Overexpression of TRPV1 activates autophagy in human lens epithelial cells under hyperosmotic stress through Ca2+-dependent AMPK/mTOR pathway.

AIM: To explore whether autophagy functions as a cellular adaptation mechanism in lens epithelial cells (LECs) under hyperosmotic stress. METHODS: LECs were treated with hyperosmotic stress at the concentration of 270, 300, 400, 500, or 600 mOsm for 6, 12, 18, 24h in vitro. Polymerase chain reaction (PCR) was employed for the mRNA expression of autophagy-related genes, while Western blotting detected the targeted protein expression. The transfection of stub-RFP-sens-GFP-LC3 autophagy-related double fluorescence lentivirus was conducted to detect the level of autophagy flux. Scanning electron microscopy was used to detect the existence of autolysosome. Short interfering RNA of autophagy-related gene (ATG) 7, transient receptor potential vanilloid (TRPV) 1 overexpression plasmid, related agonists and inhibitors were employed to their influence on autophagy related pathway. Flow cytometry was employed to test the apoptosis and intracellular Ca2+ level. Mitochondrial membrane potential was measured by JC-1 staining. The cell counting kit-8 assay was used to calculate the cellular viability. The wound healing assay was used to evaluate the wound closure rate. GraphPad 6.0 software was utilized to evaluate the data. RESULTS: The hyperosmotic stress activated autophagy in a pressure- and time-dependent manner in LECs. Beclin 1 protein expression and conversion of LC3B II to LC3B I increased, whereas sequestosome-1 (SQSTM1) protein expression decreased. Transient Ca2+ influx was stimulated caused by hyperosmotic stress, levels of mammalian target of rapamycin (mTOR) phosphorylation decreased, and the level of AMP-activated protein kinase (AMPK) phosphorylation increased in the early stage. Based on this evidence, autophagy activation through the Ca2+-dependent AMPK/mTOR pathway might represent an adaptation process in LECs under hyperosmotic stress. Hyperosmotic stress decreased cellular viability and accelerated apoptosis in LECs and cellular migration decreased. Inhibition of autophagy by ATG7 knockdown had similar results. TRPV1 overexpression increased autophagy and might be crucial in the occurrence of autophagy promoted by hyperosmotic stress. CONCLUSION: A combination of hyperosmotic stress and autophagy inhibition may be a promising approach to decrease the number of LECs in the capsular bag and pave the way for improving prevention of posterior capsular opacification and capsular fibrosis.

New insight in treating autoimmune diseases by targeting autophagy.

Autophagy is a highly conserved biological process in eukaryotes, which degrades cellular misfolded proteins, damaged organelles and invasive pathogens in the lysosome-dependent manner. Autoimmune diseases caused by genetic elements, environments and aberrant immune responses severely impact patients' living quality and even threaten life. Recently, numerous studies have reported autophagy can regulate immune responses, and play an important role in autoimmune diseases. In this review, we summarised the features of autophagy and autophagy-related genes, enumerated some autophagy-related genes involved in autoimmune diseases, and further overviewed how to treat autoimmune diseases through targeting autophagy. Finally, we outlooked the prospect of relieving and curing autoimmune diseases by targeting autophagy pathway.

Clinical observation of a modified technique for intrascleral fixation of flanged three-piece foldable intraocular lenses through a Hoffman pocket.

Purpose: To present the outcomes of a new technique for intrascleral fixation of a flanged three-piece foldable intraocular lens (IOL) without a conjunctival incision. Materials and methods: We retrospectively reviewed a consecutive series of 12 eyes of 12 patients who underwent scleral IOL fixation using this technique. Results: The follow-up period ranged 3-12 months. There was a significant improvement in best-corrected visual acuity, from 0.8 (1.6) logarithm of the minimum angle of resolution (logMAR) preoperatively to 0.45 (0.8) logMAR at the final postoperative follow-up (p = 0.012). Notable complications included one case of pupillary IOL capture and increased intraocular pressure. Conclusion: Our novel technique is a viable solution for managing secondary IOL fixation, enabling the use of a wider variety of IOLs and simplifying the reposition process for dislocated three-piece IOLs. This approach has the potential to lower complication rates and enhance patients' recovery.

