References

1. Schmidt, B.M.; Ribnicky, D.M.; Lipsky, P.E.; Raskin, I. Revisiting the ancient concept of botanical therapeutics. Nat. Chem. Biol. 2007, 3, 360–366.
2. Veeresham, C. Natural products derived from plants as a source of drugs. J. Adv. Pharm. Technol. Res. 2012, 3, 200–201.
3. Yatoo, M.I.; Gopalakrishnan, A.; Saxena, A.; Parray, O.R.; Tufani, N.A.; Chakraborty, S.; Tiwari, R.; Dhama, K.; Iqbal, H.M.N. Anti-inflammatory drugs and herbs with special emphasis on herbal medicines for countering inflammatory diseases and disorders—A review. Recent Pat. Inflamm. Allergy Drug Discov. 2018, 12, 39–58.
4. Arulselvan, P.; Fard, M.T.; Tan, W.S.; Gothai, S.; Fakurazi, S.; Norhaizan, M.E.; Kumar, S.S. Role of antioxidants and natural products in inflammation. Oxidative Med. Cell. Longev. 2016, 2016, 5276130.
5. Zhu, F.; Du, B.; Xu, B. Anti-Inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review. Crit. Rev. Food Sci. Nutr. 2018, 58, 1260–1270.
6. Hnatyszyn, A.; Hryhorowicz, S.; Kaczmarek-Rys, M.; Lis, E.; Slomski, R.; Scott, R.J.; Plawski, A. Colorectal carcinoma in the course of inflammatory bowel diseases. Hered. Cancer Clin. Pract. 2019, 17, 18.
7. Podolsky, D.K. Inflammatory bowel disease. N. Engl. J. Med. 2002, 347, 417–429.
8. Kalla, R.; Ventham, N.T.; Satsangi, J.; Arnott, I.D. Crohn’s disease. BMJ 2014, 349, g6670.
9. Ordas, I.; Eckmann, L.; Talamini, M.; Baumgart, D.C.; Sandborn, W.J. Ulcerative colitis. Lancet 2012, 380, 1606–1619.
10. Kaplan, G.G. The global burden of ibd: From 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 720–727.
11. Rogler, G. Gastrointestinal and liver adverse effects of drugs used for treating ibd. Best Pract. Res. Clin. Gastroenterol. 2010, 24, 157–165.
12. Neurath, M.F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 2014, 14, 329–342.
13. Yu, H.; MacIsaac, D.; Wong, J.J.; Sellers, Z.M.; Wren, A.A.; Bensen, R.; Kin, C.; Park, K.T. Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Aliment. Pharmacol. Ther. 2018, 47, 364–370.
14. Lamb, C.A.; Kennedy, N.A.; Raine, T.; Hendy, P.A.; Smith, P.J.; Limdi, J.K.; Hayee, B.; Lomer, M.C.E.; Parkes, G.C.; Selinger, C.; et al. British society of gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019, 68, s1–s106.
15. Strober, W.; Fuss, I.J.; Blumberg, R.S. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 2002, 20, 495–549.
16. Bevivino, G.; Monteleone, G. Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 2018, 12, 907–915.
17. Salas, A.; Hernandez-Rocha, C.; Duijvestein, M.; Faubion, W.; McGovern, D.; Vermeire, S.; Vetrano, S.; Vande Casteele, N. Jak-stat pathway targeting for the treatment of inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 323–337.
18. Schreiner, P.; Neurath, M.F.; Ng, S.C.; El-Omar, E.M.; Sharara, A.I.; Kobayashi, T.; Hisamatsu, T.; Hibi, T.; Rogler, G. Mechanism-Based treatment strategies for ibd: Cytokines, cell adhesion molecules, jak inhibitors, gut flora, and more. Inflamm. Intest. Dis. 2019, 4, 79–96.
19. Coskun, M.; Salem, M.; Pedersen, J.; Nielsen, O.H. Involvement of jak/stat signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res. 2013, 76, 1–8.
20. Soendergaard, C.; Bergenheim, F.H.; Bjerrum, J.T.; Nielsen, O.H. Targeting jak-stat signal transduction in ibd. Pharmacol. Ther. 2018, 192, 100–111.
21. Flamant, M.; Rigaill, J.; Paul, S.; Roblin, X. Advances in the development of janus kinase inhibitors in inflammatory bowel disease: Future prospects. Drugs 2017, 77, 1057–1068.
22. Kasembeli, M.M.; Bharadwaj, U.; Robinson, P.; Tweardy, D.J. Contribution of stat3 to inflammatory and fibrotic diseases and prospects for its targeting for treatment. Int. J. Mol. Sci. 2018, 19, 2299.
23. Hur, S.J.; Kang, S.H.; Jung, H.S.; Kim, S.C.; Jeon, H.S.; Kim, I.H.; Lee, J.D. Review of natural products actions on cytokines in inflammatory bowel disease. Nutr. Res. 2012, 32, 801–816.
24. Farzaei, M.H.; Bahramsoltani, R.; Abdolghaffari, A.H.; Sodagari, H.R.; Esfahani, S.A.; Rezaei, N. A mechanistic review on plant-derived natural compounds as dietary supplements for prevention of inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 2016, 10, 745–758.
25. Hossen, I.; Hua, W.; Ting, L.; Mehmood, A.; Jingyi, S.; Duoxia, X.; Yanping, C.; Hongqing, W.; Zhipeng, G.; Kaiqi, Z.; et al. Phytochemicals and inflammatory bowel disease: A review. Crit. Rev. Food Sci. Nutr. 2020, 60, 1321–1345.
