紅斑性狼瘡為一種自體免疫疾病，特徵為病人血清中含有許多種自體抗體，進而經由免疫發炎機轉，導致程度不一的全身器官病變，其中最會影響到患者預後的器官便是腎臟。因為其高好發率及高致死率，狼瘡腎炎成為紅斑性狼瘡最主要的併發症之一，許多狼瘡腎炎患者發展成為慢性腎臟病，最後甚至因為腎衰竭和尿毒症而死亡，其中又以腎臟病理型態學分類為增生型腎炎之惡化型狼瘡腎炎的預後最差。目前對狼瘡腎炎的致病機轉雖然尚未明瞭，但全身性免疫調節異常、發炎反應及活性氧導致之氧化壓力，被認為在狼瘡腎炎的發生及惡化中扮演了重要的角色。臨床上應用於狼瘡腎炎的治療主要以類固醇或免疫抑制劑單獨或合併使用，然而這些藥物通常伴隨許多相當嚴重的副作用。傳統中草藥因為安全性高，一般民眾接受度高，因此，愈來愈多研究者致力於開發中草藥成為替代治療用藥或西藥之輔佐用藥。本論文分別評估具有抗發炎功效之中草藥複方DCB-SLE1和牛樟芝純化物antroquinonol對於加速惡化型狼瘡腎炎之療效，及長期給予具有抗氧化能力之綠茶沒食子酸酯化兒茶素（epigallocatechin-3-gallate, EGCG）對於減緩自發型狼瘡腎炎發生之效果評估。結果發現：1. DCB-SLE1能藉由抑制B細胞活化及降低自體抗體產生；抑制T細胞活化及增生；降低介白素(interleukin, IL)-6、IL-17及IL-18表現及阻斷細胞核內轉錄因子nuclear factor-kappa B之活化，而達到改善小鼠加速惡化型狼瘡腎炎之惡化。2. Antroquinonol則藉由抑制T細胞活化/增生；增加調節性T細胞數量及活性並降低IL-18表現；活化nuclear factor-erythroid-2-related factor 2之抗氧化訊息傳遞路徑，達到減緩小鼠加速惡化型狼瘡腎炎之惡化。3.長期給予EGCG不僅能有效降低小鼠體內活性氧含量，更進一步能夠抑制NLRP3發炎體活化及增加調節性T細胞功能，明顯降低全身性紅斑性狼瘡發展成為狼瘡腎炎。因此，DCB-SLE1、antroquinonol或EGCG具有很大的潛能在未來開發成為狼瘡腎炎的輔佐用藥。

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving multiple organs injury due to autoantibody production and abnormal cell immunity. Lupus nephritis, one of the most severe complications of SLE, is associated with significant morbidity and mortality. The cumulative risks of end stage renal failure were particularly high in patients with severe lupus nephritis, the histopathology of which comprises distinct patterns of injury that were initially defined by the World Health Organization Classification of 1982 as category III, category IV, and categories Vc and Vd. Although the exact mechanisms for the development or the progression of lupus nephritis remain unclear, abnormal cellular and humoral autoimmunity, inflammation, and oxidative stress have been implicated. Current therapies for lupus nephritis are various combinations of corticosteroids with other cytotoxic agents or immunomodulators, but many of these have various side effects. Importantly, Chinese herbal medicines have long been considered as typically a mild remedy with little or no side effects, and endeavors on developing them to be used as complementary components or adjuvants to Western medicines have been increasingly made over the past years in pharmaceutical research and industry. This thesis study tested the hypothesis that DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, and antroquinonol, a purified compound with a major effective component of Antrodia camphorata, might ameliorate accelerated severe lupus nephritis by modulating pathophysiological pathways of abnormal immunity, inflammation, and oxidative stress. Moreover, we also tested the hypothesis that epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol presents in green tea with antioxidant and free radical scavenging activities, can prevent development of lupus nephritis by long-term administering it to New Zealand black/white (NZB/W) F1 lupus-prone mice. The results showed that: (1) DCB-SLE1 protected the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways; (2) Antroquinonol administration significantly ameliorated the development of severe renal lesions via differentially regulating T cell function and lowering interleukin-18 production, but promoting nuclear factor erythroid-2-related factor-2 (Nrf2) activation; (3) EGCG had prophylactic effects on lupus nephritis in NZB/W F1 mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic regulatory T cell activity. Therefore, DCB-SLE1, antroquinonol, and EGCG have the potential to develop as therapeutic agents or adjuvants for the prevention and treatment of lupus nephritis in the future.

