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Article: Changes in Cortisol and in Oxidative/Nitrosative Stress Indicators after ADHD Treatment.

Garre-Morata, Laura / de Haro, Tomás / Villén, Raquel González / Fernández-López, María Luisa / Escames, Germaine / Molina-Carballo, Antonio / Acuña-Castroviejo, Darío

Antioxidants (Basel, Switzerland)

2024 Volume 13, Issue 1

Abstract: Although ADHD is one of the most prevalent diseases during childhood, we still do not know its precise origin; oxidative/nitrosative stress and the hypothalamic-pituitary-adrenal axis are suggested contributors. Methylphenidate, among others, is the main ...

Abstract	Although ADHD is one of the most prevalent diseases during childhood, we still do not know its precise origin; oxidative/nitrosative stress and the hypothalamic-pituitary-adrenal axis are suggested contributors. Methylphenidate, among others, is the main drug used in ADHD patients, but its effects on relevant markers and structures remain unclear. This study, involving 59 patients diagnosed with ADHD according to DSM-5 criteria, aimed to assess changes in cortisol levels (using cortisol awakening response, CAR) and oxidative/nitrosative status with the treatment. Blood samples before and 3 months after treatment with methylphenidate were used to measure oxidative and inflammatory markers, as well as the endogenous antioxidant activity, while saliva samples tracked cortisol awakening response (CAR). The results showed a treatment-related improvement in the redox profile, with the reduction in advanced oxidation protein products (AOPP), lipid peroxidation (LPO), and nitrite plus nitrate (NOx) levels, and the increase in the enzymatic activities of glutathione reductase (GRd) and catalase (CAT). Moreover, the area under the curve (AUC) of CAR increased significantly, indicating increased reactivity of the HPA axis. These results support, for the first time, the involvement of the endogenous antioxidant system in the pathophysiology of ADHD.
Language	English
Publishing date	2024-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox13010092
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Article ; Online: Role of Melatonin in Cancer: Effect on Clock Genes.

Rodríguez-Santana, César / Florido, Javier / Martínez-Ruiz, Laura / López-Rodríguez, Alba / Acuña-Castroviejo, Darío / Escames, Germaine

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: The circadian clock is a regulatory system, with a periodicity of approximately 24 h, that generates rhythmic changes in many physiological processes. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, ... ...

Abstract	The circadian clock is a regulatory system, with a periodicity of approximately 24 h, that generates rhythmic changes in many physiological processes. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases, including cancer. In this context, tumor cells have an altered circadian machinery compared to normal cells, which deregulates the cell cycle, repair mechanisms, energy metabolism and other processes. Melatonin is the main hormone produced by the pineal gland, whose production and secretion oscillates in accordance with the light:dark cycle. In addition, melatonin regulates the expression of clock genes, including those in cancer cells, which could play a key role in the numerous oncostatic effects of this hormone. This review aims to describe and clarify the role of clock genes in cancer, as well as the possible mechanisms of the action of melatonin through which it regulates the expression of the tumor's circadian machinery, in order to propose future anti-neoplastic clinical treatments.
MeSH term(s)	Melatonin/metabolism ; Circadian Rhythm/genetics ; Pineal Gland/metabolism ; Circadian Clocks/genetics ; Photoperiod ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2023-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24031919
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Article ; Online: iMS-Bmal1

Fernández-Martínez, José / Ramírez-Casas, Yolanda / Aranda-Martínez, Paula / López-Rodríguez, Alba / Sayed, Ramy K A / Escames, Germaine / Acuña-Castroviejo, Darío

Journal of pineal research

2023 Volume 76, Issue 1, Page(s) e12912

Abstract: Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no ... ...

Abstract	Sarcopenia is an age-related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle-specific and inducible Bmal1 knockout mice (iMS-Bmal1
MeSH term(s)	Female ; Male ; Animals ; Mice ; Sarcopenia/drug therapy ; Sarcopenia/pathology ; Melatonin/pharmacology ; Melatonin/therapeutic use ; Frailty/drug therapy ; Frailty/pathology ; Muscle, Skeletal/pathology ; Microscopy, Electron
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	632697-3
ISSN	1600-079X ; 0742-3098
ISSN (online)	1600-079X
ISSN	0742-3098
DOI	10.1111/jpi.12912
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Article: Chronodisruption and Loss of Melatonin Rhythm, Associated with Alterations in Daily Motor Activity and Mitochondrial Dynamics in Parkinsonian Zebrafish, Are Corrected by Melatonin Treatment.