26. Cao, S.Y.; Ye, S.J.; Wang, W.W.; Wang, B.; Zhang, T.; Pu, Y.Q. Progress in active compounds effective on ulcerative colitis from chinese medicines. Chin. J. Nat. Med. 2019, 17, 81–102.
27. Favoino, E.; Prete, M.; Catacchio, G.; Ruscitti, P.; Navarini, L.; Giacomelli, R.; Perosa, F. Working and safety profiles of jak/stat signaling inhibitors. Are these small molecules also smart? Autoimmun. Rev. 2021, 20, 102750.
28. Banerjee, S.; Biehl, A.; Gadina, M.; Hasni, S.; Schwartz, D.M. Jak-Stat signaling as a target for inflammatory and autoimmune diseases: Current and future prospects. Drugs 2017, 77, 521–546.
29. Sanchez-Munoz, F.; Dominguez-Lopez, A.; Yamamoto-Furusho, J.K. Role of cytokines in inflammatory bowel disease. World J. Gastroenterol. 2008, 14, 4280–4288.
30. Mitsuyama, K.; Suzuki, A.; Tomiyasu, N.; Takaki, K.; Toyonaga, A.; Sata, M. Transcription factor-targeted therapies in inflammatory bowel disease. Digestion 2001, 63 (Suppl. 1), 68–72.
31. O’Shea, J.J.; Pesu, M.; Borie, D.C.; Changelian, P.S. A new modality for immunosuppression: Targeting the jak/stat pathway. Nat. Rev. Drug Discov. 2004, 3, 555–564.
32. Menet, C.J.; Rompaey, L.V.; Geney, R. Advances in the discovery of selective jak inhibitors. Prog. Med. Chem. 2013, 52, 153–223.
33. Galien, R. Janus kinases in inflammatory bowel disease: Four kinases for multiple purposes. Pharmacol. Rep. PR 2016, 68, 789–796.
34. Hedl, M.; Proctor, D.D.; Abraham, C. Jak2 disease-risk variants are gain of function and jak signaling threshold determines innate receptor-induced proinflammatory cytokine secretion in macrophages. J. Immunol. 2016, 197, 3695–3704.
35. Roskoski, R., Jr. Janus kinase (jak) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol. Res. 2016, 111, 784–803.
36. Morris, R.; Kershaw, N.J.; Babon, J.J. The molecular details of cytokine signaling via the jak/stat pathway. Protein Sci. Publ. Protein Soc. 2018, 27, 1984–2009.
37. Johnston, J.A.; Kawamura, M.; Kirken, R.A.; Chen, Y.Q.; Blake, T.B.; Shibuya, K.; Ortaldo, J.R.; McVicar, D.W.; O’Shea, J.J. Phosphorylation and activation of the jak-3 janus kinase in response to interleukin-2. Nature 1994, 370, 151–153.
38. Rochman, Y.; Spolski, R.; Leonard, W.J. New insights into the regulation of t cells by gamma(c) family cytokines. Nat. Rev. Immunol. 2009, 9, 480–490.
39. Brizzi, M.F.; Aronica, M.G.; Rosso, A.; Bagnara, G.P.; Yarden, Y.; Pegoraro, L. Granulocyte-Macrophage colony-stimulating factor stimulates jak2 signaling pathway and rapidly activates p93fes, stat1 p91, and stat3 p92 in polymorphonuclear leukocytes. J. Biol. Chem. 1996, 271, 3562–3567.
40. Han, X.; Uchida, K.; Jurickova, I.; Koch, D.; Willson, T.; Samson, C.; Bonkowski, E.; Trauernicht, A.; Kim, M.O.; Tomer, G.; et al. Granulocyte-Macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn’s disease. Gastroenterology 2009, 136, 1261–1271.
41. Hyams, J.S.; Fitzgerald, J.E.; Treem, W.R.; Wyzga, N.; Kreutzer, D.L. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 1993, 104, 1285–1292.
42. Guschin, D.; Rogers, N.; Briscoe, J.; Witthuhn, B.; Watling, D.; Horn, F.; Pellegrini, S.; Yasukawa, K.; Heinrich, P.; Stark, G.R.; et al. A major role for the protein tyrosine kinase jak1 in the jak/stat signal transduction pathway in response to interleukin-6. EMBO J. 1995, 14, 1421–1429.
43. Liu, X.; Jones, G.W.; Choy, E.H.; Jones, S.A. The biology behind interleukin-6 targeted interventions. Curr. Opin. Rheumatol. 2016, 28, 152–160.
44. Bacon, C.M.; McVicar, D.W.; Ortaldo, J.R.; Rees, R.C.; O’Shea, J.J.; Johnston, J.A. Interleukin 12 (il-12) induces tyrosine phosphorylation of jak2 and tyk2: Differential use of janus family tyrosine kinases by il-2 and il-12. J. Exp. Med. 1995, 181, 399–404.
45. Kastelein, R.A.; Hunter, C.A.; Cua, D.J. Discovery and biology of il-23 and il-27: Related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 2007, 25, 221–242.
46. Schindler, C.; Plumlee, C. Inteferons pen the jak-stat pathway. Semin. Cell Dev. Biol. 2008, 19, 311–318.
47. Marafini, I.; Sedda, S.; Dinallo, V.; Monteleone, G. Inflammatory cytokines: From discoveries to therapies in ibd. Expert Opin. Biol. Ther. 2019, 19, 1207–1217.
48. Tran, V.; Shammas, R.M.; Sauk, J.S.; Padua, D. Evaluating tofacitinib citrate in the treatment of moderate-to-severe active ulcerative colitis: Design, development and positioning of therapy. Clin. Exp. Gastroenterol. 2019, 12, 179–191.
