臺灣博碩士論文加值系統

內皮細胞（EC）存在於所有的器官系統及調控不同的營養物質和生物活性分子的流動。大腦是由連續排列的內皮細胞緊密連接，而內皮細胞的緊密連結有助於維持血腦屏障的完整性（blood-brain barrier ; BBB）。若內皮細胞緊密連結出現異常時，會造成發炎、氧化壓力或其疾病，將導致血腦障壁功能受損。（HO-1）催化裂解血紅素(Heme)分子，產生一氧化碳（CO）、膽紅素和鐵釋放。第一型血紅素氧化酶（HO-1）需要血基質的降解，且HO-1已經被指出具有不可或缺的強力抗氧化壓力，可直接活化HO-1對於腦部氧化壓力是關鍵的神經保護機制。
15脫氧前列腺素J2 (15d-PGJ2) 是一種PPARs內生性配體，透過與PPARγ相互作用能夠激活多種細胞內反應，包括生長停滯，細胞凋亡，分化，或抑制巨噬細胞活化和炎症。值得注意的是，本研究中前處理PPARγ拮抗劑並沒有抑制15脫氧前列腺素J2誘導HO-1表現。基於上述的發現，我們推測15脫氧前列腺素J2是透過間接PPARγ方式誘導HO-1表現。在神經元的保護中，15脫氧前列腺素J2可以降低氧化/亞硝化調解者，亦可抑制炎症信號，並誘導神經細胞的自噬後腦缺血性再灌注損傷，進一步保護腦免於受缺血性灌注損傷。
本論文以小鼠腦內皮細胞作為模式探討15脫氧前列腺素J2誘導HO-1表現的機制，結果指出15脫氧前列腺素J2可以誘導HO-1表現，藉由蛋白合成的時間及濃度成依賴性方式。再者，15脫氧前列腺素J2誘導HO-1表現是由NADPH所誘導，在前處理NADPH抑制劑、DPI、MitoTempo或Rotenone時，以15脫氧前列腺素J2誘導HO-1小鼠腦內皮細胞的表現有顯著降低。15脫氧前列腺素J2誘導HO-1蛋白表現也牽涉PI3K/NOX/ROS/c-Src/PYK2/Akt /FoxO1/Sp1、PI3K NOX/ROS/PKCδ/Sp1和PI3K/NOX/ROS/PKC/JNK1/2/c-Jun，因為這些反應會被相關的抑制劑如LY294002、Ro318220、DPI、MitoTempo、Rotenone、PP1、PF431396、AktVIII、Rottlerin、SP600125、AS1842856和Mithramycin A所抑制。此外，下游轉錄因子以及輔因子如: Sp1、FoxO1 和 c-Jun也參與誘導HO-1之表現。基於上述之發現，我們證實15d-PGJ2可以活化PI3K/NOX/ROS/ c-Src/PYK2/Akt/FoxO1 and Sp1、PI3K/NOX/ROS/PKCδ/Sp1、PI3K/NOX/ ROS/PKC/c-Jun 共同活化增加HO-1表現，進而達到抗腦神經發炎作用，將有助於未來發展腦神經炎症治療開發的策略。

Endothelial cells (ECs) exist in all the organ systems and regulate the flow of diverse nutrient substances and biologically active molecules. The brain is lined by continuous ECs connected by tight junctions that help to maintain the blood-brain barrier (BBB). The abnormal function(s) of bEnd.3Cs, causing by inflammation, oxidative stress or other kinds of diseases, will result in malfunction of BBB. HO-1 catalyzes the cleavage of heme molecule to produce carbon monoxide (CO), bilirubin and iron. The HO-1-catalyzed heme degradation also plays a critical role in antioxidant, and cytoprotective function during inflammatory disorders. HO-1 has been proposed to play an obligatory role in endogenous defense against oxidative stress. The direct activated HO-1 during condition of cerebral oxidative stress is critical for neuroprotection.
