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2. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations.

Author

Zhang, Ning, Tsybovsky, Yaroslav, Kolesnikov, Alexander, Rozanowska, Malgorzata, Swider, Malgorzata, Schwartz, Sharon, Stone, Edwin, Palczewska, Grazyna, Maeda, Akiko, Kefalov, Vladimir, Jacobson, Samuel, Cideciyan, Artur, and Palczewski, Krzysztof

Subjects
ATP-Binding Cassette Transporters, Adult, Age of Onset, Animals, COS Cells, Chlorocebus aethiops, Disease Progression, Gene Expression, Genetic Association Studies, HEK293 Cells, Humans, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Point Mutation, Protein Folding, Protein Transport, Retinal Degeneration
Abstract

Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4, even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all-trans-retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4(PV/PV) knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo. Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4(-/-) and Abca4(PV/PV) mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4(-/-) mice, Abca4(PV/PV) mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients.

Published
2015

3. Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin.

Author

Rozanowska, Malgorzata, Edge, Ruth, Land, Edward J., Navaratnam, Suppiah, Sarna, Tadeusz, and Truscott, T. George

Subjects
*ZEAXANTHIN, *RADICAL cations, *LUTEIN, *RETINOIDS, *TAURINE, *MELANINS, *RETINAL (Visual pigment)
Abstract

In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 107 M−1s−1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4–1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Phototoxicity of the Eye

Author

Sarna, Tadeusz, Różanowska, Małgorzata, Jori, Giulio, editor, Pottier, Roy H., editor, Rodgers, Michael A. J., editor, and Truscott, T. George, editor

Published
1994
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7. New avenues for therapy in mitochondrial optic neuropathies

Author

Ng, Wing Sum Vincent, primary, Trigano, Matthieu, additional, Freeman, Thomas, additional, Varrichio, Carmine, additional, Kandaswamy, Dinesh Kumar, additional, Newland, Ben, additional, Brancale, Andrea, additional, Rozanowska, Malgorzata, additional, and Votruba, Marcela, additional

Published
2021
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9. The microenvironment effect on the generation of reactive oxygen species by Pd-bacteriopheophorbide

Author

Vakrat-Haglili, Yahel, Scherz, Avigdor, McLlroy, Brian, Weiner, Lev, Wilson, Brian C., Brumfeld, Vlad, Pawlak, Anna, Brandis, Alexander, Rozanowska, Malgorzata, Salomon, Yoram, and Sarna, Tadeusz

Subjects
Hydrogen peroxide -- Chemical properties, Palladium -- Chemical properties, Superoxide -- Research, Chemistry
Abstract

A study is conducted to show that Pd-bacteriopheophorbide, a useful reagent for vascular targeted photodynamic therapy of solid tumors, forms appreciable amount of hydroxyl radicals, superoxide radicals, and probably hydrogen peroxide in aqueous medium. The results indicate that the sensitizer's environment strongly affects the type and yield of the photogenerated reactive oxygen species.

Published
2005

10. Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Author

Pasqualetto, Gaia, primary, Schepelmann, Martin, additional, Varricchio, Carmine, additional, Pileggi, Elisa, additional, Khogali, Caroline, additional, Morgan, Siân R., additional, Boostrom, Ian, additional, Rozanowska, Malgorzata, additional, Brancale, Andrea, additional, Ferla, Salvatore, additional, and Bassetto, Marcella, additional

Published
2020
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11. Photogeneration and quenching of reactive oxygen species by urocanic acid

Author

Haralampus-Grynaviski, Nicole, Ransom, Carla, Tong Ye, Rozanowska, Malgorzata, Simon, John D., Wrona, Marta, and Sarna, Tadeusz

Subjects
Cholesterol -- Research, Cholesterol -- Optical properties, Isomerization -- Observations, Acids -- Research, Acids -- Electric properties, Chemistry
Abstract

Urocanic acid, UCA is characterized by two electronic transitions in the UV-B (280-320nm), which comprise its broad adsorption spectrum and gave rise to wavelength-dependent isomerization quantum yields. Cholestrol hydroperoxide assays that are designed to investigate the nature of the UV-A photo reactivity of t-UCA confirm the production of reactive oxygen species.

