Mitochondrial Neuroglobin Is Necessary for Protection Induced by Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells in Astrocytic Cells Subjected to Scratch and Metabolic Injury

  • Eliana Baez-Jurado
  • Gina Guio-Vega
  • Oscar Hidalgo-Lanussa
  • Janneth González
  • Valentina Echeverria
  • Ghulam Md Ashraf
  • Amirhossein Sahebkar
  • George E. BarretoEmail author


Astrocytes are specialized cells capable of regulating inflammatory responses in neurodegenerative diseases or traumatic brain injury. In addition to playing an important role in neuroinflammation, these cells regulate essential functions for the preservation of brain tissue. Therefore, the search for therapeutic alternatives to preserve these cells and maintain their functions contributes in some way to counteract the progress of the injury and maintain neuronal survival in various brain pathologies. Among these strategies, the conditioned medium from human adipose-derived mesenchymal stem cells (CM-hMSCA) has been reported with a potential beneficial effect against several neuropathologies. In this study, we evaluated the potential effect of CM-hMSCA in a model of human astrocytes (T98G cells) subjected to scratch injury. Our findings demonstrated that CM-hMSCA regulates the cytokines IL-2, IL-6, IL-8, IL-10, GM-CSF, and TNF-α, downregulates calcium at the cytoplasmic level, and regulates mitochondrial dynamics and the respiratory chain. These actions are accompanied by modulation of the expression of different proteins involved in signaling pathways such as AKT/pAKT and ERK1/2/pERK, and may mediate the localization of neuroglobin (Ngb) at the cellular level. We also confirmed that Ngb mediated the protective effects of CM-hMSCA through regulation of proteins involved in survival pathways and oxidative stress. In conclusion, regulation of brain inflammation combined with the recovery of fundamental cellular aspects in the face of injury makes CM-hMSCA a promising candidate for the protection of astrocytes in brain pathologies.


Astrocytes Scratch assay Mesenchymal stem cells Inflammation Conditioned medium Neuroglobin 



The authors thank Dr. Jorge Andrés Afanador and the staff of the cosmetic surgery Clinic DHARA in Bogotá, Colombia, for the adipose tissue samples. This work was supported in part by grants PUJ IDs 6260 and 7115 to GEB and 6278 to JG and scholarship for doctoral studies awarded by the Vicerrectoría Académica of PUJ to EB.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1442_MOESM1_ESM.docx (364 kb)
Fig. S1 (DOCX 364 kb)


  1. 1.
    Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13(4):3391–3396. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gonzalez H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274(1–2):1–13. CrossRefPubMedGoogle Scholar
  3. 3.
    Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM (2016) Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. Curr Opin Neurobiol 36:74–81. CrossRefPubMedGoogle Scholar
  4. 4.
    Karve IP, Taylor JM, Crack PJ (2016) The contribution of astrocytes and microglia to traumatic brain injury. Br J Pharmacol 173(4):692–702. CrossRefPubMedGoogle Scholar
  5. 5.
    Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54(10):8071–8089. CrossRefPubMedGoogle Scholar
  6. 6.
    Pedraza-Alva G, Perez-Martinez L, Valdez-Hernandez L, Meza-Sosa KF, Ando-Kuri M (2015) Negative regulation of the inflammasome: keeping inflammation under control. Immunol Rev 265(1):231–257. CrossRefPubMedGoogle Scholar
  7. 7.
    Ulusoy C, Zibandeh N, Yildirim S, Trakas N, Zisimopoulou P, Kucukerden M, Tasli H, Tzartos S et al (2015) Dental follicle mesenchymal stem cell administration ameliorates muscle weakness in MuSK-immunized mice. J Neuroinflammation 12:231. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Trubiani O, Giacoppo S, Ballerini P, Diomede F, Piattelli A, Bramanti P, Mazzon E (2016) Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis. Stem Cell Res Ther 7:1. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Baez-Jurado E, Hidalgo-Lanussa O, Guio-Vega G, Ashraf GM, Echeverria V, Aliev G, Barreto GE (2018) Conditioned medium of human adipose mesenchymal stem cells increases wound closure and protects human astrocytes following scratch assay in vitro. Mol Neurobiol 55(6):5377–5392. CrossRefPubMedGoogle Scholar
  10. 10.
    Baez-Jurado E, Vega GG, Aliev G, Tarasov VV, Esquinas P, Echeverria V, Barreto GE (2018) Blockade of neuroglobin reduces protection of conditioned medium from human mesenchymal stem cells in human astrocyte model (T98G) under a scratch assay. Mol Neurobiol 55(3):2285–2300. CrossRefPubMedGoogle Scholar
  11. 11.
    Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R (2016) The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy 18(1):13–24. CrossRefPubMedGoogle Scholar
  12. 12.
