scholarly journals Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 313 ◽  
Author(s):  
Carmen Espinós ◽  
Máximo Ibo Galindo ◽  
María Adelaida García-Gimeno ◽  
José Santiago Ibáñez-Cabellos ◽  
Dolores Martínez-Rubio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rare Diseases ◽  
Reactive Nitrogen Species ◽  
Neuromuscular Disorders ◽  
Common Factor ◽  
Drug Resistant ◽  
Brain Iron ◽  
Pediatric Drug ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

: Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich’s ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies.

scholarly journals Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1033
Author(s):  
Lorena Olivares-González ◽  
Sheyla Velasco ◽  
Isabel Campillo ◽  
David Salom ◽  
Emilio González-García ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Degeneration ◽  
Antioxidant Properties ◽  
Photoreceptor Cells ◽  
Redox Status ◽  
Inherited Retinal Dystrophies ◽  
Stress Markers ◽  
Retinal Dystrophies ◽  
Progressive Degeneration ◽  
Light Stimuli

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. Methods: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. Results: NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. Conclusions: NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.

scholarly journals Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ionut-Florin Iancu ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
Maria Jose Trujillo-Tiebas ◽  
Rosa Riveiro-Alvarez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Diseases ◽  
Molecular Diagnostic ◽  
Rule Based ◽  
Variants Of Uncertain Significance ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Clinical Exome Sequencing ◽  
Uncertain Significance

AbstractInherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

scholarly journals Effects of A2E-Induced Oxidative Stress on Retinal Epithelial Cells: New Insights on Differential Gene Response and Retinal Dystrophies

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 307 ◽  
Author(s):  
Luigi Donato ◽  
Rosalia D’Angelo ◽  
Simona Alibrandi ◽  
Carmela Rinaldi ◽  
Antonina Sidoti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Genetic Diseases ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Age Related

Oxidative stress represents one of the principal inductors of lifestyle-related and genetic diseases. Among them, inherited retinal dystrophies, such as age-related macular degeneration and retinitis pigmentosa, are well known to be susceptible to oxidative stress. To better understand how high reactive oxygen species levels may be involved in retinal dystrophies onset and progression, we performed a whole RNA-Seq experiment. It consisted of a comparison of transcriptomes’ profiles among human retinal pigment epithelium cells exposed to the oxidant agent N-retinylidene-N-retinylethanolamine (A2E), considering two time points (3h and 6h) after the basal one. The treatment with A2E determined relevant differences in gene expression and splicing events, involving several new pathways probably related to retinal degeneration. We found 10 different clusters of pathways involving differentially expressed and differentially alternative spliced genes and highlighted the sub- pathways which could depict a more detailed scenario determined by the oxidative-stress-induced condition. In particular, regulation and/or alterations of angiogenesis, extracellular matrix integrity, isoprenoid-mediated reactions, physiological or pathological autophagy, cell-death induction and retinal cell rescue represented the most dysregulated pathways. Our results could represent an important step towards discovery of unclear molecular mechanisms linking oxidative stress and etiopathogenesis of retinal dystrophies.

scholarly journals NRL S50T mutation and the importance of ‘founder effects’ in inherited retinal dystrophies

2000 ◽  
Vol 8 (10) ◽  
pp. 783-787 ◽  
Author(s):  
David AR Bessant ◽  
Annette M Payne ◽  
Catherine Plant ◽  
Alan C Bird ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Founder Effects ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

2021 ◽  
Vol 13 ◽  
pp. 251584142199719
Author(s):  
Simranjeet Singh Grewal ◽  
Joseph J. Smith ◽  
Amanda-Jayne F. Carr
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Disease ◽  
Incomplete Penetrance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
High Acuity ◽  
Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

scholarly journals Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 935
Author(s):  
Manas R. Biswal ◽  
Sofia Bhatia
Keyword(s):  
Gene Delivery ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Cells ◽  
Adeno Associated Virus ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Efficient Gene ◽  
New Type ◽  
Viral Nanoparticles

Ocular gene therapy offers significant potential for preventing retinal dystrophy in patients with inherited retinal dystrophies (IRD). Adeno-associated virus (AAV) based gene transfer is the most common and successful gene delivery approach to the eye. These days, many studies are using non-viral nanoparticles (NPs) as an alternative therapeutic option because of their unique properties and biocompatibility. Here, we discuss the potential of carbon dots (CDs), a new type of nanocarrier for gene delivery to the retinal cells. The unique physicochemical properties of CDs (such as optical, electronic, and catalytic) make them suitable for biosensing, imaging, drug, and gene delivery applications. Efficient gene delivery to the retinal cells using CDs depends on various factors, such as photoluminescence, quantum yield, biocompatibility, size, and shape. In this review, we focused on different approaches used to synthesize CDs, classify CDs, various pathways for the intake of gene-loaded carbon nanoparticles inside the cell, and multiple studies that worked on transferring nucleic acid in the eye using CDs.

scholarly journals Oxidative Stress and Rare Diseases: From Molecular Crossroads to Therapeutic Avenues

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 617
Author(s):  
Carlos Romá-Mateo ◽  
José Luis García-Giménez
Keyword(s):  
Oxidative Stress ◽  
Rare Diseases ◽  
Biological Perspective

Writing an editorial about rare diseases can become a messy subject from the biological perspective [...]

scholarly journals Correction to: Patient Preferences in Rare Diseases: A Qualitative Study in Neuromuscular Disorders to Inform a Quantitative Preference Study

2021 ◽  
Author(s):  
A. Cecilia Jimenez-Moreno ◽  
Eline van Overbeeke ◽  
Cathy Anne Pinto ◽  
Ian Smith ◽  
Jenny Sharpe ◽  
...  
Keyword(s):  
Qualitative Study ◽  
Rare Diseases ◽  
Patient Preferences ◽  
Neuromuscular Disorders ◽  
Preference Study

A correction to this paper has been published: https://doi.org/10.1007/s40271-021-00523-1

scholarly journals Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells

2021 ◽  
Vol 9 (6) ◽  
pp. 1219
Author(s):  
Maria Isaguliants ◽  
Olga Krotova ◽  
Stefan Petkov ◽  
Juris Jansons ◽  
Ekaterina Bayurova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cell ◽  
Cell Response ◽  
Mammalian Cells ◽  
Metastatic Potential ◽  
T Cell Response ◽  
Dna Immunization ◽  
Drug Resistant ◽  
Metastatic Activity ◽  
Hiv 1

Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress.

scholarly journals Functional surgery in pediatric drug-resistant posterior cortex epilepsy: Electro-clinical findings, cognitive and seizure outcome

Seizure ◽  
2017 ◽  
Vol 52 ◽  
pp. 46-52 ◽  
Author(s):  
A. Sierra-Marcos ◽  
M.C. Fournier-del Castillo ◽  
J. Álvarez-Linera ◽  
M. Budke ◽  
M. García-Fernández ◽  
...  
Keyword(s):  
Clinical Findings ◽  
Seizure Outcome ◽  
Drug Resistant ◽  
Pediatric Drug ◽  
Posterior Cortex ◽  
Functional Surgery
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