Published
2002

12. List of Contributors

Author

Abad, Juan-Carlos, primary, Abelson, Mark B, additional, Abramson, David H, additional, Acquadro, Martin A, additional, Adamis, Anthony P, additional, Adams, Wesley H, additional, Afshari, Natalie A, additional, Ai, Everett, additional, Aiello, Lloyd M, additional, Aiello, Lloyd P, additional, Akduman, Levent, additional, Albano, Marissa L, additional, Albert, Daniel M., additional, Alexandrou, Terry J, additional, Alfonso, Eduardo C, additional, Alié, Jorge L, additional, Alizadeh, Hassan, additional, Al Jadaan, Ibrahim A, additional, Al-Jastaneiah, Sabah, additional, Allen, Calliope E, additional, Allen, David, additional, Allen, Robert C, additional, Alm, Albert, additional, Al-Swailem, Samar, additional, Alt, Abigail K, additional, Altaweel, Michael M, additional, Anderson, Russell, additional, Andreoli, Christopher M, additional, Androudi, Sofia, additional, Ang, Leonard PK, additional, Anzaar, Fahd, additional, Apple, David J, additional, Arrigg, Claudia A, additional, Artal, Pablo, additional, Asbell, Penny, additional, Asdourian, George K, additional, Atebara, Neal, additional, Atmaca-Sonmez, Pelin, additional, Audo, Isabelle, additional, Auffarth, Gerd U, additional, Avery, Robin K, additional, Azar, Dimitri T, additional, Baker, Ann S, additional, Balles, Mark, additional, Barnes, Scott D, additional, Barnett, Donald M, additional, Barney, Neal P, additional, Barouch, Fina C, additional, Bartley, George B, additional, Barton, Jason JS, additional, Behlau, Irmgard, additional, Belda, Jose I, additional, Bennett, Jeffrey L, additional, Bennett, Timothy J, additional, Berdy, Gregg J, additional, Bernardino, Carlo Roberto, additional, Bernardino, Vitaliano, additional, Berson, Eliot L, additional, Bharadwaj, Amitabh, additional, Bhisitkul, Robert, additional, Bhui, Ravinder D, additional, Bilyk, Jurij, additional, Biousse, Valérie, additional, Bird, Alan C, additional, Blair, Norman Paul, additional, Blodi, Barbara A, additional, Blumenkranz, Mark S, additional, Boldt, H Culver, additional, Borchert, Mark S, additional, Borrillo, Luigi, additional, Borodic, Gary E, additional, Boruchoff, S Arthur, additional, Bose, Swaraj, additional, Boulton, Michael E, additional, Bowman, RW, additional, Bradley, Elizabeth A, additional, Brazitikos, Periklis D, additional, Breeze, Robert, additional, Bressler, Neil M, additional, Bressler, Susan B, additional, Brini, Alfred, additional, Budenz, Donald L, additional, Buffenn, Angela N, additional, Burk, Scott E, additional, Butrus, Salim, additional, Callanan, David, additional, Cameron, J Douglas, additional, Cantor, Louis B, additional, Cantore, William A, additional, Cantu-Dibildox, Jorge, additional, Casas, Victoria, additional, Casper, Miriam, additional, Casten, Robin J, additional, Catoira, Yara P, additional, Cavallerano, Jerry, additional, Chai, Samantha J, additional, Chalita, Maria R, additional, Chamberlain, Sherman M, additional, Chan, Audrey S, additional, Chan, Chi-Chao, additional, Chan, Paul, additional, Chapin, Matthew J, additional, Chapman, Karen L, additional, Chen, Eric, additional, Chen, Joe, additional, Chen, Julie A, additional, Chen, Teresa C, additional, Chen, Zhou, additional, Chévez-Barrios, Patricia, additional, Chew, Emily Y, additional, Chiang, Mark, additional, Chodosh, James, additional, Chong, Eva-Marie, additional, Chun, Denise, additional, Chylack, Leo T, additional, Ciardella, Antonio P, additional, Civan, Mortimer, additional, Clamen, Liane, additional, Clark, John I, additional, Cockerham, Glenn, additional, Cohen, Andre, additional, Cohen, Elisabeth J, additional, Colby, Kathryn A, additional, Coleman, Anne L, additional, Coleman, Hanna R, additional, Colin, Joseph, additional, Collier, J Michael, additional, Comer, Grant M, additional, Conlon, M Ronan, additional, Cooper, Kim E, additional, Corbett, James J, additional, Coma, Miguel C, additional, Cyrlin, Marshall N, additional, Dagi, Linda R, additional, Dahlgren, Matthew A, additional, Daley, Timothy J, additional, Da Mata, Andrea P, additional, Damato, Bertil, additional, D'Amico, Donald J, additional, Dana, Reza, additional, Danan-Husson, Aude, additional, Danesh-Meyer, Helen B, additional, Danis, Ronald P, additional, Darlington, Jason K, additional, Davidson, Stefanie L, additional, Davis, Janet L, additional, Davis, Elizabeth A, additional, de la Cruz, Jose J, additional, de la Garza, Adam G, additional, DeAngelis, Margaret M, additional, DeMartelaere, Sheri L, additional, Demer, Joseph L, additional, Dhaliwal, Avninder, additional, Dieckert, J Paul, additional, Do, Diana V, additional, Doane, Marshall G, additional, Dodds, Christopher, additional, Dohlman, Claes H, additional, Donati, Guy, additional, Donnenfeld, Eric D, additional, Drack, Arlene, additional, Dryja, Thaddeus P, additional, Dueker, David, additional, Duker, Jay S, additional, Dunbar, Jennifer A, additional, Dunn, James P, additional, Dupps, William J, additional, Durand, Marlene L, additional, Dutton, Jonathan J, additional, Eandi, Chiara M, additional, Edward, Deepak P, additional, Egan, Robert A, additional, Eichenbaum, David A, additional, Eklund, Susan E, additional, Engle, Elizabeth C, additional, Erickson, Kristine, additional, Esmaeli, Bita, additional, Fay, Aaron, additional, Feiner, Leonard, additional, Fekrat, Sharon, additional, Ferris, Frederick L, additional, Fine, Howard F, additional, Fletcher, Donald C, additional, Flikier, Paul, additional, Floyd, Richard P, additional, Flynn, Harry W, additional, Fong, Donald S, additional, Font, Ramon L, additional, Forbes, Brian JR, additional, Foroozan, Rod, additional, Foster, Bradley S, additional, Foster, C Stephen, additional, Foster, Jill A, additional, Foulks, Gary N, additional, Fountain, Tamara R, additional, Fox, Gregory M, additional, Freddo, Thomas F, additional, Freedman, Sharon F, additional, Freund, K Bailey, additional, Friberg, Thomas R, additional, Friedman, Alan H, additional, Friedman, David, additional, Friedman, Deborah I, additional, Friedman, Ephraim, additional, Fu, Arthur D, additional, Fulton, Anne B, additional, Galal, Ahmed, additional, Galetta, Steven, additional, Gallardo, Mark, additional, Gallie, Brenda, additional, Garner, Alec, additional, Garrity, James A, additional, Gatinel, Damien, additional, Gedde, Steven J, additional, Geist, Craig E, additional, Gerber, Steve, additional, Ghanem, Ramon C, additional, Gieser, Jon P, additional, Gilmore, Michael S, additional, Gimbel, Howard V, additional, Gipson, Ilene K, additional, Glover, Tyrone, additional, Goldberg, Robert A, additional, Goldenfeld, Mordechai, additional, Goldstein, Scott M, additional, Gomi, Cintia F, additional, Gong, Haiyan, additional, Gonzales, John A, additional, Goosey, John, additional, Gottlieb, Justin