Background: Although Platycodin D (PLD) is the main active saponin of Platycodon grandiflorum (PG) and responsible for multiple therapeutic benefits, including antioxidant and antiaging, only few direct demonstrations have been reported on the role of PLD in antiaging process. The present investigation was carried out to elucidate the protection of PLD against aging in vitro and associated molecular mechanisms on H2O2-induced premature senescence model in human -fetal lung diploid fibroblasts 2BS cells. Methods: The cellular morphology, cell cycle, and senescence-associated β-galactosidase activity assays were used for senescence-like phenotypes determination in the oxidant challenged model. The oxygen-free radicals reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA) determinations were estimated by enzyme-linked immunosorbent assay assay. The potential of the mitochondria mass and the mitochondrial membrane were used to observe the alteration of mitochondria. Western blot analysis was performed to determine the protein expression. Results: The results showed that PLD significantly reversed senescence-like phenotypes in the oxidant challenged model, as well as related molecules expression such as p53, p21, and p16. Moreover, PLD treatment significantly decreased the levels of ROS, 4-HNE, and MDA in H2O2-treated 2BS cells. The mechanisms responsible for the antioxidant and antiaging effects of PLD were investigated, we found that mitochondria under PLD conditions show increase membrane potential ratio and stimulate the proliferation of mitochondria mass. In addition, the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α and its downstream targets, that is, nuclear respiratory factor and mitochondrial transcription factor A were also increased in mitochondrial biogenesis. Conclusion: These results indicated that PLD prevented H2O2-induced premature senescence in vitro by improving mitochondrial biogenesis to attenuate age-dependent endogenous oxidative damage. Key Message: The study revealed the antioxidant and antiaging potential of PLD against H2O2-induced premature senescence.

Keywords:
Platycodin D, Cellular premature senescence, Oxidative stress, Mitochondrial biogenesis
1.
Sen P, Shah PP, Nativio R, Berger SL. Epigenetic Mechanisms of Longevity and Aging.
Cell
. 2016 Aug;166(4):822–39.
2.
Harman D. Aging: a theory based on free radical and radiation chemistry.
J Gerontol
. 1956 Jul;11(3):298–300.
3.
Pomatto LC, Davies KJ. Adaptive homeostasis and the free radical theory of ageing.
Free Radic Biol Med
. 2018 Aug;124:420–30.
4.
Longo VD, Fabrizio P. Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans?
Cell Mol Life Sci
. 2002 Jun;59(6):903–8.
5.
Skochko NS, Torgalo EA, Beregova TV, Jankowski DS. Multiprobiotic administration induced longevity and decreased oxidative stress in rats.
Res J Pharm Biol Chem Sci
. 2015;6(4):599–605.
6.
Huang YF, Lu L, Zhu DJ, Wang M, Yin Y, Chen DX, et al. Effects of Astragalus -Polysaccharides on Dysfunction of Mitochondrial Dynamics Induced by Oxidative Stress.
Oxid Med Cell Longev
. 2016;2016:9573291.
7.
Biala AK, Dhingra R, Kirshenbaum LA. Mitochondrial dynamics: orchestrating the journey to advanced age.
J Mol Cell Cardiol
. 2015 Jun;83:37–43.
8.
López-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency.
Proc Natl Acad Sci USA
. 2006 Feb;103(6):1768–73.
9.
Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Mitochondrial proton and electron leaks.
Essays Biochem
. 2010;47(1):53–67.
10.
Porter C, Reidy PT, Bhattarai N, Sidossis LS, Rasmussen BB. Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle.
Med Sci Sports Exerc
. 2015 Sep;47(9):1922–31.
11.
Chung MJ, Kim SH, Park JW, Lee YJ, Ham SS. Platycodon grandiflorum root attenuates vascular endothelial cell injury by oxidized low-density lipoprotein and prevents high-fat diet-induced dyslipidemia in mice by up-regulating antioxidant proteins.
Nutr Res
. 2012 May;32(5):365–73.
12.
Nyakudya E, Jeong JH, Lee NK, Jeong YS. Platycosides from the Roots of Platycodon grandiflorum and Their Health Benefits.
Prev Nutr Food Sci
. 2014 Jun;19(2):59–68.
13.
Jin KJ, Kang SY, Kim J, Lee SK, Park YK. Effects of Platycodi Radix ethanol extract on ovalbumin-induced allergic responses in mice.
Korea J Herbol
. 2012;27(6):123–9.
14.
Zhang L, Wang Y, Yang D, Zhang C, Zhang N, Li M, et al. Platycodon grandiflorus - an ethnopharmacological, phytochemical and pharmacological review.
J Ethnopharmacol
. 2015 Apr;164:147–61.
15.
Kim EB, Kwak JH. Anti-inflammatory activity of the aerial parts of Platycodon grandiflorum and its constituents in LPS-stimulated RAW264.7 macrophages.
Planta Med
. 2015;81(16).
16.
Noh JR, Kim YH, Gang GT, Hwang JH, Kim SK, Ryu SY, et al. Hepatoprotective effect of Platycodon grandiflorum against chronic ethanol-induced oxidative stress in C57BL/6 mice.
Ann Nutr Metab
. 2011;58(3):224–31.
17.
Chung JW, Noh EJ, Zhao HL, Sim JS, Ha YW, Shin EM, et al. Anti-inflammatory activity of prosapogenin methyl ester of platycodin D via nuclear factor-kappaB pathway inhibition.
Biol Pharm Bull
. 2008 Nov;31(11):2114–20.
18.
