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Open Access 01-12-2016 | Research

A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Toll-like receptor 4 (TLR4) plays a pivotal role in the pathophysiology of stroke-induced inflammation. Both astroglia and microglia express TLR4, and endogenous ligands produced in the ischemic brain induce inflammatory responses. Reactive oxygen species (ROS), nitric oxide (NO), and inflammatory cytokines produced by TLR4 activation play harmful roles in neuronal damage after stroke. Although astroglia exhibit pro-inflammatory responses upon TLR4 stimulation by lipopolysaccharide (LPS), they may also play cytoprotective roles via the activation of the pentose phosphate pathway (PPP), reducing oxidative stress by glutathione peroxidase. We investigated the mechanisms by which astroglia reduce oxidative stress via the activation of PPP, using TLR4 stimulation and hypoxia in concert with microglia.

Methods

In vitro experiments were performed using cells prepared from Sprague–Dawley rats. Coexisting microglia in the astroglial culture were chemically eliminated using l-leucine methyl ester (LME). Cells were exposed to LPS (0.01 μg/mL) or hypoxia (1 % O₂) for 12–15 h. PPP activity was measured using [1-¹⁴C]glucose and [6-¹⁴C]glucose. ROS and NO production were measured using 2′,7′-dichlorodihydrofluorescein diacetate and diaminofluorescein-FM diacetate, respectively. The involvement of nuclear factor-erythroid-2-related factor 2 (Nrf2), a cardinal transcriptional factor under stress conditions that regulates glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of PPP, was evaluated using immunohistochemistry.

Results

Cultured astroglia exposed to LPS elicited 20 % increases in PPP flux, and these actions of astroglia appeared to involve Nrf2. However, the chemical depletion of coexisting microglia eliminated both increases in PPP and astroglial nuclear translocation of Nrf2. LPS induced ROS and NO production in the astroglial culture containing microglia but not in the microglia-depleted astroglial culture. LPS enhanced astroglial ROS production after glutathione depletion. U0126, an upstream inhibitor of mitogen-activated protein kinase, eliminated LPS-induced NO production, whereas ROS production was unaffected. U0126 also eliminated LPS-induced PPP activation in astroglial–microglial culture, indicating that microglia-derived NO mediated astroglial PPP activation. Hypoxia induced astroglial PPP activation independent of the microglia–NO pathway. Elimination of ROS and NO production by sulforaphane, a natural Nrf2 activator, confirmed the astroglial protective mechanism.

Conclusions

Astroglia in concert with microglia may play a cytoprotective role for countering oxidative stress in stroke.

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Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19:819–34. doi:10.1097/00004647-199908000-00001.CrossRefPubMed

Chamorro A, Hallenbeck J. The harms and benefits of inflammatory and immune responses in vascular disease. Stroke. 2006;37:291–3. doi:10.1161/01.STR.0000200561.69611.f8.CrossRefPubMedPubMedCentral

Becker KJ. Inflammation and acute stroke. Curr Opin Neurol. 1998;11:45–9.CrossRefPubMed

Davies CA, Loddick SA, Stroemer RP, Hunt J, Rothwell NJ. An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat. Exp Neurol. 1998;154:199–212. doi:10.1006/exnr.1998.6891.CrossRefPubMed

Hallenbeck JM. Significance of the inflammatory response in brain ischemia. Acta Neurochir Suppl. 1996;66:27–31.PubMed

Morioka T, Kalehua AN, Streit WJ. Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. J Comp Neurol. 1993;327:123–32. doi:10.1002/cne.903270110.CrossRefPubMed

Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res. 2004;26:884–92. doi:10.1179/016164104X2357.CrossRefPubMed

Szabo C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6:662–80. doi:10.1038/nrd2222.CrossRefPubMed

Shichita T, Sakaguchi R, Suzuki M, Yoshimura A. Post-ischemic inflammation in the brain. Front Immunol. 2012;3:132. doi:10.3389/fimmu.2012.00132.CrossRefPubMedPubMedCentral

10.