壹、緒論
一、紅斑性狼瘡（systemic lupus erythematosus, SLE）…………………………1
二、狼瘡腎炎（lupus nephritis）………………………………………………2
（一）狼瘡腎炎的病理分型…………………………………………………… 2
（二）惡化型狼瘡腎炎 (severe lupus nephritis)………………………………. 3
（三）狼瘡腎炎的致病機轉……………………………………………………3
三、自由基(free radicals)與活性氧(reactive oxygen species, ROS)……………6
四、Nrf2（nuclear factor-erythroid-2-related factor 2）抗氧化路徑…………… 7
五、NLRP3發炎體 (NLRP3 inflammasome)………………………………… 8
六、DCB-SLE1簡介………………………………………………………………9
七、Antroquinonol，牛樟芝純化物之簡介…………………………………11
八、沒食子酸酯化兒茶素(epigallocatechin-3-gallate, EGCG) 之簡介……12
九、研究動機與目的…………………………………………………………12
貳、實驗材料與方法
一、動物模式及實驗設計…………………………………………………14
二、尿蛋白與腎功能之偵測………………………………………………15
三、組織型態學分析………………………………………………………15
四、血清中自體抗體及補體（complement component）之偵測……………16
五、免疫螢光（immmunofluorescence）及免疫組織化學染色（immuohistochemistry staining）………………………………………………………………16
六、利用流式細胞分析儀（Flow Cytometry）分析T細胞、B細胞及調節性T細胞活化情形……………………………………………………………18
七、T細胞的增生實驗（T cell proliferation assay）…………………………18
八、調節性T細胞功能分析………………………………………………18
九、自然殺手細胞（natural killer cell）活性偵測…………………………19
十、血清中細胞激素之偵測………………………………………………19
十一、腎臟組織即時聚合酶鏈鎖反應（real-time PCR）……………………20
十二、蛋白質萃取及西方墨點法（Western blot）…………………………20
十三、腎組織中NF-κB p65 活性偵測……………………………………………21
十四、TUNEL（terminal deoxy-nucleotibyl transferase-mediated dUTP-biotin nick end labelling）染色偵測細胞凋亡……………………………………………21
十五、血液、尿液及組織中ROS偵測……………………………………………22
十六、腎臟中GPx活性分析………………………………………………………22
十七、統計分析……………………………………………………………………22
叁、結果
Part I、DCB-SLE1改善加速惡化型狼瘡腎炎小鼠動物模式………………………23
一、DCB-SLE1降低加速惡化型狼瘡腎炎之蛋白尿及血尿，改善腎功能及腎組織損傷…………………………………………………………………………23
二、DCB-SLE1降低血清中自體抗體濃度及腎臟上免疫複合物之沉積………23
三、DCB-SLE1抑制腎臟中T細胞、巨噬細胞及中性球之浸潤…………………24
四、DCB-SLE1降低腎臟中IL-6、IL-17A及IL-18 mRNA表現…………………24
五、DCB-SLE1抑制腎臟中IL-6及MCP-1蛋白質表現及NF-κB活性……………25
六、DCB-SLE1降低抑血液中發炎細胞激素之表現…………………………… 25
七、DCB-SLE1調控細胞免疫反應………………………………………………25
Part II、牛樟芝純化物antroquinonol改善加速惡化型狼瘡腎炎小鼠動物模式…28
一、Antroquinonol降低加速惡化型狼瘡腎炎之蛋白尿及血尿產生並保護腎功能……………………………………………………………………………28
二、Antroquinonol改善嚴重的腎組織損傷……………………………………….28
三、Antroquinonol調節全身免疫反應……………………………………………29
四、Antroquinonol抑制發炎細胞激素之表現……………………………………30
五、Antroquinonol減少腎臟中發炎細胞之浸潤…………………………………31
六、Antroquinonol降低ROS生成並增強Nrf2抗氧化訊息傳遞路徑……………32
Part III、EGCG減緩狼瘡腎炎小鼠動物模式之發生………………………………34
一、EGCG改善紅斑性狼瘡小鼠蛋白尿、腎功能及腎組織病變…………………34
二、EGCG降低ROS含量、增加GPx活性並活化Nrf2訊息傳遞路徑…………34
三、EGCG經由降低NF-κB活化改善腎臟中T細胞及巨噬細胞浸潤情形……………………………………………………………………………36
四、EGCG降低血清中發炎細胞激素IL-1β 及IL-18含量………………………36
五、EGCG抑制NLRP3 inflammasome活化………………………………………36
六、EGCG抑制全身免疫並增加Treg細胞活性…………………………37
肆、討論
一、全身免疫調節…………………………………………………………………39
二、發炎反應………………………………………………………………………40
三、抗氧化路徑……………………………………………………………………42
伍、結論………………………………………………………………………………44
陸、參考文獻…………………………………………………………………………45
表……………………………………………………………………………………66
圖……………………………………………………………………………………67

[1]Danchenko, N.; Satia, J. A.; Anthony, M. S. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 15:308-318; 2006.
[2]Cameron, J. S. Lupus nephritis. J Am Soc Nephrol 10:413-424; 1999.
[3]Tan, E. M.; Cohen, A. S.; Fries, J. F.; Masi, A. T.; McShane, D. J.; Rothfield, N. F.; Schaller, J. G.; Talal, N.; Winchester, R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277; 1982.
[4]Passas, C. M.; Wong, R. L.; Peterson, M.; Testa, M. A.; Rothfield, N. F. A comparison of the specificity of the 1971 and 1982 American Rheumatism Association criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 28:620-623; 1985.
[5]Tucci, M.; Stucci, S.; Strippoli, S.; Silvestris, F. Cytokine overproduction, T-cell activation, and defective T-regulatory functions promote nephritis in systemic lupus erythematosus. J Biomed Biotechnol 2010:457146; 2010.
[6]Pollak, V. E.; Pirani, C. L.; Schwartz, F. D. The Natural History of the Renal Manifestations of Systemic Lupus Erythematosus. J Lab Clin Med 63:537-550; 1964.
[7]Lenz, O.; Contreras, G. Treatment options for severe lupus nephritis. Arch Immunol Ther Exp (Warsz) 52:356-365; 2004.
[8]Weening, J. J.; D'Agati, V. D.; Schwartz, M. M.; Seshan, S. V.; Alpers, C. E.; Appel, G. B.; Balow, J. E.; Bruijn, J. A.; Cook, T.; Ferrario, F.; Fogo, A. B.; Ginzler, E. M.; Hebert, L.; Hill, G.; Hill, P.; Jennette, J. C.; Kong, N. C.; Lesavre, P.; Lockshin, M.; Looi, L. M.; Makino, H.; Moura, L. A.; Nagata, M. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 65:521-530; 2004.
