Biology of Sex Differences, Год журнала: 2024, Номер 15(1)
Опубликована: Окт. 30, 2024
Sex as a biological variable is not common consideration in molecular mechanistic or preclinical studies of retinal diseases. Understanding the sexual dimorphism adult RPE and retina under physiological conditions an important first step improving our understanding sex-based physio-pathological mechanisms.
Язык: Английский
Trends in Genetics, Год журнала: 2024, Номер unknown
Опубликована: Май 1, 2024
Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, extracellular signals. Precise global epigenomic signatures guide development homeostasis the intricate retinal structure function. Epigenomic realignment are hallmarks aging highlight link epigenome–metabolism nexus with aging-associated multifactorial traits affecting retina, including age-related macular degeneration glaucoma. Here, we focus on emerging principles control gene regulation, emphasis their contribution human disease. In addition, discuss potential mitigation strategies involving lifestyle changes that target epigenome-metabolome relationship for maintaining
Язык: Английский
Процитировано
6
Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18
Опубликована: Сен. 2, 2024
Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging the prominent factor in AMD, studies have reported higher prevalence AMD women compared to age-matched men. Higher levels innate immune response's effector proteins complement B and I were also found females males intermediate AMD. However, mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) key regulator mitochondrial biogenesis metabolic pathways. Previously, we showed Pgc-1α repression high-fat diet induce drastic AMD-like phenotypes mice. Our recent data revealed alone can retinal pigment epithelium (RPE) dysfunction mice, its inhibition vitro results lipid droplet accumulation human RPE. Whether sex contributing remains be elucidated. Using electroretinography, demonstrate could influence RPE function during independent wild-type (WT) We further show exacerbates aged-match male Gene expression analyses differentially regulates genes related antioxidant enzymes dynamics females. flat mounts immunolabeled with TOMM20 DRP1 indicated sex-dependent role for regulating fission. Analyses network morphology suggested effects on dynamics. Together, our study demonstrates induces decline These observations regulation offer novel insights into targeted therapeutic approaches age-related degeneration.
Язык: Английский
Процитировано
3
Journal of Integrative Neuroscience, Год журнала: 2025, Номер 24(3)
Опубликована: Март 4, 2025
Background: Initial manifestations of neurodegenerative ocular conditions, including age-related macular degeneration (AMD) and glaucoma, often remain undetected in the early stages can begin after age 50 years with likelihood gradually increasing each year thereafter. This study aimed to explore variances visual retinal function anatomy among C57BL/6J mice, aiming pinpoint differences between biological sex factors that potentially lead onset vision impairment. Methods: A longitudinal evaluated acuity (VA) contrast sensitivity (CS) using optomotor reflex (OMR), function, encompassing scotopic photopic measurements, was recorded by electroretinogram (ERG) at 12 months age. Tissue subsequently harvested for histological analysis, complementing vivo findings. Disparities were observed individual male female necessitating categorization impairment levels investigate further sex-specific study’s aging population. Comparisons degree conducted ANOVA followed Tukey’s or Bonferroni’s post-hoc corrections unpaired t-tests. Pearson correlation analysis determined association factors. Results: Sex-related disparities found (n = 13) 18) mice aged 5–12 months. Eyes categorized impairment: normal vision, low, moderate, severe loss end study. Male differed mean sensitivity, indicating less fine detail moving stimuli (11–12 old, p < 0.001). Spectral-domain optical coherence tomography (SD-OCT) revealed a thinner outer nuclear layer (p 0.0001), although this did not vary across different ERG indicated slower responses 0.05), while histology showed significant reduction inner plexiform thickness 0.0001). Conversely, exhibited greater thinning photoreceptor when unimpaired 0.01). Conclusions: The shows extent influence health, layers differentially changing over time.
Язык: Английский
Процитировано
0
Science Advances, Год журнала: 2025, Номер 11(15)
Опубликована: Апрель 11, 2025
Neurodegenerative disorders such as Alzheimer’s disease and macular degeneration represent major sources of human suffering, yet factors influencing severity remain poorly understood. Sex has been implicated one modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in model retinal this susceptibility caused by the presence female-specific hormones. The adverse effect hormones was specific to diseased neurons, depletion these ameliorated phenotypic effect, while reintroduction rates females. Transcriptional analysis retinas showed significant differences between genes involved pyroptosis, inflammatory responses, endoplasmic reticulum stress–induced apoptosis males females with degeneration. These findings provide crucial insights into pathogenesis neurodegenerative diseases how can affect severity. have far-reaching implications clinical trial design use hormonal therapy certain disorders.
Язык: Английский
Процитировано
0
Scientific Reports, Год журнала: 2025, Номер 15(1)
Опубликована: Апрель 15, 2025
Age-related macular degeneration (AMD) is associated with chronic inflammation of the retinal pigment epithelium (RPE) and elevated cytokines including TNFα, TGF-β, IL-6, IL-1β. As a metabolic intermediary supporting aerobic glycolysis in adjacent photoreceptors, RPE's responses to optimal methods study cytokine-driven programming remain unclear. We performed rigorous comparison ARPE-19 cells rat eyecup metabolomes, revealing key distinctions. Rat eyecups exhibit higher levels lactate palmitate but depleted glutathione high-energy nucleotides. Conversely, are enriched currency metabolites membrane phospholipid precursors phosphocholine inositol. Both models showed contrasting individual cytokines: were more sensitive while responded strongly TGF-β2. Notably, combined cytokine cocktail elicited stronger effects on cells, potently impacting both metabolite abundance (41 vs. 29) glucose carbon flux (29 5), influencing RPE such as alanine, glycine, aspartate, proline, citrate, α-ketoglutarate, palmitate. Overall, these findings position responsive platform for studying inflammatory metabolism reveal critical which may be linked AMD pathogenesis.