O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13:453–60. doi:10.1038/nri3446.CrossRefPubMed

11.

Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34:269–81. doi:10.1016/j.tins.2011.02.005.CrossRefPubMedPubMedCentral

12.

Nicholas SA, Coughlan K, Yasinska I, Lall GS, Gibbs BF, Calzolai L, et al. Dysfunctional mitochondria contain endogenous high-affinity human Toll-like receptor 4 (TLR4) ligands and induce TLR4-mediated inflammatory reactions. Int J Biochem Cell Biol. 2011;43:674–81. doi:10.1016/j.biocel.2011.01.012.CrossRefPubMed

13.

Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia. 2011;59:242–55. doi:10.1002/glia.21094.CrossRefPubMed

14.

Garcia-Nogales P, Almeida A, Fernandez E, Medina JM, Bolanos JP. Induction of glucose-6-phosphate dehydrogenase by lipopolysaccharide contributes to preventing nitric oxide-mediated glutathione depletion in cultured rat astrocytes. J Neurochem. 1999;72:1750–8.CrossRefPubMed

15.

Ben-Yoseph O, Boxer PA, Ross BD. Oxidative stress in the central nervous system: monitoring the metabolic response using the pentose phosphate pathway. Dev Neurosci. 1994;16:328–36.CrossRefPubMed

16.

Bolanos JP, Cidad P, Garcia-Nogales P, Delgado-Esteban M, Fernandez E, Almeida A. Regulation of glucose metabolism by nitrosative stress in neural cells. Mol Aspects Med. 2004;25:61–73. doi:10.1016/j.mam.2004.02.009.CrossRefPubMed

17.

Bergstrom AL, Fog K, Sager TN, Bruun AT, Thirstrup K. Competitive HIF prolyl hydroxylase inhibitors show protection against oxidative stress by a mechanism partially dependent on glycolysis. ISRN Neurosci. 2013;2013:598587. doi:10.1155/2013/598587.CrossRefPubMedPubMedCentral

18.

Biswas C, Shah N, Muthu M, La P, Fernando AP, Sengupta S, et al. Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses. J Biol Chem. 2014;289:26882–94. doi:10.1074/jbc.M114.567685.CrossRefPubMedPubMedCentral

19.

Kolamunne RT, Dias IH, Vernallis AB, Grant MM, Griffiths HR. Nrf2 activation supports cell survival during hypoxia and hypoxia/reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species. Redox Biol. 2013;1:418–26. doi:10.1016/j.redox.2013.08.002.CrossRefPubMedPubMedCentral

20.

Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2-an update. Free Radic Biol Med. 2014;66:36–44. doi:10.1016/j.freeradbiomed.2013.02.008.CrossRefPubMed

21.

Um HC, Jang JH, Kim DH, Lee C, Surh YJ. Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells. Nitric Oxide. 2011;25:161–8. doi:10.1016/j.niox.2011.06.001.CrossRefPubMed

22.

Abbas K, Breton J, Planson AG, Bouton C, Bignon J, Seguin C, et al. Nitric oxide activates an Nrf2/sulfiredoxin antioxidant pathway in macrophages. Free Radic Biol Med. 2011;51:107–14. doi:10.1016/j.freeradbiomed.2011.03.039.CrossRefPubMed

23.

Lee SJ, Lee S. Toll-like receptors and inflammation in the CNS. Curr Drug Targets Inflamm Allergy. 2002;1:181–91.CrossRefPubMed

24.

Hamby ME, Uliasz TF, Hewett SJ, Hewett JA. Characterization of an improved procedure for the removal of microglia from confluent monolayers of primary astrocytes. J Neurosci Methods. 2006;150:128–37. doi:10.1016/j.jneumeth.2005.06.016.CrossRefPubMed

25.

Pont-Lezica L, Colasse S, Bessis A. Depletion of microglia from primary cellular cultures. Methods Mol Biol. 2013;1041:55–61. doi:10.1007/978-1-62703-520-0_7.CrossRefPubMed

26.

