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Spinosin Inhibits Aβ1-42 Production and Aggregation via Activating Nrf2/HO-1 Pathway

  • Zhang, Xiaoying (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University) ;
  • Wang, Jinyu (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University) ;
  • Gong, Guowei (Department of Bioengineering, Zunyi Medical University, Zhuhai Campus) ;
  • Ma, Ruixin (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University) ;
  • Xu, Fanxing (Wuya College of Innovation, Shenyang Pharmaceutical University) ;
  • Yan, Tingxu (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University) ;
  • Wu, Bo (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University) ;
  • Jia, Ying (Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University)
  • Received : 2019.07.21
  • Accepted : 2019.10.15
  • Published : 2020.05.01

Abstract

The present research work primarily investigated whether spinosin has the potential of improving the pathogenesis of Alzheimer's disease (AD) driven by β-amyloid (Aβ) overproduction through impacting the procession of amyloid precursor protein (APP). Wild type mouse Neuro-2a cells (N2a/WT) and N2a stably expressing human APP695 (N2a/APP695) cells were treated with spinosin for 24 h. The levels of APP protein and secreted enzymes closely related to APP procession were examined by western blot analysis. Oxidative stress related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were detected by immunofluorescence assay and western blot analysis, respectively. The intracellular reactive oxygen species (ROS) level was analyzed by flow cytometry, the levels of Aβ1-42 were determined by ELISA kit, and Thioflavin T (ThT) assay was used to detect the effect of spinosin on Aβ1-42 aggregation. The results showed that ROS induced the expression of ADAM10 and reduced the expression of BACE1, while spinosin inhibited ROS production by activating Nrf2 and up-regulating the expression of HO-1. Additionally, spinosin reduced Aβ1-42 production by impacting the procession of APP. In addition, spinosin inhibited the aggregation of Aβ1-42. In conclusion, spinosin reduced Aβ1-42 production by activating the Nrf2/HO-1 pathway in N2a/WT and N2a/APP695 cells. Therefore, spinosin is expected to be a promising treatment of AD.