49. Karaman, M.W.; Herrgard, S.; Treiber, D.K.; Gallant, P.; Atteridge, C.E.; Campbell, B.T.; Chan, K.W.; Ciceri, P.; Davis, M.I.; Edeen, P.T.; et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2008, 26, 127–132.
50. Bousoik, E.; Montazeri Aliabadi, H. “Do we know jack” about jak? A closer look at jak/stat signaling pathway. Front. Oncol. 2018, 8, 287.
51. Ito, M.; Yamazaki, S.; Yamagami, K.; Kuno, M.; Morita, Y.; Okuma, K.; Nakamura, K.; Chida, N.; Inami, M.; Inoue, T.; et al. A novel jak inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. J. Pharmacol. Sci. 2017, 133, 25–33.
52. Sandborn, W.J.; Nguyen, D.D.; Beattie, D.T.; Brassil, P.; Krey, W.; Woo, J.; Situ, E.; Sana, R.; Sandvik, E.; Pulido-Rios, M.T.; et al. Development of gut-selective pan-janus kinase inhibitor td-1473 for ulcerative colitis: A translational medicine programme. J. Crohn’s Colitis 2020, 14, 1202–1213.
53. Van Rompaey, L.; Galien, R.; van der Aar, E.M.; Clement-Lacroix, P.; Nelles, L.; Smets, B.; Lepescheux, L.; Christophe, T.; Conrath, K.; Vandeghinste, N.; et al. Preclinical characterization of glpg0634, a selective inhibitor of jak1, for the treatment of inflammatory diseases. J. Immunol. 2013, 191, 3568–3577.
54. Parmentier, J.M.; Voss, J.; Graff, C.; Schwartz, A.; Argiriadi, M.; Friedman, M.; Camp, H.S.; Padley, R.J.; George, J.S.; Hyland, D.; et al. In vitro and in vivo characterization of the jak1 selectivity of upadacitinib (abt-494). BMC Rheumatol. 2018, 2, 23.
55. Clark, J.D.; Flanagan, M.E.; Telliez, J.B. Discovery and development of janus kinase (jak) inhibitors for inflammatory diseases. J. Med. Chem. 2014, 57, 5023–5038.
56. Mudter, J.; Weigmann, B.; Bartsch, B.; Kiesslich, R.; Strand, D.; Galle, P.R.; Lehr, H.A.; Schmidt, J.; Neurath, M.F. Activation pattern of signal transducers and activators of transcription (stat) factors in inflammatory bowel diseases. Am. J. Gastroenterol. 2005, 100, 64–72.
57. Miklossy, G.; Hilliard, T.S.; Turkson, J. Therapeutic modulators of stat signalling for human diseases. Nat. Rev. Drug Discov. 2013, 12, 611–629.
58. Schreiber, S.; Rosenstiel, P.; Hampe, J.; Nikolaus, S.; Groessner, B.; Schottelius, A.; Kuhbacher, T.; Hamling, J.; Folsch, U.R.; Seegert, D. Activation of signal transducer and activator of transcription (stat) 1 in human chronic inflammatory bowel disease. Gut 2002, 51, 379–385.
59. Azuma, Y.T.; Matsuo, Y.; Kuwamura, M.; Yancopoulos, G.D.; Valenzuela, D.M.; Murphy, A.J.; Nakajima, H.; Karow, M.; Takeuchi, T. Interleukin-19 protects mice from innate-mediated colonic inflammation. Inflamm. Bowel Dis. 2010, 16, 1017–1028.
60. Diegelmann, J.; Olszak, T.; Goke, B.; Blumberg, R.S.; Brand, S. A novel role for interleukin-27 (il-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (stat) protein signaling and induction of antibacterial and anti-inflammatory proteins. J. Biol. Chem. 2012, 287, 286–298.
61. Meraz, M.A.; White, J.M.; Sheehan, K.C.; Bach, E.A.; Rodig, S.J.; Dighe, A.S.; Kaplan, D.H.; Riley, J.K.; Greenlund, A.C.; Campbell, D.; et al. Targeted disruption of the stat1 gene in mice reveals unexpected physiologic specificity in the jak-stat signaling pathway. Cell 1996, 84, 431–442.
62. Kisseleva, T.; Bhattacharya, S.; Braunstein, J.; Schindler, C.W. Signaling through the jak/stat pathway, recent advances and future challenges. Gene 2002, 285, 1–24.
63. Steen, H.C.; Gamero, A.M. Stat2 phosphorylation and signaling. Jak Stat 2013, 2, e25790.
64. Schwartz, D.M.; Kanno, Y.; Villarino, A.; Ward, M.; Gadina, M.; O’Shea, J.J. Jak inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017, 17, 78.
65. Wu, F.; Dassopoulos, T.; Cope, L.; Maitra, A.; Brant, S.R.; Harris, M.L.; Bayless, T.M.; Parmigiani, G.; Chakravarti, S. Genome-Wide gene expression differences in Crohn’s disease and ulcerative colitis from endoscopic pinch biopsies: Insights into distinctive pathogenesis. Inflamm. Bowel Dis. 2007, 13, 807–821.
66. Musso, A.; Dentelli, P.; Carlino, A.; Chiusa, L.; Repici, A.; Sturm, A.; Fiocchi, C.; Rizzetto, M.; Pegoraro, L.; Sategna-Guidetti, C.; et al. Signal transducers and activators of transcription 3 signaling pathway: An essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm. Bowel Dis. 2005, 11, 91–98.
