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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The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(3), P. e1011205 - e1011205

Published: March 11, 2025

Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, often accompanied vestibular dysfunction. The identity of the cell types responsible for pathology mechanisms leading to loss USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology delete a large region coding untranslated (UTR) zebrafish clrn1 . retinas mutant larvae exhibited sensitivity stress, along with age-dependent function degeneration photoreceptor layer. Investigation revealed disorganization outer retina mutants, including actin-based structures Müller glia cells. assess cell-specific contributions pathology, specifically re-expressed either or re-expression prevented elevated death observed larval exposed high-intensity light. Notably, degree phenotypic rescue correlated level Clrn1 re-expression. Surprisingly, high levels expression enhanced both wild-type animals. However, rod- cone-specific did not reduce extent death. Taken together, our findings underscore three crucial insights. First, exhibit key pathological features USH3A; second, within plays pivotal role maintenance, its requiring controlled regulation; third, reliance photoreceptors on suggests structural support mechanism, possibly through direct interactions between mediated part protein.

Language: Английский

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Lipopolysaccharide induces apoptosis and oxidative cytotoxicity through stimulation of the TRPV1 channel in retinal pigment epithelium cell line

Journal of Cellular Neuroscience and Oxidative Stress, Journal Year: 2025, Volume and Issue: 16(3), P. 1229 - 1236

Published: Jan. 13, 2025

Common and vision-threatening inflammatory ocular disorders are major issues on a global scale. The etiology whole treatment for yet unknown. With the exception of human retinal pigment epithelial-19 (ARPE-19), numerous cells have been shown to be involved in lipopolysaccharide (LPS)-induced free reactive oxygen species (ROS) apoptosis through TRPV1 cation channel stimulation. I wanted determine how affected oxidative cytotoxicity caused by LPS ARPE-19. Two main groups ARPE-19 were induced as control (1 g/ml twenty-four hours). antagonist (100 M capsazepine (CAPZ) 1 hour) blocked channel, whereas agonist (10 M capsaicin (CAPS) stimulated groups. incubation CAPS increased amounts apoptosis, caspases (caspase -3, -8, -9), mitochondrial dysfunction, ROS groups, while CAPZ diminished these amounts. However, their additionally than control. LPS-induced increases cell viability CAPZ. In summary, inhibition contributes stress that causes cells. may viable option damage LPS.

Language: Английский

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Blue Light Irradiation Elicits Senescence of Corneal Endothelial Cells In Vitro by Provoking Energy Crisis, Inflammasome Assembly and DNA Damage

Current Eye Research, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 12

Published: May 8, 2025

The blue light from the digital screens endangers visual system among which corneas at outmost of eyes are vulnerable to irradiation. Therein, human corneal endothelial (HCE) cells crucial maintain transparency and their damage leads HCE decompensation resulting in blindness ultimately. Thus, understanding phototoxic effects on underlying mechanisms is important for taking measures protect vision clarity blue-light hazard. We pulse-irradiated cell line logarithmic phase 3 passages using 440 nm examined levels reactive oxygen species (ROS), ATP, nicotinamide adenine dinucleotide (NAD+) autophagy cytochemistry assay investigate alterations energy metabolism. Moreover, we γH2AX+ immunofluorescence expression poly(ADP-Ribose)polymerase1 (PARP1) western blotting degrees DNA repair. also monitored inflammasome senescence associated secretory phenotypes (SASPs) interleukin (IL)-8, IL-1β IL-6 qPCR ELISA assembly secretion SASPs. detected senescent features with senescence-associated-β-galactosidase assay, p16 by blotting, Lamin B1 localization observation, growth EdU incorporation confluence forming time morphology relative areas microscopy observation. exhibited after blue-light-pulse-irradiation. provokes overproduction ROS decrease NAD+ leading crisis. excess injure downregulate PARP1 stable cell-cycle arrest. facilitate hypersecretion elicits via inducing crisis, arrest SASP hypersecretion.

Language: Английский

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Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: May 15, 2025

Abstract Background Retinal degeneration is a leading cause of blindness worldwide. The induction ferroptosis has been identified as an important mechanism contributing to the loss photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate cell viability various diseases. However, effects LCN2 on remain unclear. Methods A light-induced injury model using 661W photoreceptor cells male rat were established. protein expression was assessed by western blotting. vitro investigated recombinant (rLCN2) small-interfering RNA (siRNA) targeting (siLCN2). Fe 2+ , malondialdehyde (MDA), tripeptide glutathione (GSH) levels, ferroptosis-associated proteins (solute carrier family 7 member 11 [SLC7A11] peroxidase-4 [GPX4]) measured. phosphokinase array blotting performed elucidate mechanisms underlying LCN2-modulated ferroptosis. Additionally, protective knockdown adeno-associated virus (AAV)-expressing short hairpin (shRNA) (AAV-shRNA-LCN2) structure function vivo evaluated hematoxylin eosin staining electroretinography. Results significantly upregulated following light exposure. Treatment with rLCN2 induced cells, shown decreased viability, increased inhibition SLC7A11 GPX4 expression, depletion GSH, enhanced MDA whereas siLCN2 protected against these effects. Exposure activated c-Jun N-terminal kinase (JNK), administration JNK inhibitor SP600125 from Lastly, AAV-shRNA-LCN2 inhibited retina, vivo. Conclusion key regulator modulating pathway. Therefore, presents new target for treatment

Language: Английский

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