Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling

Tsialtas, Ioannis; Gorgogietas, Vyron A.; Komninou, Aggeliki; Liakou, Eleni; Georgantopoulos, Achilleas; Kalousi, Foteini D.; Karra, Aikaterini G.; Protopapa, Evagelia; Psarra, Anna‐Maria G.

doi:10.1016/j.neuro.2020.01.004

Cited by 19 publications

(13 citation statements)

References 85 publications

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“…Moreover, via Western blot analysis using antibodies against human ERβ, the detection of the GFPERβ fusion protein in colonies of the N2AmtGFPERβ cells, but not in N2A and N2AmtGFP cells, was verified ( Figure 2 C). Endogenous levels of ERβ in N2A cells ( Figure 2 A,C) are limited and thus undetectable in accordance with previously reported observations [ 25 , 26 , 27 ]. The overexpression of mtERβ in N2A mtGFPERβ stable cell lines was also confirmed by assessment of human ERβ mRNA levels.…”

Section: Resultssupporting

confidence: 93%

“…The results from this study provide evidence for the direct involvement of the mitochondrial ERβ in this process. Thus, since endogenous ERβ levels in N2A cells are limited [ 25 , 27 ], the results from this study indicate that estrogens’ protective actions are also mediated, at least in part, via the mitochondrial estrogen receptor beta.…”

Section: Discussionmentioning

confidence: 99%

“…Images were taken using an inverted laser-scanning confocal microscope (Zeiss laser scanning microscope 800, Zeiss LSM 800, Zeiss, Jena, Germany). Image analysis and quantification of fluorescence staining were performed as previously described [ 25 ] using the ImageJ (1.52 p) analysis program. Briefly, the total corrected fluorescence of area of interest (TCF) = integrated density − (selected area × mean fluorescence of background readings) was calculated.…”

Section: Methodsmentioning

confidence: 99%

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Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Tsialtas

Georgantopoulos

Karipidou

et al. 2021

IJMS

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Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERβ) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERβ in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H2O2-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-β estradiol (E2). Thus, the direct involvement of mtERβ in antioxidant and anti-apoptotic activities is documented, rendering mtERβ a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Tsialtas

Georgantopoulos

Karipidou

et al. 2021

IJMS

Self Cite

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“…Alteration of glutathione system is also characterized by Al-induced decline in cerebral and cerebellar total, reduced, and oxidized glutathione levels (Anand and Nehru, 2006). In contrast to glutathione, data on involvement of thioredoxin system to Al-induced redox perturbations are insufficient, although recent study revealed a significant decrease in mitochondrial thioredoxin in aluminum chlorohydrate treated SH-SY5Y neuroblastoma cells (Tsialtas et al, 2020).…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 98%

Molecular mechanisms of aluminum neurotoxicity: Update on adverse effects and therapeutic strategies

Skalny

Aschner

Jiang

et al. 2021

Advances in Neurotoxicology

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…Several studies have proposed that mitochondrial dysfunction may play a critical role in the toxic effects of Al, including neurotoxicity [ 197 , 208 ]. Rao et al [ 209 ] have shown that the ROS formation and mitochondrial respiratory activity, as well as glutathione depletion, were increased in the glial cells after being treated with Al for 24 h. Other groups have also depicted that Al exposure increased ROS formation and impaired the cytochrome c oxidase, which impaired mitochondrial functions in various neuronal cell types, including PC12 [ 210 , 211 , 212 ], SH-SY5Y neuroblastoma cells [ 213 , 214 ], and rat and cerebellar granule neuronal cells [ 42 , 215 ]. Mitochondrial dysfunction was also observed in in vivo studies [ 216 , 217 ].…”

Section: Molecular Mechanisms Of Metal-induced Mitochondrial Dysfunctionmentioning

confidence: 99%

Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders

Cheng

Yang

Tao

et al. 2021

Toxics

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Metals are actively involved in multiple catalytic physiological activities. However, metal overload may result in neurotoxicity as it increases formation of reactive oxygen species (ROS) and elevates oxidative stress in the nervous system. Mitochondria are a key target of metal-induced toxicity, given their role in energy production. As the brain consumes a large amount of energy, mitochondrial dysfunction and the subsequent decrease in levels of ATP may significantly disrupt brain function, resulting in neuronal cell death and ensuing neurological disorders. Here, we address contemporary studies on metal-induced mitochondrial dysfunction and its impact on the nervous system.

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Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling

Cited by 19 publications

References 85 publications

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Anti-Apoptotic and Antioxidant Activities of the Mitochondrial Estrogen Receptor Beta in N2A Neuroblastoma Cells

Molecular mechanisms of aluminum neurotoxicity: Update on adverse effects and therapeutic strategies

Mechanisms of Metal-Induced Mitochondrial Dysfunction in Neurological Disorders

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