The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence
Human skin plays an important role protecting the body from both extrinsic and intrinsic factors. Skin aging at cellular level, which is a consequence of accumulation of irreparable senescent keratinocytes is associated with chronological aging. However, cell senescence may occur independent of chro...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Aging |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fragi.2024.1466281/full |
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| author | Gautham Yepuri Kushie Kancharla Riccardo Perfetti Shoshana Shendelman Andrew Wasmuth Ravichandran Ramasamy |
| author_facet | Gautham Yepuri Kushie Kancharla Riccardo Perfetti Shoshana Shendelman Andrew Wasmuth Ravichandran Ramasamy |
| author_sort | Gautham Yepuri |
| collection | DOAJ |
| description | Human skin plays an important role protecting the body from both extrinsic and intrinsic factors. Skin aging at cellular level, which is a consequence of accumulation of irreparable senescent keratinocytes is associated with chronological aging. However, cell senescence may occur independent of chronological aging and it may be accelerated by various pathological conditions. Recent studies have shown that oxidative stress driven keratinocyte senescence is linked to the rate limiting polyol pathway enzyme aldose reductase (AR). Here we investigated the role of three novel synthetic AR inhibitors (ARIs) AT-001, AT-003 and AT-007 in attenuating induced skin cell senescence, in primary normal human keratinocytes (NHK cells), using three different senescence inducing agents: high glucose (HG), hydrogen peroxide (H2O2) and mitomycin-c (MMC). To understand the efficacy of ARIs in reducing senescence, we have assessed markers of senescence, including SA-β-galactosidase activity, γ-H2AX foci, gene expression of CDKN1A, TP53 and SERPINE1, reactive oxygen species generation and senescence associated secretory phenotypes (SASP). Strikingly, all three ARIs significantly inhibited the assessed senescent markers, after senescence induction. Our data confirms the potential role of ARIs in reducing NHK cell senescence and paves the way for preclinical and clinical testing of these ARIs in attenuating cell aging and aging associated diseases. |
| format | Article |
| id | doaj-art-944e700d6cb44a0ebe3d909505774c1b |
| institution | Kabale University |
| issn | 2673-6217 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging |
| spelling | doaj-art-944e700d6cb44a0ebe3d909505774c1b2024-12-17T06:23:38ZengFrontiers Media S.A.Frontiers in Aging2673-62172024-12-01510.3389/fragi.2024.14662811466281The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescenceGautham Yepuri0Kushie Kancharla1Riccardo Perfetti2Shoshana Shendelman3Andrew Wasmuth4Ravichandran Ramasamy5Diabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, United StatesDiabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, United StatesApplied Therapeutics Inc, New York, NY, United StatesApplied Therapeutics Inc, New York, NY, United StatesApplied Therapeutics Inc, New York, NY, United StatesDiabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, United StatesHuman skin plays an important role protecting the body from both extrinsic and intrinsic factors. Skin aging at cellular level, which is a consequence of accumulation of irreparable senescent keratinocytes is associated with chronological aging. However, cell senescence may occur independent of chronological aging and it may be accelerated by various pathological conditions. Recent studies have shown that oxidative stress driven keratinocyte senescence is linked to the rate limiting polyol pathway enzyme aldose reductase (AR). Here we investigated the role of three novel synthetic AR inhibitors (ARIs) AT-001, AT-003 and AT-007 in attenuating induced skin cell senescence, in primary normal human keratinocytes (NHK cells), using three different senescence inducing agents: high glucose (HG), hydrogen peroxide (H2O2) and mitomycin-c (MMC). To understand the efficacy of ARIs in reducing senescence, we have assessed markers of senescence, including SA-β-galactosidase activity, γ-H2AX foci, gene expression of CDKN1A, TP53 and SERPINE1, reactive oxygen species generation and senescence associated secretory phenotypes (SASP). Strikingly, all three ARIs significantly inhibited the assessed senescent markers, after senescence induction. Our data confirms the potential role of ARIs in reducing NHK cell senescence and paves the way for preclinical and clinical testing of these ARIs in attenuating cell aging and aging associated diseases.https://www.frontiersin.org/articles/10.3389/fragi.2024.1466281/fullaldose reductasealdose reductase inhibitorsskin cell agingsenescenceoxidative stress |
| spellingShingle | Gautham Yepuri Kushie Kancharla Riccardo Perfetti Shoshana Shendelman Andrew Wasmuth Ravichandran Ramasamy The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence Frontiers in Aging aldose reductase aldose reductase inhibitors skin cell aging senescence oxidative stress |
| title | The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence |
| title_full | The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence |
| title_fullStr | The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence |
| title_full_unstemmed | The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence |
| title_short | The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence |
| title_sort | aldose reductase inhibitors at 001 at 003 and at 007 attenuate human keratinocyte senescence |
| topic | aldose reductase aldose reductase inhibitors skin cell aging senescence oxidative stress |
| url | https://www.frontiersin.org/articles/10.3389/fragi.2024.1466281/full |
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