,Parenchyma ,medicine ,Weaning ,Animals ,Female ,Sexual Maturation ,medicine.drug - Abstract
The objective of this study was to determine whether melatonin (aMT) influences the postnatal development of the mammary gland parenchyma in female mice from the time of weaning to adulthood. Twenty-one-day-old female BALBc mice were treated with daily subcutaneous injections of aMT (200 micrograms) or diluent, 3 hr before the onset of darkness (photoperiod LD 12:12). At 3, 5, 7, 9, 11, and 13 weeks of age, batches of 20 animals (ten controls and ten aMT-treated) were sacrificed and the second pair of mammary glands were dissected to evaluate their degree of development. Melatonin decreased body weight gain from 2 weeks before until 2 weeks after the onset of puberty. Treatment with aMT also resulted in a lower DNA content and smaller area of the mammary gland from the time of puberty until the end of the study. In aMT-treated mice the phase of highly positive allometric growth began 2 weeks later, but ended at the same time as in controls (11th week of life). Finally, aMT decreased the development of terminal, lateral, and alveolar buds while it increased the number of terminal ducts per gland. We conclude that pharmacological doses of aMT (1) reduce body weight gain at the peripuberal age; (2) partially inhibit postnatal mammary gland development by reducing the number of epithelial structures representing sites of growth and increasing that of structures representing the final state of ductal growth in virgin animals; (3) delay the onset of the shorten the phase of rapid mammary growth occurring in early postpuberal age.
- Published
- 1992
26. Diurnal changes in cyclic nucleotide response to pineal indoles in murine mammary glands.
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Cardinali, Daniel P., Bonanni Rey, Roberto A., Mediavilla, M. Dolores, and Sánchez-Barceló, E.
- Published
- 1992
- Full Text
- View/download PDF
27. Pharmacological profile and diurnal rhythmicity of 2‐[125I]‐iodomelatonin binding sites in murine mammary tissue
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Recio, J., primary, Mediavilla, M. D., additional, Cardinali, D. P., additional, and Sánchez‐Barceló, E. J., additional
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- 1994
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28. RETRACTION: Melatonin Attenuates Inflammation and Promotes Regeneration in Rabbits With Fulminant Hepatitis of Viral Origin.
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NF-kappa B , *VIRAL hepatitis , *LIVER failure , *GENETIC regulation , *VIRUS diseases ,RABBIT diseases - Abstract
RETRACTION: Laliena A, Miguel BS, Crespo I, Alvarez M, González‐Gallego J, Tuñón MJ. Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2012;53:270‐278. https://doi.org/10.1111/j.1600-079X.2012.00995.x The above article, published online on 19 March 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Gianluca Tosini, and John Wiley and Sons Ltd. Following publication, concerns were raised by third parties that portions of Figure 1B are duplicated in Figures 4, 2A, and 4, respectively, of two other articles by the same author group.1‐3 The authors provided some of the original data, but these were not sufficient to resolve the concerns, and the authors were unable to provide a satisfactory explanation for the concerns. The retraction has been agreed because of concerns that portions of the figure overlap with the authors' previous articles, affecting the interpretation of the data and results presented. The authors disagree with this decision. 1. Kretzmann NA, Fillmann H, Mauriz JL, Marroni, CA, Marroni N, González‐Gallego J, Tuñón MJ. Effects of glutamine on pro‐inflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS‐induced colitis. Inflamm Bowel Dis 2008;14:1504‐1513. https://doi.org/10.1002/ibd.20543 2. Crespo I, García‐Mediavilla MV, Gutiérrez B, Sánchez‐Campos S, Tuñón MJ, González‐Gallego J. A comparison of the effects of kaempferol and quercetin on cytokine‐induced pro‐inflammatory status of cultured human endothelial cells. Br J Nutr 2008;100(5):968‐976. https://doi.org/10.1017/S0007114508966083 3. Tuñón MJ, Miguel BS, Crespo I, Jorquera F, Santamaría E, Alvarez M, Prieto J, González‐Gallego J. Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus. J Pineal Res 2011;50:38‐45. https://doi.org/10.1111/j.1600-079X.2010.00807.x [ABSTRACT FROM AUTHOR]
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- 2024
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29. RETRACTION: Melatonin Attenuates Apoptotic Liver Damage in Fulminant Hepatic Failure Induced by the Rabbit Hemorrhagic Disease Virus.