CSNK1A1/CK1α suppresses autoimmunity by restraining the CGAS-STING1 signaling.

STING1 (stimulator of interferon response cGAMP interactor 1) is the quintessential protein in the CGAS-STING1 signaling pathway, crucial for the induction of type I IFN (interferon) production and eliciting innate immunity. Nevertheless, the overactivation or sustained activation of STING1 has been closely associated with the onset of autoimmune disorders. Notably, the majority of these disorders manifest as an upregulated expression of type I interferons and IFN-stimulated genes (ISGs). Hence, strict regulation of STING1 activity is paramount to preserve immune homeostasis. Here, we reported that CSNK1A1/CK1α, a serine/threonine protein kinase, was essential to prevent the overactivation of STING1-mediated type I IFN signaling through autophagic degradation of STING1. Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. Consistently, SSTC3, a selective CSNK1A1 agonist, significantly attenuated the response of the CGAS-STING1 signaling by promoting STING1 autophagic degradation. Importantly, pharmacological activation of CSNK1A1 using SSTC3 markedly repressed the systemic autoinflammatory responses in the trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CSNK1A1 in the autophagic degradation of STING1 to maintain immune homeostasis. Manipulating CSNK1A1 through SSTC3 might be a potential therapeutic strategy for alleviating STING1-mediated aberrant type I IFNs in autoimmune diseases.Abbreviations: BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HTDNA: herring testes DNA; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNA4: interferon alpha 4; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; ISGs: IFN-stimulated genes; MEFs: mouse embryonic fibroblasts; PBMCs: peripheral blood mononuclear cells; RSAD2: radical S-adenosyl methionine domain containing 2; SLE: systemic lupus erythematosus; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

Nutrient runoff loss from saline-alkali paddy fields in Songnen Plain of Northeast China via different runoff pathways: effects of nitrogen fertilizer types.

The application of nitrogen (N) fertilizer aggravates the nutrient runoff loss from paddy, causing serious agricultural non-point source pollution, and leading to a serious decline in water quality. The global area of saline-alkali paddy has expanded, but the response of nutrient loss via runoff to N-fertilizer applications in saline-alkali paddy is still unclear. This study conducted a 147-day field experiment to evaluate the nutrient runoff loss from saline-alkali paddy with different N-fertilizer application strategies in Songnen Plain of Northeast China. Regardless of N-fertilizer types, the nutrient loss via rainfall runoff in the entire rice-growing season was significantly (p < 0.05) higher than that via artificial drainage. The N and phosphorus (P) concentrations in runoff water were correlated with salinity and alkalinity. Especially, pH had a significant positive correlation with total-P (TP) (r = 0.658, p < 0.01). In the entire rice-growing season, the TN runoff losses in urea (U), microbial fertilizer (MF), and inorganic compound fertilizer (ICF) treatments were significantly (p < 0.05) lower compared with carbon-based slow-release fertilizer (CSF) and organic-inorganic compound fertilizer (OCF), respectively. Meanwhile, the TP runoff losses in OCF and ICF treatments were significantly (p < 0.05) lower than U and MF, respectively. Overall, the application of ICF is a better choice to avoid N and P losses via runoff from saline-alkali paddy fields.

Nitrogen migration and transformation in a saline-alkali paddy ecosystem with application of different nitrogen fertilizers.

