Skip to main content

Advertisement

SpringerLink
Log in

The Secretion from Bone Marrow Mesenchymal Stem Cells Pretreated with Berberine Rescues Neurons with Oxidative Damage Through Activation of the Keap1-Nrf2-HO-1 Signaling Pathway

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Oxidative stress is a potential pathological mechanism of Alzheimer’s disease (AD). Berberine (BBR) can improve antioxidative capacity and inhibit Aβ protein aggregation and tau protein hyperphosphorylation in AD, and stem cell therapy is also increasingly recognized as a therapy for AD. Bone marrow mesenchymal stem cells (BMSCs) have many advantages, as they exhibit antioxidant and anti-inflammatory activity and secrete a variety of neurotrophic factors, and play important roles in neurodegenerative disease treatment. In this study, we investigated the antioxidant effects of secretions from BMSCs pretreated with BBR on tert-butyl hydroperoxide (t-BHP)–damaged neurons. We demonstrated that BBR can enhance BMSC viability and the secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both of which are vital neurotrophic factors that maintain neuronal growth. Moreover, conditioned medium from BBR-treated BMSCs (BBR-BMSC-CM) reduced reactive oxygen species (ROS) production, attenuated a decrease in the mitochondrial membrane potential, and ameliorated neuronal apoptosis by decreasing levels of the apoptotic proteins Bax/Bcl-2, cytochrome c, and cleaved caspase-3/caspase-3. In addition, increased synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) levels indicated that neuronal synaptic function was restored. Further study revealed that BBR-BMSC-CM activated the antioxidant proteins Keap1, Nrf2, and HO-1. In conclusion, our results showed that BBR-BMSC-CM attenuated apoptosis and oxidative damage in neurons by activating the Keap1-Nrf2-HO-1 signaling pathway. Taken together, these results also suggest BBR as a drug to stimulate the secretion of nutritional cytokines with the potential to treat AD.

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. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ali T, Kim T, Rehman SU, Khan MS, Amin FU, Khan M, Ikram M, Kim MO (2018) Natural dietary supplementation of anthocyanins via PI3K/Akt/Nrf2/HO-1 pathways mitigate oxidative stress, neurodegeneration, and memory impairment in a mouse model of Alzheimer’s disease. Mol Neurobiol 55:6076–6093

    CAS  PubMed  Google Scholar 

  • Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, Maruyama K (2007) Berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Abeta secretion. Biochem Biophys Res Commun 352:498–502

    CAS  PubMed  Google Scholar 

  • Bao F, Tao L, Zhang H (2019) Neuroprotective effect of natural alkaloid Fangchinoline against oxidative glutamate toxicity: involvement of Keap1-Nrf2 axis regulation. Cell Mol Neurobiol

  • Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, Ganie SA (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother 74:101–110

    CAS  PubMed  Google Scholar 

  • Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403

    CAS  PubMed  Google Scholar 

  • Burns A, Byrne EJ, Maurer K (2002) Alzheimer’s disease. Lancet 360:163–165

    PubMed  Google Scholar 

  • Chen XQ, Sawa M, Mobley WC (2018) Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome. Free Radic Biol Med 114:52–61

    CAS  PubMed  Google Scholar 

  • Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, Kim E, Rompala A, Oram MK, Asselin C, Aronson J, Zhang C, Miller SJ, Lesinski A, Chen JW, Kim DY, van Praag H, Spiegelman BM, Gage FH, Tanzi RE (2018) Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science:361

  • Cui Y, Xu N, Xu W, Xu G (2017) Mesenchymal stem cells attenuate hydrogen peroxide-induced oxidative stress and enhance neuroprotective effects in retinal ganglion cells. In Vitro Cell Dev Biol Anim 53:328–335

    CAS  PubMed  Google Scholar 

  • Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl JA (2004) The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol 24:8477–8486

