Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats
Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that...
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| description | Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.
Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed. |
| doi_str_mv | 10.1371/journal.pone.0018980 |
| format | Article |
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Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0018980</identifier><identifier>PMID: 21541328</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Administration, Oral ; Age ; Aldehyde reductase ; Aldose reductase ; Animal care ; Animal models ; Animals ; Antioxidants ; Antioxidants (Nutrients) ; Antioxidants - administration & dosage ; Antioxidants - chemistry ; Antioxidants - therapeutic use ; Body Weight - drug effects ; Cataract - complications ; Cataract - pathology ; Cataract - prevention & control ; Cataracts ; Cortex ; Cytokinins ; Dehydrogenases ; Delay ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 1 - complications ; Diabetes Mellitus, Type 1 - pathology ; Disease Progression ; Endoplasmic reticulum ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - pathology ; Fluorenes - pharmacology ; Free radicals ; Gamma Rays ; Health care ; Heat-Shock Proteins - metabolism ; Humans ; Hydantoins - pharmacology ; Hydrogen peroxide ; Hyperglycemia ; Hyperglycemia - complications ; Hyperglycemia - pathology ; Iron ; Irradiation ; Laboratory animals ; Lens Capsule, Crystalline - drug effects ; Lens Capsule, Crystalline - pathology ; Lenses ; Medicine ; Metals ; Monosaccharides ; Ophthalmology ; Oxidative stress ; Pharmaceutical sciences ; Pigmentation - drug effects ; Proteins ; Radiation ; Radiation effects ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; Rodents ; Sorbitol ; Streptozocin ; Stress, Physiological - drug effects ; Sugar ; Sulfonamides ; Western blotting ; Xylose ; γ Radiation</subject><ispartof>PloS one, 2011-04, Vol.6 (4), p.e18980</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Randazzo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Randazzo et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-6c0fbb6c950eeeeee35bf151cd754cbbd970c9352c21d457d3a1402dc11dd4263</citedby><cites>FETCH-LOGICAL-c592t-6c0fbb6c950eeeeee35bf151cd754cbbd970c9352c21d457d3a1402dc11dd4263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082543/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082543/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21541328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Randazzo, James</creatorcontrib><creatorcontrib>Zhang, Peng</creatorcontrib><creatorcontrib>Makita, Jun</creatorcontrib><creatorcontrib>Blessing, Karen</creatorcontrib><creatorcontrib>Kador, Peter F</creatorcontrib><title>Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.
Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.</description><subject>Administration, Oral</subject><subject>Age</subject><subject>Aldehyde reductase</subject><subject>Aldose reductase</subject><subject>Animal care</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Antioxidants (Nutrients)</subject><subject>Antioxidants - administration & dosage</subject><subject>Antioxidants - chemistry</subject><subject>Antioxidants - therapeutic use</subject><subject>Body Weight - drug effects</subject><subject>Cataract - complications</subject><subject>Cataract - pathology</subject><subject>Cataract - prevention & control</subject><subject>Cataracts</subject><subject>Cortex</subject><subject>Cytokinins</subject><subject>Dehydrogenases</subject><subject>Delay</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 1 - complications</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>Disease Progression</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - pathology</subject><subject>Fluorenes - pharmacology</subject><subject>Free radicals</subject><subject>Gamma Rays</subject><subject>Health care</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Hydantoins - pharmacology</subject><subject>Hydrogen peroxide</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - complications</subject><subject>Hyperglycemia - pathology</subject><subject>Iron</subject><subject>Irradiation</subject><subject>Laboratory animals</subject><subject>Lens Capsule, Crystalline - drug effects</subject><subject>Lens Capsule, Crystalline - pathology</subject><subject>Lenses</subject><subject>Medicine</subject><subject>Metals</subject><subject>Monosaccharides</subject><subject>Ophthalmology</subject><subject>Oxidative