Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions

Abstract

:

1. Introduction

2. Cyanidin-3-O-Glucoside

2.1. Chemical Structure

2.2. Dietary Sources

2.3. Bowel Metabolism

2.4. Health Effects

3. Inflammatory Bowel Disease (IBD)

3.1. Epidemiology

3.2. Pathogenesis

3.3. Therapeutic Options

3.4. Natural Products

4. Therapeutic Effects of C3G in IBD

4.1. C3G Inhibits NF-κB Pathway Activation

4.2. C3G Activates Nrf2 Pathway and Modulates Cytoprotective Enzymes Expression

4.3. C3G Modulates IFN Pathways

4.4. C3G Reduces Reactive Species and Pro-Inflammatory Cytokines

4.5. C3G Modulates Gut Microbiota

4.6. Clinical Aspects

5. Conclusions

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Conflicts of Interest

Abbreviations

References

  1. Martins, I.; Maciel, M.G.; do Nascimento, J.L.M.; Mafra, D.; Santos, A.F.; Padilha, C.S. Anthocyanins-rich interventions on oxidative stress, inflammation and lipid profile in patients undergoing hemodialysis: Meta-analysis and meta-regression. Eur. J. Clin. Nutr. 2023, 77, 316–324. [Google Scholar] [CrossRef]
  2. Pérez-Torres, I.; Castrejón-Téllez, V.; Soto, M.E.; Rubio-Ruiz, M.E.; Manzano-Pech, L.; Guarner-Lans, V. Oxidative Stress, Plant Natural Antioxidants, and Obesity. Int. J. Mol. Sci. 2021, 22, 1786. [Google Scholar] [CrossRef]
  3. Fang, Z.; Luo, Y.; Ma, C.; Dong, L.; Chen, F. Blueberry Anthocyanins Extract Attenuates Acrylamide-Induced Oxidative Stress and Neuroinflammation in Rats. Oxidative Med. Cell. Longev. 2022, 2022, 7340881. [Google Scholar] [CrossRef] [PubMed]
  4. Zheng, F.; Wang, Y.Z.; Wu, Y.X.; Zhang, M.Y.; Li, F.T.; He, Y.; Wen, L.K.; Yue, H. Effect of stabilization malvids anthocyanins on the gut microbiota in mice with oxidative stress. J. Food Biochem. 2021, 45, 4892–4902. [Google Scholar] [CrossRef] [PubMed]
  5. Rahman, S.; Mathew, S.; Nair, P.; Ramadan, W.S.; Vazhappilly, C.G. Health benefits of cyanidin-3-glucoside as a potent modulator of Nrf2-mediated oxidative stress. Inflammopharmacology 2021, 29, 907–923. [Google Scholar] [CrossRef]
  6. Higashiyama, M.; Hokaria, R. New and Emerging Treatments for Inflammatory Bowel Disease. Digestion 2023, 104, 74–81. [Google Scholar] [CrossRef]
  7. Saez, A.; Herrero-Fernandez, B.; Gomez-Bris, R.; Sánchez-Martinez, H.; Gonzalez-Granado, J.M. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int. J. Mol. Sci. 2023, 24, 1526. [Google Scholar] [CrossRef]
  8. Dai, C.; Huang, Y.H.; Jiang, M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int. Immunopharmacol. 2023, 114, 109545. [Google Scholar] [CrossRef]
  9. Rogler, G.; Singh, A.; Kavanaugh, A.; Rubin, D.T. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology 2021, 161, 1118–1132. [Google Scholar] [CrossRef] [PubMed]
  10. Wu, X.; Prior, R.L. Systematic identification and characterization of anthocyanins by HPLC-ESI-MS/MS in common foods in the United States: Fruits and berries. J. Agric. Food Chem. 2005, 53, 2589–2599. [Google Scholar] [CrossRef]
  11. Olivas-Aguirre, F.J.; Rodrigo-García, J.; Martínez-Ruiz, N.D.R.; Cárdenas-Robles, A.I.; Mendoza-Díaz, S.O.; Álvarez-Parrilla, E.; González-Aguilar, G.A.; De la Rosa, L.A.; Ramos-Jiménez, A.; Wall-Medrano, A. Cyanidin-3-O-glucoside: Physical-chemistry, foodomics and health effects. Molecules 2016, 21, 1264. [Google Scholar] [CrossRef]
  12. Flamini, R.; De Rosso, M.; Bavaresco, L. Study of grape polyphenols by liquid chromatography-high-resolution mass spectrometry (UHPLC/QTOF) and suspect screening analysis. J. Anal. Methods Chem. 2015, 2015, 350259. [Google Scholar] [CrossRef] [PubMed]
  13. Felgines, C.; Krisa, S.; Mauray, A.; Besson, C.; Lamaison, J.-L.; Scalbert, A.; Mérillon, J.-M.; Texier, O. Radiolabelled cyanidin 3-O-glucoside is poorly absorbed in the mouse. Br. J. Nutr. 2010, 103, 1738–1745. [Google Scholar] [CrossRef]
  14. Fernandes, I.; Marques, F.; de Freitas, V.; Mateus, N. Antioxidant and antiproliferative properties of methylated metabolites of anthocyanins. Food Chem. 2013, 141, 2923–2933. [Google Scholar] [CrossRef] [PubMed]
  15. Phan, A.D.T.; Netzel, G.; Wang, D.; Flanagan, B.M.; D’Arcy, B.R.; Gidley, M.J. Binding of dietary polyphenols to cellulose: Structural and nutritional aspects. Food Chem. 2015, 171, 388–396. [Google Scholar] [CrossRef]
  16. Oliveira, A.; Pintado, M. In vitro evaluation of the effects of protein–polyphenol–polysaccharide interactions on (+)-catechin and cyanidin-3-glucoside bioaccessibility. Food Funct. 2015, 6, 3444–3453. [Google Scholar] [CrossRef]
  17. Tang, L.; Zuo, H.; Shu, L. Comparison of the interaction between three anthocyanins and human serum albumins by spectroscopy. J. Lumin. 2014, 153, 54–63. [Google Scholar] [CrossRef]
  18. Tang, L.; Li, S.; Bi, H.; Gao, X. Interaction of cyanidin-3-O-glucoside with three proteins. Food Chem. 2016, 196, 550–559. [Google Scholar] [CrossRef]
  19. Kosińska-Cagnazzo, A.; Diering, S.; Prim, D.; Andlauer, W. Identification of bioaccessible and uptaken phenolic compounds from strawberry fruits in in vitro digestion/Caco-2 absorption model. Food Chem. 2015, 170, 288–294. [Google Scholar] [CrossRef]
  20. Fernandes, A.; Brás, N.F.; Mateus, N.; de Freitas, V. Understanding the molecular mechanism of anthocyanin binding to pectin. Langmuir 2014, 30, 8516–8527. [Google Scholar] [CrossRef]
  21. Urias-Lugo, D.A.; Heredia, J.B.; Muy-Rangel, M.D.; Valdez-Torres, J.B.; Serna-Saldívar, S.; Gutierrez-Uribe, J.A. Anthocyanins and phenolic acids of hybrid and native blue maize (Zea mays L.) extracts and their antiproliferative activity in mammary (MCF7), liver (HepG2), colon (Caco2 and HT29) and prostate (PC3) cancer cells. Plant Foods Hum. Nutr. 2015, 70, 193–199. [Google Scholar] [CrossRef]
  22. Zhao, X.; Yuan, Z.; Feng, L.; Fang, Y. Cloning and expression of anthocyanin biosynthetic genes in red and white pomegranate. J. Plant Res. 2015, 128, 687–696. [Google Scholar] [CrossRef] [PubMed]
  23. Vogiatzoglou, A.; Mulligan, A.A.; Lentjes, M.A.; Luben, R.N.; Spencer, J.P.; Schroeter, H.; Khaw, K.-T.; Kuhnle, G.G. Flavonoid intake in European adults (18 to 64 years). PLoS ONE 2015, 10, e0128132. [Google Scholar] [CrossRef]
  24. Cheng, Z.; Si, X.; Tan, H.; Zang, Z.; Tian, J.; Shu, C.; Sun, X.; Li, Z.; Jiang, Q.; Meng, X.; et al. Cyanidin-3-O-glucoside and its phenolic metabolites ameliorate intestinal diseases via modulating intestinal mucosal immune system: Potential mechanisms and therapeutic strategies. Crit. Rev. Food Sci. Nutr. 2023, 63, 1629–1647. [Google Scholar] [CrossRef] [PubMed]
