Chinese Journal of Integrative Medicine

, Volume 16, Issue 1, pp 41–49 | Cite as

Endoplasmic reticulum stress induced by tunicamycin and antagonistic effect of Tiantai No.1 (天泰1号) on mesenchymal stem cells

  • Zheng-zhi Wu (吴正治)
  • Ying-hong Li (李映红)
  • Andrew C. J. Huang
  • Ming Li (李 明)
  • Xiao-li Zhang (张晓丽)
  • Ji-guo Wang (王济国)
  • Min Yang (杨 敏)
  • Man-yin Chen (陈 茵)
Experimental Research

Abstract

Objective

Changes of the internal and external cellular environments can induce calcium homeostasis disorder and unfolded protein aggregation in the endoplasmic reticulum (ER). This ER function disorder is called endoplasmic reticulum stress (ERS). Severe long-term ERS can trigger the ER apoptosis signaling pathway, resulting in cell apoptosis and organism injury. Recent researches revealed that ERS-induced cell death was involved in the neurocyte retrogradation in the progress of neuron degenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease and so on. Therefore, the protection effect of the traditional Chinese drug—Tiantai No. 1 (天泰1号) on the ERS injury of AD was investigated at the molecular gene level in this study with a view to explore the gene pharmacodynamic actions and mechanisms of this drug.

Methods

Primarily cultured marrow mesenchymal stem cells (MSCs) of rats were treated by tunicamycin (TM) in order to induce ERS. RT-PCR, fluorescence immunocytochemistry and Western blot techniques were used to determine the mRNA and protein expression levels of the protective stress protein-ER molecular chaperones GRP78 and GRP94 (which would assist cells to resist cellular stress injury), and to determine the mRNA and protein expression levels of apoptosis promoting molecule Caspase-12 on the membrane of the ER, respectively.

Results

Protein expression levels of GRP78 and GRP94 were significantly increased in the TM-induced MSCs, and the mRNA level of Caspase-12 was also remarkably increased in the TM-induced MSCs (P<0.05). All these proved that the ERS model was successfully established by TM in MSC. Meanwhile, the mRNA and protein levels of GRP78 and GRP94 were all significantly increased compared with the model group (P<0.05 or P<0.01) after MSCs were treated with Tiantai No.1 while the mRNA and protein expression levels of Caspase-12 were significantly decreased compared with the model group (P<0.05 or P<0.01). This effect showed a dose dependent manner.

Conclusion

Tiantai No.1 might attenuate the cell apoptosis induced by ERS injury, and thus protect the neurons against AD.

Keywords

endoplasmic reticulum stress Alzheimer’s disease mesenchymal stem cell tunicamycin Tiantai No.1 

