成功大學博碩士論文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	吳思宇 Wu, Szu-Yu
論文名稱：	篩選具調節白血球產生活性氧分子能力之小分子化合物作為治療氧化壓力相關免疫疾病的可能藥物 Screening for small-molecule modulators for leukocyte reactive oxygen species production as drugs for diseases caused by redox immune dysregulation
指導教授：	謝奇璋 Shieh, Chi-Chang
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	67
中文關鍵詞：	活性氧分子、小分子藥物篩選、調節氧化壓力、白血球氧化壓力、關節炎
外文關鍵詞：	ROS, small-molecules, redox modulators, ROS of leukocytes, immune-mediated arthritis
相關次數：	點閱：102 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

活性氧分子(ROS)是細胞有氧代謝的副產物與免疫反應中細胞相互傳遞訊號的分子。不平衡的氧化壓力可能會造成諸多疾病，包含神經性疾病與自體免疫疾病等。菸醯胺腺嘌呤二磷酸氧化酶(NADPH oxidase)為免疫系統中產生ROS的重要，在近年的研究中發現，NADPH oxidase影響自體免疫疾病的發展與疾病程度。以免疫介導的關節炎為例，在實驗室先前的研究中發現，當老鼠體內白血球缺乏了NADPH oxidase的情況下，以血清誘發關節炎後，會有大量白血球驅化激素與介白素-1產生，造成發炎反應明顯比起wild type老鼠來的嚴重。由此推論，氧化壓力可能扮演著調控發炎反應的角色。目前臨床上所治療關節炎的藥物，尚未有以調節ROS為治療目標的藥物。
本實驗以篩選具有調控白血球活性氧分子為目標，找尋具有潛在能力的治療藥物。我們以美國食品藥物管理局核可的藥物，建立高通量篩選平台，找出具有調節ROS的藥物。首先我們利用致關節炎血清於wild type老鼠與NADPH oxidase缺失鼠中誘發關節炎，結果如預期發現白血球NADPH oxidase缺失鼠有較嚴重的發炎反應，並且證明在這些缺失鼠中關節的氧化壓力也較低。在過去的研究中已知維生素K3 (menadione)能刺激白血球產生ROS，因此我們給予10mg/kg與25mg/kg的menadione以腹腔注射給予治療，發現相較於為治療的組別，給予維生素K3治療的血清誘發關節炎NADPH oxidase缺失鼠，關節的發炎反應有明顯的減緩，證明ROS能減緩關節的發炎反應。接著我們利用H2DCF-DA為檢測ROS產生的指示劑，並偵測嗜中性白血球所釋放的螢光值。發現在給予phorbol 12-myristate 13-acetate (PMA)與menadione皆能刺激白血球產生ROS，並且產生ROS的來源分別為依賴與非依賴NADPH oxidase路徑。我們以類嗜中性白血球細胞為模型建立MetaXpress高通量篩選平台，篩選促進氧化壓力之分子與抑制氧化壓力之分子。在此平台我們以menadione為促ROS正對照組，而PMA為給予ROS生成的刺激物進行篩選。在LOPAC1280 drug library 240隻藥物中以single-shot、3個濃度的方式進行初篩，並利用Z-factor (Z`)為quality control，normalized percentage(Np)與strictly standardized mean difference (SSMD)為計算方式篩選出”hit”。於促氧化合物的結果中，我們以Np≥3和/或SSMD≥3為基準，在240隻藥物中挑選出總共18 藥物。而在抗氧化合物中，隨著劑量而抑制ROS生成化合物為篩選標準，從中找尋到12支藥物。未來計畫近一步進行二次篩選，並將二篩後的藥物在關節炎老鼠中進行試驗。由於篩選之促氧或抑氧藥物為臨床用藥，因此我們可以利用已知的作用機制治療不同疾病，或是進行藥物包裹(如奈米包裹藥物)進行投藥，達成更為精準的治療。此研究結果能在未來臨床治療上，為氧化壓力失調的疾病提供多一個藥物治療的可能性。

Reactive oxygen species (ROS) are byproducts of cellular metabolism which may play important roles for signal transduction in immune cells. Although ROS were thought to cause toxic effects associated with various pathologies, previous studies indicated that lack of ROS production might raise the severity of the autoimmune disease. Our previous studies showed that in Ncf1-/- mice, which lack of leukocyte NADPH oxidase (NOX2), ROS act as negative feedback to regulate IL-1β-mediated inﬂammation and enhance the severity of inflammation in a model of arthritis joint than in wild-type mice. Thus, we hypothesize that modulates the leukocyte ROS production may regulate the pathogenicity of immune-mediated arthritis. However, there were no clinical drugs which regulate ROS as target for treatment in immune-mediated arthritis.