[9]Weening, J. J.; D'Agati, V. D.; Schwartz, M. M.; Seshan, S. V.; Alpers, C. E.; Appel, G. B.; Balow, J. E.; Bruijn, J. A.; Cook, T.; Ferrario, F.; Fogo, A. B.; Ginzler, E. M.; Hebert, L.; Hill, G.; Hill, P.; Jennette, J. C.; Kong, N. C.; Lesavre, P.; Lockshin, M.; Looi, L. M.; Makino, H.; Moura, L. A.; Nagata, M. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15:241-250; 2004.
[10]Appel, G. B.; Cohen, D. J.; Pirani, C. L.; Meltzer, J. I.; Estes, D. Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization. Am J Med 83:877-885; 1987.
[11]Austin, H. A., 3rd; Boumpas, D. T.; Vaughan, E. M.; Balow, J. E. High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients. Nephrol Dial Transplant 10:1620-1628; 1995.
[12]Bao, H.; Liu, Z. H.; Xie, H. L.; Hu, W. X.; Zhang, H. T.; Li, L. S. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol 19:2001-2010; 2008.
[13]Bagavant, H.; Deshmukh, U. S.; Wang, H.; Ly, T.; Fu, S. M. Role for nephritogenic T cells in lupus glomerulonephritis: progression to renal failure is accompanied by T cell activation and expansion in regional lymph nodes. J Immunol 177:8258-8265; 2006.
[14]Foster, M. H. T cells and B cells in lupus nephritis. Semin Nephrol 27:47-58; 2007.
[15]Jacobi, A. M.; Mei, H.; Hoyer, B. F.; Mumtaz, I. M.; Thiele, K.; Radbruch, A.; Burmester, G. R.; Hiepe, F.; Dorner, T. HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus. Ann Rheum Dis 69:305-308; 2010.
[16]Cheema, G. S.; Roschke, V.; Hilbert, D. M.; Stohl, W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44:1313-1319; 2001.
[17]Crow, M. K. Costimulatory molecules and T-cell-B-cell interactions. Rheum Dis Clin North Am 30:175-191, vii-viii; 2004.
[18]Scheinecker, C.; Zwolfer, B.; Koller, M.; Manner, G.; Smolen, J. S. Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies. Arthritis Rheum 44:856-865; 2001.
[19]Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531-562; 2004.
[20]Abe, J.; Ueha, S.; Suzuki, J.; Tokano, Y.; Matsushima, K.; Ishikawa, S. Increased Foxp3(+) CD4(+) regulatory T cells with intact suppressive activity but altered cellular localization in murine lupus. Am J Pathol 173:1682-1692; 2008.
[21]Crispin, J. C.; Martinez, A.; Alcocer-Varela, J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273-276; 2003.
[22]Valencia, X.; Yarboro, C.; Illei, G.; Lipsky, P. E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178:2579-2588; 2007.
[23]Scalapino, K. J.; Daikh, D. I. Suppression of glomerulonephritis in NZB/NZW lupus prone mice by adoptive transfer of ex vivo expanded regulatory T cells. PLoS One 4:e6031; 2009.
[24]Fontenot, J. D.; Rasmussen, J. P.; Williams, L. M.; Dooley, J. L.; Farr, A. G.; Rudensky, A. Y. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329-341; 2005.
[25]Tang, Q.; Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9:239-244; 2008.
[26]Zheng, S. G.; Wang, J.; Horwitz, D. A. Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 180:7112-7116; 2008.
[27]Esfandiari, E.; McInnes, I. B.; Lindop, G.; Huang, F. P.; Field, M.; Komai-Koma, M.; Wei, X.; Liew, F. Y. A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease. J Immunol 167:5338-5347; 2001.
[28]Summers, S. A.; Steinmetz, O. M.; Li, M.; Kausman, J. Y.; Semple, T.; Edgtton, K. L.; Borza, D. B.; Braley, H.; Holdsworth, S. R.; Kitching, A. R. Th1 and Th17 cells induce proliferative glomerulonephritis. J Am Soc Nephrol 20:2518-2524; 2009.
[29]Tucci, M.; Lombardi, L.; Richards, H. B.; Dammacco, F.; Silvestris, F. Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis. Clin Exp Immunol 154:247-254; 2008.
[30]Tucci, M.; Quatraro, C.; Lombardi, L.; Pellegrino, C.; Dammacco, F.; Silvestris, F. Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum 58:251-262; 2008.
[31]Yap, D. Y.; Lai, K. N. Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances. J Biomed Biotechnol 2010:365083; 2010.
[32]Hakkim, A.; Furnrohr, B. G.; Amann, K.; Laube, B.; Abed, U. A.; Brinkmann, V.; Herrmann, M.; Voll, R. E.; Zychlinsky, A. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107:9813-9818; 2010.
[33]Schiffer, L.; Bethunaickan, R.; Ramanujam, M.; Huang, W.; Schiffer, M.; Tao, H.; Madaio, M. P.; Bottinger, E. P.; Davidson, A. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 180:1938-1947; 2008.
[34]Schwartz, M. M.; Korbet, S. M.; Katz, R. S.; Lewis, E. J. Evidence of concurrent immunopathological mechanisms determining the pathology of severe lupus nephritis. Lupus 18:149-158; 2009.
