異位性皮膚炎是一種慢性的發炎疾病且其盛行率正在逐漸增加，其常常會表現出皮膚屏障失調、肌膚乾燥及發癢。然而其致病機轉仍然未知，更有效的治療方法是急需的。由於海洋環境的多樣性與複雜度，從海洋生物中尋找新穎的人類疾病藥物再度興起熱潮。表型藥物篩選是一個高效率方法來探勘未知機轉的海洋天然物。Dihydroaustrasulfone alcohol (WA-25)是austrasulfone合成的前驅物，而austrasulfone最初來自於福爾摩沙軟珊瑚。WA-25在我們的先前研究中已經展現許多治療用途，然而其在異位性皮膚炎的詳細治療機轉仍未完全釐清。因此，我們使用離體與活體模式來探討WA-25對於異位性皮膚炎的治療效果。實驗結果發現WA-25可以抑制發炎反應與氧化壓力，同時也可減少異位性皮膚炎臨床分數、降低經皮水分散失、減緩抓癢行為及癢感過敏。它的效果甚至優於現今異位性皮膚炎臨床上經常使用之藥物。更重要的是，我們也發現一旦核仁磷酸蛋白 (NPM)表現量被抑制，WA-25治療異位性皮膚炎效果也會跟著受阻。基於這個結果，我們認為NPM很有可能在發炎反應與異位性皮膚炎中扮演重要角色。總括來說，這些結果顯示WA-25是一個相當有潛力的抗發炎與異位性皮膚炎治療藥物，其效果是被NPM所調控。同時，我們也發現WA-25與其相似物可能也具有潛力治療乾癬與傷口。此外，我們利用生物資訊學與化學資訊學找到更多的化合物、藥物標的及新穎的治療機轉。總結發現之成果，這個研究不僅僅提供異位性皮膚炎的治療藥劑，也同時提供了治療發炎性疾病的新觀點。

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and its prevalence is increasing. AD usually elicits skin barrier dysfunction, dry skin, and itching. As the mechanisms of AD remain unknown, there is an urgent need to find effective therapies. Because of the diversity and complexity of marine environments, the discovery of drugs from marine organisms as novel therapeutic agents for human diseases has seen renewed interest. Phenotypic screening is a high efficiency way to discover marine natural products that may have unknown mechanisms. Dihydroaustrasulfone alcohol (WA-25), the synthetic precursor of austrasulfone, which is a natural product isolated from a Formosan soft coral, has been shown to possess many therapeutic effects in our previous studies. However, the detailed mechanisms and therapeutic effects of WA-25 on AD are incompletely understood. We performed in vitro and in vivo studies to examine the effects of WA-25 on AD. We showed that WA-25 blocks inflammation and oxidative stress. Simultaneously, we also found that WA-25 reduces the AD scores and AD-induced transepidermal water loss (TEWL), scratching behavior, and alloknesis. WA-25 is more effective in cases of AD than are the drugs that are currently used clinically. Importantly, we also found that when nucleophosmin (NPM) was inhibited or when its expression was reduced, the anti-inflammatory and anti-AD effects of WA-25 were blocked. These data suggest that NPM plays dual roles in inflammation and AD. Overall, these results suggest that WA-25 is a potential anti-inflammatory and AD therapeutic agent that is modulated by NPM. Simultaneously, we also found that WA-25 or its analogs may have potential to treat psoriasis and wound. Besides, we find more compounds, drug targets and novel therapeutic mechanisms by bioinformatics and cheminformatics. In summary, this study provides not only AD therapeutic agents but also new insight into inflammatory diseases.