The 15-Deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of PPARs, can modulate several cellular responses including growth arrest, apoptosis, differentiation, or suppression of macrophage activation and inflammation through an interaction with the PPARγ. It is important to note that pretreatment with PPARγ antagonist failed to suppress 15d-PGJ2-induced HO-1 expression. Based on these findings, the results suggested that HO-1 induction by 15d-PGJ2 is independent on PPARγ. In neuronal protection, 15d-PGJ2 can decrease oxidative/nitrosative mediators, and suppress inflammatory signaling, mediate neuronal autophagy after cerebral ischemia-reperfusion injury, to protect brain from ischemia-reperfusion injury.
In this study, mouse brain microvascular endothelial cells (bEnd.3Cs) were used as a model to investigate the mechanisms underlying 15d-PGJ2-induced HO-1 expression. The preliminary results indicated that 15d-PGJ2 can induce the HO-1 protein expression through de-novo protein synthesis in a time- and concentration-dependent manner. Furthermore, the 15d-PGJ2-induced HO-1 expression is mediated by NADPH oxidase, which was attenuated by pretreatment with the inhibitor of NADPH oxidase (DPI, MitoTempo, and Rotenone) in bEnd.3Cs. 15d-PGJ2-induced HO-1 protein expression is also involved in receptor tyrosine kinase JNK1/2, PI3K/Akt and PKC, which was attenuated by pretreatment with the inhibitor of PI3K (LY294002), PYK2(PF431396), Src (PP1), Akt (AktVIII), PKC (Ro318220 and Rottlerin), JNK1/2 (SP600125), FoxO1 (AS1842856) and Sp1 (Mithramycin A). Moreover, the downstream stream transcription factors and cofactors also involved in the HO-1 induction such as Sp1, FoxO1 and c-Jun. Based on these findings, we demonstrated that 15d-PGJ2 activates the cooperation of PI3K/NOX/ROS/ c-Src/PYK2/Akt/FoxO1 and Sp1、PI3K/NOX/ROS/PKCδ/Sp1、PI3K/NOX/ ROS/PKC/c-Jun pathway through nuclear translocation of FoxO1 and Sp1 and leading to HO-1 expression. The induction of HO-1 by 15d-PGJ2 exerts anti-inflammatory effects on brain neuroinflammation. It will facilitate the development of therapeutic strategies for the treatment of brain neuroinflammation

指導教授推薦書
口試委員會審定書
Acknowledgements---------------------------------------------------------------iii
Abbreviations------------------------------------------------------------------v
Pharmacological inhibitors-----------------------------------------------------vii
Abstract in Chinese------------------------------------------------------------viii
Abstract in English------------------------------------------------------------x
Contents-----------------------------------------------------------------------xii
List of Figures ---------------------------------------------------------------xiii
List of Table -----------------------------------------------------------------xv

Chapter I. Introduction-----------------------------------------------------------1
Chapter II. Materials and Methods ------------------------------------------19
Chapter III. Results--------------------------------------------------------------28
Chapter IV. Figures and Legends---------------------------------------------38
Chapter V. Discussion-----------------------------------------------------------59
References ---------------------------------------------------------------------64

List of Figures
Appended figures contents
Figures 1 The cell associations at the BBB-----------------------------------------13
Figures 2 Biosynthetic pathway of prostanoids--------------------------------------15
Figures 3 Potential mechanisms underlying the chemoprotective actions of
HO-1 in diabetes and hypertension--------------------------------------------------15
Figures 4 Modes of action of J2 prostaglandins-------------------------------------16
Figures 5 Proposed scheme of the effects of up-regulation of HO-1 by PPARγ