  25. Orhan Dereli, B.; Türkyılmaz, M.; Özkan, M. Clarification of pomegranate and strawberry juices: Effects of various clarification agents on turbidity, anthocyanins, colour, phenolics and antioxidant activity. Food Chem. 2023, 413, 135672. [Google Scholar] [CrossRef] [PubMed]
  26. Sebastian, R.S.; Wilkinson Enns, C.; Goldman, J.D.; Martin, C.L.; Steinfeldt, L.C.; Murayi, T.; Moshfegh, A.J. A new database facilitates characterization of flavonoid intake, sources, and positive associations with diet quality among US adults. J. Nutr. 2015, 145, 1239–1248. [Google Scholar] [CrossRef]
  27. Grosso, G.; Stepaniak, U.; Micek, A.; Stefler, D.; Bobak, M.; Pająk, A. Dietary polyphenols are inversely associated with metabolic syndrome in Polish adults of the HAPIEE study. Eur. J. Nutr. 2017, 56, 1409–1420. [Google Scholar] [CrossRef]
  28. Zamora-Ros, R.; Andres-Lacueva, C.; Lamuela-Raventós, R.M.; Berenguer, T.; Jakszyn, P.; Barricarte, A.; Ardanaz, E.; Amiano, P.; Dorronsoro, M.; Larrañaga, N.; et al. Estimation of dietary sources and flavonoid intake in a Spanish adult population (EPIC-Spain). J. Am. Diet. Assoc. 2010, 110, 390–398. [Google Scholar] [CrossRef]
  29. Jun, S.; Shin, S.; Joung, H. Estimation of dietary flavonoid intake and major food sources of Korean adults. Br. J. Nutr. 2016, 115, 480–489. [Google Scholar] [CrossRef]
  30. Peterson, J.J.; Dwyer, J.T.; Jacques, P.F.; McCullough, M.L. Improving the estimation of flavonoid intake for study of health outcomes. Nutr. Rev. 2015, 73, 553–576. [Google Scholar] [CrossRef] [PubMed]
  31. Onwude, D.I.; Chen, G.; Eke-Emezie, N.; Kabutey, A.; Khaled, A.Y.; Sturm, B. Recent advances in reducing food losses in the supply chain of fresh agricultural produce. Processes 2020, 8, 1431. [Google Scholar] [CrossRef]
  32. Huang, K.-M.; Guan, Z.; Hammami, A. The US Fresh Fruit and Vegetable Industry: An Overview of Production and Trade. Agriculture 2022, 12, 1719. [Google Scholar] [CrossRef]
  33. Felgines, C.; Talavéra, S.; Texier, O.; Besson, C.; Fogliano, V.; Lamaison, J.-L.; La Fauci, L.; Galvano, G.; Rémésy, C.; Galvano, F. Absorption and metabolism of red orange juice anthocyanins in rats. Br. J. Nutr. 2006, 95, 898–904. [Google Scholar] [CrossRef] [PubMed]
  34. Rodriguez-Mateos, A.; Vauzour, D.; Krueger, C.G.; Shanmuganayagam, D.; Reed, J.; Calani, L.; Mena, P.; Del Rio, D.; Crozier, A. Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: An update. Arch. Toxicol. 2014, 88, 1803–1853. [Google Scholar] [CrossRef] [PubMed]
  35. Woodward, G.M.; Needs, P.W.; Kay, C.D. Anthocyanin-derived phenolic acids form glucuronides following simulated gastrointestinal digestion and microsomal glucuronidation. Mol. Nutr. Food Res. 2011, 55, 378–386. [Google Scholar] [CrossRef] [PubMed]
  36. Bashllari, R.; Molonia, M.S.; Muscarà, C.; Speciale, A.; Wilde, P.J.; Saija, A.; Cimino, F. Cyanidin-3-O-glucoside protects intestinal epithelial cells from palmitate-induced lipotoxicity. Arch. Physiol. Biochem. 2023, 129, 379–386. [Google Scholar] [CrossRef]
  37. Feng, J.; Wu, Y.; Zhang, L.; Li, Y.; Liu, S.; Wang, H.; Li, C. Enhanced Chemical Stability, Intestinal Absorption, and Intracellular Antioxidant Activity of Cyanidin-3-O-glucoside by Composite Nanogel Encapsulation. J. Agric. Food Chem. 2019, 67, 10432–10447. [Google Scholar] [CrossRef]
  38. Miyazawa, T.; Nakagawa, K.; Kudo, M.; Muraishi, K.; Someya, K. Direct intestinal absorption of red fruit anthocyanins, cyanidin-3-glucoside and cyanidin-3, 5-diglucoside, into rats and humans. J. Agric. Food Chem. 1999, 47, 1083–1091. [Google Scholar] [CrossRef]
  39. Gan, Y.; Fu, Y.; Yang, L.; Chen, J.; Lei, H.; Liu, Q. Cyanidin-3-O-Glucoside and Cyanidin Protect Against Intestinal Barrier Damage and 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis. J. Med. Food 2020, 23, 90–99. [Google Scholar] [CrossRef]
  40. Fang, J. Some anthocyanins could be efficiently absorbed across the gastrointestinal mucosa: Extensive presystemic metabolism reduces apparent bioavailability. J. Agric. Food Chem. 2014, 62, 3904–3911. [Google Scholar] [CrossRef]
  41. Hanske, L.; Engst, W.; Loh, G.; Sczesny, S.; Blaut, M.; Braune, A. Contribution of gut bacteria to the metabolism of cyanidin 3-glucoside in human microbiota-associated rats. Br. J. Nutr. 2013, 109, 1433–1441. [Google Scholar] [CrossRef]
  42. Valdés, L.; Cuervo, A.; Salazar, N.; Ruas-Madiedo, P.; Gueimonde, M.; González, S. The relationship between phenolic compounds from diet and microbiota: Impact on human health. Food Funct. 2015, 6, 2424–2439. [Google Scholar] [CrossRef] [PubMed]
  43. Alves Castilho, P.; Bracht, L.; Barros, L.; Albuquerque, B.R.; Dias, M.I.; Ferreira, I.; Comar, J.F.; Barlati Vieira da Silva, T.; Peralta, R.M.; Sá-Nakanishi, A.B.; et al. Effects of a Myrciaria jaboticaba peel extract on starch and triglyceride absorption and the role of cyanidin-3-O-glucoside. Food Funct. 2021, 12, 2644–2659. [Google Scholar] [CrossRef]
  44. Shan, X.; Lv, Z.Y.; Yin, M.J.; Chen, J.; Wang, J.; Wu, Q.N. The Protective Effect of Cyanidin-3-Glucoside on Myocardial Ischemia-Reperfusion Injury through Ferroptosis. Oxidative Med. Cell. Longev. 2021, 2021, 8880141. [Google Scholar] [CrossRef] [PubMed]
  45. Sivasinprasasn, S.; Pantan, R.; Thummayot, S.; Tocharus, J.; Suksamrarn, A.; Tocharus, C. Cyanidin-3-glucoside attenuates angiotensin II-induced oxidative stress and inflammation in vascular endothelial cells. Chem. Biol. Interact. 2016, 260, 67–74. [Google Scholar] [CrossRef] [PubMed]
  46. Aloud, B.M.; Raj, P.; McCallum, J.; Kirby, C.; Louis, X.L.; Jahan, F.; Yu, L.; Hiebert, B.; Duhamel, T.A.; Wigle, J.T.; et al. Cyanidin 3-O-glucoside prevents the development of maladaptive cardiac hypertrophy and diastolic heart dysfunction in 20-week-old spontaneously hypertensive rats. Food Funct. 2018, 9, 3466–3480. [Google Scholar] [CrossRef]
  47. Hassellund, S.; Flaa, A.; Kjeldsen, S.; Seljeflot, I.; Karlsen, A.; Erlund, I.; Rostrup, M. Effects of anthocyanins on cardiovascular risk factors and inflammation in pre-hypertensive men: A double-blind randomized placebo-controlled crossover study. J. Hum. Hypertens. 2013, 27, 100–106. [Google Scholar] [CrossRef]
  48. Hidalgo, J.; Flores, C.; Hidalgo, M.A.; Perez, M.; Yañez, A.; Quiñones, L.; Caceres, D.D.; Burgos, R.A. Delphinol® standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition. Panminerva Med. 2014, 56, 1–7. [Google Scholar] [PubMed]
  49. Davinelli, S.; Bertoglio, J.C.; Zarrelli, A.; Pina, R.; Scapagnini, G. A randomized clinical trial evaluating the efficacy of an anthocyanin–maqui berry extract (Delphinol®) on oxidative stress biomarkers. J. Am. Coll. Nutr. 2015, 34, 28–33. [Google Scholar] [CrossRef]