With the increasing transformation of saline-alkali land into paddy, the nitrogen (N) loss in saline-alkali paddy fields becomes an urgent agricultural-environmental problem. However, N migration and transformation following the application of different N fertilizers in saline-alkali paddy fields remains unclear. In this study, four types of N fertilizers were tested to explore the N migration and transformation among water-soil-gas-plant media in saline-alkali paddy ecosystems. Based on the structural equation models, N fertilizer types can change the effects of electrical conductivity (EC), pH, and ammonia-N (NH4+-N) of surface water and/or soil on ammonia (NH3) volatilization and nitrous oxide (N2O) emission. Compared with urea (U), the application of urea with urease-nitrification inhibitors (UI) can reduce the potential risk of NH4+-N and nitrate-N (NO3--N) loss via runoff, and significantly (p < 0.05) reduce the N2O emission. However, the expected effectiveness of UI on NH3 volatilization control and total N (TN) uptake capacity of rice was not achieved. For organic-inorganic compound fertilizer (OCF) and carbon-based slow-release fertilizer (CSF), the average TN concentrations in surface water at panicle initiation fertilizer (PIF) stage were reduced by 45.97% and 38.63%, respectively, and the TN contents in aboveground crops were increased by 15.62% and 23.91%. The cumulative N2O emissions by the end of the entire rice-growing season were also decreased by 103.62% and 36.69%, respectively. Overall, both OCF and CSF are beneficial for controlling N2O emission and the potential risks of N loss via runoff caused by surface water discharge, and improving the TN uptake capacity of rice in saline-alkali paddy fields.

Use of an Iris Speculum for Retrolental Membrane Dissection for Stage 5 Prematurity of Retinopathy Complicated With Pupillary Adhesion.

PURPOSE: To report a novel use of an iris speculum to assist with membrane dissection and trough separation for stage 5 retinopathy of prematurity-related funnel-shaped tractional retinal detachment complicated with pupillary adhesion. METHODS: Limbus-based closed vitrectomy and membrane dissection were performed in 10 eyes (9 patients) with stage 5 retinopathy of prematurity-related tractional retinal detachment and pupillary adhesion. After synechiolysis, an iris speculum was positioned to enlarge the pupil for surgical visualization and maintain a neutral iris plane. The retrolental membrane was dissected bimanually and circumferentially along the peripheral trough and then toward the central retina with vertical scissors and end-gripping forceps. RESULTS: In all 10 eyes, retrolental membranes were entirely removed and troughs were circumferentially unraveled. Follow-up examinations performed 6 to 18 months postoperatively showed reattachment of the retina in 3 eyes with an open-narrow funnel and 6 of 7 eyes with a narrow-narrow funnel. A near-circular pupil without recurrent pupillary adhesion was preserved in all nine eyes showing retinal reattachment. CONCLUSION: This use of the iris speculum effectively exposes the surgical field for the entire removal of retrolental tissue and interruption of the peripheral trough in stage 5 retinopathy of prematurity-related tractional retinal detachment complicated with pupillary adhesion. The pupil's configuration is well preserved postoperatively.

Viscodelamination of Localized Retrolental Plaques During Lens-Sparing Vitrectomy in Eyes With Pediatric Tractional Vitreoretinopathy.

PURPOSE: To report viscodelamination of localized retrolental plaques during lens-sparing vitrectomy in eyes with pediatric tractional vitreoretinopathy. METHODS: Viscodelamination of retrolental plaques was performed during 23-gauge lens-sparing vitrectomy in 11 eyes from 11 children with a median age (range) of 12 (4-58) months. There were five eyes with Stage 4 familial exudative vitreoretinopathy, one eye with Stage 4B retinopathy of prematurity, and five eyes with anterior-posterior persistent fetal vasculature syndrome. Retrolental plaques were separated from the posterior lens capsule by the tension of viscoelastic injection in the Berger's space. RESULTS: In 10 of 11 eyes, retrolental plaques were removed from posterior surface of lens without capsular tearing. During the 12-month to 18-month follow-up period, lens clarity along the visual axis was retained in 5 eyes with familial exudative vitreoretinopathy, one eye with retinopathy of prematurity, and 2 of 5 eyes with persistent fetal vasculature. Atraumatic viscodelamination was associated with retrolental plaques that did not incorporate into the posterior lens capsule. Retinal dragging was reversed in all 11 eyes. CONCLUSION: Viscodelamination may be effective for the dissection of retrolental plaques related to pediatric vitreoretinopathy in selected cases.

Intraoperative Perfluorocarbon Liquid Tamponade Technique for Treatment of Extensive Retinal Detachment Secondary to a Myopic Macular Hole.