activation on HMGB1-RAGE signaling pathway in ALI/ARDS-----------------17

Figures of Contents
Figures 1. 15d-PGJ2 induces HO-1 protein and gene expression in bEnd.3
cells -----------------------------------------------------------------------------38
Figures 2. 15d-PGJ2 induces HO-1 expression via transcriptional and
translational levels in bEnd.3 cells ----------------------------------------------40
Figures 3.15d-PGJ2 induced HO-1 expression via NADPH oxidase activation
and Mitochondria generated ROS and Mitochondrial complex I are involved in
15d-PGJ2 induced HO-1 protein expression in bEnd.3 cells --------------------42
Figures 4. 15d-PGJ2 induced HO-1 protein expression via activation of c-Src
and PYK2 in bEnd.3 cells-----------------------------------------------------------44
Figures 5. The PI3K, Akt are involved in 15d-PGJ2 induced HO-1 expression
in in bEnd.3 cells ----------------------------------------------------------------46
Figures 6. Involvement of PKC isoforms in HO-1 protein expression induced by
15d-PGJ2 in bEnd.3 cells ----------------------------------------------------------48
Figures 7. Involvement of JNK1/2 isoforms in HO-1 protein expression induced
by 15d-PGJ2 in bEnd.3 cells -------------------------------------------------------50
Figures 8. Involvement of transcription factor FoxO1 in HO-1 protein expression
induced by 15d-PGJ2 in bEnd.3 cells -----------------------------------------------52
Figures 9. Involvement of transcription factor Sp1 in HO-1 protein expression
induced by 15d-PGJ2 in bEnd.3 cells -----------------------------------------------54
Figures 10. Involvement of transcription factor c-Jun in HO-1 protein expression
induced by 15d-PGJ2 in bEnd.3 cells -----------------------------------------------56
Figures 11. 15d-PGJ2-induced HO-1 regulates LPS-induced IL-6 secretion in
bEnd.3 cells ----------------------------------------------------------------------57
Figures 12. Schematic representation of signaling pathways involved in
15d-PGJ2-induce HO-1 expression and protected against LPS-induce IL-6
secretion in bEnd.3 cells----------------------------------------------------------58

List of table
Appended table contents
Table 1 Regulation of inflammation signaling by15d-PGJ2----------------------18

1. Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. Journal of anatomy 200: 629-638
2. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiology of disease 37: 13-25
3. Abdel-Hakeem MS, Shoukry NH (2014) Protective immunity against hepatitis C: many shades of gray. Frontiers in immunology 5: 274
4. Alberti A, Benvegnu L (2003) Management of hepatitis C. Journal of hepatology 38 Suppl 1: S104-118
5. Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nature reviews Cancer 13: 11-26
6. Araujo JA, Zhang M, Yin F (2012) Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Frontiers in pharmacology 3: 119
7. Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV, Gabrielli A (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. The New England journal of medicine 354: 2667-2676
8. Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, Leffler CW, Parfenova H (2006) HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. American journal of physiology Cell physiology 291: C897-908
9. Berberat PO, Katori M, Kaczmarek E, Anselmo D, Lassman C, Ke B, Shen X, Busuttil RW, Yamashita K, Csizmadia E, Tyagi S, Otterbein LE, Brouard S, Tobiasch E, Bach FH, Kupiec-Weglinski JW, Soares MP (2003) Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17: 1724-1726
10. Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva T, Gelse K, Sonnylal S, de Crombrugghe B, Taketo MM, Distler O, Schett G, Distler JH (2012) beta-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Annals of the rheumatic diseases 71: 761-767
11. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, P MM, P JC (2008) Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 11: 255-260
