Long-Chain Polyunsaturated Fatty Acids and Their Metabolites Regulate Inflammation in Age-Related Macular Degeneration

References

• Vogl WD, Bogunovic H, Waldstein SM, Riedl S, Schmidt-Erfurth U. Spatio-temporal alterations in retinal and choroidal layers in the progression of age-related macular degeneration (AMD) in optical coherence tomography. Sci Rep. 2021;11(1):5743. doi:10.1038/s41598-021-85110-y
   PubMed Web of Science ®Google Scholar
• Colijn JM, Buitendijk GHS, Prokofyeva E, et al. Prevalence of age-related macular degeneration in Europe: the past and the future. Ophthalmology. 2017;124(12):1753–1763. doi:10.1016/j.ophtha.2017.05.035
   PubMed Web of Science ®Google Scholar
• Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106–16. doi:10.1016/S2214-109X(13)70145-1
   PubMed Web of Science ®Google Scholar
• Domalpally A, Clemons TE, Danis RP, et al.; Writing Committee for the OPRs. Peripheral retinal changes associated with age-related macular degeneration in the age-related eye disease study 2: age-related eye disease study 2 report number 12 by the age-related eye disease study 2 Optos PEripheral RetinA (OPERA) Study Research Group. Ophthalmology. 2017;124(4):479–487. doi:10.1016/j.ophtha.2016.12.004
   PubMed Web of Science ®Google Scholar
• Jhingan M, Singh SR, Samanta A, et al. Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2021;259(9):2687–2694. doi:10.1007/s00417-021-05147-7
   PubMed Web of Science ®Google Scholar
• Tsujinaka H, Fu J, Shen J, et al. Sustained treatment of retinal vascular diseases with self-aggregating sunitinib microparticles. Nat Commun. 2020;11(1):694. doi:10.1038/s41467-020-14340-x
   PubMed Web of Science ®Google Scholar
• Remmerie A, Scott CL. Macrophages and lipid metabolism. Cell Immunol. 2018;330:27–42. doi:10.1016/j.cellimm.2018.01.020
   PubMed Web of Science ®Google Scholar
• Mukhtar S, Ambati BK. The value of nutritional supplements in treating age-related macular degeneration: a review of the literature. Int Ophthalmol. 2019;39(12):2975–2983. doi:10.1007/s10792-019-01140-6
   PubMed Web of Science ®Google Scholar
• Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016;3:34. doi:10.1186/s40662-016-0063-5
   PubMedGoogle Scholar
• Chapman NA, Jacobs RJ, Braakhuis AJ. Role of diet and food intake in age-related macular degeneration: a systematic review. Clin Exp Ophthalmol. 2019;47(1):106–127. doi:10.1111/ceo.13343
   PubMed Web of Science ®Google Scholar
• DeAngelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD). Hum Mol Genet. 2017;26(R2):R246.
   Google Scholar
• Chen L, Ma B, Liu X, Hao Y, Yang X, Liu M. H2 O2 induces oxidative stress damage through the BMP-6/SMAD/hepcidin axis. Dev Growth Differ. 2020;62(2):139–146. doi:10.1111/dgd.12650
   Google Scholar
• Bonilha VL. Oxidative stress regulation and DJ-1 function in the retinal pigment epithelium: implications for AMD. Adv Exp Med Biol. 2018;1074:3–9.
   Google Scholar
• Moreira-Neto CA, Moult EM, Fujimoto JG, Waheed NK, Ferrara D. Choriocapillaris loss in advanced age-related macular degeneration. J Ophthalmol. 2018;2018:8125267. doi:10.1155/2018/8125267
   Google Scholar
• Nassisi M, Baghdasaryan E, Borrelli E, Ip M, Sadda SR. Choriocapillaris flow impairment surrounding geographic atrophy correlates with disease progression. PLoS One. 2019;14(2):e0212563. doi:10.1371/journal.pone.0212563
   Google Scholar
• Fang Y, Du R, Jonas JB, et al. Ridge-shaped macula progressing parallel to bruch membrane defects and macular suprachoroidal cavitation. Retina. 2020;40(3):456–460. doi:10.1097/IAE.0000000000002404
   Google Scholar
• Munoz-Ramon PV, Hernandez Martinez P, Munoz-Negrete FJ. New therapeutic targets in the treatment of age-related macular degeneration. Arch Soc Esp Oftalmol. 2020;95(2):75–83. doi:10.1016/j.oftal.2019.09.011
   Google Scholar
• Rozing MP, Durhuus JA, Krogh Nielsen M, et al. Age-related macular degeneration: a two-level model hypothesis. Prog Retin Eye Res. 2020;76:100825. doi:10.1016/j.preteyeres.2019.100825
   Google Scholar
• Di Cara F, Andreoletti P, Trompier D, et al. Peroxisomes in immune response and inflammation. Int J Mol Sci. 2019;20(16):3877. doi:10.3390/ijms20163877
   PubMed Web of Science ®Google Scholar
• Karahan M, Hazar L, Erdem S, et al. Is there a relationship between hematological inflammatory parameters and age-related macular degeneration? Ther Adv Ophthalmol. 2021;13:25158414211010550. doi:10.1177/25158414211010550
   Google Scholar
• Pujol-Lereis LM, Schafer N, Kuhn LB, Rohrer B, Pauly D. Interrelation between oxidative stress and complement activation in models of age-related macular degeneration. Adv Exp Med Biol. 2016;854:87–89.
   PubMed Web of Science ®Google Scholar
• Brandstetter C, Mohr LK, Latz E, Holz FG, Krohne TU. Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. J Mol Med (Berl). 2015;93(8):905–916. doi:10.1007/s00109-015-1275-1
   PubMed Web of Science ®Google Scholar
• Iriyama A, Inoue Y, Takahashi H, Tamaki Y, Jang WD, Yanagi Y. A2E, a component of lipofuscin, is pro-angiogenic in vivo. J Cell Physiol. 2009;220(2):469–475. doi:10.1002/jcp.21792
   PubMed Web of Science ®Google Scholar
• Chandra S, Arpa C, Menon D, et al. Ten-year outcomes of antivascular endothelial growth factor therapy in neovascular age-related macular degeneration. Eye (Lond). 2020;34(10):1888–1896. doi:10.1038/s41433-020-0764-9
   PubMed Web of Science ®Google Scholar
• Jiang P, Chaparro FJ, Cuddington CT, et al. Injectable biodegradable bi-layered capsule for sustained delivery of bevacizumab in treating wet age-related macular degeneration. J Control Release. 2020;320:442–456. doi:10.1016/j.jconrel.2020.01.036
   PubMed Web of Science ®Google Scholar
• Subhi Y, Sorensen TL. Neovascular age-related macular degeneration in the very old (>/=90 years): epidemiology, adherence to treatment, and comparison of efficacy. J Ophthalmol. 2017;2017:7194927. doi:10.1155/2017/7194927
   PubMed Web of Science ®Google Scholar
• Barth T, Reiners M, Zeman F, Greslechner R, Helbig H, Gamulescu MA. [Anti-VEGF-therapy of fibrovascular and serous-vascularized pigment epithelial detachment in neovascular AMD: a retrospective five-year-analysis]. Ophthalmologe. 2021;118(12):1255–1263. German.
