Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Activation of Heme Oxygenase-1 by Mangiferin in Human Retinal Pigment Epithelial Cells Contributes to Blocking Oxidative Damage

  • Cheol Park (Division of Basic Sciences, College of Liberal Studies, Dong-eui University) ;
  • Hee-Jae Cha (Department of Parasitology and Genetics, Kosin University College of Medicine) ;
  • Hyun Hwangbo (Anti-Aging Research Center, Dong-eui University) ;
  • EunJin Bang (Anti-Aging Research Center, Dong-eui University) ;
  • Heui-Soo Kim (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Seok Joong Yun (Department of Urology, Chungbuk National University College of Medicine) ;
  • Sung-Kwon Moon (Department of Food and Nutrition, Chung-Ang University) ;
  • Wun-Jae Kim (Department of Urology, Chungbuk National University College of Medicine) ;
  • Gi-Young Kim (Department of Marine Life Sciences, Jeju National University) ;
  • Seung-On Lee (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Jung-Hyun Shim (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Yung Hyun Choi (Anti-Aging Research Center, Dong-eui University)
  • Received : 2023.10.04
  • Accepted : 2023.11.07
  • Published : 2024.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Mangiferin is a kind of natural xanthone glycosides and is known to have various pharmacological activities. However, since the beneficial efficacy of this compound has not been reported in retinal pigment epithelial (RPE) cells, this study aimed to evaluate whether mangiferin could protect human RPE ARPE-19 cells from oxidative injury mimicked by hydrogen peroxide (H2O2). The results showed that mangiferin attenuated H2O2-induced cell viability reduction and DNA damage, while inhibiting reactive oxygen species (ROS) production and preserving diminished glutathione (GSH). Mangiferin also antagonized H2O2-induced inhibition of the expression and activity of antioxidant enzymes such as manganese superoxide dismutase and GSH peroxidase, which was associated with inhibition of mitochondrial ROS production. In addition, mangiferin protected ARPE-19 cells from H2O2-induced apoptosis by increasing the Bcl-2/Bax ratio, decreasing caspase-3 activation, and blocking poly(ADP-ribose) polymerase cleavage. Moreover, mangiferin suppressed the release of cytochrome c into the cytosol, which was achieved by interfering with mitochondrial membrane disruption. Furthermore, mangiferin increased the expression and activity of heme oxygenase-1 (HO-1) and nuclear factor-erythroid-2 related factor 2 (Nrf2). However, the inhibition of ROS production, cytoprotective and anti-apoptotic effects of mangiferin were significantly attenuated by the HO-1 inhibitor, indicating that mangiferin promoted Nrf2-mediated HO-1 activity to prevent ARPE-19 cells from oxidative injury. The results of this study suggest that mangiferin, as an Nrf2 activator, has potent ROS scavenging activity and may have the potential to protect oxidative stress-mediated ocular diseases.

Keywords

Acknowledgement

This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Korean government (2021R1A2C2009549) and an NRF grant from the Korean Government (MSIT) (2022R1A5A8033794).

References

  1. Agarwala, S., Rao, B. N., Mudholkar, K., Bhuwania, R. and Rao, B. S. S. (2012) Mangiferin, a dietary xanthone protects against mercury-induced toxicity in HepG2 cells. Environ. Toxicol. 27, 117-127. https://doi.org/10.1002/tox.20620
  2. Ahmadinejad, F., Geir Moller, S., Hashemzadeh-Chaleshtori, M., Bidkhori, G. and Jami, M. S. (2017) Molecular mechanisms behind free radical scavengers function against oxidative stress. Antioxidants (Basel) 6, 51.
  3. Al-Saeedi, F. J. (2021) Mangiferin protect oxidative stress against deoxynivalenol induced damages through Nrf2 signalling pathways in endothelial cells. Clin. Exp. Pharmacol. Physiol. 48, 389-400. https://doi.org/10.1111/1440-1681.13432
  4. Alberdi, E., Sanchez-Gomez, M. V., Ruiz, A., Cavaliere, F., Ortiz-Sanz, C., Quintela-Lopez, T., Capetillo-Zarate, E., Sole-Domenech, S. and Matute, C. (2018) Mangiferin and morin attenuate oxidative stress, mitochondrial dysfunction, and neurocytotoxicity, induced by amyloid b oligomers. Oxid. Med. Cell. Longev. 2018, 2856063.
