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, Quantification of cone nuclei showed more cones in explants treated with TF than those exposed to FeSO4. Mann Whitney test (n=3), *p=0.036. (H) Western blotting and quantitative analysis of receptor-interacting protein kinase (RIP) demonstrated higher full-form and cleaved form of the proteins in iron-exposed retinal explants. The cleaved form of RIP reported on RIP full form was reduced when TF was used to treated iron-exposed explants

, Anti-apoptotic Bcl2 protein, detected by western blotting, was increased in TF-treated iron-exposed explants. Mann Whitney test (n=3), *p=0.028. (J) TUNEL positive cells in the outer nuclear layer was reduced by TF treatment. (K) Immunostaining of iron storage marker

, GCL: Ganglion cell layer; ONL: Outer nuclear layer; INL: Inner nuclear layer. Scale bars: 100 µm. All values are represented as mean ±SEM. expression was lower in TG mice compared with WT mice (arrows), Fluorescence intensity was reported relative to control conditions. One-way ANOVA, Bonferroni posttest (n=3), *p<0.05

, 0056. (F) Cellular markers of apoptosis were lower in TG compared to WT mouse retinas

, Caspase 8 mRNA level by RT-qPCR, and the ratio of cleaved/pro-caspase 3 protein levels by western blotting was performed 4 days after RD. TUNEL staining was performed in eyes collected 7 days after RD. Mann Whitney test (n=5), ** p=0.008, *p=0.028. (G) Necrotic RIP kinase protein level, detected by western blotting was reduced in TG mice compared with WT mice

, GCL: Ganglion cell layer; INL: Inner nuclear layer; IS: Inner segment; ONL: Outer nuclear layer; OS: Outer segment; RPE: Retinal pigmented epithelium. Scale bars: 100 µm (A, E, F); 50 µm (Crelative to WT explants

, GCL: Ganglion cell layer; ONL: Outer nuclear layer, vol.001

, Müller glial cells activation (B, Glial fibrillary acidic protein), lipid peroxidation (C, 4-Hydroxynonenal), and DNA damage (D, 8-Hydroxyguanosine) were significantly lower in explants treated with TF (Fe+TF) than without treatment (Fe). Fluorescence intensity was reported relative to control conditions. One-way ANOVA, Transferrin treatment preserves iron-exposed rat retinal explants from of activated macrophages/microglia (A, CD68, arrowheads), vol.4

, Supplementary Figure 5: Animal models of retinal detachment (A-C) The mouse model of retinal detachment (RD). (A) Representative fundus photographs and the corresponding optical coherence tomography (OCT) images from a control eye (no RD, left) and an eye with RD 7 days after induction (red asterisk shows subretinal space, right). (B) Retinal semi-thin sections 7 days after RD showing the detached area. The red box denotes the detached area and the black box denotes the undetached retina. (C) Higher magnification showing increased retinal thickness (brackets)

, Note the increased retinal thickness (brackets) in the detached retina compared to the undetached retina. Furthermore, higher magnification of the detached area showed a loss of the outer segments (arrowhead) and pyknotic photoreceptor nuclei (arrow), as compared with the undetached retina. INL: Inner nuclear layer; IS: Inner segment; ONL: Outer nuclear layer; OS: Outer segment; RPE: retinal pigmented epithelium, Note the subretinal space (red asterisk). (D-E) Rat model of retinal detachment. (D) Representative fundus photographs and the corresponding OCT images before RD, immediately after RD induction (red asterisk) and 7 days later, p.500

E. , 50 µm (B), 25 µm (E, high magnification)

, 3?-Diaminobenzidine (DAB) amplified Perl's reaction revealed iron accumulation (arrows) in the outer and inner segments and under the RPE layer in mice (A) and rats (B) 7 days after induction of retinal detachment (RD) (red asterisk). (C) Iron levels were increased in the ocular fluids of rats 14 days after RD. Mann Whitney test (n=4-6), p=0.042. INL: Inner nuclear layer; IS: Inner segment; ONL: Outer nuclear layer; OS: Outer segment; RPE: retinal pigmented epithelium. Nuclei were stained with toluidine blue, Supplementary Figure 6: Iron accumulates in the rodent retina following retinal detachment, vol.3

, IGFBP-3R and low-density lipoprotein receptor-related protein-1 (LRP1), and inhibits caspase-dependent apoptosis and growth inhibition through the dephosphorization of the insulin receptor substrate (IRS) by a Ser/Thr-specific protein phosphatase. ii) to enhance the interaction of IGFBP3 with multiple extracellular components including glycosaminoglycan (GAG) or receptors for its cellular uptake. IGFBP3 binding to the extracellular matrix promotes sphingosine-1-phosphate (S1P) production by inhibiting sphingomyelinase (SMase) and increasing sphingosine-1-phosphatase (SphK1). S1P interaction with S1PR receptors leads to multi pathways like preservation of blood barrier integrity, and also transactivation of EGFR leading to a caveolin-mediated endocytosis of the complex EGFR-IGFBP3. The IGFBP3-TF complex is taken up by the TF 1 receptor and internalized by a clathrin endocytosis vesicle. IGFBP3 and its binding partners (TF or EGFR) may be then found in the late endosome/multivesicular body for redistribution of molecules in the cell. iii) Nuclear import of IGFBP3 is mediated by importin beta, where it can form nuclear complexes. Phosphorylation of nuclear IGFBP3 by DNA-PKcs, resulting in activation of IGBP3-EGFR-DNA-PK complexes and favoring double-strand DNA break repair by non-homologous end-joining (NHEJ). The IGFBP3-RXR alpha interaction increased RXRalpha homodimer transcriptional activity whereas it prevented formation of the RXRalpha-RARalpha, and RXRalpha-PPRAgamma-RXRalpha-Nur77 heterodimers. The endoplasmic reticulum (ER) is one of the probable sources of the autophagosomal double membrane in mammals, and the ER-resident chaperone GPR78 is required for stress-induced autophagy, Proposed role of IGFBP3 in the protective effect of transferrin Based on genes up-and down-regulated in transcriptomic analysis, this illustration highlights the cellular protective mechanism involving the IGFBP3-transferrin (TF) interaction. The formation of the IGFBP3-TF complexes may be expected: i) to reduce IGFBP3 binding on its cell-surface specific receptors, vol.8