Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

The potential inhibitory effect of ginsenoside Rh2 on mitophagy in UV-irradiated human dermal fibroblasts

  • Lee, Hyunji (Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University) ;
  • Kong, Gyeyeong (Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University) ;
  • Park, Jisoo (Department of Life Science, Hyehwa Liberal Arts College, Daejeon University) ;
  • Park, Jongsun (Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University)
  • Received : 2022.01.04
  • Accepted : 2022.02.03
  • Published : 2022.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: In addition to its use as a health food, ginseng is used in cosmetics and shampoo because of its extensive health benefits. The ginsenoside, Rh2, is a component of ginseng that inhibits tumor cell proliferation and differentiation, promotes insulin secretion, improves insulin sensitivity, and shows antioxidant effects. Methods: The effects of Rh2 on cell survival, extracellular matrix (ECM) protein expression, and cell differentiation were examined. The antioxidant effects of Rh2 in UV-irradiated normal human dermal fibroblast (NHDF) cells were also examined. The effects of Rh2 on mitochondrial function, morphology, and mitophagy were investigated in UV-irradiated NHDF cells. Results: Rh2 treatment promoted the proliferation of NHDF cells. Additionally, Rh2 increased the expression levels of ECM proteins and growth-associated immediate-early genes in ultraviolet (UV)-irradiated NHDF cells. Rh2 also affected antioxidant protein expression and increased total antioxidant capacity. Furthermore, treatment with Rh2 ameliorated the changes in mitochondrial morphology, induced the recovery of mitochondrial function, and inhibited the initiation of mitophagy in UV-irradiated NHDF cells. Conclusion: Rh2 inhibits mitophagy and reinstates mitochondrial ATP production and membrane potential in NHDF cells damaged by UV exposure, leading to the recovery of ECM, cell proliferation, and antioxidant capacity.

Keywords

Acknowledgement

This work was supported by a grant from the Korean Society of Ginseng, Seoul, Korea, received in 2020. These studies were financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (NRF-2021R1A2C1008492, NRF-2020R1F1A1049801, NRF-2021R1C1C200845611) and by a research fund 2020 from Chungnam National University (grant to J. Park). The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http:// www.textcheck.com/certificate/e68aUv.