   PubMed Web of Science ®Google Scholar
• Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res. 2021;82:100906. doi:10.1016/j.preteyeres.2020.100906
   PubMed Web of Science ®Google Scholar
• Granstam E, Aurell S, Sjovall K, Paul A. Switching anti-VEGF agent for wet AMD: evaluation of impact on visual acuity, treatment frequency and retinal morphology in a real-world clinical setting. Graefes Arch Clin Exp Ophthalmol. 2021;259(8):2085–2093. doi:10.1007/s00417-020-05059-y
   PubMed Web of Science ®Google Scholar
• Garweg JG, Gerhardt C. Disease stability and extended dosing under anti-VEGF treatment of exudative age-related macular degeneration (AMD) - a meta-analysis. Graefes Arch Clin Exp Ophthalmol. 2021;259(8):2181–2192. doi:10.1007/s00417-020-05048-1
   PubMed Web of Science ®Google Scholar
• Thalgott V, Feucht N, Lohmann CP, Maier M. [Long-term results in neovascular age-related macular degeneration: changes in visual acuity and geographic atrophy during long-standing anti-VEGF therapy]. Ophthalmologe. 2016;113(8):668–674. German. doi:10.1007/s00347-016-0228-6
   PubMed Web of Science ®Google Scholar
• Toth CA, Tai V, Pistilli M, et al. Distribution of OCT features within areas of macular atrophy or Scar after 2 years of anti-VEGF treatment for neovascular AMD in CATT. Ophthalmol Retina. 2019;3(4):316–325. German. doi:10.1016/j.oret.2018.11.011
   PubMedGoogle Scholar
• Bilgic A, Kodjikian L, Chhablani J, et al. Sustained intraocular pressure rise after the treat and extend regimen at 3 years: aflibercept versus ranibizumab. J Ophthalmol. 2020;2020:7462098. doi:10.1155/2020/7462098
   PubMed Web of Science ®Google Scholar
• Lee JM, Bae HW, Lee SY, Seong GJ, Kim CY. Effect of anti-vascular endothelial growth factor antibody on the survival of cultured retinal ganglion cells. Korean J Ophthalmol. 2017;31(4):360–365. doi:10.3341/kjo.2017.0054
   PubMedGoogle Scholar
• Kim SY, Yoon MH, Chin HS. Changes in the ganglion cell-inner plexiform layer after consecutive intravitreal injections of anti-vascular endothelial growth factor in age-related macular degeneration patients. Korean J Ophthalmol. 2020;34(1):11–18. doi:10.3341/kjo.2019.0081
   PubMedGoogle Scholar
• Liu A, Chang J, Lin Y, Shen Z, Bernstein PS. Long-chain and very long-chain polyunsaturated fatty acids in ocular aging and age-related macular degeneration. J Lipid Res. 2010;51(11):3217–3229. doi:10.1194/jlr.M007518
   PubMed Web of Science ®Google Scholar
• McGrattan AM, McGuinness B, McKinley MC, et al. Diet and inflammation in cognitive ageing and Alzheimer’s disease. Curr Nutr Rep. 2019;8(2):53–65. doi:10.1007/s13668-019-0271-4
   PubMedGoogle Scholar
• Miller JW. Beyond VEGF-The Weisenfeld Lecture. Invest Ophthalmol Vis Sci. 2016;57(15):6911–6918. doi:10.1167/iovs.16-21201
   PubMed Web of Science ®Google Scholar
• Xu Q, Cao S, Rajapakse S, Matsubara JA. Understanding AMD by analogy: systematic review of lipid-related common pathogenic mechanisms in AMD, AD, AS and GN. Lipids Health Dis. 2018;17(1):3. doi:10.1186/s12944-017-0647-7
   PubMed Web of Science ®Google Scholar
• Gorusupudi A, Liu A, Hageman GS, Bernstein PS. Associations of human retinal very long-chain polyunsaturated fatty acids with dietary lipid biomarkers. J Lipid Res. 2016;57(3):499–508. doi:10.1194/jlr.P065540
   PubMed Web of Science ®Google Scholar
• Jacob J, Mangelschots E, Michez M, Sanak SN, Leys A. Cross-Sectional Study on vitamin D, zinc oxide and fatty acid status in a population with a moderate to high risk of AMD identified by the STARS((R)) questionnaire. Ophthalmol Ther. 2021;10(2):299–311. doi:10.1007/s40123-021-00335-4
   PubMed Web of Science ®Google Scholar
• Fernandez-Vega B, Garcia M, Olivares L, et al. The association study of lipid metabolism gene polymorphisms with AMD identifies a protective role for APOE-E2 allele in the wet form in a Northern Spanish population. Acta Ophthalmol. 2020;98(3):e282–e91. doi:10.1111/aos.14280
   PubMed Web of Science ®Google Scholar
• Jun S, Datta S, Wang L, Pegany R, Cano M, Handa JT. The impact of lipids, lipid oxidation, and inflammation on AMD, and the potential role of miRNAs on lipid metabolism in the RPE. Exp Eye Res. 2019;181:346–355. doi:10.1016/j.exer.2018.09.023
   PubMed Web of Science ®Google Scholar
• Bazan NG. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci. 2006;29(5):263–271. doi:10.1016/j.tins.2006.03.005
   PubMed Web of Science ®Google Scholar
• Schnebelen C, Viau S, Gregoire S, et al. Nutrition for the eye: different susceptibility of the retina and the lacrimal gland to dietary omega-6 and omega-3 polyunsaturated fatty acid incorporation. Ophthalmic Res. 2009;41(4):216–224. doi:10.1159/000217726
   PubMed Web of Science ®Google Scholar
• Acar N, Berdeaux O, Gregoire S, et al. Lipid composition of the human eye: are red blood cells a good mirror of retinal and optic nerve fatty acids? PLoS One. 2012;7(4):e35102. doi:10.1371/journal.pone.0035102
   PubMed Web of Science ®Google Scholar
• Skowronska-Krawczyk D, Chao DL. Long-chain polyunsaturated fatty acids and age-related macular degeneration. Adv Exp Med Biol. 2019;1185:39–43.
   PubMed Web of Science ®Google Scholar
• Winkler TW, Grassmann F, Brandl C, et al. Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease. BMC Med Genomics. 2020;13(1):120. doi:10.1186/s12920-020-00760-7
   PubMed Web of Science ®Google Scholar
• Leung HH, Ng AL, Durand T, et al. Increase in omega-6 and decrease in omega-3 polyunsaturated fatty acid oxidation elevates the risk of exudative AMD development in adults with Chinese diet. Free Radic Biol Med. 2019;145:349–356. doi:10.1016/j.freeradbiomed.2019.10.007
   PubMed Web of Science ®Google Scholar
• Merle BMJ, Buaud B, Korobelnik JF, et al. Plasma long-chain omega-3 polyunsaturated fatty acids and macular pigment in subjects with family history of age-related macular degeneration: the Limpia Study. Acta Ophthalmol. 2017;95(8):e763–e69. doi:10.1111/aos.13408
   PubMed Web of Science ®Google Scholar
• Meagher KA, Nolan JM, Beatty S. Regarding macular xanthophylls and omega-3 long-chain polyunsaturated fatty acids in age-related macular degeneration. JAMA Ophthalmol. 2014;132(2):230–231. doi:10.1001/jamaophthalmol.2013.6667
   PubMed Web of Science ®Google Scholar
• Suarez-Barrio C, Del Olmo-Aguado S, Garcia-Perez E, et al. Antioxidant role of PRGF on RPE cells after blue light insult as a therapy for neurodegenerative diseases. Int J Mol Sci. 2020;21(3):1021. doi:10.3390/ijms21031021
   PubMed Web of Science ®Google Scholar
• Shen HH, Peterson SJ, Bellner L, et al. Cold-pressed Nigella sativa oil standardized to 3% thymoquinone potentiates omega-3 protection against obesity-induced oxidative stress, inflammation, and markers of insulin resistance accompanied with conversion of white to Beige fat in mice. Antioxidants (Basel). 2020;9(6):489.