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Oliveira JS, Abdalla FH, Dornelles GL, Adefegha SA, Palma TV, Signor C, da Silva BJ, Baldissarelli J, Lenz LS, Magni LP, Rubin MA, Pillat MM, de Andrade CM (2016) Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: involvement of acetylcholinesterase and cell death. Neurotoxicology 57:241–250

    PubMed  Google Scholar 

  • de Oliveira JS, Abdalla FH, Dornelles GL, Palma TV, Signor C, da Silva BJ, Baldissarelli J, Lenz LS, de Oliveira VA, Chitolina Schetinger MR, Melchiors Morsch VM, Rubin MA, de Andrade CM (2019) Neuroprotective effects of berberine on recognition memory impairment, oxidative stress, and damage to the purinergic system in rats submitted to intracerebroventricular injection of streptozotocin. Psychopharmacology 236:641–655

    PubMed  Google Scholar 

  • Gao Y, Li J, Chu S, Zhang Z, Chen N, Li L, Zhang L (2020) Ginsenoside Rg1 protects mice against streptozotocin-induced type 1 diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathways. Eur J Pharmacol 866:172801

    PubMed  Google Scholar 

  • Guy R, Grynspan F, Ben-Zur T, Panski A, Lamdan R, Danon U, Yaffe D, Offen D (2019) Human muscle progenitor cells overexpressing neurotrophic factors improve neuronal regeneration in a sciatic nerve injury mouse model. Front Neurosci 13:151

    PubMed  PubMed Central  Google Scholar 

  • Hadjigeorgiou G (2008) Oxidative stress, mitochondrial dysfunction and Alzheimer’s disease. Ann General Psychiatry 7

  • Han D, Chen S, Fang S, Liu S, Jin M, Guo Z, Yuan Y, Wang Y, Liu C, Mei X (2017) The neuroprotective effects of muscle-derived stem cells via brain-derived neurotrophic factor in spinal cord injury model. Biomed Res Int 2017:1972608

    PubMed  PubMed Central  Google Scholar 

  • Huang C, Gan D, Fan C, Wen C, Li A, Li Q, Zhao J, Wang Z, Zhu L, Lu D (2018) The secretion from neural stem cells pretreated with lycopene protects against tert-butyl hydroperoxide-induced neuron oxidative damage. Oxidative Med Cell Longev 2018:5490218

    Google Scholar 

  • Ishii T, Warabi E, Mann GE (2019) Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis. Free Radic Biol Med 133:169–178

    CAS  PubMed  Google Scholar 

  • Jaiswal AK (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36:1199–1207

    CAS  PubMed  Google Scholar 

  • Jiang Q, Liu P, Wu X, Liu W, Shen X, Lan T, Xu S, Peng J, Xie X, Huang H (2011) Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: involvement of NF-kappaB signaling pathway. Mol Cell Endocrinol 331:34–40

    CAS  PubMed  Google Scholar 

  • Jung HY, Kim DW, Yim HS, Yoo DY, Kim JW, Won MH, Yoon YS, Choi SY, Hwang IK (2016) Heme oxygenase-1 protects neurons from ischemic damage by upregulating expression of Cu,Zn-superoxide dismutase, catalase, and brain-derived neurotrophic factor in the rabbit spinal cord. Neurochem Res 41:869–879

    CAS  PubMed  Google Scholar 

  • Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344–1351

    CAS  PubMed  Google Scholar 

  • Kwak KA, Lee SP, Yang JY, Park YS (2018) Current perspectives regarding stem cell-based therapy for Alzheimer’s disease. Stem Cells Int 2018:6392986

    PubMed  PubMed Central  Google Scholar 

  • Li W, Liu Y, Wang B, Luo Y, Hu N, Chen D, Zhang X, Xiong Y (2016) Protective effect of berberine against oxidative stress-induced apoptosis in rat bone marrow-derived mesenchymal stem cells. Exp Ther Med 12:4041–4048