    Guillen MI, Platas J, Perez Del Caz MD, Mirabet V, Alcaraz MJ (2018) Paracrine anti-inflammatory effects of adipose tissue-derived mesenchymal stem cells in human monocytes. Front Physiol 9:661. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Guo ZY, Sun X, Xu XL, Zhao Q, Peng J, Wang Y (2015) Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res 10(4):651–658. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mita T, Furukawa-Hibi Y, Takeuchi H, Hattori H, Yamada K, Hibi H, Ueda M, Yamamoto A (2015) Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer's disease. Behav Brain Res 293:189–197. CrossRefPubMedGoogle Scholar
  15. 15.
    Pischiutta F, Brunelli L, Romele P, Silini A, Sammali E, Paracchini L, Marchini S, Talamini L et al (2016) Protection of brain injury by amniotic mesenchymal stromal cell-secreted metabolites. Crit Care Med 44(11):e1118–e1131. CrossRefPubMedGoogle Scholar
  16. 16.
    Mekhemar MK, Adam-Klages S, Kabelitz D, Dorfer CE, Fawzy El-Sayed KM (2018) TLR-induced immunomodulatory cytokine expression by human gingival stem/progenitor cells. Cell Immunol 326:60–67. CrossRefPubMedGoogle Scholar
  17. 17.
    Fawzy El-Sayed KM, Dorfer CE (2016) Gingival mesenchymal stem/progenitor cells: a unique tissue engineering gem. Stem Cells Int 2016:7154327–7154316. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Torrente D, Avila MF, Cabezas R, Morales L, Gonzalez J, Samudio I, Barreto GE (2014) Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model. Hum Exp Toxicol 33(7):673–684. CrossRefPubMedGoogle Scholar
  19. 19.
    Song M, Jue SS, Cho YA, Kim EC (2015) Comparison of the effects of human dental pulp stem cells and human bone marrow-derived mesenchymal stem cells on ischemic human astrocytes in vitro. J Neurosci Res 93(6):973–983. CrossRefPubMedGoogle Scholar
  20. 20.
    Huang W, Lv B, Zeng H, Shi D, Liu Y, Chen F, Li F, Liu X et al (2015) Paracrine factors secreted by MSCs promote astrocyte survival associated with GFAP downregulation after ischemic stroke via p38 MAPK and JNK. J Cell Physiol 230(10):2461–2475. CrossRefPubMedGoogle Scholar
  21. 21.
    Sun H, Benardais K, Stanslowsky N, Thau-Habermann N, Hensel N, Huang D, Claus P, Dengler R et al (2013) Therapeutic potential of mesenchymal stromal cells and MSC conditioned medium in amyotrophic lateral sclerosis (ALS)—in vitro evidence from primary motor neuron cultures, NSC-34 cells, astrocytes and microglia. PLoS One 8(9):e72926. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Baez E, Echeverria V, Cabezas R, Avila-Rodriguez M, Garcia-Segura LM, Barreto GE (2016) Protection by neuroglobin expression in brain pathologies. Front Neurol 7:146. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Amri F, Ghouili I, Amri M, Carrier A, Masmoudi-Kouki O (2017) Neuroglobin protects astroglial cells from hydrogen peroxide-induced oxidative stress and apoptotic cell death. J Neurochem 140(1):151–169. CrossRefPubMedGoogle Scholar
  24. 24.
    Chen YX, Zeng ZC, Sun J, Zeng HY, Huang Y, Zhang ZY (2015) Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells. J Radiat Res 56(4):700–708. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yu Z, Poppe JL, Wang X (2013) Mitochondrial mechanisms of neuroglobin's neuroprotection. Oxidative Med Cell Longev 2013:756989. CrossRefGoogle Scholar
  26. 26.
    Lan WB, Lin JH, Chen XW, Wu CY, Zhong GX, Zhang LQ, Lin WP, Liu WN et al (2014) Overexpressing neuroglobin improves functional recovery by inhibiting neuronal apoptosis after spinal cord injury. Brain Res 1562:100–108. CrossRefPubMedGoogle Scholar
  27. 27.
    Lechauve C, Augustin S, Roussel D, Sahel JA, Corral-Debrinski M (2013) Neuroglobin involvement in visual pathways through the optic nerve. Biochim Biophys Acta 1834(9):1772–1778. CrossRefPubMedGoogle Scholar
  28. 28.
    Avivi A, Gerlach F, Joel A, Reuss S, Burmester T, Nevo E, Hankeln T (2010) Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax. Proc Natl Acad Sci U S A 107(50):21570–21575. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zhao S, Yu Z, Zhao G, Xing C, Hayakawa K, Whalen MJ, Lok JM, Lo EH et al (2012) Neuroglobin-overexpression reduces traumatic brain lesion size in mice. BMC Neurosci 13:67. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yu Z, Liu N, Liu J, Yang K, Wang X (2012) Neuroglobin, a novel target for endogenous neuroprotection against stroke and neurodegenerative disorders. Int J Mol Sci 13(6):6995–7014. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Taylor JM, Kelley B, Gregory EJ, Berman NE (2014) Neuroglobin overexpression improves sensorimotor outcomes in a mouse model of traumatic brain injury. Neurosci Lett 577:125–129. CrossRefPubMedGoogle Scholar
  32. 32.
