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Article ; Online: Melatonin Modulates Cell Cycle Dynamics and Promotes Hippocampal Cell Proliferation After Ischemic Injury in Neonatal Rats.

Canonico, Barbara / Carloni, Silvia / Montanari, Mariele / Ambrogini, Patrizia / Papa, Stefano / Alonso-Alconada, Daniel / Balduini, Walter

Molecular neurobiology

2024

Abstract: Promoting neural cell proliferation may represent an important strategy for enhancing brain repair after developmental brain injury. The present study aimed to assess the effects of melatonin on cell proliferation after an ischemic injury in the ... ...

Abstract	Promoting neural cell proliferation may represent an important strategy for enhancing brain repair after developmental brain injury. The present study aimed to assess the effects of melatonin on cell proliferation after an ischemic injury in the developing hippocampus, focusing on cell cycle dynamics. After in vivo neonatal hypoxia-ischemia (HI), hippocampal cell cycle dynamics were assessed by flow cytometry, together with histological evaluation of dentate gyrus cellularity and proliferation. Melatonin significantly increased the number of proliferating cells in the G2/M phase as well as the proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) labeling reduced by HI. In vivo BrdU labeling revealed a higher BrdU-positivity in the dentate gyrus of ischemic rats treated with melatonin, an effect followed by increased cellularity and preserved hippocampal tissue integrity. These results indicate that the protective effect of melatonin after ischemic injury in neonatal rats may rely on the modulation of cell cycle dynamics of newborn hippocampal cells and increased cell proliferation.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-024-04013-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 2411: Show issues

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Article ; Online: Simvastatin preconditioning confers neuroprotection against hypoxia-ischemia induced brain damage in neonatal rats via autophagy and silent information regulator 1 (SIRT1) activation.

Carloni, Silvia / Balduini, Walter

Experimental neurology

2019 Volume 324, Page(s) 113117

Abstract: Previous studies have shown that simvastatin (Sim) has neuroprotective effects in a neonatal model of hypoxia-ischemia (HI)-induced brain injury when administered before but not after HI, pointing to the preconditioning (PC)-like effects of the statin. ... ...

Abstract	Previous studies have shown that simvastatin (Sim) has neuroprotective effects in a neonatal model of hypoxia-ischemia (HI)-induced brain injury when administered before but not after HI, pointing to the preconditioning (PC)-like effects of the statin. The present study aimed to gain more insight into the PC-like effect of Sim by studying the role of autophagy and its modulation by mTOR and SIRT1 in neuroprotection. Sim potentiated the autophagy response induced by neonatal HI, as shown by the increased expression of both microtubule-associated protein 1 light chain 3 (LC3) and beclin 1, increased monodansylcadaverine (MDC) labeling, and reduced expression of p62. The autophagy inhibitor 3-methyladenine (3MA) completely blocked the neuroprotective effect of Sim. Two hours after HI, there was a reduction in the activity of mTORC1 and a concomitant increase in that of mTORC2. Sim preconditioning further decreased the activity of mTORC1, but did not affect that of mTORC2. However, 24 h after injury, mTORC2 activity was significantly preserved in Sim-treated rats. Sim preconditioning also prevented the depletion of SIRT1 induced by HI, an effect that was completely blocked by 3MA. These data show that Sim preconditioning may modulate autophagy and survival pathways by affecting mTORC1, mTORC2, and SIRT1 activities. This study provides further preclinical evidence of the PC-like effect of statins in brain tissue, supporting their beneficial effects in improving stroke outcome after prophylactic treatments.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Animals ; Animals, Newborn ; Autophagy/drug effects ; Brain Damage, Chronic/etiology ; Brain Damage, Chronic/pathology ; Brain Damage, Chronic/prevention & control ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Hypoxia-Ischemia, Brain/complications ; Hypoxia-Ischemia, Brain/drug therapy ; Hypoxia-Ischemia, Brain/pathology ; Ischemic Preconditioning ; Mechanistic Target of Rapamycin Complex 1/drug effects ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mechanistic Target of Rapamycin Complex 2/drug effects ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Simvastatin/antagonists & inhibitors ; Simvastatin/pharmacology ; Sirtuin 1/drug effects ; Sirtuin 1/metabolism
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Neuroprotective Agents ; 3-methyladenine (5142-23-4) ; Simvastatin (AGG2FN16EV) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Sirt1 protein, rat (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Adenine (JAC85A2161)
Language	English
Publishing date	2019-11-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2019.113117
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Article: Melatonin, tunneling nanotubes, mesenchymal cells, and tissue regeneration.