論文審定書…………………………………………...………………….…i
誌謝…………………………………………………...……………….…ii
中文摘要及關鍵詞…………………………………...……………….…iii
Abstract and keywords……….……………………………….…………iv
Lists of Abbreviations.……………………….……………..……...……vi
1. Introduction……………...………………………………………..…….1
1.1 The mechanisms of atopic dermatitis and the current treatments.......1
1.2 Disorders of the skin barrier in AD………………………………….2
1.3 The role of angiogenesis in atopic dermatitis………………………..2
1.4 The relations between inflammation and macrophage………………3
1.5 The zebrafish model in angiogenesis………………………………..4
1.6 The potential of drug discovery from marine……………………….5
1.7 Phenotypic screening in drug discovery…………………………….6
2. Materials and Methods.………………………………….……….....…8
2.1 Chemicals………………………………………………….…….…..8
2.2 Cell line culture……………………………………………………...8
2.3 Anti-inflammatory assay…………………………………………….9
2.4 Western blot analysis………………………………………………..9
2.5 Immunocytochemistry……………………………………….……..10
2.6 NO production and determination of intracellular ROS……………11
2.7 Induction of AD…………………………………………………….11
2.8 Preparation of Topical gel………………………………………….11
2.9 Measurement of TEWL…………………………………………….12
2.10 Evaluation of scratching behavior……………………………….12
2.11 Alloknesis assay…………………………………………………12
2.12 Immunohistochemistry…………………………………………..13
2.13 siRNA in vitro and in vivo applications…………………………13
2.14 Inflammation antibody array…………………………………….14
2.15 Anti-angiogenesis assay………………………………………….14
2.16 In-gel digestion for protein identification………………………14
2.17 MALDI MS and analysis………………………………………15
2.18 High-throughput screening (HTS) of pyruvate kinase…………..15
2.19 L1000 assay to determine gene signatures by C-map…………17
2.20 Induction of Psoriasis (PS)………………………………………17
2.21 Induction of wound………………………………………………18
2.22 Data and statistical analysis……………………………………...18
2.23 Data and statistical analysis of HTS……………………………19
3. Results.…………….…...…………………………..…………...……..20
3.1 Effects of WA-25 on inflammation and oxidative stress in LPS-stimulated macrophages……………………………………....20
3.2 Therapeutic effects of WA-25 on AD……………………………...20
3.3 Interaction between NF-B and NPM plays an important role in inflammation………………………………………………………..21
3.4 Effects of WA-25 on inflammation regulated by NPM……………22
3.5 NPM-regulated WA-25 effects on AD……………………………..23
3.6 The anti-angiogenic activity of WA-25…………………………….24
3.7 Discovery the analogs of WA-25 and their effects………………25
3.8 The therapeutic effects of WA-25 and its analogs on inflammatory skin diseases………………………………………………………..26
3.9 New insight into WA-25 by data mining from its analogs……….26
3.10 The role of pyruvate kinase on inflammation……………………27
3.11 Search possible targets of compound by Lipinski-Rule-of-5……27
3.12 Using connectivity map (C-map) to identify WA-25…………....28
Discussion………………………………………………………….....…104
References………………………………………………………………114

Ansell DM, Campbell L, Thomason HA, Brass A, Hardman MJ (2014) A statistical analysis of murine incisional and excisional acute wound models. Wound Repair Regen 22(2):281-7.
Agrawal R, Woodfolk JA (2014) Skin barrier defects in atopic dermatitis. Curr Allergy Asthma Rep 14(5):433.
Akiyama T, Carstens M, Ikoma A, Cevikbas F, Steinhoff M, Carstens E (2012) Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol 132(7):1886-91.
Alves-Filho JC, Pålsson-McDermott EM (2016) Pyruvate Kinase M2: A Potential Target for Regulating Inflammation. Front Immunol 7:145.
Anand P, Springall DR, Blank MA, Sellu D, Polak JM, Bloom SR (1991) Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis. Br J Dermatol 124(6):547-9.
Atherton DJ (2003) Topical corticosteroids in atopic dermatitis. BMJ 327(7421):942-3.
Auriemma M, Vianale G, Amerio P, Reale M (2013) Cytokines and T cells in atopic dermatitis. Eur Cytokine Netw 24(1):37-44.
Bach FH (2005) Heme oxygenase-1: a therapeutic amplification funnel. FASEB J 19(10):1216-9.
Baell J, Congreve M, Leeson P, Abad-Zapatero C (2013) Ask the experts: past, present and future of the rule of five. Future Med Chem 5(7):745-52.
Baldessari D, Mione M (2008) How to create the vascular tree? (Latest) help from the zebrafish. Pharmacol Ther 118(2):206-30.
Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol 12(8):715-23.
Bertolini A, Ottani A, Sandrini M (2002) Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks. Curr Med Chem 9(10):1033-43.
Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL (2012) Quantifying the chemical beauty of drugs. Nat Chem 4(2):90-8.
Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2013) Marine natural products. Nat Prod Rep 30(2):237-323.
Boguniewicz M, Leung DY (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242(1):233-46.
Borer RA, Lehner CF, Eppenberger HM, Nigg EA (1989) Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 56(3):379-90.
