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The intervention of epithelial-mesenchymal transition in homeostasis of human retinal pigment epithelial cells: a review

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References

  • Zou H, Shan C, Ma L, et al. Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy. PeerJ. 2020;8:e10136.
  • Song D, Yang D, Powell CA, et al. Cell–cell communication: old mystery and new opportunity. Cell Biol Toxicol. 2019;352(35):89–93.
  • Naylor A, Hopkins A, Hudson N, et al. Tight junctions of the outer blood retina barrier. Int J Mol Sci. 2020;21(1):211.
  • Strauss O. The retinal pigment epithelium. Webvision Organ Retin Vis Syst. 2011;1–26. DOI:10.1007/s00347-008-1868-y
  • Yang X, Chung JY, Rai U, et al. Cadherins in the retinal pigment epithelium (RPE) revisited: p-cadherin is the highly dominant cadherin expressed in human and mouse RPE in vivo. PLoS One. 2018;13:1–20.
  • Bok D. The retinal pigment epithelium: a versatile partner in vision, J. Cell Sci. 1993;(1993)(Supplement_17):189–195.
  • Sheedlo HJ, Li L, Turner JE. Effects of RPE-cell factors secreted from permselective fibers on retinal cells in vitro. Brain Res. 1992;587(2):327–337.
  • Perez-Moreno M, Fuchs E. Catenins: keeping cells from getting their signals crossed. Dev Cell. 2006;11:601–612.
  • Deora AA, Philp N, Hu J, et al. Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia. Proc Natl Acad Sci. 2005;102(45):16245–16250.
  • Ryeom SW, Sparrow JR, Silverstein RL CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium. J Cell Sci. 1996;109(2):387–395. DOI:10.1242/jcs.109.2.387
  • Yoon H, Fanelli A, Grollman EF, et al. Identification of a unique monocarboxylate transporter (MCT3) in retinal pigment epithelium. Biochem Biophys Res Commun. 1997;234(1):90–94.
  • Milenkovic VM, Krejcova S, Reichhart N, et al. Interaction of bestrophin-1 and Ca2+ channel β-subunits: identification of new binding domains on the bestrophin-1 C-terminus. PLoS One. 2011;6(4):e19364.
  • Bonilha VL, Finnemann SC, Rodriguez-Boulan E. Ezrin promotes morphogenesis of apical microvilli and basal infoldings in retinal pigment epithelium. J Cell Biol. 1999;147(7):1533–1547.
  • de S. Senanayake P, Calabro A, Hu JG, et al. Glucose utilization by the retinal pigment epithelium: evidence for rapid uptake and storage in glycogen, followed by glycogen utilization. Exp Eye Res. 2006;83(2):235–246.
  • Zhou M, Geathers JS, Grillo SL, et al. Role of epithelial-mesenchymal transition in retinal pigment epithelium dysfunction. Front Cell Dev Biol. 2020;8:501.
  • Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. Eur J Ophthalmol. 2011;21(6_suppl):3–9.
  • Rizzolo LJ. Development and role of tight junctions in the retinal pigment epithelium. Int Rev Cytol. 2007;258:195–234.
  • Sakakibara A, Furuse M, Saitou M, et al. Possible involvement of phosphorylation of occludin in tight junction formation, J. Cell Biol. 1997;137(6):1393–1401.
  • Mcleod DS, Grebe R, Bhutto I, et al. Relationship between RPE and choriocapillaris in age-related macular degeneration. Investig Ophthalmol Vis Sci. 2009;50(10):4982–4991.
  • Shu DY, Butcher E, Saint-Geniez M. EMT and ENDMT: emerging roles in age-related macular degeneration. Int J Mol Sci. 2020;21(12):1–26.
  • Rafii S, Butler JM, Sen Ding B. Angiocrine functions of organ-specific endothelial cells. Nature. 2016;529(7586):316–325.
  • Marneros AG, Fan J, Yokoyama Y, et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol. 2005;167(5):1451–1459.
  • Das A, Puklin JE, Frank RN, et al. Ulrastructural immunocytochemistry of subretinal neovascular membranes in age-related macular degeneration. Ophthalmology. Ophthalmology. 2009;116(10):S1–7.
  • Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs, cardiovasc. Res. 2006;69:562–573.