67. Bai, A.; Hu, P.; Chen, J.; Song, X.; Chen, W.; Peng, W.; Zeng, Z.; Gao, X. Blockade of stat3 by antisense oligonucleotide in tnbs-induced murine colitis. Int. J. Colorectal Dis. 2007, 22, 625–635.
68. Han, X.; Sosnowska, D.; Bonkowski, E.L.; Denson, L.A. Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Gastroenterology 2005, 129, 185–203.
69. Atreya, R.; Mudter, J.; Finotto, S.; Mullberg, J.; Jostock, T.; Wirtz, S.; Schutz, M.; Bartsch, B.; Holtmann, M.; Becker, C.; et al. Blockade of interleukin 6 trans signaling suppresses t-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in crohn disease and experimental colitis in vivo. Nat. Med. 2000, 6, 583–588.
70. Brand, S.; Beigel, F.; Olszak, T.; Zitzmann, K.; Eichhorst, S.T.; Otte, J.M.; Diepolder, H.; Marquardt, A.; Jagla, W.; Popp, A.; et al. Il-22 is increased in active crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J. Physiol. Gastrointest. Liver Physiol. 2006, 290, G827–G838.
71. Lindemans, C.A.; Calafiore, M.; Mertelsmann, A.M.; O’Connor, M.H.; Dudakov, J.A.; Jenq, R.R.; Velardi, E.; Young, L.F.; Smith, O.M.; Lawrence, G.; et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 2015, 528, 560–564.
72. Sugimoto, K.; Ogawa, A.; Mizoguchi, E.; Shimomura, Y.; Andoh, A.; Bhan, A.K.; Blumberg, R.S.; Xavier, R.J.; Mizoguchi, A. Il-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Investig. 2008, 118, 534–544.
73. Alonzi, T.; Newton, I.P.; Bryce, P.J.; Di Carlo, E.; Lattanzio, G.; Tripodi, M.; Musiani, P.; Poli, V. Induced somatic inactivation of stat3 in mice triggers the development of a fulminant form of enterocolitis. Cytokine 2004, 26, 45–56.
74. Takeda, K.; Clausen, B.E.; Kaisho, T.; Tsujimura, T.; Terada, N.; Forster, I.; Akira, S. Enhanced th1 activity and development of chronic enterocolitis in mice devoid of stat3 in macrophages and neutrophils. Immunity 1999, 10, 39–49.
75. Hunter, C.A. New il-12-family members: Il-23 and il-27, cytokines with divergent functions. Nat. Rev. Immunol. 2005, 5, 521–531.
76. Zundler, S.; Neurath, M.F. Immunopathogenesis of inflammatory bowel diseases: Functional role of t cells and t cell homing. Clin. Exp. Rheumatol. 2015, 33, S19–S28.
77. Zundler, S.; Neurath, M.F. Interleukin-12: Functional activities and implications for disease. Cytokine Growth Factor Rev. 2015, 26, 559–568.
78. Diaz-Gallo, L.M.; Palomino-Morales, R.J.; Gomez-Garcia, M.; Cardena, C.; Rodrigo, L.; Nieto, A.; Alcain, G.; Cueto, I.; Lopez-Nevot, M.A.; Martin, J. Stat4 gene influences genetic predisposition to ulcerative colitis but not crohn’s disease in the spanish population: A replication study. Hum. Immunol. 2010, 71, 515–519.
79. Pang, Y.H.; Zheng, C.Q.; Yang, X.Z.; Zhang, W.J. Increased expression and activation of il-12-induced stat4 signaling in the mucosa of ulcerative colitis patients. Cell. Immunol. 2007, 248, 115–120.
80. Simpson, S.J.; Shah, S.; Comiskey, M.; de Jong, Y.P.; Wang, B.; Mizoguchi, E.; Bhan, A.K.; Terhorst, C. T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/signal transducer and activator of transcription (stat)-4 pathway, but is not conditional on interferon gamma expression by t cells. J. Exp. Med. 1998, 187, 1225–1234.
81. Wirtz, S.; Finotto, S.; Kanzler, S.; Lohse, A.W.; Blessing, M.; Lehr, H.A.; Galle, P.R.; Neurath, M.F. Cutting edge: Chronic intestinal inflammation in stat-4 transgenic mice: Characterization of disease and adoptive transfer by tnf-plus ifn-gamma-producing cd4+ t cells that respond to bacterial antigens. J. Immunol. 1999, 162, 1884–1888.
82. Arai, K.I.; Lee, F.; Miyajima, A.; Miyatake, S.; Arai, N.; Yokota, T. Cytokines: Coordinators of immune and inflammatory responses. Annu. Rev. Biochem. 1990, 59, 783–836.
83. Gilbert, S.; Nivarthi, H.; Mayhew, C.N.; Lo, Y.H.; Noah, T.K.; Vallance, J.; Rulicke, T.; Muller, M.; Jegga, A.G.; Tang, W.; et al. Activated stat5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration. Stem Cell Rep. 2015, 4, 209–225.
84. Burchill, M.A.; Yang, J.; Vogtenhuber, C.; Blazar, B.R.; Farrar, M.A. Il-2 receptor beta-dependent stat5 activation is required for the development of foxp3+ regulatory t cells. J. Immunol. 2007, 178, 280–290.
85. Fantini, M.C.; Becker, C.; Tubbe, I.; Nikolaev, A.; Lehr, H.A.; Galle, P.; Neurath, M.F. Transforming growth factor beta induced foxp3+ regulatory t cells suppress th1 mediated experimental colitis. Gut 2006, 55, 671–680.