BACKGROUND/PURPOSE: To report an intraoperative perfluorocarbon liquid (PFCL) tamponade technique in treating extensive retinal detachment secondary to a myopic macular hole (MH) through pars plana vitrectomy. METHODS: The technique was applied in nine eyes with MH-RD extending two quadrants or more areas. The procedures for pars plana vitrectomy included: 1). thorough drainage of subretinal fluid through the MH with fluid-air exchange; 2). PFCL tamponade on the macular area for more than 10 minutes; and 3). repairing the MH after PFCL was removed. RESULTS: All nine eyes gained intraoperative retinal reattachment after PFCL tamponade for 22.22 ± 8.01 minutes and removal of PFCL. Procedures for MH closure included internal limiting membrane peeling in eight eyes, with internal limiting membrane free flap insertion (four eyes), internal limiting membrane inverted flap insertion (two eyes), or lens capsular flap transplantation (three eyes). All eyes received C3F8 tamponade. During 9.11 ± 3.89 months of follow-up, eight of the nine eyes (89%) achieved retinal reattachment and MH closure; one eye achieved anatomical success after reoperations. All eyes had vision improvement at the last follow-up. CONCLUSION: This new technique in pars plana vitrectomy may promote anatomical and functional recovery in the treatment of extensive retinal detachment secondary to a myopic MH.

Modified Trisection Technique: One-Trip Explantation for Foldable Intraocular Lens.

PURPOSE: We present a new technique that allows an intraocular lens to be explanted through the small incisions used in modern cataract surgery. METHODS AND RESULTS: The intraocular lens optic is cut into three connected pieces at the 1-mm-wide end with scissors. Then, with the stabilizing counterforce provided by a pair of vitreoretinal forceps through a paracentesis, the middle piece is removed first, followed by the two side pieces connected with haptics flipped over at the connected part. These two parts overlap each other when passing through the incision, eventually resulting in the explantation of the intraocular lens, as an intact piece. CONCLUSION: We believe this method provides a simple and effective way to remove intraocular lens through very small incisions, which could also reduce complications and hasten patient's recovery.

Early-onset Neovascular Inflammatory Vitreoretinopathy Due to Two de Novo CAPN5 Mutations in Chinese Patients: A Case Series.

PURPOSE: To explore the clinical and molecular characteristics, diagnosis, and treatment of early-onset autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) in Chinese patients. METHODS: A retrospective, interventional case series was assembled from three ADNIV patients. RESULTS: The three ADNIV cases harbored de novo CAPN5 mutations (p.Arg289Trp and p.Leu73Val). The ages of onset ranged from 11 months to 2 years. All the cases presented with vitreous opacity and subretinal inflammatory exudations. During the postoperative follow-up, all the patients manifested with exaggerated postoperative inflammatory responses. An intravitreal Ozurdex injection could not effectively control ocular inflammation in ADNIV. Laser spots after panretinal photocoagulation were partly visible. CONCLUSIONS: Two de novo CAPN5 mutations (p.Leu73Val and p.Arg289Trp) could cause early-onset ADNIV. Panretinal photocoagulation during vitrectomy and an intravitreal Ozurdex injection could not significantly stop the progression of subretinal exudations and ocular inflammation in early-onset ADNIV patients.

Staged lensectomy and vitrectomy in the management of stage 5C retinopathy of prematurity with corneal opacification: long-term follow up.