12. Bijli KM, Fazal F, Rahman A (2012) Regulation of Rela/p65 and endothelial cell inflammation by proline-rich tyrosine kinase 2. American journal of respiratory cell and molecular biology 47: 660-668
13. Biswas C, Shah N, Muthu M, La P, Fernando AP, Sengupta S, Yang G, Dennery PA (2014) Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses. The Journal of biological chemistry 289: 26882-26894
14. Blight AR (2002) Miracles and molecules--progress in spinal cord repair. Nature neuroscience 5 Suppl: 1051-1054
15. Brauckmann S (2000) The organism and the open system. Ervin Bauer and Ludwig von Bertalanffy. Annals of the New York Academy of Sciences 901: 291-300
16. Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. The Journal of experimental medicine 192: 1015-1026
17. Cabzas R, Avila M, Gonzalez J, El-Bacha RS, Baez E, Garcia-Segura LM, Jurado Coronel JC, Capani F, Cardona-Gomez GP, Barreto GE (2014) Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease. Frontiers in cellular neuroscience 8: 211
18. Cao J, Dummond G, Inoue K, Sodhi K, Li XY, Omura S (2008) Upregulation of heme oxygenase-1 combined with increased adiponectin lowers blood pressure in diabetic spontaneously hypertensive rats through a reduction in endothelial cell dysfunction, apoptosis and oxidative stress. International journal of molecular sciences 9: 2388-2406
19. Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck MP, Fenart L (2007) Modelling of the blood-brain barrier in drug discovery and development. Nature reviews Drug discovery 6: 650-661
20. Chang EF, Wong RJ, Vreman HJ, Igarashi T, Galo E, Sharp FR, Stevenson DK, Noble-Haeusslein LJ (2003) Heme oxygenase-2 protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 23: 3689-3696
21. Chang YC, Lai CC, Lin LF, Ni WF, Tsai CH (2005) The up-regulation of heme oxygenase-1 expression in human gingival fibroblasts stimulated with nicotine. Journal of periodontal research 40: 252-257
22. Chen K, Li J, Li S, Feng J, Wu L, Liu T, Zhang R, Xu S, Cheng K, Zhou Y, Zhou S, Wang F, Dai W, Xia Y, Lu J, Zhou Y, Guo C (2016) 15d-PGJ2 alleviates ConA-induced acute liver injury in mice by up-regulating HO-1 and reducing hepatic cell autophagy. Biomedicine & pharmacotherapy 80: 183-192
23. Chen K, Li J, Wang J, Xia Y, Dai W, Wang F, Shen M, Cheng P, Zhang Y, Wang C, Yang J, Zhu R, Zhang H, Zheng Y, Lu J, Fan Z, Zhou Y, Guo C (2014) 15-Deoxy- gamma 12,14-prostaglandin J2 Reduces Liver Impairment in a Model of ConA-Induced Acute Hepatic Inflammation by Activation of PPAR gamma and Reduction in NF- kappa B Activity. PPAR research 2014: 215631
24. Chi PL, Lin CC, Chen YW, Hsiao LD, Yang CM (2015) CO Induces Nrf2-Dependent Heme Oxygenase-1 Transcription by Cooperating with Sp1 and c-Jun in Rat Brain Astrocytes. Molecular neurobiology 52: 277-292
25. Chi PL, Lin CC, Chen YW, Hsiao LD, Yang CM (2015) CO Induces Nrf2-Dependent Heme Oxygenase-1 Transcription by Cooperating with Sp1 and c-Jun in Rat Brain Astrocytes. Molecular neurobiology 52: 277-292
26. Cruciat CM, Niehrs C (2013) Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harbor perspectives in biology 5: a015081
27. de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood-brain barrier in vitro. Journal of neuroimmunology 64: 37-43
28. del Zoppo GJ (2006) Stroke and neurovascular protection. The New England journal of medicine 354: 553-555
29. Farnesi-de-Assuncao TS, Alves CF, Carregaro V, de Oliveira JR, da Silva CA, Cheraim AB, Cunha FQ, Napimoga MH (2012) PPAR-gamma agonists, mainly 15d-PGJ(2), reduce eosinophil recruitment following allergen challenge. Cellular immunology 273: 23-29
30. Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P (2014) Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Frontiers in molecular neuroscience 7: 104