  • Neve A, Cantatore FP, Maruotti N, et al. Extracellular matrix modulates angiogenesis in physiological and pathological conditions. Biomed Res Int. 2014;2014. DOI:10.1155/2014/756078
  • Marin-Castaño ME, Csaky KG, Cousins SW. Nonlethal oxidant injury to human retinal pigment epithelium cells causes cell membrane blebbing but decreased MMP-2 activity. Investig Ophthalmol Vis Sci. 2005;46(9):3331–3340.
  • Marin-Castaño ME, Striker GE, Alcazar O, et al. Repetitive nonlethal oxidant injury to retinal pigment epithelium decreased extracellular matrix turnover in vitro and induced Sub-RPE deposits in vivo. Investig Ophthalmol Vis Sci. 2006;47(9):4098–4112.
  • Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776–1784.
  • Nisticò P, Bissell MJ, Radisky DC. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 2012;4:a011908. DOI:10.1101/cshperspect.a011908
  • Iwano M, Okada H, Neilson EG et al, Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110(3):341–350. DOI:10.1172/JCI15518.
  • Hatanaka H, Koizumi N, Okumura N, et al. Epithelial-mesenchymal transition-like phenotypic changes of retinal pigment epithelium induced by TGF-γ Are prevented by PPAR-γ agonists. Investig Ophthalmol Vis Sci. 2012;53(11):6955–6963.
  • Zhang Y, Zhao D, Yang S, et al. Protective effects of fucoidan on epithelial-mesenchymal transition of retinal pigment epithelial cells and progression of proliferative vitreoretinopathy. Cell Physiol Biochem. 2018;46(4):1704–1715.
  • Thiery JP, Acloque H, Huang RYJ, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–890. https://doi.org/10.1016/j.cell.2009.11.007
  • Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development, Mech. Dev. 2003;120:1351–1383.
  • Friedlander M. Fibrosis and diseases of the eye. J Clin Invest. 2007;117(3):576–586.
  • Bressler SB. Introduction: understanding the role of angiogenesis and antiangiogenic agents in age-related macular degeneration. Ophthalmology 2009;116(10):S1–7. DOI:10.1016/j.ophtha.2009.06.045
  • Lee KA, Nelson CM. New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis in international review of cell and molecular biology. 1st ed, 2012. Vol. 294. Amsterdam: Elsevier Inc. 173–206. DOI:10.1016/B978-0-12-394305-7.00004-5
  • Feng H, Zhao X, Guo Q, et al. Autophagy resists EMT process to maintain retinal pigment epithelium homeostasis. Int J Biol Sci. 2019;15(3):507–521.
  • Baek A, Yoon S, Kim J, et al. Autophagy and KRT8/keratin 8 protect degeneration of retinal pigment epithelium under oxidative stress. Autophagy. 2017;13(2):248–263.
  • Arjamaa O, Nikinmaa M, Salminen A, et al. Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev. 2009;8(4):349–358.
  • Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001;159(4):1465–1475.
  • Zeisberg M, Maeshima Y, Mosterman B, et al. Renal fibrosis: extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am J Pathol. 2002;160(6):61150–61159.
  • Pennock S, Kazlauskas A. Vascular endothelial growth factor a competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses. Mol Cell Biol. 2012;32(10):1955–1966.
  • Ricker LJAG, Kijlstra A, Kessels AGH, et al. Interleukin and growth factor levels in subretinal fluid in rhegmatogenous retinal detachment: a case-control study. PLoS One. 2011;6(4):e19141.
  • Lei H, Rheaume MA, Kazlauskas A. Recent developments in our understanding of how platelet-derived growth factor (PDGF) and its receptors contribute to proliferative vitreoretinopathy. Exp Eye Res. 2010;90(3):376–381.
  • Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–829.
  • Tamiya S, Liu LH, Kaplan HJ. Epithelial-mesenchymal transition and proliferation of retinal pigment epithelial cells initiated upon loss of cell-cell contact. Investig Ophthalmol Vis Sci. 2010;51(5):2755–2763.
  • Ünver YB, Yavuz GA, Bekiroǧlu N, et al. Relationships between clinical measures of visual function and anatomic changes associated with bevacizumab treatment for choroidal neovascularization in age-related macular degeneration. Eye. 2009;23(2):453–460. https://doi.org/10.1038/eye.2008.349
  • D’Amico DJ. Primary retinal detachment. N Engl J Med. 2008;359(22):2346–2354. https://doi.org/10.1056/nejmcp0804591
  • Tan X, Chen C, Zhu Y, et al. Proteotoxic stress desensitizes TGF-beta signaling through receptor downregulation in retinal pigment epithelial cells. Curr Mol Med. 2017;17(3):189–199.