AIM: To verify the feasibility and safety of staged lensectomy and vitrectomy in stage 5C retinopathy of prematurity (ROP) with corneal opacification. METHODS: This was a retrospective, interventional, consecutive case series. Twenty-two eyes of 18 stage 5C ROP patients with corneal opacification were included. Regular combined lensectomy and vitrectomy were not prescribed due to the invisible fundus. Staged lensectomy and posterior vitrectomy were performed. The anatomical and visual outcomes were reviewed at the final follow-up visit. RESULTS: The mean gestational age of ROP patients was 29.3±1.6wk (range: 27-32wk), comprising 8 males and 10 females. The average birth weight was 1363.0±300.0 g. All the eyes had corneal opacity and flat or disappeared anterior chambers pre-operatively. Two eyes had complicated cataract and 7 eyes had retrolental fibroplasia. Six eyes had posterior pupillary synechiae or membranes. Seven (31.8%) eyes had vascularly active retinas. The average interval between two procedures was 6.8±4.6mo (2.5-18.5mo). After surgeries, all the patients had normal anterior chambers. Fourteen eyes had clear corneas. The intraocular pressure of 3 eyes with glaucoma was controlled by medication. Two eyes had ocular phthisis. The retina was reattached in 3 eyes and partially attached in 11 eyes. Visual acuity ranged from no light perception to hand motion. CONCLUSION: Staged lensectomy and vitrectomy are procedures that can halt progression to further complications and preserve some useful eyesight in stage 5C ROP patients with corneal opacification. The earlier the lensectomy is performed, the better the prognosis is.

Repeated intravitreal ranibizumab for reactivated retinopathy of prematurity after intravitreal ranibizumab monotherapy: vascular development analysis.

PURPOSE: To evaluate the retinal vascularization of repeated intravitreal ranibizumab (IVR) for reactivated retinopathy of prematurity (ROP) treated with IVR monotherapy. METHODS: The retrospective study reviewed ROP infants who accepted IVR injection as the first treatment in our department from January 2017 to December 2018. The ratio of the distance from the center of the optic disc to the border of the vascularized zone (DB) to the distance from the center of the disc to the fovea (DF) was used for the vascular outgrowth analysis. RESULTS: Seventy-eight infants were included in the study. A total of 54.3% of the reactivated ROP patients could achieve complete vascularization after repeated IVR injections. Gestational age (GA) > 29 weeks and a temporal DB/DF ratio ≥ 3 in the first IVR were potential predictors for complete retinal vascularization after IVR monotherapy. The temporal DB/DF ratio ≥ 3.6 in the second IVR injection was a potential predictor for complete retinal vascularization after repeated IVR for ROP reactivation. CONCLUSIONS: Reactivated ROP after IVR monotherapy can be treated successfully with repeated IVR injections. GA and temporal DB/DF ratio are potential predictors of complete retinal vascularization in ROP infants treated with IVR.

Secondary glaucoma caused by a special type of persistent fetal vasculature.

PURPOSE: To investigate the clinical features and surgical outcomes in infants with glaucoma secondary to a special anterior-anterior type of persistent fetal vasculature (AAPFV). METHODS: This study retrospectively reviewed the medical records of infants who underwent of the synechialysis, pupilloplasty, with or without lensectomy and limbal vitrectomy due to AAPFV and with at least 6 months of postoperative follow-up. RESULTS: Eleven patients were included. The median age at surgery was 4.0 months (interquartile range: 7 months). The mean follow-up was 21.0 ± 11.3 months. All patients achieved a normal anterior chamber, improved pupillary configuration, and normal intraocular pressure (IOP), except one that developed phthisis bulbi at the last visit. A total of 81.8% (9/11) eyes exhibited improved corneal transparency. Histopathologic findings of four pupillary membranous specimens under light microscopy showed similar components compared with PFV. Two eyes developed postoperative complications, including retinal detachment and hyphema, requiring additional surgeries. Postoperative visual acuity changed from no light perception to light perception in 6/9 patients. CONCLUSIONS: AAPFV is a special type of PFV with a potential for secondary glaucoma. Surgery treatment may offer better vision with improved cosmetic outcomes and a better controlled IOP. TRIAL REGISTRATION: The study was approved by the local institutional review board (IRB) (Approval No. XHEC-D-2021-043, Ethical Committee of Xin Hua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China).

[Mineral nitrogen accumulation and its spatial distribution in soils in dense planting dwarf rootstock apple orchard on the Weibei dry plateau, Northwest China]. / æ¸­åŒ—æ—±å¡¬çŸ®ç §å¯†æ¤è‹¹æžœå›­åœŸå£¤çŸ¿è´¨æ°®ç§¯ç´¯ä¸Žç©ºé—´åˆ†å¸ƒç‰¹å¾.