L, additional, Gould, Joshua, additional, Gragoudas, Evangelos S, additional, Granet, David B, additional, Greaney, Michael J, additional, Green, Daniel G, additional, Grehn, Franz, additional, Greiner, Jack V, additional, Greven, Craig M, additional, Griepentrog, Gregory J, additional, Groenewald, Carl, additional, Grosskreutz, Cynthia L, additional, Grover, Lori Latowski, additional, Gullapalli, Vamsi K, additional, Gulur, Padma, additional, Gunther, Jonathan, additional, Gupta, Manish, additional, Gupta, Mayank, additional, Guyer, David R, additional, Haivala, Darin R, additional, Haller, Julia A, additional, Halmagyi, GM, additional, Halperin, Lawrence S, additional, Hamdi, Islam M, additional, Hamilton, Steven R, additional, Hammersmith, Kristin M, additional, Han, Dennis P, additional, Hansen, Ronald M, additional, Harbour, J William, additional, Hariprasad, Seenu M, additional, Harissi-Dagher, Mona, additional, Hassan, Shirin E., additional, Hatton, Mark P, additional, Hawley, Pamela, additional, Hayashida, Yasutaka, additional, Heckenlively, John R, additional, Hedges, Thomas R, additional, Heggie, Alfred D, additional, Heher, Katrinka L, additional, Heier, Jeffrey S, additional, Hejtmancik, J Fielding, additional, Henderson, Bonnie A, additional, Hersh, Peter S, additional, Hidayat, Ahmed A, additional, Higginbotham, Eva Juliet, additional, Hirose, Tatsuo, additional, Ho, Allen C, additional, Ho, ThucAnh T, additional, Hogan, R Nick, additional, Holck, David E, additional, Holekamp, Nancy M, additional, Hovland, Peter G, additional, Hsu, Thomas C, additional, Hsu, William C, additional, Huang, Andrew JW, additional, Hughes, Mark S, additional, Hui, Jennifer, additional, Hunter, David G, additional, Huryn, Laryssa A, additional, Husain, Deeba, additional, Hyndiuk, Robert A, additional, Ip, Michael, additional, Jacobs, Brian J, additional, Jakobiec, Frederick A, additional, Jampol, Lee M, additional, Jensen, Harold G, additional, Ji, Fei, additional, Johnson, David L, additional, Johnson, Douglas H, additional, Johnson, Mark W, additional, Johnson, R Paul, additional, Johnson, Robert N, additional, Joos, Karen M, additional, Joyce, Nancy C, additional, Jumper, J Michael, additional, Jurkunas, Ula V., additional, Kahana, Alon, additional, Kahook, Malik Y, additional, Kanner, Elliott, additional, Kalwerisky, Kevin, additional, Kaplan, Henry J, additional, Karatza, Ekaterini C, additional, Kardon, Randy, additional, Katowitz, James A, additional, Katowitz, William R, additional, Kazlas, Melanie, additional, Keefe, Kelly S, additional, Kelley, Lara, additional, Kent, Charles J, additional, Kenyon, Kenneth R, additional, Khan, Bilal F, additional, Khan, Jemshed A, additional, Khan, Naheed W, additional, Khaw, Peng Tee, additional, Kherani, Femida, additional, Kim, Eva C, additional, Kim, Hee Joon, additional, Kim, Ivana K, additional, Kim, Jonathan W, additional, Kim, Rosa Y, additional, Kim, Stella K, additional, Kim, Tae-Im, additional, Klais, Christina M, additional, Klapper, Stephen R, additional, Klein, Barbara EK, additional, Kleinmann, Guy, additional, Klink, Thomas, additional, Klisovic, Dino D, additional, Klyce, Stephen D, additional, Kocaturk, Tolga, additional, Kohnen, Thomas, additional, Kojima, Takeshi, additional, Koller, Tobias, additional, Kostick, David A, additional, Kraut, Joel A, additional, Krishnan, Chandrasekharan, additional, Krueger, Ronald R, additional, Krug, Joseph H, additional, Krupsky, Sara, additional, Kuchtey, Rachel W, additional, Kurban, Ramsay S, additional, Kurz, Paul A, additional, Kuszak, JR, additional, Kwon, Young H, additional, Labbe, Thad A, additional, Lam, Deborah L, additional, Lamkin, Jeffrey C, additional, Lamping, Kathleen A, additional, Lane, Anne Marie, additional, Lane, Katherine A, additional, Lane, Keith J, additional, Lass, Jonathan H, additional, Lawrence, Mary G, additional, Lee, Andrew G, additional, Lee, Carol M, additional, Lee, Michael S, additional, Lee, Paul P, additional, Lee, William B, additional, Leibovitch, Igal, additional, Lemke, Bradley N, additional, Lemley, Craig A, additional, Leonardi, Andrea, additional, Lessell, Simmons, additional, Levin, Leonard A, additional, Levy-Clarke, Grace A, additional, Lew, Julie C, additional, Lewis, Craig, additional, Li, Wei, additional, Lim, Laurence S, additional, Lim, Lyndell L, additional, Lim, Wee-Kiak, additional, Liu, Grant T, additional, Loewenstein, John I, additional, Lott, McGregor N, additional, Lowry, Jonathan C, additional, Lyon, David B, additional, Lytle, Robert E, additional, MacCumber, Mathew, additional, Mackool, Bonnie T, additional, Madiwale, Nalini A, additional, Mah, Francis, additional, Mainster, Martin A, additional, Manning, Michael H, additional, Mansberger, Steven L, additional, Marc, Robert E, additional, Marchong, Mellone, additional, Marcus, Dennis M, additional, Mares, Julie A, additional, Marr, Brian P, additional, Martinez, Carlos E, additional, Massof, Robert W, additional, Matsumoto, Yukihiro, additional, Mattox, Cynthia, additional, Maus, Marlon, additional, McCabe, Cathleen M, additional, McCormick, Steven A, additional, McCrakken, Michael, additional, McCulley, James P, additional, McDermott, John A, additional, McDonald, H Richard, additional, McDonald, Marguerite B, additional, McDonnell, Peter J, additional, McGillivray, Robert, additional, McKeown, Craig A, additional, McLaughlin, James, additional, McMullen, W Wynn, additional, Melamed, Shlomo, additional, Meligonis, George, additional, Mendrinos, Efstratios, additional, Meyer, Dale R, additional, Meyerle, Catherine B, additional, Mieler, William F, additional, Migliori, Michael, additional, Mihm, Martin C, additional, Miller, Darlene, additional, Miller, David, additional, Miller, Joan W, additional, Miller, Neil R, additional, Mills, David M, additional, Mills, Monte D, additional, Milman, Tatyana, additional, Mogk, Lylas, additional, Mogk, Marja, additional, Monés, Jordi, additional, Montes-Micó, Robert, additional, Morse, Christie L, additional, Morton, Asa D, additional, Moskowitz, Anne, additional, Mukai, Shizuo, additional, Murphree, A Linn, additional, Murphy, Robert P, additional, Murray, Timothy G, additional, Murray, Philip I, additional, Nagao, Karina, additional, Neitz, Jay, additional, Neitz, Maureen, additional, Netland, Peter A, additional, Neufeld, Arthur H, additional, Newman, Nancy J, additional, Ng, Eugene WM, additional, Nguyen, Quan Dong, additional, Niederkorn, Jerry Y, additional, Noecker, Robert J, additional, Nussenblatt, Robert B, additional, O'Brien, Joan M, additional, O'Brien, Paul D, additional, O'Brien, Terrence P, additional, O'Day, Denis, additional, Olk, R Joseph, additional, Olsen, Karl R, additional, Onal, Sumru, additional, Ooi, Yen Hoong, additional, Opremcak, E