  50. Zhu, Y.; Ling, W.; Guo, H.; Song, F.; Ye, Q.; Zou, T.; Li, D.; Zhang, Y.; Li, G.; Xiao, Y. Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: A randomized controlled trial. Nutr. Metab. Cardiovasc. Dis. 2013, 23, 843–849. [Google Scholar] [CrossRef]
  51. Edirisinghe, I.; Banaszewski, K.; Cappozzo, J.; Sandhya, K.; Ellis, C.L.; Tadapaneni, R.; Kappagoda, C.T.; Burton-Freeman, B.M. Strawberry anthocyanin and its association with postprandial inflammation and insulin. Br. J. Nutr. 2011, 106, 913–922. [Google Scholar] [CrossRef]
  52. Zhu, Y.; Xia, M.; Yang, Y.; Liu, F.; Li, Z.; Hao, Y.; Mi, M.; Jin, T.; Ling, W. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin. Chem. 2011, 57, 1524–1533. [Google Scholar] [CrossRef]
  53. Knobloch, T.J.; Uhrig, L.K.; Pearl, D.K.; Casto, B.C.; Warner, B.M.; Clinton, S.K.; Sardo-Molmenti, C.L.; Ferguson, J.M.; Daly, B.T.; Riedl, K.; et al. Suppression of Proinflammatory and Prosurvival Biomarkers in Oral Cancer Patients Consuming a Black Raspberry Phytochemical-Rich Troche. Cancer Prev. Res. (Phila. Pa.) 2016, 9, 159–171. [Google Scholar] [CrossRef] [PubMed]
  54. Wang, L.-S.; Arnold, M.; Huang, Y.-W.; Sardo, C.; Seguin, C.; Martin, E.; Huang, T.H.-M.; Riedl, K.; Schwartz, S.; Frankel, W.; et al. Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: A phase I pilot study. Clin. Cancer Res. 2011, 17, 598–610. [Google Scholar] [CrossRef] [PubMed]
  55. Cheynier, V.G.C.; Ageorges, A. Flavonoids: Anthocyanins. In Handbook of Analysis of Active Compounds in Functional Foods, 1st ed.; Nollet, L.M.C., Toldrá, F., Eds.; CRC Press/Taylor & Francis Group: Boca Raton, FL, USA, 2012; pp. 379–403. [Google Scholar]
  56. Acquaviva, R.; Russo, A.; Galvano, F.; Galvano, G.; Barcellona, M.; Volti, G.L.; Vanella, A. Cyanidin and cyanidin 3-O-[beta]-D-glucoside as DNA cleavage protectors and antioxidants. Cell Biol. Toxicol. 2003, 19, 243. [Google Scholar] [CrossRef]
  57. Guo, H.; Xia, M.; Zou, T.; Ling, W.; Zhong, R.; Zhang, W. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J. Nutr. Biochem. 2012, 23, 349–360. [Google Scholar] [CrossRef]
  58. Ziberna, L.; Tramer, F.; Moze, S.; Vrhovsek, U.; Mattivi, F.; Passamonti, S. Transport and bioactivity of cyanidin 3-glucoside into the vascular endothelium. Free Radic. Biol. Med. 2012, 52, 1750–1759. [Google Scholar] [CrossRef]
  59. Tsuda, T.; Ueno, Y.; Yoshikawa, T.; Kojo, H.; Osawa, T. Microarray profiling of gene expression in human adipocytes in response to anthocyanins. Biochem. Pharmacol. 2006, 71, 1184–1197. [Google Scholar] [CrossRef]
  60. Björk, C.; Wilhelm, U.; Mandrup, S.; Larsen, B.D.; Bordoni, A.; Hedén, P.; Rydén, M.; Arner, P.; Laurencikiene, J. Effects of selected bioactive food compounds on human white adipocyte function. Nutr. Metab. 2016, 13, 4. [Google Scholar] [CrossRef] [PubMed]
  61. Tsuda, T.; Ueno, Y.; Kojo, H.; Yoshikawa, T.; Osawa, T. Gene expression profile of isolated rat adipocytes treated with anthocyanins. Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids 2005, 1733, 137–147. [Google Scholar] [CrossRef]
  62. Neveu, V.; Perez-Jiménez, J.; Vos, F.; Crespy, V.; du Chaffaut, L.; Mennen, L.; Knox, C.; Eisner, R.; Cruz, J.; Wishart, D.; et al. Phenol-Explorer: An online comprehensive database on polyphenol contents in foods. Database 2010, 2010, bap024. [Google Scholar] [CrossRef] [PubMed]
  63. Pimpao, R.C.; Ventura, M.R.; Ferreira, R.B.; Williamson, G.; Santos, C.N. Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit purée. Br. J. Nutr. 2015, 113, 454–463. [Google Scholar] [CrossRef] [PubMed]
  64. Kiemlian Kwee, J. Yin and Yang of polyphenols in cancer prevention: A short review. Anti-Cancer Agents Med. Chem. (Former. Curr. Med. Chem. -Anti-Cancer Agents) 2016, 16, 832–840. [Google Scholar] [CrossRef] [PubMed]
  65. Sheng, F.; Wang, Y.; Zhao, X.; Tian, N.; Hu, H.; Li, P. Separation and identification of anthocyanin extracted from mulberry fruit and the pigment binding properties toward human serum albumin. J. Agric. Food Chem. 2014, 62, 6813–6819. [Google Scholar] [CrossRef]
  66. Zhang, C.; Guo, X.; Cai, W.; Ma, Y.; Zhao, X. Binding Characteristics and Protective Capacity of Cyanidin-3-Glucoside and its Aglycon to Calf Thymus DNA. J. Food Sci. 2015, 80, H889–H893. [Google Scholar] [CrossRef]
  67. Shi, J.h.; Wang, J.; Zhu, Y.y.; Chen, J. Characterization of intermolecular interaction between cyanidin-3-glucoside and bovine serum albumin: Spectroscopic and molecular docking methods. Luminescence 2014, 29, 522–530. [Google Scholar] [CrossRef]
  68. Cahyana, Y.; Gordon, M.H. Interaction of anthocyanins with human serum albumin: Influence of pH and chemical structure on binding. Food Chem. 2013, 141, 2278–2285. [Google Scholar] [CrossRef]
  69. Akkarachiyasit, S.; Charoenlertkul, P.; Yibchok-Anun, S.; Adisakwattana, S. Inhibitory activities of cyanidin and its glycosides and synergistic effect with acarbose against intestinal α-glucosidase and pancreatic α-amylase. Int. J. Mol. Sci. 2010, 11, 3387–3396. [Google Scholar] [CrossRef]
  70. Flynn, S.; Eisenstein, S. Inflammatory Bowel Disease Presentation and Diagnosis. Surg. Clin. N. Am. 2019, 99, 1051–1062. [Google Scholar] [CrossRef]
  71. Butterworth, J. Chemoprevention of colorectal cancer in inflammatory bowel disease. Dig. Liver Dis. 2009, 41, 338–339. [Google Scholar] [CrossRef]
  72. Yu, Y.R.; Rodriguez, J.R. Clinical presentation of Crohn’s, ulcerative colitis, and indeterminate colitis: Symptoms, extraintestinal manifestations, and disease phenotypes. Semin. Pediatr. Surg. 2017, 26, 349–355. [Google Scholar] [CrossRef] [PubMed]
  73. Carroll, M.W.; Kuenzig, M.E.; Mack, D.R.; Otley, A.R.; Griffiths, A.M.; Kaplan, G.G.; Bernstein, C.N.; Bitton, A.; Murthy, S.K.; Nguyen, G.C.; et al. The Impact of Inflammatory Bowel Disease in Canada 2018: Children and Adolescents with IBD. J. Can. Assoc. Gastroenterol. 2019, 2, S49–S67. [Google Scholar] [CrossRef] [PubMed]
  74. Thia, K.T.; Loftus Jr, E.V.; Sandborn, W.J.; Yang, S.-K. An update on the epidemiology of inflammatory bowel disease in Asia. Off. J. Am. Coll. Gastroenterol.|ACG 2008, 103, 3167–3182. [Google Scholar] [CrossRef]
  75. Chouraki, V.; Savoye, G.; Dauchet, L.; Vernier-Massouille, G.; Dupas, J.L.; Merle, V.; Laberenne, J.E.; Salomez, J.L.; Lerebours, E.; Turck, D. The changing pattern of Crohn’s disease incidence in northern France: A continuing increase in the 10-to 19-year-old age bracket (1988–2007). Aliment. Pharmacol. Ther. 2011, 33, 1133–1142. [Google Scholar] [CrossRef] [PubMed]
  76. Lakatos, P.L. Recent trends in the epidemiology of inflammatory bowel diseases: Up or down? World J. Gastroenterol. WJG 2006, 12, 6102. [Google Scholar] [CrossRef]
