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Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy

Year 2025, Volume: 15 Issue: 1, 175 - 181, 28.03.2025
https://doi.org/10.33808/clinexphealthsci.1550061

Abstract

Objective: The aim of this study was to investigate the anti-inflammatory and antioxidant effects of Escin molecule obtained from horse chestnut seed extract on retinal pigment epithelial cell lines (ARPE-19).
Methods: In this research, the ARPE-19 cell line, which is a commercially available retinal pigment epithelial cell line derived from the normal eyes of a 19-year-old male, was utilized. Escin was administered to the cells in varying concentrations of 100, 50, 10, 5, and 1 micromolar throughout a 48-hour timeframe. The IC50 concentration was subsequently determined through MTT cell viability assays. To determine cell migration, a wound healing assay was executed. To quantify MMP9 and AKT protein levels, analysis was conducted using Western blot. Additionally, the mRNA expression levels of EGF, EGFR, PDGF-β, PDGFβ-R, and HIF1A were analyzed using RT-PCR.
Results: Escin inhibited cell migration in RPE cells. Western blot analysis showed that escin decreased the levels of AKT and MMP9 proteins. Furthermore, it was found that the mRNA expression levels of PDGFß, PDGFβ-R, and HIF1A were suppressed following escin administration.
Conclusion: Escin has the potential to slow disease progression by suppressing cell migration in retinal pigment epithelial cells. With its anti-angiogenic properties, escin shows promise for developing new therapeutic approaches for the treatment of retinal diseases.

Ethical Statement

Since this is a cell culture study, ethical approval is not required according to relevant guidelines.