Mitchel, additional, Ousler, George, additional, Ozment, Randall R, additional, Packer, Samuel, additional, Palmer, Millicent L, additional, Papaliodis, George N, additional, Park, DJ John, additional, Parke, David W, additional, Parsa, Cameron F, additional, Parsons, M Andrew, additional, Pasquale, Louis R, additional, Patel, Neha N, additional, Patel, Sayjal J, additional, Patrianakos, Thomas D, additional, Patrinely, James R, additional, Pavan-Langston, Deborah, additional, Peli, Eli, additional, Pepin, Susan M, additional, Perez, Victor L, additional, Pérez-Santonja, Juan J, additional, Perfect, John R, additional, Perry, Henry D, additional, Piatigorsky, Joram, additional, Pieramici, Dante, additional, Pierce, Eric A, additional, Pineda, Roberto, additional, Pless, Misha L, additional, Pomeranz, Howard D, additional, Pournaras, Constantin J, additional, Power, William, additional, Prakash, Manvi, additional, Prasad, Anita G, additional, Purvin, Valerie, additional, Quillen, David A, additional, Quinn, Graham E, additional, Rabena, Melvin D, additional, Rae, James L, additional, Raizman, Michael B, additional, Randazzo, Alessandro, additional, Rao, Narsing A, additional, Rapuano, Christopher J, additional, Reeves, Sherman W, additional, Regillo, Carl D, additional, Reichel, Elias, additional, Reinke, Martin H, additional, Rhee, Douglas, additional, Richter, Claudia U, additional, Rizzo, Joseph F, additional, Robb, Richard M, additional, Roden, Anja C, additional, Rodgers, I Rand, additional, Rodrigues, Merlyn M, additional, Ron, Yonina, additional, Rose, Geoffrey E, additional, Rosen, Emanuel S, additional, Rosenbaum, James T, additional, Rosenthal, Perry, additional, Rouse, Strutha C, additional, Rovner, Barry W, additional, Rozanowska, Malgorzata, additional, Rubin, Michael P, additional, Rubin, Peter AD, additional, Rumelt, Shimon, additional, Rustgi, Anil K, additional, Rutar, Tina, additional, Ruttum, Mark S, additional, Rutzen, Allan R, additional, Ryan, Edward T, additional, Sadun, Alfredo A, additional, Sahel, José-Alain, additional, Saligan, Leorey, additional, Salim, Sarwat, additional, Salmon, John F, additional, Salomão, Diva R, additional, Sami, David, additional, Sandberg, Michael A, additional, Sangwan, Virender S, additional, Saornil, Maria A, additional, Sassani, Joseph W, additional, Sayegh, Rony R, additional, Schachat, Andrew P, additional, Schell, Wiley A, additional, Schefler, Amy C, additional, Scheufele, Tina, additional, Schiedler, Vivian, additional, Schneider, Gretchen, additional, Schroeder, Alison, additional, Schuchard, Ronald A, additional, Schuman, Joel S, additional, Schwab, Ivan R, additional, Scott, Adrienne, additional, Scott, Ingrid U, additional, Sears, Marvin L, additional, Seddon, Johanna M, additional, Seiler, Theo, additional, Selkin, Robert P, additional, Semba, Richard D, additional, Serbanescu, Irina, additional, Sexton, Briar, additional, Shaarawy, Tarek M, additional, Shah, Peter, additional, Shapiro, Aron, additional, Sharma, Savitri, additional, Shein, Jean, additional, Shetlar, Debra J, additional, Shields, M Bruce, additional, Shields, Carol L, additional, Shields, Jerry A, additional, Shingleton, Bradford J, additional, Shore, John W, additional, Shuba, Lesya M, additional, Simon, Guy J Ben, additional, Simmons, Richard J, additional, Simpson, Michael, additional, Singh, Arun D, additional, Singh, Omah S, additional, Sisley, Karen, additional, Sit, Arthur J, additional, Smerdon, David, additional, Smiddy, William E, additional, Smith, Ronald E, additional, Smith, Terry J, additional, Snebold, Neal G, additional, Sobrin, Lucia, additional, Sorenson, John A, additional, Soukiasian, Sarkis H, additional, Spaeth, George L, additional, Spaide, Richard F, additional, Srivastava, Monika, additional, Srivastava, Sunil K, additional, Stangos, Alexandros N, additional, Starck, Tomy, additional, Stark, Walter J, additional, Stein, Joshua D, additional, Steinert, Roger F, additional, Strauss, Leon, additional, Streeten, Barbara W, additional, Streilein, J Wayne, additional, Strong, James D, additional, Sugino, Ilene K, additional, Suhler, Eric B, additional, Sullivan, Timothy J, additional, Sun, Jennifer K, additional, Sunness, Janet S, additional, Sutula, Francis C, additional, Syed, Nasreen A, additional, Ta, Christopher N, additional, Takei, Hidehiro, additional, Talamo, Jonathan H, additional, Tamesis, Richard R, additional, Tamhankar, Madhura, additional, Tarbet, Kristen J, additional, Tarver-Carr, Michelle, additional, Terry, Mark A, additional, Thomas, Joseph M, additional, Thompson, Vance, additional, Thorne, Jennifer E, additional, Thurtell, Matthew J, additional, Tingey, David P, additional, To, King W, additional, Tobaigy, Faisal M, additional, Tolentino, Michael J, additional, Tong, Melissa G, additional, Torkildsen, Gail, additional, Toth, Cynthia A, additional, Traboulsi, Elias I, additional, Trucksis, Michele, additional, Tsai, James C, additional, Tsai, Julie H, additional, Tse, David T, additional, Tseng, Scheffer CG, additional, Tu, Elmer Y, additional, Udell, Ira J, additional, Valenzuela, Alejandra A, additional, Van Gelder, Russell N, additional, Van Stavern, Gregory P, additional, Vander Veen, Deborah K, additional, Vavvas, Demetrios, additional, Verity, David H, additional, Vinciguerra, Paolo, additional, Vinger, Paul F, additional, Volpe, Nicholas J, additional, Wackernagel, Werner, additional, Wadhwa, Sonal Desai, additional, Wagoner, Michael D, additional, Waheed, Nadia K, additional, Walton, David S, additional, Wand, Martin, additional, Wang, Jie Jin, additional, Warden, Scott M, additional, Webb, Lennox, additional, Weber, David, additional, Wee, Daniel, additional, Westerfeld, Corey B, additional, Westfall, Christopher T, additional, Whitcup, Scott M, additional, White, Valerie A, additional, White, William L, additional, Wickens, Jason, additional, Wiggs, Janey L, additional, Wilensky, Jacob T, additional, Wilkinson, Charles P, additional, Williams, Patrick D, additional, Wilson, David J, additional, Wilson, M Roy, additional, Wilson, Steven E, additional, Winokur, Jules, additional, Wirostko, William J, additional, Wollstein, Gadi, additional, Wong, Albert Chak Ming, additional, Wong, Tien Y, additional, Woog, John J, additional, Wride, Michael, additional, Wu, Carolyn S, additional, WuDunn, Darrell, additional, Yang, Jean, additional, Yannuzzi, Lawrence A, additional, Yaremchuk, Michael J, additional, Yeatts, R Patrick, additional, Yee, Richard W, additional, Yeh, Steven, additional, Young, Lucy HY, additional, Yu, Jenny Y, additional, Yue, Beatrice YJT, additional, Zacks, Charles M, additional, Zagelbaum, Bruce M, additional, Zamani, Maryam, additional, Zarbin, Marco, additional, Zografos, Leonidas, additional, and Zoumalan, Christopher I, additional