  • Sivagurunathan S, Raman R, Chidambaram S. PIWI-like protein, HIWI2: a novel player in proliferative diabetic retinopathy. Exp Eye Res. 2018;177(2018):191–196.
  • Chen Z, Shao Y, Li X. The roles of signaling pathways in epithelial-to-mesenchymal transition of PVR. Mol Vis. 2015;21:706–710.
  • Pastor JC, De La Rúa ER, Martín F. Proliferative vitreoretinopathy: risk factors and pathobiology. Prog Retin Eye Res. 2002;21(1):127–144.
  • Antonetti DA, Klein R, Gardner TW Diabetic retinopathy. N Engl J Med. 2012;366(13):1227–1239. DOI:10.1056/NEJMra1005073.
  • Nagineni CN, Samuel W, Nagineni S, et al. Transforming growth factor-β induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol. 2003;197(3):453–462.
  • Jo DH, Cho CS, Kim JH, et al., Animal models of diabetic retinopathy : doors to investigate pathogenesis and potential therapeutics, (2013) 1–13.
  • Zhang XY, Ng TK, Brelén ME, et al. Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction. Sci Rep. 2016;6:1–13.
  • Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369–390.
  • Siemerink MJ, Augustin AJ, Schlingemann RO. Mechanisms of ocular angiogenesis and its molecular mediators. Dev Ophthalmol. 2010;46:4–20.
  • Heller JP, Martin KR. Enhancing RPE cell-based therapy outcomes for AMD: the Role of Bruch’s membrane. Transl Vis Sci Technol. 2014;3(4):4.
  • Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye. 1988;2(5):552–577. DOI:10.1038/eye.1988.106.
  • Zanzottera EC, Messinger JD, Ach T, et al. Subducted and melanotic cells in advanced age-related macular degeneration are derived from retinal pigment epithelium. Investig Ophthalmol Vis Sci. 2015;56(5):3269–3278.
  • Liu Z, Li C, Kang N, et al. Transforming growth factor (TGF) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem. 2019;294(9):3137–3151.
  • Roy R, Saurabh K, Shah D, et al. Choroidal hyperreflective foci: a novel spectral domain optical coherence tomography biomarker in eyes with diabetic macular edema. Asia-Pacific J Ophthalmol. 2019;8:314–318.
  • Miura M, Makita S, Sugiyama S, et al. Evaluation of intraretinal migration of retinal pigment epithelial cells in age-related macular degeneration using polarimetric imaging, Sci. Rep. 2017;7:1–12.
  • Chen KC, Jung JJ, Curcio CA, et al. Intraretinal hyperreflective foci in acquired vitelliform lesions of the macula: clinical and histologic study. Am J Ophthalmol. 2016;164:89–98.
  • Christenbury JG, Folgar FA, O’Connell RV, et al. Progression of intermediate age-related macular degeneration with proliferation and inner retinal migration of hyperreflective foci. Ophthalmology. 2013;120(5):1038–1045.
  • Aghdam KA, Pielen A, Framme C, et al. Correlation between hyperreflective foci and clinical outcomes in neovascular age-related macular degeneration after switching to aflibercept. Investig Ophthalmol Vis Sci. 2015;56(11):6448–6455.
  • Ishikawa K, Sreekumar PG, Spee C, et al. αb-crystallin regulates subretinal fibrosis by modulation of epithelial-mesenchymal transition. Am J Pathol. 2016;186(4):859–873.
  • Ghosh S, Shang P, Terasaki H, et al., A role for βA3/A1-crystallin in type 2 EMT of RPE cells occurring in dry age-related Macular degeneration. Investig Ophthalmol Vis Sci. 2018;59:AMD104–AMD113. DOI:10.1167/iovs.18-24132.
  • Simó R, Villarroel M, Corraliza L, et al. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier-implications for the pathogenesis of diabetic retinopathy. J Biomed Biotechnol. 2010;2010(2010):1–15.
  • Zhang Y, Wang K, Pan J, et al. Exosomes mediate an epithelial-mesenchymal transition cascade in retinal pigment epithelial cells: implications for proliferative vitreoretinopathy. J Cell Mol Med. 2020;24(22):13324–13335.
  • Connor TB, Roberts AB, Sporn MB, et al. Correlation of fibrosis and transforming growth factor-β type 2 levels in the eye. J Clin Invest. 1989;83(5):1661–1666.
  • Kita T, Hata Y, Arita R, et al. Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc Natl Acad Sci. 2008;105(45):17504–17509.