In this study, we aim to set up a high-content screening system with FDA approve drugs to screen redox modulators. We developed an image-based high-throughput screening platform on differentiated neutrophil-like HL-60 (dHL-60) to identify anti- or pro-oxidant molecules. We also performed the experiment to characterize the level of ROS in the WT and Ncf1-/- serum-induced arthritis.
We found that serum-induced joint inﬂammation was more severe but the ROS level was lower in Ncf1-/- mice compared with WT mice. The severity of inflammation attenuated in the treatment of giving 10 mg/kg or 25 mg/kg menadione which may regulate the redox level in arthritic joints in Ncf1-/- mice. ROS level was stained with H2DCF-DA and measured with flow cytometry, we found that phorbol 12-myristate 13-acetate (PMA) and menadione could stimulate neutrophils to produce ROS by NOX2-dependent and NOX2-independent pathway, respectively. We set up the high-content screening system with MetaXpress acquisition system to screen anti- or pro-oxidants. We screened 240 compounds from LOPAC1280 library in a single-shot, 3-point interpolate titration (final concentrations: 5,10 and 20 M). Z-factors were considered as the quality control readouts while Strictly standardized median difference (SSMD) ≥ 3 and normalization ≥0.3 were used as the criterion for hit selection in the assay. We found 18 of the drugs enhanced the ROS production while 12 of the compounds established anti-oxidant.
As the compounds we discovered were FDA approved drugs which were already used in clinical treatment, we could further classify their mechanism and delivered this compounds with different packing components such as nanoparticles to enhance the specificities of treatment. These compounds will further undergo a secondary screening and animal disease model. The potential drugs we discovered in this project may establish a new strategy for treating redox-related inflammatory diseases.

Content
Abstract	I
中文摘要	III
致    謝	V
Abbreviations	VI
Chapter 1 Introduction	1
1.1	Innate immune response and phagocytes	2
1.2	Respiratory burst and leukocyte NADPH oxidase	3
1.2.1	Respiratory burst	3
1.2.2 Leukocyte NADPH oxidase system	4
1.3 Reactive oxygen species and redox homeostasis	5
1.3.1 Reactive oxygen species	5
1.3.2 ROS homeostasis	6
1.4 Regulation of ROS in immune-mediated disease	7
1.5 Drug repurposing and high-content screening	9
1.5.1 Drug repurposing	9
1.5.2 High-content screening system	10
1.6 The aim of this study	11
Chapter 2 Materials and Methods	12
2.1 Reagents	13
2.2 Mice	13
2.3 Serum-induced arthritis	14
2.4 Preparation of protein extracts from wrists and ankles	14
2.5 Measured the ROS level of joints	14
2.5.1 Evaluation of the lipid peroxidation by Malondialdehyde assay	14
2.5.2 Assessment the level of protein oxidation	15
2.6 Cell culture	15
2.7 Granulocytes isolation	16
2.8 ROS measurement by FACS analysis	16
2.9 Preparation for the primary screening of LOPAC 1280 drug library	17
2.10 High-throughput screening for ROS-modulators in the LOPAC 1280 drug library	17
2.11 Data analysis for ROS assays on the high-content platform for LOPAC1280 screening	18
2.12 Statistical analysis	19
Chapter 3 Results	20
3.1 Arthritogenic serum transfer induced more severe joint inflammation and lower levels of tissue oxidation in the NOX2-deficient mice	21
3.2 PMA and Menadione induced ROS production through NADPH oxidase-dependent and independent pathways in dHL-60 cells	21
3.3 The development and optimization of the ROS assays on the image-based high-throughput high-content acquisition system	22
3.4 Establishment of methods measuring ROS production by leukocytes	23
