Skip to main content
SpringerLink
Log in

Higenamine mitigates interleukin-1β-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Intervertebral disc degeneration (IDD) is a natural problem linked to the inflammation. Higenamine exerts multiple pharmacological properties in inflammation-related disorders. Our study aimed to explore the function of higenamine on interleukin (IL)-1β-caused apoptosis of human nucleus pulposus cells (HNPCs). Cell apoptosis was investigated by TUNEL and flow cytometry. Apoptosis-related biomarkers were determined by qRT-PCR or Western blotting. The protein in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling was measured by Western blotting. We found that higenamine showed little effect on cell apoptosis, but mitigated IL-1β-caused apoptosis in a dose-dependent pattern. Higenamine attenuated IL-1β-induced decrease of Bcl-2 and increase of Bax and cleaved caspase-3. Higenamine did not affect the reactive oxygen species (ROS) level and the PI3K/Akt signaling, but attenuated IL-1β-induced ROS production and inhibition of the PI3K/Akt signaling. IL-1β repressed the activation of the PI3K/Akt pathway, but ROS inhibition using N-acetylcysteine (NAC) rescued this pathway. The PI3K/Akt signaling suppression using LY294002 reversed the inhibitive effect of higenamine on IL-1β-caused apoptosis, and this effect was weakened by ROS inhibition. In conclusion, higenamine attenuates IL-1β-caused apoptosis of HNPCs via ROS-mediated PI3K/Akt pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The analyzed data are available from the corresponding author on reasonable request.

References

  1. Kos N, Gradisnik L, Velnar T (2019) A brief review of the degenerative intervertebral disc disease. Med Arch 73:421–424

    Article  Google Scholar 

  2. Wang Y, Che M, Xin J, Zheng Z, Li J, Zhang S (2020) The role of IL-1β and TNF-α in intervertebral disc degeneration. Biomed Pharmacother 131:110660

    Article  CAS  Google Scholar 

  3. Priyadarshani P, Li Y, Yao L (2016) Advances in biological therapy for nucleus pulposus regeneration. Osteoarthr Cartil 24:206–212

    Article  CAS  Google Scholar 

  4. Zhu L, Yu C, Zhang X, Yu Z, Zhan F, Yu X, Wang S, He F, Han Y, Zhao H (2020) The treatment of intervertebral disc degeneration using Traditional Chinese Medicine. J Ethnopharmacol 263:113117

    Article  CAS  Google Scholar 

  5. Chen Y, Guo B, Zhang H, Hu L, Wang J (2019) Higenamine, a dual agonist for β1- and β2-adrenergic receptors identified by screening a traditional Chinese medicine library. Planta Med 85:738–744

    Article  CAS  Google Scholar 

  6. Feng S, Jiang J, Hu P, Zhang JY, Liu T, Zhao Q, Li BL (2012) A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacol Sin 33:1353–1358

    Article  CAS  Google Scholar 

  7. Erasto P, Omolo J, Sunguruma R, Munissi JJ, Wiketye V, de Konig C, Ahmed AF (2018) Evaluation of antimycobacterial activity of higenamine using Galleria mellonella as an in vivo infection model. Nat Prod Bioprospect 8:63–69

    Article  CAS  Google Scholar 

  8. Romeo I, Parise A, Galano A, Russo N, Alvarez-Idaboy JR, Marino T (2020) The antioxidant capability of higenamine: insights from theory. Antioxidants (Basel) 9:38

    Article  Google Scholar 

  9. Yang S, Chu S, Ai Q, Zhang Z, Gao Y, Lin M, Liu Y, Hu Y, Li X, Peng Y, Pan Y, He Q, Chen N (2020) Anti-inflammatory effects of higenamine (Hig) on LPS-activated mouse microglia (BV2) through NF-κB and Nrf2/HO-1 signaling pathways. Int Immunopharmacol 85:106629

    Article  CAS  Google Scholar 

  10. Bai X, Ding W, Yang S, Guo X (2019) Higenamine inhibits IL-1β-induced inflammation in human nucleus pulposus cells. Biosci Rep 39:BSR20190857

    Article  CAS  Google Scholar 

  11. Ha YM, Kim MY, Park MK, Lee YS, Kim YM, Kim HJ, Lee JH, Chang KC (2012) Higenamine reduces HMGB1 during hypoxia-induced brain injury by induction of heme oxygenase-1 through PI3K/Akt/Nrf-2 signal pathways. Apoptosis 17:463–474