Keywords

References

  1. Agati, G., Azzarello, E., Pollastri, S. and Tattini, M. (2012) Flavonoids as antioxidants in plants: location and functional significance. Plant Sci. 196, 67-76. https://doi.org/10.1016/j.plantsci.2012.07.014
  2. Ahmad, W., Ijaz, B., Shabbiri, K., Ahmed, F. and Rehman, S. (2017) Oxidative toxicity in diabetes and Alzheimer's disease: mechanisms behind ROS/ RNS generation. J. Biomed. Sci. 24, 76. https://doi.org/10.1186/s12929-017-0379-z
  3. Bao, L., Li, J., Zha, D., Zhang, L., Gao, P., Yao, T. and Wu, X. (2018) Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-kB pathways. Int. Immunopharmacol. 54, 245-253. https://doi.org/10.1016/j.intimp.2017.11.021
  4. Bao, T., Wang, Y., Li, Y. T., Gowd, V., Niu, X. H., Yang, H. Y., Chen, L. S., Chen, W. and Sun, C. D. (2016) Antioxidant and antidiabetic properties of tartary buckwheat rice flavonoids after in vitro digestion. J. Zhejiang Univ. Sci. B 17, 941-951. https://doi.org/10.1631/jzus.B1600243
  5. Bloom, G. S., Ren, K. and Glabe, C. G. (2005) Cultured cell and transgenic mouse models for tau pathology linked to $\beta$-amyloid. Biochim. Biophys. Acta 1739, 116-124. https://doi.org/10.1016/j.bbadis.2004.08.008
  6. Cervellati, C., Wood, P. L., Romani, A., Valacchi, G., Squerzanti, M., Sanz, J. M., Ortolani, B. and Zuliani, G. (2016) Oxidative challenge in Alzheimer's disease: state of knowledge and future needs. J. Investig. Med. 64, 21-32. https://doi.org/10.1136/jim-2015-000017
  7. Corbett, G. T., Gonzalez, F. J. and Pahan, K. (2015) Activation of peroxisome proliferator-activated receptor alpha stimulates ADAM10-mediated proteolysis of APP. Proc. Natl. Acad. Sci. U.S.A. 112, 8445-8450. https://doi.org/10.1073/pnas.1504890112
  8. Das, U., Wang, L., Ganguly, A., Saikia, J. M., Wagner, S. L., Koo, E. H. and Roy, S. (2016) Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat. Neurosci. 19, 55-64. https://doi.org/10.1038/nn.4188
  9. Dawkins, E. and Small, D. H. (2014) Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer's disease. J. Neurochem. 129, 756-769. https://doi.org/10.1111/jnc.12675
  10. Fang, X., Hao, J. F., Zhou, H. Y., Zhu, L. X., Wang, J. H. and Song, F. Q. (2010) Pharmacological studies on the sedative-hypnotic effect of Semen Ziziphi spinosae (Suanzaoren) and Radix et Rhizoma Salviae miltiorrhizae (Danshen) extracts and the synergistic effect of their combinations. Phytomedicine 17, 75-80. https://doi.org/10.1016/j.phymed.2009.07.004
  11. Guan, L. P. and Liu, B. Y. (2016) Antidepressant-like effects and mechanisms of flavonoids and related analogues. Eur. J. Med. Chem. 121, 47-57. https://doi.org/10.1016/j.ejmech.2016.05.026
  12. Jeong, H., Liu, Y. and Kim, H. S. (2017) Dried plum and chokeberry ameliorate d-galactose-induced aging in mice by regulation of Pl3k/Akt-mediated Nrf2 and Nf-kB pathways. Exp. Gerontol. 95, 16-25. https://doi.org/10.1016/j.exger.2017.05.004
  13. Jia, M., Chen, X., Liu, J. and Chen, J. (2018) PTEN promotes apoptosis of H2O2injured rat nasal epithelial cells through PI3K/Akt and other pathways. Mol. Med. Rep. 17, 571-579.
  14. Jiang, N., Ding, J., Liu, J., Sun, X., Zhang, Z., Mo, Z., Li, X., Yin, H., Tang, W. and Xie, S. S. (2019) Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with beta-amyloid antiaggregation properties for the treatment of Alzheimer's disease. Bioorg. Chem. 89, 103027. https://doi.org/10.1016/j.bioorg.2019.103027