86. Rosen, M.J.; Chaturvedi, R.; Washington, M.K.; Kuhnhein, L.A.; Moore, P.D.; Coggeshall, S.S.; McDonough, E.M.; Weitkamp, J.H.; Singh, A.B.; Coburn, L.A.; et al. Stat6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and th2-inducing cytokines. J. Immunol. 2013, 190, 1849–1858.
87. Van Kampen, C.; Gauldie, J.; Collins, S.M. Proinflammatory properties of il-4 in the intestinal microenvironment. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G111–G117.
88. Li, Y.; Deuring, J.; Peppelenbosch, M.P.; Kuipers, E.J.; de Haar, C.; van der Woude, C.J. Stat1, stat6 and adenosine 3′,5′-cyclic monophosphate (camp) signaling drive socs3 expression in inactive ulcerative colitis. Mol. Med. 2012, 18, 1412–1419.
89. Rosen, M.J.; Frey, M.R.; Washington, M.K.; Chaturvedi, R.; Kuhnhein, L.A.; Matta, P.; Revetta, F.L.; Wilson, K.T.; Polk, D.B. Stat6 activation in ulcerative colitis: A new target for prevention of il-13-induced colon epithelial cell dysfunction. Inflamm. Bowel Dis. 2011, 17, 2224–2234.
90. Lai, P.S.; Rosa, D.A.; Magdy Ali, A.; Gomez-Biagi, R.F.; Ball, D.P.; Shouksmith, A.E.; Gunning, P.T. A stat inhibitor patent review: Progress since 2011. Expert Opin. Ther. Pat. 2015, 25, 1397–1421.
91. Wu, X.; Guo, W.; Wu, L.; Gu, Y.; Gu, L.; Xu, S.; Wu, X.; Shen, Y.; Ke, Y.; Tan, R.; et al. Selective sequestration of stat1 in the cytoplasm via phosphorylated shp-2 ameliorates murine experimental colitis. J. Immunol. 2012, 189, 3497–3507.
92. Turkson, J.; Ryan, D.; Kim, J.S.; Zhang, Y.; Chen, Z.; Haura, E.; Laudano, A.; Sebti, S.; Hamilton, A.D.; Jove, R. Phosphotyrosyl peptides block stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 2001, 276, 45443–45455.
93. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Zoheir, K.M.A.; Bakheet, S.A.; Alsaad, A.M.S.; Al-Shabanah, O.A.; Attia, S.M. Sta-21, a stat-3 inhibitor, attenuates the development and progression of inflammation in collagen antibody-induced arthritis. Immunobiology 2017, 222, 206–217.
94. Gavino, A.C.; Nahmod, K.; Bharadwaj, U.; Makedonas, G.; Tweardy, D.J. Stat3 inhibition prevents lung inflammation, remodeling, and accumulation of th2 and th17 cells in a murine asthma model. Allergy 2016, 71, 1684–1692.
95. Odate, S.; Veschi, V.; Yan, S.; Lam, N.; Woessner, R.; Thiele, C.J. Inhibition of stat3 with the generation 2.5 antisense oligonucleotide, azd9150, decreases neuroblastoma tumorigenicity and increases chemosensitivity. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2017, 23, 1771–1784.
96. Oh, D.Y.; Lee, S.H.; Han, S.W.; Kim, M.J.; Kim, T.M.; Kim, T.Y.; Heo, D.S.; Yuasa, M.; Yanagihara, Y.; Bang, Y.J. Phase i study of opb-31121, an oral stat3 inhibitor, in patients with advanced solid tumors. Cancer Res. Treat. 2015, 47, 607–615.
97. Sandborn, W.J.; Su, C.; Sands, B.E.; D’Haens, G.R.; Vermeire, S.; Schreiber, S.; Danese, S.; Feagan, B.G.; Reinisch, W.; Niezychowski, W.; et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2017, 376, 1723–1736.
98. Vermeire, S.; Schreiber, S.; Petryka, R.; Kuehbacher, T.; Hebuterne, X.; Roblin, X.; Klopocka, M.; Goldis, A.; Wisniewska-Jarosinska, M.; Baranovsky, A.; et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the fitzroy study): Results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017, 389, 266–275.
99. Ma, C.; Lee, J.K.; Mitra, A.R.; Teriaky, A.; Choudhary, D.; Nguyen, T.M.; Vande Casteele, N.; Khanna, R.; Panaccione, R.; Feagan, B.G.; et al. Systematic review with meta-analysis: Efficacy and safety of oral janus kinase inhibitors for inflammatory bowel disease. Aliment. Pharmacol. Ther. 2019, 50, 5–23.
100. Sands, B.E.; Sandborn, W.J.; Feagan, B.G.; Lichtenstein, G.R.; Zhang, H.; Strauss, R.; Szapary, P.; Johanns, J.; Panes, J.; Vermeire, S.; et al. Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: Results from a randomised, phase 2 study. J. Crohn’s Colitis 2018, 12, 1158–1169.
101. Sung, M.K.; Park, M.Y. Nutritional modulators of ulcerative colitis: Clinical efficacies and mechanistic view. World J. Gastroenterol. 2013, 19, 994–1004.
102. Shahidi, F.; Yeo, J. Bioactivities of phenolics by focusing on suppression of chronic diseases: A review. Int. J. Mol. Sci. 2018, 19, 1573.
103. Yahfoufi, N.; Alsadi, N.; Jambi, M.; Matar, C. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients 2018, 10, 1618.
104. Duvoix, A.; Blasius, R.; Delhalle, S.; Schnekenburger, M.; Morceau, F.; Henry, E.; Dicato, M.; Diederich, M. Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 2005, 223, 181–190.