Luchetti, Francesca / Carloni, Silvia / Nasoni, Maria G / Reiter, Russel J / Balduini, Walter

Neural regeneration research

2022 Volume 18, Issue 4, Page(s) 760–762

Abstract: Mesenchymal stem cells are multipotent stem cells that reside in many human tissues and organs. Mesenchymal stem cells are widely used in experimental and clinical regenerative medicine due to their capability to transdifferentiate into various lineages. ...

Abstract	Mesenchymal stem cells are multipotent stem cells that reside in many human tissues and organs. Mesenchymal stem cells are widely used in experimental and clinical regenerative medicine due to their capability to transdifferentiate into various lineages. However, when transplanted, they lose part of their multipotency and immunomodulatory properties, and most of them die after injection into the damaged tissue. In this review, we discuss the potential utility of melatonin in preserving mesenchymal stem cells' survival and function after transplantation. Melatonin is a pleiotropic molecule regulating critical cell functions including apoptosis, endoplasmic reticulum stress, and autophagy. Melatonin is also synthesized in the mitochondria where it reduces oxidative stress, the opening of the mitochondrial permeability transition pore and the downstream caspase activation, activates uncoupling proteins, and curtails the proinflammatory response. In addition, recent findings showed that melatonin also promotes the formation of tunneling nanotubes and the transfer of mitochondria between cells through the connecting tubules. As mitochondrial dysfunction is a primary cause of mesenchymal stem cells death and senescence and a critical issue for survival after transplantation, we propose that melatonin by favoring mitochondria functionality and their transfer through tunneling nanotubes from healthy to suffering cells could improve mesenchymal stem cell-based therapy in a large number of diseases for which basic and clinical trials are underway.
Language	English
Publishing date	2022-10-17
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.353480
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Article ; Online: Tunneling nanotubes and mesenchymal stem cells: New insights into the role of melatonin in neuronal recovery.

Luchetti, Francesca / Carloni, Silvia / Nasoni, Maria G / Reiter, Russel J / Balduini, Walter

Journal of pineal research

2022 Volume 73, Issue 1, Page(s) e12800

Abstract: Efficient cell-to-cell communication is essential for tissue development, homeostasis, and the maintenance of cellular functions after injury. Tunneling nanotubes (TNTs) have emerged as a new important method of cell-to-cell communication. TNTs are ... ...

