Co-delivery of antioxidants and siRNA-VEGF: promising treatment for age-related macular degeneration

Drug Delivery and Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

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Single-cell sequencing reveals an important role of SPP1 and microglial activation in age-related macular degeneration

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 8, 2024

Purpose To investigate the role of senescence-related cytokines (SRCs) in pathophysiology age-related macular degeneration (AMD). Design The whole study is based on single-cell and bulk tissue transcriptomic analysis human neuroretinas with or without AMD. data was obtained from Gene-Expression Omnibus (GEO) database. Methods For analysis, gene expression matrix goes through quality control (QC) filtering, being normalized, scaled integrated for downstream analysis. further analyses were performed using Seurat R package CellChat package. After cell type annotation, phenotype functional markers microglia investigated cell-cell communication performed. GSE29801 dataset contains neuroretina ( n = 118) group AMD patients. SPP1 subtypes compared by Student’s t -test. In addition, classified into SPP1-low SPP1-high groups according to level SPP1. differentially expressed genes between these two subsequently identified pathway enrichment conducted. Results Secreted phosphoprotein 1, as an SRC, revealed be highly SPP1-receptor signaling activated neuroretina. associated pro-inflammatory phagocytic state microglia. elevated late dry wet inflammatory pathways found Conclusion Our findings indicated that microglial activation might play important Therefore, serve a potential therapeutic target More vitro vivo studies are required confirm results effect SPP1-targeting strategy.

Language: Английский

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Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 28, 2025

Abstract Background The retinal degenerative diseases retinitis pigmentosa (RP) and atrophic age- related macular degeneration (AMD) are characterized by vision loss from photoreceptor (PR) degeneration. Unfortunately, current treatments for these limited at best. Genetic other preclinical evidence suggest a relationship between inflammation. To further explore this relationship, we tested whether Ibuprofen (IBU), an FDA-approved non-steroidal anti-inflammatory drug (NSAID), could promote PR survival function in mouse model of light damage (LD)-induced Methods LD was induced exposing mice to 4000 lx 2–4 hours (h). IBU (100 or 200 mg/kg) vehicle administered daily intraperitoneal injection. Retinal structure were evaluated spectral-domain optical coherence tomography (SD-OCT) electroretinography (ERG). Cell death genes analyzed 24 72 h after using the Mouse Pan-Cell Death Pathway PCR Array (88 genes). cellular location protein expression key necroptosis assessed immunohistochemistry. Results outer nuclear layer (ONL) thickness vehicle-injected animals 8.7 ± 0.6% retinas without ( p < 0.0001). In mg/kg treated mice, central ONL 74.9 7.7% untreated 0.001). A-wave b-wave ERG amplitudes significantly preserved IBU-treated animals. inhibited Twenty-four hour LD, mRNA inflammatory-factors tumor necrosis factor Tnf ), interleukin-1 beta Il1B C-C motif chemokine ligand 2 Ccl2 ) increased 10-, 17-, 533-fold, respectively; animals, levels inflammatory factors not different no-LD controls. Expression genes, including Ripk3 Mlkl , upregulated vehicle-treated but dramatically reduced near no mice. Microglia activation MLKL upregulation observed primarily photoreceptors 12 as microglia migration plexiform (OPL) retinas. Conclusions Systemic administration partially protected light-induced photochemical both inflammation cell pathways. Our results that NSAIDs may provide promising therapeutic approach treatment human diseases.

Language: Английский

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Suppression of astrocyte elevated gene-1 protects against light-induced photoreceptor apoptosis and inflammation in retina

Immunobiology, Journal Year: 2025, Volume and Issue: 230(3), P. 152889 - 152889

Published: March 12, 2025

To research the function of astrocyte elevated gene-1 (AEG-1) in light-induced retinal degeneration. The retinas BALB/c mice and 661W cells damage were induced by exposure to light; Lipopolysaccharide (LPS) was used stimulate BV2 cells. AEG-1 siRNA transfection inhibit AEG-1. Expressions AEG-1, TLR4, TNF-α, phosphor-NF-κB (p-NF-κB) total NF-κB (t-NF-κB) detected. Photoreceptor apoptosis evaluated flow cytometry or TUNEL. Histological analyses performed hematoxylin eosin (HE) staining. highly expressed light damaged (LD) retinas. photoreceptor thinning outer nuclear layer (ONL) inhibited LD pretreatment significantly down-regulated expression levels p-NF-κB TNF-α In vitro, upregulated stimulated LPS. prevented cells, expressions pro-inflammatory cytokine caused LPS is degeneration LD. Suppression protects against rescues ONL also diminishes inflammation degeneration, which may be regulated through pathway. Therefore, perhaps become a potential therapeutic target for this type degenerative disease.