Takahashi S, Driscoll BF, Law MJ, Sokoloff L. Role of sodium and potassium ions in regulation of glucose metabolism in cultured astroglia. Proc Natl Acad Sci U S A. 1995;92:4616–20.CrossRefPubMedPubMedCentral

27.

Giulian D, Baker TJ. Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci. 1986;6:2163–78.PubMed

28.

Saura J. Microglial cells in astroglial cultures: a cautionary note. J Neuroinflammation. 2007;4:26. doi:10.1186/1742-2094-4-26.CrossRefPubMedPubMedCentral

29.

Thiele DL, Kurosaka M, Lipsky PE. Phenotype of the accessory cell necessary for mitogen-stimulated T and B cell responses in human peripheral blood: delineation by its sensitivity to the lysosomotropic agent, L-leucine methyl ester. J Immunol. 1983;131:2282–90.PubMed

30.

Jebelli J, Piers T, Pocock J. Selective depletion of microglia from cerebellar granule cell cultures using L-leucine methyl ester. J Vis Exp. 2015:e52983. doi:10.3791/52983

31.

Gross J, Ungethum U, Andreeva N, Heldt J, Priem F, Marschhausen G, et al. Glutamate-induced efflux of protein, neuron-specific enolase and lactate dehydrogenase from a mesencephalic cell culture. Eur J Clin Chem Clin Biochem. 1996;34:305–10.PubMed

32.

Danilov CA, Chandrasekaran K, Racz J, Soane L, Zielke C, Fiskum G. Sulforaphane protects astrocytes against oxidative stress and delayed death caused by oxygen and glucose deprivation. Glia. 2009;57:645–56. doi:10.1002/glia.20793.CrossRefPubMedPubMedCentral

33.

Cheung KL, Kong AN. Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. AAPS J. 2010;12:87–97. doi:10.1208/s12248-009-9162-8.CrossRefPubMedPubMedCentral

34.

Guerrero-Beltran CE, Calderon-Oliver M, Pedraza-Chaverri J, Chirino YI. Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicol Pathol. 2012;64:503–8. doi:10.1016/j.etp.2010.11.005.CrossRefPubMed

35.

Singh RJ, Hogg N, Joseph J, Kalyanaraman B. Mechanism of nitric oxide release from S-nitrosothiols. J Biol Chem. 1996;271:18596–603.CrossRefPubMed

36.

Griffith OW. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem. 1982;257:13704–12.PubMed

37.

Gao L, Mejias R, Echevarria M, Lopez-Barneo J. Induction of the glucose-6-phosphate dehydrogenase gene expression by chronic hypoxia in PC12 cells. FEBS Lett. 2004;569:256–60. doi:10.1016/j.febslet.2004.06.004.CrossRefPubMed

38.

Amaral AI, Teixeira AP, Martens S, Bernal V, Sousa MF, Alves PM. Metabolic alterations induced by ischemia in primary cultures of astrocytes: merging 13C NMR spectroscopy and metabolic flux analysis. J Neurochem. 2010;113:735–48. doi:10.1111/j.1471-4159.2010.06636.x.CrossRefPubMed

39.

Abe T, Takahashi S, Suzuki N. Oxidative metabolism in cultured rat astroglia: effects of reducing the glucose concentration in the culture medium and of D-aspartate or potassium stimulation. J Cereb Blood Flow Metab. 2006;26:153–60. doi:10.1038/sj.jcbfm.9600175.CrossRefPubMed

40.

Waniewski RA, Martin DL. Astrocytes and synaptosomes transport and metabolize lactate and acetate differently. Neurochem Res. 2004;29:209–17.CrossRefPubMed

41.

Hothersall JS, Baquer N, Greenbaum AL, McLean P. Alternative pathways of glucose utilization in brain. Changes in the pattern of glucose utilization in brain during development and the effect of phenazine methosulfate on the integration of metabolic routes. Arch Biochem Biophys. 1979;198:478–92.CrossRefPubMed

42.

Gomes A, Fernandes E, Lima JL. Fluorescence probes used for detection of reactive oxygen species. J Biochem Biophys Methods. 2005;65:45–80. doi:10.1016/j.jbbm.2005.10.003.CrossRefPubMed

43.