  15. Jung, H. A., Abdul, Q. A., Byun, J. S., Joung, E. J., Gwon, W. G., Lee, M. S., Kim, H. R. and Choi, J. S. (2017) Protective effects of flavonoids isolated from Korean milk thistle Cirsium japonicum var. maackii (Maxim.) Matsum on tert-butyl hydroperoxide-induced hepatotoxicity in HepG2 cells. J. Ethnopharmacol. 209, 62-72. https://doi.org/10.1016/j.jep.2017.07.027
  16. Kim, C. Y., Kang, B., Suh, H. J. and Choi, H. S. (2018) Red ginsengderived saponin fraction suppresses the obesity-induced inflammatory responses via Nrf2-HO-1 pathway in adipocyte-macrophage co-culture system. Biomed. Pharmacother. 108, 1507-1516. https://doi.org/10.1016/j.biopha.2018.09.169
  17. Ko, S. Y., Lee, H. E., Park, S. J., Jeon, S. J., Kim, B., Gao, Q., Jang, D. S. and Ryu, J. H. (2015) Spinosin, a C-glucosylflavone, from Zizyphus jujuba var. spinosa ameliorates Abeta1-42 oligomer-induced memory impairment in mice. Biomol. Ther. (Seoul) 23, 156-164. https://doi.org/10.4062/biomolther.2014.110
  18. Ko, S. Y., Lin, Y. P., Lin, Y. S. and Chang, S. S. (2010) Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species. Free Radic. Biol. Med. 49, 474-480. https://doi.org/10.1016/j.freeradbiomed.2010.05.005
  19. Lane, C. A., Hardy, J. and Schott, J. M. (2018) Alzheimer's disease. Eur. J. Neurol. 25, 59-70. https://doi.org/10.1111/ene.13439
  20. Lee, H. J., Ryu, J. M., Jung, Y. H., Lee, S. J., Kim, J. Y., Lee, S. H., Hwang, I. K., Seong, J. K. and Han, H. J. (2016a) High glucose upregulates BACE1-mediated Abeta production through ROSdependent HIF-1alpha and LXRalpha/ABCA1-regulated lipid raft reorganization in SK-N-MC cells. Sci. Rep. 6, 36746. https://doi.org/10.1038/srep36746
  21. Lee, Y., Jeon, S. J., Lee, H. E., Jung, I. H., Jo, Y. W., Lee, S., Cheong, J. H., Jang, D. S. and Ryu, J. H. (2016b) Spinosin, a C-glycoside flavonoid, enhances cognitive performance and adult hippocampal neurogenesis in mice. Pharmacol. Biochem. Behav. 145, 9-16. https://doi.org/10.1016/j.pbb.2016.03.007
  22. Li, X., Smid, S. D., Lin, J., Gong, Z., Chen, S., You, F., Zhang, Y., Hao, Z., Lin, H., Yu, X. and Jin, X. (2019) Neuroprotective and anti-amyloid beta effect and main chemical profiles of white tea: comparison against green, oolong and black tea. Molecules 24, E1926.
  23. Li, Y. J., Dai, Y. H., Yu, Y. L., Li, Y. and Deng, Y. L. (2007) Pharmacokinetics and tissue distribution of spinosin after intravenous administration in rats. Yakugaku Zasshi 127, 1231-1235. https://doi.org/10.1248/yakushi.127.1231
  24. Liu, J., Zhai, W. M., Yang, Y. X., Shi, J. L., Liu, Q. T., Liu, G. L., Fang, N., Li, J. and Guo, J. Y. (2015) GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice. Pharmacol. Biochem. Behav. 128, 41-49. https://doi.org/10.1016/j.pbb.2014.11.003
  25. Liu, X., Wang, L., Cai, J., Liu, K., Liu, M., Wang, H. and Zhang, H. (2019) N-acetylcysteine alleviates H2O2-induced damage via regulating the redox status of intracellular antioxidants in H9c2 cells. Int. J. Mol. Med. 43, 199-208.
  26. Loboda, A., Damulewicz, M., Pyza, E., Jozkowicz, A. and Dulak, J. (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell. Mol. Life Sci. 73, 3221-3247. https://doi.org/10.1007/s00018-016-2223-0
  27. Lu, X. Z., Yang, Z. H., Zhang, H. J., Zhu, L. L., Mao, X. L. and Yuan, Y. (2017) MiR-214 protects MC3T3-E1 osteoblasts against H2O2-induced apoptosis by suppressing oxidative stress and targeting ATF4. Eur. Rev. Med. Pharmacol. Sci. 21, 4762-4770.
  28. Meng, Q. T., Cao, C., Wu, Y., Liu, H. M., Li, W., Sun, Q., Chen, R., Xiao, Y. G., Tang, L. H., Jiang, Y., Leng, Y., Lei, S. Q., Lee, C. C., Barry, D. M., Chen, X. and Xia, Z. Y. (2016) Ischemic post-conditioning attenuates acute lung injury induced by intestinal ischemia-reperfusion in mice: role of Nrf2. Lab. Invest. 96, 1087-1104. https://doi.org/10.1038/labinvest.2016.87