   PubMedGoogle Scholar
• Harauma A, Yasuda H, Hatanaka E, Nakamura MT, Salem N Jr, Moriguchi T. The essentiality of arachidonic acid in addition to docosahexaenoic acid for brain growth and function. Prostaglandins Leukot Essent Fatty Acids. 2017;116:9–18. doi:10.1016/j.plefa.2016.11.002
   PubMed Web of Science ®Google Scholar
• Lister T. Nutritional, alternative, and complementary therapies for age-related macular degeneration. Integr Med (Encinitas). 2019;18(6):30–36.
   PubMedGoogle Scholar
• Carneiro A, Andrade JP. Nutritional and lifestyle interventions for age-related macular degeneration: a review. Oxid Med Cell Longev. 2017;2017:6469138. doi:10.1155/2017/6469138
   PubMed Web of Science ®Google Scholar
• Wu J, Cho E, Giovannucci EL, et al. Dietary intakes of eicosapentaenoic acid and docosahexaenoic acid and risk of age-related macular degeneration. Ophthalmology. 2017;124(5):634–643. doi:10.1016/j.ophtha.2016.12.033
   PubMed Web of Science ®Google Scholar
• Christen WG, Schaumberg DA, Glynn RJ, Buring JE. Dietary omega-3 fatty acid and fish intake and incident age-related macular degeneration in women. Arch Ophthalmol. 2011;129(7):921–929. doi:10.1001/archophthalmol.2011.34
   PubMedGoogle Scholar
• Yanai R, Chen S, Uchi SH, Nanri T, Connor KM, Kimura K. Attenuation of choroidal neovascularization by dietary intake of omega-3 long-chain polyunsaturated fatty acids and lutein in mice. PLoS One. 2018;13(4):e0196037. doi:10.1371/journal.pone.0196037
   PubMed Web of Science ®Google Scholar
• Arslan S, Kadayifcilar S, Samur G. The potential role of dietary antioxidant capacity in preventing age-related macular degeneration. J Am Coll Nutr. 2019;38(5):424–432. doi:10.1080/07315724.2018.1538830
   PubMed Web of Science ®Google Scholar
• SanGiovanni JP, Agron E, Clemons TE, Chew EY. Omega-3 long-chain polyunsaturated fatty acid intake inversely associated with 12-year progression to advanced age-related macular degeneration. Arch Ophthalmol. 2009;127(1):110–112. doi:10.1001/archophthalmol.2008.518
   PubMedGoogle Scholar
• Aoki A, Inoue M, Nguyen E, et al. Dietary n-3 fatty acid, alpha-tocopherol, zinc, vitamin D, vitamin C, and beta-carotene are associated with age-related macular degeneration in Japan. Sci Rep. 2016;6:20723. doi:10.1038/srep20723
   PubMed Web of Science ®Google Scholar
• Roh M, Shin HJ, Lains I, et al. Higher intake of polyunsaturated fatty acid and monounsaturated fatty acid is inversely associated with AMD. Invest Ophthalmol Vis Sci. 2020;61(2):20. doi:10.1167/iovs.61.2.20
   PubMed Web of Science ®Google Scholar
• Ho L, van leeuwen R, Witteman JC, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and omega-3 fatty acids: the Rotterdam study. Arch Ophthalmol. 2011;129(6):758–766. doi:10.1001/archophthalmol.2011.141
   PubMedGoogle Scholar
• Ng AL, Leung HH, Kawasaki R, et al. Dietary habits, fatty acids and carotenoid levels are associated with neovascular age-related macular degeneration in Chinese. Nutrients. 2019;11(8):1720. doi:10.3390/nu11081720
   PubMed Web of Science ®Google Scholar
• Van Asten F, Chiu CY, Agron E, et al. No CFH or ARMS2 interaction with omega-3 fatty acids, low versus high zinc, or beta-carotene versus lutein and zeaxanthin on progression of age-related macular degeneration in the age-related eye disease study 2: age-related eye disease study 2 report no. 18. Ophthalmology. 2019;126(11):1541–1548. doi:10.1016/j.ophtha.2019.06.004
   PubMed Web of Science ®Google Scholar
• Souied EH, Delcourt C, Querques G, et al. Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 study. Ophthalmology. 2013;120(8):1619–1631. doi:10.1016/j.ophtha.2013.01.005
   PubMed Web of Science ®Google Scholar
• Korobelnik JF, Rougier MB, Delyfer MN, et al. Effect of dietary supplementation with lutein, zeaxanthin, and omega-3 on macular pigment: a randomized clinical trial. JAMA Ophthalmol. 2017;135(11):1259–1266. doi:10.1001/jamaophthalmol.2017.3398
   PubMed Web of Science ®Google Scholar
• Acar N, Merle BMJ, Ajana S, et al. Predicting the retinal content in omega-3 fatty acids for age-related macular-degeneration. Clin Transl Med. 2021;11(7):e404. doi:10.1002/ctm2.404
   PubMed Web of Science ®Google Scholar
• Agron E, Mares J, Clemons TE, et al. Dietary nutrient intake and progression to late age-related macular degeneration in the age-related eye disease studies 1 and 2. Ophthalmology. 2021;128(3):425–442. doi:10.1016/j.ophtha.2020.08.018
   PubMed Web of Science ®Google Scholar
• Hellstrom A, Pivodic A, Granse L, et al. Association of docosahexaenoic acid and arachidonic acid serum levels with retinopathy of prematurity in preterm infants. JAMA Netw Open. 2021;4(10):e2128771. doi:10.1001/jamanetworkopen.2021.28771
   PubMed Web of Science ®Google Scholar
• Hellstrom A, Nilsson AK, Wackernagel D, et al. Effect of enteral lipid supplement on severe retinopathy of prematurity: a randomized clinical trial. JAMA Pediatr. 2021;175(4):359–367. doi:10.1001/jamapediatrics.2020.5653
   PubMed Web of Science ®Google Scholar
• Romero-Vazquez S, Llorens V, Soler-Boronat A, Figueras-Roca M, Adan A, Molins B. Interlink between inflammation and oxidative stress in age-related macular degeneration: role of complement Factor H. Biomedicines. 2021;9(7):763. doi:10.3390/biomedicines9070763
   PubMed Web of Science ®Google Scholar
• Caceres PS, Rodriguez-Boulan E. Retinal pigment epithelium polarity in health and blinding diseases. Curr Opin Cell Biol. 2020;62:37–45. doi:10.1016/j.ceb.2019.08.001
   PubMed Web of Science ®Google Scholar
• Song Y, Tian X, Wang X, Feng H. Vascular protection of salicin on IL-1beta-induced endothelial inflammatory response and damages in retinal endothelial cells. Artif Cells Nanomed Biotechnol. 2019;47(1):1995–2002. doi:10.1080/21691401.2019.1608220
   PubMed Web of Science ®Google Scholar
• Cheng SC, Huang WC, S Pang JH, Wu YH, Cheng CY. Quercetin inhibits the production of IL-1beta-induced inflammatory cytokines and chemokines in ARPE-19 cells via the MAPK and NF-kappaB signaling pathways. Int J Mol Sci. 2019;20(12):2957. doi:10.3390/ijms20122957
   PubMed Web of Science ®Google Scholar
• Ten Berge JC, Fazil Z, van den Born I, et al. Intraocular cytokine profile and autoimmune reactions in retinitis pigmentosa, age-related macular degeneration, glaucoma and cataract. Acta Ophthalmol. 2019;97(2):185–192. doi:10.1111/aos.13899
   PubMed Web of Science ®Google Scholar
• Knickelbein JE, Chan CC, Sen HN, Ferris FL, Nussenblatt RB. Inflammatory mechanisms of age-related macular degeneration. Int Ophthalmol Clin. 2015;55(3):63–78. doi:10.1097/IIO.0000000000000073
   PubMedGoogle Scholar
• Wang H, Han X, Wittchen ES, Hartnett ME. TNF-alpha mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent beta-catenin activation. Mol Vis. 2016;22:116–128.