Published
2008
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14. Atomic force microscopy and near-field scanning optical microscopy measurements of single human retinal lipofuscin granules

Author

Clancy, Christine M.R., Krogmeier, Jeffrey R., Pawlak, Anna, Rozanowska, Malgorzata, Sarna, Tadeusz, Simon, John D., and Dunn, Robert C.

Subjects
Atomic force microscopy -- Analysis, Epithelial cells -- Research, Chemicals, plastics and rubber industries
Abstract

Studies done to characterize the spatial distribution of orange emitting fluorophores, such as, A2E, in lipofuscin granules isolated from human retinal pigment epithelium cells by using novel high-resolution microscopic techniques is reported. Granules are imaged using atomic force microscopy (AFM) and near field- scanning optical microscopy (NSOM) and the results demonstrate that the orange fluorophores may not be the dominant photoactive species in lipofuscin.

Published
2000

15. Carotenoid radical-melanin interactions

Author

Edge, Ruth, Land, Edward J., Rozanowska, Malgorzata, Sarna, Tadeusz, and Truscott, T. George

Subjects
Melanin -- Research, Carotenoid metabolism -- Research, Chemicals, plastics and rubber industries
Abstract

The radical cations of five dietary carotenoids are shown to react with dopamelanin and cysteinyldopamelanin in both micellar and homogenous environments. The previously unidentified protective roles for melanin/carotenoid combinations are demonstrated by the repair reactions, especially where the maintenance of the small carotenoid concentration is vital to avoid deleterious effects.

