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SS31 Confers Cerebral Protection by Reversing Mitochondrial Dysfunction in Early Brain Injury Following Subarachnoid Hemorrhage, via the Nrf2- and PGC-1α-Dependent Pathways

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Abstract

In early brain injury (EBI), oxidative stress occurs following subarachnoid hemorrhage (SAH), and mitochondria are intricately linked to this process. SS31, a mitochondria-targeting antioxidative peptide, has been demonstrated to be beneficial for multiple diseases because of its powerful antioxidant and neuroprotective properties. Although our previous study revealed that SS31 was involved in the powerful antioxidant effect following SAH, the underlying molecular mechanisms remained unclear. Thus, our study aimed to investigate the neuroprotective effects of SS31 by reversing mitochondrial dysfunction in EBI following SAH, via activating the Nrf2 signaling and PGC-1α pathways. Our findings confirmed that SS31 ameliorated SAH-triggered oxidative insult. SS31 administration decreased redundant reactive oxygen species, alleviated lipid peroxidation, and elevated the activities of antioxidant enzymes. Concomitant with the inhibited oxidative insult, SS31 dramatically attenuated neurological deficits, cerebral edema, neural apoptosis, and blood–brain barrier disruption following SAH. Moreover, SS31 remarkably promoted nuclear factor-erythroid 2 related factor 2 (Nrf2) nuclear shuttle and upregulated the expression levels of heme oxygenase-1 and NADPH: quinine oxidoreductase1. Additionally, SS31 enhanced the expression levels of PGC-1α and its target genes, and increased the mtDNA copy number, promoting mitochondrial function. However, PGC-1α-specific inhibitor SR-18292 pretreatment dramatically suppressed SS31-induced Nrf2 expression and PGC-1α activation. Furthermore, pretreatment with SR-18292 reversed the neuroprotective and antioxidant roles of SS31. These significant beneficial effects were associated with the activation of the Nrf2 signaling and PGC-1α pathways and were antagonized by SR-18292 administration. Our findings reveal that SS31 exhibits its neuroprotective activity by reversing mitochondrial dysfunction via activating the Nrf2 signaling pathway, which could be mediated through PGC-1α activation.

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In this study, all the data used to support the findings were incorporated in the article and for further questions or query a direct request to the corresponding author can be made.

References

  1. Ogunlaja OI, Cowan R (2019) Subarachnoid hemorrhage and headache. Curr Pain Headache Rep 23:44

    Article  PubMed  Google Scholar 

  2. Long B, Koyfman A, Runyon MS (2017) Subarachnoid hemorrhage: updates in diagnosis and management. Emerg Med Clin North Am 35:803–824

    Article  PubMed  Google Scholar 

  3. Sun XG, Duan H, Jing G, Wang G, Hou Y, Zhang M (2019) Inhibition of TREM-1 attenuates early brain injury after subarachnoid hemorrhage via downregulation of p38MAPK/MMP-9 and preservation of ZO-1. Neuroscience 406:369–375

    Article  CAS  PubMed  Google Scholar 

  4. Muehlschlegel S (2018) Subarachnoid hemorrhage. Continuum (Minneap Minn) 24:1623–1657

    PubMed  Google Scholar 

  5. Christophe M, Nicolas S (2006) Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr Pharm Des. https://doi.org/10.2174/138161206775474242

    Article  PubMed  Google Scholar 

  6. Shen R, Zhou J, Li G, Chen W, Zhong W, Chen Z (2020) SS31 attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage possibly by the mitochondrial pathway. Neurosci Lett 717:134654. https://doi.org/10.1016/j.neulet.2019.134654

    Article  CAS  PubMed  Google Scholar 

  7. Petri S, Kiaei M, Damiano M, Hiller A, Wille E, Manfredi G, Calingasan NY, Szeto HH, Beal MF (2006) Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. J Neurochem. https://doi.org/10.1111/j.1471-4159.2006.04018.x