  5. Bock, F. J. and Tait, S. W. G. (2020) Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 21, 85-100. https://doi.org/10.1038/s41580-019-0173-8
  6. Cao, M., Fan, B., Zhen, T., Das, A. and Wang, J. (2023) Ruthenium biochanin-A complex ameliorates lung carcinoma through the downregulation of the TGF-β/PPARγ/PI3K/TNF-α pathway in association with caspase-3-mediated apoptosis. Toxicol. Res. 39, 455-475. https://doi.org/10.1007/s43188-023-00177-1
  7. Chae, S., Piao, M. J., Kang, K. A., Zhang, R., Kim, K. C., Youn, U. J., Nam, K. W., Lee, J. H. and Hyun, J. W. (2011) Inhibition of matrix metalloproteinase-1 induced by oxidative stress in human keratinocytes by mangiferin isolated from Anemarrhena asphodeloides. Biosci. Biotechnol. Biochem. 75, 2321-2325. https://doi.org/10.1271/bbb.110465
  8. Choi, Y. H. (2023) Activation of Nrf2/HO-1 antioxidant signaling correlates with the preventive effect of loganin on oxidative injury in ARPE-19 human retinal pigment epithelial cells. Genes Genomics 45, 271-284. https://doi.org/10.1007/s13258-022-01302-4
  9. Clementi, M. E., Pizzoferrato, M., Bianchetti, G., Brancato, A., Sampaolese, B., Maulucci, G. and Tringali, G. (2022) Cytoprotective effect of idebenone through modulation of the intrinsic mitochondrial pathway of apoptosis in human retinal pigment epithelial cells exposed to oxidative stress induced by hydrogen peroxide. Biomedicines 10, 503.
  10. Cordelli, E., Bignami, M. and Pacchierotti, F. (2021) Comet assay: a versatile but complex tool in genotoxicity testing. Toxicol. Res. (Camb.) 10, 68-78.
  11. Das, J., Ghosh, J., Roy, A. and Sil, P. C. (2012) Mangiferin exerts hepatoprotective activity against D-galactosamine induced acute toxicity and oxidative/nitrosative stress via Nrf2-NFκB pathways. Toxicol. Appl. Pharmacol. 260, 35-47. https://doi.org/10.1016/j.taap.2012.01.015
  12. Ding, L. Z., Teng, X., Zhang, Z. B., Zheng, C. J. and Chen, S. H. (2018) Mangiferin inhibits apoptosis and oxidative stress via BMP2/Smad-1 signaling in dexamethasone-induced MC3T3-E1 cells. Int. J. Mol. Med. 41, 2517-2526.
  13. Dutta, T., Das, T., Gopalakrishnan, A. V., Saha, S. C., Ghorai, M., Nandy, S., Kumar, M., Radha, Ghosh, A., Mukerjee, N. and Dey, A. (2023) Mangiferin: the miraculous xanthone with diverse pharmacological properties. Naunyn-Schmiedeberg's Arch. Pharmacol. 396, 851-863. https://doi.org/10.1007/s00210-022-02373-6
  14. Enns, G. M. and Cowan, T. M. (2017) Glutathione as a redox biomarker in mitochondrial disease-implications for therapy. J. Clin. Med. 6, 50.
  15. Gendy, A. M., El-Gazar, A. A., Ragab, G. M., Al-Mokaddem, A. K., ElHaddad, A. E., Selim, H. M. R. M., Yousef, E. M., Hamed, N. O. and Ibrahim, S. S. A. (2022) Possible implication of Nrf2, PPAR-γ and MAPKs signaling in the protective role of mangiferin against renal ischemia/reperfusion in rats. Pharmaceuticals (Basel) 16, 6.
  16. Hahm, J. Y., Park, J., Jang, E. S. and Chi, S. W. (2022) 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification. Exp. Mol. Med. 54, 1626-1642. https://doi.org/10.1038/s12276-022-00822-z
  17. Hernandez, M., Recalde, S., Gonzalez-Zamora, J., Bilbao-Malave, V., Saenz de Viteri, M., Bezunartea, J., Moreno-Orduna, M., Belza, I., Barrio-Barrio, J., Fernandez-Robredo, P. and Garcia-Layana, A. (2021) Anti-inflammatory and anti-oxidative synergistic effect of vitamin D and nutritional complex on retinal pigment epithelial and endothelial cell lines against age-related macular degeneration. Nutrients 13, 1423.
  18. Hou, J., Zheng, D., Xiao, W., Li, D., Ma, J. and Hu, Y. (2018) Mangiferin enhanced autophagy via inhibiting mTORC1 pathway to prevent high glucose-induced cardiomyocyte injury. Front. Pharmacol. 9, 383.
  19. Jenkins, T. and Gouge, J. (2021) Nrf2 in cancer, detoxifying enzymes and cell death programs. Antioxidants (Basel) 10, 1030.