3.5 Verification of the performance of a high-content screening assay with known redox-active compounds	23
3.6 Identification of compounds with redox modulating activity on leukocytes from 240 drugs of LOPAC1280	24
3.6.1 Identification of 18 Pro-oxidants	24
3.6.2 Identification of 12 Anti-oxidants	25
3.6.3 Identification of priming substances	25
3.7 Menadione treatment decreased the severity of serum-induced arthritis in Ncf1-/- mice	26
Chapter 4 Discussion	27
4.1 The mechanism of regulating ROS production in the compounds of primary screening	29
4.2 Nanoparticles package the ROS modulators for specific drug delivery	32
Chapter 5 Tables and Figures	34
Table 1. Multiple cell scoring analysis and top-hat segmentation method of cell definition	35
Table 2. Pro-oxidants screened from 240 drugs of LOPAC1280	36
Table 3. The anti-oxidants screened from 240 drugs of LOPAC1280 library	37
Figure 1.	38
Figure 1. Flowchart of assays to assess the ROS modulator activity and the design of the platform for high-throughput screening.	39
Figure 2.	40
Figure 2. The severity of arthritis on Ncf1-/- mice was higher while the ROS production in the inflamed joint was lower when compared with those in WT mice	41
Figure 3.	42
Figure 3. Differentiated HL-60 cells produced more ROS after PMA stimulation when compared with undifferentiated HL-60 cells.	43
Figure 4.	44
Figure 4. Neutrophils treated with PMA and menadione produce ROS through NOX2-dependent and independent pathways respectively.	45
Figure 5.	46
Figure 5. Menadione induced the ROS formation in neutrophil-like differentiated HL-60 (dHL-60) cells measured with the high-content screening assay.	47
Figure 6.	48
Figure 6. ROS production measured with high-content screening assays for fMLP-primed neutrophil-like differentiated HL-60 (dHL-60) cells stimulated with PMA showed apparent priming effects of fMLP.	49
Figure 7.	50
Figure 7. The multiple scoring analysis and the pre-test of a high-content screening assay for redox-active compounds.	51
Figure 8.	52
Figure 8. The “hit” compounds which induce the dHL-60 cells to enhance ROS production in the primary screening.	53
Figure 9.	54
Figure 9. The “hit” compounds which reduce the dHL-60 cell ROS production after 50 nM PMA treatment in the primary screening.	55
Figure 10.	56
Figure 10. Menadione treatment attenuated the swelling level of serum-induced arthritic joints in Ncf1-/- mice.	57
Chapter 6 References	58
                                    

Assas, B.M., M.H. Wakid, H.A. Zakai, J.A. Miyan, and J.L. Pennock. 2016. Transient receptor potential vanilloid 1 expression and function in splenic dendritic cells: a potential role in immune homeostasis. Immunology 147:292-304.
Ayala, A., M.F. Munoz, and S. Arguelles. 2014. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438.
Babior, B.M. 1984. The respiratory burst of phagocytes. J Clin Invest 73:599-601.
Babior, B.M. 1999. NADPH oxidase: an update. Blood 93:1464-1476.
Babior, B.M., R.S. Kipnes, and J.T. Curnutte. 1973. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 52:741-744.
Bae, Y.S., H. Oh, S.G. Rhee, and Y.D. Yoo. 2011. Regulation of reactive oxygen species generation in cell signaling. Mol Cells 32:491-509.
Baehner, R.L., N. Gilman, and M.L. Karnovsky. 1970. Respiration and glucose oxidation in human and guinea pig leukocytes: comparative studies. J Clin Invest 49:692-700.
Baral, P., B.D. Umans, L. Li, A. Wallrapp, M. Bist, T. Kirschbaum, Y. Wei, Y. Zhou, V.K. Kuchroo, and P.R. Burkett. 2018. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nature medicine 24:417.
Barletta, K.E., K. Ley, and B. Mehrad. 2012. Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol 32:856-864.