Bosma-den Boer MM, van Wetten ML, Pruimboom L (2012) Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. Nutr Metab 9(1):32.
Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y, Liao H, Northstone K, Henderson J, Alizadehfar R, Ben-Shoshan M, Morgan K, Roberts G, Masthoff LJ, Pasmans SG, van den Akker PC, Wijmenga C, Hourihane JO, Palmer CN, Lack G, Clarke A, Hull PR, Irvine AD, McLean WH (2011) Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 127(3):661-7.
Chan CC, Liou CJ, Xu PY, Shen JJ, Kuo ML, Len WB, Chang LE, Huang WC (2013) Effect of dehydroepiandrosterone on atopic dermatitis-like skin lesions induced by 1-chloro-2,4-dinitrobenzene in mouse. J Dermatol Sci 72(2):149-57.
Chen SC, Chien YC, Pan CH, Sheu JH, Chen CY, Wu CH (2014) Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a Lewis lung carcinoma-bearing tumor model in C57BL/6J mice. Mar Drugs 12(1):196-213.
Chen T, Zhang RH, He SC, Xu QY, Ma L, Wang GC, Qiu N, Peng F, Chen JY, Qiu JX, Peng AH, Chen LJ (2012) Synthesis and antiangiogenic activity of novel gambogic acid derivatives. Molecules 17(6):6249-68.
Chen W, Li J, Qu H, Song Z, Yang Z, Huo J, Jiang H, Huang Q, Huo M, Liu B, Zhang Q (2013) The melanocortin 1 receptor (MC1R) inhibits the inflammatory response in Raw 264.7 cells and atopic dermatitis (AD) mouse model. Mol Biol Rep 40(2):1987-96.
Cheng J, Yang L, Kumar V, Agarwal P (2014) Systematic evaluation of connectivity map for disease indications. Genome Med 6(12):540.
Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, Guy RH, Macgowan AL, Tazi-Ahnini R, Ward SJ (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129(8):1892-908.
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860-7.
Dahiya Y, Pandey RK, Bhatt KH, Sodhi A (2010) Role of prostaglandin E2 in peptidoglycan mediated iNOS expression in mouse peritoneal macrophages in vitro. FEBS Lett 584(19):4227-32.
Desnick RJ, Schuchman EH (2002) Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet 3(12):954-66.
Genovese A, Detoraki A, Granata F, Galdiero MR, Spadaro G, Marone G (2012) Angiogenesis, lymphangiogenesis and atopic dermatitis. Chem Immunol Allergy 96:50-60.
Falini B, Bolli N, Liso A, Martelli MP, Mannucci R, Pileri S, Nicoletti I (2009) Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia 23(10):1731-43.
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD (2015) Molecular docking and structure-based drug design strategies. Molecules 20(7):13384-421.
Futamura Y, Yamamoto K, Osada H (2017) Phenotypic screening meets natural products in drug discovery. Biosci Biotechnol Biochem 81(1):28-31.
Genovese A, Detoraki A, Granata F, Galdiero MR, Spadaro G, Marone G (2012) Angiogenesis, lymphangiogenesis and atopic dermatitis. Chem Immunol Allergy 96:50-60.
Gerwick WH, Moore BS (2012) Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem Biol 19(1):85-98.
Gittler JK, Krueger JG, Guttman-Yassky E (2013) Atopic dermatitis results in intrinsic barrier and immune abnormalities: implications for contact dermatitis. J Allergy Clin Immunol 131(2):300-13.
Glaser KB, Mayer AM (2009) A renaissance in marine pharmacology: from preclinical curiosity to clinical reality. Biochem Pharmacol 78(5):440-8.
Green D, Dong X (2015) Supporting itch: a new role for astrocytes in chronic itch. Nat Med 21(8):841-2.
Harper JI, Ahmed I, Barclay G, Lacour M, Hoeger P, Cork MJ, Finlay AY, Wilson NJ, Graham-Brown RA, Sowden JM, Beard AL, Sumner MJ, Berth-Jones J (2000) Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 142(1):52-8.
Hegde V, Hickerson RP, Nainamalai S, Campbell PA, Smith FJ, McLean WH, Pedrioli DM (2014) In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation. J Control Release 196:355-62.
He ZH, Zhou R, He MF, Lau CB, Yue GG, Ge W, But PP (2011) Anti-angiogenic effect and mechanism of rhein from Rhizoma Rhei. Phytomedicine 18(6):470-8.