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NF-kappa B , *VIRAL hepatitis , *LIVER failure , *VIRUS diseases , *GENETIC regulation ,RABBIT diseases - Abstract
RETRACTION: Tuñón MJ, Miguel BS, Crespo I, Jorquera F, Santamaría E, Alvarez M, Prieto J, González‐Gallego J. Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus. J Pineal Res 2011;50:38‐45. https://doi.org/10.1111/j.1600-079X.2010.00807.x The above article, published online on 22 October 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Gianluca Tosini, and John Wiley and Sons Ltd. Following publication, concerns were raised by third parties that portions of Figure 4 are duplicated in Figures 4, 2A, and 1B, respectively, of three other articles by the same author group.1‐3 The authors provided some of the original data, but these were not sufficient to resolve the concerns, and the authors were unable to provide a satisfactory explanation for the concerns. The retraction has been agreed because of concerns that portions of the figure overlap with the authors' previous articles, affecting the interpretation of the data and results presented. The authors disagree with this decision. 1. Kretzmann NA, Fillmann H, Mauriz JL, Marroni, CA, Marroni N, González‐Gallego J, Tuñón MJ. Effects of glutamine on pro‐inflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS‐induced colitis. Inflamm Bowel Dis 2008;14:1504‐1513. doi:10.1002/ibd.20543 2. Crespo I, García‐Mediavilla MV, Gutiérrez B, Sánchez‐Campos S, Tuñón MJ, González‐Gallego J. A comparison of the effects of kaempferol and quercetin on cytokine‐induced pro‐inflammatory status of cultured human endothelial cells. Br J Nutr 2008;100(5):968‐976. doi:10.1017/S0007114508966083 3. Laliena A, Miguel BS, Crespo I, Alvarez M, González‐Gallego J, Tuñón MJ. Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2012;53:270‐278. doi:10.1111/j.1600-079X.2012.00995.x [ABSTRACT FROM AUTHOR]
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- 2024
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30. RETRACTION: Melatonin Prevents Oxidative Stress and Changes in Antioxidant Enzyme Expression and Activity in the Liver of Aging Rats.
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OXIDATIVE stress , *INTERNET publishing , *RATS , *AGING , *LIVER - Abstract
RETRACTION: Mauriz JL, Molpeceres V, García‐Mediavilla MV, González P, Barrio JP, González‐Gallego J. Melatonin prevents oxidative stress and changes in antioxidant enzyme expression and activity in the liver of aging rats. J Pineal Res 2007;42:222‐230. https://doi.org/10.1111/j.1600-079X.2006.00409.x The above article, published online on 12 December 2006 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor‐in‐Chief, Gianluca Tosini, and John Wiley and Sons Ltd. Following publication, concerns were raised by third parties regarding Figure 4A. The authors could not provide the original data for this figure, and were unable to provide a satisfactory explanation to resolve the concerns. The retraction has been agreed because of concerns that portions of the figure were duplicated, affecting the interpretation of the data and results presented. The authors disagree with this decision. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Antigonadal Actions of Olfactory and Light Deprivation. I. Effects of Blindness Combined With Olfactory Bulb Deafferentation, Transection of Vomeronasal Nerves, or Bulbectomy.
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Sánchez-Barceló, E. J., Mediavilla, M. D., Sánchez-Criado, J. E., Cos, S., and Cortines, M. D. G.
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- 1985
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32. Antigonadal actions of olfactory and light deprivation. I. Effects of blindness combined with olfactory bulb deafferentation, transection of vomeronasal nerves, or bulbectomy
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M. D. G. Cortines, M. D. Mediavilla, J. E. Sánchez-Criado, Emilio J. Sánchez-Barceló, and Samuel Cos
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Olfactory system ,Male ,medicine.medical_specialty ,Olfactory Nerve ,Anosmia ,Olfaction ,Genitalia, Male ,Melatonin ,Endocrinology ,Internal medicine ,Testis ,medicine ,Animals ,Testosterone ,Vision, Ocular ,business.industry ,Rats, Inbred Strains ,medicine.disease ,Privation ,Olfactory Bulb ,Peripheral ,Olfactory bulb ,Rats ,Smell ,Pituitary Gland ,medicine.symptom ,Sensory Deprivation ,business ,Spermatogenesis ,medicine.drug - Abstract
Olfactory bulbectomy is known to potentiate the antigonadal effects of light deprivation. However, the physiological interpretation of the effects of bulbar ablation is complex, since it simultaneously implies sequelae like: a) the loss of olfactory sensitivity (anosmia), b) the suppression of the accessory olfactory system (AOS), and c) the suppression of nonsensorial functions of the bulbs. To study the participation of these three mechanisms in the effects of bulbectomy + light deprivation, we compared, in 28-day-old male rats, the effects of olfactory bulb deafferentation (peripheral anosmia) with those induced by either olfactory bulbectomy or blocking the AOS, alone or associated with blindness. As compared to the intact or blinded animals, both blinded deafferented (EA) and blinded bulbectomized (EB) rats showed various reductions in weights of body, testes, accessory sexual glands, and prostates; serum testosterone levels were also depressed. Testes of EA rats showed various degrees of alterations in spermatogenesis. The only difference between EA and EB groups was in the pituitary weight, significantly lower in EA rats.