References

  1. Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer 1997;73(2):198-203. https://doi.org/10.1002/(SICI)1097-0215(19971009)73:2<198::AID-IJC6>3.0.CO;2-R
  2. Fernandez-Garcia E. Photoprotection of human dermal fibroblasts against ultraviolet light by antioxidant combinations present in tomato. Food Funct 2014;5(2):285-90. https://doi.org/10.1039/C3FO60471C
  3. Bowman A, Birch-Machin MA. Mitochondrial DNA as a sensitive biomarker of UV-induced cellular damage in human skin. Methods Mol Biol 2021;2277:345-56. https://doi.org/10.1007/978-1-0716-1270-5_21
  4. Godar DE. UV and reactive oxygen species activate human papillomaviruses causing skin cancers. Curr Probl Dermatol 2021;55:339-53. https://doi.org/10.1159/000517643
  5. Kang W, et al. UV-irradiation- and inflammation-induced skin barrier dysfunction is associated with the expression of olfactory receptor genes in human keratinocytes. Int J Mol Sci 2021;22(6).
  6. Eckhart L, Zeeuwen P. The skin barrier: epidermis vs environment. Exp Dermatol 2018;27(8):805-6. https://doi.org/10.1111/exd.13731
  7. Kholmogorskaia OV, Ivanishchuk PP, Surakova TV. [Change in synthetic activity of epidermis cells in rats during burn wound healing under a scab and in liquid environment]. Tsitologiia 2005;47(5):388-92.
  8. Pratzel H, Fries P. [Modification of relative amount of free amino acids in the stratum corneum of human epidermis by special factors of the environment. I. The influence of UV-irradiation (author's transl)]. Arch Dermatol Res 1977;259(2):157-60. https://doi.org/10.1007/BF00557956
  9. Hideg E, Jansen MA, Strid A. UV-B exposure, ROS, and stress: inseparable companions or loosely linked associates? Trends Plant Sci 2013;18(2):107-15. https://doi.org/10.1016/j.tplants.2012.09.003
  10. Ma H, et al. Impact of solar UV radiation on toxicity of ZnO nanoparticles through photocatalytic reactive oxygen species (ROS) generation and photoinduced dissolution. Environ Pollut 2014;193:165-72. https://doi.org/10.1016/j.envpol.2014.06.027
  11. Yokawa K, Baluska F. Pectins, ROS homeostasis and UV-B responses in plant roots. Phytochemistry 2015;112:80-3. https://doi.org/10.1016/j.phytochem.2014.08.016
  12. Kuczler MD, et al. ROS-induced cell cycle arrest as a mechanism of resistance in polyaneuploid cancer cells (PACCs). Prog Biophys Mol Biol 2021;165:3-7. https://doi.org/10.1016/j.pbiomolbio.2021.05.002
  13. Sharma N, et al. Genomic dissection of ROS detoxifying enzyme encoding genes for their role in antioxidative defense mechanism against Tomato leaf curl New Delhi virus infection in tomato. Genomics 2021;113(3):889-99. https://doi.org/10.1016/j.ygeno.2021.01.022
  14. Sho T, Xu J. Role and mechanism of ROS scavengers in alleviating NLRP3- mediated inflammation. Biotechnol Appl Biochem 2019;66(1):4-13. https://doi.org/10.1002/bab.1700
  15. Song SB, Hwang ES. A rise in ATP, ROS, and mitochondrial content upon glucose withdrawal correlates with a dysregulated mitochondria turnover mediated by the activation of the protein deacetylase SIRT1. Cells 2018;8(1).
  16. Cui Y, et al. ROS-mediated mitophagy and apoptosis are involved in aluminum-induced femoral impairment in mice. Chem Biol Interact 2021;349:109663. https://doi.org/10.1016/j.cbi.2021.109663
  17. Dhar SK, Batinic-Haberle I, St Clair DK. UVB-induced inactivation of manganese-containing superoxide dismutase promotes mitophagy via ROSmediated mTORC2 pathway activation. J Biol Chem 2019;294(17):6831-42. https://doi.org/10.1074/jbc.RA118.006595
  18. Lin Q, et al. PINK1-parkin pathway of mitophagy protects against contrastinduced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol 2019;26:101254. https://doi.org/10.1016/j.redox.2019.101254
  19. Bian S, et al. Knockdown of p62/sequestosome enhances ginsenoside Rh2- induced apoptosis in cervical cancer HeLa cells with no effect on autophagy. Biosci Biotechnol Biochem 2021;85(5):1097-103. https://doi.org/10.1093/bbb/zbab019
  20. Ma J, et al. Reversal effect of ginsenoside Rh2 on oxaliplatin-resistant colon cancer cells and its mechanism. Exp Ther Med 2019;18(1):630-6.
  21. Zhang BP, et al. Anti-cancer effect of 20(S)-Ginsenoside-Rh2 on oral squamous cell carcinoma cells via the decrease in ROS and downregulation of MMP-2 and VEGF. Biomed Environ Sci 2020;33(9):713-7.
  22. Zhou DB, et al. [Effect of ginsenoside Rh2 on immunocompetence of alveolar macrophages in patients with non-small cell lung cancer]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2007;32(5):868-72.
  23. Oh SJ, et al. Skin anti-photoaging properties of ginsenoside Rh2 epimers in UV-B-irradiated human keratinocyte cells. J Biosci 2014;39(4):673-82. https://doi.org/10.1007/s12038-014-9460-x
  24. Lee H, et al. A new role for the ginsenoside RG3 in antiaging via mitochondria function in ultraviolet-irradiated human dermal fibroblasts. J Ginseng Res 2019;43(3):431-41. https://doi.org/10.1016/j.jgr.2018.07.003
  25. Lee H, et al. Yin Yang 1 is required for PHD finger protein 20-mediated myogenic differentiation in vitro and in vivo. Cell Death Differ 2020;27(12): 3321-36. https://doi.org/10.1038/s41418-020-0580-6
  26. Hong Y, et al. Beneficial effects of Diplectria barbata (Wall. Ex C. B. Clarke) Franken et Roos extract on aging and antioxidants in vitro and in vivo. Toxicol Res 2021;37(1):71-83. https://doi.org/10.1007/s43188-020-00064-z
  27. Park J, et al. Involvement of S6K1 in mitochondria function and structure in HeLa cells. Cell Signal 2016;28(12):1904-15. https://doi.org/10.1016/j.cellsig.2016.09.003