Hingorani K, Szebeni A, Olson MO (2000) Mapping the functional domains of nucleolar protein B23. J Biol Chem 275(32):24451-7.
Homey B, Steinhoff M, Ruzicka T, Leung DY (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118(1):178-89.
Honda T, Egawa G, Grabbe S, Kabashima K (2013) Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J Invest Dermatol 133(2):303-15.
Imhof BA, Aurrand-Lions M (2006) Angiogenesis and inflammation face off. Nat Med 12(2):171-2.
Inagaki N, Igeta K, Kim JF, Nagao M, Shiraishi N, Nakamura N, Nagai H (2002) Involvement of unique mechanisms in the induction of scratching behavior in BALB/c mice by compound 48/80. Eur J Pharmacol 448(2-3):175-83.
Israelsen WJ, Vander Heiden MG (2015) Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol 43:43-51.
Itoh K, Mochizuki M, Ishii Y, Ishii T, Shibata T, Kawamoto Y, Kelly V, Sekizawa K, Uchida K, Yamamoto M (2004) Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). Mol Cell Biol 24(1):36-45.
Jean YH, Chen WF, Duh CY, Huang SY, Hsu CH, Lin CS, Sung CS, Chen IM, Wen ZH (2008) Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory and analgesic effects of the natural marine compound lemnalol from Formosan soft coral Lemnalia cervicorni. Eur J Pharmacol 578(2-3):323-31.
Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM (2014) Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17(1):109-18.
Jung BG, Cho SJ, Koh HB, Han DU, Lee BJ (2010) Fermented Maesil (Prunus mume) with probiotics inhibits development of atopic dermatitis-like skin lesions in NC/Nga mice. Vet Dermatol 21(2):184-91.
Jung MK, Hur DY, Song SB, Park Y, Kim TS, Bang SI, Kim S, Song HK, Park H, Cho DH (2010) Tannic acid and quercetin display a therapeutic effect in atopic dermatitis via suppression of angiogenesis and TARC expression in Nc/Nga mice. J Invest Dermatol 130(5):1459-63.
Kanno S, Kakuta M, Kitajima Y, Osanai Y, Kurauchi K, Ohtake T, Ujibe M, Uwai K, Takeshita M, Ishikawa M (2007) Inhibitory effect of trimidox on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages. J Pharmacol Sci 104(3):278-81.
Karki R, Jung MA, Kim KJ, Kim DW (2012) Inhibitory Effect of Nelumbo nucifera (Gaertn.) on the Development of Atopic Dermatitis-Like Skin Lesions in NC/Nga Mice. Evid Based Complement Alternat Med 2012:153568.
Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136(1):62-74.
Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell LE, McLean WH, Irvine AD (2015) Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol 135(4):930-5.e1.
Keller TH, Pichota A, Yin Z (2006) A practical view of 'druggability'. Curr Opin Chem Biol 10(4):357-61.
Kim BH, Lee YG, Lee J, Lee JY, Cho JY (2010) Regulatory effect of cinnamaldehyde on monocyte/macrophage-mediated inflammatory responses. Mediators Inflamm 2010:529359.
Kim TH, Kim GD, Jin YH, Park YS, Park CS (2012) Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice. Int Immunopharmacol 14(4):384-91.
Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30(1):16-34.
Lam HW, Lin HC, Lao SC, Gao JL, Hong SJ, Leong CW, Yue PY, Kwan YW, Leung AY, Wang YT, Lee SM (2008) The angiogenic effects of Angelica sinensis extract on HUVEC in vitro and zebrafish in vivo. J Cell Biochem 103(1):195-211.
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929-35.
Lamb J (2007) The Connectivity Map: a new tool for biomedical research. Nat Rev Cancer 7(1):54-60.
Landén NX, Li D, Ståhle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73(20):3861-85.
Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248(2):307-18.
Leal MC, Puga J, Serôdio J, Gomes NC, Calado R (2012) Trends in the discovery of new marine natural products from invertebrates over the last two decades--where and what are we bioprospecting? PLoS One 7(1):e30580.
Lee HS, Ka SO, Lee SM, Lee SI, Park JW, Park BH (2013) Overexpression of sirtuin 6 suppresses inflammatory responses and bone destruction in mice with collagen-induced arthritis. Arthritis Rheum 65(7):1776-85.