- Published
- 1985
33. Shift and longtime light induces endometrioid adenocarcinoma via activation of PKC‐α/Akt pathway in female golden hamster: Involvement of altered Aanat and Bmal1 rhythm.
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Das, Megha, Haldar, Chandana, and Yadav, Sanjeev Kumar
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GOLDEN hamster ,ADENOCARCINOMA ,WESTERN immunoblotting ,STAINS & staining (Microscopy) ,SCANNING electron microscopy - Abstract
Female night‐workers get exposed to frequent light shifts, hence have altered circadian rhythm and are at high risk of endometrial cancer; the underlying mechanism however is still not clear. We, therefore examined the effect of long light exposure (16L:8D, LD1) and regular shift (8 h) in long nighttime (LD2) on endometrial changes of female golden hamsters. Morphometric analysis, scanning electron microscopy imaging, alcian blue staining, and cytological nuclear atypia of endometrial stromal cells confirmed the incidence of endometrial adenocarcinoma in LD2 exposed hamsters. But, less severe pathomorphological alterations were noted in uterus of LD1 exposed hamsters. Altered Aanat and Bmal1 mRNA, melatonin rhythm, downregulation of important marker gene of adenocarcinoma like Akt, 14‐3‐3, and PR protein expression and upregulation PKCα, pAkt‐S473 and vascular epithelial growth factor (VEGF) were observed in LD2 exposed hamsters suggesting the endometrial adenocarcinoma. Further, our western blot analysis supported the immunohistochemical localization of PR, PKCα, and VEGF in uterine tissues along low progesterone. Overall, our data indicates that light shift and long light exposure potentially induced endometrioid adenocarcinoma via activation of PKC‐α/Akt pathway in female hamsters. Therefore, duration of light is essential for female normal uterine function. [ABSTRACT FROM AUTHOR]
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- 2023
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34. Physiological consequences of space flight, including abnormal bone metabolism, space radiation injury, and circadian clock dysregulation: Implications of melatonin use and regulation as a countermeasure.
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Hirayama, Jun, Hattori, Atsuhiko, Takahashi, Akihisa, Furusawa, Yukihiro, Tabuchi, Yoshiaki, Shibata, Masahiro, Nagamatsu, Aiko, Yano, Sachiko, Maruyama, Yusuke, Matsubara, Hajime, Sekiguchi, Toshio, and Suzuki, Nobuo
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ASTROPHYSICAL radiation ,CHRONOBIOLOGY disorders ,SPACE flight ,BONE metabolism ,RADIATION injuries - Abstract
Exposure to the space environment induces a number of pathophysiological outcomes in astronauts, including bone demineralization, sleep disorders, circadian clock dysregulation, cardiovascular and metabolic dysfunction, and reduced immune system function. A recent report describing experiments aboard the Space Shuttle mission, STS‐132, showed that the level of melatonin, a hormone that provides the biochemical signal of darkness, was decreased during microgravity in an in vitro culture model. Additionally, abnormal lighting conditions in outer space, such as low light intensity in orbital spacecraft and the altered 24‐h light–dark cycles, may result in the dysregulation of melatonin rhythms and the misalignment of the circadian clock from sleep and work schedules in astronauts. Studies on Earth have demonstrated that melatonin regulates various physiological functions including bone metabolism. These data suggest that the abnormal regulation of melatonin in outer space may contribute to pathophysiological conditions of astronauts. In addition, experiments with high‐linear energy transfer radiation, a ground‐based model of space radiation, showed that melatonin may serve as a protectant against space radiation. Gene expression profiling using an in vitro culture model exposed to space flight during the STS‐132 mission, showed that space radiation alters the expression of DNA repair and oxidative stress response genes, indicating that melatonin counteracts the expression of these genes responsive to space radiation to promote cell survival. These findings implicate the use of exogenous melatonin and the regulation of endogenous melatonin as countermeasures for the physiological consequences of space flight. [ABSTRACT FROM AUTHOR]
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- 2023
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35. Activation of melatonin receptor 1 by CRISPR‐Cas9 activator ameliorates cognitive deficits in an Alzheimer's disease mouse model.