Barrios, J., K.R. Patel, L. Aven, R. Achey, M.S. Minns, Y. Lee, V.E. Trinkaus-Randall, and X. Ai. 2017. Early life allergen-induced mucus overproduction requires augmented neural stimulation of pulmonary neuroendocrine cell secretion. The FASEB Journal 31:4117-4128.
Bedard, K., and K.H. Krause. 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245-313.
Bellinger, D.L., and D. Lorton. 2014. Autonomic regulation of cellular immune function. Autonomic Neuroscience 182:15-41.
Brand, M.D. 2010. The sites and topology of mitochondrial superoxide production. Experimental gerontology 45:466-472.
Brandes, R.P., N. Weissmann, and K. Schroder. 2014. Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med 76:208-226.
Cardoso, V., J. Chesné, H. Ribeiro, B. García-Cassani, T. Carvalho, T. Bouchery, K. Shah, N.L. Barbosa-Morais, N. Harris, and H. Veiga-Fernandes. 2017. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549:277.
Carvalho, D.P., and C. Dupuy. 2013. Role of the NADPH Oxidases DUOX and NOX4 in Thyroid Oxidative Stress. Eur Thyroid J 2:160-167.
Chan, T.Y., C.L. Yen, Y.F. Huang, P.C. Lo, P.A. Nigrovic, C.Y. Cheng, W.Z. Wang, S.Y. Wu, and C.C. Shieh. 2019. Increased ILC3s associated with higher levels of IL-1beta aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase. European journal of immunology
Chandel, N.S., E. Maltepe, E. Goldwasser, C.E. Mathieu, M.C. Simon, and P.T. Schumacker. 1998. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proceedings of the National Academy of Sciences of the United States of America 95:11715-11720.
Christensen, A.D., C. Haase, A.D. Cook, and J.A. Hamilton. 2016. K/BxN Serum-Transfer Arthritis as a Model for Human Inflammatory Arthritis. Front Immunol 7:213.
Collins, J.A., S.T. Wood, K.J. Nelson, M.A. Rowe, C.S. Carlson, S. Chubinskaya, L.B. Poole, C.M. Furdui, and R.F. Loeser. 2016. Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes. J Biol Chem 291:6641-6654.
Collins, S.J. 1987. The HL-60 promyelocytic leukemia cell line: proliferation, differentiation, and cellular oncogene expression. Blood 70:1233-1244.
Colombo, G., M. Clerici, M.E. Garavaglia, D. Giustarini, R. Rossi, A. Milzani, and I. Dalle-Donne. 2016. A step-by-step protocol for assaying protein carbonylation in biological samples. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1019:178-190.
Cronstein, B.N., and M. Sitkovsky. 2016. Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nature Reviews Rheumatology 13:41.
Dahlgren, C., and A. Karlsson. 1999. Respiratory burst in human neutrophils. Journal of immunological methods 232:3-14.
De Minicis, S., R. Bataller, and D.A. Brenner. 2006. NADPH Oxidase in the Liver: Defensive, Offensive, or Fibrogenic? Gastroenterology 131:272-275.
Di Meo, S., T.T. Reed, P. Venditti, and V.M. Victor. 2016. Role of ROS and RNS Sources in Physiological and Pathological Conditions. Oxid Med Cell Longev 2016:1245049.
Domej, W., K. Oettl, and W. Renner. 2014. Oxidative stress and free radicals in COPD–implications and relevance for treatment. International journal of chronic obstructive pulmonary disease 9:1207.
Duró, E., A. Pallai, K. Köröskényi, Z. Sarang, and Z. Szondy. 2014. Adenosine A3 receptors negatively regulate the engulfment-dependent apoptotic cell suppression of inflammation. Immunology letters 162:292-301.
Gabanyi, I., Paul A. Muller, L. Feighery, Thiago Y. Oliveira, Frederico A. Costa-Pinto, and D. Mucida. 2016. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages. Cell 164:378-391.
Galluzzi, L., E. Morselli, O. Kepp, I. Vitale, A. Rigoni, E. Vacchelli, M. Michaud, H. Zischka, M. Castedo, and G. Kroemer. 2010. Mitochondrial gateways to cancer. Molecular aspects of medicine 31:1-20.