References

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  • Wilkinson C. P. Retinal detachment. Pathologic Myopia. 2021;347-356. https://doi.org/10.1007/978-3-030-74334-5_23
  • Fleckenstein M, Keenan TD, Guymer RH, Chakravarthy U, Schimitz-Valckenberg S, Klaver CC, Wong WT, Chew EY. Age-related macular degeneration. Nature reviews Disease primers. 2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2
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  • Lendzioszek M, Bryl A, Poppe E, Zorena K, Mrugacz M. Retinal Vein Occlusion–Background Knowledge and Foreground Knowledge Prospects—A Review. Journal of ClinicalMedicine. 2024;13(13):3950. https://doi.org/10.3390/jcm13133950
  • Idrees S, Sridhar J, Kuriyan AE. Proliferative Vitreoretinopathy: A Review. IntOphthalmolClin. 2019;59(1):221-240. https://doi.org/10.1097/IIO.0000000000000258
  • Kwon OW, Song JH, RohMI. Retinal detachment and proliferative vitreoretinopathy. Retinal Pharmaco therapeutics. 2016;55:154-162. https://doi.org/10.1159/000438972
  • Rogers SL, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY, . The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319.e1 https://doi.org/10.1016/j.ophtha.2009.07.017
  • Yue S, Wang T, Yang Y, Fan Y, Zhou L, Li M, Fu F. Lipopolysaccharide/D-galactosamine-induced acute liver injury could be attenuated by dopamine receptor agonist rotigotine via regulating NF-κB signaling pathway. Int Immunopharmacol. 2021;96:107798. https://doi.org/10.1016/j.intimp.2021.107798.
  • Zhang L, Chen X, Wu L, Li Y, Wang L, Zhao X, Zhao T, Zhang L, Yan Z, Wei G. Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve. J Ethnopharmacol. 2021 Mar 1;267:113503. https://doi.org/10.1016/j.jep.2020.113503.
  • Yang Y, Wang L, Yuan M, Yu Q, Fu F. Anti-Inflammatory and Gastroprotective Effects of Escin. Natural Product Communications. 2020;15(12). https://doi.org/10.1177/1934578X20982111
  • Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 2010; 141(1), 52-67. https://doi.org/10.1016/j.cell.2010.03.015
  • Caley MP, Martins VL, O'Toole EA. Metalloproteinases and wound healing. Advances in Wound Care. 2015;4(4):225-234. https://doi.org/10.1089/wound.2014.0581
  • Rundhaug JE. Matrix metalloproteinases and angiogenesis. Journal of Cellular and Molecular Medicine. 2005;9(2):267-285. https://doi.org/10.1111/j.1582-4934.2005.tb00355.x
  • Armstrong DG, Jude EB. (2002). The role of matrixmetallo proteinases in wound healing. Journal of the American Podiatric Medical Association. 2002;92(1):12-18. https://doi.org/10.7547/87507315-92-1-12
  • Fang J, Shing Y, Wiederschain D. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proceedings of the National Academy of Sciences. 2000;97(8), 3884-3889. https://doi.org/10.1073/pnas.97.8.3884
  • Han YP, Tuan TL, Wu H, Hughes M, Garner WL. TNF-α stimulates activation of pro-MMP2 in human skin through NF-(κ)B mediated induction of MT1-MMP. Journal of Cell Science. 2001;114(1), 131-139. https://doi.org/10.1242/jcs.114.1.131
  • Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Molecular CancerResearch. 2011;9(5), 259-270. https://doi.org/10.1158/1541-7786.MCR-05-0261
  • Yang S, Zhou J, Li D. Functions and Diseases of the Retinal Pigment Epithelium. Front Pharmacol. 2021;12:727870. https://doi.org/10.3389/fphar.2021.727870
  • Chaudhary R, Scott RA, Wallace G, Berry M, Logan A, Blanch RJ. Inflammatory and fibrogenic factors in proliferative vitreoretinopathy development. Translational vision science&technology. 2020;9(3):23-23. https://doi.org/10.1167/tvst.9.3.23
  • Kaczmarek R, Misiuk-Hojło M. Patomechanisms in proliferative vitreoretinopathy. Klinika Oczna. 2011;113(1-3):64-67. PMID: 21853955.
  • Du YH, Hirooka K, Miyamoto O, Bao YQ, Zhang B, An JB, Ma JX. . Retinoic acid suppresses the adhesion and migration of human retinal pigment epithelial cells. ExperimentalEyeResearch. 2013;109:22-30. https://doi.org/10.1016/j.exer.2013.01.006
  • Umazume K, Liu L, Scott PA, Fernandez de Castro JP, McDonald K, Kaplan HJ, Tamiya S. Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in theswine. Investigative ophthalmology&visual science. 2013;54(2):1150-1159. https://doi.org/10.1167/iovs.12-10418
  • Wang K, Jiang Y, Wang W, Ma J, Chen M. Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress. Biochem BiophysResCommun. 2015;468:541-547. https://doi.org/10.1016/j.bbrc.2015.10.117
  • Hollborn M, Stathopoulos C, Steffen A, Wiedemann P, Kohen L, Bringmann A. Positive feedback regulation between MMP-9 and VEGF in human RPE cells. InvestOphthalmolVisSci. 2007;48:4360-4367. https://doi.org/10.1167/iovs.06-1234
  • Sen S, Kasikci M. Low-dose rosmarinic acid and thymoquinone accelerate wound healing in retinal pigment epithelialcells. IntOphthalmol. 2023;43:3811-3821. https://doi.org/10.1007/s10792-023-02799-8
  • Wang XH, Xu B, LiuJT, Cui JR. Effect of β-escin sodium on proliferation, migration and apoptosis of endothelial cells. Vascular pharmacology. 2008;49(4-6):158-165. https://doi.org/10.1016/j.vph.2008.07.005
  • Zou X, Tang XY, Qu ZY, Sun ZW, Ji CF, Li, YJ, Guo SD. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: A review. International Journal of Biological Macromolecules. 2022;202:539-557. https://doi.org/10.1016/j.ijbiomac.2022.01.113
  • Keller S, Schmidt MH. EGFR and EGFRvIII promote angiogenesis and cell invasion in glioblastoma: combination therapies for an effective treatment. International journal of molecular sciences, 2017; 18(6), 1295. https://doi.org/10.3390/ijms18061295
  • Deng W, Huang K, Cui L, Niu Z, Ke D, Jiang L, Tang N, Zhong H, Lan Q, Xu F, Tang F. SN promote retinal pathological neovascularization through activation of EGFR, IR and IGF-1R. ExpEyeRes. 2024;15(250):110158. https://doi.org/10.1016/j.exer.2024.110158
  • Mudhar HS. A brief review of the histopathology of proliferative vitreoretinopathy (PVR). Eye. 2020;34(2):246-250. https://doi.org/10.1038/s41433-019-0724-4
  • Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, Adam V. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. Journal of hematology&oncology. 2022;15(1):77. https://doi.org/10.1186/s13045-022-01292-6
Year 2025, Volume: 15 Issue: 1, 175 - 181, 28.03.2025
https://doi.org/10.33808/clinexphealthsci.1550061