  28. Park J, et al. Recognition of transmembrane protein 39A as a tumor-specific marker in brain tumor. Toxicol Res 2017;33(1):63-9. https://doi.org/10.5487/TR.2017.33.1.063
  29. Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell 2002;111(3):293-303. https://doi.org/10.1016/S0092-8674(02)01083-8
  30. Itoh N, et al. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 2002;94(12):3127-34. https://doi.org/10.1002/cncr.10591
  31. Shin I, et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 2002;8(10):1145-52. https://doi.org/10.1038/nm759
  32. Huang C, et al. UV Induces phosphorylation of protein kinase B (Akt) at Ser473 and Thr-308 in mouse epidermal Cl 41 cells through hydrogen peroxide. J Biol Chem 2001;276(43):40234-40. https://doi.org/10.1074/jbc.M103684200
  33. Johnston A, et al. EGFR and IL-1 signaling synergistically promote keratinocyte antimicrobial defenses in a differentiation-dependent manner. J Invest Dermatol 2011;131(2):329-37. https://doi.org/10.1038/jid.2010.313
  34. Bhattacharjee O, et al. Unraveling the ECM-immune cell crosstalk in skin diseases. Front Cell Dev Biol 2019;7:68. https://doi.org/10.3389/fcell.2019.00068
  35. Plikus MV, Krieg T. More than just bricks and mortar: fibroblasts and ECM in skin health and disease. Exp Dermatol 2021;30(1):4-9. https://doi.org/10.1111/exd.14257
  36. Ishida A. [Localization of basement membrane collagen (type IV) in foreign body granulation tissue]. Nihon Ika Daigaku Zasshi 1988;55(4):346-54. https://doi.org/10.1272/jnms1923.55.346
  37. Minchin JE, et al. Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. Proc Natl Acad Sci U S A 2015;112(14):4363-8. https://doi.org/10.1073/pnas.1416412112
  38. Ribeiro WG, et al. Analysis of tissue inflammatory response, fibroplasia, and foreign body reaction between the polyglactin suture of abdominal aponeurosis in rats and the intraperitoneal implant of polypropylene, polypropylene/ polyglecaprone and polyester/porcine collagen meshes. Acta Cir Bras 2021;36(7):e360706. https://doi.org/10.1590/acb360706
  39. Schuppan D, Ruhlmann T, Hahn EG. Radioimmunoassay for human type VI collagen and its application to tissue and body fluids. Anal Biochem 1985;149(1):238-47. https://doi.org/10.1016/0003-2697(85)90501-9
  40. Suchy T, et al. Various simulated body fluids lead to significant differences in collagen tissue engineering scaffolds. Materials 2021;14(16).
  41. Zischka-Konorsa W. [Pathology of collagen diseases as a manifestation of disorders in connective tissue perfusion, connective tissue cleansing and foreign-body elimination]. Wien Z Inn Med 1973;54(11-12):559-66.
  42. Hsieh PC, et al. Elastin in oral connective tissue modulates the keratinization of overlying epithelium. J Clin Periodontol 2010;37(8):705-11.
  43. Uitto J, Santa Cruz DJ, Eisen AZ. Connective tissue nevi of the skin. Clinical, genetic, and histopathologic classification of hamartomas of the collagen, elastin, and proteoglycan type. J Am Acad Dermatol 1980;3(5):441-61. https://doi.org/10.1016/S0190-9622(80)80106-X
  44. Werb Z, Banda MJ, Jones PA. Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. J Exp Med 1980;152(5):1340-57. https://doi.org/10.1084/jem.152.5.1340
  45. Emonard H, Grimaud JA. Matrix metalloproteinases. A review. Cell Mol Biol 1990;36(2):131-53.
  46. Snezhkina AV, et al. ROS generation and antioxidant defense systems in normal and malignant cells, vol. 2019. Oxid Med Cell Longev; 2019. p. 6175804.
  47. Liu C, et al. UV-A irradiation activates nrf2-regulated antioxidant defense and induces p53/caspase3-dependent apoptosis in corneal endothelial cells. Invest Ophthalmol Vis Sci 2016;57(4):2319-27. https://doi.org/10.1167/iovs.16-19097
  48. Loboda A, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016;73(17):3221-47. https://doi.org/10.1007/s00018-016-2223-0
  49. Hoppins S, Lackner L, Nunnari J. The machines that divide and fuse mitochondria. Annu Rev Biochem 2007;76:751-80. https://doi.org/10.1146/annurev.biochem.76.071905.090048
  50. Friedman JR, et al. ER tubules mark sites of mitochondrial division. Science 2011;334(6054):358-62. https://doi.org/10.1126/science.1207385
  51. Bockler S, et al. Fusion, fission, and transport control asymmetric inheritance of mitochondria and protein aggregates. J Cell Biol 2017;216(8):2481-98. https://doi.org/10.1083/jcb.201611197
  52. Jourdain I, Gachet Y, Hyams JS. The dynamin related protein Dnm1 fragments mitochondria in a microtubule-dependent manner during the fission yeast cell cycle. Cell Motil Cytoskeleton 2009;66(8):509-23. https://doi.org/10.1002/cm.20351
  53. Ashrafi G, et al. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 2014;206(5): 655-70. https://doi.org/10.1083/jcb.201401070
  54. Barazzuol L, et al. PINK1/Parkin mediated mitophagy, Ca(2+) signalling, and ER-mitochondria contacts in Parkinson's disease. Int J Mol Sci 2020;21(5).
  55. Gehrke S, et al. PINK1 and Parkin control localized translation of respiratory chain component mRNAs on mitochondria outer membrane. Cell Metabol 2015;21(1):95-108. https://doi.org/10.1016/j.cmet.2014.12.007
  56. Kawajiri S, et al. PINK1 is recruited to mitochondria with parkin and associates with LC3 in mitophagy. FEBS Lett 2010;584(6):1073-9. https://doi.org/10.1016/j.febslet.2010.02.016
  57. Vincow ES, et al. The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Natl Acad Sci U S A 2013;110(16):6400-5. https://doi.org/10.1073/pnas.1221132110