  77. Cosnes, J.; Gower–Rousseau, C.; Seksik, P.; Cortot, A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011, 140, 1785–1794.e1784. [Google Scholar] [CrossRef]
  78. Loftus Jr, E.V. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004, 126, 1504–1517. [Google Scholar] [CrossRef]
  79. Dixon, L.J.; Kabi, A.; Nickerson, K.P.; McDonald, C. Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis. Inflamm. Bowel Dis. 2015, 21, 912–922. [Google Scholar] [CrossRef] [PubMed]
  80. Leone, V.; Chang, E.B.; Devkota, S. Diet, microbes, and host genetics: The perfect storm in inflammatory bowel diseases. J. Gastroenterol. 2013, 48, 315–321. [Google Scholar] [CrossRef]
  81. Debnath, T.; Hasnat, M.A.; Pervin, M.; Lee, S.Y.; Park, S.R.; Kim, D.H.; Kweon, H.J.; Kim, J.M.; Lim, B.O. Chaga mushroom (Inonotus obliquus) grown on germinated brown rice suppresses inflammation associated with colitis in mice. Food Sci. Biotechnol. 2012, 21, 1235–1241. [Google Scholar] [CrossRef]
  82. Baumgart, D.C.; Carding, S.R. Inflammatory bowel disease: Cause and immunobiology. Lancet 2007, 369, 1627–1640. [Google Scholar] [CrossRef]
  83. Lucas, A.; Cobelens, P.; Kavelaars, A.; Heijnen, C.; Holtmann, G.; Haag, S.; Gerken, G.; Langhorst, J.; Dobos, G.; Schedlowski, M.; et al. Disturbed in vitro adrenergic modulation of cytokine production in inflammatory bowel diseases in remission. J. Neuroimmunol. 2007, 182, 195–203. [Google Scholar] [CrossRef]
  84. Sies, H. Oxidative stress: Oxidants and antioxidants. Exp. Physiol. Transl. Integr. 1997, 82, 291–295. [Google Scholar] [CrossRef]
  85. Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn. Rev. 2010, 4, 118–126. [Google Scholar] [CrossRef]
  86. Halliwell, B.; Gutteridge, J.M. Free Radicals in Biology and Medicine; Pergamon: Oxford, UK, 1985. [Google Scholar]
  87. Turpin, W.; Goethel, A.; Bedrani, L.; Croitoru Mdcm, K. Determinants of IBD Heritability: Genes, Bugs, and More. Inflamm. Bowel Dis. 2018, 24, 1133–1148. [Google Scholar] [CrossRef] [PubMed]
  88. Lee, Y.K.; Mazmanian, S.K. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 2010, 330, 1768–1773. [Google Scholar] [CrossRef]
  89. Elinav, E.; Strowig, T.; Kau, A.L.; Henao-Mejia, J.; Thaiss, C.A.; Booth, C.J.; Peaper, D.R.; Bertin, J.; Eisenbarth, S.C.; Gordon, J.I.; et al. NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis. Cell 2011, 145, 745–757. [Google Scholar] [CrossRef] [PubMed]
  90. Dheer, R.; Santaolalla, R.; Davies, J.M.; Lang, J.K.; Phillips, M.C.; Pastorini, C.; Vazquez-Pertejo, M.T.; Abreu, M.T. Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis. Infect. Immun. 2016, 84, 798–810. [Google Scholar] [CrossRef]
  91. Hansen, J.J.; Sartor, R.B. Therapeutic Manipulation of the Microbiome in IBD: Current Results and Future Approaches. Curr. Treat. Options Gastroenterol. 2015, 13, 105–120. [Google Scholar] [CrossRef] [PubMed]
  92. Lane, E.R.; Zisman, T.L.; Suskind, D.L. The microbiota in inflammatory bowel disease: Current and therapeutic insights. J. Inflamm. Res. 2017, 10, 63–73. [Google Scholar] [CrossRef]
  93. Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2017, 2, 17023. [Google Scholar] [CrossRef]
  94. Wullaert, A.; Bonnet, M.C.; Pasparakis, M. NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Res. 2011, 21, 146–158. [Google Scholar] [CrossRef] [PubMed]
  95. Zaidi, D.; Wine, E. Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-kappabeta) in Inflammatory Bowel Diseases. Front. Pediatr. 2018, 6, 317. [Google Scholar] [CrossRef]
  96. Rogler, G.; Brand, K.; Vogl, D.; Page, S.; Hofmeister, R.; Andus, T.; Knuechel, R.; Baeuerle, P.A.; Scholmerich, J.; Gross, V. Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 1998, 115, 357–369. [Google Scholar] [CrossRef] [PubMed]
  97. Sanmarco, L.M.; Chao, C.C.; Wang, Y.C.; Kenison, J.E.; Li, Z.; Rone, J.M.; Rejano-Gordillo, C.M.; Polonio, C.M.; Gutierrez-Vazquez, C.; Piester, G.; et al. Identification of environmental factors that promote intestinal inflammation. Nature 2022, 611, 801–809. [Google Scholar] [CrossRef]
  98. Arisawa, T.; Tahara, T.; Shibata, T.; Nagasaka, M.; Nakamura, M.; Kamiya, Y.; Fujita, H.; Yoshioka, D.; Okubo, M.; Sakata, M.; et al. Nrf2 gene promoter polymorphism is associated with ulcerative colitis in a Japanese population. Hepatogastroenterology 2008, 55, 394–397. [Google Scholar]
  99. Myers, J.N.; Schaffer, M.W.; Korolkova, O.Y.; Williams, A.D.; Gangula, P.R.; M’Koma, A.E. Implications of the colonic deposition of free hemoglobin-alpha chain: A previously unknown tissue by-product in inflammatory bowel disease. Inflamm. Bowel Dis. 2014, 20, 1530–1547. [Google Scholar] [CrossRef]
  100. Sabzevary-Ghahfarokhi, M.; Shohan, M.; Shirzad, H.; Rahimian, G.; Soltani, A.; Ghatreh-Samani, M.; Deris, F.; Bagheri, N.; Shafigh, M.; Tahmasbi, K. The regulatory role of Nrf2 in antioxidants phase2 enzymes and IL-17A expression in patients with ulcerative colitis. Pathol. Res. Pract. 2018, 214, 1149–1155. [Google Scholar] [CrossRef]
  101. Stachel, I.; Geismann, C.; Aden, K.; Deisinger, F.; Rosenstiel, P.; Schreiber, S.; Sebens, S.; Arlt, A.; Schafer, H. Modulation of nuclear factor E2-related factor-2 (Nrf2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: A novel mechanism of cellular adaption to inflammatory stress. J. Biol. Chem. 2014, 289, 1917–1929. [Google Scholar] [CrossRef] [PubMed]
  102. Kim, J.; Cha, Y.N.; Surh, Y.J. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat. Res. 2010, 690, 12–23. [Google Scholar] [CrossRef]
  103. Singh, S.; Vrishni, S.; Singh, B.K.; Rahman, I.; Kakkar, P. Nrf2-ARE stress response mechanism: A control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. Free. Radic. Res. 2010, 44, 1267–1288. [Google Scholar] [CrossRef]
  104. Joshi, R.; Kumar, S.; Unnikrishnan, M.; Mukherjee, T. Free radical scavenging reactions of sulfasalazine, 5-aminosalicylic acid and sulfapyridine: Mechanistic aspects and antioxidant activity. Free Radic. Res. 2005, 39, 1163–1172. [Google Scholar] [CrossRef]
  105. Lakatos, P.L.; Lakatos, L. Ulcerative proctitis: A review of pharmacotherapy and management. Expert Opin. Pharmacother. 2008, 9, 741–749. [Google Scholar] [CrossRef] [PubMed]
  106. State, M.; Negreanu, L. Defining the Failure of Medical Therapy for Inflammatory Bowel Disease in the Era of Advanced Therapies: A Systematic Review. Biomedicines 2023, 11, 544. [Google Scholar] [CrossRef]
  107. Langhorst, J.; Anthonisen, I.B.; Steder-Neukamm, U.; Lüdtke, R.; Spahn, G.; Michalsen, A.; Dobos, G.J. Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease. Results from a German national survey. Inflamm. Bowel Dis. 2005, 11, 287–295. [Google Scholar] [CrossRef]