31. Fucci A, Colangelo T, Votino C, Pancione M, Sabatino L, Colantuoni V (2012) The role of peroxisome proliferator-activated receptors in the esophageal, gastric, and colorectal cancer. PPAR research 2012: 242498
32. Fukano Y, Oishi M, Chibana F, Numazawa S, Yoshida T (2006) Analysis of the expression of heme oxygenase-1 gene in human alveolar epithelial cells exposed to cigarette smoke condensate. The Journal of toxicological sciences 31: 99-109
33. Gaffen SL, McGeachy MJ (2015) Integrating p38alpha MAPK immune signals in nonimmune cells. Science signaling 8: fs5
34. Garcia-Bueno B, Madrigal JL, Lizasoain I, Moro MA, Lorenzo P, Leza JC (2005) The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats. Psychopharmacology 180: 513-522
35. Geraldes P, Yagi K, Ohshiro Y, He Z, Maeno Y, Yamamoto-Hiraoka J, Rask-Madsen C, Chung SW, Perrella MA, King GL (2008) Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway. The Journal of biological chemistry 283: 34327-34336
36. Gren DE, Sutliff RL, Hart CM (2011) Is peroxisome proliferator-activated receptor gamma (PPARgamma) a therapeutic target for the treatment of pulmonary hypertension? Pulmonary circulation 1: 33-47
37. Grozanovic Z, Gossrau R (1996) Expression of heme oxygenase-2 (HO-2)-like immunoreactivity in rat tissues. Acta histochemica 98: 203-214
38. Grzschik SM, Maier CM, Chan PH (2003) Effects of cold injury-induced trauma in manganese superoxide dismutase-deficient mice. Journal of neurotrauma 20: 571-581
39. Hn Z, Varadharaj S, Giedt RJ, Zweier JL, Szeto HH, Alevriadou BR (2009) Mitochondria-derived reactive oxygen species mediate heme oxygenase-1 expression in sheared endothelial cells. The Journal of pharmacology and experimental therapeutics 329: 94-101
40. HarrisGK, Shi X (2003) Signaling by carcinogenic metals and metal-induced reactive oxygen species. Mutation research 533: 183-200
41. Haskew-Layton RE, Payappilly JB, Xu H, Bennett SA, Ratan RR (2013) 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) protects neurons from oxidative death via an Nrf2 astrocyte-specific mechanism independent of PPARgamma. Journal of neurochemistry 124: 536-547
42. Ho YY, Lagares D, Tager AM, Kapoor M (2014) Fibrosis--a lethal component of systemic sclerosis. Nature reviews Rheumatology 10: 390-402
43. Hwang YS, Jeong M, Park JS, Kim MH, Lee DB, Shin BA, Mukaida N, Ellis LM, Kim HR, Ahn BW, Jung YD (2004) Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells. Oncogene 23: 6603-6611
44. Ji JD, Kim HJ, Rho YH, Choi SJ, Lee YH, Cheon HJ, Sohn J, Song GG (2005) Inhibition of IL-10-induced STAT3 activation by 15-deoxy-Delta12,14-prostaglandin J2. Rheumatology 44: 983-988
45. Jones TB, McDaniel EE, Popovich PG (2005) Inflammatory-mediated injury and repair in the traumatically injured spinal cord. Current pharmaceutical design 11: 1223-1236
46. Kadoya C, Domino EF, Yang GY, Stern JD, Betz AL (1995) Preischemic but not postischemic zinc protoporphyrin treatment reduces infarct size and edema accumulation after temporary focal cerebral ischemia in rats. Stroke; a journal of cerebral circulation 26: 1035-1038
47. Kalaria RN (1992) The blood-brain barrier and cerebral microcirculation in Alzheimer disease. Cerebrovascular and brain metabolism reviews 4: 226-260
48. Kansanen E, Kivela AM, Levonen AL (2009) Regulation of Nrf2-dependent gene expression by 15-deoxy-Delta12,14-prostaglandin J2. Free radical biology & medicine 47: 1310-1317
49. Kapadia R, Yi JH, Vemuganti R (2008) Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Frontiers in bioscience : a journal and virtual library 13: 1813-1826
50. Karnovsky MJ (1967) The ultrastructural basis of capillary permeability studied with peroxidase as a tracer. The Journal of cell biology 35: 213-236
51. Kawai N, Kawanishi M, Okada M, Matsumoto Y, Nagao S (2003) Treatment of cold injury-induced brain edema with a nonspecific matrix metalloproteinase inhibitor MMI270 in rats. Journal of neurotrauma 20: 649-657