[35]Schwartz, M. M.; Korbet, S. M.; Lewis, E. J. The prognosis and pathogenesis of severe lupus glomerulonephritis. Nephrol Dial Transplant 23:1298-1306; 2008.
[36]Morimoto, S.; Tokano, Y.; Nakano, S.; Watanabe, T.; Tamayama, Y.; Mitsuo, A.; Suzuki, J.; Kaneko, H.; Sekigawa, I.; Takasaki, Y. Chemoattractant mechanism of Th1 cells in class III and IV lupus nephritis. Autoimmunity 42:143-149; 2009.
[37]Calvani, N.; Tucci, M.; Richards, H. B.; Tartaglia, P.; Silvestris, F. Th1 cytokines in the pathogenesis of lupus nephritis: the role of IL-18. Autoimmun Rev 4:542-548; 2005.
[38]Wiekowski, M. T.; Leach, M. W.; Evans, E. W.; Sullivan, L.; Chen, S. C.; Vassileva, G.; Bazan, J. F.; Gorman, D. M.; Kastelein, R. A.; Narula, S.; Lira, S. A. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol 166:7563-7570; 2001.
[39]Aggarwal, S.; Ghilardi, N.; Xie, M. H.; de Sauvage, F. J.; Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910-1914; 2003.
[40]Harrington, L. E.; Hatton, R. D.; Mangan, P. R.; Turner, H.; Murphy, T. L.; Murphy, K. M.; Weaver, C. T. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123-1132; 2005.
[41]Veldhoen, M.; Stockinger, B. TGFbeta1, a "Jack of all trades": the link with pro-inflammatory IL-17-producing T cells. Trends Immunol 27:358-361; 2006.
[42]Roussel, L.; Houle, F.; Chan, C.; Yao, Y.; Berube, J.; Olivenstein, R.; Martin, J. G.; Huot, J.; Hamid, Q.; Ferri, L.; Rousseau, S. IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J Immunol 184:4531-4537; 2010.
[43]Shahrara, S.; Pickens, S. R.; Mandelin, A. M., 2nd; Karpus, W. J.; Huang, Q.; Kolls, J. K.; Pope, R. M. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. J Immunol 184:4479-4487; 2010.
[44]Zepp, J.; Wu, L.; Li, X. IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends Immunol 32:232-239; 2011.
[45]Tucci, M.; Ciavarella, S.; Strippoli, S.; Dammacco, F.; Silvestris, F. Oversecretion of cytokines and chemokines in lupus nephritis is regulated by intraparenchymal dendritic cells: a review. Ann N Y Acad Sci 1173:449-457; 2009.
[46]Akhtar, S.; Li, X.; Kovacs, E. J.; Gamelli, R. L.; Choudhry, M. A. Interleukin-18 Delays Neutrophil Apoptosis Following Alcohol Intoxication and Burn Injury. Mol Med 17:88-94; 2011.
[47]Costantini, C.; Micheletti, A.; Calzetti, F.; Perbellini, O.; Pizzolo, G.; Cassatella, M. A. Neutrophil activation and survival are modulated by interaction with NK cells. Int Immunol 22:827-838; 2010.
[48]Chang, J. T.; Segal, B. M.; Nakanishi, K.; Okamura, H.; Shevach, E. M. The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta2 subunit. Eur J Immunol 30:1113-1119; 2000.
[49]He, Z.; Lu, L.; Altmann, C.; Hoke, T. S.; Ljubanovic, D.; Jani, A.; Dinarello, C. A.; Faubel, S.; Edelstein, C. L. Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury. Am J Physiol Renal Physiol 295:F1414-1421; 2008.
[50]Liu, X.; Bao, C.; Hu, D. Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis. Rheumatol Int.
[51]Shui, H. A.; Ka, S. M.; Wu, W. M.; Lin, Y. F.; Hou, Y. C.; Su, L. C.; Chen, A. LPS-evoked IL-18 expression in mesangial cells plays a role in accelerating lupus nephritis. Rheumatology (Oxford) 46:1277-1284; 2007.
[52]Faust, J.; Menke, J.; Kriegsmann, J.; Kelley, V. R.; Mayet, W. J.; Galle, P. R.; Schwarting, A. Correlation of renal tubular epithelial cell-derived interleukin-18 up-regulation with disease activity in MRL-Faslpr mice with autoimmune lupus nephritis. Arthritis Rheum 46:3083-3095; 2002.
[53]Yoon, J. W.; Pahl, M. V.; Vaziri, N. D. Spontaneous leukocyte activation and oxygen-free radical generation in end-stage renal disease. Kidney Int 71:167-172; 2007.
[54]Anrather, J.; Racchumi, G.; Iadecola, C. NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem 281:5657-5667; 2006.
[55]Kim, H. J.; Vaziri, N. D. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol 298:F662-671; 2010.
[56]Modlinger, P. S.; Wilcox, C. S.; Aslam, S. Nitric oxide, oxidative stress, and progression of chronic renal failure. Semin Nephrol 24:354-365; 2004.
[57]Wang, G.; Pierangeli, S. S.; Papalardo, E.; Ansari, G. A.; Khan, M. F. Markers of oxidative and nitrosative stress in systemic lupus erythematosus: correlation with disease activity. Arthritis Rheum 62:2064-2072; 2010.
[58]Moroni, G.; Novembrino, C.; Quaglini, S.; De Giuseppe, R.; Gallelli, B.; Uva, V.; Montanari, V.; Messa, P.; Bamonti, F. Oxidative stress and homocysteine metabolism in patients with lupus nephritis. Lupus 19:65-72; 2010.