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Park, Hanseul and Kim, Jongpil
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ALZHEIMER'S disease ,LABORATORY mice ,CRISPRS ,ANIMAL disease models ,MELATONIN - Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of neurotoxic beta‐amyloid (Aβ) in the brain. Melatonin receptors have been reported to associate with aging and AD, and their expression decreased with the progression of AD. As an alternative to AD treatment, overexpression of melatonin receptors may lead to melatonin‐like effects to treat alleviate the symptoms of AD. Here, we successfully activated the type 1 melatonin receptor (Mt1) in vivo brain using a Cas9 activator as a novel AD therapeutic strategy. The Cas9 activator efficiently activated the endogenous Mt1 gene in the brain. Activation of Mt1 via Cas9 activators modulated anti‐amyloidogenic and anti‐inflammatory roles in 5xFAD AD mice brain. Moreover, activation of Mt1 with the CRISPR/Cas9 activator improved cognitive deficits in an AD model. These results demonstrated the therapeutic potential of melatonin receptor activation via CRISPR/Cas9 activator for AD. [ABSTRACT FROM AUTHOR]
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- 2022
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36. Specific binding of melatonin to purified cell nuclei from mammary gland of swiss mice: day–night variations and effect of continuous light.
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Coto-Montes, Ana, Tomás-Zapico, Cristina, Escames, Germaine, León, Josefa, Rodríguez-Colunga, María Josefa, Tolivia, Delio, and Acuña-Castroviejo, Darío
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MELATONIN ,CELL nuclei ,BINDING sites ,MAMMARY glands - Abstract
Melatonin binding sites were characterized in the nuclei of mouse mammary glands. The specific binding of 2-
125 I-iodomelatonin by homogenates of purified mammary gland cell nuclei was found to be rapid, reversible and saturable. Binding of125 I-melatonin exhibited day–night variations with the highest binding affinity observed during the dark period and the lowest affinity at midday. However, when the animals were maintained under continuous light exposure, binding of125 I-melatonin to cell nuclei showed a higher affinity than the daytime values found in animals maintained in normal photoperiod. Scatchard analysis of the binding data revealed the existence of a significant night–day variation in the binding kinetics, compatible with the existence of two classes of binding sites: a high-affinity binding site expressed during the night, with KD = 185 ± 36 pm and a binding capacity of 6.24 ± 0.4 fmol/mg protein, and a low-affinity site with KD = 562 ± 57 nm and Bmax = 7.56 ± 0.49 pmol/mg protein during the day. Interestingly, after 2 wk of continuous exposure to light, the animals killed at an equivalent midday time showed a significant increase in binding affinity, with KD = 1.43 ± 0.2 nm and Bmax = 24.75 ± 3.5 fmol/mg protein. Displacement experiments show an IC50 value compatible with the affinity constants obtained in the saturation experiments. These results indicate that the low-affinity binding site may be saturated by the high levels of melatonin found in the mouse mammary gland, and sustain the hypothesis of a circadian regulation of these melatonin binding sites by the photoperiod. [ABSTRACT FROM AUTHOR]- Published
- 2003
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37. The potential remedy of melatonin on osteoarthritis.
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Lu, Ko‐Hsiu, Lu, Peace Wun‐Ang, Lu, Eric Wun‐Hao, Tang, Chih‐Hsin, Su, Shih‐Chi, Lin, Chiao‐Wen, and Yang, Shun‐Fa
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NUCLEAR receptors (Biochemistry) ,OSTEOARTHRITIS ,ARYL hydrocarbon receptors ,FREE radical scavengers ,CLOCK genes ,MELATONIN ,DISEASE progression - Abstract
Osteoarthritis (OA), the most common arthritis worldwide, is a degenerative joint disease characterized by progressive cartilage breakdown, subchondral remodeling, and synovial inflammation. Although conventional pharmaceutical therapies aimed to prevent further cartilage loss and joint dysfunction, there are no ideal strategies that target the pathogenesis of OA. Melatonin exhibits a variety of regulatory properties by binding to specific receptors and downstream molecules and exerts a myriad of receptor‐independent actions via intracellular targets as a chondrocyte protector, an anti‐inflammation modulator, and a free radical scavenger. Melatonin also modulates cartilage regeneration and degradation by directly/indirectly regulating the expression of main circadian clock genes, such as transcriptional activators [brain and muscle aryl hydrocarbon receptor nuclear translocator‐like protein (Bmal) and circadian locomotor output cycles kaput (Clock)], transcriptional repressors [period circadian regulator (Per)1/2, cryptochrome (Cry)1/2, and Dec2], and nuclear hormone receptors [Rev‐Erbs and retinoid acid‐related orphan receptors (Rors)]. Owing to its effects on cartilage homeostasis, we propose a potential role for melatonin in the prevention and therapy of OA via the modulation of circadian clock genes, mitigation of chondrocyte apoptosis, anti‐inflammatory activity, and scavenging of free radicals. [ABSTRACT FROM AUTHOR]
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- 2021
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38. Melatonin effects on bone: Implications for use as a therapy for managing bone loss.
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Munmun, Fahima and Witt‐Enderby, Paula A.