52. Kelly FJ (2003) Oxidative stress: its role in air pollution and adverse health effects. Occupational and environmental medicine 60: 612-616
53. Kim DH, Song NY, Kim EH, Na HK, Joe Y, Chung HT, Surh YJ (2014) 15-deoxy-Delta12,14-prostaglandin J(2) induces p53 expression through Nrf2-mediated upregulation of heme oxygenase-1 in human breast cancer cells. Free radical research 48: 1018-1027
54. Kim WJ, Kim JH, Jang SK (2007) Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A. The EMBO journal 26: 5020-5032
55. Kushida T, Li Volti G, Quan S, Goodman A, Abraham NG (2002) Role of human heme oxygenase-1 in attenuating TNF-alpha-mediated inflammation injury in endothelial cells. Journal of cellular biochemistry 87: 377-385
56. Lee JH, Woo JH, Woo SU, Kim KS, Park SM, Joe EH, Jou I (2008) The 15-deoxy-delta 12,14-prostaglandin J2 suppresses monocyte chemoattractant protein-1 expression in IFN-gamma-stimulated astrocytes through induction of MAPK phosphatase-1. Journal of immunology 181: 8642-8649
57. Lee TS, Tsai HL, Chau LY (2003) Induction of heme oxygenase-1 expression in murine macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-Delta 12,14-prostaglandin J2. The Journal of biological chemistry 278: 19325-19330
58. Liang JQ, Xu HB, Wu YL, Sun SR, Jia ZH, Wei C, You JH (2009) Effect of serum from overfatigue rats on JNK/c-Jun/HO-1 pathway in human umbilical vein endothelial cells and the intervening effect of Tongxinluo superfine powder. Chinese journal of integrative medicine 15: 121-127
59. Lin TH, Tang CH, Wu K, Fong YC, Yang RS, Fu WM (2011) 15-deoxy-Delta(12,14) -prostaglandin-J2 and ciglitazone inhibit TNF-alpha-induced matrix metalloproteinase 13 production via the antagonism of NF-kappaB activation in human synovial fibroblasts. Journal of cellular physiology 226: 3242-3250
60. Liu JD, Tsai SH, Lin SY, Ho YS, Hung LF, Pan S, Ho FM, Lin CM, Liang YC (2004) Thiol antioxidant and thiol-reducing agents attenuate 15-deoxy-delta 12,14-prostaglandin J2-induced heme oxygenase-1 expression. Life sciences 74: 2451-2463
61. Liu X, Cui Y, Li M, Xu H, Zuo J, Fang F, Chang Y (2013) Cobalt protoporphyrin induces HO-1 expression mediated partially by FOXO1 and reduces mitochondria-derived reactive oxygen species production. PloS one 8: e80521
62. Manns MP, Cornberg M (2013) Sofosbuvir: the final nail in the coffin for hepatitis C? The Lancet Infectious diseases 13: 378-379
63. Martinez AE, Sanchez-Gomez FJ, Diez-Dacal B, Oeste CL, Perez-Sala D (2012) 15-Deoxy-Delta(12,14)-prostaglandin J2 exerts pro- and anti-inflammatory effects in mesangial cells in a concentration-dependent manner. Inflammation & allergy drug targets 11: 58-65
64. Mazieres J, He B, You L, Xu Z, Lee AY, Mikami I, Reguart N, Rosell R, McCormick F, Jablons DM (2004) Wnt inhibitory factor-1 is silenced by promoter hypermethylation in human lung cancer. Cancer research 64: 4717-4720
65. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T (1996) Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease. Neuroscience letters 211: 13-16
66. Morita T, Mitsialis SA, Koike H, Liu Y, Kourembanas S (1997) Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. The Journal of biological chemistry 272: 32804-32809
67. Munoz-Sanchez J, Chanez-Cardenas ME (2014) A review on hemeoxygenase-2: focus on cellular protection and oxygen response. Oxidative medicine and cellular longevity 2014: 604981
68. Murakami K, Kondo T, Yang G, Chen SF, Morita-Fujimura Y, Chan PH (1999) Cold injury in mice: a model to study mechanisms of brain edema and neuronal apoptosis. Progress in neurobiology 57: 289-299
69. Mylroie H, Dumont O, Bauer A, Thornton CC, Mackey J, Calay D, Hamdulay SS, Choo JR, Boyle JJ, Samarel AM, Randi AM, Evans PC, Mason JC (2015) PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovascular research 106: 509-519