Godinho-Silva, C., F. Cardoso, and H. Veiga-Fernandes. 2019. Neuro–Immune Cell Units: A New Paradigm in Physiology. Annual review of immunology 37:19-46.
Graff, L.A., J.R. Walker, and C.N. Bernstein. 2009. Depression and anxiety in inflammatory bowel disease: a review of comorbidity and management. Inflammatory bowel diseases 15:1105-1118.
Halasi, M., M. Wang, T.S. Chavan, V. Gaponenko, N. Hay, and A.L. Gartel. 2013. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors. The Biochemical journal 454:201-208.
Halliwell, B., and C.E. Cross. 1994. Oxygen-derived species: their relation to human disease and environmental stress. Environ Health Perspect 102 Suppl 10:5-12.
Hanes, W.M., P.S. Olofsson, K. Kwan, L.K. Hudson, S.S. Chavan, V.A. Pavlov, and K.J. Tracey. 2015. Galantamine attenuates type 1 diabetes and inhibits anti-insulin antibodies in nonobese diabetic mice. Molecular Medicine 21:702-708.
Holmdahl, R., O. Sareila, L.M. Olsson, L. Backdahl, and K. Wing. 2016. Ncf1 polymorphism reveals oxidative regulation of autoimmune chronic inflammation. Immunological reviews 269:228-247.
Horiguchi, H., T.J. Loftus, R.B. Hawkins, S.L. Raymond, J.A. Stortz, M.K. Hollen, B.P. Weiss, E.S. Miller, A. Bihorac, S.D. Larson, A.M. Mohr, S.C. Brakenridge, H. Tsujimoto, H. Ueno, F.A. Moore, L.L. Moldawer, P.A. Efron, Sepsis, and I. Critical Illness Research Center. 2018. Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy. Front Immunol 9:595.
Huang, Y.F., P.C. Lo, C.L. Yen, P.A. Nigrovic, W.C. Chao, W.Z. Wang, G.C. Hsu, Y.S. Tsai, and C.C. Shieh. 2015. Redox Regulation of Pro-IL-1beta Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice. Antioxidants & redox signaling 23:973-984.
Hultqvist, M., L.M. Olsson, K.A. Gelderman, and R. Holmdahl. 2009. The protective role of ROS in autoimmune disease. Trends Immunol 30:201-208.
Ibiza, S., B. García-Cassani, H. Ribeiro, T. Carvalho, L. Almeida, R. Marques, A.M. Misic, C. Bartow-McKenney, D.M. Larson, and W.J. Pavan. 2016. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535:440.
Iizawa, O., H. Akamatsu, and Y. Niwa. 1995. Neutrophil chemotaxis, phagocytosis, and generation of reaction oxygen species show a hierarchy of responsiveness to increasing concentrations of N-formyl-Met-Leu-Phe. Biol Signals 4:14-18.
Jia, Z., and J. He. 2016. Paeoniflorin ameliorates rheumatoid arthritis in rat models through oxidative stress, inflammation and cyclooxygenase 2. Experimental and therapeutic medicine 11:655-659.
Karnad, A.B., K.L. Hartshorn, J. Wright, J.B. Myers, J.H. Schwartz, and A.I. Tauber. 1989. Priming of human neutrophils with N-formyl-methionyl-leucyl-phenylalanine by a calcium-independent, pertussis toxin-insensitive pathway. Blood 74:2519-2526.
Kawai, T., and S. Akira. 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature immunology 11:373-384.
Kazzaz, N.M., G. Sule, and J.S. Knight. 2016. Intercellular Interactions as Regulators of NETosis. Front Immunol 7:453.
Khoubnasabjafari, M., K. Ansarin, and A. Jouyban. 2015. Reliability of malondialdehyde as a biomarker of oxidative stress in psychological disorders. BioImpacts : BI 5:123-127.
Koenderman, L., W. Buurman, and M.R. Daha. 2014. The innate immune response. Immunology letters 162:95-102.
Kwon, J., K.E. Shatynski, H. Chen, S. Morand, X. de Deken, F. Miot, T.L. Leto, and M.S. Williams. 2010. The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling. Sci Signal 10.1126/scisignal.2000976.