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MELANOPSIN ,FREE radicals ,MELATONIN ,FREE radical scavengers ,BONE density ,QUALITY of life ,SHIFT systems - Abstract
Melatonin is the primary circadian output signal from the brain and is mainly synthesized in pinealocytes. The rhythm and secretion of melatonin are under the control of an endogenous oscillator located in the SCN or the master biological clock. Disruptions in circadian rhythms by shift work, aging, or light at night are associated with bone loss and increased fracture risk. Restoration of nocturnal melatonin peaks to normal levels or therapeutic levels through timed melatonin supplementation has been demonstrated to provide bone‐protective actions in various models. Melatonin is a unique molecule with diverse molecular actions targeting melatonin receptors located on the plasma membrane or mitochondria or acting independently of receptors through its actions as an antioxidant or free radical scavenger to stimulate osteoblastogenesis, inhibit osteoclastogenesis, and improve bone density. Its additional actions on entraining circadian rhythms and improving quality of life in an aging population coupled with its safety profile make it an ideal therapeutic candidate for protecting against bone loss in susceptible populations. The intent of this review is to provide a focused discussion on bone loss and disorders of the bone as it relates to melatonin and conditions that modify melatonin levels with the hope that future therapies include those that include melatonin and correct those factors that modify melatonin levels like circadian disruption. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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39. Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia.
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Aridas, James DS., Yawno, Tamara, Sutherland, Amy E., Nitsos, Ilias, Wong, Flora Y., Hunt, Rod W., Ditchfield, Michael, Fahey, Michael C., Malhotra, Atul, Wallace, Euan M., Gunn, Alistair J., Jenkin, Graham, and Miller, Suzanne L.
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ASPHYXIA neonatorum ,NUCLEAR magnetic resonance spectroscopy ,CESAREAN section ,LAMBS ,NEUROPROTECTIVE agents - Abstract
Therapeutic hypothermia (TH) is standard care in high‐resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 ± 3 mm Hg in sham controls to 18‐20 mm Hg (10.1 ± 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole‐body cooling to 35.1 ± 0.8°C vs. 38.3 ± 0.17°C in sham controls, from 4‐28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P =.003) and reduced NAA:Choline (P =.005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P <.05), and increased neuroinflammation and oxidative stress (P <.05). TH and MLT were independently associated with region‐specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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40. Melatonin rescues the reproductive toxicity of low‐dose glyphosate‐based herbicide during mouse oocyte maturation via the GPER signaling pathway.
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Cao, Mingjun, Wang, Yufeng, Yang, Fan, Li, Jizhou, and Qin, Xunsi
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OVUM ,HERBICIDES ,MELATONIN ,REACTIVE oxygen species - Abstract
Glyphosate‐based herbicides (GBHs) are a group of widely used broad‐spectrum agricultural pesticides. Due to the recalcitrance of GBH, it has been found in food and environment as a contaminant, posing a threat to public health. The health risks associated with GBH have been indicated by reporting acute toxicity data (an acute exposure of GBH at a 0.5% dose), which primarily discuss toxicity in relation to accidental high‐rate exposure. Currently, there is little information regarding the toxicity of GBH at environmentally relevant levels. In this study, we used mature mouse oocytes to study the toxic effects of low‐dose GBH exposure in vitro (0.00001%–0.00025%) and in vivo (0.0005%, orally administered through daily drinking water) during meiotic maturation. GBH exposure led to meiotic maturation failure with spindle defects and chromosome misalignment. In addition, GBH treatment severely reduced sperm‐binding ability and disrupted early embryo cleavage. Moreover, GBH exposure significantly increased the reactive oxygen species (ROS) levels and apoptotic rates. Evidence indicates that such effects in GBH‐exposed oocytes are likely due to overexpression of the G‐protein estrogen receptor (GPER/GPR30). Remarkably, we found that melatonin administration elicited significant protection against GBH‐induced oocyte deterioration via preserving the expression of GPR30, along with activation of its downstream signaling event (pERK/ERK). Taken together, these results revealed that low‐dose glyphosate has a certain adverse effect on oocyte maturation and early embryo cleavage, and highlight the protective roles of melatonin. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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41. Melatonin attenuates choroidal neovascularization by regulating macrophage/microglia polarization via inhibition of RhoA/ROCK signaling pathway.