  20. Kanoi, R., Loachan, P., Das, S. and Rao, B. S. S. (2021) Mangiferin, a naturally occurring polyphenol, mitigates oxidative stress induced premature senescence in human dermal fibroblast cells. Mol. Biol. Rep. 48, 457-466. https://doi.org/10.1007/s11033-020-06074-2
  21. Kim, S. J., Sung, M. S., Heo, H., Lee, J. H. and Park, S. W. (2016) Mangiferin protects retinal ganglion cells in ischemic mouse retina via SIRT1. Curr. Eye Res. 41, 844-855. https://doi.org/10.3109/02713683.2015.1050736
  22. Kopp, B., Khoury, L. and Audebert, M. (2019) Validation of the γH2AX biomarker for genotoxicity assessment: a review. Arch. Toxicol. 93, 2103-2114. https://doi.org/10.1007/s00204-019-02511-9
  23. Lalier, L., Vallette, F. and Manon, S. (2022) Bcl-2 family members and the mitochondrial import machineries: the roads to death. Biomolecules 12, 162.
  24. Liu, M., Sun, X., Chen, B., Dai, R., Xi, Z. and Xu, H. (2022) Insights into manganese superoxide dismutase and human diseases. Int. J. Mol. Sci. 23, 15893.
  25. Liu, R., Liu, Z., Zhang, C. and Zhang, B. (2012) Nanostructured lipid carriers as novel ophthalmic delivery system for mangiferin: Improving in vivoocular bioavailability. J. Pharm. Sci. 101, 3833-3844. https://doi.org/10.1002/jps.23251
  26. Liu, X., Ward, K., Xavier, C., Jann, J., Clark, A. F., Pang, I. H. and Wu, H. (2016) The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation. Redox Biol. 8, 98-109. https://doi.org/10.1016/j.redox.2015.12.005
  27. Lou, M. F. (2022) Glutathione and glutaredoxin in redox regulation and cell signaling of the lens. Antioxidants (Basel) 11, 1973.
  28. Lum, P. T., Sekar, M., Gan, S. H., Jeyabalan, S., Bonam, S. R., Rani, N. N. I. M., Ku-Mahdzir, K. M., Seow, L. J., Wu, Y. S., Subramaniyan, V., Fuloria, N. K. and Fuloria, S. (2022) Therapeutic potential of mangiferin against kidney disorders and its mechanism of action: a review. Saudi J. Biol. Sci. 29, 1530-1542. https://doi.org/10.1016/j.sjbs.2021.11.016
  29. Mei, S., Perumal, M., Battino, M., Kitts, D. D., Xiao, J., Ma, H. and Chen, X. (2023) Mangiferin: a review of dietary sources, absorption, metabolism, bioavailability, and safety. Crit. Rev. Food Sci. Nutr. 63, 3046-3064. https://doi.org/10.1080/10408398.2021.1983767
  30. Mukherjee, S., Park, J. P. and Yun, J. W. (2022) Carboxylesterase3 (Ces3) interacts with bone morphogenetic protein 11 and promotes differentiation of osteoblasts via Smad1/5/9 pathway. Biotechnol. Bioprocess Eng. 27, 1-16. https://doi.org/10.1007/s12257-021-0133-y
  31. Munro, D. and Treberg, J. R. (2017) A radical shift in perspective: mitochondria as regulators of reactive oxygen species. J. Exp. Biol. 220, 1170-1180. https://doi.org/10.1242/jeb.132142
  32. Pal, P. B., Sinha, K. and Sil, P. C. (2014) Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFα related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats. PLoS One 9, e107220.
  33. Pal, P. B., Sinha, K. and Sil, P. C. (2013) Mangiferin, a natural xanthone, protects murine liver in Pb (II) induced hepatic damage and cell death via MAP kinase, NF-κB and mitochondria dependent pathways. PLoS One 8, e56894.
  34. Palma, F. R., He, C., Danes, J. M., Paviani, V., Coelho, D. R., Gantner, B. N. and Bonini, M. G. (2020) Mitochondrial superoxide dismutase: what the established, the intriguing, and the novel reveal about a key cellular redox switch. Antioxid. Redox Signal. 32, 701-714. https://doi.org/10.1089/ars.2019.7962
  35. Park, C., Cha, H. J., Song, K. S., Kim, H. S., Bang, E., Lee, H., Jin, C. Y., Kim, G. Y. and Choi, Y. H. (2023) Nrf2-mediated activation of HO-1 is required in the blocking effect of compound K, a ginseng saponin metabolite, against oxidative stress damage in ARPE-19 human retinal pigment epithelial cells. J. Ginseng Res. 47, 311-318. https://doi.org/10.1016/j.jgr.2022.09.007
  36. Park, C., Lee, H., Hong, S. H., Kim, J. H., Park, S. K., Jeong, J. W., Kim, G. Y., Hyun, J. W., Yun, S. J., Kim, B. W., Kim, W. J. and Choi, Y. H. (2019) Protective effect of diphlorethohydroxycarmalol against oxidative stress-induced DNA damage and apoptosis in retinal pigment epithelial cells. Cutan. Ocul. Toxicol. 38, 298-308. https://doi.org/10.1080/15569527.2019.1613425
  37. Park, C., Noh, J. S., Jung, Y., Leem, S. H., Hyun, J. W., Chang, Y. C., Kwon, T. K., Kim, G. Y., Lee, H. and Choi, Y. H. (2022) Fisetin attenuated oxidative stress-induced cellular damage in ARPE-19 human retinal pigment epithelial cells through Nrf2-mediated activation of heme oxygenase-1. Front. Pharmacol. 13, 927898.