Lamson, D.W., and S.M. Plaza. 2003. The anticancer effects of vitamin K. Alternative Medicine Review 8:303-318.
Li, J.M., and A.M. Shah. 2003. ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy. Journal of the American Society of Nephrology : JASN 14:S221-226.
Li, Y., and M.A. Trush. 1998. Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem Biophys Res Commun 253:295-299.
Liam J. O’Neil, M.J.K. 2019. Neutrophils in rheumatoid arthritis: breaking immune tolerance and fueling disease. Trends in molecular medicine 25:215-277.
Lim, J.J., S. Grinstein, and Z. Roth. 2017. Diversity and Versatility of Phagocytosis: Roles in Innate Immunity, Tissue Remodeling, and Homeostasis. Front Cell Infect Microbiol 7:191.
Liu, S.Y., W.Z. Wang, C.L. Yen, M.Y. Tsai, P.W. Yang, J.Y. Wang, C.Y. Ho, and C.C. Shieh. 2011. Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation. The Journal of allergy and clinical immunology 127:1014-1023.
Loor, G., J. Kondapalli, J.M. Schriewer, N.S. Chandel, T.L. Vanden Hoek, and P.T. Schumacker. 2010. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radic Biol Med 49:1925-1936.
Mangialaio, S., H. Ji, A.S. Korganow, V. Kouskoff, C. Benoist, and D. Mathis. 1999. The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis. Arthritis Rheum 42:2517-2523.
Marinho, H.S., C. Real, L. Cyrne, H. Soares, and F. Antunes. 2014. Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox biology 2:535-562.
Marino, F., and M. Cosentino. 2013. Adrenergic modulation of immune cells: an update. Amino acids 45:55-71.
Marino, F., A. Scanzano, L. Pulze, M. Pinoli, E. Rasini, A. Luini, R. Bombelli, M. Legnaro, M. de Eguileor, and M. Cosentino. 2018. beta2 -Adrenoceptors inhibit neutrophil extracellular traps in human polymorphonuclear leukocytes. J Leukoc Biol 104:603-614.
Mattiazzi Usaj, M., E.B. Styles, A.J. Verster, H. Friesen, C. Boone, and B.J. Andrews. 2016. High-Content Screening for Quantitative Cell Biology. Trends Cell Biol 26:598-611.
Mikocka-Walus, A.A., D.A. Turnbull, N.T. Moulding, I.G. Wilson, J.M. Andrews, and G.J. Holtmann. 2006. Antidepressants and inflammatory bowel disease: a systematic review. Clinical practice and epidemiology in mental health : CP & EMH 2:24.
Miralda, I., S.M. Uriarte, and K.R. McLeish. 2017. Multiple Phenotypic Changes Define Neutrophil Priming. Front Cell Infect Microbiol 7:217.
Nabavi, S.F., A.J. Barber, C. Spagnuolo, G.L. Russo, M. Daglia, S.M. Nabavi, and E. Sobarzo-Sanchez. 2016. Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy. Critical reviews in clinical laboratory sciences 53:293-312.
Nathan, C., and M.U. Shiloh. 2000. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proceedings of the National Academy of Sciences of the United States of America 97:8841-8848.
Nauseef, W.M. 2014. Isolation of human neutrophils from venous blood. Methods Mol Biol 1124:13-18.
Nguyen, G.T., E.R. Green, and J. Mecsas. 2017. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Frontiers in Cellular and Infection Microbiology 7:
Nierode, G., P.S. Kwon, J.S. Dordick, and S.J. Kwon. 2016. Cell-Based Assay Design for High-Content Screening of Drug Candidates. J Microbiol Biotechnol 26:213-225.
Okamoto, H. 2008. Vitamin K and rheumatoid arthritis. IUBMB Life 60:355-361.
Pacheco, R., F. Contreras, and C. Prado. 2012. Cells, molecules and mechanisms involved in the neuro-immune interaction. Cell interaction 139-166.
Palipoch, S., and P. Koomhin. 2015. Oxidative Stress-Associated Pathology: A Review. 1441-1451 pp.
Panday, A., M.K. Sahoo, D. Osorio, and S. Batra. 2014. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cellular And Molecular Immunology 12:5.