Abstract

References

  • Strauss O. Theretinal pigment epithelium in visualfunction. PhysiolRev. 2005;85(3):845-881. https://doi.org/10.1152/physrev.00021.2004
  • Wilkinson C. P. Retinal detachment. Pathologic Myopia. 2021;347-356. https://doi.org/10.1007/978-3-030-74334-5_23
  • Fleckenstein M, Keenan TD, Guymer RH, Chakravarthy U, Schimitz-Valckenberg S, Klaver CC, Wong WT, Chew EY. Age-related macular degeneration. Nature reviews Disease primers. 2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2
  • Amjad M, Gupta H, Anamika, Kumar R. (2024). DiabeticRetinopathy: CurrentUnderstanding, MechanismsandTreatmentStrategies. JournalforResearch in AppliedSciencesandBiotechnology. 2024;3(2):252-260. https://doi.org/10.55544/jrasb.3.2.42
  • Lendzioszek M, Bryl A, Poppe E, Zorena K, Mrugacz M. Retinal Vein Occlusion–Background Knowledge and Foreground Knowledge Prospects—A Review. Journal of ClinicalMedicine. 2024;13(13):3950. https://doi.org/10.3390/jcm13133950
  • Idrees S, Sridhar J, Kuriyan AE. Proliferative Vitreoretinopathy: A Review. IntOphthalmolClin. 2019;59(1):221-240. https://doi.org/10.1097/IIO.0000000000000258
  • Kwon OW, Song JH, RohMI. Retinal detachment and proliferative vitreoretinopathy. Retinal Pharmaco therapeutics. 2016;55:154-162. https://doi.org/10.1159/000438972
  • Rogers SL, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY, . The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology. 2010;117(2):313-319.e1 https://doi.org/10.1016/j.ophtha.2009.07.017
  • Yue S, Wang T, Yang Y, Fan Y, Zhou L, Li M, Fu F. Lipopolysaccharide/D-galactosamine-induced acute liver injury could be attenuated by dopamine receptor agonist rotigotine via regulating NF-κB signaling pathway. Int Immunopharmacol. 2021;96:107798. https://doi.org/10.1016/j.intimp.2021.107798.
  • Zhang L, Chen X, Wu L, Li Y, Wang L, Zhao X, Zhao T, Zhang L, Yan Z, Wei G. Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve. J Ethnopharmacol. 2021 Mar 1;267:113503. https://doi.org/10.1016/j.jep.2020.113503.
  • Yang Y, Wang L, Yuan M, Yu Q, Fu F. Anti-Inflammatory and Gastroprotective Effects of Escin. Natural Product Communications. 2020;15(12). https://doi.org/10.1177/1934578X20982111
  • Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 2010; 141(1), 52-67. https://doi.org/10.1016/j.cell.2010.03.015
  • Caley MP, Martins VL, O'Toole EA. Metalloproteinases and wound healing. Advances in Wound Care. 2015;4(4):225-234. https://doi.org/10.1089/wound.2014.0581
  • Rundhaug JE. Matrix metalloproteinases and angiogenesis. Journal of Cellular and Molecular Medicine. 2005;9(2):267-285. https://doi.org/10.1111/j.1582-4934.2005.tb00355.x
  • Armstrong DG, Jude EB. (2002). The role of matrixmetallo proteinases in wound healing. Journal of the American Podiatric Medical Association. 2002;92(1):12-18. https://doi.org/10.7547/87507315-92-1-12
  • Fang J, Shing Y, Wiederschain D. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proceedings of the National Academy of Sciences. 2000;97(8), 3884-3889. https://doi.org/10.1073/pnas.97.8.3884
  • Han YP, Tuan TL, Wu H, Hughes M, Garner WL. TNF-α stimulates activation of pro-MMP2 in human skin through NF-(κ)B mediated induction of MT1-MMP. Journal of Cell Science. 2001;114(1), 131-139. https://doi.org/10.1242/jcs.114.1.131
  • Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Molecular CancerResearch. 2011;9(5), 259-270. https://doi.org/10.1158/1541-7786.MCR-05-0261
  • Yang S, Zhou J, Li D. Functions and Diseases of the Retinal Pigment Epithelium. Front Pharmacol. 2021;12:727870. https://doi.org/10.3389/fphar.2021.727870
  • Chaudhary R, Scott RA, Wallace G, Berry M, Logan A, Blanch RJ. Inflammatory and fibrogenic factors in proliferative vitreoretinopathy development. Translational vision science&technology. 2020;9(3):23-23. https://doi.org/10.1167/tvst.9.3.23
  • Kaczmarek R, Misiuk-Hojło M. Patomechanisms in proliferative vitreoretinopathy. Klinika Oczna. 2011;113(1-3):64-67. PMID: 21853955.
  • Du YH, Hirooka K, Miyamoto O, Bao YQ, Zhang B, An JB, Ma JX. . Retinoic acid suppresses the adhesion and migration of human retinal pigment epithelial cells. ExperimentalEyeResearch. 2013;109:22-30. https://doi.org/10.1016/j.exer.2013.01.006
  • Umazume K, Liu L, Scott PA, Fernandez de Castro JP, McDonald K, Kaplan HJ, Tamiya S. Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in theswine. Investigative ophthalmology&visual science. 2013;54(2):1150-1159. https://doi.org/10.1167/iovs.12-10418
  • Wang K, Jiang Y, Wang W, Ma J, Chen M. Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress. Biochem BiophysResCommun. 2015;468:541-547. https://doi.org/10.1016/j.bbrc.2015.10.117
  • Hollborn M, Stathopoulos C, Steffen A, Wiedemann P, Kohen L, Bringmann A. Positive feedback regulation between MMP-9 and VEGF in human RPE cells. InvestOphthalmolVisSci. 2007;48:4360-4367. https://doi.org/10.1167/iovs.06-1234
  • Sen S, Kasikci M. Low-dose rosmarinic acid and thymoquinone accelerate wound healing in retinal pigment epithelialcells. IntOphthalmol. 2023;43:3811-3821. https://doi.org/10.1007/s10792-023-02799-8
  • Wang XH, Xu B, LiuJT, Cui JR. Effect of β-escin sodium on proliferation, migration and apoptosis of endothelial cells. Vascular pharmacology. 2008;49(4-6):158-165. https://doi.org/10.1016/j.vph.2008.07.005
  • Zou X, Tang XY, Qu ZY, Sun ZW, Ji CF, Li, YJ, Guo SD. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: A review. International Journal of Biological Macromolecules. 2022;202:539-557. https://doi.org/10.1016/j.ijbiomac.2022.01.113
  • Keller S, Schmidt MH. EGFR and EGFRvIII promote angiogenesis and cell invasion in glioblastoma: combination therapies for an effective treatment. International journal of molecular sciences, 2017; 18(6), 1295. https://doi.org/10.3390/ijms18061295
  • Deng W, Huang K, Cui L, Niu Z, Ke D, Jiang L, Tang N, Zhong H, Lan Q, Xu F, Tang F. SN promote retinal pathological neovascularization through activation of EGFR, IR and IGF-1R. ExpEyeRes. 2024;15(250):110158. https://doi.org/10.1016/j.exer.2024.110158
  • Mudhar HS. A brief review of the histopathology of proliferative vitreoretinopathy (PVR). Eye. 2020;34(2):246-250. https://doi.org/10.1038/s41433-019-0724-4
  • Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, Adam V. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. Journal of hematology&oncology. 2022;15(1):77. https://doi.org/10.1186/s13045-022-01292-6
There are 32 citations in total.