Aranda-Martínez, Paula / Fernández-Martínez, José / Ramírez-Casas, Yolanda / Rodríguez-Santana, César / Rusanova, Iryna / Escames, Germaine / Acuña-Castroviejo, Darío

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 4

Abstract: Beyond sleep/wake, clock genes regulate the daily rhythms of melatonin production, motor activity, innate immunity, and mitochondrial dynamics, among others. All these rhythms are affected in Parkinson's disease (PD), suggesting that chronodisruption may ...

Abstract	Beyond sleep/wake, clock genes regulate the daily rhythms of melatonin production, motor activity, innate immunity, and mitochondrial dynamics, among others. All these rhythms are affected in Parkinson's disease (PD), suggesting that chronodisruption may be an early stage of the disease. The aim of this study was to evaluate the connection between clock genes and these rhythms in PD, and whether melatonin administration reestablished the normal clock function. Parkinsonism was induced with 600 μM MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in 24-120 h post fertilization (hpf) zebrafish embryos and melatonin was administered at a dose of 1 μM. Day-night melatonin rhythm disappeared in MPTP-treated embryos, which showed an advance in the activity phase in parallel with changes in the rhythm of clock genes. An alteration in the fission-to-fusion mitochondrial dynamics was also detected in parkinsonian embryos, increasing the former and leading to apoptosis. Melatonin administration to MPTP-treated embryos fully restored the circadian system, including the rhythms of clock genes, motor activity, melatonin rhythm, and mitochondrial dynamics, and decreasing apoptosis. Because clock-controlled rhythms such as sleep/wake alterations are early events in PD, the data here reported may point to chronodisruption as one initial pathophysiological event of the disease.
Language	English
Publishing date	2023-04-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12040954
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Article ; Online: From Chronodisruption to Sarcopenia: The Therapeutic Potential of Melatonin.

Fernández-Martínez, José / Ramírez-Casas, Yolanda / Yang, Yang / Aranda-Martínez, Paula / Martínez-Ruiz, Laura / Escames, Germaine / Acuña-Castroviejo, Darío

Biomolecules

2023 Volume 13, Issue 12

Abstract: Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like ... ...

Abstract	Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.
MeSH term(s)	Humans ; Sarcopenia/drug therapy ; Sarcopenia/metabolism ; Melatonin/pharmacology ; Melatonin/therapeutic use ; Melatonin/metabolism ; Aging/metabolism ; Muscle, Skeletal/metabolism ; Oxidative Stress
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2023-12-12
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13121779
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Article ; Online: Patient-derived tumor models in cancer research: Evaluation of the oncostatic effects of melatonin.

Martinez-Ruiz, Laura / López-Rodríguez, Alba / Florido, Javier / Rodríguez-Santana, Cesar / Rodríguez Ferrer, José M / Acuña-Castroviejo, Darío / Escames, Germaine

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 167, Page(s) 115581

Abstract: The development of new anticancer therapies tends to be very slow. Although their impact on potential candidates is confirmed in preclinical studies, ∼95 % of these new therapies are not approved when tested in clinical trials. One of the main reasons ... ...

Abstract	The development of new anticancer therapies tends to be very slow. Although their impact on potential candidates is confirmed in preclinical studies, ∼95 % of these new therapies are not approved when tested in clinical trials. One of the main reasons for this is the lack of accurate preclinical models. In this context, there are different patient-derived models, which have emerged as a powerful oncological tool: patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived cells (PDCs). Although all these models are widely applied, PDXs, which are created by engraftment of patient tumor tissues into mice, is considered more reliable. In fundamental research, the PDX model is used to evaluate drug-sensitive markers and, in clinical practice, to select a personalized therapeutic strategy. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. However, the literature regarding the oncostatic effect of melatonin in patient-derived tumor models is scant. This review aims to describe the important role of patient-derived models in the development of anticancer treatments, focusing, in particular, on PDX models, as well as their use in cancer research. This review also summarizes the existing literature on the anti-tumoral effect of melatonin in patient-derived models in order to propose future anti-neoplastic clinical applications.
Language	English
Publishing date	2023-09-23
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.115581
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Article ; Online: The Zebrafish, an Outstanding Model for Biomedical Research in the Field of Melatonin and Human Diseases.