Pavlov, V.A., W.R. Parrish, M. Rosas-Ballina, M. Ochani, M. Puerta, K. Ochani, S. Chavan, Y. Al-Abed, and K.J. Tracey. 2009. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain, behavior, and immunity 23:41-45.
Pinho-Ribeiro, F.A., B. Baddal, R. Haarsma, M. O’Seaghdha, N.J. Yang, K.J. Blake, M. Portley, W.A. Verri, J.B. Dale, and M.R. Wessels. 2018. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173:1083-1097. e1022.
Pushpakom, S., F. Iorio, P.A. Eyers, K.J. Escott, S. Hopper, A. Wells, A. Doig, T. Guilliams, J. Latimer, C. McNamee, A. Norris, P. Sanseau, D. Cavalla, and M. Pirmohamed. 2018. Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery 18:41.
Rahman, K. 2007. Studies on free radicals, antioxidants, and co-factors. Clinical interventions in aging 2:219-236.
Remijsen, Q., T.W. Kuijpers, E. Wirawan, S. Lippens, P. Vandenabeele, and T. Vanden Berghe. 2011. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell death and differentiation 18:581-588.
Rivera, A., M.C. Siracusa, G.S. Yap, and W.C. Gause. 2016. Innate cell communication kick-starts pathogen-specific immunity. Nature immunology 17:356-363.
Rossi, F., and M. Zatti. 1964. Biochemical aspects of phagocytosis in polymorphonuclear leucocytes. NADH and NADPH oxidation by the granules of resting and phagocytizing cells. Experientia 20:21-23.
Salzano, S., P. Checconi, E.M. Hanschmann, C.H. Lillig, L.D. Bowler, P. Chan, D. Vaudry, M. Mengozzi, L. Coppo, S. Sacre, K.R. Atkuri, B. Sahaf, L.A. Herzenberg, L.A. Herzenberg, L. Mullen, and P. Ghezzi. 2014. Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proceedings of the National Academy of Sciences of the United States of America 111:12157-12162.
Sareila, O., C. Hagert, T. Kelkka, M. Linja, B. Xu, J. Kihlberg, and R. Holmdahl. 2017. Reactive Oxygen Species Regulate Both Priming and Established Arthritis, but with Different Mechanisms. Antioxid Redox Signal 27:1473-1490.
Sato, T., T. Hongu, M. Sakamoto, Y. Funakoshi, and Y. Kanaho. 2013. Molecular mechanisms of N-formyl-methionyl-leucyl-phenylalanine-induced superoxide generation and degranulation in mouse neutrophils: phospholipase D is dispensable. Mol Cell Biol 33:136-145.
Scanzano, A., and M. Cosentino. 2015. Adrenergic regulation of innate immunity: a review. Frontiers in Pharmacology 6:
Segal, A.W., and O.T. Jones. 1978. Novel cytochrome b system in phagocytic vacuoles of human granulocytes. Nature 276:515-517.
Segal, A.W., O.T. Jones, D. Webster, and A.C. Allison. 1978. Absence of a newly described cytochrome b from neutrophils of patients with chronic granulomatous disease. Lancet (London, England) 2:446-449.
Shepherd, V.L. 1986. The role of the respiratory burst of phagocytes in host defense. Semin Respir Infect 1:99-106.
Shimizu, M.H., T.M. Coimbra, M. de Araujo, L.F. Menezes, and A.C. Seguro. 2005. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney international 68:2208-2217.
Shukla, V., S.K. Mishra, and H.C. Pant. 2011. Oxidative stress in neurodegeneration. Advances in pharmacological sciences 2011:572634.
Sieprath, T., T. Corne, J. Robijns, W.J.H. Koopman, and W.H. De Vos. 2017. Cellular Redox Profiling Using High-content Microscopy. J Vis Exp
Silva, M.T., and M. Correia-Neves. 2012. Neutrophils and macrophages: the main partners of phagocyte cell systems. Front Immunol 3:174.