  108. Santino, A.; Scarano, A.; De Santis, S.; De Benedictis, M.; Giovinazzo, G.; Chieppa, M. Gut Microbiota Modulation and Anti-Inflammatory Properties of Dietary Polyphenols in IBD: New and Consolidated Perspectives. Curr. Pharm. Des. 2017, 23, 2344–2351. [Google Scholar] [CrossRef] [PubMed]
  109. Pereira, S.R.; Pereira, R.; Figueiredo, I.; Freitas, V.; Dinis, T.C.; Almeida, L.M. Comparison of anti-inflammatory activities of an anthocyanin-rich fraction from Portuguese blueberries (Vaccinium corymbosum L.) and 5-aminosalicylic acid in a TNBS-induced colitis rat model. PLoS ONE 2017, 12, e0174116. [Google Scholar] [CrossRef] [PubMed]
  110. Zhang, G.; Gu, Y.; Dai, X. Protective Effect of Bilberry Anthocyanin Extracts on Dextran Sulfate Sodium-Induced Intestinal Damage in Drosophila melanogaster. Nutrients 2022, 14, 2875. [Google Scholar] [CrossRef] [PubMed]
  111. Thipart, K.; Gruneck, L.; Phunikhom, K.; Sharpton, T.J.; Sattayasai, J.; Popluechai, S. Dark-purple rice extract modulates gut microbiota composition in acetic acid- and indomethacin-induced inflammatory bowel disease in rats. Int. Microbiol. 2023, 26, 423–434. [Google Scholar] [CrossRef]
  112. Farzaei, M.H.; Khanavi, M.; Moghaddam, G.; Dolatshahi, F.; Rahimi, R.; Shams-Ardekani, M.R.; Amin, G.; Hajimahmoodi, M. Standardization of Tragopogon graminifolius DC. extract based on phenolic compounds and antioxidant activity. J. Chem. 2014, 2014, 425965. [Google Scholar] [CrossRef]
  113. Tan, C.; Tong, Y.; Deng, H.; Wang, M.; Zhao, Y.; Wan, M.; Lin, S.; Liu, X.; Meng, X.; Ma, Y. Anti-apoptotic effects of high hydrostatic pressure treated cyanidin-3-glucoside and blueberry pectin complexes on lipopolysaccharide-induced inflammation in Caco-2 cells. J. Funct. Foods 2021, 86, 104709. [Google Scholar] [CrossRef]
  114. Ferrari, D.; Speciale, A.; Cristani, M.; Fratantonio, D.; Molonia, M.S.; Ranaldi, G.; Saija, A.; Cimino, F. Cyanidin-3-O-glucoside inhibits NF-kB signalling in intestinal epithelial cells exposed to TNF-α and exerts protective effects via Nrf2 pathway activation. Toxicol. Lett. 2016, 264, 51–58. [Google Scholar] [CrossRef]
  115. Serra, D.; Paixao, J.; Nunes, C.; Dinis, T.C.; Almeida, L.M. Cyanidin-3-glucoside suppresses cytokine-induced inflammatory response in human intestinal cells: Comparison with 5-aminosalicylic acid. PLoS ONE 2013, 8, e73001. [Google Scholar] [CrossRef] [PubMed]
  116. Serra, D.; Almeida, L.M.; Dinis, T.C. Anti-inflammatory protection afforded by cyanidin-3-glucoside and resveratrol in human intestinal cells via Nrf2 and PPAR-gamma: Comparison with 5-aminosalicylic acid. Chem. Biol. Interact. 2016, 260, 102–109. [Google Scholar] [CrossRef]
  117. Xia, Y.; Tian, L.M.; Liu, Y.; Guo, K.S.; Lv, M.; Li, Q.T.; Hao, S.Y.; Ma, C.H.; Chen, Y.X.; Tanaka, M. Low Dose of Cyanidin-3-O-Glucoside Alleviated Dextran Sulfate Sodium-Induced Colitis, Mediated by CD169+ Macrophage Pathway. Inflamm. Bowel Dis. 2019, 25, 1510–1521. [Google Scholar] [CrossRef]
  118. Cremonini, E.; Mastaloudis, A.; Hester, S.N.; Verstraeten, S.V.; Anderson, M.; Wood, S.M.; Waterhouse, A.L.; Fraga, C.G.; Oteiza, P.I. Anthocyanins inhibit tumor necrosis alpha-induced loss of Caco-2 cell barrier integrity. Food Funct. 2017, 8, 2915–2923. [Google Scholar] [CrossRef]
  119. Speciale, A.; Bashllari, R.; Muscara, C.; Molonia, M.S.; Saija, A.; Saha, S.; Wilde, P.J.; Cimino, F. Anti-Inflammatory Activity of an In Vitro Digested Anthocyanin-Rich Extract on Intestinal Epithelial Cells Exposed to TNF-α. Molecules 2022, 27, 5386. [Google Scholar] [CrossRef]
  120. Wang, Y.; Chen, J.; Wang, Y.; Zheng, F.; Qu, M.; Huang, Z.; Yan, J.; Bao, F.; Li, X.; Sun, C.; et al. Cyanidin-3-O-glucoside extracted from the Chinese bayberry (Myrica rubra Sieb. et Zucc.) alleviates antibiotic-associated diarrhea by regulating gut microbiota and down-regulating inflammatory factors in NF-kappaB pathway. Front. Nutr. 2022, 9, 970530. [Google Scholar] [CrossRef] [PubMed]
  121. Ferrari, D.; Cimino, F.; Fratantonio, D.; Molonia, M.S.; Bashllari, R.; Busa, R.; Saija, A.; Speciale, A. Cyanidin-3-O-Glucoside Modulates the In Vitro Inflammatory Crosstalk between Intestinal Epithelial and Endothelial Cells. Mediat. Inflamm. 2017, 2017, 3454023. [Google Scholar] [CrossRef]
  122. Min, S.W.; Ryu, S.N.; Kim, D.H. Anti-inflammatory effects of black rice, cyanidin-3-O-beta-D-glycoside, and its metabolites, cyanidin and protocatechuic acid. Int. Immunopharmacol. 2010, 10, 959–966. [Google Scholar] [CrossRef]
  123. Speciale, A.; Anwar, S.; Canali, R.; Chirafisi, J.; Saija, A.; Virgili, F.; Cimino, F. Cyanidin-3-O-glucoside counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway. Mol. Nutr. Food Res. 2013, 57, 1979–1987. [Google Scholar] [CrossRef]
  124. Tan, C.; Wang, M.; Kong, Y.; Wan, M.; Deng, H.; Tong, Y.; Lyu, C.; Meng, X. Anti-inflammatory and intestinal microbiota modulation properties of high hydrostatic pressure treated cyanidin-3-glucoside and blueberry pectin complexes on dextran sodium sulfate-induced ulcerative colitis mice. Food Funct. 2022, 13, 4384–4398. [Google Scholar] [CrossRef]
  125. Triebel, S.; Trieu, H.-L.; Richling, E. Modulation of inflammatory gene expression by a bilberry (Vaccinium myrtillus L.) extract and single anthocyanins considering their limited stability under cell culture conditions. J. Agric. Food Chem. 2012, 60, 8902–8910. [Google Scholar] [CrossRef]
  126. Liso, M.; Sila, A.; Verna, G.; Scarano, A.; Donghia, R.; Castellana, F.; Cavalcanti, E.; Pesole, P.L.; Sommella, E.M.; Lippolis, A. Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study. Antioxidants 2022, 11, 138. [Google Scholar] [CrossRef] [PubMed]
  127. Hayden, M.S.; Ghosh, S. Regulation of NF-kappaB by TNF family cytokines. Semin. Immunol. 2014, 26, 253–266. [Google Scholar] [CrossRef] [PubMed]
  128. Speciale, A.; Saija, A.; Bashllari, R.; Molonia, M.S.; Muscara, C.; Occhiuto, C.; Cimino, F.; Cristani, M. Anthocyanins As Modulators of Cell Redox-Dependent Pathways in Non-Communicable Diseases. Curr. Med. Chem. 2020, 27, 1955–1996. [Google Scholar] [CrossRef]
  129. Pasparakis, M. IKK/NF-kappaB signaling in intestinal epithelial cells controls immune homeostasis in the gut. Mucosal Immunol. 2008, 1 (Suppl. 1), S54–S57. [Google Scholar] [CrossRef] [PubMed]
  130. Andresen, L.; Jorgensen, V.L.; Perner, A.; Hansen, A.; Eugen-Olsen, J.; Rask-Madsen, J. Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis. Gut 2005, 54, 503–509. [Google Scholar] [CrossRef]