[59]Tang, S.; Lui, S. L.; Lai, K. N. Pathogenesis of lupus nephritis: an update. Nephrology (Carlton) 10:174-179; 2005.
[60]Nguyen, T.; Nioi, P.; Pickett, C. B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291-13295; 2009.
[61]Yoh, K.; Itoh, K.; Enomoto, A.; Hirayama, A.; Yamaguchi, N.; Kobayashi, M.; Morito, N.; Koyama, A.; Yamamoto, M.; Takahashi, S. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60:1343-1353; 2001.
[62]Chen, X. L.; Dodd, G.; Thomas, S.; Zhang, X.; Wasserman, M. A.; Rovin, B. H.; Kunsch, C. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol 290:H1862-1870; 2006.
[63]Rahman, I.; Biswas, S. K.; Kirkham, P. A. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 72:1439-1452; 2006.
[64]Thimmulappa, R. K.; Lee, H.; Rangasamy, T.; Reddy, S. P.; Yamamoto, M.; Kensler, T. W.; Biswal, S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 116:984-995; 2006.
[65]Jin, W.; Wang, H.; Yan, W.; Xu, L.; Wang, X.; Zhao, X.; Yang, X.; Chen, G.; Ji, Y. Disruption of Nrf2 enhances upregulation of nuclear factor-kappaB activity, proinflammatory cytokines, and intercellular adhesion molecule-1 in the brain after traumatic brain injury. Mediators Inflamm 2008:725174; 2008.
[66]Jin, W.; Wang, H.; Ji, Y.; Zhu, L.; Yan, W.; Qiao, L.; Yin, H. Genetic ablation of Nrf2 enhances susceptibility to acute lung injury after traumatic brain injury in mice. Exp Biol Med (Maywood) 234:181-189; 2009.
[67]Sriram, N.; Kalayarasan, S.; Sudhandiran, G. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling. Pulm Pharmacol Ther 22:221-236; 2009.
[68]Chaaya, R.; Alfarano, C.; Guilbeau-Frugier, C.; Coatrieux, C.; Kesteman, A. S.; Parini, A.; Fares, N.; Gue, M.; Schanstra, J. P.; Bascands, J. L. Pargyline reduces renal damage associated with ischaemia-reperfusion and cyclosporin. Nephrol Dial Transplant 26:489-498; 2011.
[69]Mukhopadhyay, P.; Rajesh, M.; Pan, H.; Patel, V.; Mukhopadhyay, B.; Batkai, S.; Gao, B.; Hasko, G.; Pacher, P. Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 48:457-467; 2010.
[70]Ye, Z.; Ting, J. P. NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol 20:3-9; 2008.
[71]Schroder, K.; Tschopp, J. The inflammasomes. Cell 140:821-832.
[72]Franchi, L.; Eigenbrod, T.; Munoz-Planillo, R.; Nunez, G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10:241-247; 2009.
[73]Chen, M.; Wang, H.; Chen, W.; Meng, G. Regulation of adaptive immunity by the NLRP3 inflammasome. Int Immunopharmacol 11:549-554; 2011.
[74]Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417-426; 2002.
[75]Agostini, L.; Martinon, F.; Burns, K.; McDermott, M. F.; Hawkins, P. N.; Tschopp, J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319-325; 2004.
[76]Pontillo, A.; Brandao, L.; Guimaraes, R.; Segat, L.; Araujo, J.; Crovella, S. Two SNPs in NLRP3 gene are involved in the predisposition to type-1 diabetes and celiac disease in a pediatric population from northeast Brazil. Autoimmunity 43:583-589; 2010.
[77]Gris, D.; Ye, Z.; Iocca, H. A.; Wen, H.; Craven, R. R.; Gris, P.; Huang, M.; Schneider, M.; Miller, S. D.; Ting, J. P. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol 185:974-981; 2010.
[78]Liu-Bryan, R. Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome. Immunol Cell Biol 88:20-23; 2010.
[79]Vilaysane, A.; Chun, J.; Seamone, M. E.; Wang, W.; Chin, R.; Hirota, S.; Li, Y.; Clark, S. A.; Tschopp, J.; Trpkov, K.; Hemmelgarn, B. R.; Beck, P. L.; Muruve, D. A. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol 21:1732-1744; 2010.
[80]Li, R.; Sakwiwatkul, K.; Yutao, L.; Hu, S. Enhancement of the immune responses to vaccination against foot-and-mouth disease in mice by oral administration of an extract made from Rhizoma Atractylodis Macrocephalae (RAM). Vaccine 27:2094-2098; 2009.
[81]Ha, H.; Ho, J.; Shin, S.; Kim, H.; Koo, S.; Kim, I. H.; Kim, C. Effects of Eucommiae Cortex on osteoblast-like cell proliferation and osteoclast inhibition. Arch Pharm Res 26:929-936; 2003.
[82]Hu, S.; Cai, W.; Ye, J.; Qian, Z.; Sun, Z. Influence of medicinal herbs on phagocytosis by bovine neutrophils. Zentralbl Veterinarmed A 39:593-599; 1992.
[83]Xu, H.; Xu, H. E. Analysis of trace elements in Chinese therapeutic foods and herbs. Am J Chin Med 37:625-638; 2009.
[84]Lee, T. H.; Lee, C. K.; Tsou, W. L.; Liu, S. Y.; Kuo, M. T.; Wen, W. C. A new cytotoxic agent from solid-state fermented mycelium of Antrodia camphorata. Planta Med 73:1412-1415; 2007.