Kojima H, Nakatsubo N, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, et al. Detection and imaging of nitric oxide with novel fluorescent indicators: diaminofluoresceins. Anal Chem. 1998;70:2446–53.CrossRefPubMed

44.

Chatterjee S, Noack H, Possel H, Keilhoff G, Wolf G. Glutathione levels in primary glial cultures: monochlorobimane provides evidence of cell type-specific distribution. Glia. 1999;27:152–61.CrossRefPubMed

45.

Takahashi S, Izawa Y, Suzuki N. Astroglial pentose phosphate pathway rates in response to high-glucose environments. ASN Neuro. 2012;4. doi:10.1042/an20120002

46.

Brea D, Sobrino T, Ramos-Cabrer P, Castillo J. Inflammatory and neuroimmunomodulatory changes in acute cerebral ischemia. Cerebrovasc Dis. 2009;27 Suppl 1:48–64. doi:10.1159/000200441.CrossRefPubMed

47.

Gehrmann J, Banati RB, Wiessner C, Hossmann KA, Kreutzberg GW. Reactive microglia in cerebral ischaemia: an early mediator of tissue damage? Neuropathol Appl Neurobiol. 1995;21:277–89.CrossRefPubMed

48.

Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol. 1998;56:149–71.CrossRefPubMed

49.

Wen YD, Zhang HL, Qin ZH. Inflammatory mechanism in ischemic neuronal injury. Neurosci Bull. 2006;22:171–82.PubMed

50.

Xia W, Han J, Huang G, Ying W. Inflammation in ischaemic brain injury: current advances and future perspectives. Clin Exp Pharmacol Physiol. 2010;37:253–8. doi:10.1111/j.1440-1681.2009.05279.x.CrossRefPubMed

51.

Cuenca-Lopez MD, Brea D, Galindo MF, Anton-Martinez D, Sanz MJ, Agulla J, et al. Inflammatory response during ischaemic processes: adhesion molecules and immunomodulation. Rev Neurol. 2010;51:30–40.PubMed

52.

Denes A, Thornton P, Rothwell NJ, Allan SM. Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun. 2010;24:708–23. doi:10.1016/j.bbi.2009.09.010.CrossRefPubMed

53.

Wang Y, Ge P, Zhu Y. TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediators Inflamm. 2013;2013:124614. doi:10.1155/2013/124614.PubMedPubMedCentral

54.

Hamanaka J, Hara H. Involvement of Toll-like receptors in ischemia-induced neuronal damage. Cent Nerv Syst Agents Med Chem. 2011;11:107–13.CrossRefPubMed

55.

Gadani SP, Walsh JT, Lukens JR, Kipnis J. Dealing with danger in the CNS: the response of the immune system to injury. Neuron. 2015;87:47–62. doi:10.1016/j.neuron.2015.05.019.CrossRefPubMed

56.

Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, et al. Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab. 2008;28:927–38. doi:10.1038/sj.jcbfm.9600582.CrossRefPubMed

57.

Kuang X, Wang LF, Yu L, Li YJ, Wang YN, He Q, et al. Ligustilide ameliorates neuroinflammation and brain injury in focal cerebral ischemia/reperfusion rats: involvement of inhibition of TLR4/peroxiredoxin 6 signaling. Free Radic Biol Med. 2014;71:165–75. doi:10.1016/j.freeradbiomed.2014.03.028.CrossRefPubMed

58.

Yoo KY, Yoo DY, Hwang IK, Park JH, Lee CH, Choi JH, et al. Time-course alterations of Toll-like receptor 4 and NF-kappaB p65, and their co-expression in the gerbil hippocampal CA1 region after transient cerebral ischemia. Neurochem Res. 2011;36:2417–26. doi:10.1007/s11064-011-0569-0.CrossRefPubMed

59.

Kacimi R, Giffard RG, Yenari MA. Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappaB, JAK-STAT and JNK stress kinase pathways. J Inflamm (Lond). 2011;8:7. doi:10.1186/1476-9255-8-7.CrossRef

60.