    Article  PubMed  Google Scholar 

  8. Dai DF, Chiao YA, Martin GM, Marcinek DJ, Basisty N, Quarles EK, Rabinovitch PS (2017) Chapter seven—mitochondrial-targeted catalase: extended longevity and the roles in various disease models. In: Reddy PH (ed) Progress in molecular biology and translational science. Academic Press, Cambridge, pp 203–241

    Google Scholar 

  9. Wu X, Pang Y, Zhang Z, Li X, Wang C, Lei Y, Li A, Yu L, Ye J (2019) Mitochondria-targeted antioxidant peptide SS-31 mediates neuroprotection in a rat experimental glaucoma model. Acta Biochim Biophys Sin (Shanghai) 51(4):411–421. https://doi.org/10.1093/abbs/gmz020

    Article  CAS  PubMed  Google Scholar 

  10. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH (2004) Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. https://doi.org/10.1074/jbc.M402999200

    Article  PubMed  Google Scholar 

  11. Kim EH, Tolhurst AT, Szeto HH, Cho SH (2015) Targeting CD36-mediated inflammation reduces acute brain injury in transient, but not permanent, ischemic stroke. CNS Neurosci Ther 21:385–391

    Article  CAS  PubMed  Google Scholar 

  12. Szeto HH (2008) Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 10:601–619

    Article  CAS  PubMed  Google Scholar 

  13. Petri S, Kiaei M, Damiano M, Hiller A, Wille E, Manfredi G, Calingasan NY, Szeto HH, Beal MF (2006) Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. J Neurochem 98:1141–1148

    Article  CAS  PubMed  Google Scholar 

  14. Yin X, Manczak M, Reddy PH (2016) Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington’s disease. Hum Mol Genet 25:1739–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reddy PH, Manczak M, Kandimalla R (2017) Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of alzheimer’s disease. Hum Mol Genet 26:1597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reddy PH, Manczak M, Yin X, Reddy AP (2018) Synergistic protective effects of mitochondrial division inhibitor 1 and mitochondria-targeted small peptide SS31 in alzheimer’s disease. J Alzheimers Dis 62:1549–1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jia YL, Sun SJ, Chen JH, Jia Q, Huo TT, Chu LF, Bai JT, Yu YJ, Yan XX, Wang JH (2016) SS31, a small molecule antioxidant peptide, attenuates β-amyloid elevation, mitochondrial/synaptic deterioration and cognitive deficit in SAMP8 mice. Curr Alzheimer Res 13:297–306

    Article  CAS  PubMed  Google Scholar 

  18. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum Mol Genet 20:4515–4529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu Y, Wang H, Fang J, Dai W, Zhou J, Wang X, Zhou M (2018) SS-31 provides neuroprotection by reversing mitochondrial dysfunction after traumatic brain injury. Oxid Med Cell Longev 2018:4783602

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mukwevho E, Joseph JS (2014) Calmodulin dependent protein kinase II activation by exercise regulates saturated & unsaturated fatty acids and improves some metabolic syndrome markers. Life Sci 111:53–61

    Article  CAS  PubMed  Google Scholar 

  21. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127:397–408

    Article  CAS  PubMed  Google Scholar 

  22. Zhang K, Cheng H, Song L, Wei W (2020) Inhibition of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/Sirtuin 3 (SIRT3) pathway aggravates oxidative stress after experimental subarachnoid hemorrhage. Med Sci Monit 26:e923688

    CAS  PubMed  PubMed Central  Google Scholar 

  23. de Vries HE, Witte M, Hondius D, Rozemuller AJ, Drukarch B, Hoozemans J, van Horssen J (2008) Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radical Biol Med 45:1375–1383

    Article  Google Scholar 

  24. Salama A, Fayed HM, Elgohary R (2021) L-carnitine alleviated acute lung injuries induced by potassium dichromate in rats: involvement of Nrf2/HO-1 signaling pathway. Heliyon 7:e07207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cho HY, Reddy SP, Debiase A, Yamamoto M, Kleeberger SR (2005) Gene expression profiling of NRF2-mediated protection against oxidative injury. Free Radical Biol Med 38:325–343