  • Hiscott P, Sheridan C, Magee RM, et al. Matrix and the retinal pigment epithelium in proliferative retinal disease. Prog Retin Eye Res. 1999;18(2):167–190.
  • Charteris DG. Proliferative vitreoretinopathy: pathobiology, surgical management, and adjunctive treatment. Br J Ophthalmol. 1995;79(10):953–960.
  • Tamiya S, Kaplan HJ. Role of epithelial - mesenchymal transition in proliferative vitreoretinopathy. Exp Eye Res. 2016;142:26–31.
  • Farjood F, Vargis E. Physical disruption of cell–cell contact induces VEGF expression in RPE cells. Mol Vis. 2017;23:431–446.
  • Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–196.
  • Morino I, Hiscott P, McKechnie N, et al. Variation in epiretinal membrane components with clinical duration of the proliferative tissue. Br J Ophthalmol. 1990;74(7):393–399.
  • Feist RM, King JL, Morris R, et al. Myofibroblast and extracellular matrix origins in proliferative vitreoretinopathy. Graefe’s Arch Clin Exp Ophthalmol. 2014;252(2):347–357.
  • Saika S, Kono-Saika S, Tanaka T, et al. Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice. Lab Invest. 2004;84(10):1245–1258.
  • Yoo K, Son BK, Kim S, et al. Substance P prevents development of proliferative vitreoretinopathy in mice by modulating TNF-α. Mol Vis. 2017;23:933–943.
  • Zhang J, Yuan G, Dong M, et al. Notch signaling modulates proliferative vitreoretinopathy via regulating retinal pigment epithelial-to-mesenchymal transition. Histochem Cell Biol. 2017;147:367–375.
  • Nagasaka Y, Kaneko H, Ye F, et al. Role of caveolin-1 for blocking the epithelial- mesenchymal transition in proliferative vitreoretinopathy. Investig Ophthalmol Vis Sci. 2017;58(1):221–229.
  • Bian ZM, Elner SG, Elner VM. Thrombin-induced VEGF expression in human retinal pigment epithelial cells. Investig Ophthalmol Vis Sci. 2007;48(6):2738–2746.
  • Liang CM, Tai MC, Chang YH, et al. Glucosamine inhibits epithelial-to-mesenchymal transition and migration of retinal pigment epithelium cells in culture and morphologic changes in a mouse model of proliferative vitreoretinopathy. Acta Ophthalmol. 2011;89(6):505–514.
  • Ma X, Long C, Wang F, et al. METTL3 attenuates proliferative vitreoretinopathy and epithelial-mesenchymal transition of retinal pigment epithelial cells via wnt/β-catenin pathway. J Cell Mol Med. 2021;25(9):4220–4234.
  • Cinar AK, Ozal SA, Serttas R, et al. Eupatilin attenuates TGF-β2-induced proliferation and epithelial-mesenchymal transition of retinal pigment epithelial cells. Cutan Ocul Toxicol. 2021;40(2):103–114.
  • Chen Y, Wu B, He JF, et al. Effectively intervening epithelial-mesenchymal transition of retinal pigment epithelial cells with a combination of ROCK and TGF-β signaling inhibitors. Investig Ophthalmol Vis Sci. 2021;62. DOI:10.1167/iovs.62.4.21.
  • Homma K, Toda E, Osada H, et al. , Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium. Redox Biol. 2021;41:101921.
  • Bin Park G, Kim D. Cigarette smoke-induced EGFR activation promotes Epithelial mesenchymal migration of human retinal pigment Epithelial cells through regulation of the fak-mediated Syk/Src pathway. Mol Med Rep. 2018;17(3):3563–3574.
  • Ko JA, Sotani Y, Ibrahim DG, et al. Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells. Cell Biochem Funct. 2017;35:426–432.
  • Jin WK, Kyung HK, Burrola P, et al. Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium. Genes Dev. 2008;22(22):3147–3157.
  • Ohana R, Weiman-Kelman B, Raviv S, et al. MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors. Dev. 2015;142:2487–2498.
  • Wei Q, Liu Q, Ren C, et al. Effects of bradykinin on TGF-β1-induced epithelial-mesenchymal transition in ARPE-19 cells. Mol Med Rep. 2018;17(4):5878–5886.
  • Hazim RA, Volland S, Yen A, et al. Rapid differentiation of the human RPE cell line, ARPE-19, induced by nicotinamide. Exp Eye Res. 2019;179:18–24.