   PubMed Web of Science ®Google Scholar
• Lavalette S, Raoul W, Houssier M, et al. Interleukin-1beta inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am J Pathol. 2011;178(5):2416–2423. doi:10.1016/j.ajpath.2011.01.013
   PubMed Web of Science ®Google Scholar
• Chen X, Han R, Hao P, et al. Nepetin inhibits IL-1beta induced inflammation via NF-kappaB and MAPKs signaling pathways in ARPE-19 cells. Biomed Pharmacother. 2018;101:87–93. doi:10.1016/j.biopha.2018.02.054
   PubMed Web of Science ®Google Scholar
• Tan W, Zou J, Yoshida S, Jiang B, Zhou Y. The role of inflammation in age-related macular degeneration. Int J Biol Sci. 2020;16(15):2989–3001. doi:10.7150/ijbs.49890
   PubMed Web of Science ®Google Scholar
• Ogura S, Baldeosingh R, Bhutto IA, et al. A role for mast cells in geographic atrophy. FASEB J. 2020;34(8):10117–10131. doi:10.1096/fj.202000807R
   PubMed Web of Science ®Google Scholar
• McLeod DS, Bhutto I, Edwards MM, Gedam M, Baldeosingh R, Lutty GA. Mast cell-derived tryptase in geographic atrophy. Invest Ophthalmol Vis Sci. 2017;58(13):5887–5896. doi:10.1167/iovs.17-22989
   PubMed Web of Science ®Google Scholar
• Clare AJ, Liu J, Copland DA, Theodoropoulou S, Dick AD. Unravelling the therapeutic potential of IL-33 for atrophic AMD. Eye (Lond). 2021. doi:10.1038/s41433-021-01725-5
   Web of Science ®Google Scholar
• Chen J, Wang W, Li Q. Increased Th1/Th17 responses contribute to low-grade inflammation in age-related macular degeneration. Cell Physiol Biochem. 2017;44(1):357–367. doi:10.1159/000484907
   PubMedGoogle Scholar
• Ishikawa K, Kannan R, Hinton DR. Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res. 2016;142:19–25. doi:10.1016/j.exer.2015.03.009
   PubMed Web of Science ®Google Scholar
• Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103(7):2328–2333. doi:10.1073/pnas.0408835103
   PubMed Web of Science ®Google Scholar
• Bora PS, Sohn JH, Cruz JM, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization. J Immunol. 2005;174(1):491–497. doi:10.4049/jimmunol.174.1.491
   PubMed Web of Science ®Google Scholar
• Sakamoto S, Takahashi H, Tan X, et al. Changes in multiple cytokine concentrations in the aqueous humour of neovascular age-related macular degeneration after 2 months of ranibizumab therapy. Br J Ophthalmol. 2018;102(4):448–454. doi:10.1136/bjophthalmol-2017-310284
   PubMed Web of Science ®Google Scholar
• Yuan J. Role of inflammatory factors in the effects of aflibercept or ranibizumab treatment for alleviating wet age-associated macular degeneration. Exp Ther Med. 2019;17(5):4249–4258. doi:10.3892/etm.2019.7427
   PubMed Web of Science ®Google Scholar
• Sato T, Takeuchi M, Karasawa Y, Enoki T, Ito M. Intraocular inflammatory cytokines in patients with neovascular age-related macular degeneration before and after initiation of intravitreal injection of anti-VEGF inhibitor. Sci Rep. 2018;8(1):1098. doi:10.1038/s41598-018-19594-6
   PubMed Web of Science ®Google Scholar
• Clark SJ, Bishop PN. The eye as a complement dysregulation hotspot. Semin Immunopathol. 2018;40(1):65–74. doi:10.1007/s00281-017-0649-6
   PubMed Web of Science ®Google Scholar
• Zhang X, Sivaprasad S. Drusen and pachydrusen: the definition, pathogenesis, and clinical significance. Eye (Lond). 2021;35(1):121–133. doi:10.1038/s41433-020-01265-4
   PubMed Web of Science ®Google Scholar
• Tarallo V, Hirano Y, Gelfand BD, et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell. 2012;149(4):847–859. doi:10.1016/j.cell.2012.03.036
   PubMed Web of Science ®Google Scholar
• Kassa E, Ciulla TA, Hussain RM, Dugel PU. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol Ther. 2019;19(4):335–342. doi:10.1080/14712598.2019.1575358
   PubMed Web of Science ®Google Scholar
• Ebrahimi KB, Fijalkowski N, Cano M, Handa JT. Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration. J Pathol. 2013;229(5):729–742. doi:10.1002/path.4128
   PubMed Web of Science ®Google Scholar
• Vogt SD, Curcio CA, Wang L, et al. Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy. Exp Eye Res. 2011;93(4):413–423. doi:10.1016/j.exer.2011.06.002
   PubMed Web of Science ®Google Scholar
• Yerramothu P, Vijay AK, Willcox MDP. Inflammasomes, the eye and anti-inflammasome therapy. Eye (Lond). 2018;32(3):491–505. doi:10.1038/eye.2017.241
   PubMed Web of Science ®Google Scholar
• Kauppinen A, Paterno JJ, Blasiak J, Salminen A, Kaarniranta K. Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci. 2016;73(9):1765–1786. doi:10.1007/s00018-016-2147-8
   PubMed Web of Science ®Google Scholar
• Tseng WA, Thein T, Kinnunen K, et al. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54(1):110–120. doi:10.1167/iovs.12-10655
   PubMed Web of Science ®Google Scholar
• Pool FM, Kiel C, Serrano L, Luthert PJ. Repository of proposed pathways and protein-protein interaction networks in age-related macular degeneration. NPJ Aging Mech Dis. 2020;6:2. doi:10.1038/s41514-019-0039-5
   PubMed Web of Science ®Google Scholar
• Lee KS, Lin S, Copland DA, Dick AD, Liu J. Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. J Neuroinflammation. 2021;18(1):32. doi:10.1186/s12974-021-02088-0
   PubMed Web of Science ®Google Scholar
• Chen W, Esselman WJ, Jump DB, Busik JV. Anti-inflammatory effect of docosahexaenoic acid on cytokine-induced adhesion molecule expression in human retinal vascular endothelial cells. Invest Ophthalmol Vis Sci. 2005;46(11):4342–4347. doi:10.1167/iovs.05-0601
   PubMed Web of Science ®Google Scholar
• Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004;23(1):71–78. doi:10.1080/07315724.2004.10719345
   PubMed Web of Science ®Google Scholar