  29. Nesi, G., Sestito, S., Digiacomo, M. and Rapposelli, S. (2017) Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease. Curr. Top. Med. Chem. 17, 3062-3079.
  30. Park, W. H. (2016) Exogenous H2O2 induces growth inhibition and cell death of human pulmonary artery smooth muscle cells via glutathione depletion. Mol. Med. Rep. 14, 936-942. https://doi.org/10.3892/mmr.2016.5307
  31. Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., Flamez, P., Dequenne, A., Godaux, E., van Leuven, F. and Fahrenholz, F. (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1456-1464. https://doi.org/10.1172/JCI20864
  32. Ren, J., Yuan, L., Wang, W., Zhang, M., Wang, Q., Li, S., Zhang, L. and Hu, K. (2019) Tricetin protects against 6-OHDA-induced neurotoxicity in Parkinson's disease model by activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway. Toxicol. Appl. Pharmacol. 378, 114617. https://doi.org/10.1016/j.taap.2019.114617
  33. Singh, A., Venkannagari, S., Oh, K. H., Zhang, Y. Q., Rohde, J. M., Liu, L., Nimmagadda, S., Sudini, K., Brimacombe, K. R., Gajghate, S., Ma, J., Wang, A., Xu, X., Shahane, S. A., Xia, M., Woo, J., Mensah, G. A., Wang, Z., Ferrer, M., Gabrielson, E., Li, Z., Rastinejad, F., Shen, M., Boxer, M. B. and Biswal, S. (2016) Small Molecule Inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem. Biol. 11, 3214-3225. https://doi.org/10.1021/acschembio.6b00651
  34. Suzuki, T., Motohashi, H. and Yamamoto, M. (2013) Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol. Sci. 34, 340-346. https://doi.org/10.1016/j.tips.2013.04.005
  35. Takekoshi, S., Nagata, H. and Kitatani, K. (2014) Flavonoids enhance melanogenesis in human melanoma cells. Tokai J. Exp. Clin. Med. 39, 116-121.
  36. Wang, X., Zhou, X., Li, G., Zhang, Y., Wu, Y. and Song, W. (2017) Modifications and trafficking of APP in the pathogenesis of Alzheimer's disease. Front. Mol. Neurosci. 10, 294. https://doi.org/10.3389/fnmol.2017.00294
  37. Wang, X. J., Hayes, J. D., Henderson, C. J. and Wolf, C. R. (2007) Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc. Natl. Acad. Sci. U.S.A. 104, 19589-19594. https://doi.org/10.1073/pnas.0709483104
  38. Wang, Z., Huang, X., Zhao, P., Zhao, L. and Wang, Z. Y. (2018) Catalpol inhibits amyloid-beta generation through promoting alphacleavage of APP in Swedish mutant APP overexpressed N2a cells. Front. Aging Neurosci. 10, 66. https://doi.org/10.3389/fnagi.2018.00066
  39. Xu, F., He, B., Xiao, F., Yan, T., Bi, K., Jia, Y. and Wang, Z. (2019) Neuroprotective effects of Spinosin on recovery of learning and memory in a mouse model of Alzheimer's disease. Biomol. Ther. (Seoul) 27, 71-77. https://doi.org/10.4062/biomolther.2018.051
  40. Yang, H., Xie, Y., Yang, D. and Ren, D. (2017) Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget 8, 25310-25322. https://doi.org/10.18632/oncotarget.15813
  41. Zhang, J., Dong, Y., Xu, Z., Zhang, Y., Pan, C., McAuliffe, S., Ichinose, F., Yue, Y., Liang, W. and Xie, Z. (2011) 2-Deoxy-D-glucose attenuates isoflurane-induced cytotoxicity in an in vitro cell culture model of H4 human neuroglioma cells. Anesth. Analg. 113, 1468-1475. https://doi.org/10.1213/ane.0b013e31822e913c
  42. Zhang, X. and Song, W. (2013) The role of APP and BACE1 trafficking in APP processing and amyloid-beta generation. Alzheimers Res. Ther. 5, 46. https://doi.org/10.1186/alzrt211

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