  • Boles NC, Fernandes M, Swigut T, et al. Epigenomic and transcriptomic changes during human RPE EMT in a stem cell model of epiretinal membrane pathogenesis and prevention by nicotinamide. Stem Cell Reports. 2020;14(4):631–647.
  • Saini JS, Corneo B, Miller JD, et al. Nicotinamide ameliorates disease phenotypes in a human ipsc model of age-related macular degeneration. Cell Stem Cell. 2017;20(5):635–647.e7.
  • Meng Y, Ren Z, Xu F, et al. Nicotinamide promotes cell survival and differentiation as kinase inhibitor in human pluripotent stem cells. Stem Cell Reports. 2018;11(6):1347–1356.
  • Zhou L, Shi DP, Chu WJ, et al. Nicotinamide suppresses bevacizumab-induced epithelial-mesenchymal transition of ARPE-19 cells by attenuating oxidative stress. Int J Ophthalmol. 2021;14(4):481–488.
  • Yao H, Ge T, Zhang Y, et al. BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro. FASEB J. 2019;33(3):3212–3224.
  • Ferrington DA, Fisher CR, Kowluru RA. Mitochondrial defects drive degenerative retinal diseases. Trends Mol Med. 2020;26:105–118.
  • Hu B, Zhang Y, Zeng Q, et al. Intravitreal injection of ranibizumab and CTGF shRNA improves retinal gene expression and microvessel ultrastructure in a rodent model of diabetes. Int J Mol Sci. 2014;15(1):1606–1624.
  • Shukal D, Bhadresha K, Shastri B, et al. Dichloroacetate prevents TGFβ-induced epithelial-mesenchymal transition of retinal pigment epithelial cells. Exp Eye Res. 2020;197:108072.
  • Zhang R, Liu Z, Zhang H, et al. The COX-2-selective antagonist (NS-398) inhibits choroidal neovascularization and subretinal fibrosis. PLoS One. 2016;11. DOI:10.1371/journal.pone.0146808.
  • Geoff Williams R, Chang S, Comaratta MR. Does the presence of heparin and dexamethasone in the vitrectomy infusate reduce reproliferation in proliferative vitreoretinopathy? Graefe’s Arch Clin Exp Ophthalmol. 1996;234(8):496–503.
  • Wiedemann P, Hilgers RD, Bauer P, et al. Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Am J Ophthalmol. 1998;126(4):550–559.
  • Wickham L, Bunce C, Wong D, et al. Randomized controlled trial of combined 5-fluorouracil and low-molecular-weight heparin in the management of unselected rhegmatogenous retinal detachments undergoing primary vitrectomy. Ophthalmology. 2007;114(4):698–704.
  • Ahmadieh H, Feghhi M, Tabatabaei H, et al. Triamcinolone acetonide in silicone-filled eyes as adjunctive treatment for proliferative vitreoretinopathy. A Randomized Clinical Trial, Ophthalmology. 2008;115 1938–1943. DOI:10.1016/j.ophtha.2008.05.016.
  • He H, Kuriyan AE, Su CW, et al. Inhibition of proliferation and epithelial mesenchymal transition in retinal pigment epithelial cells by heavy chain-hyaluronan/pentraxin 3. Sci Rep. 2017;7. DOI:10.1038/srep43736.
  • Bochaton-Piallat ML, Kapetanios AD, Donati G, et al. TGF-β1, TGF-β receptor II and ED-A fibronectin expression in myofibroblast of vitreoretinopathy. Investig Ophthalmol Vis Sci. 2000;41:2336–2342.
  • Patz A, Fine S, Prout T, et al., Preliminary report on effects of photocoagulation therapy, Am. J. Ophthalmol. 185 (2018) 14–24. 10.1016/j.ajo.2017.11.010.
  • Kohly RP, Muni RH, Kertes PJ. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular EDEMA. Evidence-Based Ophthalmol. 2010;11(4):199–201.
  • Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013–2022.
  • Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the Vista and VIVID Studies. Int Ophthalmology. 2016;123(11):2376–2385.
  • Wells JA, Glassman AR, Ayala AR, et al. Or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193–1203.
  • Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125–2132.
  • Boyer DS, Yoon YH, Belfort R, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 1904–1914;121(2014). DOI:10.1016/j.ophtha.2014.04.024
  • Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2:1–13.
  • Yamada M, Kuwano K, Maeyama T, et al. Gene transfer of soluble transforming growth factor type II receptor by in vivo electroporation attenuates lung injury and fibrosis. J Clin Pathol. 2007;60(8):916–920.