- Author
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Xu, Yue, Cui, Kaixuan, Li, Jia, Tang, Xiaoyu, Lin, Jianqiang, Lu, Xi, Huang, Rong, Yang, Boyu, Shi, Yuxun, Ye, Dan, Huang, Jingjing, Yu, Shanshan, and Liang, Xiaoling
- Subjects
MELATONIN ,MICROGLIA ,NEOVASCULARIZATION ,RANIBIZUMAB ,OLDER patients ,RETINAL degeneration ,PATHOLOGIC neovascularization - Abstract
Choroidal neovascularization (CNV) is an important characteristic of advanced wet age‐related macular degeneration (AMD) and leads to severe visual impairment among elderly patients. Previous studies have demonstrated that melatonin induces several biological effects related to antioxidation, anti‐inflammation, and anti‐angiogenesis. However, the role of melatonin in CNV, and its underlying mechanisms, has not been investigated thus far. In this study, we found that melatonin administration significantly reduced the scale and volume of CNV lesions, suppressed vascular leakage, and inhibited the capacity of vascular proliferation in the laser‐induced mouse CNV model. Additionally, the results also show that the melatonin‐treated retinal microglia in the laser‐induced mice exhibited enhanced expression of M1‐type markers, such as iNOS, CCL‐3, CCL‐5, and TNF‐α, as well as decreased production of M2‐type markers, such as Arg‐1, Fizz‐1, IL‐10, YM‐1, and CD206, indicating that melatonin switched the macrophage/microglia polarization from pro‐angiogenic M2 phenotype to anti‐angiogenic M1 phenotype. Furthermore, the RhoA/ROCK signaling pathway was activated during CNV formation, yet was suppressed after an intraperitoneal injection of melatonin. In conclusion, melatonin attenuated CNV, reduced vascular leakage, and inhibited vascular proliferation by switching the macrophage/microglia polarization from M2 phenotype to M1 phenotype via inhibition of RhoA/ROCK signaling pathway in CNV. This suggests that melatonin could be a novel agent for the treatment of AMD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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42. Melatonin and its analogues for the prevention of postoperative delirium: A systematic review and meta‐analysis.
- Author
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Han, Yunyang, Wu, Jie, Qin, Zaisheng, Fu, Weijun, Zhao, Bingcheng, Li, Xue, Wang, Wenyan, Sha, Tong, Sun, Maomao, Li, Jiaxin, Zeng, Zhenhua, and Chen, Zhongqing
- Subjects
META-analysis ,MELATONIN ,DELIRIUM ,ODDS ratio ,CARDIAC surgery - Abstract
It remains unclear whether melatonin and its analogues prevent postoperative delirium (POD). Therefore, we conducted a systematic review and meta‐analysis to evaluate the effect of melatonin and its analogues on POD prevention. PubMed, Cochrane Library, Web of Science, Embase and CINAHL databases were searched. Primary outcome was the incidence of POD. Six randomized controlled trials, 2 cohort studies and 1 case‐control study were included in this meta‐analysis. Results showed that melatonin and its analogue ramelteon decreased the incidence of POD in the entire adult surgical population (odds ratio [OR] = 0.45, 95% confidence interval [CI] 0.24‐0.84, P =.01). When administered at a higher dose (5 mg), melatonin was effective in reducing the POD incidence (OR = 0.32, 95% CI 0.20‐0.52, P <.00001). Melatonin administered less than 5 elimination half‐lives before the surgery significantly reduced the POD incidence (OR = 0.31, 95% CI 0.19‐0.49, P <.00001). Current literature supports the effectiveness of melatonin and its analogue ramelteon in POD prevention. However, the present study was limited by the significant heterogeneity of the included studies. More studies are needed to ascertain the preventive effect of melatonin and its analogues on the incidence of delirium after cardiac and noncardiac surgeries. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Melatonin attenuates osteosarcoma cell invasion by suppression of C‐C motif chemokine ligand 24 through inhibition of the c‐Jun N‐terminal kinase pathway.
- Author
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Lu, Ko‐Hsiu, Su, Shih‐Chi, Lin, Chiao‐Wen, Hsieh, Yi‐Hsien, Lin, Ya‐Chiu, Chien, Ming‐Hsien, Reiter, Russel J., and Yang, Shun‐Fa
- Subjects
MELATONIN ,OSTEOSARCOMA in children ,CHEMOKINES ,CELL migration ,CELL-mediated cytotoxicity - Abstract
Abstract: Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor‐suppressing properties for a myriad of tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C‐C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal‐regulated kinase (ERK) 1/2 and c‐Jun N‐terminal kinase (JNK) 1/2, respectively, in a dose‐dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN‐JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin‐mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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44. Melatonin and its derivatives counteract the ultraviolet B radiation‐induced damage in human and porcine skin ex vivo.
- Author
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Skobowiat, Cezary, Brożyna, Anna A., Janjetovic, Zorica, Jeayeng, Saowanee, Oak, Allen S. W., Kim, Tae‐Kang, Panich, Uraiwan, Reiter, Russel J., and Slominski, Andrzej T.