Aranda-Martínez, Paula / Fernández-Martínez, José / Ramírez-Casas, Yolanda / Guerra-Librero, Ana / Rodríguez-Santana, César / Escames, Germaine / Acuña-Castroviejo, Darío

International journal of molecular sciences

2022 Volume 23, Issue 13

Abstract: The zebrafish has become an excellent model for the study of human diseases because it offers many advantages over other vertebrate animal models. The pineal gland, as well as the biological clock and circadian rhythms, are highly conserved in zebrafish, ...

Abstract	The zebrafish has become an excellent model for the study of human diseases because it offers many advantages over other vertebrate animal models. The pineal gland, as well as the biological clock and circadian rhythms, are highly conserved in zebrafish, and melatonin is produced in the pineal gland and in most organs and tissues of the body. Zebrafish have several copies of the clock genes and of
MeSH term(s)	Animals ; Antioxidants/metabolism ; Biomedical Research ; Circadian Rhythm/physiology ; Humans ; Mammals/metabolism ; Melatonin/metabolism ; Pineal Gland/metabolism ; Zebrafish/genetics
Chemical Substances	Antioxidants ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-07-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23137438
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Article: Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells.

Florido, Javier / Rodriguez-Santana, César / Martinez-Ruiz, Laura / López-Rodríguez, Alba / Acuña-Castroviejo, Darío / Rusanova, Iryna / Escames, Germaine

Antioxidants (Basel, Switzerland)

2022 Volume 11, Issue 8

Abstract: Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as ... ...

Abstract	Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.
Language	English
Publishing date	2022-08-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11081621
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Article ; Online: Cardiometabolic impact of changing internal time during daylight saving time: a window for a deleterious role within sleep-related breathing disorders.

Meira E Cruz, Miguel / Acuña-Castroviejo, Dario

Internal and emergency medicine

2018 Volume 13, Issue 8, Page(s) 1345–1346

MeSH term(s)	Cardiovascular System ; Circadian Rhythm ; Humans ; Respiration ; Time
Language	English
Publishing date	2018-08-27
Publishing country	Italy
Document type	Letter ; Comment
ZDB-ID	2454173-4
ISSN	1970-9366 ; 1828-0447
ISSN (online)	1970-9366
ISSN	1828-0447
DOI	10.1007/s11739-018-1934-7
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Article ; Online: A phase II, single-center, double-blind, randomized placebo-controlled trial to explore the efficacy and safety of intravenous melatonin in surgical patients with severe sepsis admitted to the intensive care unit.

Mansilla-Roselló, Alfonso / Hernández-Magdalena, Jorge / Domínguez-Bastante, Mireia / Olmedo-Martín, Carmen / Comino-Pardo, Ana / Escames, Germaine / Acuña-Castroviejo, Darío

Journal of pineal research

2022 Volume 74, Issue 2, Page(s) e12845

Abstract: To determine whether IV melatonin therapy improves redox status and inflammatory responses in surgical patients with severe sepsis, a unicenter, phase II double-blind, randomized, placebo-controlled trial was carried out. The study included patients with ...

Abstract	To determine whether IV melatonin therapy improves redox status and inflammatory responses in surgical patients with severe sepsis, a unicenter, phase II double-blind, randomized, placebo-controlled trial was carried out. The study included patients with severe sepsis marked by infectious systemic inflammatory response syndrome (SIRS), associated with organ dysfunction, hypoperfusion or hypotension requiring surgical intervention. IV melatonin at a daily dose of 60 mg, which was dissolved in 500 ml of 5% dextrose serum, was continuously administered to the patients for over 30 min starting on the day of the diagnoses during a 5-day period. A total of 14 patients received a placebo treatment and 15 melatonin doses. Redox status decreased in melatonin-treated patients during the 5 days of treatment as compared to the placebo-treated patients. Procalcitonin performed better in the melatonin group, whose neutrophil to lymphocyte ratio was also significantly reduced, resulting in an improved evolution of the disease. Moreover, hospital stays decreased by 19.60% from 26.64 days for the placebo group to 21.42 days for the melatonin group. The placebo group recorded five mortalities, as compared to three for the melatonin group. IV melatonin administration improved the course of the disease in surgical patients with severe sepsis, with no side effects. Additional studies with higher doses of melatonin and a long duration of therapy need to be carried out to assess its clinical use.
MeSH term(s)	Humans ; Melatonin/therapeutic use ; Sepsis/drug therapy ; Intensive Care Units ; Double-Blind Method
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-12-02
Publishing country	England
Document type	Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	632697-3
ISSN	1600-079X ; 0742-3098
ISSN (online)	1600-079X
ISSN	0742-3098
DOI	10.1111/jpi.12845
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