    Zhou Z, Chen Y, Zhang H, Min S, Yu B, He B, Jin A (2013) Comparison of mesenchymal stromal cells from human bone marrow and adipose tissue for the treatment of spinal cord injury. Cytotherapy 15(4):434–448. CrossRefPubMedGoogle Scholar
  33. 33.
    Avila-Rodriguez M, Garcia-Segura LM, Hidalgo-Lanussa O, Baez E, Gonzalez J, Barreto GE (2016) Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression. Mol Cell Endocrinol 433:35–46. CrossRefPubMedGoogle Scholar
  34. 34.
    Sasaki S, Futagi Y, Kobayashi M, Ogura J, Iseki K (2015) Functional characterization of 5-oxoproline transport via SLC16A1/MCT1. J Biol Chem 290(4):2303–2311. CrossRefPubMedGoogle Scholar
  35. 35.
    Cabezas R, Avila MF, Gonzalez J, El-Bacha RS, Barreto GE (2015) PDGF-BB protects mitochondria from rotenone in T98G cells. Neurotox Res 27(4):355–367. CrossRefPubMedGoogle Scholar
  36. 36.
    Mimura J, Kosaka K, Maruyama A, Satoh T, Harada N, Yoshida H, Satoh K, Yamamoto M et al (2011) Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes. J Biochem 150(2):209–217. CrossRefPubMedGoogle Scholar
  37. 37.
    Bourguignon LY, Gilad E, Peyrollier K, Brightman A, Swanson RA (2007) Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes. J Neurochem 101(4):1002–1017. CrossRefPubMedGoogle Scholar
  38. 38.
    Ouyang YB, Xu LJ, Emery JF, Lee AS, Giffard RG (2011) Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11(2):279–286. CrossRefPubMedGoogle Scholar
  39. 39.
    Vomelova I, Vaníčková Z, Šedo A (2009) Technical note methods of RNA purification. All ways (should) lead to Rome. Folia Biologica (Praha) 55:243–251Google Scholar
  40. 40.
    Scientific TF (2015) Real-time PCR Solutions.Google Scholar
  41. 41.
    Taylor SC, Berkelman T, Yadav G, Hammond M (2013) A defined methodology for reliable quantification of Western blot data. Mol Biotechnol 55(3):217–226. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gassmann M, Grenacher B, Rohde B, Vogel J (2009) Quantifying Western blots: pitfalls of densitometry. Electrophoresis 30(11):1845–1855. CrossRefPubMedGoogle Scholar
  43. 43.
    Voloboueva LA, Lee SW, Emery JF, Palmer TD, Giffard RG (2010) Mitochondrial protection attenuates inflammation-induced impairment of neurogenesis in vitro and in vivo. J Neurosci 30(37):12242–12251. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP et al (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28(16):4115–4122. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wang H, Joseph JA (1999) Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med 27(5–6):612–616CrossRefPubMedGoogle Scholar
  46. 46.
    Alarifi S, Ali D, Alkahtani S (2015) Nanoalumina induces apoptosis by impairing antioxidant enzyme systems in human hepatocarcinoma cells. Int J Nanomedicine 10:3751–3760. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pokrzywinski KL, Tilney CL, Warner ME, Coyne KJ (2017) Cell cycle arrest and biochemical changes accompanying cell death in harmful dinoflagellates following exposure to bacterial algicide IRI-160AA. Sci Rep 7:45102. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Jeong SH, Kim HK, Song IS, Noh SJ, Marquez J, Ko KS, Rhee BD, Kim N et al (2014) Echinochrome a increases mitochondrial mass and function by modulating mitochondrial biogenesis regulatory genes. Marine Drugs 12(8):4602–4615. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Oliva CR, Moellering DR, Gillespie GY, Griguer CE (2011) Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One 6(9):e24665. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hidalgo-Lanussa O, Avila-Rodriguez M, Baez-Jurado E, Zamudio J, Echeverria V, Garcia-Segura LM, Barreto GE (2018) Tibolone reduces oxidative damage and inflammation in microglia stimulated with palmitic acid through mechanisms involving estrogen receptor beta. Mol Neurobiol 55(7):5462–5477. CrossRefPubMedGoogle Scholar
  51. 51.
    Li Q, Lau A, Morris TJ, Guo L, Fordyce CB, Stanley EF (2004) A syntaxin 1, Galpha(o), and N-type calcium channel complex at a presynaptic nerve terminal: analysis by quantitative immunocolocalization. J Neurosci 24(16):4070–4081. CrossRefPubMedGoogle Scholar
  52. 52.
    Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129(2):154–169. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154(2):204–219. CrossRefPubMedGoogle Scholar
  54. 54.
    Kokiko-Cochran ON, Godbout JP (2018) The inflammatory continuum of traumatic brain injury and Alzheimer's disease. Front Immunol 9:672. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Chung WS, Allen NJ, Eroglu C (2015) Astrocytes control synapse formation, function, and elimination. Cold Spring Harb Perspect Biol 7(9):a020370. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Becerra-Calixto A, Cardona-Gomez GP (2017) The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci 10:88. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Kimelberg HK, Nedergaard M (2010) Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics 7(4):338–353. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13(4):685–701. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37(9):608–620. CrossRefPubMedGoogle Scholar
  60. 60.
    Le Thuc O, Blondeau N, Nahon JL, Rovere C (2015) The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects. Ann N Y Acad Sci 1351:127–140. CrossRefPubMedGoogle Scholar
  61. 61.
    Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, Zahoor H, Saeed D et al (2017) Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci 11:216. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Cunningham CJ, Redondo-Castro E, Allan SM (2018) The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism:271678X18776802.
  63. 63.
    Valencia J, Blanco B, Yanez R, Vazquez M, Herrero Sanchez C, Fernandez-Garcia M, Rodriguez Serrano C, Pescador D et al (2016) Comparative analysis of the immunomodulatory capacities of human bone marrow- and adipose tissue-derived mesenchymal stromal cells from the same donor. Cytotherapy 18(10):1297–1311. CrossRefPubMedGoogle Scholar
  64. 64.
    Gimeno ML, Fuertes F, Barcala Tabarrozzi AE, Attorressi AI, Cucchiani R, Corrales L, Oliveira TC, Sogayar MC et al (2017) Pluripotent nontumorigenic adipose tissue-derived muse cells have immunomodulatory capacity mediated by transforming growth factor-beta1. Stem Cells Transl Med 6(1):161–173. CrossRefPubMedGoogle Scholar
  65. 65.
    Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL et al (2016) Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 7:e2062. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Hariri RJ, Chang VA, Barie PS, Wang RS, Sharif SF, Ghajar JB (1994) Traumatic injury induces interleukin-6 production by human astrocytes. Brain Res 636(1):139–142CrossRefPubMedGoogle Scholar
  67. 67.
    Liu C, Cui G, Zhu M, Kang X, Guo H (2014) Neuroinflammation in Alzheimer's disease: chemokines produced by astrocytes and chemokine receptors. Int J Clin Exp Pathol 7(12):8342–8355PubMedPubMedCentralGoogle Scholar
  68. 68.
    Phuagkhaopong S, Ospondpant D, Kasemsuk T, Sibmooh N, Soodvilai S, Power C, Vivithanaporn P (2017) Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-kappaB pathways. Neurotoxicology 60:82–91. CrossRefPubMedGoogle Scholar
  69. 69.
    Gijbels K, Van Damme J, Proost P, Put W, Carton H, Billiau A (1990) Interleukin 6 production in the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol 20(1):233–235. CrossRefPubMedGoogle Scholar
  70. 70.
    Jiang Y, Deacon R, Anthony DC, Campbell SJ (2008) Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases. Neurobiol Dis 32(1):125–132. CrossRefPubMedGoogle Scholar
  71. 71.
    Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–S240. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Tehranian R, Andell-Jonsson S, Beni SM, Yatsiv I, Shohami E, Bartfai T, Lundkvist J, Iverfeldt K (2002) Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist. J Neurotrauma 19(8):939–951. CrossRefPubMedGoogle Scholar
  73. 73.
    Guida E, Stewart A (1998) Influence of hypoxia and glucose deprivation on tumour necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor expression in human cultured monocytes. Cell Physiol Biochem 8(1–2):75–88. CrossRefPubMedGoogle Scholar
  74. 74.
    Opal SM, DePalo VA (2000) Anti-inflammatory cytokines. Chest 117(4):1162–1172CrossRefPubMedGoogle Scholar
  75. 75.
    Xia W, Peng GY, Sheng JT, Zhu FF, Guo JF, Chen WQ (2015) Neuroprotective effect of interleukin-6 regulation of voltage-gated Na(+) channels of cortical neurons is time- and dose-dependent. Neural Regen Res 10(4):610–617. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8(9):1254–1266. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell 13(6):1059–1067. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Chen XL, Wang Y, Peng WW, Zheng YJ, Zhang TN, Wang PJ, Huang JD, Zeng QY (2018) Effects of interleukin-6 and IL-6/AMPK signaling pathway on mitochondrial biogenesis and astrocytes viability under experimental septic condition. Int Immunopharmacol 59:287–294. CrossRefPubMedGoogle Scholar
  79. 79.
    Jiang CL, Lu CL (1998) Interleukin-2 and its effects in the central nervous system. Biol Signals Recept 7(3):148–156. CrossRefPubMedGoogle Scholar
  80. 80.