Language: Английский

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Anti-TNFα and Anti-IL-1β Monoclonal Antibodies Preserve BV-2 Microglial Homeostasis Under Hypoxia by Mitigating Inflammatory Reactivity and ATF4/MAPK-Mediated Apoptosis

Antioxidants, Journal Year: 2025, Volume and Issue: 14(3), P. 363 - 363

Published: March 19, 2025

The disruption of microglial homeostasis and cytokine release are critical for neuroinflammation post-injury strongly implicated in retinal neurodegenerative diseases like glaucoma. This study examines responses to chemical hypoxia induced by cobalt chloride (CoCl2) BV-2 murine cells, focusing on signaling pathways proteomic alterations. We assessed the protective effects monoclonal antibodies against TNFα IL-1β. CoCl2 exposure led decreased cell viability, reduced mitochondrial membrane potential, increased lactate dehydrogenase release, elevated reactive oxygen species generation, activation inflammatory pathways, including nitric oxide synthase (iNOS), STAT1, NF-κB/NLRP3. These were significantly mitigated treatment with anti-TNFα anti-IL-1β, suggesting their dual role reducing damage inhibiting reactivity. Additionally, these treatments apoptosis modulating ATF4 p38 MAPK/caspase-3 pathways. Label-free quantitative mass spectrometry-based proteomics Gene Ontology revealed that upregulation proteins primarily involved endoplasmic reticulum catabolic processes, while downregulated associated biosynthesis. Anti-TNFα anti-IL-1β partially restored profile toward normalcy, network analysis identifying heat shock protein family A member 8 (HSPA8) as a central mediator recovery. findings offer insights into pathogenesis hypoxic impairment suggest potential therapeutic targets.

Language: Английский

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Advancing Neurological Health: Insights into Aging, Immunity, and Vascular Dynamics

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

This editorial provides an overview of recent advancements in the understanding and treatment neurological disorders, focusing on aging, immunity, blood flow, as featured this special issue. The first section explores importance identifying biomarkers aging aging-related diseases, such Alzheimer's Disease, highlighting emerging role saliva-based gut-brain axis disease diagnosis management. In subsequent section, dysregulated immune systems associated with are discussed, emphasizing intricate landscape system during its bidirectional relationship neuroinflammation. Additionally, insights into involvement Myeloid-Derived Suppressor Cells (MDSCs) Multiple Sclerosis (MS) pathogenesis presented. third examines microglia neuroinflammation various including age-related macular degeneration (AMD) Tuberculous Meningitis (TBM). Furthermore, therapeutic potential stem cell extracellular vesicle-based therapies for stroke is explored, along molecular mechanism how inflammation regulates cerebral myocardial ischemia. Finally, flow maintaining vascular health impact disorders novel assessment methods optimizing patient care. Overall, issue offers valuable complex mechanisms underlying identifies avenues intervention.

Language: Английский

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Retinal Inflammation and Reactive Müller Cells: Neurotrophins’ Release and Neuroprotective Strategies

Biology, Journal Year: 2024, Volume and Issue: 13(12), P. 1030 - 1030

Published: Dec. 9, 2024

Millions of people worldwide suffer from retinal disorders. Retinal diseases require prompt attention to restore function or reduce progressive impairments. Genetics, epigenetics, life-styling/quality and external environmental factors may contribute developing diseases. In the physiological retina, some glial cell types sustain neuron activities by guaranteeing ion homeostasis allowing effective interaction in synaptic transmission. Upon insults, cells interact with neuronal other non-neuronal cells, at least part counteracting biomolecular changes that trigger complications vision loss. Several epigenetic oxidative stress mechanisms are quickly activated release concert growth, fibrogenic angiogenic can influence overall microenvironment cell-to-cell response. Reactive Müller participate secreting neurotrophic/growth/angiogenic factors, cytokines/chemokines, cytotoxic/stress molecules neurogenic inflammation peptides. Any attempt maintain/restore condition be interrupted perpetuating vascular dysfunction neurodegeneration. Herein, we critically revise current knowledge on cell-to-mediator interplay between astrocytes microglia, respect pro-con modulators neuroprotective/detrimental activities, as observed using experimental models analyzing ocular fluids, altogether contributing a new point view field research precision medicine.

Language: Английский

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Senescence-associated secretory phenotype constructed detrimental and beneficial subtypes and prognostic index for prostate cancer patients undergoing radical prostatectomy