With the rapid development of dense apple tree plantings with the dwarf rootstock cultivation method, determining accumulation and distribution characteristics of soil mineral nitrogen in densely planted orchards with dwarf rootstock is important to enable scientific fertilization of apple orchards. We investigated densely planted apple orchards with dwarf rootstocks and different plant ages (6 a, 9 a, and 12 a). We collected soil samples under trees, between trees, between rows, and at the midpoints between the trees and rows, and examined the accumulation and distribution characteristics of nitrate, ammonium, and mineral nitrogen. The cumulative amount of nitrate in the 0-300 cm soil layer increased with plant age. The difference between orchards with different plant ages was significant and showed the trend 6 a<9 a<12 a. The cumulative amount of nitrate increased from 1729 kg·hm-2 to 3771 kg·hm-2 with increasing plant age. The ammonium content was low for orchards of all plant ages and had little effect on the accumulation and spatial distribution of mineral nitrogen. There were two accumulation peaks of nitrate nitrogen in the vertical direction. The depth of soil layer where the second accumulation peak was located decreased from 180 cm to 220 cm with increasing plant age. In the horizontal direction, soil nitrate nitrogen content between rows increased from 27 mg·kg-1 to 138 mg·kg-1 with increasing plant age, representing a more than 400% increase. The difference between orchards with different plant ages was significant. In summary, excessive usage of nitrogen fertilizer and serious leaching of nitrate were problematic in all orchards with different ages. Less nitrogen fertilizer should be applied, and anti-seepage measures should be used at the fertilization location to prevent the leaching of nitrate to deep layers.

CLINICAL FEATURES AND SURGICAL OUTCOMES OF ENCIRCLING SCLERAL BUCKLING WITH CRYOTHERAPY IN FAMILIAL EXUDATIVE VITREORETINOPATHY-ASSOCIATED RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To report the clinical features and surgical outcomes of encircling scleral buckling surgery with cryotherapy in familial exudative vitreoretinopathy (FEVR) patients with rhegmatogenous RD. METHODS: This study was a consecutive, retrospective interventional case series. Clinical features, including the FEVR stage, proliferative vitreoretinopathy grade, range of RD and degeneration, and presence of retinal breaks, and surgical outcomes, including the success rate, best-corrected visual acuity, and myopic shift, were analyzed. RESULTS: There were 16 eyes with Stage 3A FEVR and eight eyes with Stage 4A FEVR. 13 eyes had Grade A proliferative vitreoretinopathy, and 11 eyes had Grade B proliferative vitreoretinopathy. Retinal reattachment was achieved in 22 of 24 eyes (91.67%) with FEVR-rhegmatogenous RD after initial encircling scleral buckling surgery. The best-corrected visual acuity improved from a mean of 1.08 ± 0.86 logarithm of the minimum angle of resolution preoperatively to 0.45 ± 0.41 logarithm of the minimum angle of resolution postoperatively (P < 0.01). A myopic shift of -2.39 ± 1.38 (range, -1 to -6) diopter (P < 0.01) was observed. The mean follow-up period was 34.5 ± 27.7 (range, 7-104) months. CONCLUSION: Our study clarified the efficacy of encircling scleral buckling surgery with cryotherapy in FEVR-rhegmatogenous RD with Stage 3A or 4A FEVR and Grade A or B proliferative vitreoretinopathy, especially in patients with multiple retinal holes.

[Survey of dentists' knowledge and behavior of medications used during pregnancy in Beijing area].

PURPOSE: To investigate dentists' knowledge and behavior of drugs used during pregnancy in Beijing and analyze sources of influence. METHODS: A cross sectional survey was undertaken among 259 dentists in Beijing. The percentage frequency distributions of correct responses regarding medication safety during pregnancy and the use of drugs were calculated. Logistic regression model was used to explore factors associated with dentists' knowledge of medications used during pregnancy with SAS 9.4 software package. RESULTS: The correct rate on medication safety during pregnancy ranged from 1.93%-57.92%. The percentage of knowledge scores exceeding 8 point was only 10.42% (out of 16 points). In addition, the percentage of drugs prescribed and used during pregnancy was generally low(2.8%-27.09%). CONLUSIONS: Dentists in Beijing do not have sufficient knowledge about medication used during pregnancy. Continuing education is needed and professional authorities should develop unified guidelines to standardize their clinical practice.