• Wang TM, Chen CJ, Lee TS, et al. Docosahexaenoic acid attenuates VCAM-1 expression and NF-kappaB activation in TNF-alpha-treated human aortic endothelial cells. J Nutr Biochem. 2011;22(2):187–194. doi:10.1016/j.jnutbio.2010.01.007
   PubMed Web of Science ®Google Scholar
• Devassy JG, Leng S, Gabbs M, Monirujjaman M, Aukema HM. Omega-3 polyunsaturated fatty acids and oxylipins in neuroinflammation and management of Alzheimer disease. Adv Nutr. 2016;7(5):905–916. doi:10.3945/an.116.012187
   PubMed Web of Science ®Google Scholar
• Nakamura M, Kuse Y, Tsuruma K, Shimazawa M, Hara H. The involvement of the oxidative stress in murine blue LED light-induced retinal damage model. Biol Pharm Bull. 2017;40(8):1219–1225. doi:10.1248/bpb.b16-01008
   PubMed Web of Science ®Google Scholar
• Heitmar R, Brown J, Kyrou I. Saffron (Crocus sativus L.) in ocular diseases: a narrative review of the existing evidence from clinical studies. Nutrients. 2019;11(3):649. doi:10.3390/nu11030649
   PubMed Web of Science ®Google Scholar
• Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2017;7:CD000254. doi:10.1002/14651858.CD000254.pub4
   PubMed Web of Science ®Google Scholar
• Delmas D, Cornebise C, Courtaut F, Xiao J, Aires V. New highlights of resveratrol: a review of properties against ocular diseases. Int J Mol Sci. 2021;22(3):1295. doi:10.3390/ijms22031295
   PubMed Web of Science ®Google Scholar
• Blasiak J, Pawlowska E, Chojnacki J, Szczepanska J, Chojnacki C, Kaarniranta K. Zinc and autophagy in age-related macular degeneration. Int J Mol Sci. 2020;21(14):4994. doi:10.3390/ijms21144994
   PubMed Web of Science ®Google Scholar
• Vallee A, Lecarpentier Y, Guillevin R, Vallee JN. PPARgamma agonists: potential treatments for exudative age-related macular degeneration. Life Sci. 2017;188:123–130. doi:10.1016/j.lfs.2017.09.008
   PubMed Web of Science ®Google Scholar
• Fu Z, Liegl R, Wang Z, et al. Adiponectin mediates dietary omega-3 long-chain polyunsaturated fatty acid protection against choroidal neovascularization in mice. Invest Ophthalmol Vis Sci. 2017;58(10):3862–3870. doi:10.1167/iovs.17-21796
   PubMed Web of Science ®Google Scholar
• Nashine S. Potential therapeutic candidates for age-related macular degeneration (AMD). Cells. 2021;10(9):2483. doi:10.3390/cells10092483
   PubMed Web of Science ®Google Scholar
• Zhang R, Liu Z, Zhang H, Zhang Y, Lin D. The COX-2-selective antagonist (NS-398) inhibits choroidal neovascularization and subretinal fibrosis. PLoS One. 2016;11(1):e0146808. doi:10.1371/journal.pone.0146808
   PubMed Web of Science ®Google Scholar
• Qiu F, Matlock G, Chen Q, et al. Therapeutic effects of PPARalpha agonist on ocular neovascularization in models recapitulating neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2017;58(12):5065–5075. doi:10.1167/iovs.17-22091
   PubMed Web of Science ®Google Scholar
• Sulaiman RS, Park B, Sheik Pran Babu SP, et al. Chemical proteomics reveals soluble epoxide hydrolase as a therapeutic target for ocular neovascularization. ACS Chem Biol. 2018;13(1):45–52. doi:10.1021/acschembio.7b00854
   PubMed Web of Science ®Google Scholar
• Sulaiman RS, Merrigan S, Quigley J, et al. A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy. Sci Rep. 2016;6:25509. doi:10.1038/srep25509
   PubMed Web of Science ®Google Scholar
• Kojetin DJ, Burris TP. REV-ERB and ROR nuclear receptors as drug targets. Nat Rev Drug Discov. 2014;13(3):197–216. doi:10.1038/nrd4100
   PubMed Web of Science ®Google Scholar
• Zapadka TE, Lindstrom SI, Taylor BE, et al. RORgammat inhibitor-SR1001 Halts retinal inflammation, capillary degeneration, and the progression of diabetic retinopathy. Int J Mol Sci. 2020;21(10):3547. doi:10.3390/ijms21103547
   PubMed Web of Science ®Google Scholar
• Fu Z, Sun Y, Cakir B, et al. Targeting neurovascular interaction in retinal disorders. Int J Mol Sci. 2020;21(4):1503. doi:10.3390/ijms21041503
   PubMed Web of Science ®Google Scholar
• Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2021;128(4):576–586. doi:10.1016/j.ophtha.2020.08.027
   PubMed Web of Science ®Google Scholar
• Sapieha P, Stahl A, Chen J, et al. 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of omega-3 polyunsaturated fatty acids. Sci Transl Med. 2011;3(69):69ra12. doi:10.1126/scitranslmed.3001571
   PubMed Web of Science ®Google Scholar
• Nelson AJ, Stephenson DJ, Cardona CL, et al. Macrophage polarization is linked to Ca(2+)-independent phospholipase A2 beta-derived lipids and cross-cell signaling in mice. J Lipid Res. 2020;61(2):143–158. doi:10.1194/jlr.RA119000281
   PubMed Web of Science ®Google Scholar
• Joffre C, Rey C, Laye S. N-3 polyunsaturated fatty acids and the resolution of neuroinflammation. Front Pharmacol. 2019;10:1022. doi:10.3389/fphar.2019.01022
   PubMed Web of Science ®Google Scholar
• Elmasry K, Ibrahim AS, Abdulmoneim S, Al-Shabrawey M. Bioactive lipids and pathological retinal angiogenesis. Br J Pharmacol. 2019;176(1):93–109. doi:10.1111/bph.14507
   PubMed Web of Science ®Google Scholar
• Leuti A, Maccarrone M, Chiurchiu V. Proresolving lipid mediators: endogenous modulators of oxidative stress. Oxid Med Cell Longev. 2019;2019:8107265. doi:10.1155/2019/8107265
   PubMed Web of Science ®Google Scholar
• Rivera JC, Dabouz R, Noueihed B, Omri S, Tahiri H, Chemtob S. Ischemic retinopathies: oxidative stress and inflammation. Oxid Med Cell Longev. 2017;2017:3940241. doi:10.1155/2017/3940241
   PubMed Web of Science ®Google Scholar
• Calder PC. n-3 PUFA and inflammation: from membrane to nucleus and from bench to bedside. Proc Nutr Soc. 2020;79:404–416.