  131. Bernotti, S.; Seidman, E.; Sinnett, D.; Brunet, S.; Dionne, S.; Delvin, E.; Levy, E. Inflammatory reaction without endogenous antioxidant response in Caco-2 cells exposed to iron/ascorbate-mediated lipid peroxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 285, G898–G906. [Google Scholar] [CrossRef]
  132. Machado, A.; Geraldi, M.V.; do Nascimento, R.P.; Moya, A.; Vezza, T.; Diez-Echave, P.; Galvez, J.J.; Cazarin, C.B.B.; Marostica Junior, M.R. Polyphenols from food by-products: An alternative or complementary therapy to IBD conventional treatments. Food Res. Int. 2021, 140, 110018. [Google Scholar] [CrossRef]
  133. Piechota-Polanczyk, A.; Fichna, J. Review article: The role of oxidative stress in pathogenesis and treatment of inflammatory bowel diseases. Naunyn Schmiedebergs Arch. Pharmacol. 2014, 387, 605–620. [Google Scholar] [CrossRef]
  134. Kannan, N.; Guruvayoorappan, C. Protective effect of Bauhinia tomentosa on acetic acid induced ulcerative colitis by regulating antioxidant and inflammatory mediators. Int. Immunopharmacol. 2013, 16, 57–66. [Google Scholar] [CrossRef]
  135. Cromer, W.E.; Mathis, J.M.; Granger, D.N.; Chaitanya, G.V.; Alexander, J.S. Role of the endothelium in inflammatory bowel diseases. World J. Gastroenterol. 2011, 17, 578–593. [Google Scholar] [CrossRef]
  136. Dvornikova, K.A.; Platonova, O.N.; Bystrova, E.Y. Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int. J. Mol. Sci. 2023, 24, 2425. [Google Scholar] [CrossRef]
  137. Aggeletopoulou, I.; Marangos, M.; Assimakopoulos, S.F.; Mouzaki, A.; Thomopoulos, K.; Triantos, C. Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis. Am. J. Pathol. 2023; In press. [Google Scholar] [CrossRef]
  138. Czank, C.; Cassidy, A.; Zhang, Q.; Morrison, D.J.; Preston, T.; Kroon, P.A.; Botting, N.P.; Kay, C.D. Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: A (13)C-tracer study. Am. J. Clin. Nutr. 2013, 97, 995–1003. [Google Scholar] [CrossRef] [PubMed]
  139. Daveri, E.; Cremonini, E.; Mastaloudis, A.; Hester, S.N.; Wood, S.M.; Waterhouse, A.L.; Anderson, M.; Fraga, C.G.; Oteiza, P.I. Cyanidin and delphinidin modulate inflammation and altered redox signaling improving insulin resistance in high fat-fed mice. Redox Biol. 2018, 18, 16–24. [Google Scholar] [CrossRef] [PubMed]
  140. Fratantonio, D.; Speciale, A.; Ferrari, D.; Cristani, M.; Saija, A.; Cimino, F. Palmitate-induced endothelial dysfunction is attenuated by cyanidin-3-O-glucoside through modulation of Nrf2/Bach1 and NF-kappaB pathways. Toxicol. Lett. 2015, 239, 152–160. [Google Scholar] [CrossRef] [PubMed]
  141. Dinkova-Kostova, A.T.; Talalay, P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol. Nutr. Food Res. 2008, 52 (Suppl. 1), S128–S138. [Google Scholar] [CrossRef]
  142. Lee, J.M.; Johnson, J.A. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J. Biochem. Mol. Biol. 2004, 37, 139–143. [Google Scholar] [CrossRef]
  143. Asano, K.; Takahashi, N.; Ushiki, M.; Monya, M.; Aihara, F.; Kuboki, E.; Moriyama, S.; Iida, M.; Kitamura, H.; Qiu, C.H.; et al. Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes. Nat. Commun. 2015, 6, 7802. [Google Scholar] [CrossRef]
  144. Junt, T.; Moseman, E.A.; Iannacone, M.; Massberg, S.; Lang, P.A.; Boes, M.; Fink, K.; Henrickson, S.E.; Shayakhmetov, D.M.; Di Paolo, N.C.; et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 2007, 450, 110–114. [Google Scholar] [CrossRef] [PubMed]
  145. Kuka, M.; Iannacone, M. The role of lymph node sinus macrophages in host defense. Ann. N. Y. Acad. Sci. 2014, 1319, 38–46. [Google Scholar] [CrossRef] [PubMed]
  146. Saunderson, S.C.; Dunn, A.C.; Crocker, P.R.; McLellan, A.D. CD169 mediates the capture of exosomes in spleen and lymph node. Blood 2014, 123, 208–216. [Google Scholar] [CrossRef]
  147. Ravishankar, B.; Shinde, R.; Liu, H.; Chaudhary, K.; Bradley, J.; Lemos, H.P.; Chandler, P.; Tanaka, M.; Munn, D.H.; Mellor, A.L.; et al. Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc. Natl. Acad. Sci. USA 2014, 111, 4215–4220. [Google Scholar] [CrossRef] [PubMed]
  148. Hiemstra, I.H.; Beijer, M.R.; Veninga, H.; Vrijland, K.; Borg, E.G.; Olivier, B.J.; Mebius, R.E.; Kraal, G.; den Haan, J.M. The identification and developmental requirements of colonic CD169(+) macrophages. Immunology 2014, 142, 269–278. [Google Scholar] [CrossRef]
  149. Makita, S.; Kanai, T.; Nemoto, Y.; Totsuka, T.; Okamoto, R.; Tsuchiya, K.; Yamamoto, M.; Kiyono, H.; Watanabe, M. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J. Immunol. 2007, 178, 4937–4946. [Google Scholar] [CrossRef]
  150. Sakuraba, A.; Sato, T.; Kamada, N.; Kitazume, M.; Sugita, A.; Hibi, T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn’s disease. Gastroenterology 2009, 137, 1736–1745. [Google Scholar] [CrossRef]
  151. Wang, D.; Li, Q.; Yang, Y.; Hao, S.; Han, X.; Song, J.; Yin, Y.; Li, X.; Tanaka, M.; Qiu, C.H. Macrophage Subset Expressing CD169 in Peritoneal Cavity-Regulated Mucosal Inflammation Together with Lower Levels of CCL22. Inflammation 2017, 40, 1191–1203. [Google Scholar] [CrossRef]
  152. Li, Q.; Wang, D.; Hao, S.; Han, X.; Xia, Y.; Li, X.; Chen, Y.; Tanaka, M.; Qiu, C.H. CD169 Expressing Macrophage, a Key Subset in Mesenteric Lymph Nodes Promotes Mucosal Inflammation in Dextran Sulfate Sodium-Induced Colitis. Front. Immunol. 2017, 8, 669. [Google Scholar] [CrossRef]
  153. Lee, S.G.; Kim, B.; Yang, Y.; Pham, T.X.; Park, Y.K.; Manatou, J.; Koo, S.I.; Chun, O.K.; Lee, J.Y. Berry anthocyanins suppress the expression and secretion of proinflammatory mediators in macrophages by inhibiting nuclear translocation of NF-kappaB independent of NRF2-mediated mechanism. J. Nutr. Biochem. 2014, 25, 404–411. [Google Scholar] [CrossRef]
  154. Brennan, K.; Lyons, C.; Fernandes, P.; Doyle, S.; Houston, A.; Brint, E. Engagement of Fas differentially regulates the production of LPS-induced proinflammatory cytokines and type I interferons. FEBS J. 2019, 286, 523–535. [Google Scholar] [CrossRef] [PubMed]
  155. Wang, Z.; Zhang, M.; Wang, Z.; Guo, Z.; Wang, Z.; Chen, Q. Cyanidin-3-O-glucoside attenuates endothelial cell dysfunction by modulating miR-204-5p/SIRT1-mediated inflammation and apoptosis. Biofactors 2020, 46, 803–812. [Google Scholar] [CrossRef] [PubMed]
  156. Morais, C.A.; de Rosso, V.V.; Estadella, D.; Pisani, L.P. Anthocyanins as inflammatory modulators and the role of the gut microbiota. J. Nutr. Biochem. 2016, 33, 1–7. [Google Scholar] [CrossRef]
  157. Lee, S.; Keirsey, K.I.; Kirkland, R.; Grunewald, Z.I.; Fischer, J.G.; de La Serre, C.B. Blueberry Supplementation Influences the Gut Microbiota, Inflammation, and Insulin Resistance in High-Fat-Diet-Fed Rats. J. Nutr. 2018, 148, 209–219. [Google Scholar] [CrossRef]