Lee SH, Lee YP, Kim SY, Jeong MS, Lee MJ, Kang HW, Jeong HJ, Kim DW, Sohn EJ, Jang SH, Kim YH, Kwon HJ, Cho SW, Park J, Eum WS, Choi SY (2008) Inhibition of LPS-induced cyclooxygenase 2 and nitric oxide production by transduced PEP-1-PTEN fusion protein in Raw 264.7 macrophage cells. Exp Mol Med 40(6):629-38.
Lele Z, Krone PH (1996) The zebrafish as a model system in developmental, toxicological and transgenic research. Biotechnol Adv 14(1):57-72.
Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA (2004) New insights into atopic dermatitis. J Clin Invest 113(5):651-7.
Lin SW, Huang SC, Kuo HM, Chen CH, Ma YL, Chu TH, Bee YS, Wang EM, Wu CY, Sung PJ, Wen ZH, Wu DC, Sheu JH, Tai MH (2015) Coral-derived compound WA-25 inhibits angiogenesis by attenuating the VEGF/VEGFR2 signaling pathway. Mar Drugs 13(2):861-78.
Liu T, Han Q, Chen G, Huang Y, Zhao LX, Berta T, Gao YJ, Ji RR (2016) Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 157(4):806-17.
Luo J, Qi C, Xu W, Kamel-Reid S, Brandwein J, Chang H (2010) Cytoplasmic expression of nucleophosmin accurately predicts mutation in the nucleophosmin gene in patients with acute myeloid leukemia and normal karyotype. Am J Clin Pathol 133(1):34-40.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677-86.
Marsella R, Olivry T, Carlotti DN; International Task Force on Canine Atopic Dermatitis (2011) Current evidence of skin barrier dysfunction in human and canine atopic dermatitis. Vet Dermatol 22(3):239-48.
Martin L, Pingle SC, Hallam DM, Rybak LP, Ramkumar V (2006) Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2. J Pharmacol Exp Ther 316(1):71-8.
Ming M, Zhao B, Shea CR, Shah P, Qiang L, White SR, Sims DM, He YY (2015) Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge. J Allergy Clin Immunol 135(4):936-45.e4.
Mirzapoiazova T, Kolosova IA, Moreno L, Sammani S, Garcia JG, Verin AD (2008) Suppression of endotoxin-induced inflammation by taxol. Eur Respir J 30(3):429-35.
Montaser R, Luesch H (2011) Marine natural products: a new wave of drugs? Future Med Chem 3(12):1475-89.
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958-69.
Mueller K (2013) Inflammation's yin-yang. Science 339(6116):155.
Naik E, Dixit VM (2011) Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 208(3):417-20.
Nakai K, Yoneda K, Hosokawa Y, Moriue T, Presland RB, Fallon PG, Kabashima K, Kosaka H, Kubota Y (2012) Reduced expression of epidermal growth factor receptor, E-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies. Am J Pathol 181(3):969-77.
Nawa Y, Kawahara K, Tancharoen S, Meng X, Sameshima H, Ito T, Masuda Y, Imaizumi H, Hashiguchi T, Maruyama I (2009) Nucleophosmin may act as an alarmin: implications for severe sepsis. J Leukoc Biol 86(3):645-53.
Newman DJ, Cragg GM (2004) Marine natural products and related compounds in clinical and advanced preclinical trials. J Nat Prod 67(8):1216-38.
Nguyen A, Hoang V, Laquer V, Kelly KM (2009) Angiogenesis in cutaneous disease: part I. J Am Acad Dermatol 61(6):921-42.
Noda S, Krueger JG, Guttman-Yassky E (2015) The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 135(2):324-36.
Oaklander AL (2011) Neuropathic itch. Semin Cutan Med Surg 30:87-92.
Omata N, Tsukahara H, Ito S, Ohshima Y, Yasutomi M, Yamada A, Jiang M, Hiraoka M, Nambu M, Deguchi Y, Mayumi M (2001) Increased oxidative stress in childhood atopic dermatitis. Life Sci 69(2):223-8.
Otterbein LE, Choi AM (2000) Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279(6):L1029-37.
Orosz F, Oláh J, Ovádi J (2006) Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life 58(12):703-15.
Park CM, Park JY, Noh KH, Shin JH, Song YS (2011) Taraxacum officinale Weber extracts inhibit LPS-induced oxidative stress and nitric oxide production via the NF-κB modulation in RAW 264.7 cells. J Ethnopharmacol 133(2):834-42.