stress</subject><subject>Pharmaceutical sciences</subject><subject>Pigmentation - drug effects</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Radiation effects</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Sorbitol</subject><subject>Streptozocin</subject><subject>Stress, Physiological - drug effects</subject><subject>Sugar</subject><subject>Sulfonamides</subject><subject>Western blotting</subject><subject>Xylose</subject><subject>γ Radiation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uktv1DAQjhCIlsI_QGCJCxyy-J3kUqmqeFSq1AucrfEji1dJvNhOxXLkl-PtplVXAvswD3_zeWb0VdVrgleENeTjJsxxgmG1DZNbYUzarsVPqlPSMVpLitnTR_5J9SKlDcaCtVI-r04oEZww2p5Wf24iDMMOgcn-1qFxHrKv-3kqYSjsCKbi_PK22ISsG2CHDGSIBY_6EEfY45CfUMrRbXP4HXIwJXyfd1uHyAdkPWiXvSlMFq1hHKH2MUJJZ2dRhJxeVs96GJJ7tdiz6vvnT98uv9bXN1-uLi-uayM6mmtpcK-1NJ3A7u4woXsiiLGN4EZr2zXYdExQQ4nlorEMCMfUGkKs5VSys-rtgXc7hKSW9SVFaCel6FrRFsTVAWEDbNQ2-hHiTgXw6i4R4lpBLLMMTnXWMcc10Q4aDoJrsJbKhje8x4ayPdf58tusR2eNm3LZ9BHp8cvkf6h1uFUMt1RwVgjeLQQx_Jxdyv9peUGtoXTlpz4UMjP6ZNQFb2TbFamQglr9A1WudaM3RUC9L_mjAn4oMDGkFF3_0DjBai-_-2bUXn5qkV8pe_N46Ieie72xv0mp21E</recordid><startdate>20110426</startdate><enddate>20110426</enddate><creator>Randazzo, James</creator><creator>Zhang, Peng</creator><creator>Makita, Jun</creator><creator>Blessing, Karen</creator><creator>Kador, Peter F</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110426</creationdate><title>Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats</title><author>Randazzo, James ; Zhang, Peng ; Makita, Jun ; Blessing, Karen ; Kador, Peter F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-6c0fbb6c950eeeeee35bf151cd754cbbd970c9352c21d457d3a1402dc11dd4263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Age</topic><topic>Aldehyde reductase</topic><topic>Aldose reductase</topic><topic>Animal care</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Antioxidants - 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Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.
Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.
Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21541328</pmid><doi>10.1371/journal.pone.0018980</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-04, Vol.6 (4), p.e18980 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1296659858 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Administration, Oral Age Aldehyde reductase Aldose reductase Animal care Animal models Animals Antioxidants Antioxidants (Nutrients) Antioxidants - administration & dosage Antioxidants - chemistry Antioxidants - therapeutic use Body Weight - drug effects Cataract - complications Cataract - pathology Cataract - prevention & control Cataracts Cortex Cytokinins Dehydrogenases Delay Diabetes Diabetes mellitus Diabetes Mellitus, Type 1 - complications Diabetes Mellitus, Type 1 - pathology Disease Progression Endoplasmic reticulum Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - pathology Fluorenes - pharmacology Free radicals Gamma Rays Health care Heat-Shock Proteins - metabolism Humans Hydantoins - pharmacology Hydrogen peroxide Hyperglycemia Hyperglycemia - complications Hyperglycemia - pathology Iron Irradiation Laboratory animals Lens Capsule, Crystalline - drug effects Lens Capsule, Crystalline - pathology Lenses Medicine Metals Monosaccharides Ophthalmology Oxidative stress Pharmaceutical sciences Pigmentation - drug effects Proteins Radiation Radiation effects Rats Rats, Long-Evans Rats, Sprague-Dawley Rodents Sorbitol Streptozocin Stress, Physiological - drug effects Sugar Sulfonamides Western blotting Xylose γ Radiation |
| title | Orally active multi-functional antioxidants delay cataract formation in streptozotocin (type 1) diabetic and gamma-irradiated rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T18%3A22%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Orally%20active%20multi-functional%20antioxidants%20delay%20cataract%20formation%20in%20streptozotocin%20(type%201)%20diabetic%20and%20gamma-irradiated%20rats&rft.jtitle=PloS%20one&rft.au=Randazzo,%20James&rft.date=2011-04-26&rft.volume=6&rft.issue=4&rft.spage=e18980&rft.pages=e18980-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0018980&rft_dat=%3Cgale_plos_%3EA476893711%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1296659858&rft_id=info:pmid/21541328&rft_galeid=A476893711&rft_doaj_id=oai_doaj_org_article_9de3e4b1bea74a54badd267474f0c238&rfr_iscdi=true |