70. Naumann M, Scheidereit C (1994) Activation of NF-kappa B in vivo is regulated by multiple phosphorylations. The EMBO journal 13: 4597-4607
71. Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annual review of pharmacology and toxicology 43: 233-260
72. Nita DA, Nita V, Spulber S, Moldovan M, Popa DP, Zagrean AM, Zagrean L (2001) Oxidative damage following cerebral ischemia depends on reperfusion - a biochemical study in rat. Journal of cellular and molecular medicine 5: 163-170
73. Ogasawara N, Kojima T, Go M, Ohkuni T, Koizumi J, Kamekura R, Masaki T, Murata M, Tanaka S, Fuchimoto J, Himi T, Sawada N (2010) PPARgamma agonists upregulate the barrier function of tight junctions via a PKC pathway in human nasal epithelial cells. Pharmacological research : the official journal of the Italian Pharmacological Society 61: 489-498
74. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nature medicine 6: 422-428
75. Palozza P, Serini S, Curro D, Calviello G, Igarashi K, Mancuso C (2006) beta-Carotene and cigarette smoke condensate regulate heme oxygenase-1 and its repressor factor Bach1: relationship with cell growth. Antioxidants & redox signaling 8: 1069-1080
76. Pang C, Zheng Z, Shi L, Sheng Y, Wei H, Wang Z, Ji L (2015) Caffeic acid prevents acetaminophen-induced liver injury by activating the Keap1-Nrf2 antioxidative defense system. Free radical biology & medicine 91: 236-246
77. Parfenova H, Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, Leffler CW (2006) Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection. American journal of physiology Cell physiology 290: C1399-1410
78. Parfenova H, Neff RA, 3rd, Alonso JS, Shlopov BV, Jamal CN, Sarkisova SA, Leffler CW (2001) Cerebral vascular endothelial heme oxygenase: expression, localization, and activation by glutamate. American journal of physiology Cell physiology 281: C1954-1963
79. Paul R, Angele B, Popp B, Klein M, Riedel E, Pfister HW, Koedel U (2007) Differential regulation of blood-brain barrier permeability in brain trauma and pneumococcal meningitis-role of Src kinases. Experimental neurology 203: 158-167
80. Pearl-Yafe M, Halperin D, Halevy A, Kalir H, Bielorai B, Fabian I (2003) An oxidative mechanism of interferon induced priming of the Fas pathway in Fanconi anemia cells. Biochemical pharmacology 65: 833-842
81. Platt JL, Nath KA (1998) Heme oxygenase: protective gene or Trojan horse. Nature medicine 4: 1364-1365
82. Ricciotti E, FitzGerald GA (2011) Prostaglandins and inflammation. Arteriosclerosis, thrombosis, and vascular biology 31: 986-1000
83. Richmon JD, Fukuda K, Maida N, Sato M, Bergeron M, Sharp FR, Panter SS, Noble LJ (1998) Induction of heme oxygenase-1 after hyperosmotic opening of the blood-brain barrier. Brain research 780: 108-118
84. Rogers RL, Meyer JS, Shaw TG, Mortel KF, Hardenberg JP, Zaid RR (1983) Cigarette smoking decreases cerebral blood flow suggesting increased risk for stroke. Jama 250: 2796-2800
85. Rojo AI, Salina M, Salazar M, Takahashi S, Suske G, Calvo V, de Sagarra MR, Cuadrado A (2006) Regulation of heme oxygenase-1 gene expression through the phosphatidylinositol 3-kinase/PKC-zeta pathway and Sp1. Free radical biology & medicine 41: 247-261
86. Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological reviews 86: 583-650
87. Schaller B (2005) Prospects for the future: the role of free radicals in the treatment of stroke. Free radical biology & medicine 38: 411-425
88. Scher JU, Pillinger MH (2005) 15d-PGJ2: the anti-inflammatory prostaglandin? Clinical immunology 114: 100-109
89. Seo GS, Jiang WY, Park PH, Sohn DH, Cheon JH, Lee SH (2014) Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction. Biochemical pharmacology 90: 115-125
90. Shih RH, Cheng SE, Hsiao LD, Kou YR, Yang CM (2011) Cigarette smoke extract upregulates heme oxygenase-1 via PKC/NADPH oxidase/ROS/PDGFR/PI3K/Akt pathway in mouse brain endothelial cells. Journal of neuroinflammation 8: 104