Park SY, Lee SW, Baek SH, Lee SJ, Lee WS, Rhim BY, Hong KW, Kim CD (2011) Induction of heme oxygenase-1 expression by cilostazol contributes to its anti-inflammatory effects in J774 murine macrophages. Immunol Lett 136(2):138-45.
Park YD, Lyou YJ, Yang JM (2007) Two-dimensional electrophoresis analyses of atopic dermatitis and the chances to detect new candidate proteins by the variations in immobilized pH gradient strips. J Dermatol Sci 47(1):9-17.
Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, Dormont D, Gras G (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142(3):481-9.
Potenzieri C, Undem BJ (2012) Basic mechanisms of itch. Clin Exp Allergy 42(1):8-19.
Poulsen NA, Andersen V, Møller JC, Møller HS, Jessen F, Purup S, Larsen LB (2012) Comparative analysis of inflamed and non-inflamed colon biopsies reveals strong proteomic inflammation profile in patients with ulcerative colitis. BMC Gastroenterol 12:76.
Qi W, Shakalya K, Stejskal A, Goldman A, Beeck S, Cooke L, Mahadevan D (2008) NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells. Oncogene 27(30):4210-20.
Qui M, Paromov VM, Yang H, Smith M, Stone WL (2006) Inhibition of inducible Nitric Oxide Synthase by a mustard gas analog in murine macrophages. BMC Cell Biol 7:39.
Raghunath M, Sy Wong Y, Farooq M, Ge R (2009) Pharmacologically induced angiogenesis in transgenic zebrafish. Biochem Biophys Res Commun 378(4):766-71.
Rahman MF, Nandi AK, Kabir S, Kamal M, Basher MS, Banu LA (2015) Topical Tacrolimus versus Hydrocortisone on Atopic Dermatitis in Paediatric Patients: A Randomized Controlled Trial. Mymensingh Med J 24(3):457-63.
Reich K (2012) The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol 26 Suppl 2:3-11.
Rishton GM (2008) Natural products as a robust source of new drugs and drug leads: past successes and present day issues. Am J Cardiol 101(10A):43D-49D.
Rocha J, Peixe L, Gomes NC, Calado R (2011) Cnidarians as a source of new marine bioactive compounds--an overview of the last decade and future steps for bioprospecting. Mar Drugs 9(10):1860-86.
Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS (2001) Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci 947:271-92.
Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86(2):583-650.
Ryu KR, Choi JY, Chung S, Kim DH (2011) Anti-scratching behavioral effect of the essential oil and phytol isolated from Artemisia princeps Pamp. in mice. Planta Med 77(1):22-6.
Sandilands A, Sutherland C, Irvine AD, McLean WH (2009) Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 122(Pt 9):1285-94.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 64(5):625-39.
Sirota M, Dudley JT, Kim J, Chiang AP, Morgan AA, Sweet-Cordero A, Sage J, Butte AJ (2011) Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci Transl Med 3(96):96ra77.
Sluimer JC, Daemen MJ (2009) Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 218(1):7-29.
Standl M, Tesch F, Baurecht H, Rodríguez E, Müller-Nurasyid M, Gieger C, Peters A, Wang-Sattler R, Prehn C, Adamski J, Kronenberg F, Schulz H, Koletzko S, Schikowski T, von Berg A, Lehmann I, Berdel D, Heinrich J, Schmitt J, Weidinger S (2017) Association of Atopic Dermatitis with Cardiovascular Risk Factors and Diseases. J Invest Dermatol 137(5):1074-1081.
Sulzberger MB, Witten VH (1952) The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 19(2):101-2.
Sumiyoshi K, Nakao A, Ushio H, Mitsuishi K, Okumura K, Tsuboi R, Ra C, Ogawa H (2002) Transforming growth factor-beta1 suppresses atopic dermatitis-like skin lesions in NC/Nga mice. Clin Exp Allergy 32(2):309-14.
Sun J, Zhao Y, Hu J (2013) Curcumin inhibits imiquimod-induced psoriasis-like inflammation by inhibiting IL-1beta and IL-6 production in mice. PLoS One 8(6):e67078.
Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10(7):507-19.
Szekanecz Z, Koch AE (2007) Mechanisms of Disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol 3(11):635-43.