    Xie L, Choudhury GR, Winters A, Yang SH, Jin K (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45(1):180–191. CrossRefPubMedGoogle Scholar
  81. 81.
    Bhela S, Varanasi SK, Jaggi U, Sloan SS, Rajasagi NK, Rouse BT (2017) The plasticity and stability of regulatory T cells during viral-induced inflammatory lesions. J Immunol 199(4):1342–1352. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Rothhammer V, Quintana FJ (2015) Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 37(6):625–638. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Bajetto A, Bonavia R, Barbero S, Schettini G (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 82(6):1311–1329CrossRefPubMedGoogle Scholar
  84. 84.
    Hao P, Liang Z, Piao H, Ji X, Wang Y, Liu Y, Liu R, Liu J (2014) Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression. Metab Brain Dis 29(1):193–205. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Bruno V, Copani A, Besong G, Scoto G, Nicoletti F (2000) Neuroprotective activity of chemokines against N-methyl-D-aspartate or beta-amyloid-induced toxicity in culture. Eur J Pharmacol 399(2–3):117–121CrossRefPubMedGoogle Scholar
  86. 86.
    Mamik MK, Ghorpade A (2016) CXCL8 as a potential therapeutic target for HIV-associated neurocognitive disorders. Curr Drug Targets 17(1):111–121CrossRefPubMedGoogle Scholar
  87. 87.
    Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N (2008) CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med 205(11):2643–2655. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, Nagarkatti M (2013) Role of cytokines as a double-edged sword in sepsis. In Vivo 27(6):669–684PubMedPubMedCentralGoogle Scholar
  89. 89.
    Linero I, Chaparro O (2014) Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration. PLoS One 9(9):e107001. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A, Ludlow JW, Stricker DM et al (2007) Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol 212(3):702–709. CrossRefPubMedGoogle Scholar
  91. 91.
    Wei X, Du Z, Zhao L, Feng D, Wei G, He Y, Tan J, Lee WH et al (2009) IFATS collection: the conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells 27(2):478–488. CrossRefPubMedGoogle Scholar
  92. 92.
    Kupcova Skalnikova H (2013) Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie 95(12):2196–2211. CrossRefPubMedGoogle Scholar
  93. 93.
    Deng LX, Hu J, Liu N, Wang X, Smith GM, Wen X, Xu XM (2011) GDNF modifies reactive astrogliosis allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury. Exp Neurol 229(2):238–250. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Cirillo G, Bianco MR, Colangelo AM, Cavaliere C, Daniele de L, Zaccaro L, Alberghina L, Papa M (2011) Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor. Neurobiol Dis 41(3):630–639. CrossRefPubMedGoogle Scholar
  95. 95.
    Dimitrov DH, Lee S, Yantis J, Honaker C, Braida N (2014) Cytokine serum levels as potential biological markers for the psychopathology in schizophrenia. Adv Psychiatry 2014:1–7CrossRefGoogle Scholar
  96. 96.
    Holliday J, Gruol DL (1993) Cytokine stimulation increases intracellular calcium and alters the response to quisqualate in cultured cortical astrocytes. Brain Res 621(2):233–241CrossRefPubMedGoogle Scholar
  97. 97.
    Galic MA, Riazi K, Pittman QJ (2012) Cytokines and brain excitability. Front Neuroendocrinol 33(1):116–125. CrossRefPubMedGoogle Scholar
  98. 98.
    Shinotsuka T, Yasui M, Nuriya M (2014) Astrocytic gap junctional networks suppress cellular damage in an in vitro model of ischemia. Biochem Biophys Res Commun 444(2):171–176. CrossRefPubMedGoogle Scholar
  99. 99.
    Helleringer R, Chever O, Daniel H, Galante M (2017) Oxygen and glucose deprivation induces Bergmann glia membrane depolarization and ca(2+) rises mainly mediated by K(+) and ATP increases in the extracellular space. Front Cell Neurosci 11:349. CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Reuss B, von Bohlen und Halback O (2003) Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 313(2):139–157. CrossRefPubMedGoogle Scholar
  101. 101.
    Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N (2009) Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res 3(1):63–70. CrossRefPubMedGoogle Scholar
  102. 102.
    Papazian I, Kyrargyri V, Evangelidou M, Voulgari-Kokota A, Probert L (2018) Mesenchymal stem cell protection of neurons against glutamate excitotoxicity involves reduction of NMDA-triggered calcium responses and surface GluR1, and is partly mediated by TNF. Int J Mol Sci 19 (3).
  103. 103.
    Taoufik E, Valable S, Muller GJ, Roberts ML, Divoux D, Tinel A, Voulgari-Kokota A, Tseveleki V et al (2007) FLIP(L) protects neurons against in vivo ischemia and in vitro glucose deprivation-induced cell death. J Neurosci 27(25):6633–6646. CrossRefPubMedGoogle Scholar
  104. 104.
    Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL (2004) Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. J Biol Chem 279(31):32869–32881. CrossRefPubMedGoogle Scholar
  105. 105.
    Probert L (2015) TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience 302:2–22. CrossRefPubMedGoogle Scholar
  106. 106.
    Morales AP, Carvalho AC, Monteforte PT, Hirata H, Han SW, Hsu YT, Smaili SS (2011) Endoplasmic reticulum calcium release engages Bax translocation in cortical astrocytes. Neurochem Res 36(5):829–838. CrossRefPubMedGoogle Scholar
  107. 107.
    Verkhratsky A, Rodriguez JJ, Parpura V (2012) Calcium signalling in astroglia. Mol Cell Endocrinol 353(1–2):45–56. CrossRefPubMedGoogle Scholar
  108. 108.
    Johnson GG, White MC, Wu JH, Vallejo M, Grimaldi M (2014) The deadly connection between endoplasmic reticulum, Ca2+, protein synthesis, and the endoplasmic reticulum stress response in malignant glioma cells. Neuro-Oncology 16(8):1086–1099. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Begum G, Kintner D, Liu Y, Cramer SW, Sun D (2012) DHA inhibits ER Ca2+ release and ER stress in astrocytes following in vitro ischemia. J Neurochem 120(4):622–630. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82(3):415–424CrossRefPubMedGoogle Scholar
  111. 111.
    Reyes RC, Parpura V (2008) Mitochondria modulate Ca2+−dependent glutamate release from rat cortical astrocytes. J Neurosci 28(39):9682–9691. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Parpura V, Grubisic V, Verkhratsky A (2011) Ca(2+) sources for the exocytotic release of glutamate from astrocytes. Biochim Biophys Acta 1813(5):984–991. CrossRefPubMedGoogle Scholar
  113. 113.
    Voulgari-Kokota A, Fairless R, Karamita M, Kyrargyri V, Tseveleki V, Evangelidou M, Delorme B, Charbord P et al (2012) Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function. Exp Neurol 236(1):161–170. CrossRefPubMedGoogle Scholar
  114. 114.
    Cheng B, Furukawa K, O'Keefe JA, Goodman Y, Kihiko M, Fabian T, Mattson MP (1995) Basic fibroblast growth factor selectively increases AMPA-receptor subunit GluR1 protein level and differentially modulates Ca2+ responses to AMPA and NMDA in hippocampal neurons. J Neurochem 65(6):2525–2536CrossRefPubMedGoogle Scholar
  115. 115.
    Ranieri M, Brajkovic S, Riboldi G, Ronchi D, Rizzo F, Bresolin N, Corti S, Comi GP (2013) Mitochondrial fusion proteins and human diseases. Neurol Res Int 2013:293893. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Burte F, Carelli V, Chinnery PF, Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11(1):11–24. CrossRefPubMedGoogle Scholar
  117. 117.
    Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22(2):256–265. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT (2004) Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 117(Pt 7):1201–1210. CrossRefPubMedGoogle Scholar
  119. 119.
    Elgass K, Pakay J, Ryan MT, Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochim Biophys Acta 1833(1):150–161. CrossRefPubMedGoogle Scholar
  120. 120.
    Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, Wieckowski MR, Rizzuto R (2006) Mitochondrial dynamics and Ca2+ signaling. Biochim Biophys Acta 1763(5–6):442–449. CrossRefPubMedGoogle Scholar
  121. 121.
    Bravo-Sagua R, Parra V, Lopez-Crisosto C, Diaz P, Quest AF, Lavandero S (2017) Calcium transport and signaling in mitochondria. Comp Physiol 7(2):623–634. CrossRefGoogle Scholar
  122. 122.
    Ogunbileje JO, Porter C, Herndon DN, Chao T, Abdelrahman DR, Papadimitriou A, Chondronikola M, Zimmers TA et al (2016) Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma. Am J Phys Endocrinol Metab 311(2):E436–E448. CrossRefGoogle Scholar
  123. 123.
    Eisner V, Picard M, Hajnóczky G (2018) Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 1Google Scholar
  124. 124.
    Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28(11):1589–1600. CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Jagasia R, Grote P, Westermann B, Conradt B (2005) DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433(7027):754–760. CrossRefPubMedGoogle Scholar
  126. 126.
    Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G et al (2004) Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 18(22):2785–2797. CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34–39. CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Alavi MV, Fuhrmann N (2013) Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics. Mol Neurodegener 8:32. CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Mishra P, Chan DC (2016) Metabolic regulation of mitochondrial dynamics. J Cell Biol 212(4):379–387. CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598. CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15(11):5001–5011. CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Cereghetti GM, Costa V, Scorrano L (2010) Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ 17(11):1785–1794. CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515–525CrossRefPubMedGoogle Scholar
  134. 134.
    Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126(1):177–189. CrossRefPubMedGoogle Scholar
  135. 135.
