Redox Imbalance and Morphological Changes in Skin Fibroblasts in Typical Rett Syndrome

Signorini, Cinzia; Leoncini, Silvia; Felice, Claudio De; Pecorelli, Alessandra; Meloni, Ilaria; Ariani, Francesca; Mari, Francesca; Amabile, Sonia; Paccagnini, Eugenio; Gentile, Mariangela; Belmonte, Giuseppe; Zollo, Gloria; Valacchi, Giuseppe; Durand, Thierry; Galano, Jean‐Marie; Ciccoli, Lucia; Renieri, Alessandra; Hayek, Joussef

doi:10.1155/2014/195935

Cited by 51 publications

(48 citation statements)

References 68 publications

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“…Overall, these data confirm the relevance of mechanisms controlling thiol/disulfide equilibria in the pathogenesis RTT and, in this respect, extend to neurodevelopmental disorders previous findings obtained in chronic neurodegenerative diseases [42,43]. It should be also mentioned that in previous work we have detected a decreased levels of GSH in RTT cells [44] and this can indirectly affect TrxR by maintaining Trx in the reduced state during oxidative stress. Although GSH does not directly interact with TrxR.…”

Section: Discussionsupporting

confidence: 90%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A strong correlation between oxidative stress (OS) and Rett syndrome (RTT), a rare neurodevelopmental disorder affecting females in the 95% of the cases, has been well documented although the source of OS and the effect of a redox imbalance in this pathology has not been yet investigated. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have demonstrated in RTT cells high levels of H2O2 and HNE protein adducts. These findings correlated with the constitutive activation of NADPH-oxidase (NOX) and that was prevented by a NOX inhibitor and iron chelator pre-treatment, showing its direct involvement. In parallel, we demonstrated an increase in mitochondrial oxidant production, altered mitochondrial biogenesis and impaired proteasome activity in RTT samples. Further, we found that the key cellular defensive enzymes: glutathione peroxidase, superoxide dismutase and thioredoxin reductases activities were also significantly lower in RTT. Taken all together, our findings suggest that the systemic OS levels in RTT can be a consequence of both: increased endogenous oxidants as well as altered mitochondrial biogenesis with a decreased activity of defensive enzymes that leads to posttranslational oxidant protein modification and a proteasome activity impairment.

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Section: Discussionsupporting

confidence: 90%

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Cervellati

Sticozzi

Romani

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…8 Redox imbalance and abnormally low reduced glutathione levels may occur in both primary genetic mitochondrial disorders and conditions associated with secondary mitochondrial impairment, including organic acidemias, Friedreich ataxia, Parkinson disease, and Rett syndrome. 4,[9][10][11][12][13][14] As such, there has been an interest in developing mitochondrial therapies that have the potential to improve the intracellular glutathione status. EPI-743 (a-tocotrienol quinone) and RP103 (cysteamine bitartrate) are investigational therapies that are currently in clinical trials focusing on the treatment of mitochondrial dysfunction related to primary genetic mitochondrial disease.…”

mentioning

confidence: 99%

Clinical Trials in Mitochondrial Disease

Enns

Cohen

2017

Journal of Inborn Errors of Metabolism and Screening

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Mitochondrial dysfunction results in the production of an abnormally high amount of reactive oxygen and nitrogen species, which results in redox imbalance and glutathione deficiency. Therapeutics such as EPI-743 (a-tocotrienol quinone) and RP103 (cysteamine bitartrate) have the theoretical potential to improve redox imbalance by increasing intracellular glutathione and are currently under investigation in multiple clinical trials. This review provides an update on the use of these compounds in clinical trials related to primary and secondary mitochondrial disorders. These clinical trials have not only provided hope to affected patients and their families and caregivers, but also will serve as important stepping stones for further studies as our understanding of mitochondrial disease pathogenesis continues to improve.

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“…In addition, free thiols can be modified by reactive lipids such as malondialdehyde, nitrated fatty acids, and 4-hydroxynonenal. Broad-spectrum antibodies are then developed against malondialdehyde-or the nitrated fatty acidsmodified proteins [91]. However, antibodies may not identify all redox modifications due to the limited recognization of specific epitopes.…”

Section: Antibody-based Methods To Detect the Oxidative State Of Thiolsmentioning

confidence: 99%

High-throughput screening of cellular redox sensors using modern redox proteomics approaches

Jiang

Wang

Nice

et al. 2015

Expert Review of Proteomics

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Cancer cells are characterized by higher levels of intracellular reactive oxygen species (ROS) due to metabolic aberrations. ROS are widely accepted as second messengers triggering pivotal signaling pathways involved in the process of cell metabolism, cell cycle, apoptosis, and autophagy. However, the underlying cellular mechanisms remain largely unknown. Recently, accumulating evidence has demonstrated that ROS initiate redox signaling through direct oxidative modification of the cysteines of key redox-sensitive proteins (termed redox sensors). Uncovering the functional changes underlying redox regulation of redox sensors is urgently required, and the role of different redox sensors in distinct disease states still remains to be identified. To assist this, redox proteomics has been developed for the high-throughput screening of redox sensors, which will benefit the development of novel therapeutic strategies for cancer treatment. Highlighted here are recent advances in redox proteomics approaches and their applications in identifying redox sensors involved in tumor development.

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Redox Imbalance and Morphological Changes in Skin Fibroblasts in Typical Rett Syndrome

Cited by 51 publications

References 68 publications

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

Clinical Trials in Mitochondrial Disease

High-throughput screening of cellular redox sensors using modern redox proteomics approaches

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