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Tang Z, Chu P, Song Y, Yang Y, Sun B, Niu M, Qaed E, Shopit A, Han G, Ma X, Peng J, Hu M, Tang Z (2018) Neuroprotective effect of phosphocreatine on oxidative stress and mitochondrial dysfunction induced apoptosis in vitro and in vivo: involvement of dual PI3K/Akt and Nrf2/HO-1 pathways. Free Radic Biol Med 120:228–238

    PubMed  Google Scholar 

  • Liang F, Fang Y, Cao W, Zhang Z, Pan S, Xu X (2018) Attenuation of tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in HepG2 cells by tangeretin: relevance of the Nrf2-ARE and MAPK signaling pathways. J Agric Food Chem 66:6317–6325

    CAS  PubMed  Google Scholar 

  • Lin X, Zhang N (2018) Berberine: pathways to protect neurons. Phytother Res 32:1501–1510

    PubMed  Google Scholar 

  • Lin TH, Kuo HC, Chou FP, Lu FJ (2008) Berberine enhances inhibition of glioma tumor cell migration and invasiveness mediated by arsenic trioxide. BMC Cancer 8:58

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lindvall O, Kokaia Z (2010) Stem cells in human neurodegenerative disorders—time for clinical translation? J Clin Invest 120:29–40

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lu D, Xu A, Mai H, Zhao J, Zhang C, Qi R, Wang H, Lu D, Zhu L (2015) The synergistic effects of heat shock protein 70 and ginsenoside Rg1 against tert-butyl hydroperoxide damage model in vitro. Oxidative Med Cell Longev 2015:1–22

    Google Scholar 

  • Lv H, Liu Q, Zhou J, Tan G, Deng X, Ci X (2017) Daphnetin-mediated Nrf2 antioxidant signaling pathways ameliorate tert-butyl hydroperoxide (t-BHP)-induced mitochondrial dysfunction and cell death. Free Radic Biol Med 106:38–52

    CAS  PubMed  Google Scholar 

  • Martinez-Morales PL, Revilla A, Ocana I, Gonzalez C, Sainz P, McGuire D, Liste I (2013) Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev 9:685–699

    CAS  Google Scholar 

  • Naaldijk Y, Jager C, Fabian C, Leovsky C, Bluher A, Rudolph L, Hinze A, Stolzing A (2017) Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol 43:299–314

    CAS  PubMed  Google Scholar 

  • Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem 280:32485–32492

    CAS  PubMed  Google Scholar 

  • Panahi N, Mahmoudian M, Mortazavi P, Hashjin GS (2013) Effects of berberine on beta-secretase activity in a rabbit model of Alzheimer’s disease. Arch Med Sci 9:146–150

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, Kim D, Choi EK, Choi KC, Kim SU, Kang SK, Ra JC, Kim YB (2013) Human adipose tissue-derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res 91:660–670

    CAS  PubMed  Google Scholar 

  • Qi D, Ouyang C, Wang Y, Zhang S, Ma X, Song Y, Yu H, Tang J, Fu W, Sheng L, Yang L, Wang M, Zhang W, Miao L, Li T, Huang X, Dong H (2014) HO-1 attenuates hippocampal neurons injury via the activation of BDNF-TrkB-PI3K/Akt signaling pathway in stroke. Brain Res 1577:69–76

    CAS  PubMed  Google Scholar 

  • Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62:1984–1989

    CAS  PubMed  Google Scholar 

  • Wang CY, Wang ZY, Xie JW, Wang T, Wang X, Xu Y, Cai JH (2016) Dl-3-n-butylphthalide-induced upregulation of antioxidant defense is involved in the enhancement of cross talk between CREB and Nrf2 in an Alzheimer’s disease mouse model. Neurobiol Aging 38:32–46

    CAS  PubMed  Google Scholar 

  • Wu CL, Yin JH, Hwang CS, Chen SD, Yang DY, Yang DI (2012) c-Jun-dependent sulfiredoxin induction mediates BDNF protection against mitochondrial inhibition in rat cortical neurons. Neurobiol Dis 46:450–462