   Web of Science ®Google Scholar
• Kuhn H, Banthiya S, van Leyen K. Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta. 2015;1851(4):308–330. doi:10.1016/j.bbalip.2014.10.002
   PubMed Web of Science ®Google Scholar
• Subramanian P, Mendez EF, Becerra SP, Novel A. Inhibitor of 5-lipoxygenase (5-LOX) prevents oxidative stress-induced cell death of Retinal Pigment Epithelium (RPE) cells. Invest Ophthalmol Vis Sci. 2016;57(11):4581–4588. doi:10.1167/iovs.15-19039
   PubMed Web of Science ®Google Scholar
• Gong Y, Fu Z, Liegl R, Chen J, Hellstrom A, Smith LE. omega-3 and omega-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr. 2017;106(1):16–26. doi:10.3945/ajcn.117.153825
   PubMed Web of Science ®Google Scholar
• Gubitosi-Klug RA, Talahalli R, Du Y, Nadler JL, Kern TS. 5-Lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy. Diabetes. 2008;57(5):1387–1393. doi:10.2337/db07-1217
   PubMed Web of Science ®Google Scholar
• Othman A, Ahmad S, Megyerdi S, et al. 12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase. PLoS One. 2013;8(2):e57254. doi:10.1371/journal.pone.0057254
   PubMed Web of Science ®Google Scholar
• Arnold C, Konkel A, Fischer R, Schunck WH. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol Rep. 2010;62(3):536–547. doi:10.1016/S1734-1140(10)70311-X
   PubMed Web of Science ®Google Scholar
• Fleming I. New lipid mediators in retinal angiogenesis and retinopathy. Front Pharmacol. 2019;10:739. doi:10.3389/fphar.2019.00739
   PubMed Web of Science ®Google Scholar
• Shao Z, Fu Z, Stahl A, et al. Cytochrome P450 2C8 omega3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization–brief report. Arterioscler Thromb Vasc Biol. 2014;34(3):581–586. doi:10.1161/ATVBAHA.113.302927
   PubMed Web of Science ®Google Scholar
• Gong Y, Fu Z, Edin ML, et al. Cytochrome P450 oxidase 2C inhibition adds to omega-3 long-chain polyunsaturated fatty acids protection against retinal and choroidal neovascularization. Arterioscler Thromb Vasc Biol. 2016;36(9):1919–1927. doi:10.1161/ATVBAHA.116.307558
   PubMed Web of Science ®Google Scholar
• Hasegawa E, Inafuku S, Mulki L, et al. Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. Proc Natl Acad Sci U S A. 2017;114(36):E7545–E53. doi:10.1073/pnas.1620898114
   PubMed Web of Science ®Google Scholar
• Ontko CD, Capozzi ME, Kim MJ, McCollum GW, Penn JS. Cytochrome P450-epoxygenated fatty acids inhibit Muller glial inflammation. Sci Rep. 2021;11(1):9677. doi:10.1038/s41598-021-89000-1
   PubMed Web of Science ®Google Scholar
• Capozzi ME, Hammer SS, McCollum GW, Penn JS. Epoxygenated fatty acids inhibit retinal vascular inflammation. Sci Rep. 2016;6:39211. doi:10.1038/srep39211
   PubMed Web of Science ®Google Scholar
• Gong Y, Shao Z, Fu Z, et al. Fenofibrate inhibits cytochrome P450 epoxygenase 2C activity to suppress pathological ocular angiogenesis. EBioMedicine. 2016;13:201–211. doi:10.1016/j.ebiom.2016.09.025
   PubMed Web of Science ®Google Scholar
• Parmar VM, Parmar T, Arai E, Perusek L, Maeda A. A2E-associated cell death and inflammation in retinal pigmented epithelial cells from human induced pluripotent stem cells. Stem Cell Res. 2018;27:95–104. doi:10.1016/j.scr.2018.01.014
   PubMed Web of Science ®Google Scholar
• Green CJ, Pramfalk C, Charlton CA, et al. Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism. BMJ Open Diabetes Res Care. 2020;8(1):e000871. doi:10.1136/bmjdrc-2019-000871
   PubMed Web of Science ®Google Scholar
• Xie H, Yin F, Liu Z, et al. Oxidation kinetics of polyunsaturated fatty acids esterified into triacylglycerols and phospholipids in dried scallop (Argopecten irradians) adductor muscles during storage. Food Funct. 2020;11(3):2349–2357. doi:10.1039/D0FO00051E
   PubMed Web of Science ®Google Scholar
• Cheng YS, Linetsky M, Gu X, Ayyash N, Gardella A, Salomon RG. Light-induced generation and toxicity of docosahexaenoate-derived oxidation products in retinal pigmented epithelial cells. Exp Eye Res. 2019;181:325–345. doi:10.1016/j.exer.2018.09.012
   PubMed Web of Science ®Google Scholar
• Kaarniranta K, Koskela A, Felszeghy S, Kivinen N, Salminen A, Kauppinen A. Fatty acids and oxidized lipoproteins contribute to autophagy and innate immunity responses upon the degeneration of retinal pigment epithelium and development of age-related macular degeneration. Biochimie. 2019;159:49–54. doi:10.1016/j.biochi.2018.07.010
   PubMed Web of Science ®Google Scholar
• Kim SY, Kambhampati SP, Bhutto IA, McLeod DS, Lutty GA, Kannan RM. Evolution of oxidative stress, inflammation and neovascularization in the choroid and retina in a subretinal lipid induced age-related macular degeneration model. Exp Eye Res. 2021;203:108391. doi:10.1016/j.exer.2020.108391
   PubMed Web of Science ®Google Scholar
• Datta S, Cano M, Ebrahimi K, Wang L, Handa JT. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res. 2017;60:201–218. doi:10.1016/j.preteyeres.2017.03.002
   PubMed Web of Science ®Google Scholar
• Kaarniranta K, Tokarz P, Koskela A, Paterno J, Blasiak J. Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration. Cell Biol Toxicol. 2017;33(2):113–128. doi:10.1007/s10565-016-9371-8
   PubMed Web of Science ®Google Scholar
• Li W, Cao T, Luo C, et al. Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. Appl Microbiol Biotechnol. 2020;104(14):6129–6140. doi:10.1007/s00253-020-10614-y
   PubMed Web of Science ®Google Scholar
• Celkova L, Doyle SL, Campbell M. NLRP3 inflammasome and pathobiology in AMD. J Clin Med. 2015;4(1):172–192. doi:10.3390/jcm4010172
   PubMed Web of Science ®Google Scholar
• Brandstetter C, Patt J, Holz FG, Krohne TU. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B. 2016;161:177–183. doi:10.1016/j.jphotobiol.2016.05.018
   PubMed Web of Science ®Google Scholar
• Gallo G, Sprovieri P, Martino G. 4-hydroxynonenal and oxidative stress in several organelles and its damaging effects on cell functions. J Physiol Pharmacol. 2020;71(1):15–33.
   Web of Science ®Google Scholar
• Sharma A, Sharma R, Chaudhary P, et al. 4-Hydroxynonenal induces p53-mediated apoptosis in retinal pigment epithelial cells. Arch Biochem Biophys. 2008;480(2):85–94. doi:10.1016/j.abb.2008.09.016
   PubMed Web of Science ®Google Scholar
• Vatsyayan R, Chaudhary P, Sharma A, et al. Role of 4-hydroxynonenal in epidermal growth factor receptor-mediated signaling in retinal pigment epithelial cells. Exp Eye Res. 2011;92(2):147–154. doi:10.1016/j.exer.2010.11.010
   PubMed Web of Science ®Google Scholar
• Kaarniranta K, Kajdanek J, Morawiec J, Pawlowska E, Blasiak J. PGC-1alpha protects RPE cells of the aging retina against oxidative stress-induced degeneration through the regulation of senescence and mitochondrial quality control. The significance for AMD pathogenesis. Int J Mol Sci. 2018;19(8):2317. doi:10.3390/ijms19082317
   PubMed Web of Science ®Google Scholar
• Lin CH, Wu MR, Huang WJ, Chow DS, Hsiao G, Cheng YW. Low-luminance blue light-enhanced phototoxicity in A2E-laden RPE cell cultures and rats. Int J Mol Sci. 2019;20(7):1799. doi:10.3390/ijms20071799
   PubMed Web of Science ®Google Scholar
• Allingham MJ, Loksztejn A, Cousins SW, Mettu PS. Immunological aspects of age-related macular degeneration. Adv Exp Med Biol. 2021;1256:143–189. doi:10.1007/978-3-030-66014-7_6
   PubMed Web of Science ®Google Scholar
• Meri S, Haapasalo K. Function and dysfunction of complement factor H during formation of lipid-rich deposits. Front Immunol. 2020;11:611830. doi:10.3389/fimmu.2020.611830
   PubMed Web of Science ®Google Scholar
• Ardeljan D, Tuo J, Chan CC. Carboxyethylpyrrole plasma biomarkers in age-related macular degeneration. Drugs Future. 2011;36(9):712–718. doi:10.1358/dof.2011.036.09.1678338
   PubMed Web of Science ®Google Scholar
• Koscielniak A, Serafin M, Duda M, et al. Oxidation-induced increase in photoreactivity of bovine retinal lipid extract. Cell Biochem Biophys. 2017;75(3–4):443–454. doi:10.1007/s12013-017-0832-3
