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Activating PPARγ Increases NQO1 and γ-GCS Expression via Nrf2 in Thrombin-activated Microglia

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Summary

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.

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References

  1. Duan X, Wen Z, Shen H, et al. Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy. Oxid Med Cell Longev, 2016:1203285

  2. Van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol, 2010,9(2):167–76

    Article  PubMed  Google Scholar 

  3. Zhao X, Sun G, Ting SM, et al. Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance. J Neurochem, 2015,133(1):144–152

    Article  CAS  PubMed  Google Scholar 

  4. Hu X, Tao C, Gan Q, et al. Oxidative Stress in Intracerebral Hemorrhage: Sources, Mechanisms, and Therapeutic Targets. Oxid Med Cell Longevity, 2016:3215391

  5. Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci, 2014,8:388

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jesberger JA, Richardson JS. Oxygen free radicals and brain dysfunction. Int J Neurosci, 1991,57(1–2):1–17

    Article  CAS  PubMed  Google Scholar 

  7. Han N, Ding SJ, Wu T, et al. Correlation of free radical level and apoptosis after intracerebral hemorrhage in rats. Neurosci Bull, 2008,24(6):351–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xu W, Li F, Liu Z, et al. MicroRNA-27b inhibition promotes Nrf2/ARE pathway activation and alleviates intracerebral hemorrhage-induced brain injury. Oncotarget, 2017,8(41):70669–70684

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cai W, Yang T, Liu H, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma): A master gatekeeper in CNS injury and repair. Prog Neurobiol, 2018,163:27–58

    Article  PubMed  CAS  Google Scholar 

  10. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke, 2011,42(6):1781–1786

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jin J, Albertz J, Guo Z, et al. Neuroprotective effects of PPAR-gamma agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease. J Neurochem, 2013,125(3):410–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fagerholm R, Hofstetter B, Tommiska J, et al. NAD(P) H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet, 2008,40(7):844–853

    Article  CAS  PubMed  Google Scholar 

  13. Kauffman MA, Consalvo D, Moron DG, et al. ApoE epsilon4 genotype and the age at onset of temporal lobe epilepsy: a case-control study and meta-analysis. Epilepsy Res, 2010,90(3):234–239

    Article  CAS  PubMed  Google Scholar 

  14. Qaisiya M, Coda Zabetta CD, Bellarosa C, et al. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal, 2014,26(3):512–520

    Article  CAS  PubMed  Google Scholar 

  15. Song A, Wu G, Hang H, et al. Rosiglitazone pretreatment influences thrombin-induced anti-oxidative action via activating NQO1and gamma-GCS in rat microglial cells. Neurol Res, 2017,40(2):139–145

    Article  CAS  Google Scholar 

  16. Zhao X, Sun G, Zhang J, et al. Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke, 2007,38(12):3280–3286

    Article  CAS  PubMed  Google Scholar 

  17. Itoh K, Wakabayashi N, Katoh Y, et al. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells, 2003,8(4):379–391

    Article  CAS  PubMed  Google Scholar 

  18. Giudice A, Montella M. Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention. BioEssays, 2006,28(2):169–181

    Article  CAS  PubMed  Google Scholar 

  19. Villegas I, Martin AR, Toma W, et al. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, protects against gastric ischemia-reperfusion damage in rats: role of oxygen free radicals generation. Eur J Pharmacol, 2004,505(1–3):195–203

    Article  CAS  PubMed  Google Scholar 

  20. Asada K, Sasaki S, Suda T, et al. Antiinflammatory roles of peroxisome proliferator-activated receptor gamma in human alveolar macrophages. Am J Respir Crit Care Med, 2004,169(2):195–200

    Article  PubMed  Google Scholar 

  21. Siegel D, Bolton EM, Burr JA, et al. The reduction of alpha-tocopherolquinone by human NAD(P) H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant. Mol Pharmacol, 1997,52(2):300–305

    Article  CAS  PubMed  Google Scholar 

  22. Myhrstad MC, Carlsen H, Nordstrom O, et al. Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Free Radic Biol Med, 2002,32(5):386–393

    Article  CAS  PubMed  Google Scholar 

  23. Wu G, Li C, Wang L, et al. Minimally invasive procedures for evacuation of intracerebral hemorrhage reduces perihematomal glutamate content, blood-brain barrier permeability and brain edema in rabbits. Neurocrit Care, 2011,14(1):118–126

    Article  CAS  PubMed  Google Scholar 

  24. Wu G, Sheng F, Wang L, et al. The pathophysiological time window study of performing minimally invasive procedures for the intracerebral hematoma evacuation in rabbit. Brain Res, 2012,1465:57–65

    Article  CAS  PubMed  Google Scholar 

  25. Wu G, Wang L, Hong Z, et al. Effects of minimally invasive procedures for removal of intracranial hematoma on matrix metalloproteinase expression and blood-brain barrier permeability in perihematomal brain tissues. Neurol Res, 2011,33(3):300–306

    Article  PubMed  CAS  Google Scholar 

  26. Wu G, Wang L, Hong Z, et al. Effects of minimally invasive techniques for evacuation of hematoma in basal ganglia on cortical spinal tract from patients with spontaneous hemorrhage: observed by diffusion tensor imaging. Neurol Res, 2010,32(10):1103–1109

    Article  PubMed  Google Scholar 

  27. Wu G, Zhong W. Effect of minimally invasive surgery for cerebral hematoma evacuation in different stages on motor evoked potential and thrombin in dog model of intracranial hemorrhage. Neurol Res, 2009,32(2):127–133

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Hang Hang, Li-kun Wang, Si-ying Ren, An-jun Song & Guo-feng Wu

Authors
  1. Hang Hang
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  2. Li-kun Wang
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  3. Si-ying Ren
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  4. An-jun Song
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  5. Guo-feng Wu
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Corresponding authors

Correspondence to Li-kun Wang or Guo-feng Wu.

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Conflict of Interest Statement

The authors declare that there are no potential conflicts of interests in this study.

This research was supported by grants from the National Natural Science Foundation of China (No. 81560222) and the Guizhou Science and Technology Foundation (No. [2017]7187, and No. [2013]2043).

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Hang, H., Wang, Lk., Ren, Sy. et al. Activating PPARγ Increases NQO1 and γ-GCS Expression via Nrf2 in Thrombin-activated Microglia. CURR MED SCI 40, 55–62 (2020). https://doi.org/10.1007/s11596-020-2146-8

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  • DOI: https://doi.org/10.1007/s11596-020-2146-8

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