molecules Review Phytochemicals Targeting JAK–STAT Pathways in Inflammatory Bowel Disease: Insights from Animal Models Sun Young Moon 1,2, Kwang Dong Kim 1,2, Jiyun Yoo 1,2, Jeong-Hyung Lee 3 and Cheol Hwangbo 1,2,* 1 Division of Applied Life Science (BK21), PMBBRC and Research Institute of Life Sciences, Gyeongsang National University, Jinju 52828, Korea; [email protected] (S.Y.M.); [email protected] (K.D.K.); [email protected] (J.Y.) 2 Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea 3 Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 24341, Korea; [email protected] * Correspondence: [email protected]; Tel.:+82-55-772-1341 Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that consists of Crohn’s disease (CD) and ulcerative colitis (UC). Cytokines are thought to be key mediators of inflammation-mediated pathological processes of IBD. These cytokines play a crucial role through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. Several small molecules inhibiting JAK have been used in clinical trials, and one of them has been approved for IBD treatment. Many anti-inflammatory phytochemicals have been shown to have potential as new drugs for IBD treatment. This review describes the significance of the JAK–STAT pathway as a current therapeutic target for IBD and discusses the recent findings that phytochemicals can ameliorate disease symptoms by affecting the JAK–STAT pathway in vivo in IBD disease models. Thus, we suggest that phytochemicals modulating JAK–STAT pathways are Citation: Moon, S.Y.; Kim, K.D.; potential candidates for developing new therapeutic drugs, alternative medicines, and nutraceutical Yoo, J.; Lee, J.-H.; Hwangbo, C. Phytochemicals Targeting JAK–STAT agents for the treatment of IBD. Pathways in Inflammatory Bowel Disease: Insights from Animal Keywords: inflammatory bowel disease (IBD); janus kinase (JAK); signal transducer and activator of Models. Molecules 2021, 26, 2824. transcription (STAT); phytochemicals https://doi.org/10.3390/ molecules26092824 Academic Editor: Silvie Rimpelová 1. Introduction Plants’ phytochemicals have been used as a source of traditional medicine for millen- Received: 13 April 2021 nia [1]. A large portion of current drugs for disease treatment have originated from plants, Accepted: 7 May 2021 even though new drugs have been developed using synthetic chemistry [2]. Recently, Published: 10 May 2021 the significance of phytochemicals has been emphasized for therapeutic applications with fewer side effects in various inflammation-related diseases, including cancer, diabetes, Publisher’s Note: MDPI stays neutral rheumatoid arthritis, and inflammatory bowel disease (IBD) [3,4]. Phytochemicals are good with regard to jurisdictional claims in sources of new anti-inflammatory drugs that regulate various inflammatory responses published maps and institutional affil- against inflammatory diseases [5]. iations. Inflammatory bowel disease is a typical chronic inflammation-mediated disease of the gastrointestinal (GI) tract [6]. IBD is typically classified into two major forms of chronic and relapsing-remitting inflammation: Crohn’s disease (CD) and ulcerative colitis (UC), which is increasing in incidence and prevalence worldwide [7]. Although both diseases Copyright: © 2021 by the authors. have common clinical features, such as diarrhea and abdominal pain, they differ in various Licensee MDPI, Basel, Switzerland. aspects. Crohn’s disease is characterized by discontinuous inflammation at any location in This article is an open access article the digestive tract, from the mouth to the anus, which can spread into the deeper layers of distributed under the terms and the bowel [8]. On the other hand, ulcerative colitis is a long-standing chronic inflammation conditions of the Creative Commons Attribution (CC BY) license (https:// of the colonic mucosa, which affects certain parts or the entire colon, and is most commonly creativecommons.org/licenses/by/ limited to the mucosal surface [9]. Despite the fact that CD and UC are distinct entities, 4.0/). the precise causes of disease pathogenesis remain largely unknown. Molecules 2021, 26, 2824. https://doi.org/10.3390/molecules26092824 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 19 Molecules 2021, 26, 2824 2 of 20 most commonly limited to the mucosal surface [9]. Despite the fact that CD and UC are distinct entities, the precise causes of disease pathogenesis remain largely unknown. TheThe significance significance of of treatment treatment and and prevention prevention of of IBD IBD has has been been steadily steadily increasing increasing [10]. [10]. AlthoughAlthough many drugs drugs have have been been developed developed to treat treat IBD, IBD, these these drugs drugs have have adverse adverse effects effects onon the GIGI tracttract [ 11[11].]