Abstract
Aim:
To investigate the effects of ginsenoside Rg1 on the radiation-induced aging of hematopoietic stem/progenitor cells (HSC/HPCs) in mice and the underlying mechanisms.
Methods:
Male C57BL/6 mice were treated with ginsenoside Rg1 (20 mg·kg−1·d−1, ip) or normal saline (NS) for 7 d, followed by exposure to 6.5 Gy X-ray total body irradiation. A sham-irradiated group was treated with NS but without irradiation. Sca-1+ HSC/HPCs were isolated and purified from their bone marrow using MACS. DNA damage was detected on d 1. The changes of anti-oxidative activities, senescence-related markers senescence-associated β-galactosidase (SA-β-gal) and mixed colony-forming unit (CFU-mix), P16INK4a and P21Cip1/Waf1 expression on d 7, and cell cycle were examined on d 1, d 3, and d 7.
Results:
The irradiation caused dramatic reduction in the number of Sca-1+ HSC/HPCs on d 1 and the number barely recovered until d 7 compared to the sham-irradiated group. The irradiation significantly decreased SOD activity, increased MDA contents and caused DNA damage in Sca-1+ HSC/HPCs. Moreover, the irradiation significantly increased SA-β-gal staining, reduced CFU-mix forming, increased the expression of P16INK4a and P21Cip1/Waf1 in the core positions of the cellular senescence signaling pathways and caused G1 phase arrest of Sca-1+ HSC/HPCs. Administration of ginsenoside Rg1 caused small, but significant recovery in the number of Sca-1+ HSC/HPCs on d 3 and d 7. Furthermore, ginsenoside Rg1 significantly attenuated all the irradiation-induced changes in Sca-1+ HSC/HPCs, including oxidative stress reaction, DNA damage, senescence-related markers and cellular senescence signaling pathways and cell cycle, etc.
Conclusion:
Administration of ginsenoside Rg1 enhances the resistance of HSC/HPCs to ionizing radiation-induced senescence in mice by inhibiting the oxidative stress reaction, reducing DNA damage, and regulating the cell cycle.
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References
Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 2005; 102: 9194–9.
Rossi DJ, Bryder D, Weissman IL . Hematopoietic stem cell aging: mechanism and consequence. Exp Gerontol 2007; 42: 385–90.
Gazit R, Weissman H, Rossl DJ . Hematopoietic stem cells and the aging hematopoietic system. Strain Hematol 2008; 45: 218–23.
Chambers SM, Goodell MA . Hematopoietic stem cell aging: wrinkles in stem cell potential. Stem Cell Rev 2007; 3: 201–11.
Cheng Y, Shen LH, Zhang JT . Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin 2005; 26: 143–9.
Chen X, Zhang J, Fang Y, Zhao C, Zhu Y . Ginsenoside Rg1 delays tert-butyl hydroperoxide-induced premature senescence in human WI-38 diploid fibroblast cells. J Gerontol A Biol Sci Med Sci 2008; 63: 253–64.
Wang Y, Schulte BA, LaRue AC, Ogawa M, Zhou D . Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 2006; 107: 358–66.
Wang Y, Liu L, Pazhanisamy SK, Li H, Meng A, Zhou D . Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic Biol Med 2010; 48: 348–56.
Zhou Y, Yang B, Yao X, Wang YP . Establishment of an aging model of Sca-1+ hematopoietic stem cell and studies on its relative biological mechanisms. In Vitro Cell Dev Biol Anim 2011; 47: 149–56.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995; 92: 9363–7.
Stein GH, Beeson M, Gordon L . Failure to phosphorylate the retinoblastoma gene produce in senescent human fibroblasts. Science 1990; 249: 666–9
Kamminga LM, van Os R, Ausema A, Noach EJ, Weersing E, Dontje B, et al. Impaired hematopoietic stem cell functioning after serial transplantation and normal aging. Stem Cells 2005; 23: 82–92.
Jang YY, Sharkis SJ . A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may re-side in the low-oxygenic niche. Blood 2007; 110: 3056–63.
Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 2004; 431: 997–1002.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 2006; 12: 446–51.
Chen XC, Zhou YC, Chen Y, Zhu YG, Fang F, Chen LM . Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress. Acta Pharmacol Sin 2005; 26: 56–62.
Korivi M, Hou CW, Huang CY, Lee SD, Hsu MF, Yu SH, et al. Ginsenoside-Rg1 protects the liver against exhaustive exercise-induced oxidative stress in rats. Evid Based Complement Alternat Med 2012; 2012: 932165.
Shen L, Han JZ, Li C, Yue SJ, Liu Y, Qin XQ, et al. Protective effect of ginsenoside Rg1 on glutamate-induced lung injury. Acta Pharmacol Sin 2007; 28: 392–7.
Chen JH, Hales CN, Ozanne SE . DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 2007; 35: 7417–28.
Fairbairn DW, Olive PL, Oneill KL . The comet assay: a comprehensive review. Mutation Res 1995; 339: 37–59.
Olive PL, Durand RE . Heterogeneity in DNA damage using the comet assay. Cytometry A 2005; 66: 1–8.
Spitz DR, Azzam EI, Li JJ, Gius D . Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev 2004; 23: 311–22.
Wu LJ, Randers-Pehrson G, Xu A, Waldren CA, Geard CR, Yu Z, et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci U S A 1999; 96: 4959–64.
Morisaki H, Ando A, Nagata Y, Pereira-Smith O, Smith JR, Ikeda K, et al. Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative senescence: roles of p16, p21, and cyclin D1. Exp Cell Res 1999; 253: 503–10.
Gerland LM, Ffrench M, Magaud JP . Cyclin dependent kinase inhibitors and replicative senescence. Pathol Biol 2001; 49: 830–9.
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 2001; 409: 1067–70.
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Natue 2006; 443: 421–6.
Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–16.
Sandhu C, Donovan J, Bhattacharya N, Stampfer M, Worland P, Slingerland J . Reduction of Cdc25A contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells. Oncogene 2000; 19: 5314–23.
Sherr CJ . G1 phase progression: cycling on cue. Cell 1994; 79: 551–5.
Chen XC, Zhu YG, Zhu LA, Huang C, Chen Y, Chen LM, et al. Ginsenoside Rg1 attenuates dopamine-induced apoptosis in PC12 cells by suppressing oxidative stress. Eur J Pharmacol 2003; 473: 1–7.
Acknowledgements
This study was supported by the National Natural Science Foundation of China, No 81173398, 30973818, 30970872, and 81202785.
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Chen, C., Mu, Xy., Zhou, Y. et al. Ginsenoside Rg1 enhances the resistance of hematopoietic stem/progenitor cells to radiation-induced aging in mice. Acta Pharmacol Sin 35, 143–150 (2014). https://doi.org/10.1038/aps.2013.136
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DOI: https://doi.org/10.1038/aps.2013.136
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