Submit a Manuscript: http://www.f6publishing.com World J Gastroenterol 2017 July 28; 23(28): 5097-5114 DOI: 10.3748/wjg.v23.i28.5097 ISSN 1007-9327 (print) ISSN 2219-2840 (online) REVIEW Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review Ali Salaritabar, Behrad Darvishi, Farzaneh Hadjiakhoondi, Azadeh Manayi, Antoni Sureda, Seyed Fazel Nabavi, Leo R Fitzpatrick, Seyed Mohammad Nabavi, Anupam Bishayee Ali Salaritabar, Behrad Darvishi, Department of Integrative work non-commercially, and license their derivative works on Oncology, Breast Cancer Research Center, Motamed Cancer different terms, provided the original work is properly cited and Institute, ACECR, Tehran 15179-64311, Iran the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Ali Salaritabar, Behrad Darvishi, Department of Recombinant Protein, Breast Cancer Research Center, Motamed Cancer Manuscript source: Invited manuscript Institute, ACECR, Tehran 15179-64311, Iran Correspondence to: Anupam Bishayee, PhD, Department Farzaneh Hadjiakhoondi, Azadeh Manayi, Medicinal Plants of Pharmaceutical Sciences, College of Pharmacy, Larkin Research Center, Faculty of Pharmacy, Tehran University of University, Miami, FL 33169, Medical Sciences, Tehran 14176-14411, Iran United States. [email protected] Telephone: +1-305-7607511 Antoni Sureda, Research Group on Community Nutrition and Oxidative Stress and CIBEROBN - Physiopathology of Obesity Received: February 16, 2017 and Nutrition, University of Balearic Islands, Palma de Mallorca, Peer-review started: February 19, 2017 E-07122 Balearic Islands, Spain First decision: March 3, 2017 Revised: May 12, 2017 Seyed Fazel Nabavi, Seyed Mohammad Nabavi, Applied Accepted: July 4, 2017 Biotechnology Research Center, Baqiyatallah University of Article in press: July 4, 2017 Medical Sciences, Tehran 14359-16471, Iran Published online: July 28, 2017 Leo R Fitzpatrick, Department of Pharmaceutical and Biomedical Sciences, California Northstate University College of Pharmacy, Elk Grove, CA 95757, United States Abstract Anupam Bishayee, Department of Pharmaceutical Sciences, The inflammatory process plays a central role in the College of Pharmacy, Larkin University, Miami, FL 33169, United States development and progression of numerous patho- logical situations, such as inflammatory bowel disease Author contributions: Manayi A, Nabavi SF, Nabavi SM (IBD), autoimmune and neurodegenerative diseases, and Bishayee A designed the review; Salaritabar A, Darvishi metabolic syndrome, and cardiovascular disorders. ibds B, Hadjiakhoondi F, Manayi A and Sureda A performed the involve inflammation of the gastrointestinal area and literature search and wrote the paper; Fitzpatrick LR, Nabavi SM mainly comprise Crohn’s disease (CD) and ulcerative and Bishayee A improved and revised the final version. colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight Conflict-of-interest statement: The authors declare no conflict loss. There is at present no pharmacological cure for of interests for this article. CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external the symptoms and prevent and/or delay new painful reviewers. It is distributed in accordance with the Creative episodes. Flavonoid compounds are a large family Commons Attribution Non Commercial (CC BY-NC 4.0) license, of hydroxylated polyphenolic molecules abundant in which permits others to distribute, remix, adapt, build upon this plants, including vegetables and fruits which are the WJG|www.wjgnet.com 5097 July 28, 2017|Volume 23|Issue 28| Salaritabar A et al . Flavonoids and IBD major dietary sources of these compounds for humans, of the produced mediators, mainly cytokines, are able together with wine and tea. Flavonoids are becoming to activate signaling by nuclear factor-kappa B (NF- very popular because they have many health-promoting κB), a transcription factor which also mediates the and disease-preventive effects. Most interest has been inflammatory response[5-7]. directed towards the antioxidant activity of flavonoids, IBDs include a group of pathologies characterized evidencing a remarkable free-radical scavenging by chronic and uncontrolled inflammation associated capacity. However, accumulating evidence suggests with deregulation of both adaptive and innate immunity that flavonoids have many other biological properties, that affects the gastrointestinal tract[8,9]. The bowel including anti-inflammatory, antiviral, anticancer, and inflammation results in symptoms, such as abdominal neuroprotective activities through different mechanisms [8,9] pain, bleeding, recurrent diarrhea and weight loss . of action. The present