    CAS  PubMed  Google Scholar 

  • Xu S, Yang X, Qian Y, Xiao Q (2018) Parkinson’s disease-related DJ-1 modulates the expression of uncoupling protein 4 against oxidative stress. J Neurochem 145:312–322

    CAS  PubMed  Google Scholar 

  • Yang S, Zheng Y, Hou X (2019) Lipoxin A4 restores oxidative stress-induced vascular endothelial cell injury and thrombosis-related factor expression by its receptor-mediated activation of Nrf2-HO-1 axis. Cell Signal 60:146–153

    CAS  PubMed  Google Scholar 

  • Yu G, Li Y, Tian Q, Liu R, Wang Q, Wang JZ, Wang X (2011) Berberine attenuates calyculin A-induced cytotoxicity and tau hyperphosphorylation in HEK293 cells. J Alzheimers Dis 24:525–535

    CAS  PubMed  Google Scholar 

  • Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, Wang SK, Zhou ZX, Song DQ, Wang YM, Pan HN, Kong WJ, Jiang JD (2010) Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 59:285–292

    PubMed  Google Scholar 

  • Zhang C, Li C, Chen S, Li Z, Jia X, Wang K, Bao J, Liang Y, Wang X, Chen M, Li P, Su H, Wan JB, Lee SMY, Liu K, He C (2017) Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol 11:1–11

    PubMed  Google Scholar 

  • Zhao W, Feng H, Sun W, Liu K, Lu JJ, Chen X (2017) Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: roles of NOX4 and mitochondrion. Redox Biol 11:524–534

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the staff of the Department of Pathophysiology, Institute of Brain Science Research in Jinan University (Guangzhou, Guangdong Province, China), for their technical assistance. The authors are also grateful to AJE for polishing the language of the article.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81471236 and 81371442).

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Institute of Brain Science Research, Key Laboratory of State Administration of Traditional Chinese Medicine of the People’s Republic of China, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

    Caiyan Wen, Cuiqin Huang, Mei Yang, Chongzhu Fan, Qin Li, Jiayi Zhao, Danhui Gan, An Li, Lihong Zhu & Daxiang Lu

Authors
  1. Caiyan Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cuiqin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chongzhu Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiayi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danhui Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. An Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lihong Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daxiang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Caiyan Wen and Cuiqin Huang contributed equally to this work. Caiyan Wen: methodology, data analysis, and writing of original draft; Cuiqin Huang: methodology and data analysis; Mei Yang: methodology and data analysis; Chongzhu Fan: review and editing; Qin Li: review and editing; Jiayi Zhao: methodology; Danhui Gan: review and editing; An Li: review and editing; Lihong Zhu: supervision, review, and editing; Daxiang Lu: conceptualization, supervision, funding acquisition, review, and editing. All authors have read, revised, and approved the final manuscript.

Corresponding author

Correspondence to Daxiang Lu.

Ethics declarations

Conflict of Interest

All authors declare that they have no conflict of interest.

Ethical Approval

The experimental protocols were approved by the Ethics Committee of the Institute of Laboratory Animal Science, Jinan University (certificate number: 20160503112404). This article does not contain any studies with human participants performed by any of the authors.

Informed Consent

Informed consent was not required for the studies reported in this manuscript. Experiments were carried out in vitro using cell.

Additional information

Publisher’s Note

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

Electronic supplementary material

ESM 1

(DOCX 472 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, C., Huang, C., Yang, M. et al. The Secretion from Bone Marrow Mesenchymal Stem Cells Pretreated with Berberine Rescues Neurons with Oxidative Damage Through Activation of the Keap1-Nrf2-HO-1 Signaling Pathway. Neurotox Res 38, 59–73 (2020). https://doi.org/10.1007/s12640-020-00178-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-020-00178-0

Keywords

Search

Navigation