Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Cytoprotective Effects of Schisandrin A against Hydrogen Peroxide-induced Oxidative Stress in SW1353 Human Chondrocytes

SW1353 인간 연골세포에서 산화적 스트레스에 대한 schisandrin A의 세포 보호 효과

  • Jeong, Jin-Woo (Open Lab. for Muscular & Skeletal Disease Control and Department of Biochemistry and Dongeui University College of Korean Medicine) ;
  • Choi, Eun Ok (Open Lab. for Muscular & Skeletal Disease Control and Department of Biochemistry and Dongeui University College of Korean Medicine) ;
  • Kwon, Da Hye (Open Lab. for Muscular & Skeletal Disease Control and Department of Biochemistry and Dongeui University College of Korean Medicine) ;
  • Kim, Bum Hoi (Department of Anatomy, Dongeui University College of Korean Medicine) ;
  • Park, Dong Il (Department of Internal Medicine, Dongeui University College of Korean Medicine) ;
  • Hwang, Hye Jin (Anti-Aging Research Center and Blue Bio Industry RIC, Dongeui University) ;
  • Kim, Byung Woo (Anti-Aging Research Center and Blue Bio Industry RIC, Dongeui University) ;
  • Choi, Yung Hyun (Open Lab. for Muscular & Skeletal Disease Control and Department of Biochemistry and Dongeui University College of Korean Medicine)
  • 정진우 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 최은옥 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 권다혜 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실) ;
  • 김범회 (동의대학교 한의과대학 해부학교실) ;
  • 박동일 (동의대학교 한의과대학 내과학교실) ;
  • 황혜진 (동의대학교 항노화연구소 및 블루바이오소재개발 및 실용화지원센터) ;
  • 김병우 (동의대학교 항노화연구소 및 블루바이오소재개발 및 실용화지원센터) ;
  • 최영현 (동의대학교 근.골격계 질환제어 융합연구실 및 한의과대학 생화학교실)
  • Received : 2017.07.12
  • Accepted : 2017.09.08
  • Published : 2017.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Chondrocyte apoptosis induced by reactive oxygen species (ROS) plays an important role in the pathogenesis of osteoarthritis. Schisandrin A, a bioactive compound found in fruits of the Schisandra genus, has been reported to possess multiple pharmacological and therapeutic properties. Although several studies have described the antioxidant effects of analogues of schisandrin A, the underlying molecular mechanisms of this bioactive compound remain largely unresolved. The present study investigated the cytoprotective effect of schisandrin A against oxidative stress (hydrogen peroxide [$H_2O_2$]) in SW1353 human chondrocyte cells. The results showed that schisandrin A preconditioning significantly inhibited $H_2O_2-induced$ growth inhibition and apoptotic cell death by blocking the degradation of poly (ADP-ribose) polymerase proteins and down-regulating pro-caspase-3. These antiapoptotic effects of schisandrin A were associated with attenuation of mitochondrial dysfunction and normalization of expression changes of proapoptotic Bax and antiapoptotic Bcl-2 in $H_2O_2-stimulated$ SW1353 chondrocytes. Furthermore, schisandrin A effectively abrogated $H_2O_2-induced$ intracellular ROS accumulation and phosphorylation of histone H2AX at serine 139, a widely used marker of DNA damage. Thus, the present study demonstrates that schisandrin A provides protection against $H_2O_2-induced$ apoptosis and DNA damage in SW1353 chondrocytes, possibly by prevention of ROS generation. Collectively, our data indicate that schisandrin A has therapeutic potential in the treatment of oxidative disorders caused by overproduction of ROS.

활성산소종으로 유도되는 연골 세포의 apoptosis는 퇴행성 관절염의 발병 기전에 중요한 역할을 한다. Schisandrin 속의 과일에서 발견되는 생체 활성 화합물인 schisandrin A는 여러 가지 약리학적 작용을 하는 것으로 보고되고 있다. 현재까지 schisandrin A의 유도체들의 항산화 효과에 대해서는 여러 연구가 보고되었지만, schisandrin A의 항산화 효능의 분자 기전은 아직 미해결 상태로 남아 있다. 본 연구는 SW1353 인간 연골세포에서 산화적 스트레스($H_2O_2$)에 대한 schisandrin A의 세포 보호 여부를 조사하였다. 본 연구의 결과에 의하면 schisandrin A는 PARP 단백질의 분해와 caspase-3의 활성 차단을 통해 $H_2O_2$에 의해 유도된 성장 억제와 apoptosis를 유의적으로 억제하였다. 이러한 schisandrin A의 anti-apoptotic 효과는 미토콘드리아 기능 손상의 억제와 pro-apoptotic Bax의 발현 증가 및 anti-apoptotic Bcl-2의 발현 감소의 차단과도 관련이 있었다. 또한, schisandrin A는 ROS의 생성과 DNA 손상 마커인 H2AX의 인산화도 효과적으로 저해하였다. 따라서 SW1353 연골세포에서 schisandrin A는 산화적 스트레스에 의한 ROS 생성의 억제를 통하여 apoptosis와 DNA 손상을 보호하였음을 알 수 있었다. 결론적으로 본 연구의 결과는 schisandrin A가 ROS의 과잉 생산으로 인한 산화적 장애에 치료적 잠재력이 있음을 보여준다.