Abstract	Efficient cell-to-cell communication is essential for tissue development, homeostasis, and the maintenance of cellular functions after injury. Tunneling nanotubes (TNTs) have emerged as a new important method of cell-to-cell communication. TNTs are primarily established between stressed and unstressed cells and can transport a variety of cellular components. Mitochondria are important trafficked entities through TNTs. Transcellular mitochondria transfer permits the incorporation of healthy mitochondria into the endogenous network of recipient cells, changing the bioenergetic profile and other functional properties of the recipient and may allow the recipient cells to recuperate from apoptotic processes and return to a normal operating state. Mesenchymal cells (MSCs) can form TNTs and transfer mitochondria and other constituents to target cells. This occurs under both physiological and pathological conditions, leading to changes in cellular energy metabolism and functions. This review summarizes the newly described capacity of melatonin to improve mitochondrial fusion/fission dynamics and promote TNT formation. This new evidence suggests that melatonin's protective effects could be attributed to its ability to prevent mitochondrial damage in injured cells, reduce senescence, and promote anastasis, a natural cell recovery phenomenon that rescues cells from the brink of death. The modulation of these new routes of intercellular communication by melatonin could play a key role in increasing the therapeutic potential of MSCs.
MeSH term(s)	Cell Communication/physiology ; Cell Membrane Structures ; Melatonin/metabolism ; Melatonin/pharmacology ; Mesenchymal Stem Cells/metabolism ; Nanotubes
Chemical Substances	Tunneling Nanotubes ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-04-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632697-3
ISSN	1600-079X ; 0742-3098
ISSN (online)	1600-079X
ISSN	0742-3098
DOI	10.1111/jpi.12800
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Zs.A 2114: Show issues

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Article ; Online: MiR-126 and miR-146a as Melatonin-Responsive Biomarkers for Neonatal Brain Ischemia.

Albertini, Maria Cristina / Vanzolini, Tania / Perrone, Serafina / Weiss, Michael D / Buonocore, Giuseppe / Dell'Orto, Valentina / Balduini, Walter / Carloni, Silvia

Journal of molecular neuroscience : MN

2023 Volume 73, Issue 9-10, Page(s) 763–772

Abstract: Despite advances in obstetric and neonatal care, challenges remain in early identification of neonates with encephalopathy due to hypoxia-ischemia who are undergoing therapeutic hypothermia. Therefore, there is a deep search for biomarkers that can ... ...

Abstract	Despite advances in obstetric and neonatal care, challenges remain in early identification of neonates with encephalopathy due to hypoxia-ischemia who are undergoing therapeutic hypothermia. Therefore, there is a deep search for biomarkers that can identify brain injury. The aims of this study were to investigate the serum and brain expressions of two potential biomarkers, miR-126/miR-146a, in a preclinical model of hypoxia-ischemia (HI)-induced brain injury, and to explore their modulation during melatonin treatment. Seven-day-old rats were subjected to permanent ligation of the right carotid artery followed by 2.5 h hypoxia (HI). Melatonin (15 mg/kg) was administered 5 min after HI. Serum and brain samples were collected 1, 6 and 24 h after HI. Results show that HI caused a significant increase in the circulating levels of both miR-126 and miR-146a during the early phase of ischemic brain damage development (i.e. 1 h), with a parallel and opposite pattern in the ischemic cerebral cortex. These effects are not observed 24 h later. Treatment with melatonin restored the HI-induced effects on miR-126/miR-146a expressions, both in the cerebral cortex and in serum. We conclude that miR-126/miR-146a are promising biomarkers of HI injury and demonstrate an associated change in concentration following melatonin treatment.
MeSH term(s)	Female ; Pregnancy ; Animals ; Rats ; Melatonin/therapeutic use ; Animals, Newborn ; Hypoxia-Ischemia, Brain/drug therapy ; Brain/metabolism ; Brain Injuries/metabolism ; Biomarkers/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Ischemia/drug therapy ; Ischemia/metabolism
Chemical Substances	Melatonin (JL5DK93RCL) ; Biomarkers ; MicroRNAs ; MIRN126 microRNA, rat
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1043392-2
ISSN	1559-1166 ; 0895-8696
ISSN (online)	1559-1166
ISSN	0895-8696
DOI	10.1007/s12031-023-02155-6
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Zs.A 3006: Show issues

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Article ; Online: Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress

Perrone, Serafina / Romeo, Carmelo / Marseglia, Lucia / Manti, Sara / Rizzo, Cristina / Carloni, Silvia / Albertini, Maria Cristina / Balduini, Walter / Buonocore, Giuseppe / Weiss, Michael D. / Gitto, Eloisa

Antioxidants. 2023 Feb. 24, v. 12, no. 3

2023

Abstract: Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the ... ...