   PubMed Web of Science ®Google Scholar
• Yang Y, Liu F, Tang M, et al. Macrophage polarization in experimental and clinical choroidal neovascularization. Sci Rep. 2016;6:30933. doi:10.1038/srep30933
   PubMed Web of Science ®Google Scholar
• Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 2014;17(1):109–118. doi:10.1007/s10456-013-9381-6
   PubMed Web of Science ®Google Scholar
• Ueta T, Ishihara K, Notomi S, et al. RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization. Proc Natl Acad Sci U S A. 2019;116(47):23705–23713. doi:10.1073/pnas.1908355116
   PubMed Web of Science ®Google Scholar
• Zhou Y, Yoshida S, Kubo Y, et al. Different distributions of M1 and M2 macrophages in a mouse model of laser-induced choroidal neovascularization. Mol Med Rep. 2017;15(6):3949–3956. doi:10.3892/mmr.2017.6491
   PubMed Web of Science ®Google Scholar
• Xu Y, Cui K, Li J, et al. Melatonin attenuates choroidal neovascularization by regulating macrophage/microglia polarization via inhibition of RhoA/ROCK signaling pathway. J Pineal Res. 2020;69(1):e12660. doi:10.1111/jpi.12660
   PubMed Web of Science ®Google Scholar
• Daftarian N, Zandi S, Piryaie G, et al. Peripheral blood CD163(+) monocytes and soluble CD163 in dry and neovascular age-related macular degeneration. FASEB J. 2020;34(6):8001–8011. doi:10.1096/fj.201901902RR
   PubMed Web of Science ®Google Scholar
• Xu J, Tu Y, Wang Y, et al. Prodrug of epigallocatechin-3-gallate alleviates choroidal neovascularization via down-regulating HIF-1alpha/VEGF/VEGFR2 pathway and M1 type macrophage/microglia polarization. Biomed Pharmacother. 2020;121:109606. doi:10.1016/j.biopha.2019.109606
   PubMed Web of Science ®Google Scholar
• Ravi R, Ragavachetty Nagaraj N, Subramaniam Rajesh B. Effect of advanced glycation end product on paraoxonase 2 expression: its impact on endoplasmic reticulum stress and inflammation in HUVECs. Life Sci. 2020;246:117397. doi:10.1016/j.lfs.2020.117397
   PubMed Web of Science ®Google Scholar
• Sun Q, Gong L, Qi R, et al. Oxidative stress-induced KLF4 activates inflammatory response through IL17RA and its downstream targets in retinal pigment epithelial cells. Free Radic Biol Med. 2020;147:271–281. doi:10.1016/j.freeradbiomed.2019.12.029
   PubMed Web of Science ®Google Scholar
• Wang K, Zheng M, Lester KL, Han Z. Light-induced Nrf2(-/-) mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel. Sci Rep. 2019;9(1):14573. doi:10.1038/s41598-019-51151-7
   PubMed Web of Science ®Google Scholar
• Ramchani-Ben Othman K, Cercy C, Amri M, Doly M, Ranchon-Cole I. Dietary supplement enriched in antioxidants and omega-3 protects from progressive light-induced retinal degeneration. PLoS One. 2015;10(6):e0128395. doi:10.1371/journal.pone.0128395
   PubMed Web of Science ®Google Scholar
• Narimatsu T, Ozawa Y, Miyake S, Nagai N, Tsubota K. Angiotensin II type 1 receptor blockade suppresses light-induced neural damage in the mouse retina. Free Radic Biol Med. 2014;71:176–185. doi:10.1016/j.freeradbiomed.2014.03.020
   PubMed Web of Science ®Google Scholar
• Blasiak J, Piechota M, Pawlowska E, Szatkowska M, Sikora E, Kaarniranta K. Cellular senescence in age-related macular degeneration: can autophagy and DNA damage response play a role? Oxid Med Cell Longev. 2017;2017:5293258. doi:10.1155/2017/5293258
   PubMed Web of Science ®Google Scholar
• Blasiak J. Senescence in the pathogenesis of age-related macular degeneration. Cell Mol Life Sci. 2020;77(5):789–805. doi:10.1007/s00018-019-03420-x
   PubMed Web of Science ®Google Scholar
• SanGiovanni JP, Chen J, Sapieha P, et al. DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the omega-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways. PLoS One. 2013;8(1):e53155. doi:10.1371/journal.pone.0053155
   PubMed Web of Science ®Google Scholar
• Choudhary M, Ding JD, Qi X, et al. PPARbeta/delta selectively regulates phenotypic features of age-related macular degeneration. Aging (Albany NY). 2016;8(9):1952–1978. doi:10.18632/aging.101031
   PubMedGoogle Scholar
• Moran E, Ding L, Wang Z, et al. Protective and antioxidant effects of PPARalpha in the ischemic retina. Invest Ophthalmol Vis Sci. 2014;55(7):4568–4576. doi:10.1167/iovs.13-13127
   PubMed Web of Science ®Google Scholar
• Echeverria F, Ortiz M, Valenzuela R, Videla LA. Long-chain polyunsaturated fatty acids regulation of PPARs, signaling: relationship to tissue development and aging. Prostaglandins Leukot Essent Fatty Acids. 2016;114:28–34. doi:10.1016/j.plefa.2016.10.001
   PubMed Web of Science ®Google Scholar
• Choudhary M, Malek G. A brief discussion on lipid activated nuclear receptors and their potential role in regulating microglia in age-related macular degeneration (AMD). Adv Exp Med Biol. 2016;854:45–51.
   PubMed Web of Science ®Google Scholar
• Pearsall EA, Cheng R, Zhou K, et al. PPAR alpha is essential for retinal lipid metabolism and neuronal survival. BMC Biol. 2017;15(1):113. doi:10.1186/s12915-017-0451-x
   PubMed Web of Science ®Google Scholar
• Bouhlel MA, Derudas B, Rigamonti E, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007;6(2):137–143. doi:10.1016/j.cmet.2007.06.010
   PubMed Web of Science ®Google Scholar
• Fontaine V, Fournie M, Monteiro E, et al. A2E-induced inflammation and angiogenesis in RPE cells in vitro are modulated by PPAR-alpha, -beta/delta, -gamma, and RXR antagonists and by norbixin. Aging (Albany NY). 2021;13(18):22040–22058. doi:10.18632/aging.203558
   PubMedGoogle Scholar
• Krezel W, Ruhl R, de Lera AR. Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol. 2019;491:110436. doi:10.1016/j.mce.2019.04.016
   PubMed Web of Science ®Google Scholar
• Sridevi Gurubaran I, Viiri J, Koskela A, et al. Mitophagy in the retinal pigment epithelium of dry age-related macular degeneration investigated in the NFE2L2/PGC-1alpha(-/-) mouse model. Int J Mol Sci. 2020;21(6):1976. doi:10.3390/ijms21061976
   PubMed Web of Science ®Google Scholar
• Zhang M, Chu Y, Mowery J, et al. Pgc-1alpha repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice. Dis Model Mech. 2018;11(9). doi:10.1242/dmm.032698
   Web of Science ®Google Scholar
• Felszeghy S, Viiri J, Paterno JJ, et al. Loss of NRF-2 and PGC-1alpha genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration. Redox Biol. 2019;20:1–12. doi:10.1016/j.redox.2018.09.011
   PubMed Web of Science ®Google Scholar
• Ammar MJ, Hsu J, Chiang A, Ho AC, Regillo CD. Age-related macular degeneration therapy: a review. Curr Opin Ophthalmol. 2020;31(3):215–221. doi:10.1097/ICU.0000000000000657
   PubMed Web of Science ®Google Scholar
• Wang S, Wang X, Cheng Y, et al. Autophagy dysfunction, cellular senescence, and abnormal immune-inflammatory responses in AMD: from mechanisms to therapeutic potential. Oxid Med Cell Longev. 2019;2019:3632169. doi:10.1155/2019/3632169
   PubMed Web of Science ®Google Scholar
• Yao J, Jia L, Khan N, et al. Deletion of autophagy inducer RB1CC1 results in degeneration of the retinal pigment epithelium. Autophagy. 2015;11(6):939–953. doi:10.1080/15548627.2015.1041699
   PubMed Web of Science ®Google Scholar
• Yumnamcha T, Devi TS, Singh LP. Auranofin mediates mitochondrial dysregulation and inflammatory cell death in human retinal pigment epithelial cells: implications of retinal neurodegenerative diseases. Front Neurosci. 2019;13:1065. doi:10.3389/fnins.2019.01065
   PubMed Web of Science ®Google Scholar
• Su LJ, Zhang JH, Gomez H, et al. Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019;2019:5080843. doi:10.1155/2019/5080843
   PubMed Web of Science ®Google Scholar
• Kaarniranta K, Petrovski G, Kauppinen A. The Nobel Prized cellular target autophagy in eye diseases. Acta Ophthalmol. 2017;95(4):335–336. doi:10.1111/aos.13344
   PubMed Web of Science ®Google Scholar
• Fernandez-Albarral JA, de Julian-lopez E, Soler-Dominguez C, et al. The role of autophagy in eye diseases. Life (Basel). 2021;11(3):189.