Keywords

References

  1. Asada, S., Fukuda, K., Nishisaka, F., Matsukawa, M. and Hamanisi, C. 2001. Hydrogen peroxide induces apoptosis of chondrocytes; involvement of calcium ion and extracellular signal-regulated protein kinase. Inflamm. Res. 50, 19-23. https://doi.org/10.1007/s000110050719
  2. Ba, Q., Cui, C., Wen, L., Feng, S., Zhou, J. and Yang, K. 2015. Schisandrin B shows neuroprotective effect in 6-OHDA-induced Parkinson's disease via inhibiting the negative modulation of miR-34a on Nrf2 pathway. Biomed. Pharmacother. 75, 165-172. https://doi.org/10.1016/j.biopha.2015.07.034
  3. Checker, R., Patwardhan, R. S., Sharma, D., Menon, J., Thoh, M., Bhilwade, H. N., Konishi, T. and Sandur, S. K. 2012. Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-${\kappa}B$. Free Radic. Biol. Med. 53, 1421-130. https://doi.org/10.1016/j.freeradbiomed.2012.08.006
  4. Chun, J. N., Cho, M., So, I. and Jeon, J. H. 2014. The protective effects of Schisandra chinensis fruit extract and its lignans against cardiovascular disease: a review of the molecular mechanisms. Fitoterapia 97, 224-233. https://doi.org/10.1016/j.fitote.2014.06.014
  5. Dave, M., Attur, M., Palmer, G., Al-Mussawir, H. E., Kennish, L., Patel, J. and Abramson, S. B. 2008. The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. Arthritis Rheum. 58, 2786-2797. https://doi.org/10.1002/art.23799
  6. Decker, P. and Muller, S. 2002. Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr. Pharm. Biotechnol. 3, 275-283. https://doi.org/10.2174/1389201023378265
  7. Dong, Q., Hou, H., Wu, J. and Chen, Y. 2016. The Nrf2-ARE pathway is associated with schisandrin b attenuating benzo(a)pyrene-induced HTR cells damages in vitro. Environ. Toxicol. 31, 1439-1449. https://doi.org/10.1002/tox.22149
  8. Fleury, C., Mignotte, B. and Vayssiere, J. L. 2002. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84, 131-141. https://doi.org/10.1016/S0300-9084(02)01369-X
  9. Galluzzi, L., Morselli, E., Kepp, O. and Kroemer, G. 2009. Targeting post-mitochondrial effectors of apoptosis for neuroprotection. Biochim. Biophys. Acta. 1787, 402-413. https://doi.org/10.1016/j.bbabio.2008.09.006
  10. Gao, C., Chen, H., Niu, C., Hu, J. and Cao, B. 2017. Protective effect of Schizandrin B against damage of UVB irradiated skin cells depend on inhibition of inflammatory pathways. Bioengineered 8, 36-44. https://doi.org/10.1080/21655979.2016.1227572
  11. Goldring, M. B. and Goldring, S. R. 2007. Osteoarthritis. J. Cell. Physiol. 213, 626-634. https://doi.org/10.1002/jcp.21258
  12. Hadjigogos, K. 2003. The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva. Med. 45, 7-13.
  13. Huyke, C., Engel, K., Simon-Haarhaus, B., Quirin, K. W. and Schempp, C. M. 2007. Composition and biological activity of different extracts from Schisandra sphenanthera and Schisandra chinensis. Planta Med. 73, 1116-1126. https://doi.org/10.1055/s-2007-981559
  14. Hwang, H. S. and Kim, H. A. 2015. Chondrocyte apoptosis in the pathogenesis of ssteoarthritis. Int. J. Mol. Sci. 16, 26035-26054. https://doi.org/10.3390/ijms161125943
  15. Kim, S. R., Lee, M. K., Koo, K. A., Kim, S. H., Sung, S. H., Lee, N. G., Markelonis, G. J., Oh, T. H., Yang, J. H. and Kim, Y. C. 2004. Dibenzocyclooctadiene lignans from Schisandra chinensis protect primary cultures of rat cortical cells from glutamate-induced toxicity. J. Neurosci. Res. 76, 397-405. https://doi.org/10.1002/jnr.20089