[85]Chang, J. M.; Lee, Y. R.; Hung, L. M.; Liu, S. Y.; Kuo, M. T.; Wen, W. C.; Chen, P. An Extract of Antrodia camphorata Mycelia Attenuates the Progression of Nephritis in Systemic Lupus Erythematosus-Prone NZB/W F1 Mice. Evid Based Complement Alternat Med; 2008.
[86]Hseu, Y. C.; Wu, F. Y.; Wu, J. J.; Chen, J. Y.; Chang, W. H.; Lu, F. J.; Lai, Y. C.; Yang, H. L. Anti-inflammatory potential of Antrodia Camphorata through inhibition of iNOS, COX-2 and cytokines via the NF-kappaB pathway. Int Immunopharmacol 5:1914-1925; 2005.
[87]Shen, Y. C.; Wang, Y. H.; Chou, Y. C.; Chen, C. F.; Lin, L. C.; Chang, T. T.; Tien, J. H.; Chou, C. J. Evaluation of the anti-inflammatory activity of zhankuic acids isolated from the fruiting bodies of Antrodia camphorata. Planta Med 70:310-314; 2004.
[88]Hseu, Y. C.; Chang, W. C.; Hseu, Y. T.; Lee, C. Y.; Yech, Y. J.; Chen, P. C.; Chen, J. Y.; Yang, H. L. Protection of oxidative damage by aqueous extract from Antrodia camphorata mycelia in normal human erythrocytes. Life Sci 71:469-482; 2002.
[89]Yang, H. L.; Chen, C. S.; Chang, W. H.; Lu, F. J.; Lai, Y. C.; Chen, C. C.; Hseu, T. H.; Kuo, C. T.; Hseu, Y. C. Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by Antrodia camphorata. Cancer Lett 231:215-227; 2006.
[90]Yang, S. S.; Wang, G. J.; Wang, S. Y.; Lin, Y. Y.; Kuo, Y. H.; Lee, T. H. New constituents with iNOS inhibitory activity from mycelium of Antrodia camphorata. Planta Med 75:512-516; 2009.
[91]Chiang, P. C.; Lin, S. C.; Pan, S. L.; Kuo, C. H.; Tsai, I. L.; Kuo, M. T.; Wen, W. C.; Chen, P.; Guh, J. H. Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: a crucial role of AMPK and mTOR pathways. Biochem Pharmacol 79:162-171; 2010.
[92]Frei, B.; Higdon, J. V. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr 133:3275S-3284S; 2003.
[93]Singh, R.; Akhtar, N.; Haqqi, T. M. Green tea polyphenol epigallocatechin-3-gallate: inflammation and arthritis. [corrected]. Life Sci 86:907-918; 2010.
[94]Melgarejo, E.; Medina, M. A.; Sanchez-Jimenez, F.; Urdiales, J. L. Targeting of histamine producing cells by EGCG: a green dart against inflammation? J Physiol Biochem 66:265-270; 2010.
[95]Ahmad, N.; Gupta, S.; Mukhtar, H. Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells. Arch Biochem Biophys 376:338-346; 2000.
[96]Watson, J. L.; Vicario, M.; Wang, A.; Moreto, M.; McKay, D. M. Immune cell activation and subsequent epithelial dysfunction by Staphylococcus enterotoxin B is attenuated by the green tea polyphenol (-)-epigallocatechin gallate. Cell Immunol 237:7-16; 2005.
[97]Yun, J. M.; Jialal, I.; Devaraj, S. Effects of epigallocatechin gallate on regulatory T cell number and function in obese v. lean volunteers. Br J Nutr 103:1771-1777; 2010.
[98]Molino, C.; Fabbian, F.; Longhini, C. Clinical approach to lupus nephritis: recent advances. Eur J Intern Med 20:447-453; 2009.
[99]Benseler, S. M.; Bargman, J. M.; Feldman, B. M.; Tyrrell, P. N.; Harvey, E.; Hebert, D.; Silverman, E. D. Acute renal failure in paediatric systemic lupus erythematosus: treatment and outcome. Rheumatology (Oxford) 48:176-182; 2009.
[100]Flanc, R. S.; Roberts, M. A.; Strippoli, G. F.; Chadban, S. J.; Kerr, P. G.; Atkins, R. C. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 43:197-208; 2004.
[101]Illei, G. G.; Austin, H. A.; Crane, M.; Collins, L.; Gourley, M. F.; Yarboro, C. H.; Vaughan, E. M.; Kuroiwa, T.; Danning, C. L.; Steinberg, A. D.; Klippel, J. H.; Balow, J. E.; Boumpas, D. T. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 135:248-257; 2001.
[102]Ka, S. M.; Kuo, Y. C.; Ho, P. J.; Tsai, P. Y.; Hsu, Y. J.; Tsai, W. J.; Lin, Y. L.; Shen, C. C.; Chen, A. (S)-armepavine from Chinese medicine improves experimental autoimmune crescentic glomerulonephritis. Rheumatology (Oxford) 49:1840-1851; 2010.
[103]Behara, V. Y.; Whittier, W. L.; Korbet, S. M.; Schwartz, M. M.; Martens, M.; Lewis, E. J. Pathogenetic features of severe segmental lupus nephritis. Nephrol Dial Transplant 25:153-159; 2010.
[104]Hill, G. S.; Delahousse, M.; Nochy, D.; Bariety, J. Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis. Kidney Int 68:2288-2297; 2005.
[105]Bagavant, H.; Fu, S. M. Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol 21:489-494; 2009.