Abstract	Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, p < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, p < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL p = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, p = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, p = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, p = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.
Keywords	antioxidants ; blood ; lipids ; melatonin ; neonates ; oxidation ; oxidative stress ; peroxidation ; surgery
Language	English
Dates of publication	2023-0224
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12030563
Database	NAL-Catalogue (AGRICOLA)

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Article: The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic-Ischemic Brain Injury.

Duranti, Andrea / Beldarrain, Gorane / Álvarez, Antonia / Sbriscia, Matilde / Carloni, Silvia / Balduini, Walter / Alonso-Alconada, Daniel

Biomedicines

2022 Volume 11, Issue 1

Abstract: The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This ... ...

Abstract	The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response to endogenous and environmental insults, being of special relevance in the prevention and/or treatment of vascular disorders, such as stroke and neuroprotection after neonatal brain injury. Perinatal hypoxia-ischemia leading to neonatal encephalopathy is a devastating condition with no therapeutic approach apart from moderate hypothermia, which is effective only in some cases. This overview, therefore, gives a current description of the main components of the EC system (including cannabinoid receptors, ligands, and related enzymes), to later analyze the EC system as a target for neonatal neuroprotection with a special focus on its neurogenic potential after hypoxic-ischemic brain injury.
Language	English
Publishing date	2022-12-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11010028
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Article ; Online: Automated-Mechanical Procedure Compared to Gentle Enzymatic Tissue Dissociation in Cell Function Studies.

Montanari, Mariele / Burattini, Sabrina / Ciacci, Caterina / Ambrogini, Patrizia / Carloni, Silvia / Balduini, Walter / Lopez, Daniele / Panza, Giovanna / Papa, Stefano / Canonico, Barbara

Biomolecules

2022 Volume 12, Issue 5

Abstract: The first step to obtain a cellular suspension from tissues is the disaggregation procedure. The cell suspension method has to provide a representative sample of the different cellular subpopulations and to maximize the number of viable functional cells. ...

Abstract	The first step to obtain a cellular suspension from tissues is the disaggregation procedure. The cell suspension method has to provide a representative sample of the different cellular subpopulations and to maximize the number of viable functional cells. Here, we analyzed specific cell functions in cell suspensions from several rat tissues obtained by two different methods, automated-mechanical and enzymatic disaggregation. Flow cytometric, confocal, and ultrastructural (TEM) analyses were applied to the spleen, testis, liver and other tissues. Samples were treated by an enzymatic trypsin solution or processed by the Medimachine II (MMII). The automated-mechanical and enzymatic disaggregation procedures have shown to work similarly in some tissues, which displayed comparable amounts of apoptotic/necrotic cells. However, cells obtained by the enzyme-free Medimachine II protocols show a better preservation lysosome and mitochondria labeling, whereas the enzymatic gentle dissociation appears to constantly induce a lower amount of intracellular ROS; nevertheless, lightly increased ROS can be recognized as a complimentary signal to promote cell survival. Therefore, MMII represents a simple, fast, and standardized method for tissue processing, which allows to minimize bias arising from the operator's ability. Our study points out technical issues to be adopted for specific organs and tissues to obtain functional cells.
MeSH term(s)	Animals ; Cell Count ; Cell Survival ; Flow Cytometry/methods ; Male ; Rats ; Reactive Oxygen Species ; Testis
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2022-05-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12050701
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Article: Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress.

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 3

Abstract	Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL,
Language	English
Publishing date	2023-02-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12030563
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Article: Preclinical randomized controlled multicenter trials (pRCT) in stroke research: a new and valid approach to improve translation?

Balduini, Walter / Carloni, Silvia / Cimino, Mauro

Annals of translational medicine

2017 Volume 4, Issue 24, Page(s) 549

Language	English
Publishing date	2017-01-18
Publishing country	China
Document type	Journal Article ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2016.12.41
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