    Elachouri G, Vidoni S, Zanna C, Pattyn A, Boukhaddaoui H, Gaget K, Yu-Wai-Man P, Gasparre G et al (2011) OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res 21(1):12–20. CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278(10):7743–7746. CrossRefPubMedGoogle Scholar
  137. 137.
    Mizushima N (2005) The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ 12(Suppl 2):1535–1541. CrossRefPubMedGoogle Scholar
  138. 138.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Wu YT, Tan HL, Huang Q, Kim YS, Pan N, Ong WY, Liu ZG, Ong CN et al (2008) Autophagy plays a protective role during zVAD-induced necrotic cell death. Autophagy 4(4):457–466CrossRefPubMedGoogle Scholar
  140. 140.
    Cecconi F, Levine B (2008) The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell 15(3):344–357. CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    White KE, Davies VJ, Hogan VE, Piechota MJ, Nichols PP, Turnbull DM, Votruba M (2009) OPA1 deficiency associated with increased autophagy in retinal ganglion cells in a murine model of dominant optic atrophy. Invest Ophthalmol Vis Sci 50(6):2567–2571. CrossRefPubMedGoogle Scholar
  142. 142.
    Kane MS, Alban J, Desquiret-Dumas V, Gueguen N, Ishak L, Ferre M, Amati-Bonneau P, Procaccio V et al (2017) Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. J Cell Mol Med 21(10):2284–2297. CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Gomes LC, Scorrano L (2011) Mitochondrial elongation during autophagy: a stereotypical response to survive in difficult times. Autophagy 7(10):1251–1253. CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Gomes LC, Scorrano L (2013) Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta 1833(1):205–212. CrossRefPubMedGoogle Scholar
  145. 145.
    Hackenbrock CR (1968) Chemical and physical fixation of isolated mitochondria in low-energy and high-energy states. Proc Natl Acad Sci U S A 61(2):598–605CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Pidoux G, Witczak O, Jarnaess E, Myrvold L, Urlaub H, Stokka AJ, Kuntziger T, Tasken K (2011) Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. EMBO J 30(21):4371–4386. CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Seo BB, Nakamaru-Ogiso E, Flotte TR, Matsuno-Yagi A, Yagi T (2006) In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease. J Biol Chem 281(20):14250–14255. CrossRefPubMedGoogle Scholar
  148. 148.
    Marella M, Seo BB, Yagi T, Matsuno-Yagi A (2009) Parkinson's disease and mitochondrial complex I: a perspective on the Ndi1 therapy. J Bioenerg Biomembr 41(6):493–497. CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Seo BB, Nakamaru-Ogiso E, Cruz P, Flotte TR, Yagi T, Matsuno-Yagi A (2004) Functional expression of the single subunit NADH dehydrogenase in mitochondria in vivo: a potential therapy for complex I deficiencies. Hum Gene Ther 15(9):887–895. CrossRefPubMedGoogle Scholar
  150. 150.
    Yu Z, Zhang Y, Liu N, Yuan J, Lin L, Zhuge Q, Xiao J, Wang X (2016) Roles of neuroglobin binding to mitochondrial complex III subunit cytochrome c1 in oxygen-glucose deprivation-induced neurotoxicity in primary neurons. Mol Neurobiol 53(5):3249–3257. CrossRefPubMedGoogle Scholar
  151. 151.
    Ma WW, Hou CC, Zhou X, Yu HL, Xi YD, Ding J, Zhao X, Xiao R (2013) Genistein alleviates the mitochondria-targeted DNA damage induced by beta-amyloid peptides 25-35 in C6 glioma cells. Neurochem Res 38(7):1315–1323. CrossRefPubMedGoogle Scholar
  152. 152.
    Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through class I PI3Ks in mammalian cells. Biochem Soc Trans 34(Pt 5):647–662. CrossRefPubMedGoogle Scholar
  153. 153.
    Anderson CN, Tolkovsky AM (1999) A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 19(2):664–673CrossRefPubMedGoogle Scholar
  154. 154.
    de Oliveira MR, Ferreira GC, Schuck PF, Dal Bosco SM (2015) Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem Biol Interact 242:396–406. CrossRefPubMedGoogle Scholar
  155. 155.
    Le Belle JE, Orozco NM, Paucar AA, Saxe JP, Mottahedeh J, Pyle AD, Wu H, Kornblum HI (2011) Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 8(1):59–71. CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Zhang Q, Liu G, Wu Y, Sha H, Zhang P, Jia J (2011) BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/Akt pathway. Molecules 16(12):10146–10156. CrossRefPubMedGoogle Scholar
  157. 157.
    Zhao J, Cheng YY, Fan W, Yang CB, Ye SF, Cui W, Wei W, Lao LX et al (2015) Botanical drug puerarin coordinates with nerve growth factor in the regulation of neuronal survival and neuritogenesis via activating ERK1/2 and PI3K/Akt signaling pathways in the neurite extension process. CNS Neurosci Ther 21(1):61–70. CrossRefPubMedGoogle Scholar
  158. 158.