Mallard C, Wang X, Hagberg H. The role of Toll-like receptors in perinatal brain injury. Clin Perinatol. 2009;36:763–72. doi:10.1016/j.clp.2009.07.009. v-vi.CrossRefPubMed

61.

Barbierato M, Facci L, Argentini C, Marinelli C, Skaper SD, Giusti P. Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype. CNS Neurol Disord Drug Targets. 2013;12:608–18.CrossRefPubMed

62.

Chistyakov DV, Aleshin S, Sergeeva MG, Reiser G. Regulation of peroxisome proliferator-activated receptor beta/delta expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes. J Neurochem. 2014;130:563–74. doi:10.1111/jnc.12757.CrossRefPubMed

63.

Ko HM, Lee SH, Kim KC, Joo SH, Choi WS, Shin CY. The role of TLR4 and Fyn interaction on lipopolysaccharide-stimulated PAI-1 expression in astrocytes. Mol Neurobiol. 2015;52:8–25. doi:10.1007/s12035-014-8837-z.CrossRefPubMed

64.

Schafer S, Calas AG, Vergouts M, Hermans E. Immunomodulatory influence of bone marrow-derived mesenchymal stem cells on neuroinflammation in astrocyte cultures. J Neuroimmunol. 2012;249:40–8. doi:10.1016/j.jneuroim.2012.04.018.CrossRefPubMed

65.

Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001;4:702–10. doi:10.1038/89490.CrossRefPubMed

66.

Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440:1054–9. doi:10.1038/nature04671.CrossRefPubMed

67.

Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A. 2012;109:E197–205. doi:10.1073/pnas.1111098109.CrossRefPubMedPubMedCentral

68.

Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell. 2009;137:47–59. doi:10.1016/j.cell.2009.01.038.CrossRefPubMedPubMedCentral

69.

Dodson M, Darley-Usmar V, Zhang J. Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med. 2013;63:207–21. doi:10.1016/j.freeradbiomed.2013.05.014.CrossRefPubMedPubMedCentral

70.

Lamonte G, Tang X, Chen JL, Wu J, Ding CK, Keenan MM, et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer Metab. 2013;1:23. doi:10.1186/2049-3002-1-23.CrossRefPubMedPubMedCentral

71.

Morgan WA, Kaler B, Bach PH. The role of reactive oxygen species in adriamycin and menadione-induced glomerular toxicity. Toxicol Lett. 1998;94:209–15.CrossRefPubMed

72.

Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. 2007;27:1129–38. doi:10.1523/jneurosci.4468-06.2007.CrossRefPubMed

73.

Kuroda S, Siesjo BK. Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci. 1997;4:199–212.PubMed

74.

Marrif H, Juurlink BH. Astrocytes respond to hypoxia by increasing glycolytic capacity. J Neurosci Res. 1999;57:255–60.CrossRefPubMed

75.

Cakir T, Alsan S, Saybasili H, Akin A, Ulgen KO. Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: application to cerebral hypoxia. Theor Biol Med Model. 2007;4:48. doi:10.1186/1742-4682-4-48.CrossRefPubMed

76.

Kelleher JA, Chan PH, Chan TY, Gregory GA. Energy metabolism in hypoxic astrocytes: protective mechanism of fructose-1,6-bisphosphate. Neurochem Res. 1995;20:785–92.CrossRefPubMed

77.

Wakade AR, Wakade TD. Sympathetic neurons grown in culture generate ATP by glycolysis: correlation between ATP content and [3H]norepinephrine uptake and storage. Brain Res. 1985;359:397–401.CrossRefPubMed

78.

Gjedde A, Marrett S, Vafaee M. Oxidative and nonoxidative metabolism of excited neurons and astrocytes. J Cereb Blood Flow Metab. 2002;22:1–14. doi:10.1097/00004647-200201000-00001.CrossRefPubMed

79.

Hertz L, Peng L. Energy metabolism at the cellular level of the CNS. Can J Physiol Pharmacol. 1992;70(Suppl):S145–57.CrossRefPubMed

80.