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References

  1. 1.
    Lin L, Tang CS, Yuan WJ. Endoplasmic reticulum stress. Prog Physiol Sci (Chin) 2003;34:333–335.Google Scholar
  2. 2.
    Imaizumi K, Tohyama M. The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes. Nippon Yakurigaku Zasshi 2004;124:383–390.PubMedGoogle Scholar
  3. 3.
    Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol 2001;3:E255–E263.CrossRefPubMedGoogle Scholar
  4. 4.
    Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 2004;4:966–977.CrossRefPubMedGoogle Scholar
  5. 5.
    Li ZQ, Zhou AR, Tang CS. Molecular mechanism on endoplasmic reticulum stress responses. Chin J Biochem Mol Biol (Chin) 2004;20:283–288.Google Scholar
  6. 6.
    Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003;22:8608–8618.CrossRefPubMedGoogle Scholar
  7. 7.
    Liu H, Miller E, van de Water B, Stevens JL. Endoplasmic reticulum stress proteins block oxidantinduced Ca2+ increases and cell death. J Biol Chem 1998;273:12858–12862.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhang PL, Lun M, Teng J, Huang J, Blasick TM, Yin L, et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann Clin Lab Sci 2004;34:449–457.PubMedGoogle Scholar
  9. 9.
    Xu CY, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 2005;115:2656–2664.CrossRefPubMedGoogle Scholar
  10. 10.
    Hu P, Han Z, Couvillon AD, Exton JH. Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting ER stress-induced cell death. J Biol Chem 2004;279:49420–49429.CrossRefPubMedGoogle Scholar
  11. 11.
    Verkhratsky A, Toescu EC. Endoplasmic reticulum Ca2+ homoestasis and neuronal death. J Cell Mol Med 2003;7:351–361.CrossRefPubMedGoogle Scholar
  12. 12.
    Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yanker BA. Aging renders the brain vulnerable to amyloid-beta-protein neurotoxicity. Nat Med 1998;4:827–831.CrossRefPubMedGoogle Scholar
  13. 13.
    Chu K, Jung KH, Kim SJ, Lee ST, Kim J, Park HK, et al. Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1 alpha stabilization in the host brain. Brain Res 2008;1207C:182–192.CrossRefGoogle Scholar
  14. 14.
    Miller FD. Riding the waves: neural and nonneural origins for mesenchymal stem cells. Cell Stem Cell 2007;1:129–130.CrossRefPubMedGoogle Scholar
  15. 15.
    Whittemore SR, Zhang YP, Shields CB, Magnuson DS. Optimizing stem cell grafting into the CNS. Methods Mol Biol 2008;438:375–382.CrossRefPubMedGoogle Scholar
  16. 16.
    Newman MB, Bakay RA. Therapeutic potentials of human embryonic stem cells in Parkinson’s disease. Neurotherapeutics 2008;5:237–251.CrossRefPubMedGoogle Scholar
  17. 17.
    Sugaya K, Alvarez A, Marutle A, Kwak YD, Choumkina E. Stem cell strategies for Alzheimer’s disease therapy. Panminerva Med 2006;48:87–96.PubMedGoogle Scholar
  18. 18.
    Biorklund A, Lindvatll O. Cell replacement therapies for central nervous system disorder. Nat Neurosci 2000;3:537–544.CrossRefGoogle Scholar
  19. 19.
    Chai LH, Wu SX, Yan WH, Ma YF. Human bone marrow mesenchymal stem cells differentiated into dopaminergenic neurons in vitro. Chin J Biotechnol (Chin) 2007;23:252–256.Google Scholar
  20. 20.
    Sotiropoulou PA, Papamichail M. Immune properties of mesenchymal stem cells. Methods Mol Biol 2007;407:225–243.CrossRefPubMedGoogle Scholar
  21. 21.
    Sensebe L. Clinical grade production of mesenchymal stem cells. Biomed Mater Engl 2008;18(1 Suppl):S3–10.Google Scholar
  22. 22.
    Singh S, Joned BJ, Crawford R, Xiao Y. Characterization of a mesenchymal-like stem cell population from osteophyte tissue. Stem Cells Dev 2008;17:245–254.CrossRefPubMedGoogle Scholar
  23. 23.
    Hosseinkhani H, Hosseinkhani M, Kobayashi H. Proliferation and differentiation of mesenchymal stem cells using self-assembled peptide amphiphile nanofibers. Biomed Mater 2006;1:8–15.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang L, Li Y, Lu DY. Neurotrophins promote bone marrow stromal cells (MSCs) to express neural proteins in vitro. Stroke 2001;32:334.CrossRefGoogle Scholar
  25. 25.
    Sanchez RJ, Song S, Cardozo PF, Hazzi C, Stedeford T, Willing A, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000;164:247–256.CrossRefGoogle Scholar
