Search

Abstract Leber’s hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression of LHON disease.

Ocular cells like, retinal pigment epithelium (RPE) is a highly specialized pigmented monolayer of post-mitotic cells, which is located in the posterior segment of the eye between neuro sensory retina and vascular choroid. It functions as a selective barrier and nourishes retinal visual cells. As a result of high-level oxygen consumption of retinal cells, RPE cells are vulnerable to chronic oxidative stress and an increased level of reactive oxygen species (ROS) generated from mitochondria. These oxidative stress and ROS generation in retinal cells lead to RPE degeneration. Various sources including mtDNA damage could be an important factor of oxidative stress in RPE. Gene therapy and mitochondrial transfer studies are emerging fields in ocular disease research. For retinal degenerative diseases stem cell-based transplantation methods are developed from basic research to preclinical and clinical trials. Translational research contributions of gene and cell therapy would be a new strategy to prevent, treat and cure various ocular diseases. This review focuses on the effect of oxidative stress in ocular cell degeneration and recent translational researches on retinal degenerative diseases to cure blindness.

Introduction: Neurodegenerative diseases are reliant on neurons which demand high energy for its functioning, which depends on systems like mitochondrial oxidative phosphorylation (OXPHOS). This energy generated by mitochondria occurs through different respiratory complexes ranging from complex I to IV. Complexes are also known as NADH, including complex I because it is the first enzyme and largest chain of the given respiratory chain; however, complex 1 is called the ubiquinone oxidoreductase. Majority of neurodegenerative cases demonstrate irresistible evidence of plenty of mitochondrial subtleties that are impaired, as inhibition of complex 1 could lead to excessive reactive oxygen species (ROS) production. Development: In this review we try to discuss on how epigenetic modifications could cause a drift in smooth functioning of mitochondria and its function leading to neurodegenerative diseases like Leber's hereditary optic neuropathy (LHON). The reference articles were collected from NCBI-Pubmed, Scopus and Web of science. This review tries to deliver a summarizing overview related to Complex 1 mediated mitochondrial dysfunction and studies done so far in this aspect, along with the epigenetic modifications. Conclusion: In this review we discussed the different roles of mitochondria and its related dysfunction in the pathogenesis of neurodegenerative diseases. Resumen: Introducción: Las neuronas necesitan grandes cantidades de energía para su funcionamiento y dependen de sistemas como la fosforilación oxidativa mitocondrial. Dicha energía se genera en las mitocondrias a través de diferentes complejos respiratorios (complejos I-IV). El complejo I, también conocido como nicotinamida adenina dinucleótido (NADH por sus siglas en inglés) o ubiquinona oxidorreductasa, es la primera enzima y el mayor complejo de la cadena respiratoria. La mayoría de enfermedades neurodegenerativas se asocian de forma inequívoca a una gran variedad de alteraciones mitocondriales, como la inhibición del complejo I, que podría desencadenar una sobreproducción de especies reactivas de oxígeno. Desarrollo: El objetivo de nuestra revisión es analizar cómo las modificaciones epigenéticas pueden alterar el funcionamiento normal de las mitocondrias, lo que puede a su vez favorecer el desarrollo de enfermedades neurodegenerativas como la neuropatía óptica hereditaria de Leber. Hemos usado las bases de datos PubMed, Scopus y Web of Science para identificar artículos relacionados. Esta revisión presenta un resumen de la evidencia disponible hasta la fecha sobre la disfunción del complejo I mitocondrial y las modificaciones epigenéticas identificadas. Conclusión: Analizamos el papel de las mitocondrias y las disfunciones mitocondriales en la patogénesis de las enfermedades neurodegenerativas.

Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a ‘disease-in-a-dish’ model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development. This article has an associated First Person interview with the first author of the paper.

Artificial intelligence (AI) based on deep learning (DL) has sparked tremendous global interest in recent years. Deep Learning has been widely adopted in speech and image recognition, natural language processing which has an impact on healthcare. In the recent decade, the application of DL has exponentially grown in the field of Ophthalmology. The fundoscopy, slit lamp photography, optical coherence tomography (OCT), and magnetic resonance imaging (MRI) were employed for clinical examination of various ocular conditions. These data served as a perfect platform for the development of DL models in Ophthalmology. Currently, the application of DL in ocular disorders is majorly studied in Diabetic retinopathy (DR), age-related macular degeneration (AMD), macular oedema, retinopathy of prematurity (ROP), glaucoma, and cataract. In Ophthalmology, DL models are gradually expanding their scope in optic neuropathies. Glaucoma and optic neuritis are optic nerve disorders, where DL models are currently studied for clinical applications. For further expansion of DL application in inherited optic neuropathies, we discussed the recent observational studies revealing the pathophysiological changes at the optic nerve in Leber's hereditary optic neuropathy (LHON). LHON is an inherited optic neuropathy leading to bilateral loss of vision in early age groups. Hence for early management, further footsteps in the application of DL in LHON will benefit both ophthalmologists and patients. In this review, we discuss the recent advancements of AI in the Ophthalmology and prospective of applying DL models in LHON for clinical precision and timely diagnosis.

For centuries, traditional medicines of Ayurveda have been in use to manage infectious and non-infectious diseases. The key embodiment of traditional medicines is the holistic system of approach in the management of human diseases. SARS-CoV-2 (COVID-19) infection is an ongoing pandemic, which has emerged as the major health threat worldwide and is causing significant stress, morbidity and mortality. Studies from the individuals with SARS-CoV-2 infection have shown significant immune dysregulation and cytokine overproduction. Neutrophilia and neutrophil to lymphocyte ratio has been correlated to poor outcome due to the disease. Neutrophils, component of innate immune system, upon stimulation expel DNA along with histones and granular proteins to form extracellular traps (NETs). Although, these DNA lattices possess beneficial activity in trapping and eliminating pathogens, NETs may also cause adverse effects by inducing immunothrombosis and tissue damage in diseases including Type 2 Diabetes and atherosclerosis. Tissues of SARS-CoV-2 infected subjects showed microthrombi with neutrophil-platelet infiltration and serum showed elevated NETs components, suggesting large involvement and uncontrolled activation of neutrophils leading to pathogenesis and associated organ damage. Hence, traditional Ayurvedic herbs exhibiting anti-inflammatory and antioxidant properties may act in a manner that might prove beneficial in targeting over-functioning of neutrophils and there by promoting normal immune homeostasis. In the present manuscript, we have reviewed and discussed pathological importance of NETs formation in SARS-CoV-2 infections and discuss how various Ayurvedic herbs can be explored to modulate neutrophil function and inhibit NETs formation in the context of a) anti-microbial activity to enhance neutrophil function, b) immunomodulatory effects to maintain neutrophil mediated immune homeostasis and c) to inhibit NETs mediated thrombosis.