Discover Oncology, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 25, 2023

Cellular senescence is growing in popularity cancer. A dual function played by the senescence-associated secretory phenotype (SASP) that senescent cells produce development of pro-inflammatory niches, tissue regeneration or destruction, propagation, and malignant transformation. In this study, we conducted thorough bioinformatic analysis meta-analysis to discover detrimental beneficial subtypes prognostic index for prostate cancer (PCa) patients using experimentally confirmed SASP genes.We identified differentially expressed prognosis-related genes used them construct two molecular risk score. Another external cohorts were confirm effect above score was further conducted. Additionally, functional analysis, tumor stemness heterogeneity microenvironment also evaluated. We completed analyses software R 3.6.3 its suitable packages. Meta-analysis performed Stata 14.0.Through multivariate Cox regression consensus clustering VGF, IGFBP3 ANG establish TCGA cohort, which validated through other independent cohorts. showed group had significantly higher biochemical recurrence (BCR) than (HR: 2.48). Moreover, constructed based on these better guide clinical practice. DNA repair, MYC target, oxidative phosphorylation, proteasome ribosome highly enriched group. Detrimental levels B cells, CD8+ T homologous recombination deficiency, loss heterozygosity, microsatellite instability, purity, mutation burden, mRNAsi, methylated probes epigenetically regulated RNA expression The top between groups SPOP, FOXA1, KMT2C, APC, BSN, DNAH17, MYH6, EPPK1, ZNF536 ZC3H13 with statistical significance.From perspective SASP, found closely associated BCR-free survival PCa patients, might be important furture research field PCa.

Language: Английский

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Investigating Chemokine-Induced NF-κB Activation in Retinal Cells and Its Contribution to Age-Related Macular Degeneration Pathogenesis: A Systematic Review

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 8, 2024

Abstract Objective To investigate the roles of chemokines in activating NF-κB signaling pathway retinal pigment epithelium (RPE) and photoreceptor cells, their contribution to pathogenesis age-related macular degeneration (AMD). Background AMD is a leading cause vision loss older adults, driven by chronic inflammation oxidative stress. The transcription factor plays key role regulating these processes, with various chemokines, such as CCL2 CX3CL1, influencing activation. Despite advances treatment, deeper understanding how affect activation RPE cells remains critical for developing effective therapies. This study seeks address this gap improve management. Methods A comprehensive search databases, including PubMed, MEDLINE, Google Scholar, was conducted identify relevant studies on cells. covered (MCP-1), CX3CL1 (Fractalkine), CCL3 (MIP-1α), CCL5 (RANTES), CXCL8 (IL-8), CXCL10 (IP-10), CXCL1 (GRO-α), CXCL12 (SDF-1), CCL11 (Eotaxin), CXCL16, CXCL9 (MIG), CXCL11 (I-TAC). Studies were systematically reviewed following PRISMA guidelines assess involvement Results analysis revealed that CCL2, CCL3, CCL5, significantly activated increased apoptosis through enhanced cytokine production reactive oxygen species (ROS) generation. Additionally, CXCL8, CXCL10, CXCL1, triggered activation, contributing stress extracellular matrix (ECM) remodeling, which disrupts structure function. Other CCL11, CXCL9, CXCL11, sustained modulated metalloproteinases (MMPs), further implicating them progression. Conclusion Chemokines, CXCL12, activate driving inflammation, stress, ECM remodeling AMD. These findings highlight potential therapeutic targets mitigate disease

Language: Английский

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Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

Background The retinal degenerative diseases retinitis pigmentosa (RP) and atrophic age- related macular degeneration (AMD) are characterized by vision loss from photoreceptor (PR) degeneration. Unfortunately, current treatments for these limited at best. Genetic other preclinical evidence suggest a relationship between inflammation. To further explore this relationship, we tested whether Ibuprofen (IBU), an FDA-approved non-steroidal anti-inflammatory drug (NSAID), could promote PR survival function in mouse model of light damage (LD)-induced Methods LD was induced exposing mice to 4000 lux 2–4 hrs. IBU (100 or 200 mg/kg) vehicle administered daily intraperitoneal injection. Retinal structure were evaluated spectral-domain optical coherence tomography (SD-OCT) electroretinography (ERG). cell death genes analyzed 24 72 hours (hrs) after the Mouse Pan-Cell Death Pathway PCR Array (88 genes). cellular location protein expression key necroptosis gene assessed immunohistochemistry. Results outer nuclear layer (ONL) thickness vehicle-injected animals 8.7 ± 0.6% retinas without (p < 0.0001). In 200mg/kg treated mice, central ONL 74.9 7.7% untreated 0.001). A-wave b-wave ERG amplitudes significantly preserved IBU-treated animals. inhibited Twenty-four hrs LD, mRNA inflammatory-factors tumor necrosis factor (Tnf), interleukin-1 beta (Il1b), C-C motif chemokine ligand 2 (Ccl2) increased 10, 17 533-fold, respectively; animals, levels inflammatory factors not different no-LD controls. Expression genes, including Ripk3 Mlkl, upregulated vehicle-treated but dramatically reduced near no mice. Microglia activation MLKL upregulation observed primarily photoreceptors 12 as microglia migration plexiform (OPL) retinas. Conclusions Systemic administration partially protected light-induced photochemical both inflammation pathways. Our results that NSAIDs may provide promising therapeutic approach treatment human diseases.

Language: Английский

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