  158. Zhao, S.; Liu, W.; Wang, J.; Shi, J.; Sun, Y.; Wang, W.; Ning, G.; Liu, R.; Hong, J. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. J. Mol. Endocrinol. 2017, 58, 1–14. [Google Scholar] [CrossRef]
  159. Rinttila, T.; Kassinen, A.; Malinen, E.; Krogius, L.; Palva, A. Development of an extensive set of 16S rDNA-targeted primers for quantification of pathogenic and indigenous bacteria in faecal samples by real-time PCR. J. Appl. Microbiol. 2004, 97, 1166–1177. [Google Scholar] [CrossRef] [PubMed]
  160. Fiore, E.; Van Tyne, D.; Gilmore, M.S. Pathogenicity of Enterococci. Microbiol. Spectr. 2019, 7. [Google Scholar] [CrossRef]
  161. Wen, X.; Wang, H.G.; Zhang, M.N.; Zhang, M.H.; Wang, H.; Yang, X.Z. Fecal microbiota transplantation ameliorates experimental colitis via gut microbiota and T-cell modulation. World J. Gastroenterol. 2021, 27, 2834–2849. [Google Scholar] [CrossRef] [PubMed]
  162. Wang, C.; Li, W.; Wang, H.; Ma, Y.; Zhao, X.; Zhang, X.; Yang, H.; Qian, J.; Li, J. Saccharomyces boulardii alleviates ulcerative colitis carcinogenesis in mice by reducing TNF-alpha and IL-6 levels and functions and by rebalancing intestinal microbiota. BMC Microbiol. 2019, 19, 246. [Google Scholar] [CrossRef]
  163. Sun, Q.; Ji, Y.C.; Wang, Z.L.; She, X.; He, Y.; Ai, Q.; Li, L.Q. Sodium Butyrate Alleviates Intestinal Inflammation in Mice with Necrotizing Enterocolitis. Mediat. Inflamm. 2021, 2021, 6259381. [Google Scholar] [CrossRef] [PubMed]
  164. Hempel, S.; Newberry, S.J.; Maher, A.R.; Wang, Z.; Miles, J.N.; Shanman, R.; Johnsen, B.; Shekelle, P.G. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: A systematic review and meta-analysis. JAMA 2012, 307, 1959–1969. [Google Scholar] [CrossRef]
  165. Guo, M.; Li, Z. Polysaccharides isolated from Nostoc commune Vaucher inhibit colitis-associated colon tumorigenesis in mice and modulate gut microbiota. Food Funct. 2019, 10, 6873–6881. [Google Scholar] [CrossRef]
  166. Wu, S.; Hu, R.; Nakano, H.; Chen, K.; Liu, M.; He, X.; Zhang, H.; He, J.; Hou, D.X. Modulation of Gut Microbiota by Lonicera caerulea L. Berry Polyphenols in a Mouse Model of Fatty Liver Induced by High Fat Diet. Molecules 2018, 23, 3213. [Google Scholar] [CrossRef]
  167. Wang, K.; Wan, Z.; Ou, A.; Liang, X.; Guo, X.; Zhang, Z.; Wu, L.; Xue, X. Monofloral honey from a medical plant, Prunella Vulgaris, protected against dextran sulfate sodium-induced ulcerative colitis via modulating gut microbial populations in rats. Food Funct. 2019, 10, 3828–3838. [Google Scholar] [CrossRef]
  168. Wang, K.; Jin, X.; Li, Q.; Sawaya, A.; Le Leu, R.K.; Conlon, M.A.; Wu, L.; Hu, F. Propolis from Different Geographic Origins Decreases Intestinal Inflammation and Bacteroides spp. Populations in a Model of DSS-Induced Colitis. Mol. Nutr. Food Res. 2018, 62, e1800080. [Google Scholar] [CrossRef]
  169. Ajiboye, T.O.; Habibu, R.S.; Saidu, K.; Haliru, F.Z.; Ajiboye, H.O.; Aliyu, N.O.; Ibitoye, O.B.; Uwazie, J.N.; Muritala, H.F.; Bello, S.A.; et al. Involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality. Microbiologyopen 2017, 6, e00472. [Google Scholar] [CrossRef] [PubMed]
  170. Nishitani, Y.; Sasaki, E.; Fujisawa, T.; Osawa, R. Genotypic analyses of lactobacilli with a range of tannase activities isolated from human feces and fermented foods. Syst. Appl. Microbiol. 2004, 27, 109–117. [Google Scholar] [CrossRef] [PubMed]
  171. Szwajgier, D.; Jakubczyk, A. Biotransformation of ferulic acid by Lactobacillus acidophilus KI and selected Bifidobacterium strains. ACTA Sci. Pol. Technol. Aliment. 2010, 9, 45–59. [Google Scholar]
  172. Gowd, V.; Bao, T.; Chen, W. Antioxidant potential and phenolic profile of blackberry anthocyanin extract followed by human gut microbiota fermentation. Food Res. Int. 2019, 120, 523–533. [Google Scholar] [CrossRef] [PubMed]
  173. Keppler, K.; Humpf, H.-U. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorganic Med. Chem. 2005, 13, 5195–5205. [Google Scholar] [CrossRef]
  174. Shishir, M.R.I.; Suo, H.; Liu, X.; Kang, Q.; Xiao, J.; Wang, M.; Chen, F.; Cheng, K.W. Development and evaluation of a novel nanofibersolosome for enhancing the stability, in vitro bioaccessibility, and colonic delivery of cyanidin-3-O-glucoside. Food Res. Int. 2021, 149, 110712. [Google Scholar] [CrossRef]
  175. Schroeder, K.W.; Tremaine, W.J.; Ilstrup, D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N. Engl. J. Med. 1987, 317, 1625–1629. [Google Scholar] [CrossRef]
  176. Travis, S.P.; Schnell, D.; Krzeski, P.; Abreu, M.T.; Altman, D.G.; Colombel, J.F.; Feagan, B.G.; Hanauer, S.B.; Lichtenstein, G.R.; Marteau, P.R.; et al. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterology 2013, 145, 987–995. [Google Scholar] [CrossRef]
  177. Chen, M.; Shen, B. Overview of Diagnosis and Medical Treatment of Inflammatory Bowel Diseases. In Interventional Inflammatory Bowel Disease: Endoscopic Management and Treatment of Complications; Academic Press: Cambridge, MA, USA, 2018. [Google Scholar]
  178. Jesse, K.; Liu, G.R.L. Inflammatory Bowel Disease. In Clinical Gastrointestinal Endoscopy, 2nd ed.; Elsevier: Amsterdam, The Netherlands, 2012; pp. 243–264. [Google Scholar]
  179. Niv, Y.; Gal, E.; Gabovitz, V.; Hershkovitz, M.; Lichtenstein, L.; Avni, I. Capsule Endoscopy Crohn’s Disease Activity Index (CECDAIic or Niv Score) for the Small Bowel and Colon. J. Clin. Gastroenterol. 2018, 52, 45–49. [Google Scholar] [CrossRef] [PubMed]
  180. Burri, E.; Maillard, M.H.; Schoepfer, A.M.; Seibold, F.; Van Assche, G.; Riviere, P.; Laharie, D.; Manz, M. Treatment Algorithm for Mild and Moderate-to-Severe Ulcerative Colitis: An Update. Digestion 2020, 101 (Suppl. 1), 2–15. [Google Scholar] [CrossRef]
  181. Johnson, T.O.; Akinsanmi, A.O.; Ejembi, S.A.; Adeyemi, O.E.; Oche, J.R.; Johnson, G.I.; Adegboyega, A.E. Modern drug discovery for inflammatory bowel disease: The role of computational methods. World J. Gastroenterol. 2023, 29, 310–331. [Google Scholar] [CrossRef] [PubMed]
  182. Chen, Y.; Zhang, G.; Yang, Y.; Zhang, S.; Jiang, H.; Tian, K.; Arenbaoligao; Chen, D. The treatment of inflammatory bowel disease with monoclonal antibodies in Asia. Biomed. Pharmacother. Biomed. Pharmacother. 2023, 157, 114081. [Google Scholar] [CrossRef] [PubMed]
Year; Author Study Type Subjects (Animal/Cell Models/Individuals) Dose IBD Indicators Related Molecular Mechanisms in Regulation of IBD
[125] In vitro CM stimulated T84 cells 25, 50, 100 μM for 4 h NA ↓ IP-10 (CXCL10)
[115] In vitro Cytokine stimulated HT-29 cells 12.5 to 50 μM for 24 h NA ↓ NO,↓ PGE2, ↓ IL-8, ↓ iNOS