Язык: Английский
Процитировано
0
Frontiers in Molecular Biosciences, Год журнала: 2024, Номер 11
Опубликована: Март 21, 2024
Background: Lipid metabolism disorders were observationally associated with chalazion, but the causality of related circulating metabolites on chalazion remained unknown. Here, we investigated potential causal relationship between and using two-sample Mendelian randomization (MR) analysis. Methods: For primary analysis, 249 metabolic biomarkers obtained from UK Biobank, 123 publication by Kuttunen et al. for secondary Chalazion summary data FinnGen database. Inverse variance weighted (IVW) is main MR analysis method, assumptions evaluated in sensitivity colocalization analyses. Results: Two analyses results showed that common metabolite, alanine, exhibited a genetic protective effect against (primary analysis: odds ratio [OR] = 0.680; 95% confidence interval [CI], 0.507–0.912; p 0.010; OR 0.578; CI, 0.439–0.759; 0.00008). The robustness findings was supported heterogeneity horizontal pleiotropy alanine did not share region variation PPH 4 1.95%; 25.3%). Moreover, previous studies have suggested an increase degree unsaturation elevated risk (OR 1.216; 1.055–1.401; 0.007), omega-3 fatty acids 1.204; 1.054–1.377; 0.006) appearing to be major contributing factor, as opposed omega-6 0.850; 0.735–0.982; 0.027). Conclusion: This study suggests several unsaturated are candidate molecules mechanistic exploration drug target selection chalazion.
Язык: Английский
Процитировано
2
Aging Cell, Год журнала: 2024, Номер 23(11)
Опубликована: Авг. 5, 2024
Abstract Neuronal senescence is a major risk factor for the development of many neurodegenerative disorders. The mechanisms that drive neurons to remain largely elusive; however, dysregulated mitochondrial physiology seems play pivotal role in this process. Consequently, strategies aimed preserve function may hold promise mitigating neuronal senescence. For example, dietary restriction has shown reduce senescence, via mechanism still remains far from being totally understood, but could be at least partially mediated by mitochondria. Here, we address inorganic polyphosphate (polyP) intersection between and restriction. PolyP highly present mammalian mitochondria; its regulatory bioenergetics already been described us others. Our data demonstrate depletion polyP exacerbates independently whether present. However, polyP‐depleted cells activates AMPK, it restores some components physiology, even if not sufficient revert increased effects on levels AMPK activation are conserved differentiated SH‐SY5Y brain tissue male mice. results identify as an important component they highlight importance organelle intersection.
Язык: Английский
Процитировано
2
Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11
Опубликована: Авг. 4, 2023
Elucidation of the cellular changes that occur in degenerating photoreceptors people with inherited retinal diseases (IRDs) has been a focus for many research teams, leading to numerous theories on how these affect cell death process. What is clearly emerging from studies there are common denominators across multiple models IRD, regardless underlying genetic mutation. These markers could open avenues broad neuroprotective therapeutics prevent photoreceptor loss and preserve functional vision. In recent years, role epigenetic modifications contributing pathology IRDs particular point interest, due noting modifications, which coincide death. This review will discuss two categories changes, DNA methylation histone have received attention IRD models. We altered regulatory events believed contribute therapeutic potential targeting alterations.
Язык: Английский
Процитировано
4
Experimental Gerontology, Год журнала: 2024, Номер 194, С. 112510 - 112510
Опубликована: Июль 5, 2024
Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of fasting, the amount for food intake is regulated without restricting intake. TRF beneficial central nervous system support brain context aging. Therefore, we here ask whether also exerts effects retina. We compared mice (24 months) on paradigm (access six hours per day) either 6 or 12 months against young control (8 an ad libitum diet. examined changes retina at functional (electroretinography), structural (histology fluorescein angiograms) molecular (gene expression) level. treatment showed amelioration age-related reductions both scotopic photopic b-wave amplitudes suggesting retinal interneuron signaling. did not affect signs inflammation microglial activation histological Our data indicate that helps preserve some aspects function are decreased with aging, adding our understanding altered patterns may confer.
Язык: Английский
Процитировано
1
Communications Biology, Год журнала: 2024, Номер 7(1)
Опубликована: Авг. 21, 2024
Abstract The retina is light-sensitive neuronal tissue in the back of eye. phospholipid composition unique and highly enriched polyunsaturated fatty acids, including docosahexaenoic acid (DHA). While it generally accepted that a high DHA content important for vision, surprisingly little known about mechanisms enrichment retina. Furthermore, biological processes controlled by eye remain poorly defined as well. Here, we combined genetic manipulations with lipidomic analysis mice to demonstrate acyl-CoA synthetase 6 ( Acsl6 ) serves regulator retinal membranes. Inactivation reduced levels DHA-containing phospholipids, led progressive loss rod photoreceptor neurons, attenuated light responses these cells, evoked distinct transcriptional response involving Srebf1/2 (sterol regulatory element binding transcription factors 1/2) pathway. This study identifies one major enzymes responsible membranes introduces model allowing an evaluation functioning pathology caused impaired incorporation/retention
Язык: Английский
Процитировано
1