91. Shih RH, Lee IT, Hsieh HL, Kou YR, Yang CM (2010) Cigarette smoke extract induces HO-1 expression in mouse cerebral vascular endothelial cells: involvement of c-Src/NADPH oxidase/PDGFR/JAK2/STAT3 pathway. Journal of cellular physiology 225: 741-750
92. Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature reviews Molecular cell biology 14: 197-210
93. Silva BR, Pernomian L, Bendhack LM (2012) Contribution of oxidative stress to endothelial dysfunction in hypertension. Frontiers in physiology 3: 441
94. Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui TY, Bach FH (2004) Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. Journal of immunology 172: 3553-3563
95. Song R, Kubo M, Morse D, Zhou Z, Zhang X, Dauber JH, Fabisiak J, Alber SM, Watkins SC, Zuckerbraun BS, Otterbein LE, Ning W, Oury TD, Lee PJ, McCurry KR, Choi AM (2003) Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. The American journal of pathology 163: 231-242
96. Summy JM, Gallick GE (2003) Src family kinases in tumor progression and metastasis. Cancer metastasis reviews 22: 337-358
97. Surh YJ, Na HK, Park JM, Lee HN, Kim W, Yoon IS, Kim DD (2011) 15-Deoxy-Delta(1)(2),(1)(4)-prostaglandin J(2), an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling. Biochemical pharmacology 82: 1335-1351
98. Szydlowski M, Jablonska E, Juszczynski P (2014) FOXO1 transcription factor: a critical effector of the PI3K-AKT axis in B-cell development. International reviews of immunology 33: 146-157
99. Tenhunen R, Marver HS, Schmid R (1969) Microsomal heme oxygenase. Characterization of the enzyme. The Journal of biological chemistry 244: 6388-6394
100. Tornavaca O, Chia M, Dufton N, Almagro LO, Conway DE, Randi AM, Schwartz MA, Matter K, Balda MS (2015) ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. The Journal of cell biology 208: 821-838
101. Traystman RJ, Kirsch JR, Koehler RC (1991) Oxygen radical mechanisms of brain injury following ischemia and reperfusion. Journal of applied physiology 71: 1185-1195
102. Valle A, Oliver J, Roca P (2010) Role of uncoupling proteins in cancer. Cancers 2: 567-591
103. Vile GF, Basu-Modak S, Waltner C, Tyrrell RM (1994) Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 91: 2607-2610
104. Vincent SR, Das S, Maines MD (1994) Brain heme oxygenase isoenzymes and nitric oxide synthase are co-localized in select neurons. Neuroscience 63: 223-231
105. Wall SB, Oh JY, Diers AR, Landar A (2012) Oxidative modification of proteins: an emerging mechanism of cell signaling. Frontiers in physiology 3: 369
106. Wang G, Han D, Zhang Y, Xie X, Wu Y, Li S, Li M (2013) A novel hypothesis: up-regulation of HO-1 by activation of PPARgamma inhibits HMGB1-RAGE signaling pathway and ameliorates the development of ALI/ARDS. Journal of thoracic disease 5: 706-710
107. Willis CL, Camire RB, Brule SA, Ray DE (2013) Partial recovery of the damaged rat blood-brain barrier is mediated by adherens junction complexes, extracellular matrix remodeling and macrophage infiltration following focal astrocyte loss. Neuroscience 250: 773-785
108. Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, Yang X, Hong J, Songyang Z, Chen ZJ, Wang RF (2011) NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKK. Immunity 34: 843-853
109. Xu F, Li J, Ni W, Shen YW, Zhang XP (2013) Peroxisome proliferator-activated receptor-gamma agonist 15d-prostaglandin J2 mediates neuronal autophagy after cerebral ischemia-reperfusion injury. PloS one 8: e55080
110. Yang CM, Lin CC, Lee IT, Hsu CK, Tai YC, Hsieh HL, Chi PL, Hsiao LD (2015) c-Src-dependent transactivation of EGFR mediates CORM-2-induced HO-1 expression in human tracheal smooth muscle cells. Journal of cellular physiology 230: 2351-2361
111. Yoo SJ, Nakra NK, Ronnett GV, Moon C (2014) Protective Effects of Inducible HO-1 on Oxygen Toxicity in Rat Brain Endothelial Microvessel Cells. Endocrinology and metabolism 29: 356-362