    Article  CAS  Google Scholar 

  26. Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Ann Rev Pharmacol Toxicol 53:401–426

    Article  CAS  Google Scholar 

  27. Zhang X, Wu Q, Lu Y, Wan J, Dai H, Zhou X, Lv S, Chen X, Zhang X, Hang C, Wang J (2018) Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways. Free Radic Biol Med 124:504–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou J, Wang H, Shen R, Fang J, Yang Y, Dai W, Zhu Y, Zhou M (2018) Mitochondrial-targeted antioxidant MitoQ provides neuroprotection and reduces neuronal apoptosis in experimental traumatic brain injury possibly via the Nrf2-ARE pathway. Am J Transl Res 10:1887–1899

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yan W, Wang HD, Feng XM, Ding YS, Jin W, Tang K (2009) The expression of NF-E2-related factor 2 in the rat brain after traumatic brain injury. J Trauma 66:1431–1435

    CAS  PubMed  Google Scholar 

  30. Gureev AP, Shaforostova EA, Popov VN (2019) Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Front Genet 10:435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li J, Chen J, Mo H, Chen J, Qian C, Yan F, Gu C, Hu Q, Wang L, Chen G (2016) Minocycline protects against NLRP3 inflammasome-induced inflammation and p53-associated apoptosis in early brain injury after subarachnoid hemorrhage. Mol Neurobiol 53:2668–2678

    Article  CAS  PubMed  Google Scholar 

  32. Sugawara T, Ayer R, Jadhav V, Zhang JH (2008) A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods 167:327–334

    Article  PubMed  Google Scholar 

  33. Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L, Wu L, Wei Y, Ding H, Hang C, Zhou M, Shi J (2015) Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment. J Neuroinflam 12:200

    Article  Google Scholar 

  34. Wang Z, Shi XY, Yin J, Zuo G, Zhang J, Chen G (2012) Role of autophagy in early brain injury after experimental subarachnoid hemorrhage. J Mol Neurosci 46:192–202

    Article  CAS  PubMed  Google Scholar 

  35. Zhang XS, Wu Q, Wu LY, Ye ZN, Jiang TW, Li W, Zhuang Z, Zhou ML, Zhang X, Hang CH (2016) Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. Cell Death Dis. https://doi.org/10.1038/cddis.2016.292

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yang J, Li Q, Wang Z, Qi C, Han X, Lan X, Wan J, Wang W, Zhao X, Hou Z (2017) Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice. Sci Rep 7:40358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen R, Zhou J, Li G, Chen W, Zhong W, Chen Z (2020) SS31 attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage possibly by the mitochondrial pathway. Neurosci Lett 717:134654

    Article  CAS  PubMed  Google Scholar 

  38. Zhou J, Yang Z, Shen R, Zhong W, Zheng H, Chen Z, Tang J, Zhu J (2021) Resveratrol improves mitochondrial biogenesis function and activates PGC-1α pathway in a preclinical model of early brain injury following subarachnoid hemorrhage. Front Mol Biosci 8:620683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang T, Xu S, Wu P, Zhou K, Wu L, Xie Z, Xu W, Luo X, Li P, Ocak U, Ocak PE, Travis ZD, Tang J, Shi H, Zhang JH (2019) Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 pathway after subarachnoid hemorrhage in rats. Exp Neurol 317:1–9

    Article  CAS  PubMed  Google Scholar 

  40. Wu Q, Zhang XS, Wang HD, Zhang X, Yu Q, Li W, Zhou ML, Wang XL (2014) Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Mar Drugs 12:6125–6141

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhou J, Yang Z, Shen R, Zhong W, Zheng H, Chen Z, Tang J, Zhu J (2021) Resveratrol improves mitochondrial biogenesis function and activates PGC-1alpha pathway in a preclinical model of early brain injury following Subarachnoid hemorrhage. Front Mol Biosci 8:620683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang XS, Zhang X, Wu Q, Li W, Zhang QR, Wang CX, Zhou XM, Li H, Shi JX, Zhou ML (2014) Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: possible involvement of Akt/bad signaling. Mar Drugs 12:4291–4310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ostrowski RP, Colohan AR, Zhang JH (2006) Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 28:399–414

