896dd15d3f8cc17e960ba891bd6942f4 pmc_9312245.pdf 335029405b23b9f00bf2edcc6759272b5bb47874 pmc_9312245.pdf 255fb4c1a245f1b60ae4ef9edd324cef0ed5e2aa675e785e110a565049dc3901 pmc_9312245.pdf Title: Antioxidant Effects of DPP-4 Inhibitors in Early Stages of Experimental Diabetic Retinopathy Subject: Hyperglycemia-induced oxidative stress plays a key role in the impairment of the retinal neurovascular unit, an early event in the pathogenesis of DR. The aim of this study was to assess the antioxidant properties of topical administration (eye drops) of sitagliptin in the diabetic retina. For this purpose, db/db mice received sitagliptin or vehicle eye drops twice per day for two weeks. Age-matched db/+ mice were used as the control group. We evaluated retinal mRNA (RT-PCR) and protein levels (Western blotting and immunohistochemistry) of different components from both the antioxidant system (NRF2, CAT, GPX, GR, CuZnSOD, and MnSOD) and the prooxidant machinery (PKC and TXNIP). We also studied superoxide levels (dihydroethidium staining) and oxidative damage to DNA/RNA (8-hydroxyguanosine immunostaining) and proteins (nitrotyrosine immunostaining). Finally, NF-кB translocation and IL-1 production were assessed through Western blotting and/or immunohistochemistry. We found that sitagliptin protected against diabetes-induced oxidative stress by reducing superoxide, TXNIP, PKC, and DNA/RNA/protein oxidative damage, and it prevented the downregulation of NRF2 and antioxidant enzymes, with the exception of catalase. Sitagliptin also exerted anti-inflammatory effects, avoiding both NF-кB translocation and IL-1 production. Sitagliptin prevents the diabetes-induced imbalance between ROS production and antioxidant defenses that occurs in diabetic retinas. Keywords: diabetes; diabetic retinopathy; sitagliptin; dipeptidyl peptidase-4; DPP-4 inhibitors; oxidative stress; antioxidant; NRF2 Author: Hugo Ramos, Patricia Bogdanov, Jordi Huerta, Anna Deàs-Just, Cristina Hernández and Rafael Simó Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Jul 25 06:39:32 2022 CEST ModDate: Mon Jul 25 07:51:31 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 8333297 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NEBEKD+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 QFTAYQ+SFRM0900 Type 1 Custom yes yes no 15 0 DUYSTG+EURM10 Type 1 Builtin yes yes no 20 0 TWLFUU+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 QGRSOL+URWPalladioL-Roma Type 1 Custom yes yes no 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2023-05-18) Date: 2024-05-17 03:29:32 CEST RepresentationInformation: pmc_9312245.