    Nguyen TL, Kim CK, Cho JH, Lee KH, Ahn JY (2010) Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7/IGF-IR [corrected]. Exp Mol Med 42(8):583–595. CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Lotfinia M, Kadivar M, Piryaei A, Pournasr B, Sardari S, Sodeifi N, Sayahpour FA, Baharvand H (2016) Effect of secreted molecules of human embryonic stem cell-derived mesenchymal stem cells on acute hepatic failure model. Stem Cells Dev 25(24):1898–1908. CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Zagoura DS, Roubelakis MG, Bitsika V, Trohatou O, Pappa KI, Kapelouzou A, Antsaklis A, Anagnou NP (2012) Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut 61(6):894–906. CrossRefPubMedGoogle Scholar
  161. 161.
    Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105(1):93–98CrossRefPubMedGoogle Scholar
  162. 162.
    Na HK, Kim EH, Jung JH, Lee HH, Hyun JW, Surh YJ (2008) (−)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. Arch Biochem Biophys 476(2):171–177. CrossRefPubMedGoogle Scholar
  163. 163.
    Liu J, Yu Z, Guo S, Lee SR, Xing C, Zhang C, Gao Y, Nicholls DG et al (2009) Effects of neuroglobin overexpression on mitochondrial function and oxidative stress following hypoxia/reoxygenation in cultured neurons. J Neurosci Res 87(1):164–170. CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Duong TT, Witting PK, Antao ST, Parry SN, Kennerson M, Lai B, Vogt S, Lay PA et al (2009) Multiple protective activities of neuroglobin in cultured neuronal cells exposed to hypoxia re-oxygenation injury. J Neurochem 108(5):1143–1154. CrossRefPubMedGoogle Scholar
  165. 165.
    Yu Z, Xu J, Liu N, Wang Y, Li X, Pallast S, van Leyen K, Wang X (2012) Mitochondrial distribution of neuroglobin and its response to oxygen-glucose deprivation in primary-cultured mouse cortical neurons. Neuroscience 218:235–242. CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Fiocchetti M, Cipolletti M, Leone S, Naldini A, Carraro F, Giordano D, Verde C, Ascenzi P et al (2016) Neuroglobin in breast cancer cells: effect of hypoxia and oxidative stress on protein level, localization, and anti-apoptotic function. PLoS One 11(5):e0154959. CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    De Marinis E, Fiocchetti M, Acconcia F, Ascenzi P, Marino M (2013) Neuroglobin upregulation induced by 17beta-estradiol sequesters cytocrome c in the mitochondria preventing H2O2-induced apoptosis of neuroblastoma cells. Cell Death Dis 4:e508. CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Gorgun FM, Zhuo M, Singh S, Englander EW (2014) Neuroglobin mitigates mitochondrial impairments induced by acute inhalation of combustion smoke in the mouse brain. Inhal Toxicol 26(6):361–369. CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Cabezas R, Vega-Vela NE, Gonzalez-Sanmiguel J, Gonzalez J, Esquinas P, Echeverria V, Barreto GE (2018) PDGF-BB preserves mitochondrial morphology, attenuates ROS production, and upregulates neuroglobin in an astrocytic model under rotenone insult. Mol Neurobiol 55(4):3085–3095. CrossRefPubMedGoogle Scholar
  170. 170.
    Jin K, Mao X, Xie L, Greenberg DA (2012) Interactions between vascular endothelial growth factor and neuroglobin. Neurosci Lett 519(1):47–50. CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Zhu L, Huang L, Wen Q, Wang T, Qiao L, Jiang L (2017) Recombinant human erythropoietin offers neuroprotection through inducing endogenous erythropoietin receptor and neuroglobin in a neonatal rat model of periventricular white matter damage. Neurosci Lett 650:12–17. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Eliana Baez-Jurado
    • 1
  • Gina Guio-Vega
    • 1
  • Oscar Hidalgo-Lanussa
    • 1
  • Janneth González
    • 1
  • Valentina Echeverria
    • 2
    • 3
  • Ghulam Md Ashraf
    • 4
  • Amirhossein Sahebkar
    • 5
    • 6
    • 7
  • George E. Barreto
    • 1
    Email author
  1. 1.Departamento de Nutrición y Bioquímica, Facultad de CienciasPontificia Universidad JaverianaBogotá, D.C.Colombia
  2. 2.Facultad de Ciencias de la SaludUniversidad San SebastianConcepciónChile
  3. 3.Research & Development Service, Bay Pines VA Healthcare SystemBay PinesUSA
  4. 4.King Fahd Medical Research CenterKing Abdulaziz UniversityJeddahSaudi Arabia
  5. 5.Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
  6. 6.Biotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
  7. 7.School of PharmacyMashhad University of Medical SciencesMashhadIran

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