  16. Kroemer, G., Galluzzi, L. and Brenner, C. 2007. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99-163. https://doi.org/10.1152/physrev.00013.2006
  17. Leong, P. K., Wong, H. S., Chen, J., Chan, W. M., Leung, H. Y. and Ko, K. M. 2016: Differential action between schisandrin A and schisandrin B in eliciting an anti-inflammatory action: The depletion of reduced glutathione and the induction of an antioxidant response. PLoS One 11, e0155879. https://doi.org/10.1371/journal.pone.0155879
  18. Park, S. Y., Park, S. J., Park, T. G., Rajasekar, S., Lee, S. J. and Choi, Y. W. 2013. Schizandrin C exerts anti-neuroinflammatory effects by upregulating phase II detoxifying/ antioxidant enzymes in microglia. Int. Immunopharmacol. 17, 415-426. https://doi.org/10.1016/j.intimp.2013.06.032
  19. Qun, E., Tang, M., Zhang, X., Shi, Y., Wang, D., Gu, Y., Li, S., Liang, X., Wang, Z. and Wang, C. 2015. Protection of seven dibenzocyclooctadiene lignans from Schisandra chinensis against serum and glucose deprivation injury in SH-SY5Y cells. Cell Biol. Int. 39, 1418-1424. https://doi.org/10.1002/cbin.10537
  20. Rahmati, M., Mobasheri, A. and Mozafari, M. 2016. Inflammatory mediators in osteoarthritis: A critical review of the state-of-the-art, current prospects, and future challenges. Bone 85, 81-90. https://doi.org/10.1016/j.bone.2016.01.019
  21. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. and Bonner, W. M. 1998. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858-5868. https://doi.org/10.1074/jbc.273.10.5858
  22. Rosen, A. and Casciola-Rosen, L. 1997. Macromolecular substrates for the ICE-like proteases during apoptosis. J. Cell. Biochem. 64, 50-54. https://doi.org/10.1002/(SICI)1097-4644(199701)64:1<50::AID-JCB8>3.0.CO;2-Z
  23. Sakata, S., Hayashi, S., Fujishiro, T., Kawakita, K., Kanzaki, N., Hashimoto, S., Iwasa, K., Chinzei, N., Kihara, S., Haneda, M., Ueha, T., Nishiyama, T., Kuroda, R. and Kurosaka, M. 2015. Oxidative stress-induced apoptosis and matrix loss of chondrocytes is inhibited by eicosapentaenoic acid. J. Orthop. Res. 33, 359-365. https://doi.org/10.1002/jor.22767
  24. Song, F., Zeng, K., Liao, L., Yu, Q., Tu, P. and Wang, X. 2016. Schizandrin A inhibits microglia-mediated neuroninflammation through inhibiting TRAF6-NF-${\kappa}B$ and Jak2-Stat3 signaling pathways. PLoS One 11, e0149991. https://doi.org/10.1371/journal.pone.0149991
  25. Sutipornpalangkul, W., Morales, N. P. and Harnroongroj, T. 2009. Free radicals in primary knee osteoarthritis. J. Med. Assoc. Thai 92, S268-S274.
  26. Wang, C. P., Li, G. C., Shi, Y. W., Zhang, X. C., Li, J. L., Wang, Z. W., Ding, F. and Liang, X. M. 2014. Neuroprotective effect of schizandrin A on oxygen and glucose deprivation/ reperfusion-induced cell injury in primary culture of rat cortical neurons. J. Physiol. Biochem. 70, 735-747. https://doi.org/10.1007/s13105-014-0342-3
  27. Xiao, W. L., Huang, S. X., Wang, R. R., Zhong, J. L., Gao, X. M., He, F., Pu, J. X., Lu, Y., Zheng, Y. T., Zheng, Q. T. and Sun, H. D. 2008. Nortriterpenoids and lignans from Schisandra sphenanthera. Phytochemistry 69, 2862-2866. https://doi.org/10.1016/j.phytochem.2008.09.010
  28. Xie, Y., Hao, H., Wang, H., Guo, C., Kang, A. and Wang, G. 2014. Reversing effects of lignans on$CCl_4$-induced hepatic CYP450 down regulation by attenuating oxidative stress. J. Ethnopharmacol. 155, 213-221. https://doi.org/10.1016/j.jep.2014.05.016