- Subjects
PHYSIOLOGICAL effects of melatonin ,ULTRAVIOLET radiation ,SEROTONIN ,DNA damage ,TUMOR suppressor genes ,THERAPEUTICS - Abstract
Abstract: Melatonin and its derivatives (N
1 ‐acetyl‐N2 ‐formyl‐5‐methoxykynurenine [AFMK] and N‐acetyl serotonin [NAS]) have broad‐spectrum protective effects against photocarcinogenesis, including both direct and indirect antioxidative actions, regulation of apoptosis and DNA damage repair; these data were primarily derived from in vitro models. This study evaluates possible beneficial effects of melatonin and its active derivatives against ultraviolet B (UVB)‐induced harm to human and porcine skin ex vivo and to cultured HaCaT cells. The topical application of melatonin, AFMK, or NAS protected epidermal cells against UVB‐induced 8‐OHdG formation and apoptosis with a further increase in p53ser15 expression, especially after application of melatonin or AFMK but not after NAS use. The photoprotective action was observed in pre‐ and post‐UVB treatment in both human and porcine models. Melatonin along with its derivatives upregulated also the expression of antioxidative enzymes after UVB radiation of HaCaT cells. The exogenous application of melatonin or its derivatives represents a potent and promising tool for preventing UVB‐induced oxidative stress and DNA damage. This protection results in improved genomic, cellular, and tissue integrity against UVB‐induced carcinogenesis, especially when applied prior to UV exposure. In addition, our ex vivo experiments provide fundamental justification for further testing the clinical utility of melatonin and metabolites as protectors again UVB in human subjects. Our ex vivo data constitute the bridge between vitro to vivo translation and thus justifies the pursue for further clinical utility of melatonin in maintaining skin homeostasis. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
45. Melatonin is involved in skotomorphogenesis by regulating brassinosteroid biosynthesis in rice plants.
- Author
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Hwang, Ok Jin and Back, Kyoungwhan
- Subjects
MELATONIN ,BRASSINOSTEROIDS ,RICE yields ,BIOCHEMICAL engineering ,CIRCADIAN rhythms - Abstract
Abstract: Serotonin N‐acetyltransferase (SNAT) is the penultimate enzyme in melatonin biosynthesis catalyzing the conversion of serotonin into N‐acetylserotonin. In plants, SNAT is encoded by 2 isogenes of which SNAT1 is constitutively expressed and its overexpression confers increased yield in rice. However, the role of SNAT2 remains to be clarified. In contrast to SNAT1, the diurnal rhythm of SNAT2 mRNA expression peaks at night. In this study, transgenic rice plants in which SNAT2 expression were suppressed by RNAi technology showed a decrease in melatonin and a dwarf phenotype with erect leaves, reminiscent of brassinosteroids (BR)‐deficient mutants. Of note, the dwarf phenotype was dependent on the presence of dark, suggesting that melatonin is involved in dark growth (skotomorphogenesis). In support of this suggestion, SNAT2 RNAi lines exhibited photomorphogenic phenotypes such as inhibition of internodes and increased expression of light‐inducible CAB genes in the dark. The causative gene for the melatonin‐mediated BR biosynthetic gene was DWARF4, a rate‐limiting BR biosynthetic gene. Exogenous melatonin treatment induced several BR biosynthetic genes, including DWARF4, D11, and RAVL1. As expected from the erect leaves, the SNAT2 RNAi lines produced less BR than the wild type. Our results show for the first time that melatonin is a positive regulator of dark growth or shade outgrowth by regulating BR biosynthesis in plants. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
46. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection.
- Author
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Galano, Annia and Reiter, Russel J.
- Subjects
MELATONIN ,METABOLITES ,OXIDATIVE stress ,BIOMOLECULES ,ANTIOXIDANTS - Abstract
Abstract: Oxidative stress (OS) represents a threat to the chemical integrity of biomolecules including lipids, proteins, and DNA. The associated molecular damage frequently results in serious health issues, which justifies our concern about this phenomenon. In addition to enzymatic defense mechanisms, there are compounds (usually referred to as antioxidants) that offer chemical protection against oxidative events. Among them, melatonin and its metabolites constitute a particularly efficient chemical family. They offer protection against OS as individual chemical entities through a wide variety of mechanisms including electron transfer, hydrogen transfer, radical adduct formation, and metal chelation, and by repairing biological targets. In fact, many of them including melatonin can be classified as multipurpose antioxidants. However, what seems to be unique to the melatonin's family is their collective effects. Because the members of this family are metabolically related, most of them are expected to be present in living organisms wherever melatonin is produced. Therefore, the protection exerted by melatonin against OS may be viewed as a result of the combined antioxidant effects of the parent molecule and its metabolites. Melatonin's family is rather exceptional in this regard, offering versatile and collective antioxidant protection against OS. It certainly seems that melatonin is one of the best nature's defenses against oxidative damage. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