  38. Pei, J., Pan, X., Wei, G. and Hua, Y. (2023) Research progress of glutathione peroxidase family (GPX) in redoxidation. Front. Pharmacol. 14, 1147414.
  39. Remali, J., Sahidin, I. and Aizat, W. M. (2022) Xanthone biosynthetic pathway in plants: a review. Front. Plant Sci. 13, 809497.
  40. Saha, S., Sadhukhan, P., Sinha, K., Agarwal, N. and Sil, P. C. (2016) Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways. Biochem. Biophys. Rep. 5, 313-327. https://doi.org/10.1016/j.bbrep.2016.01.011
  41. Savion, N., Dahamshi, S., Morein, M. and Kotev-Emeth, S. (2019) Sallylmercapro-N-acetylcysteine attenuates the oxidation-induced lens opacification and retinal pigment epithelial cell death in vitro. Antioxidants (Basel) 8, 25.
  42. Shaw, P. and Chattopadhyay, A. (2020) Nrf2-ARE signaling in cellular protection: mechanism of action and the regulatory mechanisms. J. Cell. Physiol. 235, 3119-3130. https://doi.org/10.1002/jcp.29219
  43. Tiwari, S., Dewry, R. K., Srivastava, R., Nath, S. and Mohanty, T. K. (2022) Targeted antioxidant delivery modulates mitochondrial functions, ameliorates oxidative stress and preserve sperm quality during cryopreservation. Theriogenology 179, 22-31. https://doi.org/10.1016/j.theriogenology.2021.11.013
  44. Tong, Y., Zhang, Z. and Wang, S. (2022) Role of mitochondria in retinal pigment epithelial aging and degeneration. Front. Aging 3, 926627.
  45. Walia, V., Chaudhary, S. K. and Kumar Sethiya, N. (2021) Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders. Neurochem. Int. 143, 104939.
  46. Wang, J., Li, M., Geng, Z., Khattak, S., Ji, X., Wu, D. and Dang, Y. (2022a) Role of oxidative stress in retinal disease and the early intervention strategies: a review. Oxid. Med. Cell. Longev. 2022, 7836828.
  47. Wang, M., Liang, Y., Chen, K., Wang, M., Long, X., Liu, H., Sun, Y. and He, B. (2022b) The management of diabetes mellitus by mangiferin: advances and prospects. Nanoscale 14, 2119-2135. https://doi.org/10.1039/D1NR06690K
  48. Xu, G. K., Sun, C. Y., Qin, X. Y., Han, Y., Li, Y., Xie, G. Y. and Min-Jian, Q. (2017) Effects of ethanol extract of Bombax ceiba leaves and its main constituent mangiferin on diabetic nephropathy in mice. Chin. J. Nat. Med. 15, 597-605.
  49. Yan, J., Jiang, J., He, L. and Chen, L. (2020) Mitochondrial superoxide/ hydrogen peroxide: an emerging therapeutic target for metabolic diseases. Free Radic. Biol. Med. 152, 33-42. https://doi.org/10.1016/j.freeradbiomed.2020.02.029
  50. Yu, Z. Y., Ma, D., He, Z. C., Liu, P., Huang, J., Fang, Q., Zhao, J. Y. and Wang, J. S. (2018) Heme oxygenase-1 protects bone marrow mesenchymal stem cells from iron overload through decreasing reactive oxygen species and promoting IL-10 generation. Exp. Cell Res. 362, 28-42. https://doi.org/10.1016/j.yexcr.2017.10.029
  51. Zhang, S. M., Fan, B., Li, Y. L., Zuo, Z. Y. and Li, G. Y. (2023) Oxidative stress-involved mitophagy of retinal pigment epithelium and retinal degenerative diseases. Cell. Mol. Neurobiol. 43, 3265-3276. https://doi.org/10.1007/s10571-023-01383-z
  52. Zhou, H., Mao, Z., Zhang, X., Li, R., Yin, J. and Xu, Y. (2023) Neuroprotective effect of mangiferin against Parkinson's disease through G-protein-coupled receptor-interacting protein 1 (GIT1)-mediated antioxidant defense. ACS Chem. Neurosci. 14, 1379-1387.