↓ COX-2↓ STAT1

[116] In vitro Cytokine stimulated HT-29 cells 25 μM, for 1 h ↑ Nrf2 pathway,

↑ HO-1,↑ GCLC and GCLM

↑ GSH/GSSG

↓ Reactive species
[114] In vitro Caco-2 cells + TNF-α 20–40 μM for24 h ↑ Nrf2 pathway,

↑ GSH

↑ HO-1 and NQO-1 mRNA Levels

↓ TNF-α, ↓ IKKα/β

phosphorylation/activation and IκBα, ↓ NF-κB pathway

↓ Il-6 induced by TNF-α, COX-2, PGE2 and TXB2

[118] In vitro Caco-2 cells 0.25, 0.5 and 1 μM for 24 h ↑ FITC-dextran permeability ↓ IKKα, ↓ p65 phosphorylation, ↓ MLC, ↓ TNFα, ↓ NF-kB pathway,

↓ TEER

[121] In vitro Caco-2-HUVECs 20 or 40 μM for 24 h NA ↓ NF-κB pathway, ↓ TNF-α, ↓ IL-8

↓ endothelial cells activation:

↓ E-selectin, ↓ VCAM-1 mRNA, ↓ leukocyte adhesion

[39] In vivo and in vitro BALB/c TNBS-induced colitic mice

Caco-2 cell monolayer model +LPS

200 μL for 12 h before TNBS injection

24.2–96.8 g/kgBW daily for 3 days

NA ↓ MPO, ↓ TEER, ↓ LY flux values.

↓ NO, ↓ TNF-α, ↓ IL-1b, ↓ IL-6, ↓ IFN-γ

↓ histological damage

[117] In vitro (Cell culture: RAW 264.7 cells+ IFNα+ IFNβ, 24 h)

Naïve mouse peritoneal macrophages, lymphocytes removed + 1 ug/mL LPS, 24 h

1 ug/mL for 24 h NA Direct inhibition of CD80 and

CD86

Inhibition of CD169 Expression induced by Type I IFN

↓ IL-1β, IL-18, IL-6, IL-17, and TNF-α

[36] In vitro Caco-2 cells + 100 μM PA

(basolateral side)

10 or 20 μM for 24 h ↑ Nrf2/EpRE pathway

↑ NQO-1

↓ NF-κB pathway

↓ IL-6 and IL-8 mRNA levels

↓ COX-2

↓ ROS

[113] In vitro Caco-2 cells+ LPS ± HPP C3G-BP complexes (100–100 μg/mL) ↑ IL-10 ↓ depolarization of mitochondria,

↓ ROS

↓ IL-1β, TNF-α, and IL-8

↓ iNOS, COX-2, Bcl-2 and cleaved caspase-3 levels

Inhibition of apoptosis

[119] In vitro Caco-2 cells +TNF- α 0.18, 0.37, 0.75, 1.5 μg C3G eq./mL for 24 h

(ACN-rich purified and standardized bilberry and blackcurrant extract (BBE))

Activation of Nrf2/ Keap1 pathway Inhibition of NF-κB pathway activated by TNF-α

↓ IL-8 and ↓ IL-6 mRNA levels

[124] In vivo DSS-induced colitic UC mice + HHP treatment HPP 200 mg/kg C3G+ blueberry pectin complex (Oral administration) ↑ protein levels of the ratio Bcl-2/Bax and caspase-3/cleaved caspase-3 genes

↑ Bacteroidetes, Verrucomicrobia Candidatus Saccharibacteria.

↓ mRNA expression of pro-inflammatory factors

↓ NF-κB P65, ↓ NF-κB pathway

↓ Firmicutes, Proteobacteria,

↓ Firmicutes to Bacteroidetes (F/B) ratio

[126] Cohort study 47 IBD patients

Administration of a purple corn supplement to IBD patients receiving infliximab

Purple corn supplement composed by 2 mg GAE/g DW (gallic acid equivalents per g of dry weight) and total anthocyanin content

of 0.5 mg cyanidin 3-glucoside (C3G)

NA CD group only, not UC:

↓ CRP, ↓ IFN-γ

↓ TNF-α, IL-5, IL-9, IL-10, IL-12p70, and IL-17A

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Share and Cite

Frountzas, M.; Karanikki, E.; Toutouza, O.; Sotirakis, D.; Schizas, D.; Theofilis, P.; Tousoulis, D.; Toutouzas, K.G. Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions. Int. J. Mol. Sci. 2023, 24, 9399. https://doi.org/10.3390/ijms24119399

Frountzas M, Karanikki E, Toutouza O, Sotirakis D, Schizas D, Theofilis P, Tousoulis D, Toutouzas KG. Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions. International Journal of Molecular Sciences. 2023; 24(11):9399. https://doi.org/10.3390/ijms24119399

Chicago/Turabian Style

Frountzas, Maximos, Eva Karanikki, Orsalia Toutouza, Demosthenis Sotirakis, Dimitrios Schizas, Panagiotis Theofilis, Dimitris Tousoulis, and Konstantinos G. Toutouzas. 2023. “Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions” International Journal of Molecular Sciences 24, no. 11: 9399. https://doi.org/10.3390/ijms24119399

You are watching: Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions. Info created by GBee English Center selection and synthesis along with other related topics.