105. Ashrafizadeh, M.; Rafiei, H.; Mohammadinejad, R.; Afshar, E.G.; Farkhondeh, T.; Samarghandian, S. Potential therapeutic effects of curcumin mediated by jak/stat signaling pathway: A review. Phytother. Res. PTR 2020, 34, 1745–1760.
106. Yang, J.Y.; Zhong, X.; Yum, H.W.; Lee, H.J.; Kundu, J.K.; Na, H.K.; Surh, Y.J. Curcumin inhibits stat3 signaling in the colon of dextran sulfate sodium-treated mice. J. Cancer Prev. 2013, 18, 186–191.
107. Bromberg, J.; Wang, T.C. Inflammation and cancer: Il-6 and stat3 complete the link. Cancer Cell 2009, 15, 79–80.
108. Zhao, H.M.; Xu, R.; Huang, X.Y.; Cheng, S.M.; Huang, M.F.; Yue, H.Y.; Wang, X.; Zou, Y.; Lu, A.P.; Liu, D.Y. Curcumin suppressed activation of dendritic cells via jak/stat/socs signal in mice with experimental colitis. Front. Pharmacol. 2016, 7, 455.
109. Bright, J.J. Curcumin and autoimmune disease. Adv. Exp. Med. Biol. 2007, 595, 425–451.
110. Negah, S.S.; Ghazavi, H.; Vafaee, F.; Rashidi, R.; Aminian, A.R.; Forouzanfar, F. The potential role of green tea and its main constituent (epigallocatechin—3-gallate) in pain relief: A mechanistic review. Curr. Drug Discov. Technol. 2020.
111. Ding, S.; Xu, S.; Fang, J.; Jiang, H. The protective effect of polyphenols for colorectal cancer. Front. Immunol. 2020, 11, 1407.
112. Zhang, S.; Zhu, Q.; Chen, J.Y.; OuYang, D.; Lu, J.H. The pharmacological activity of epigallocatechin-3-gallate (egcg) on Alzheimer’s disease animal model: A systematic review. Phytomed. Int. J. Phytother. Phytopharmacol. 2020, 79, 153316.
113. Ran, Z.H.; Chen, C.; Xiao, S.D. Epigallocatechin-3-gallate ameliorates rats colitis induced by acetic acid. Biomed. Pharmacother. 2008, 62, 189–196.
114. Bruckner, M.; Westphal, S.; Domschke, W.; Kucharzik, T.; Lugering, A. Green tea polyphenol epigallocatechin-3-gallate shows therapeutic antioxidative effects in a murine model of colitis. J. Crohn’s Colitis 2012, 6, 226–235.
115. Xu, Z.; Wei, C.; Zhang, R.U.; Yao, J.; Zhang, D.; Wang, L. Epigallocatechin-3-gallate-induced inhibition of interleukin-6 release and adjustment of the regulatory t/t helper 17 cell balance in the treatment of colitis in mice. Exp. Ther. Med. 2015, 10, 2231–2238.
116. Baradaran Rahimi, V.; Ghadiri, M.; Ramezani, M.; Askari, V.R. Antiinflammatory and anti-cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies. Phytother. Res. PTR 2020, 34, 685–720.
117. Colombo, E.; Sangiovanni, E.; Dell’agli, M. A review on the anti-inflammatory activity of pomegranate in the gastrointestinal tract. Evid. Based Complement. Altern. Med. eCAM 2013, 2013, 247145.
118. Ogawa, Y.; Kanatsu, K.; Iino, T.; Kato, S.; Jeong, Y.I.; Shibata, N.; Takada, K.; Takeuchi, K. Protection against dextran sulfate sodium-induced colitis by microspheres of ellagic acid in rats. Life Sci. 2002, 71, 827–839.
119. Singh, K.; Jaggi, A.S.; Singh, N. Exploring the ameliorative potential of punica granatum in dextran sulfate sodium induced ulcerative colitis in mice. Phytother. Res. PTR 2009, 23, 1565–1574.
120. Marin, M.; Maria Giner, R.; Rios, J.L.; Recio, M.C. Intestinal anti-inflammatory activity of ellagic acid in the acute and chronic dextrane sulfate sodium models of mice colitis. J. Ethnopharmacol. 2013, 150, 925–934.
121. Rosillo, M.A.; Sanchez-Hidalgo, M.; Cardeno, A.; de la Lastra, C.A. Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn’s disease. Biochem. Pharmacol. 2011, 82, 737–745.
122. Yang, K.; Zhang, L.; Liao, P.; Xiao, Z.; Zhang, F.; Sindaye, D.; Xin, Z.; Tan, C.; Deng, J.; Yin, Y.; et al. Impact of gallic acid on gut health: Focus on the gut microbiome, immune response, and mechanisms of action. Front. Immunol. 2020, 11, 580208.
123. Bai, J.; Zhang, Y.; Tang, C.; Hou, Y.; Ai, X.; Chen, X.; Zhang, Y.; Wang, X.; Meng, X. Gallic acid: Pharmacological activities and molecular mechanisms involved in inflammation-related diseases. Biomed. Pharmacother. 2021, 133, 110985.
124. Pandurangan, A.K.; Mohebali, N.; Esa, N.M.; Looi, C.Y.; Ismail, S.; Saadatdoust, Z. Gallic acid suppresses inflammation in dextran sodium sulfate-induced colitis in mice: Possible mechanisms. Int. Immunopharmacol. 2015, 28, 1034–1043.
125. Pandurangan, A.K.; Mohebali, N.; Norhaizan, M.E.; Looi, C.Y. Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in balb/c mice. Drug Des. Dev. Ther. 2015, 9, 3923–3934.