    Article  CAS  PubMed  Google Scholar 

  44. Smith JA, Park S, Krause JS, Banik NL (2013) Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 62:764–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hou Y, Shi Y, Han B, Liu X, Qiao X, Qi Y, Wang L (2018) The antioxidant peptide SS31 prevents oxidative stress, downregulates CD36 and improves renal function in diabetic nephropathy. Nephrol Dial Transplant 33:1908–1918

    Article  CAS  PubMed  Google Scholar 

  46. Liu Y, Yang W, Sun X, Xie L, Yang Y, Sang M, Jiao R (2019) SS31 ameliorates sepsis-induced heart injury by inhibiting oxidative stress and inflammation. Inflammation 42:2170–2180

    Article  CAS  PubMed  Google Scholar 

  47. Lee FY, Shao PL, Wallace CG, Chua S, Sung PH, Ko SF, Chai HT, Chung SY, Chen KH, Lu HI, Chen YL, Huang TH, Sheu JJ, Yip HK (2018) Combined therapy with SS31 and mitochondria mitigates myocardial ischemia-reperfusion injury in rats. Int J Mol Sci. https://doi.org/10.3390/ijms19092782

    Article  PubMed  PubMed Central  Google Scholar 

  48. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH (2014) Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol 171:2017–2028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sandoval-Acuña C, Ferreira J, Speisky H (2014) Polyphenols and mitochondria: an update on their increasingly emerging ROS-scavenging independent actions. Arch Biochem Biophys 559:75–90

    Article  PubMed  Google Scholar 

  50. Wang X, Tang D, Zou Y, Wu X, Chen Y, Li H, Chen S, Shi Y, Niu H (2019) A mitochondrial-targeted peptide ameliorated podocyte apoptosis through a HOCl-alb-enhanced and mitochondria-dependent signalling pathway in diabetic rats and in vitro. J Enzyme Inhib Med Chem 34:394–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Reddy PH, Manczak M, Kandimalla R (2017) Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer’s disease. Hum Mol Genet 26:1483–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Calkins MJ, Manczak M, Reddy PH (2012) Mitochondria-targeted antioxidant SS31 prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in alzheimer’s disease. Pharmaceuticals (Basel) 5:1103–1119

    Article  CAS  PubMed  Google Scholar 

  53. Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, Szeto HH, Park B, Reddy PH (2010) Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in alzheimer’s disease neurons. J Alzheimers Dis 20(Suppl 2):S609-631

    Article  PubMed  PubMed Central  Google Scholar 

  54. Cho J, Won K, Wu D, Soong Y, Liu S, Szeto HH, Hong MK (2007) Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coron Artery Dis 18:215–220

    Article  PubMed  Google Scholar 

  55. Cho S, Szeto HH, Kim E, Kim H, Tolhurst AT, Pinto JT (2007) A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36. J Biol Chem 282:4634–4642

    Article  CAS  PubMed  Google Scholar 

  56. Zhang CX, Cheng Y, Liu DZ, Liu M, Cui H, Zhang BL, Mei QB, Zhou SY (2019) Mitochondria-targeted cyclosporin A delivery system to treat myocardial ischemia reperfusion injury of rats. J Nanobiotechnol 17:18

    Article  Google Scholar 

  57. Piantadosi CA, Carraway MS, Babiker A, Suliman HB (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103:1232–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ, Cuzzocrea S (2013) Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal 19:836–853

    Article  CAS  PubMed  Google Scholar 

  59. Li X, Wang H, Gao Y, Li L, Tang C, Wen G, Zhou Y, Zhou M, Mao L, Fan Y (2016) Protective Effects of Quercetin on Mitochondrial Biogenesis in Experimental Traumatic Brain Injury via the Nrf2 Signaling Pathway. PLoS ONE 11:e0164237

