Alzheimer’s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 211, P. 115522 - 115522

Published: March 28, 2023

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions people worldwide, with both prevalence and incidence increasing age. It characterized by cognitive decline associated, specifically, degeneration cholinergic neurons. The problem this even more fundamental as available therapies remain fairly limited mainly focused on symptoms' relief. Although aetiology remains elusive, two main pathological hallmarks are described: i) presence neurofibrillary tangles formed unfolded protein aggregates (hyperphosphorylated Tau protein) ii) extracellular amyloid-beta peptide. Given complexity surrounding pathogenesis disease, several potential targets have been highlighted interrelated upon its progression, such oxidative stress accumulation metal ions. Thus, advances made development innovative multitarget therapeutical compounds to delay progression restore cell function. This review focuses ongoing research new insights emerging disease-modifying drugs for AD treatment. Furthermore, classical novel biomarkers early diagnosis their role in assisting improvement targeted will also be approached.

Language: Английский

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Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 189, P. 114485 - 114485

Published: Aug. 12, 2022

Language: Английский

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Retinitis Pigmentosa: Progress in Molecular Pathology and Biotherapeutical Strategies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4883 - 4883

Published: April 28, 2022

Retinitis pigmentosa (RP) is genetically heterogeneous retinopathy caused by photoreceptor cell death and retinal pigment epithelial atrophy that eventually results in blindness bilateral eyes. Various types pathological phenotypic changes have been disclosed RP demand in-depth research of its pathogenic mechanism may account for inter-patient responses to mainstream drug treatment. As the primary method studying genetic characteristics RP, molecular biology has widely used disease diagnosis clinical trials. Current technology iterations, such as gene therapy, stem optogenetics, are advancing towards precise applications. Specifically, technologies, effective delivery vectors, CRISPR/Cas9 technology, iPSC-based transplantation, hasten pace personalized precision medicine RP. The combination conventional therapy state-of-the-art medication promising revolutionizing treatment strategies. This article provides an overview latest on pathogenesis, diagnosis, retinitis pigmentosa, aiming a convenient reference what achieved so far.

Language: Английский

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Diabetic Retinopathy Detection from Fundus Images of the Eye Using Hybrid Deep Learning Features

Diagnostics, Journal Year: 2022, Volume and Issue: 12(7), P. 1607 - 1607

Published: July 1, 2022

Diabetic Retinopathy (DR) is a medical condition present in patients suffering from long-term diabetes. If diagnosis not carried out at an early stage, it can lead to vision impairment. High blood sugar diabetic the main source of DR. This affects vessels within retina. Manual detection DR difficult task since affect retina, causing structural changes such as Microaneurysms (MAs), Exudates (EXs), Hemorrhages (HMs), and extra vessel growth. In this work, hybrid technique for classification fundus images eye proposed. Transfer learning (TL) used on pre-trained Convolutional Neural Network (CNN) models extract features that are combined generate feature vector. vector passed various classifiers binary multiclass images. System performance measured using metrics results compared with recent approaches detection. The proposed method provides significant improvement For classification, modified achieved highest accuracy 97.8% 89.29% classification.

Language: Английский

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Advanced Glycation End-Products and Diabetic Neuropathy of the Retina

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2927 - 2927

Published: Feb. 2, 2023

Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and 2 diabetes. Several pathological factors are involved progressive interdependence between cells that consist units (NVUs). The advanced glycation end-products (AGEs) one major cause impairments coupling diabetic retinopathy. Although exact mechanisms for toxicities AGEs have not been definitively determined, AGE-receptor AGE (RAGE) axis, production reactive oxygen species, inflammatory reactions, activation cell death pathways associated NVUs More specifically, neuronal an irreversible change directly vision reduction patients. Thus, neuroprotective therapies must be established therapeutic targets to examine ameliorate changes This review focuses on basic findings AGE-induced abnormalities potential approaches, including use anti-glycated drugs protect

Language: Английский

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Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

Cells, Journal Year: 2022, Volume and Issue: 11(5), P. 813 - 813

Published: Feb. 25, 2022

The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between neural cells and blood vessels in human brain, focused mainly on brain gray matter. major components of NVU are neurons, astrocytes (astroglia), microvessels, pericytes, microglia. In addition, we believe oligodendrocytes should also be included as an indispensable component white Of all these components, particular have attracted interest researchers because their unique anatomical location; interposed neurons microvessels brain. Their location suggests might regulate cerebral flow (CBF) response neuronal activity, so ensure adequate supply glucose oxygen meet metabolic demands neurons. fact, adult which accounts for only 2% entire body weight, consumes approximately 20–25% total amount consumed by whole body. needs continuous essential energy sources through CBF, there practically no stores or brain; both acute chronic cessation CBF can adversely affect functions. another important putative function elimination heat waste materials produced activity. Recent evidence play pivotal roles not supplying glucose, but fatty acids amino Loss astrocytic support expected lead malfunction whole, underlies numerous neurological disorders. this review, shall focus historical recent findings with regard contributions NVU.