Tabas I, Glass CK (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339(6116):166-72.
Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107(1):7-11.
Tran TC, Sneed B, Haider J, Blavo D, White A, Aiyejorun T, Baranowski TC, Rubinstein AL, Doan TN, Dingledine R, Sandberg EM (2007) Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish. Cancer Res 67(23):11386-92.
Tripathi S, Bruch D, Kittur DS (2008) Ginger extract inhibits LPS induced macrophage activation and function. BMC Complement Altern Med 8:1.
Valdman-Grinshpoun Y, Ben-Amitai D, Zvulunov A (2012) Barrier-restoring therapies in atopic dermatitis: current approaches and future perspectives. Dermatol Res Pract 2012:923134.
van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182(9):5836-45.
Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, de Prost Y; Flare Reduction in Eczema with Elidel (Children) Multicenter Investigator Study Group (2002) Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 110(1 Pt 1):e2.
Walters WP (2012) Going further than Lipinski's rule in drug design. Expert Opin Drug Discov 7(2):99-107.
Wang F, Wang K, Xu W, Zhao S, Ye D, Wang Y, Xu Y, Zhou L, Chu Y, Zhang C, Qin X, Yang P, Yu H (2017) SIRT5 Desuccinylates and Activates Pyruvate Kinase M2 to Block Macrophage IL-1β Production and to Prevent DSS-Induced Colitis in Mice. Cell Rep 19(11):2331-2344.
Wang YC, Hung HC, Feng CW, Huang SY, Chen CH, Lin YY, Chen YC, Yang SN, Su JH, Sheu JH, Wen ZH (2015) Dihydroaustrasulfone Alcohol (WA-25) Impedes Macrophage Foam Cell Formation by Regulating the Transforming Growth Factor-β1 Pathway. Int J Mol Sci 16(5):10507-25.
Wei WC, Sung PJ, Duh CY, Chen BW, Sheu JH, Yang NS (2013) Anti-inflammatory activities of natural products isolated from soft corals of Taiwan between 2008 and 2012. Mar Drugs 11(10):4083-126.
Wen ZH, Chao CH, Wu MH, Sheu JH (2010) A neuroprotective sulfone of marine origin and the in vivo anti-inflammatory activity of an analogue. Eur J Med Chem 45(12):5998-6004.
Williams DH (1938) Skin Temperature Reaction to Histamine in Atopic Dermatitis (Disseminated Neurodermatitis). J Invest Dermatol 1:119-29
Wishart DS (2005) Bioinformatics in drug development and assessment. Drug Metab Rev 37(2):279-310.
Wona SJ, Yen CH, Hsieh HW, Chang SW, Lin CN, Huang CY, Su CL (2017) Using connectivity map to identify natural lignan justicidin A as a NF-B suppressor. J Funct Foods 34:68–76
Wu GJ, Chen WF, Hung HC, Jean YH, Sung CS, Chakraborty C, Lee HP, Chen NF, Wen ZH (2011) Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: new insights into neuroprotection. Brain Res 1384:42-50.
Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 18;269(7):4705-8.
Xia X (2017) Bioinformatics and Drug Discovery. Curr Top Med Chem 17(15):1709-1726.
Yáñez M, Gil-Longo J, Campos-Toimil M (2012) Calcium binding proteins. Adv Exp Med Biol 740:461-82.
Yang P, Li Z, Li H, Lu Y, Wu H, Li Z (2015) Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer. Cell Signal 27(7):1525-32.
Yarbrough KB, Neuhaus KJ, Simpson EL (2013) The effects of treatment on itch in atopic dermatitis. Dermatol Ther 26(2):110-9.
Yu J, Silva JM (2018) Bayesian Network to Infer Drug-Induced Apoptosis Circuits from Connectivity Map Data. Methods Mol Biol 1783:361-378.
Zirwas MJ, Barkovic S (2017) Anti-Pruritic Efficacy of Itch Relief Lotion and Cream in Patients With Atopic History: Comparison With Hydrocortisone Cream. J Drugs Dermatol 16(3):243-247.
Zheng W, Thorne N, McKew JC (2013) Phenotypic screens as a renewed approach for drug discovery. Drug Discov Today 18(21-22):1067-73.
Zhivkova ZD, Russeva VN (2000) Binding of kebuzone to human serum albumin studied by high performance liquid affinity chromatography. Arzneimittelforschung 50(3):272-5.