Details

Primary Language English
Subjects Vision Science, Regenerative Medicine (Incl. Stem Cells)
Journal Section Articles
Authors

Serkan Şen 0000-0002-2884-4753

Murat Kaşıkcı 0000-0002-2748-9702

Sabahattin Sül 0000-0003-4812-7636

Ozan Tekin 0000-0002-8339-0571

Early Pub Date March 23, 2025
Publication Date March 28, 2025
Submission Date September 14, 2024
Acceptance Date January 20, 2025
Published in Issue Year 2025 Volume: 15 Issue: 1

Cite

APA Şen, S., Kaşıkcı, M., Sül, S., Tekin, O. (2025). Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy. Clinical and Experimental Health Sciences, 15(1), 175-181. https://doi.org/10.33808/clinexphealthsci.1550061
AMA Şen S, Kaşıkcı M, Sül S, Tekin O. Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy. Clinical and Experimental Health Sciences. March 2025;15(1):175-181. doi:10.33808/clinexphealthsci.1550061
Chicago Şen, Serkan, Murat Kaşıkcı, Sabahattin Sül, and Ozan Tekin. “Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy”. Clinical and Experimental Health Sciences 15, no. 1 (March 2025): 175-81. https://doi.org/10.33808/clinexphealthsci.1550061.
EndNote Şen S, Kaşıkcı M, Sül S, Tekin O (March 1, 2025) Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy. Clinical and Experimental Health Sciences 15 1 175–181.
IEEE S. Şen, M. Kaşıkcı, S. Sül, and O. Tekin, “Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy”, Clinical and Experimental Health Sciences, vol. 15, no. 1, pp. 175–181, 2025, doi: 10.33808/clinexphealthsci.1550061.
ISNAD Şen, Serkan et al. “Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy”. Clinical and Experimental Health Sciences 15/1 (March 2025), 175-181. https://doi.org/10.33808/clinexphealthsci.1550061.
JAMA Şen S, Kaşıkcı M, Sül S, Tekin O. Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy. Clinical and Experimental Health Sciences. 2025;15:175–181.
MLA Şen, Serkan et al. “Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy”. Clinical and Experimental Health Sciences, vol. 15, no. 1, 2025, pp. 175-81, doi:10.33808/clinexphealthsci.1550061.
Vancouver Şen S, Kaşıkcı M, Sül S, Tekin O. Modulation of MMP9 and AKT by Escin in Retinal Pigment Epithelial Cells: Exploring Novel Therapeutic Approaches for Proliferative Vitreoretinopathy. Clinical and Experimental Health Sciences. 2025;15(1):175-81.

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