47. Melatonin and cardioprotection against ischaemia/reperfusion injury: What's new? A review.
- Author
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Lochner, Amanda, Marais, Erna, and Huisamen, Barbara
- Subjects
MELATONIN ,CARDIOTONIC agents ,ISCHEMIA prevention ,REPERFUSION injury ,CYTOSOL ,THERAPEUTICS - Abstract
Abstract: Melatonin is a pleiotropic hormone with several functions. It binds to specific receptors and to a number of cytosolic proteins, activating a vast array of signalling pathways. Its potential to protect the heart against ischaemia/reperfusion damage has attracted much attention, particularly in view of its possible clinical applications. This review will focus mainly on the possible signalling pathways involved in melatonin‐induced cardioprotection. In particular, the role of the melatonin receptors and events downstream of receptor activation, for example, the reperfusion injury salvage kinase (RISK), survivor activating factor enhancement (SAFE) and Notch pathways, the sirtuins, nuclear factor E2–related factor 2 (Nrf2) and translocases in the outer membrane (TOM70) will be discussed. Particular attention is given to the role of the mitochondrion in melatonin‐induced cardioprotection. In addition, a brief overview will be given regarding the status quo of the clinical application of melatonin in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
48. Rapid modulation of the silent information regulator 1 by melatonin after hypoxia-ischemia in the neonatal rat brain.
- Author
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Carloni, Silvia, Riparini, Giulia, Buonocore, Giuseppe, and Balduini, Walter
- Subjects
MELATONIN ,HYPOXEMIA ,ISCHEMIA ,LABORATORY rats ,NEUROGLIA - Abstract
Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia ( HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 ( SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
49. The role and therapeutic potential of melatonin in age-related ocular diseases.
- Author
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Crooke, Almudena, Huete‐Toral, Fernando, Colligris, Basilio, and Pintor, Jesús
- Subjects
MELATONIN ,SOLAR ultraviolet radiation ,RETINAL diseases ,NEOVASCULARIZATION ,INFLAMMATION - Abstract
The eye is continuously exposed to solar UV radiation and pollutants, making it prone to oxidative attacks. In fact, oxidative damage is a major cause of age-related ocular diseases including cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy. As the nature of lens cells, trabecular meshwork cells, retinal ganglion cells, retinal pigment epithelial cells, and photoreceptors is postmitotic, autophagy plays a critical role in their cellular homeostasis. In age-related ocular diseases, this process is impaired, and thus, oxidative damage becomes irreversible. Other conditions such as low-grade chronic inflammation and angiogenesis also contribute to the development of retinal diseases (glaucoma, age-related macular degeneration and diabetic retinopathy). As melatonin is known to have remarkable qualities such as antioxidant/antinitridergic, mitochondrial protector, autophagy modulator, anti-inflammatory, and anti-angiogenic, it can represent a powerful tool to counteract all these diseases. The present review analyzes the role and therapeutic potential of melatonin in age-related ocular diseases, focusing on nitro-oxidative stress, autophagy, inflammation, and angiogenesis mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
50. Chloroplast overexpression of rice caffeic acid O-methyltransferase increases melatonin production in chloroplasts via the 5-methoxytryptamine pathway in transgenic rice plants.
- Author
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Choi, Geun‐Hee, Lee, Hyoung Yool, and Back, Kyoungwhan
- Subjects
MELATONIN ,ENZYME regulation ,PHYSIOLOGICAL effects of cadmium ,METHYLTRANSFERASES ,SEROTONIN ,CHLOROPLASTS - Abstract
Recent analyses of the enzymatic features of various melatonin biosynthetic genes from bacteria, animals, and plants have led to the hypothesis that melatonin could be synthesized via the 5-methoxytryptamine (5- MT) pathway. 5- MT is known to be synthesized in vitro from serotonin by the enzymatic action of O-methyltransferases, including N-acetylserotonin methyltransferase ( ASMT) and caffeic acid O-methyltransferase ( COMT), leading to melatonin synthesis by the subsequent enzymatic reaction with serotonin N-acetyltransferase ( SNAT). Here, we show that 5- MT was produced and served as a precursor for melatonin synthesis in plants. When rice seedlings were challenged with senescence treatment, 5- MT levels and melatonin production were increased in transgenic rice seedlings overexpressing the rice COMT in chloroplasts, while no such increases were observed in wild-type or transgenic seedlings overexpressing the rice COMT in the cytosol, suggesting a 5- MT transport limitation from the cytosol to chloroplasts. In contrast, cadmium treatment led to results different from those in senescence. The enhanced melatonin production was not observed in the chloroplast COMT lines relative over the cytosol COMT lines although 5- MT levels were equally induced in all genotypes upon cadmium treatment. The transgenic seedlings with enhanced melatonin in their chloroplasts exhibited improved seedling growth vs the wild type under continuous light conditions. This is the first report describing enhanced melatonin production in chloroplasts via the 5- MT pathway with the ectopic overexpression of COMT in chloroplasts in plants. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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