Competing endogenous RNA network associated with oxygen-induced retinopathy: Expression of the network and identification of the MALAT1/miR-124-3p/EGR1 regulatory axis.

Retinopathy of prematurity (ROP) is a severe retinal dysfunction in prematurely born babies. The relationship between non-coding RNAs and retinopathy of prematurity (ROP) remain unclear. Microarray analysis of lncRNAs, miRNAs, and mRNAs was conducted in a mouse model of ROP. A competing endogenous RNA (ceRNA) network was constructed. The relationship among MALAT1, miR-124-3p, and Early growth response protein 1 (EGR1) was assessed in hypoxia-induced primary human umbilical vein endothelial cells (HUVECs) and ROP mouse model. In the study, we found 2252 lncRNAs, 1239 mRNAs, and 36 miRNAs were differentially regulated. ceRNA network consisting of 21 lncRNAs, 10 miRNAs, and 19 mRNAs was established. Of the most down-regulated miRNAs, miR-124-3p was selected for additional study. miR-124-3p ceased the migration and proliferation of primary HUVECs in hypoxic conditions, and directly suppressed EGR1. Additionally, MALAT1 directly sponged miR-124-3p. Knockdown of MALAT1 decreased EGR1 expression and inhibited the migration and proliferation of primary HUVECs in hypoxia. Furthermore, these changes were rescued by depletion of miR-124-3p. In vivo, intravitreal injection of miR-124-3p, shMALAT1 decreased EGR1 expression and markedly suppressed retinal neovascularization in OIR models. Intravitreal injection of shMALAT1 and miR-124-3p antagomir at the same time can promote retinal neovascularization, which reversed the suppression of retinal neovascularization functioned by shMALAT1. In conclusion, the expression profiles of lncRNAs and miRNAs and the ceRNA network in a mouse model of ROP may be indicative of the underlying mechanisms of retinal angiogenesis and neural activity. The MALAT1/miR-124-3p/EGR1 regulatory axis is partly responsible for retinal neovascularization, which may provide a novel theoretical basis for the pathogenesis of ROP.

INTRAVITREAL RANIBIZUMAB TREATMENT FOR ADVANCED FAMILIAL EXUDATIVE VITREORETINOPATHY WITH HIGH VASCULAR ACTIVITY.

PURPOSE: To determine the efficacy of intravitreal ranibizumab (IVR) treatment for advanced familial exudative vitreoretinopathy with high vascular activity. METHODS: The retrospective interventional case series included 28 eyes (20 patients) that had IVR in combination or not with other treatment, for Stage 3 to 5 familial exudative vitreoretinopathy with active fibrovascular proliferation and prominent subretinal exudation. Outcome measures were fundus features after treatment, associated clinical variables, and genetic mutations. RESULTS: The age of patients at the first IVR ranged from 0.2 to 36 months. An average of 1.3 IVR injections per eye were given. Familial exudative vitreoretinopathy regressed in 16 (57%) eyes and progressed in 12 eyes (43%) after IVR. Laser and/or vitrectomy was performed on 13 eyes. The retina was reattached in 22 eyes (78%) after 24 to 58 months follow-up. Clinical variables associated with progression after IVR were preexisting fibrovascular proliferation over one quadrant and persistent vascular activity after the initial injection (P < 0.05). Familial exudative vitreoretinopathy-causative genetic mutations in 11 patients were related to variable response to IVR treatment. CONCLUSION: Intravitreal ranibizumab treatment may effectively regress advanced familial exudative vitreoretinopathy with high vascular activity in selected cases. Different treatment outcomes may be relevant to variable presentation and genetic heterogeneity of familial exudative vitreoretinopathy.