126. Wang, J.; Wu, G.; Chu, H.; Wu, Z.; Sun, J. Paeonol derivatives and pharmacological activities: A review of recent progress. Mini Rev. Med. Chem. 2020, 20, 466–482.
127. Zhang, L.; Li, D.C.; Liu, L.F. Paeonol: Pharmacological effects and mechanisms of action. Int. Immunopharmacol. 2019, 72, 413–421.
128. Ishiguro, K.; Ando, T.; Maeda, O.; Hasegawa, M.; Kadomatsu, K.; Ohmiya, N.; Niwa, Y.; Xavier, R.; Goto, H. Paeonol attenuates tnbs-induced colitis by inhibiting nf-kappab and stat1 transactivation. Toxicol. Appl. Pharmacol. 2006, 217, 35–42.
129. Jin, X.; Wang, J.; Xia, Z.M.; Shang, C.H.; Chao, Q.L.; Liu, Y.R.; Fan, H.Y.; Chen, D.Q.; Qiu, F.; Zhao, F. Anti-Inflammatory and anti-oxidative activities of paeonol and its metabolites through blocking mapk/erk/p38 signaling pathway. Inflammation 2016, 39, 434–446.
130. Zong, S.Y.; Pu, Y.Q.; Xu, B.L.; Zhang, T.; Wang, B. Study on the physicochemical properties and anti-inflammatory effects of paeonol in rats with tnbs-induced ulcerative colitis. Int. Immunopharmacol. 2017, 42, 32–38.
131. Cao, Y.; Smith, W.; Yan, L.; Kong, L. Overview of cellular mechanisms and signaling pathways of piceatannol. Curr. Stem Cell Res. Ther. 2020, 15, 4–10.
132. Banik, K.; Ranaware, A.M.; Harsha, C.; Nitesh, T.; Girisa, S.; Deshpande, V.; Fan, L.; Nalawade, S.P.; Sethi, G.; Kunnumakkara, A.B. Piceatannol: A natural stilbene for the prevention and treatment of cancer. Pharmacol. Res. 2020, 153, 104635.
133. Dvorakova, M.; Landa, P. Anti-Inflammatory activity of natural stilbenoids: A review. Pharmacol. Res. 2017, 124, 126–145.
134. Liu, L.; Li, J.; Kundu, J.K.; Surh, Y.J. Piceatannol inhibits phorbol ester-induced expression of cox-2 and inos in hr-1 hairless mouse skin by blocking the activation of nf-kappab and ap-1. Inflamm. Res. 2014, 63, 1013–1021.
135. Yum, S.; Jeong, S.; Lee, S.; Nam, J.; Kim, W.; Yoo, J.W.; Kim, M.S.; Lee, B.L.; Jung, Y. Colon-Targeted delivery of piceatannol enhances anti-colitic effects of the natural product: Potential molecular mechanisms for therapeutic enhancement. Drug Des. Dev. Ther. 2015, 9, 4247–4258.
136. Kim, Y.H.; Kwon, H.S.; Kim, D.H.; Cho, H.J.; Lee, H.S.; Jun, J.G.; Park, J.H.; Kim, J.K. Piceatannol, a stilbene present in grapes, attenuates dextran sulfate sodium-induced colitis. Int. Immunopharmacol. 2008, 8, 1695–1702.
137. Guo, C.; He, J.; Song, X.; Tan, L.; Wang, M.; Jiang, P.; Li, Y.; Cao, Z.; Peng, C. Pharmacological properties and derivatives of shikonin-a review in recent years. Pharmacol. Res. 2019, 149, 104463.
138. Lu, L.; Qin, A.; Huang, H.; Zhou, P.; Zhang, C.; Liu, N.; Li, S.; Wen, G.; Zhang, C.; Dong, W.; et al. Shikonin extracted from medicinal chinese herbs exerts anti-inflammatory effect via proteasome inhibition. Eur. J. Pharmacol. 2011, 658, 242–247.
139. Yang, J.; Wang, Z.; Chen, D.L. Shikonin ameliorates isoproterenol (iso)-induced myocardial damage through suppressing fibrosis, inflammation, apoptosis and er stress. Biomed. Pharmacother. 2017, 93, 1343–1357.
140. Lin, M.X.; Yi, Y.X.; Fang, P.P.; Huang, S.S.; Pan, C.W.; Jin, L.X.; Zhang, T.; Zhou, G.Y. Shikonin protects against d-galactosamine and lipopolysaccharide-induced acute hepatic injury by inhibiting tlr4 signaling pathway. Oncotarget 2017, 8, 91542–91550.
141. Andujar, I.; Rios, J.L.; Giner, R.M.; Miguel Cerda, J.; Recio Mdel, C. Beneficial effect of shikonin on experimental colitis induced by dextran sulfate sodium in balb/c mice. Evid. Based Complement. Altern. Med. eCAM 2012, 2012, 271606.
142. Salminen, A.; Lehtonen, M.; Suuronen, T.; Kaarniranta, K.; Huuskonen, J. Terpenoids: Natural inhibitors of nf-kappab signaling with anti-inflammatory and anticancer potential. Cell. Mol. Life Sci. CMLS 2008, 65, 2979–2999.
143. Kim, T.; Song, B.; Cho, K.S.; Lee, I.S. Therapeutic potential of volatile terpenes and terpenoids from forests for inflammatory diseases. Int. J. Mol. Sci. 2020, 21, 2187.