. In In addition addition to to conventional conventional drugs, drugs, there there have have been been important important advances ad- vancesin IBD in therapy IBD therapy targeting targeting cytokines cytokines that have that been have well been documented well documented to play to a keyplay role a key in roleboth in the both chronic the andchronic relapsing and relapsing phases of phases IBD [12 of]. ForIBD example, [12]. For tumor example, necrosis tumor factor necrosis (TNF) factorinhibitors (TNF) have inhibitors been progressively have been progressively used as therapies used foras therapies IBD. However, for IBD. the However, development the developmentof new drugs of has new been drugs emphasized has been because emphasiz unresponsiveed because patientsunresponsive or patients patients who or have pa- tientslost response who have to anti-TNFlost response therapy to anti-TNF are growing, therapy and are a wide growing, array and of cytokines a wide array besides of cyto- TNF kinesare involved besides inTNF the are pathogenesis involved in ofthe IBD pathogen [13–15].esis Currently, of IBD [13–15]. inhibitors Currently, of JAK andinhibitors STAT ofthat JAK prevent and STAT multiple that prevent pro-inflammatory multiple pro-inflammatory cytokine signaling cytokine pathways signaling in IBD pathways have been in IBDconsidered have been as new considered therapeutic as new approaches therapeuti [16c,17 approaches]. Most cytokines [16,17]. in Mo IBDst cytokines play crucial in rolesIBD playin chronic crucial inflammatory roles in chronic responses inflammatory by activating responses the JAK–STAT by activating pathways the JAK–STAT (Figure1 )[path-18]. waysBinding (Figure of cytokines 1) [18]. toBinding their respective of cytokines transmembrane to their respective receptors transmembrane promotes the activationreceptors promotesof JAK, which the activation allows the of translocation JAK, which allows of STATs the to translocation the nucleus. Eventually,of STATs to they the nucleus. regulate Eventually,the transcription they regulate of specific the target transcription genes [19 ].of Accumulating specific target evidence genes [19]. supports Accumulating the idea thatev- idencetherapeutic supports intervention the idea ofthat the therapeutic JAK–STAT intervention pathway can of efficiently the JAK–STAT modulate pathway the complex can ef- ficientlyinflammation modulate driven the bycomplex various inflammation cytokines in driven IBD [20 by]. various In particular, cytokines tofacitinib, in IBD [20]. a JAK In particular,inhibitor, hastofacitinib, already a been JAK approvedinhibitor, andhas already is clinically been used approved for UC and patients, is clinically and manyused forother UC inhibitors patients, and are nowmany being other studied inhibitors in preclinicalare now being and studied clinical in trial preclinical phases [and17]. clin- JAK icalinhibitors trial phases are small [17]. moleculesJAK inhibitors that blockare sm JAKall molecules activity, whichthat block transduces JAK activity, signals which from transducescytokine-receptors signals from to STAT cytokine-receptors [21]. In addition, to direct STAT inhibitors [21]. In addition, of STAT direct have beeninhibitors studied of STATin preclinical have been models studied of IBD, in preclinical even though models no clinical of IBD, trials even have though been no undertaken clinical trials for have IBD beenpatients undertaken [22]. Compared for IBD topatients conventional [22]. Comp treatments,ared to targetingconventional the JAK–STAT treatments, pathway targeting is theconsidered JAK–STAT a new pathway therapeutic is considered strategy a for new IBD th patientserapeutic [20 strategy]. for IBD patients [20]. Figure 1. JAK–STAT signaling pathway activated in response to cytokines. Binding of cytokines to Figure 1. JAK–STAT signaling pathway activated in response to cytokines. Binding of cytokines to their cognate receptors triggers the phosphorylation of JAK and its receptors. After that, recruited their cognate receptors triggers the phosphorylation of JAK and its receptors. After that, recruited STAT is phosphorylated and translocated as homo- or heterodimers to the nucleus, where they upregulateSTAT is phosphorylated the transcription and of translocatedcytokine-responsive as homo- genes. or heterodimers to the nucleus, where they upregulate the transcription of cytokine-responsive genes. Anti-inflammatory phytochemicals are known to have anti-IBD activity by modulat- Anti-inflammatory phytochemicals