Hertz L, Peng L, Lai JC. Functional studies in cultured astrocytes. Methods. 1998;16:293–310. doi:10.1006/meth.1998.0686.CrossRefPubMed

81.

Brown DR, Schmidt B, Kretzschmar HA. A neurotoxic prion protein fragment enhances proliferation of microglia but not astrocytes in culture. Glia. 1996;18:59–67. doi:10.1002/(SICI)1098-1136(199609)18:1<59::AID-GLIA6>3.0.CO;2-Z.CrossRefPubMed

82.

Ciccarelli R, Di Iorio P, D'Alimonte I, Giuliani P, Florio T, Caciagli F, et al. Cultured astrocyte proliferation induced by extracellular guanosine involves endogenous adenosine and is raised by the co-presence of microglia. Glia. 2000;29:202–11.CrossRefPubMed

83.

Xiong H, Yamada K, Jourdi H, Kawamura M, Takei N, Han D, et al. Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells. Mol Pharmacol. 1999;56:339–47.PubMedPubMedCentral

84.

Parke DV, Dhami MS, Afzal M. The effect of nutrition on chemical toxicity. Drug Metabol Drug Interact. 1997;13:161–93. doi:10.1515/dmdi.1997.13.3.161.CrossRefPubMed

85.

Zhang HS, Wang SQ. Nrf2 is involved in the effect of tanshinone IIA on intracellular redox status in human aortic smooth muscle cells. Biochem Pharmacol. 2007;73:1358–66. doi:10.1016/j.bcp.2007.01.004.CrossRefPubMed

86.

Antelmann H, Helmann JD. Thiol-based redox switches and gene regulation. Antioxid Redox Signal. 2011;14:1049–63. doi:10.1089/ars.2010.3400.CrossRefPubMedPubMedCentral

87.

Burhans WC, Heintz NH. The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radic Biol Med. 2009;47:1282–93. doi:10.1016/j.freeradbiomed.2009.05.026.CrossRefPubMed

88.

Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88. doi:10.1038/cdd.2014.150.CrossRefPubMedPubMedCentral

89.

Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med. 2014;66:75–87. doi:10.1016/j.freeradbiomed.2013.07.036.CrossRefPubMed

90.

Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem. 2002;277:42769–74. doi:10.1074/jbc.M206911200.CrossRefPubMed

91.

Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med. 2004;36:1199–207. doi:10.1016/j.freeradbiomed.2004.02.074.CrossRefPubMed

92.

Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47:1304–9. doi:10.1016/j.freeradbiomed.2009.07.035.CrossRefPubMedPubMedCentral

93.

Niture SK, Jain AK, Jaiswal AK. Antioxidant-induced modification of INrf2 cysteine 151 and PKC-delta-mediated phosphorylation of Nrf2 serine 40 are both required for stabilization and nuclear translocation of Nrf2 and increased drug resistance. J Cell Sci. 2009;122:4452–64. doi:10.1242/jcs.058537.CrossRefPubMedPubMedCentral

94.

Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM, Woodruff TM. Toll-like receptors in ischemia-reperfusion injury. Shock. 2009;32:4–16. doi:10.1097/SHK.0b013e318193e333.CrossRefPubMed

95.

Brea D, Blanco M, Ramos-Cabrer P, Moldes O, Arias S, Perez-Mato M, et al. Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab. 2011;31:1424–31. doi:10.1038/jcbfm.2010.231.CrossRefPubMedPubMedCentral

96.

Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H. Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J Neurochem. 2012;123 Suppl 2:29–38. doi:10.1111/j.1471-4159.2012.07941.x.CrossRefPubMed

97.

Brekke EM, Morken TS, Wideroe M, Haberg AK, Brubakk AM, Sonnewald U. The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury. J Cereb Blood Flow Metab. 2014;34:724–34. doi:10.1038/jcbfm.2014.8.CrossRefPubMedPubMedCentral

Title: A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system
Publication date: 01-12-2016
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0564-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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