Published
2000

17. Scavenging of Retinoid Cation Radicals by Urate, Trolox, and α-, β-, γ-, and δ-Tocopherols

Author

Rozanowska, Malgorzata, Edge, Ruth, Land, Edward J., Navaratnam, Suppiah, Sarna, Tadeusz, and Truscott, T. George

Subjects
retina, skin, Tocopherols, food and beverages, free radicals, Free Radical Scavengers, vitamin E, tocopherol, retinal, Article, vitamin A, Uric Acid, lcsh:Chemistry, Retinoids, antioxidants, ResearchInstitutes_Networks_Beacons/dalton_nuclear_institute, lcsh:Biology (General), lcsh:QD1-999, Cations, retinoic acid, Dalton Nuclear Institute, Chromans, lcsh:QH301-705.5, retinol
Abstract

Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed as a result of the interaction between retinoids and other radicals or photoexcitation with light. It has been shown that such semi-oxidized retinoids can oxidize certain amino acids and proteins, and that α-tocopherol can scavenge the cation radicals of retinol and retinoic acid. The aim of this study was to determine (i) whether β-, γ-, and δ-tocopherols can also scavenge these radicals, and (ii) whether tocopherols can scavenge the cation radicals of another form of vitamin A—retinal. The retinoid cation radicals were generated by the pulse radiolysis of benzene or aqueous solution in the presence of a selected retinoid under oxidizing conditions, and the kinetics of retinoid cation radical decays were measured in the absence and presence of different tocopherols, Trolox or urate. The bimolecular rate constants are the highest for the scavenging of cation radicals of retinal, (7 to 8) × 109 M−1·s−1, followed by retinoic acid, (0.03 to 5.6) × 109 M−1·s−1, and retinol, (0.08 to 1.6) × 108 M−1·s−1. Delta-tocopherol is the least effective scavenger of semi-oxidized retinol and retinoic acid. The hydrophilic analogue of α-tocopherol, Trolox, is substantially less efficient at scavenging retinoid cation radicals than α-tocopherol and urate, but it is more efficient at scavenging the cation radicals of retinoic acid and retinol than δ-tocopherol. The scavenging rate constants indicate that tocopherols can effectively compete with amino acids and proteins for retinoid cation radicals, thereby protecting these important biomolecules from oxidation. Our results provide another mechanism by which tocopherols can diminish the oxidative damage to the skin and retina and thereby protect from skin photosensitivity and the development and/or progression of changes in blinding retinal diseases such as Stargardt’s disease and age-related macular degeneration (AMD).

Published
2019

28. Lipofuscin-associated photo-oxidative stress during fundus autofluorescence imaging

Author

Lewin, Alfred S, Teussink, Michel M., Lambertus, Stanley, de Mul, Frits F., Rozanowska, Malgorzata Barbara, Hoyng, Carel B., Klevering, B. Jeroen, and Theelen, Thomas

Subjects
0301 basic medicine, Pigments, Photoreceptors, Male, Pathology, Sensory Receptors, Light, genetic structures, Social Sciences, lcsh:Medicine, Sensory disorders Radboud Institute for Health Sciences [Radboudumc 12], Retinal Pigment Epithelium, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Melanin, Scattering, chemistry.chemical_compound, Macular Degeneration, 0302 clinical medicine, Animal Cells, Psychology, Stargardt Disease, Fluorescein Angiography, lcsh:Science, Neurons, Multidisciplinary, Photosensitizing Agents, Physics, Electromagnetic Radiation, Optical Imaging, Middle Aged, Photochemical Processes, Chemistry, medicine.anatomical_structure, Physical Sciences, Sunlight, Sensory Perception, Solar Radiation, Female, Cellular Types, Phototoxicity, Elementary Particles, Tomography, Optical Coherence, Research Article, Chemical Elements, Signal Transduction, Photoreceptor Cells, Vertebrate, Adult, medicine.medical_specialty, Fundus Oculi, Materials Science, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Biology, Lipofuscin, 03 medical and health sciences, medicine, Humans, Particle Physics, Materials by Attribute, Melanins, Photons, Retinal pigment epithelium, Organic Pigments, lcsh:R, Light Scattering, Biology and Life Sciences, Afferent Neurons, Retinal, Cell Biology, medicine.disease, eye diseases, Stargardt disease, Oxygen, Oxidative Stress, 030104 developmental biology, chemistry, Cellular Neuroscience, 030221 ophthalmology & optometry, lcsh:Q, sense organs, Oxidative stress, Neuroscience
Abstract

Contains fulltext : 170506.pdf (Publisher’s version ) (Open Access) PURPOSE: Current standards and guidelines aimed at preventing retinal phototoxicity during intentional exposures do not specifically evaluate the contribution of endogenous photosensitizers. However, certain retinal diseases are characterized by abnormal accumulations of potential photosensitizers such as lipofuscin bisretinoids in the retinal pigment epithelium (RPE). We sought to determine these contributions by a numerical assessment of in-vivo photo-oxidative stress during irradiation of RPE lipofuscin. METHODS: Based on the literature, we calculated the retinal exposure levels, optical filtering of incident radiation by the ocular lens, media, photoreceptors, and RPE melanin, light absorption by lipofuscin, and photochemical effects in the RPE in two situations: exposure to short-wavelength (lambda = 488 nm) fundus autofluorescence (SW-AF) excitation light and exposure to indirect (diffuse) sunlight. RESULTS: In healthy persons at age 20, 40, and 60, respectively, the rate of oxygen photoconsumption by lipofuscin increases by 1.3, 1.7, and 2.4 fold during SW-AF-imaging as compared to diffuse sunlight. In patients with STGD1 below the age of 30, this rate was 3.3-fold higher compared to age-matched controls during either sunlight or SW-AF imaging. CONCLUSIONS: Our results suggest that the RPE of patients with STGD1 is generally at increased risk of photo-oxidative stress, while exposure during SW-AF-imaging amplifies this risk. These theoretical results have not yet been verified with in-vivo data due to a lack of sufficiently sensitive in-vivo measurement techniques.