review analyzes the available The two main pathologies are Crohn’s disease (CD) data about the different types of flavonoids and their and ulcerative colitis (UC). CD can affect any area of potential effectiveness as adjuvant therapy of ibds. the gastrointestinal tract, from the mouth to the anus, Key words: Antioxidant; Inflammation; Gastrointestinal although the ileum is the most affected section. In tract; Flavonoids; Polyphenols contrast, UC primarily affects the colon and the rectum. The exact cause of IBD is not fully known, although © The Author(s) 2017. Published by Baishideng Publishing there is an interaction between diverse factors, such as Group Inc. All rights reserved. an immune system disturbance, genetic predisposition, and environmental factors, which activates the Core tip: Inflammatory bowel diseases (ibds) damaging immune response in the intestines. Today, involve inflammation of the gastrointestinal tract and there is no effective pharmacological treatment that primarily comprise Crohn's disease and ulcerative allows for cure of the disease. Medical therapy is colitis. Currently, there is no cure for most of the ibds. focused on non-specific immunosuppressive therapies, Emerging evidence suggests that flavonoids have many including thiopurines and methotrexate[10,11]. The biological and pharmacological properties, including occurrence and prevalence of IBDs are progressively anti-inflammatory, antiviral, anticancer, and neuro- growing in all areas around the world, suggesting its protective activities through different mechanisms appearance as a global disease in the near future[12]. of action. The present review critically analyzes the The term flavonoid derives from the Latin word current experimental evidence on the therapeutic “flavus”, meaning yellow, and comprises a group potential of flavonoids in IBD. of secondary metabolic compounds widely found in plants well known for the distinctive blue, red, and purple anthocyanin pigments of their different Salaritabar A, Darvishi B, Hadjiakhoondi F, Manayi A, structures. Although they are not stated as nutrients Sureda A, Nabavi SF, Fitzpatrick LR, Nabavi SM, Bishayee and regardless of their physiological functions A. Therapeutic potential of flavonoids in inflammatory bowel in plants, flavonoids are key ingredients of the disease: A comprehensive review. World J Gastroenterol 2017; [13] 23(28): 5097-5114 Available from: URL: http://www.wjgnet. human diet . Based on epidemiological studies, com/1007-9327/full/v23/i28/5097.htm DOI: http://dx.doi. diets rich in flavonoids are in direct correlation with org/10.3748/wjg.v23.i28.5097 increased longevity and decreased cardiovascular disease incidence, despite consuming diets with high fat content[14-17]. Many biological effects have been attributed to the flavonoids, in addition to their INTRODUCTION antioxidant properties, some of which include anti-infla- mmatory, antimicrobial, vasodilatory, anti-ischemia and Inflammation is a protective and complex process anticancer effects[16,18-20]. consisting of a set of molecular, cellular and vascular Recently, owing to their significant antioxidant defensive responses against any injury, including and free radical scavenging properties observed in chemical, physical, or biological attacks, and focused vitro, interest towards investigating new possible [1] on restoring tissue function . Inflammatory diseases health benefits has significantly increased. In comprise a group of illnesses characterized by a fact, flavonoids are of great nutritional value in in- [2] long-term pro-inflammatory state . A large number flammatory diseases because they can block many of pathologies are considered as inflammatory pro-inflammatory proteins and can be considered diseases, such as autoimmune and cardiovascular natural inhibitors of inflammation, ameliorating disorders, chronic obstructive pulmonary diseases, the intensity of inflammation[21]. In addition to the neurodegenerative diseases, and chronic inflammatory direct antioxidant activity, flavonoids are capable of bowel disease (IBD). This inflammatory response activating diverse antioxidant and protective genes is associated with changes in vascular permeability, via nuclear transcription factors and also of inhibiting increases in blood flow, leukocyte mobilization and rise inflammatory pathways[22]. Flavonoids influence the in the production of inflammatory mediators[3,4]. Some composition of the microbial flora, favoring the growth WJG|www.wjgnet.com 5098 July 28, 2017|Volume 23|Issue 28| Salaritabar A et al . Flavonoids and IBD of flavonols have suggested that the hydrophilic