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Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6

3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these nove...

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Autores principales: Bellusci, Lorenza, Runfola, Massimiliano, Carnicelli, Vittoria, Sestito, Simona, Fulceri, Federica, Santucci, Filippo, Lenzi, Paola, Fornai, Francesco, Rapposelli, Simona, Origlia, Nicola, Zucchi, Riccardo, Chiellini, Grazia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179148/
https://www.ncbi.nlm.nih.gov/pubmed/32110992
http://dx.doi.org/10.3390/molecules25051054
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author Bellusci, Lorenza
Runfola, Massimiliano
Carnicelli, Vittoria
Sestito, Simona
Fulceri, Federica
Santucci, Filippo
Lenzi, Paola
Fornai, Francesco
Rapposelli, Simona
Origlia, Nicola
Zucchi, Riccardo
Chiellini, Grazia
author_facet Bellusci, Lorenza
Runfola, Massimiliano
Carnicelli, Vittoria
Sestito, Simona
Fulceri, Federica
Santucci, Filippo
Lenzi, Paola
Fornai, Francesco
Rapposelli, Simona
Origlia, Nicola
Zucchi, Riccardo
Chiellini, Grazia
author_sort Bellusci, Lorenza
collection PubMed
description 3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.
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spelling pubmed-71791482020-04-28 Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6 Bellusci, Lorenza Runfola, Massimiliano Carnicelli, Vittoria Sestito, Simona Fulceri, Federica Santucci, Filippo Lenzi, Paola Fornai, Francesco Rapposelli, Simona Origlia, Nicola Zucchi, Riccardo Chiellini, Grazia Molecules Article 3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment. MDPI 2020-02-26 /pmc/articles/PMC7179148/ /pubmed/32110992 http://dx.doi.org/10.3390/molecules25051054 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bellusci, Lorenza
Runfola, Massimiliano
Carnicelli, Vittoria
Sestito, Simona
Fulceri, Federica
Santucci, Filippo
Lenzi, Paola
Fornai, Francesco
Rapposelli, Simona
Origlia, Nicola
Zucchi, Riccardo
Chiellini, Grazia
Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title_full Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title_fullStr Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title_full_unstemmed Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title_short Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
title_sort endogenous 3-iodothyronamine (t1am) and synthetic thyronamine-like analog sg-2 act as novel pleiotropic neuroprotective agents through the modulation of sirt6
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179148/
https://www.ncbi.nlm.nih.gov/pubmed/32110992
http://dx.doi.org/10.3390/molecules25051054
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