   PubMed Web of Science ®Google Scholar
• Yang X, Pan X, Zhao X, et al. Autophagy and age-related eye diseases. Biomed Res Int. 2019;2019:5763658. doi:10.1155/2019/5763658
   PubMed Web of Science ®Google Scholar
• Mitter SK, Song C, Qi X, et al. Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy. 2014;10(11):1989–2005. doi:10.4161/auto.36184
   PubMed Web of Science ®Google Scholar
• Abokyi S, To CH, Lam TT, Tse DY. Central role of oxidative stress in age-related macular degeneration: evidence from a review of the molecular mechanisms and animal models. Oxid Med Cell Longev. 2020;2020:7901270. doi:10.1155/2020/7901270
   PubMed Web of Science ®Google Scholar
• Roubeix C, Sahel JA, Guillonneau X, Delarasse C, Sennlaub F. [On the inflammatory origins of AMD]. Med Sci (Paris). 2020;36(10):886–892. French. doi:10.1051/medsci/2020159
   PubMed Web of Science ®Google Scholar
• Saadat KA, Murakami Y, Tan X, et al. Inhibition of autophagy induces retinal pigment epithelial cell damage by the lipofuscin fluorophore A2E. FEBS Open Bio. 2014;4:1007–1014. doi:10.1016/j.fob.2014.11.003
   PubMed Web of Science ®Google Scholar
• Zhang J, Bai Y, Huang L, et al. Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration. Cell Death Dis. 2015;6:e1972. doi:10.1038/cddis.2015.330
   PubMed Web of Science ®Google Scholar
• Kaarniranta K, Sinha D, Blasiak J, et al. Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration. Autophagy. 2013;9(7):973–984. doi:10.4161/auto.24546
   PubMed Web of Science ®Google Scholar
• Terluk MR, Kapphahn RJ, Soukup LM, et al. Investigating mitochondria as a target for treating age-related macular degeneration. J Neurosci. 2015;35(18):7304–7311. doi:10.1523/JNEUROSCI.0190-15.2015
   PubMed Web of Science ®Google Scholar
• Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, Ferrington DA. Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49(7):2848–2855. doi:10.1167/iovs.07-1352
   PubMed Web of Science ®Google Scholar
• Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–414. doi:10.1016/j.immuni.2012.01.009
   PubMed Web of Science ®Google Scholar
• Bazan NG. Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. Mol Aspects Med. 2018;64:18–33. doi:10.1016/j.mam.2018.09.003
   PubMed Web of Science ®Google Scholar
• Bhattacharjee S, Jun B, Belayev L, et al. Elovanoids are a novel class of homeostatic lipid mediators that protect neural cell integrity upon injury. Sci Adv. 2017;3(9):e1700735. doi:10.1126/sciadv.1700735
   PubMed Web of Science ®Google Scholar
• Do KV, Kautzmann MI, Jun B, et al. Elovanoids counteract oligomeric beta-amyloid-induced gene expression and protect photoreceptors. Proc Natl Acad Sci U S A. 2019;116(48):24317–24325. doi:10.1073/pnas.1912959116
   PubMed Web of Science ®Google Scholar
• Voigt AP, Mulfaul K, Mullin NK, et al. Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration. Proc Natl Acad Sci U S A. 2019;116(48):24100–24107. doi:10.1073/pnas.1914143116
   PubMed Web of Science ®Google Scholar
• Mau T, Yung R. Adipose tissue inflammation in aging. Exp Gerontol. 2018;105:27–31. doi:10.1016/j.exger.2017.10.014
   PubMed Web of Science ®Google Scholar
• Schnabolk G. Systemic inflammatory disease and AMD comorbidity. Adv Exp Med Biol. 2019;1185:27–31.
   PubMed Web of Science ®Google Scholar
• Opreanu M, Lydic TA, Reid GE, McSorley KM, Esselman WJ, Busik JV. Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid. Invest Ophthalmol Vis Sci. 2010;51(6):3253–3263. doi:10.1167/iovs.09-4731
   PubMed Web of Science ®Google Scholar
• Sasaki H, Sueyasu T, Tokuda H, et al. Aging and FADS1 polymorphisms decrease the biosynthetic capacity of long-chain PUFAs: a human trial using [U-(13)C] linoleic acid. Prostaglandins Leukot Essent Fatty Acids. 2019;148:1–8. doi:10.1016/j.plefa.2019.07.003
   PubMed Web of Science ®Google Scholar
• Chataigner M, Mortessagne P, Lucas C, et al. Dietary fish hydrolysate supplementation containing n-3 LC-PUFAs and peptides prevents short-term memory and stress response deficits in aged mice. Brain Behav Immun. 2021;91:716–730. doi:10.1016/j.bbi.2020.09.022
   PubMed Web of Science ®Google Scholar
• Hadley KB, Bauer J, Milgram NW. The oil-rich alga Schizochytrium sp. as a dietary source of docosahexaenoic acid improves shape discrimination learning associated with visual processing in a canine model of senescence. Prostaglandins Leukot Essent Fatty Acids. 2017;118:10–18. doi:10.1016/j.plefa.2017.01.011
   PubMed Web of Science ®Google Scholar
• Tokuda H, Ito M, Sueyasu T, et al. Effects of combining exercise with long-chain polyunsaturated fatty acid supplementation on cognitive function in the elderly: a randomised controlled trial. Sci Rep. 2020;10(1):12906. doi:10.1038/s41598-020-69560-4
   PubMed Web of Science ®Google Scholar
• Erhardt R, Cardoso BR, Meyer BJ, et al. Omega-3 long-chain polyunsaturated fatty acids: are they beneficial for physical and cognitive functioning in older adults? J Nutr Health Aging. 2021;25(4):454–461. doi:10.1007/s12603-020-1553-7
   PubMed Web of Science ®Google Scholar
• Wang J, Feng Y, Han P, et al. Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence. Cell Death Dis. 2018;9(2):178. doi:10.1038/s41419-017-0200-7
   PubMed Web of Science ®Google Scholar
• Zhong Y, Wang K, Jiang L, et al. Dietary fatty acid intake, plasma fatty acid levels, and the risk of age-related macular degeneration (AMD): a dose-response meta-analysis of prospective cohort studies. Eur J Nutr. 2021;60(6):3013–3027. doi:10.1007/s00394-020-02445-4
   PubMed Web of Science ®Google Scholar