Language: Английский

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Catalytic Bioswitch of Platinum Nanozymes: Mechanistic Insights of Reactive Oxygen Species Scavenging in the Neurovascular Unit

Nano Letters, Journal Year: 2023, Volume and Issue: 23(10), P. 4660 - 4668

Published: May 8, 2023

Oxidative stress is known to be the cause of several neurovascular diseases, including neurodegenerative disorders, since increase reactive oxygen species (ROS) levels can lead cellular damage, blood-brain barrier leaking, and inflammatory pathways. Herein, we demonstrate therapeutic potential 5 nm platinum nanoparticles (PtNPs) effectively scavenge ROS in different models unit. We investigated mechanism underlying PtNP biological activities, analyzing influence evolving environment during particle trafficking disclosing a key role protein corona, which elicited an effective switch-off catalytic properties, promoting their selective

Language: Английский

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The impact of modifier genes on cone-rod dystrophy heterogeneity: An explorative familial pilot study and a hypothesis on neurotransmission impairment

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(12), P. e0278857 - e0278857

Published: Dec. 9, 2022

Cone-rod dystrophies (CORDs) are a heterogeneous group of inherited retinopathies (IRDs) with more than 30 already known disease-causing genes. Uncertain phenotypes and extended range intra- interfamilial heterogenicity make still difficult to determine precise genotype-phenotype correlation. Here, we used next-generation sequencing approach study Sicilian family suspected form CORD. Affected members underwent ophthalmological examinations proband, blind from 50 years, whole genome exome sequencing. Variant analysis was enriched by pathway relevant variants were, then, investigated in other 100 healthy controls Messina. CORD diagnosis an intricate pattern symptoms confirmed examinations. A total about 50,000 were identified both proband's exome. All affected presented specific genotypes mainly determined mutated GUCY2D gene, different phenotypical traits, related focus color perception. Thus, looked for possible modifier According relationship GUCY2D, predicted functional effects, eye localization, ocular disease affinity, only 9 variants, carried 6 genes (CACNG8, PAX2, RXRG, CCDC175, PDE4DIP LTF), survived the filtering. These encode key proteins involved cone development survival, retina neurotransmission. Among analyzed CACNG8c.*6819A>T new CCDC175 c.76C>T showed extremely low frequency control group, suggesting role on phenotypes. Such discovery could enforce into onset/progression, contributing improve diagnostic test towards better personalized medicine.

Language: Английский

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Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration

Antioxidants, Journal Year: 2022, Volume and Issue: 11(10), P. 1967 - 1967

Published: Sept. 30, 2022

Oxidative stress represents one of the principal causes inherited retinal dystrophies, with many related molecular mechanisms still unknown. We investigated posttranscriptional RNA editing landscape human pigment epithelium cells (RPE) exposed to oxidant agent N-retinylidene-N-retinyl ethanolamine (A2E) for 1 h, 2 3 h and 6 h. Using a transcriptomic approach, refined specific multialgorithm pipeline, 62,880 already annotated de novo sites within about 3000 genes were identified among all samples. Approximately 19% these found 3' UTR, including common time points that predicted change binding capacity 359 miRNAs towards 9654 target genes. A2E exposure also determined significant gene expression differences in deaminase family ADAR, APOBEC ADAT members, involved canonical tRNA events. On GO KEGG enrichment analyses, showed different levels are mainly pathways strongly linked possible neovascularization tissue, induced apoptosis mediated by ECM surface protein altered signaling. Collectively, this work demonstrated dynamic editome profiles RPE first shed more light on new at basis degeneration.

Language: Английский

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N6-methyladenosine demethylase FTO regulates inflammatory cytokine secretion and tight junctions in retinal pigment epithelium cells

Clinical Immunology, Journal Year: 2022, Volume and Issue: 241, P. 109080 - 109080

Published: July 22, 2022

Language: Английский

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