Published
2017

33. Photoreactivity of aged human RPE melanosomes: A comparison with lipofuscin

Author

Rozanowska, Malgorzata Barbara, Korytowski, Witold, Rozanowski, Bartosz, Skumatz, Christine, Boulton, Michael Edwin, Burke, Janice M., and Sarna, Tadeusz

Subjects
sense organs, eye diseases
Abstract

purpose. To determine whether aging is accompanied by changes in aerobic photoreactivity of retinal pigment epithelial (RPE) melanosomes isolated from human donors of different ages, and to compare the photoreactivity of aged melanosomes with that of RPE lipofuscin.\ud \ud methods. Human RPE pigment granules were isolated from RPE cells pooled into groups according to the age of the donors. Photoreactivity was determined by blue-light-induced oxygen uptake and photogeneration of reactive oxygen species. Short-lived radical intermediates were detected by spin-trapping, hydrogen peroxide by an oxidase electrode, singlet oxygen by cholesterol assay, and lipid hydroperoxides by iodometric assay.\ud \ud results. Blue-light photoexcitation of melanosomes resulted in age-related increases in both oxygen uptake and the accumulation of superoxide anion spin adducts. The efficiencies of these processes, however, were still significantly lower than that induced by photoexcited lipofuscin. During irradiation of melanosomes, a substantial amount of oxygen was converted into hydrogen peroxide, whereas for lipofuscin, hydrogen peroxide accounted for not more than 3% of oxygen consumed. In contrast to lipofuscin, photoexcited melanosomes did not substantially increase the rate of oxidative reactions in the presence of polyunsaturated lipids or albumin. However, oxygen uptake was significantly elevated in the presence of ascorbate. Thus, the rate of photo-induced oxygen uptake in samples containing both ascorbate and melanosomes approached that observed in lipofuscin samples.\ud \ud conclusions. Blue-light-induced photoreactivity of melanosomes increases with age, perhaps providing a source of reactive oxygen species and leading to depletion of vital cellular reductants, which, together with lipofuscin, may contribute to cellular dysfunction.

Published
2002

40. Novel small-molecule chaperones to overcome opsin misfolding, mistrafficking and aggregation in retinal blinding diseases

Author

Pasqualetto, Gaia, Pileggi, Elisa, Schepelmann, Martin, Heard, Charles, Young, Mark Thomas, Rozanowska, Malgorzata B., Brancale, Andrea, Bassetto, Marcella, Pasqualetto, Gaia, Pileggi, Elisa, Schepelmann, Martin, Heard, Charles, Young, Mark Thomas, Rozanowska, Malgorzata B., Brancale, Andrea, and Bassetto, Marcella

Abstract

Purpose : Opsin misfolding and its incorrect trafficking represent the main biomolecular causes of photoreceptor death leading to retinal degeneration in Leber’s congenital amaurosis (LCA) and Retinitis pigmentosa (RP). This study aims to develop novel small-molecule chaperones binding opsin in order to promote its proper folding and trafficking to the membrane with consequent reduction of the endoplasmic reticulum (ER) stress caused by protein accumulation that leads to cell death. Methods : Small-molecule chaperon candidates were identified through in silico studies of the retinal-binding pocket based on the available opsin crystal structures and subsequently purchased or synthetized in-house. The compounds ability to bind wild-type opsin isolated from bovine eyes was evaluated through competitive binding assay by measuring via spectrophotometer the rate of formation of isorhodopsin in presence of 9-cis-retinal and the compounds in comparison to 9-cis-retinal alone. The compound ability to rescue opsin trafficking and proper subcellular localization was evaluated by immunofluorescence microscopy in a cell-based model expressing P23H mutant human opsin – an intrinsically instable mutant previously demonstrated to be accumulated in the ER and partially rescued by 9-cis-retinal. Results : 20 opsin-binding candidates were selected based on the structure-based virtual screening of a commercially available compound library, and further 55 novel chemical entities have been rationally designed to improve binding site occupancy and subsequently synthetized. The competitive binding test on a total of 67 compounds has revealed that multiple small molecules were able to decrease the rate of isorhodopsin formation by over 10%. Furthermore, multiple compounds visibly improved P23H mutant opsin proper localization on the cell surface reducing the opsin accumulation in the ER observed in the vehicle control. Conclusions : This work has led to the design, synthesis and identificat

41. Novel small-molecule chaperones to overcome opsin misfolding, mistrafficking and aggregation in retinal blinding diseases

Author

Pasqualetto, Gaia, Pileggi, Elisa, Schepelmann, Martin, Heard, Charles, Young, Mark Thomas, Rozanowska, Malgorzata B., Brancale, Andrea, Bassetto, Marcella, Pasqualetto, Gaia, Pileggi, Elisa, Schepelmann, Martin, Heard, Charles, Young, Mark Thomas, Rozanowska, Malgorzata B., Brancale, Andrea, and Bassetto, Marcella

Abstract

Purpose : Opsin misfolding and its incorrect trafficking represent the main biomolecular causes of photoreceptor death leading to retinal degeneration in Leber’s congenital amaurosis (LCA) and Retinitis pigmentosa (RP). This study aims to develop novel small-molecule chaperones binding opsin in order to promote its proper folding and trafficking to the membrane with consequent reduction of the endoplasmic reticulum (ER) stress caused by protein accumulation that leads to cell death. Methods : Small-molecule chaperon candidates were identified through in silico studies of the retinal-binding pocket based on the available opsin crystal structures and subsequently purchased or synthetized in-house. The compounds ability to bind wild-type opsin isolated from bovine eyes was evaluated through competitive binding assay by measuring via spectrophotometer the rate of formation of isorhodopsin in presence of 9-cis-retinal and the compounds in comparison to 9-cis-retinal alone. The compound ability to rescue opsin trafficking and proper subcellular localization was evaluated by immunofluorescence microscopy in a cell-based model expressing P23H mutant human opsin – an intrinsically instable mutant previously demonstrated to be accumulated in the ER and partially rescued by 9-cis-retinal. Results : 20 opsin-binding candidates were selected based on the structure-based virtual screening of a commercially available compound library, and further 55 novel chemical entities have been rationally designed to improve binding site occupancy and subsequently synthetized. The competitive binding test on a total of 67 compounds has revealed that multiple small molecules were able to decrease the rate of isorhodopsin formation by over 10%. Furthermore, multiple compounds visibly improved P23H mutant opsin proper localization on the cell surface reducing the opsin accumulation in the ER observed in the vehicle control. Conclusions : This work has led to the design, synthesis and identificat