Simm, J., G. Klambauer, A. Arany, M. Steijaert, J.K. Wegner, E. Gustin, V. Chupakhin, Y.T. Chong, J. Vialard, P. Buijnsters, I. Velter, A. Vapirev, S. Singh, A.E. Carpenter, R. Wuyts, S. Hochreiter, Y. Moreau, and H. Ceulemans. 2018. Repurposing High-Throughput Image Assays Enables Biological Activity Prediction for Drug Discovery. Cell Chem Biol 25:611-618 e613.
Sulciner, D.J., K. Irani, Z.X. Yu, V.J. Ferrans, P. Goldschmidt-Clermont, and T. Finkel. 1996. rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol 16:7115-7121.
Talbot, S., R.-E.E. Abdulnour, P.R. Burkett, S. Lee, S.J. Cronin, M.A. Pascal, C. Laedermann, S.L. Foster, J.V. Tran, and N. Lai. 2015. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87:341-354.
Teixeira, J., R. Amorim, K. Santos, P. Soares, S. Datta, G.A. Cortopassi, T.L. Serafim, V.A. Sardao, J. Garrido, F. Borges, and P.J. Oliveira. 2018. Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative. Toxicology 393:123-139.
Terrando, N., T. Yang, J.K. Ryu, P.T. Newton, C. Monaco, M. Feldmann, D. Ma, K. Akassoglou, and M. Maze. 2014. Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Molecular Medicine 20:667-675.
Thaiss, C.A., N. Zmora, M. Levy, and E. Elinav. 2016. The microbiome and innate immunity. Nature 535:65.
Trachootham, D., J. Alexandre, and P. Huang. 2009. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nature Reviews Drug Discovery 8:579-591.
Umar, S., J. Zargan, K. Umar, S. Ahmad, C.K. Katiyar, and H.A. Khan. 2012. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chemico-biological interactions 197:40-46.
Valko, M., D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, and J. Telser. 2007. Free radicals and antioxidants in normal physiological functions and human disease. The international journal of biochemistry & cell biology 39:44-84.
Veiga-Fernandes, H., and D. Mucida. 2016. Neuro-Immune Interactions at Barrier Surfaces. Cell 165:801-811.
Wallrapp, A., S.J. Riesenfeld, P.R. Burkett, R.-E.E. Abdulnour, J. Nyman, D. Dionne, M. Hofree, M.S. Cuoco, C. Rodman, and D. Farouq. 2017. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351.
Wheeler, D.W., A.J. Thompson, F. Corletto, J. Reckless, J.C. Loke, N. Lapaque, A.J. Grant, P. Mastroeni, D.J. Grainger, C.L. Padgett, J.A. O'Brien, N.G. Miller, J. Trowsdale, S.C. Lummis, D.K. Menon, and J.S. Beech. 2011. Anaesthetic impairment of immune function is mediated via GABA(A) receptors. PloS one 6:e17152.
Xie, C., J. Yi, J. Lu, M. Nie, M. Huang, J. Rong, Z. Zhu, J. Chen, X. Zhou, B. Li, H. Chen, N. Lu, and X. Shu. 2018. N-Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Helicobacter pylori Infection. Oxid Med Cell Longev 2018:1874985.
Xie, H., F. Zhou, L. Liu, G. Zhu, Q. Li, C. Li, and T. Gao. 2016. Vitiligo: How do oxidative stress-induced autoantigens trigger autoimmunity? Journal of dermatological science 81:3-9.
Xue, H., J. Li, H. Xie, and Y. Wang. 2018. Review of Drug Repositioning Approaches and Resources. Int J Biol Sci 14:1232-1244.
Yen, C.L., Y.C. Liao, R.F. Chen, Y.F. Huang, W.C. Chung, P.C. Lo, C.F. Chang, P.C. Wu, D.B. Shieh, S.T. Jiang, and C.C. Shieh. 2019. Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis. Journal of immunology (Baltimore, Md. : 1950) 202:3394-3403.
Zhang, J.H., T.D. Chung, and K.R. Oldenburg. 1999. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen 4:67-73.
Zhu, H., and Y.R. Li. 2012. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. Experimental biology and medicine 237:474-480.

校內：2024-09-01公開
校外：不公開電子論文尚未授權公開，紙本請查館藏目錄

簡易檢索 / 詳目顯示

相關論文