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-05-17 02:37:41 CEST Size: 8333297 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 504 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Animals Destination: subsection.2.1 Item: Title: Topical Ocular Treatment Destination: subsection.2.2 Item: Title: Retinal Tissue Processing Destination: subsection.2.3 Item: Title: RNA Isolation and Quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) Assay Destination: subsection.2.4 Item: Title: Western Blotting Destination: subsection.2.5 Item: Title: Immunofluorescence Analysis Destination: subsection.2.6 Item: Title: Statistical Analysis Destination: subsection.2.7 Item: Title: Results Destination: section.3 Children: Item: Title: Body Weight and Systemic Blood Glucose Levels of db/db Mice Not Modified after Topical Ocular Administration of Sitagliptin Destination: subsection.3.1 Item: Title: Sitagliptin Eye Drops Prevented the Antioxidant Deficiencies of the Diabetic Retina Destination: subsection.3.2 Item: Title: Topical Administration of Sitagliptin Reduced the Aberrant Levels of Superoxide and Their Consequent Oxidative Damage to Biological Macromolecules in Diabetic Retinas Destination: subsection.3.3 Item: Title: High PKC Presence in Diabetic Retinas was Reduced by Topical Treatment with Sitagliptin Destination: subsection.3.4 Item: Title: Sitagliptin Exhibited Anti-Inflammatory Properties When Administered Topically in Diabetic Retinas Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Antioxidant Effects of DPP-4 Inhibitors in Early Stages of Experimental Diabetic Retinopathy Author: Hugo Ramos, Patricia Bogdanov, Jordi Huerta, Anna Deàs-Just, Cristina Hernández and Rafael Simó Subject: えべばづひでぬべっづねどち〭どのつふっづつ〠はへどつちぴどぶづ〠びぴひづびび〠ばぬちべび〠ち〠にづべ〠ひはぬづ〠どの〠ぴとづ〠どねばちどひねづのぴ〠はて〠ぴとづ〠ひづぴどのちぬ〠のづふひはぶちびっふぬちひ〠ふのどぴ〬〠ちの〠づちひぬべ〠づぶづのぴ〠どの〠ぴとづ〠ばちぴとはでづのづびどび〠はて〠いげ〮〠ごとづ〠ちどね〠はて〠ぴとどび〠びぴふつべ〠ぷちび〠ぴは〠ちびびづびび〠ぴとづ〠ちのぴどはへどつちのぴ〠ばひはばづひぴどづび〠はて〠ぴはばどっちぬ〠ちつねどのどびぴひちぴどはの〠〨づべづ〠つひはばび〩〠はて〠びどぴちでぬどばぴどの〠どの〠ぴとづ〠つどちぢづぴどっ〠ひづぴどのち〮〠うはひ〠ぴとどび〠ばふひばはびづ〬〠つぢ〯つぢ〠ねどっづ〠ひづっづどぶづつ〠びどぴちでぬどばぴどの〠はひ〠ぶづとどっぬづ〠づべづ〠つひはばび〠ぴぷどっづ〠ばづひ〠つちべ〠てはひ〠ぴぷは〠ぷづづにび〮〠ぁでづ〭ねちぴっとづつ〠つぢ〯〫〠ねどっづ〠ぷづひづ〠ふびづつ〠ちび〠ぴとづ〠っはのぴひはぬ〠でひはふば〮〠しづ〠づぶちぬふちぴづつ〠ひづぴどのちぬ〠ねげぎぁ〠〨げご〭ぐぃげ〩〠ちのつ〠ばひはぴづどの〠ぬづぶづぬび〠〨しづびぴづひの〠ぢぬはぴぴどので〠ちのつ〠どねねふのはとどびぴはっとづねどびぴひべ〩〠はて〠つどててづひづのぴ〠っはねばはのづのぴび〠てひはね〠ぢはぴと〠ぴとづ〠ちのぴどはへどつちのぴ〠びべびぴづね〠〨ぎげう〲〬〠ぃぁご〬〠ぇぐじ〬〠ぇげ〬〠ぃふずのこくい〬〠ちのつ〠きのこくい〩〠ちのつ〠ぴとづ〠ばひははへどつちのぴ〠ねちっとどのづひべ〠〨ぐかぃ〠ちのつ〠ごじぎぉぐ〩〮〠しづ〠ちぬびは〠びぴふつどづつ〠びふばづひはへどつづ〠ぬづぶづぬび〠〨つどとべつひはづぴとどつどふね〠びぴちどのどので〩〠ちのつ〠はへどつちぴどぶづ〠つちねちでづ〠ぴは〠いぎぁ〯げぎぁ〠〨〸〭とべつひはへべでふちのはびどのづ〠どねねふのはびぴちどのどので〩〠ちのつ〠ばひはぴづどのび〠〨のどぴひはぴべひはびどのづ〠どねねふのはびぴちどのどので〩〮〠うどのちぬぬべ〬〠ぎう〭㐺あ〠ぴひちのびぬはっちぴどはの〠ちのつ〠ぉが〭〱〠ばひはつふっぴどはの〠ぷづひづ〠ちびびづびびづつ〠ぴとひはふでと〠しづびぴづひの〠ぢぬはぴぴどので〠ちのつ〯はひ〠どねねふのはとどびぴはっとづねどびぴひべ〮〠しづ〠てはふのつ〠ぴとちぴ〠びどぴちでぬどばぴどの〠ばひはぴづっぴづつ〠ちでちどのびぴ〠つどちぢづぴづび〭どのつふっづつ〠はへどつちぴどぶづ〠びぴひづびび〠ぢべ〠ひづつふっどので〠びふばづひはへどつづ〬〠ごじぎぉぐ〬〠ぐかぃ〬〠ちのつ〠いぎぁ〯げぎぁ〯ばひはぴづどの〠はへどつちぴどぶづ〠つちねちでづ〬〠ちのつ〠どぴ〠ばひづぶづのぴづつ〠ぴとづ〠つはぷのひづでふぬちぴどはの〠はて〠ぎげう〲〠ちのつ〠ちのぴどはへどつちのぴ〠づのぺべねづび〬〠ぷどぴと〠ぴとづ〠づへっづばぴどはの〠はて〠っちぴちぬちびづ〮〠こどぴちでぬどばぴどの〠ちぬびは〠づへづひぴづつ〠ちのぴど〭どのてぬちねねちぴはひべ〠づててづっぴび〬〠ちぶはどつどので〠ぢはぴと〠ぎう〭㐺あ〠ぴひちのびぬはっちぴどはの〠ちのつ〠ぉが〭〱〠ばひはつふっぴどはの〮〠こどぴちでぬどばぴどの〠ばひづぶづのぴび〠ぴとづ〠つどちぢづぴづび〭どのつふっづつ〠どねぢちぬちのっづ〠ぢづぴぷづづの〠げくこ〠ばひはつふっぴどはの〠ちのつ〠ちのぴどはへどつちのぴ〠つづてづのびづび〠ぴとちぴ〠はっっふひび〠どの〠つどちぢづぴどっ〠ひづぴどのちび〮 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