43. Scavenging of Cation Radicals of the Visual Cycle Retinoids by Lutein, Zeaxanthin, Taurine, and Melanin.

Author

Rozanowska M, Edge R, Land EJ, Navaratnam S, Sarna T, and Truscott TG

Subjects
Melanins, Retinaldehyde, Lutein, Zeaxanthins, Taurine, Cations, Retinoids, Vitamin A
Abstract

In the retina, retinoids involved in vision are under constant threat of oxidation, and their oxidation products exhibit deleterious properties. Using pulse radiolysis, this study determined that the bimolecular rate constants of scavenging cation radicals of retinoids by taurine are smaller than 2 × 10 7 M -1 s -1 whereas lutein scavenges cation radicals of all three retinoids with the bimolecular rate constants approach the diffusion-controlled limits, while zeaxanthin is only 1.4-1.6-fold less effective. Despite that lutein exhibits greater scavenging rate constants of retinoid cation radicals than other antioxidants, the greater concentrations of ascorbate in the retina suggest that ascorbate may be the main protectant of all visual cycle retinoids from oxidative degradation, while α-tocopherol may play a substantial role in the protection of retinaldehyde but is relatively inefficient in the protection of retinol or retinyl palmitate. While the protection of retinoids by lutein and zeaxanthin appears inefficient in the retinal periphery, it can be quite substantial in the macula. Although the determined rate constants of scavenging the cation radicals of retinol and retinaldehyde by dopa-melanin are relatively small, the high concentration of melanin in the RPE melanosomes suggests they can be scavenged if they are in proximity to melanin-containing pigment granules., Competing Interests: The authors declare no conflicts. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Published
2023
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44. Scavenging of Retinoid Cation Radicals by Urate, Trolox, and α-, β-, γ-, and δ-Tocopherols.

Author

Rozanowska M, Edge R, Land EJ, Navaratnam S, Sarna T, and Truscott TG

Subjects
Cations chemistry, Chromans chemistry, Free Radical Scavengers chemistry, Retinoids chemistry, Tocopherols chemistry, Uric Acid chemistry
Abstract

Retinoids are present in human tissues exposed to light and under increased risk of oxidative stress, such as the retina and skin. Retinoid cation radicals can be formed as a result of the interaction between retinoids and other radicals or photoexcitation with light. It has been shown that such semi-oxidized retinoids can oxidize certain amino acids and proteins, and that α-tocopherol can scavenge the cation radicals of retinol and retinoic acid. The aim of this study was to determine (i) whether β-, γ-, and δ-tocopherols can also scavenge these radicals, and (ii) whether tocopherols can scavenge the cation radicals of another form of vitamin A-retinal. The retinoid cation radicals were generated by the pulse radiolysis of benzene or aqueous solution in the presence of a selected retinoid under oxidizing conditions, and the kinetics of retinoid cation radical decays were measured in the absence and presence of different tocopherols, Trolox or urate. The bimolecular rate constants are the highest for the scavenging of cation radicals of retinal, (7 to 8) × 10 9 M -1 ·s -1 , followed by retinoic acid, (0.03 to 5.6) × 10 9 M -1 ·s -1 , and retinol, (0.08 to 1.6) × 10 8 M -1 ·s -1 . Delta-tocopherol is the least effective scavenger of semi-oxidized retinol and retinoic acid. The hydrophilic analogue of α-tocopherol, Trolox, is substantially less efficient at scavenging retinoid cation radicals than α-tocopherol and urate, but it is more efficient at scavenging the cation radicals of retinoic acid and retinol than δ-tocopherol. The scavenging rate constants indicate that tocopherols can effectively compete with amino acids and proteins for retinoid cation radicals, thereby protecting these important biomolecules from oxidation. Our results provide another mechanism by which tocopherols can diminish the oxidative damage to the skin and retina and thereby protect from skin photosensitivity and the development and/or progression of changes in blinding retinal diseases such as Stargardt's disease and age-related macular degeneration (AMD)., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Published
2019
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45. The photoreactivity of ocular lipofuscin.

Author

Boulton M, Rozanowska M, Rozanowski B, and Wess T

Subjects
Eye Diseases etiology, Humans, Light, Lipofuscin physiology, Lipofuscin radiation effects, Retina chemistry, Lipofuscin chemistry, Photochemistry
Abstract

Lipofuscin or "age pigment" is a lipid-protein complex which accumulates in a variety of postmitotic, metabolically active cells throughout the body. These complexes, which are thought to result from the incomplete degradation of oxidised substrate, have the potential for photoreactivity. This is particularly so in the retina in which the lipofuscin not only contains retinoid metabolites but is also exposed to high oxygen and fluxes of visible light all of which provide an ideal environment for the generation of reactive oxygen species (ROS). Lipofuscin is a potent photoinducible generator of ROS with the potential to damage proteins, lipids and DNA. Retinal cell dysfunction may be strongly associated with photoreactivity of lipofuscin and may contribute to age-related disease and vision loss.

Published
2004
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