144. Tong, L.; Zhao, Q.; Datan, E.; Lin, G.Q.; Minn, I.; Pomper, M.G.; Yu, B.; Romo, D.; He, Q.L.; Liu, J.O. Triptolide: Reflections on two decades of research and prospects for the future. Nat. Prod. Rep. 2020, 843–860.
145. Li, Y.; Yu, C.; Zhu, W.M.; Xie, Y.; Qi, X.; Li, N.; Li, J.S. Triptolide ameliorates il-10-deficient mice colitis by mechanisms involving suppression of il-6/stat3 signaling pathway and down-regulation of il-17. Mol. Immunol. 2010, 47, 2467–2474.
146. Wang, Z.; Jin, H.; Xu, R.; Mei, Q.; Fan, D. Triptolide downregulates rac1 and the jak/stat3 pathway and inhibits colitis-related colon cancer progression. Exp. Mol. Med. 2009, 41, 717–727.
147. Speisky, H.; Cassels, B.K. Boldo and boldine: An emerging case of natural drug development. Pharmacol. Res. 1994, 29, 1–12.
148. Stevigny, C.; Bailly, C.; Quetin-Leclercq, J. Cytotoxic and antitumor potentialities of aporphinoid alkaloids. Curr. Med. Chem. Anticancer Agents 2005, 5, 173–182.
149. O’Brien, P.; Carrasco-Pozo, C.; Speisky, H. Boldine and its antioxidant or health-promoting properties. Chem. Biol. Interact. 2006, 159, 1–17.
150. Pandurangan, A.K.; Mohebali, N.; Hasanpourghadi, M.; Looi, C.Y.; Mustafa, M.R.; Mohd Esa, N. Boldine suppresses dextran sulfate sodium-induced mouse experimental colitis: Nf-kappab and il-6/stat3 as potential targets. BioFactors 2016, 42, 247–258.
151. Habtemariam, S. Berberine and inflammatory bowel disease: A concise review. Pharmacol. Res. 2016, 113, 592–599.
152. Li, C.; Xi, Y.; Li, S.; Zhao, Q.; Cheng, W.; Wang, Z.; Zhong, J.; Niu, X.; Chen, G. Berberine ameliorates tnbs induced colitis by inhibiting inflammatory responses and th1/th17 differentiation. Mol. Immunol. 2015, 67, 444–454.
153. Li, Y.H.; Xiao, H.T.; Hu, D.D.; Fatima, S.; Lin, C.Y.; Mu, H.X.; Lee, N.P.; Bian, Z.X. Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in c57bl/6 mice by suppressing th17 responses. Pharmacol. Res. 2016, 110, 227–239.
154. Zhang, L.C.; Wang, Y.; Tong, L.C.; Sun, S.; Liu, W.Y.; Zhang, S.; Wang, R.M.; Wang, Z.B.; Li, L. Berberine alleviates dextran sodium sulfate-induced colitis by improving intestinal barrier function and reducing inflammation and oxidative stress. Exp. Ther. Med. 2017, 13, 3374–3382.
155. Li, H.; Feng, C.; Fan, C.; Yang, Y.; Yang, X.; Lu, H.; Lu, Q.; Zhu, F.; Xiang, C.; Zhang, Z.; et al. Intervention of oncostatin m-driven mucosal inflammation by berberine exerts therapeutic property in chronic ulcerative colitis. Cell Death Dis. 2020, 11, 271.
156. El-Saber Batiha, G.; Magdy Beshbishy, A.; Wasef, L.G.; Elewa, Y.H.A.; Al-Sagan, A.A.; Abd El-Hack, M.E.; Taha, A.E.; Abd-Elhakim, Y.M.; Prasad Devkota, H. Chemical constituents and pharmacological activities of garlic (Allium sativum L.): A review. Nutrients 2020, 12, 872.
157. Trio, P.Z.; You, S.; He, X.; He, J.; Sakao, K.; Hou, D.X. Chemopreventive functions and molecular mechanisms of garlic organosulfur compounds. Food Funct. 2014, 5, 833–844.
158. Borlinghaus, J.; Albrecht, F.; Gruhlke, M.C.; Nwachukwu, I.D.; Slusarenko, A.J. Allicin: Chemistry and biological properties. Molecules 2014, 19, 12591–12618.
159. Pandurangan, A.K.; Ismail, S.; Saadatdoust, Z.; Esa, N.M. Allicin alleviates dextran sodium sulfate- (dss-) induced ulcerative colitis in balb/c mice. Oxidative Med. Cell. Longev. 2015, 2015, 605208.
160. Lee, H.J.; Lee, H.G.; Choi, K.S.; Surh, Y.J.; Na, H.K. Diallyl trisulfide suppresses dextran sodium sulfate-induced mouse colitis: Nf-kappab and stat3 as potential targets. Biochem. Biophys. Res. Commun. 2013, 437, 267–273.
161. Shi, L.; Lin, Q.; Li, X.; Nie, Y.; Sun, S.; Deng, X.; Wang, L.; Lu, J.; Tang, Y.; Luo, F. Alliin, a garlic organosulfur compound, ameliorates gut inflammation through mapk-nf-kappab/ap-1/stat-1 inactivation and ppar-gamma activation. Mol. Nutr. Food Res. 2017, 61, 1601013.
162. Soundararajan, P.; Kim, J.S. Anti-Carcinogenic glucosinolates in cruciferous vegetables and their antagonistic effects on prevention of cancers. Molecules 2018, 23, 2983.
163. Dey, M.; Kuhn, P.; Ribnicky, D.; Premkumar, V.; Reuhl, K.; Raskin, I. Dietary phenethylisothiocyanate attenuates bowel inflammation in mice. BMC Chem. Biol. 2010, 10, 4.