    Article  CAS  Google Scholar 

  12. Chen YL, Zhuang XD, Xu ZW, Lu LH, Guo HL, Wu WK, Liao XX (2013) Higenamine combined with [6]-gingerol suppresses doxorubicin-triggered oxidative stress and apoptosis in cardiomyocytes via upregulation of PI3K/Akt pathway. Evid Based Complement Altern Med 2013:970490

    Google Scholar 

  13. An X, Long C, Deng X, Tang A, Xie J, Chen L, Wang Z (2017) Higenamine inhibits apoptosis and maintains survival of gastric smooth muscle cells in diabetic gastroparesis rat model via activating the β2-AR/PI3K/AKT pathway. Biomed Pharmacother 95:1710–1717

    Article  CAS  Google Scholar 

  14. Guo X, Bai X, Zhang F, Zheng L, Ding W, Yang S (2020) Resveratrol protects against apoptosis induced by interleukin-1β in nucleus pulposus cells via activating mTOR/caspase-3 and GSK-3β/caspase-3 pathways. Biosci Rep 40:BSR20202019

    Article  CAS  Google Scholar 

  15. Qi W, Ren D, Wang P, Song Z, Wu H, Yao S, Geng L, Su Y, Bai X (2020) Upregulation of Sirt1 by tyrosol suppresses apoptosis and inflammation and modulates extracellular matrix remodeling in interleukin-1β-stimulated human nucleus pulposus cells through activation of PI3K/Akt pathway. Int Immunopharmacol 88:106904

    Article  CAS  Google Scholar 

  16. Wang W, Li P, Xu J, Wu X, Guo Z, Fan L, Song R, Wang J, Wei L, Teng H (2018) Resveratrol attenuates high glucose-induced nucleus pulposus cell apoptosis and senescence through activating the ROS-mediated PI3K/Akt pathway. Biosci Rep 38:BSR20171454

    Article  CAS  Google Scholar 

  17. Xu Y, Yao H, Wang Q, Xu W, Liu K, Zhang J, Zhao H, Hou G (2018) Aquaporin-3 attenuates oxidative stress-induced nucleus pulposus cell apoptosis through regulating the P38 MAPK pathway. Cell Physiol Biochem 50:1687–1697

    Article  CAS  Google Scholar 

  18. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402–408

    Article  CAS  Google Scholar 

  19. Oichi T, Taniguchi Y, Oshima Y, Tanaka S, Saito T (2020) Pathomechanism of intervertebral disc degeneration. JOR Spine 3:e1076

    Article  Google Scholar 

  20. Tendulkar G, Chen T, Ehnert S, Kaps HP, Nussler AK (2019) Intervertebral disc nucleus repair: hype or hope? Int J Mol Sci 20:3622

    Article  CAS  Google Scholar 

  21. Wang D, He X, Wang D, Peng P, Xu X, Gao B, Zheng C, Wang H, Jia H, Shang Q, Sun Z, Luo Z, Yang L (2020) Quercetin suppresses apoptosis and attenuates intervertebral disc degeneration via the SIRT1-autophagy pathway. Front Cell Dev Biol 8:613006

    Article  Google Scholar 

  22. Guo HY, Guo MK, Wan ZY, Song F, Wang HQ (2020) Emerging evidence on noncoding-RNA regulatory machinery in intervertebral disc degeneration: a narrative review. Arthritis Res Ther 22:270

    Article  CAS  Google Scholar 

  23. Zhang Y, Zhang J, Wu C, Guo S, Su J, Zhao W, Xing H (2019) Higenamine protects neuronal cells from oxygen-glucose deprivation/reoxygenation-induced injury. J Cell Biochem 120:3757–3764

    Article  CAS  Google Scholar 

  24. Nagata S (2018) Apoptosis and clearance of apoptotic cells. Annu Rev Immunol 36:489–517

    Article  CAS  Google Scholar 

  25. Warren CFA, Wong-Brown MW, Bowden NA (2019) BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 10:177

    Article  Google Scholar 

  26. Tang JY, Ou-Yang F, Hou MF, Huang HW, Wang HR, Li KT, Fayyaz S, Shu CW, Chang HW (2019) Oxidative stress-modulating drugs have preferential anticancer effects—involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration. Semin Cancer Biol 58:109–117

    Article  CAS  Google Scholar 

  27. Xu W, Zhang X, Liu G, Zhu M, Wu Y, Jie Z, Xie Z, Wang S, Ma Q, Fan S, Fang X (2020) Oxidative stress abrogates the degradation of KMT2D to promote degeneration in nucleus pulposus. Biochim Biophys Acta 1866:165888