[106]Deocharan, B.; Qing, X.; Lichauco, J.; Putterman, C. Alpha-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J Immunol 168:3072-3078; 2002.
[107]Cunningham, M. A.; Huang, X. R.; Dowling, J. P.; Tipping, P. G.; Holdsworth, S. R. Prominence of cell-mediated immunity effectors in "pauci-immune" glomerulonephritis. J Am Soc Nephrol 10:499-506; 1999.
[108]Kyttaris, V. C.; Tsokos, G. C. T lymphocytes in systemic lupus erythematosus: an update. Curr Opin Rheumatol 16:548-552; 2004.
[109]Crispin, J. C.; Tsokos, G. C. IL-17 in systemic lupus erythematosus. J Biomed Biotechnol 2010:943254; 2010.
[110]Dong, G.; Ye, R.; Shi, W.; Liu, S.; Wang, T.; Yang, X.; Yang, N.; Yu, X. IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J (Engl) 116:543-548; 2003.
[111]Mok, M. Y.; Wu, H. J.; Lo, Y.; Lau, C. S. The Relation of Interleukin 17 (IL-17) and IL-23 to Th1/Th2 Cytokines and Disease Activity in Systemic Lupus Erythematosus. J Rheumatol 37:2046-2052; 2010.
[112]Shah, K.; Lee, W. W.; Lee, S. H.; Kim, S. H.; Kang, S. W.; Craft, J.; Kang, I. Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 12:R53; 2010.
[113]Postol, E.; Meyer, A.; Cardillo, F.; de Alencar, R.; Pessina, D.; Nihei, J.; Mariano, M.; Mengel, J. Long-term administration of IgG2a anti-NK1.1 monoclonal antibody ameliorates lupus-like disease in NZB/W mice in spite of an early worsening induced by an IgG2a-dependent BAFF/BLyS production. Immunology 125:184-196; 2008.
[114]Kretzler, M.; Koeppen-Hagemann, I.; Kriz, W. Podocyte damage is a critical step in the development of glomerulosclerosis in the uninephrectomised-desoxycorticosterone hypertensive rat. Virchows Arch 425:181-193; 1994.
[115]Kinter, M.; Wolstenholme, J. T.; Thornhill, B. A.; Newton, E. A.; McCormick, M. L.; Chevalier, R. L. Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during sodium depletion. Kidney Int 55:1327-1334; 1999.
[116]Smeets, B.; Te Loeke, N. A.; Dijkman, H. B.; Steenbergen, M. L.; Lensen, J. F.; Begieneman, M. P.; van Kuppevelt, T. H.; Wetzels, J. F.; Steenbergen, E. J. The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice. J Am Soc Nephrol 15:928-939; 2004.
[117]Haas, K. M.; Watanabe, R.; Matsushita, T.; Nakashima, H.; Ishiura, N.; Okochi, H.; Fujimoto, M.; Tedder, T. F. Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol 184:4789-4800; 2010.
[118]Hseu, Y. C.; Huang, H. C.; Hsiang, C. Y. Antrodia camphorata suppresses lipopolysaccharide-induced nuclear factor-kappaB activation in transgenic mice evaluated by bioluminescence imaging. Food Chem Toxicol 48:2319-2325; 2010.
[119]Hong Byun, E.; Fujimura, Y.; Yamada, K.; Tachibana, H. TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. J Immunol 185:33-45; 2010.
[120]Kaspar, J. W.; Niture, S. K.; Jaiswal, A. K. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304-1309; 2009.
[121]Jiang, T.; Huang, Z.; Lin, Y.; Zhang, Z.; Fang, D.; Zhang, D. D. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59:850-860; 2010.
[122]Chan, K.; Han, X. D.; Kan, Y. W. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A 98:4611-4616; 2001.
[123]Tipping, P. G.; Holdsworth, S. R. T cells in crescentic glomerulonephritis. J Am Soc Nephrol 17:1253-1263; 2006.
[124]Martin-Fontecha, A.; Thomsen, L. L.; Brett, S.; Gerard, C.; Lipp, M.; Lanzavecchia, A.; Sallusto, F. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5:1260-1265; 2004.
[125]Goto, M.; Tanimoto, K.; Horiuchi, Y. Natural cell mediated cytotoxicity in systemic lupus erythematosus: suppression by antilymphocyte antibody. Arthritis Rheum 23:1274-1281; 1980.
[126]Hoffman, T. Natural killer funciton in systemic lupus erythematosus. Arthritis Rheum 23:30-35; 1980.
[127]Shi, F. D.; Wang, H. B.; Li, H.; Hong, S.; Taniguchi, M.; Link, H.; Van Kaer, L.; Ljunggren, H. G. Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol 1:245-251; 2000.
[128]Pae, M.; Ren, Z.; Meydani, M.; Shang, F.; Meydani, S. N.; Wu, D. Epigallocatechin-3-gallate directly suppresses T cell proliferation through impaired IL-2 utilization and cell cycle progression. J Nutr 140:1509-1515; 2010.
[129]Gillespie, K.; Kodani, I.; Dickinson, D. P.; Ogbureke, K. U.; Camba, A. M.; Wu, M.; Looney, S.; Chu, T. C.; Qin, H.; Bisch, F.; Sharawy, M.; Schuster, G. S.; Hsu, S. D. Effects of oral consumption of the green tea polyphenol EGCG in a murine model for human Sjogren's syndrome, an autoimmune disease. Life Sci 83:581-588; 2008.