  26. 26.
    Wu ZZ, Li M, Li YF, Zhang YF. Effects of Tiantai No.1 on relative neuropeptides of spontaneous aged dementia mice. Neuroscience Bull 2004;20:167–170.Google Scholar
  27. 27.
    Wu ZZ, Li YH, Li M, Zhang YP, Jia XQ, Chen MY. Influence of Buganyangshui recipe on synaptic plasticity of the hippocampal CA1 region of spontaneous Alzheimer disease models: Quantitative research of ultrastructure. Chin J Tradit Med Sci Technol (Chin) 2007;14:444–446.Google Scholar
  28. 28.
    Wu ZZ, Li M, Li YF, Zhang YF, Jia XQ, Chen MY. Quantitative study of Tiantai No. 1 on superoxidative dismutase and lipofuscin in relevant cerebral areas of spontaneous Alzheimer disease in mice. Chin J Clin Rehabil (Chin) 2005;9:178–181.Google Scholar
  29. 29.
    Woodbury D, Sehwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurous. J Nourosci Res 2000;61:364–370.CrossRefGoogle Scholar
  30. 30.
    Seshareddy K, Troyer D, Weiss ML. Method to isolate mesenchymal-like cells from Wharton’s Jelly of umbilical Cord. Methods Cell Biol 2008;86:101–119.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang GP, Li YY, Lu JC, Ou HJ. Ursolic acid induces apoptosis through effects on Bax and Bcl-2 expression in human MCF-7 cells. J Fourth Military Med Univ 2005;26:1877–1880.Google Scholar
  32. 32.
    Chen KJ, Lu AP. From Chinese version of integrative medicine to globalized integrative medicine: Impression on the 3rd World Integrative Medicine Congress. Chin J Integr Med 2007;13:244–245.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang XM, Fu H, Liu GX, Zhu W, Li L, Yang JX. Effect of modified Wuzi Yanzong Granule on patients with mild cognitive impairment from oxidative damage aspect. Chin J lntegr Med 2007;13:258–263.CrossRefGoogle Scholar
  34. 34.
    Wang XM, Fu H, Liu GX, Song P, Tu PF, Wang YH. Clinical study on treatment of mild cognitive impairment by modified Wuzi Yanzong Granule. Chin J Integr Tradit West Med (Chin) 2004;24:392–395.Google Scholar
  35. 35.
    Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999;397:271–274.CrossRefPubMedGoogle Scholar
  36. 36.
    Sato N, Imaizumi K, Manabe T, Taniguchi M, Hitomi J, Katayama T, et al. Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin-2. J Biol Chem 2001;276:2108–2114.CrossRefPubMedGoogle Scholar
  37. 37.
    Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 2000;275:35661–35664.CrossRefPubMedGoogle Scholar
  38. 38.
    Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001;105:891–902.CrossRefPubMedGoogle Scholar
  39. 39.
    Imaizumi K, Miyoshi K, Katayama T, Yoneda T, Taniguchi M, Kudo T, et al. The unfolded protein response and Alzheimer’s disease. Biophys Biochem Acta 2001;1536:85–96.Google Scholar
  40. 40.
    Imaizumi K, Katayama T, Tohyama M. Presenilin and UPR. Nat Cell Biol 2001;3:E104.CrossRefPubMedGoogle Scholar
  41. 41.
    Katayama T, Imatzumi K, Sate N, Miyoshi K, Kudo T, Hitomi J, et al. Presenilin-1 mutations down-regulate the signaling pathway of the unfolded-protein response. Nat Cell Biol 1999;1:479–485.CrossRefPubMedGoogle Scholar
  42. 42.
    Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M. Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 2004;28:67–78.CrossRefPubMedGoogle Scholar
  43. 43.
    Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134:877–886.CrossRefPubMedGoogle Scholar
  44. 44.
    Li YH, Wu ZZ, Wu WK, Li M, Wang JG, Yang M, et al. Rat mesenchymal stem cells oriented differentiation into neuron-like cells induced by natural cerebrolysin. Chin J Pathophysiol (Chin) 2009;25:1548–1553.Google Scholar

Copyright information

© Chinese Association of the Integration of Traditional and Western Medicine and Springer Berlin Heidelberg 2010

Authors and Affiliations

  • Zheng-zhi Wu (吴正治)
    • 1
  • Ying-hong Li (李映红)
    • 1
  • Andrew C. J. Huang
    • 2
  • Ming Li (李 明)
    • 1
  • Xiao-li Zhang (张晓丽)
    • 1
  • Ji-guo Wang (王济国)
    • 1
  • Min Yang (杨 敏)
    • 1
  • Man-yin Chen (陈 茵)
    • 1
  1. 1.Shenzhen Hospital of Southern Medical UniversityShenzhen, Guangdong ProvinceChina
  2. 2.Larry Hillblom Islet Research Center, David Geffen School of MedicineUCLALos AngelesUSA

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