  • Nassar K, Grisanti S, Tura A, et al. A TGF-β receptor 1 inhibitor for prevention of proliferative vitreoretinopathy. Exp Eye Res. 2014;123:72–86.
  • Plantner JJ, Smine A, Quinn TA. Matrix metalloproteinases and metalloproteinase inhibitors in human interphotoreceptor matrix and vitreous, Curr. Eye Res. 1998;17(2):132–140.
  • Chan ESL, Cronstein BN. Methotrexatehow does it really work? Nat Rev Rheumatol. 2010;6(3):175–178.
  • Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188–2198.e1.
  • Kurup SK, Gee C, Greven CM. Intravitreal methotrexate in therapeutically resistant exudative age-related macular degeneration. Acta Ophthalmol. 2010;88(4):e145–e146. DOI:10.1111/j.1755-3768.2009.01560.x.
  • Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92(3):383–388.
  • The GUARD Trial. Part 1: a phase 3 clinical trial of repeated intravitreal injections for prevention of proliferaivie vitreoretinopathy. Case Med Res. 2019. DOI:10.31525/ct1-nct04136366
  • Gehrs KM, Anderson DH, Johnson LV, et al. Age-related macular degeneration - emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38:450–471.
  • Klein BEK, Howard KP, Lee KE, et al. The relationship of cataract and cataract extraction to age-related macular degeneration: the Beaver dam eye study. Ophthalmology. 1628–1633;119(2012). DOI:10.1016/j.ophtha.2012.01.050
  • Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS report no. 18, Arch. Ophthalmol. 2005;123:1570–1574.
  • Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease. Curr Mol Med. 2010;10(9):802–823. https://doi.org/10.2174/156652410793937813
  • Heier JS, Shapiro H, Singh AA.Randomized, controlled phase III study of ranibizumab (LucentisTM) for minimally classic or occult neovascular age–related macular degeneration: two–year efficacy results of the MARINA study. Invest Ophthalmol Vis Sci. 2006;47(13):2959.
  • Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin®) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331–335.
  • Slaker JS, Miller JW, Lane AM. Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology. 2003;110:2372–2383.
  • Quiram PA, Gonzales CR, Schwartz SD. Severe steroid-induced glaucoma following intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 2006;141(3):580–582.
  • Maguire MG, Klein ML, Olk RJ, et al. Persistent and recurrent neovascularization after laser photocoagulation for subfoveal choroidal neovascularization of age-related macular degeneration. Arch Ophthalmol. 1994;112:489–499.
  • Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313–1330.
  • Park DH, Sun HJ, Lee SJ. A comparison of responses to intravitreal bevacizumab, ranibizumab, or aflibercept injections for neovascular age-related macular degeneration. Int Ophthalmol. 2017;37:1205–1214.
  • Au A, Parikh VS, Singh RP, et al. Comparison of anti-VEGF therapies on fibrovascular pigment epithelial detachments in age-related macular degeneration. Br J Ophthalmol. 2017;101(7):970–975.
  • Ba J, Peng RS, Xu D, et al. Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: a systematic review and meta-analysis. Drug Des Devel Ther. 2015;9:5397–5405.
  • Hamblin MR. Shining light on the head: photobiomodulation for brain disorders. BBA Clinical. 2016;6:113–124.
  • Tang J, Herda AA, Kern TS. Photobiomodulation in the treatment of patients with non-center-involving diabetic macular oedema. Br J Ophthalmol. 2014;98(8):1013–1015.
  • Brown EE, Ball JD, Chen Z, et al. The common antidiabetic drug metformin reduces odds of developing age-related macular degeneration. Investig Ophthalmol Vis Sci. 2019;60(5):1470–1477.
  • Chua KN, Ma J, Thiery JP. Targeted therapies incontrol of EMT in carcinoma and fibrosis. Drug Discov Today Dis Mech. 2007;4(4):261–267.
  • Feldmann G, Dhara S, Fendrich V, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67(5):2187–2196.
  • Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nature Reviews Cancer. 2008;8(12):915–928.
  • Barr S, Thomson S, Buck E, et al. Bypassing cellular EGF receptor dependence through epithelial-to- mesenchymal-like transitions. Clin Exp Metastasis. 2008;25(6):685–693.
  • Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(25):5892–5899.
  • Gumireddy K, Li A, Gimotty PA, et al. KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nat Cell Biol. 2009;11(11):1297–1304.

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