    Article  PubMed  PubMed Central  Google Scholar 

  60. Liu Y, Qiu J, Wang Z, You W, Wu L, Ji C, Chen G (2015) Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system. J Neurosurg 123:915–923

    Article  CAS  PubMed  Google Scholar 

  61. Li T, Wang H, Ding Y, Zhou M, Zhou X, Zhang X, Ding K, He J, Lu X, Xu J, Wei W (2014) Genetic elimination of Nrf2 aggravates secondary complications except for vasospasm after experimental subarachnoid hemorrhage in mice. Brain Res 1558:90–99

    Article  CAS  PubMed  Google Scholar 

  62. Lu HI, Lee FY, Wallace CG, Sung PH, Chen KH, Sheu JJ, Chua S, Tong MS, Huang TH, Chen YL, Shao PL, Yip HK (2017) SS31 therapy effectively protects the heart against transverse aortic constriction-induced hypertrophic cardiomyopathy damage. Am J Transl Res 9:5220–5237

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hao ZH, Huang Y, Wang MR, Huo TT, Jia Q, Feng RF, Fan P, Wang JH (2017) SS31 ameliorates age-related activation of NF-κB signaling in senile mice model, SAMP8. Oncotarget 8:1983–1992

    Article  PubMed  Google Scholar 

  64. Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009) PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons. J Biol Chem 284(32):21379–21385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127(2):397–408. https://doi.org/10.1016/j.cell.2006.09.024

    Article  CAS  PubMed  Google Scholar 

  66. Valle I, Alvarez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66(3):562–573. https://doi.org/10.1016/j.cardiores.2005.01.026

    Article  CAS  PubMed  Google Scholar 

  67. Athale J, Ulrich A, MacGarvey NC, Bartz RR, Welty-Wolf KE, Suliman HB, Piantadosi CA (2012) Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice. Free Radic Biol Med 53:1584–1594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Baldelli S, Aquilano K, Ciriolo MR (2013) Punctum on two different transcription factors regulated by PGC-1α: nuclear factor erythroid-derived 2-like 2 and nuclear respiratory factor 2. Biochim Biophys Acta 1830:4137–4146

    Article  CAS  PubMed  Google Scholar 

  69. Joe Y, Zheng M, Kim HJ, Uddin MJ, Kim SK, Chen Y, Park J, Cho GJ, Ryter SW, Chung HT (2015) Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis. Am J Physiol Gastrointest Liver Physiol 309:G21-29

    Article  CAS  PubMed  Google Scholar 

  70. Whitman SA, Long M, Wondrak GT, Zheng H, Zhang DD (2013) Nrf2 modulates contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic atrophy. Exp Cell Res 319:2673–2683

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the project supported by Hainan Province Clinical Medical Center for funding of this work.

Funding

This study was supported by grants from the High-level Talent Project of Hainan Provincial Natural Science Foundation (Grant Nos. 821RC697, 822RC833).

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  1. Jian Zhou and Ruiming Shen have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Hainan Medical University, 31 Longhua Road, Haikou, 570102, Hainan Province, China

    Jian Zhou, Wangwang Zhong, Zhenggang Chen & Qiuhu Huang

  2. Department of Rheumatology, The First Affiliated Hospital of Hainan Medical University, Haikou, China

    Ruiming Shen

  3. Department of General Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, China

    Emmanuel C. Makale

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  1. Jian Zhou
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Contributions

QH conceived of the project. The study manuscript was drafted by JZ. All experiments were done by JZ, WZ, and RS. Data analysis and interpretation of findings were performed by ZC and RS. JZ and EM edited the manuscript. Reading and approval of the final manuscript were done equally by all authors.

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Correspondence to Qiuhu Huang.

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Zhou, J., Shen, R., Makale, E.C. et al. SS31 Confers Cerebral Protection by Reversing Mitochondrial Dysfunction in Early Brain Injury Following Subarachnoid Hemorrhage, via the Nrf2- and PGC-1α-Dependent Pathways. Neurochem Res 48, 1580–1595 (2023). https://doi.org/10.1007/s11064-022-03850-3

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