Li W, Liu Y, Wang Z, Han Y, Tian YH, Zhang GS, et al. Platycodin D isolated from the aerial parts of Platycodon grandiflorum protects alcohol-induced liver injury in mice.
Food Funct
. 2015 May;6(5):1418–27.
19.
Kim TW, Lee HK, Song IB, Lim JH, Cho ES, Son HY, et al. Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice.
Food Chem Toxicol
. 2013 Jan;51(1):364–9.
20.
Kim TW, Song IB, Lee HK, Lim JH, Cho ES, Son HY, et al. Platycodin D, a triterpenoid sapoinin from Platycodon grandiflorum, ameliorates cisplatin-induced nephrotoxicity in mice.
Food Chem Toxicol
. 2012 Dec;50(12):4254–9.
21.
Choi JH, Jin SW, Choi CY, Kim HG, Kim SJ, Lee HS, et al. Saponins from the roots of Platycodon grandiflorum ameliorate high fat diet-induced non-alcoholic steatohepatitis.
Biomed Pharmacother
. 2017 Feb;86:205–12.
22.
Gao W, Guo Y, Yang H. Platycodin D protects against cigarette smoke-induced lung inflammation in mice.
Int Immunopharmacol
. 2017 Jun;47:53–8.
23.
Qiu Q, Mao GX, Shen JJ, Deng HB, Li DD, Wang Z. Protection of salidroside against lidamycin-induced cellular senescence in human fetal lung fibroblasts 2BS cells.
Zhongguo Xin Yao Zazhi
. 2012;21(1):82–7.
24.
Pu X, Yu S, Fan W, Liu L, Ma X, Ren J. Guiqi polysaccharide protects the normal human fetal lung fibroblast WI-38 cells from H2O2-induced premature senescence.
Int J Clin Exp Pathol
. 2015 May;8(5):4398–407.
25.
Shi X, Tian B, Ma C, Liu L, Zhang N, Na Y, et al. GSK3β activity is essential for senescence-associated heterochromatin foci (SAHF) formation induced by HMGA2 in WI38 cells.
Am J Transl Res
. 2017 Jan;9(1):167–74.
26.
Esteras N, Wray S, Preza E, Abramov AY. Higher Mitochondrial Membrane Potential Induces ROS Production in the Familiar Form of Frontotemporal Dementia with MAPT Mutations.
Biophys J
. 2015;108(2):611a.
27.
Mao GX, Wang Y, Qiu Q, Deng HB, Yuan LG, Li RG, et al. Salidroside protects human fibroblast cells from premature senescence induced by H(2)O(2) partly through modulating oxidative status.
Mech Ageing Dev
. 2010 Nov-Dec;131(11-12):723–31.
28.
Davalli P, Mitic T, Caporali A, Lauriola A, D’Arca D. ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases.
Oxid Med Cell Longev
. 2016;2016:3565127.
29.
Ristow M, Schmeisser S. Extending life span by increasing oxidative stress.
Free Radic Biol Med
. 2011 Jul;51(2):327–36.
30.
Indo HP, Davidson M, Yen HC, Suenaga S, Tomita K, Nishii T, et al. Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage.
Mitochondrion
. 2007 Feb-Apr;7(1-2):106–18.
31.
Chattopadhyay M, Khemka VK, Chatterjee G, Ganguly A, Mukhopadhyay S, Chakrabarti S. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects.
Mol Cell Biochem
. 2015 Jan;399(1-2):95–103.
32.
Chen T, Gao J, Xiang P, Chen Y, Ji J, Xie P, et al. Protective effect of platycodin D on liver injury in alloxan-induced diabetic mice via regulation of Treg/Th17 balance.
Int Immunopharmacol
. 2015 Jun;26(2):338–48.
33.
Wu J, Yang G, Wen W, Zhang F, Yuan J, An L. Cholesterol metabolism regulation and antioxidant effect of platycodin D on hyperlipidemic emulsion- reduced rats.
Afr J Pharm Pharmacol
. 2011;5(22):2444–53.
34.
Wu J, Yang G, Zhu W, Wen W, Zhang F, Yuan J, et al. Anti-atherosclerotic activity of platycodin D derived from roots of Platycodon grandiflorum in human endothelial cells.
Biol Pharm Bull
. 2012;35(8):1216–21.
35.
Huang YS, Wang XY, Jing LI, Zhao M, Yang JX. Effect of Total Saponins from Platycodon grandiflorum on Biological Activity of Caenorhabditis elegans.
Heilongjiang Nongye Kexue
. 2015;4:148–51.
36.
García-Mesa Y, Colie S, Corpas R, Cristòfol R, Comellas F, Nebreda AR, et al. Oxidative Stress Is a Central Target for Physical Exercise Neuroprotection Against Pathological Brain Aging.
J Gerontol A Biol Sci Med Sci
. 2016 Jan;71(1):40–9.
37.
Shaker ME, Salem HA, Shiha GE, Ibrahim TM. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.
Fundam Clin Pharmacol
. 2011 Apr;25(2):248–57.
38.
Lee KJ, Choi CY, Chung YC, Kim YS, Ryu SY, Roh SH, et al. Protective effect of saponins derived from roots of Platycodon grandiflorum on tert-butyl hydroperoxide-induced oxidative hepatotoxicity.
Toxicol Lett
. 2004 Mar;147(3):271–82.
39.
Sharma DR, Sunkaria A, Wani WY, Sharma RK, Kandimalla RJ, Bal A, et al. Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.
Toxicol Appl Pharmacol
. 2013 Dec;273(2):365–80.
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2020
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