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- Dionysopoulou, Stavroula, et al.
(författare)
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Topically Administered NOX4 Inhibitor, GLX7013114, Is Efficacious in Treating the Early Pathological Events of Diabetic Retinopathy
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:5, s. 638-652
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Tidskriftsartikel (refereegranskat)abstract
- NADPH oxidases (NOXs) are major players in generating reactive oxygen species (ROS) and are implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of a NOX4 inhibitor (GLX7013114) in two in vivo, experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Animals in the diabetic treated group received GLX7013114 topically (20 mu L/eye, 10 mg/mL, once daily) for 14 days (paradigm A: preventive) and 7 days (paradigm B: treated) at 48 h and 4 weeks after STZ injection, respectively. Several methodologies were used (immunohistochemistry, Western blot, real-time PCR, ELISA, pattern electroretinography [PERG]) to assess the diabetes-induced early events of DR, namely oxidative stress, neurodegeneration, and neuroinflammation, and the effect of GLX7013114 on the diabetic insults. GLX7013114, administered as eye drops (paradigms A and B), was beneficial in treating the oxidative nitrative stress, activation of caspase-3 and micro- and macroglia, and attenuation of neuronal markers. It also attenuated the diabetes-induced increase in vascular endothelial growth factor, Evans blue dye leakage, and proinflammatory cytokine (TNF-alpha protein, IL-1 beta/IL-6 mRNA) levels. PERG amplitude values suggested that GLX7013114 protected retinal ganglion cell function (paradigm B). This study provides new findings regarding the pharmacological profile of the novel NOX4 inhibitor GLX7013114 as a promising therapeutic candidate for the treatment of the early stage of DR.
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| 2. |
- Georgakis, Spiros, et al.
(författare)
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NETs decorated with bioactive IL-33 infiltrate inflamed tissues and induce IFN-α production in patients with SLE
- 2021
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Ingår i: JCI Insight. - : American Society For Clinical Investigation. - 2379-3708. ; 6:21
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Tidskriftsartikel (refereegranskat)abstract
- IL-33, a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells, eliciting potent inflammatory responses. We screened blood, skin, and kidney tissues from patients with systemic lupus erythematosus (SLE), a systemic autoimmune disease driven by unabated type I IFN production, and found increased amounts of extracellular IL-33 complexed with neutrophil extracellular traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging, and proteomic approaches, we show that SLE neutrophils, activated by disease immunocomplexes, release IL-33-decorated NETs that stimulate robust IFN-α synthesis by plasmacytoid DCs in a manner dependent on the IL-33 receptor ST2L. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, NETs derived from patients with SLE are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFN-α production elicited by NETs. We believe these data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production, and end-organ inflammation, with skin pathology mirroring that observed in the kidneys.
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