[130]Ka, S. M.; Cheng, C. W.; Shui, H. A.; Wu, W. M.; Chang, D. M.; Lin, Y. C.; Chen, A. Mesangial cells of lupus-prone mice are sensitive to chemokine production. Arthritis Res Ther 9:R67; 2007.
[131]Kim, K. A.; Lee, J. S.; Park, H. J.; Kim, J. W.; Kim, C. J.; Shim, I. S.; Kim, N. J.; Han, S. M.; Lim, S. Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci 74:2769-2779; 2004.
[132]Gautam, R.; Jachak, S. M. Recent developments in anti-inflammatory natural products. Med Res Rev 29:767-820; 2009.
[133]Giner-Larza, E. M.; Manez, S.; Recio, M. C.; Giner, R. M.; Prieto, J. M.; Cerda-Nicolas, M.; Rios, J. L. Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity. Eur J Pharmacol 428:137-143; 2001.
[134]Subbaramaiah, K.; Michaluart, P.; Sporn, M. B.; Dannenberg, A. J. Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 60:2399-2404; 2000.
[135]Cruz, C. M.; Rinna, A.; Forman, H. J.; Ventura, A. L.; Persechini, P. M.; Ojcius, D. M. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 282:2871-2879; 2007.
[136]Gross, O.; Poeck, H.; Bscheider, M.; Dostert, C.; Hannesschlager, N.; Endres, S.; Hartmann, G.; Tardivel, A.; Schweighoffer, E.; Tybulewicz, V.; Mocsai, A.; Tschopp, J.; Ruland, J. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459:433-436; 2009.
[137]Dostert, C.; Petrilli, V.; Van Bruggen, R.; Steele, C.; Mossman, B. T.; Tschopp, J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674-677; 2008.
[138]Cassel, S. L.; Eisenbarth, S. C.; Iyer, S. S.; Sadler, J. J.; Colegio, O. R.; Tephly, L. A.; Carter, A. B.; Rothman, P. B.; Flavell, R. A.; Sutterwala, F. S. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A 105:9035-9040; 2008.
[139]Bauernfeind, F. G.; Horvath, G.; Stutz, A.; Alnemri, E. S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B. G.; Fitzgerald, K. A.; Hornung, V.; Latz, E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787-791; 2009.
[140]Yamabe, N.; Yokozawa, T.; Oya, T.; Kim, M. Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J Pharmacol Exp Ther 319:228-236; 2006.
[141]Syed, D. N.; Afaq, F.; Kweon, M. H.; Hadi, N.; Bhatia, N.; Spiegelman, V. S.; Mukhtar, H. Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene 26:673-682; 2007.
[142]Zhang, Z. M.; Yang, X. Y.; Yuan, J. H.; Sun, Z. Y.; Li, Y. Q. Modulation of NRF2 and UGT1A expression by epigallocatechin-3-gallate in colon cancer cells and BALB/c mice. Chin Med J (Engl) 122:1660-1665; 2009.
[143]Romeo, L.; Intrieri, M.; D'Agata, V.; Mangano, N. G.; Oriani, G.; Ontario, M. L.; Scapagnini, G. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, induces heme oxygenase in rat neurons and acts as an effective neuroprotective agent against oxidative stress. J Am Coll Nutr 28 Suppl:492S-499S; 2009.
[144]Sahin, K.; Tuzcu, M.; Gencoglu, H.; Dogukan, A.; Timurkan, M.; Sahin, N.; Aslan, A.; Kucuk, O. Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci 87:240-245; 2010.
[145]Zhu, H.; Itoh, K.; Yamamoto, M.; Zweier, J. L.; Li, Y. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett 579:3029-3036; 2005.
[146]Zhu, H.; Zhang, L.; Itoh, K.; Yamamoto, M.; Ross, D.; Trush, M. A.; Zweier, J. L.; Li, Y. Nrf2 controls bone marrow stromal cell susceptibility to oxidative and electrophilic stress. Free Radic Biol Med 41:132-143; 2006.
[147]Zhu, H.; Jia, Z.; Zhang, L.; Yamamoto, M.; Misra, H. P.; Trush, M. A.; Li, Y. Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress. Exp Biol Med (Maywood) 233:463-474; 2008.
[148]Brigelius-Flohe, R. Tissue-specific functions of individual glutathione peroxidases. Free Radic Biol Med 27:951-965; 1999.
[149]Vernet, P.; Rock, E.; Mazur, A.; Rayssiguier, Y.; Dufaure, J. P.; Drevet, J. R. Selenium-independent epididymis-restricted glutathione peroxidase 5 protein (GPX5) can back up failing Se-dependent GPXs in mice subjected to selenium deficiency. Mol Reprod Dev 54:362-370; 1999.
[150]Banning, A.; Deubel, S.; Kluth, D.; Zhou, Z.; Brigelius-Flohe, R. The GI-GPx gene is a target for Nrf2. Mol Cell Biol 25:4914-4923; 2005.
[151]Ichikawa, I.; Kiyama, S.; Yoshioka, T. Renal antioxidant enzymes: their regulation and function. Kidney Int 45:1-9; 1994.
[152]Kawamura, T.; Yoshioka, T.; Bills, T.; Fogo, A.; Ichikawa, I. Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries. Kidney Int 40:291-301; 1991.
[153]Yoshioka, T.; Homma, T.; Meyrick, B.; Takeda, M.; Moore-Jarrett, T.; Kon, V.; Ichikawa, I. Oxidants induce transcriptional activation of manganese superoxide dismutase in glomerular cells. Kidney Int 46:405-413; 1994.