    Article  CAS  Google Scholar 

  28. Chen ZB, Yu YB, Wa QB, Zhou JW, He M, Cen Y (2020) The role of quinazoline in ameliorating intervertebral disc degeneration by inhibiting oxidative stress and anti-inflammation via NF-κB/MAPKs signaling pathway. Eur Rev Med Pharmacol Sci 24:2077–2086

    PubMed  Google Scholar 

  29. Yu W, Fu J, Liu Y, Wu Y, Jiang D (2018) Osteogenic protein-1 inhibits nucleus pulposus cell apoptosis through regulating the NF-κB/ROS pathway in an inflammation environment. Biosci Rep 38:BSR20181530

    Article  Google Scholar 

  30. Koundouros N, Poulogiannis G (2018) Phosphoinositide 3-kinase/Akt signaling and redox metabolism in cancer. Front Oncol 8:160

    Article  Google Scholar 

  31. Ming-Yan Y, Jing Z, Shu-Qin G, Xiao-Liang B, Zhi-Hong L, Xue Z (2019) Liraglutide inhibits the apoptosis of human nucleus pulposus cells induced by high glucose through PI3K/Akt/caspase-3 signaling pathway. Biosci Rep 39:BSR20190109

    Article  Google Scholar 

  32. Guan J, Lin H, Xie M, Huang M, Zhang D, Ma S, Bian W, Zhan Q, Zhao G (2019) Higenamine exerts an antispasmodic effect on cold-induced vasoconstriction by regulating the PI3K/Akt, ROS/α2C-AR and PTK9 pathways independently of the AMPK/eNOS/NO axis. Exp Ther Med 18:1299–1308

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Duan W, Chen J, Wu Y, Zhang Y, Xu Y (2016) Protective effect of higenamine ameliorates collagen-induced arthritis through heme oxygenase-1 and PI3K/Akt/Nrf-2 signaling pathways. Exp Ther Med 12:3107–3112

    Article  CAS  Google Scholar 

  34. Zhang N, Lian Z, Peng X, Li Z, Zhu H (2017) Applications of Higenamine in pharmacology and medicine. J Ethnopharmacol 196:242–252

    Article  CAS  Google Scholar 

  35. Wen J, Ma X, Niu M, Hao J, Huang Y, Wang R, Li R, Wang J, Zhao Y (2020) Metabolomics coupled with integrated approaches reveal the therapeutic effects of higenamine combined with [6]-gingerol on doxorubicin-induced chronic heart failure in rats. Chin Med 15:120

    Article  CAS  Google Scholar 

  36. Lee YS, Kang YJ, Kim HJ, Park MK, Seo HG, Lee JH, Yun-Choi HS, Chang KC (2006) Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. Apoptosis 11:1091–1100

    Article  CAS  Google Scholar 

  37. Wu MP, Zhang YS, Zhou QM, Xiong J, Dong YR, Yan C (2016) Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway. Pharmacol Res 104:115–123

    Article  CAS  Google Scholar 

  38. Yang X, Du W, Zhang Y, Wang H, He M (2020) Neuroprotective effects of higenamine against the Alzheimer’s disease via amelioration of cognitive impairment, Aβ burden, apoptosis and regulation of Akt/GSK3β signaling pathway. Dose Response 18:1559325820972205

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

None.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Geriatrics, Baoding No. 1 Central Hospital, Baoding, 071000, China

    Xiaojuan Zhu, Zhijiao Cao & Yulan Li

  2. Emergency Department, Baoding No. 1 Central Hospital, Baoding, 071000, China

    Shichao Liu

  3. Department of Anesthesiology, Baoding No. 1 Central Hospital, Baoding, 071000, China

    Lei Yang

  4. Department of Orthopedic, Baoding No. 1 Central Hospital, No. 320 North Changcheng Avenue, Baoding, 071000, China

    Fang Lu & Xiaoliang Bai

  5. Department of Respiratory Medicine, Laishui County Hospital, Baoding, 071000, China

    Lili Hu

Authors
  1. Xiaojuan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shichao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhijiao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yulan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lili Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoliang Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XZ performed the experiments and drafted the paper. SL and ZC performed the experiments. LY, FL, and YL collected and analyzed the data. LH and XB designed the study.

Corresponding author

Correspondence to Xiaoliang Bai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, X., Liu, S., Cao, Z. et al. Higenamine mitigates interleukin-1β-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling. Mol Cell Biochem 476, 3889–3897 (2021). https://doi.org/10.1007/s11010-021-04197-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04197-z

Keywords

Search

Navigation