Phytochemicals Targeting JAK–STAT Pathways in Inflammatory Bowel Disease Models

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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 are known to have anti-IBD activity by mod- ing the production of inflammatory cytokines [23]. To investigate the function of phyto- ulating the production of inflammatory cytokines [23]. To investigate the function of chemicals targeting JAK–STAT pathways in IBD, we searched for articles in PubMed with phytochemicals targeting JAK–STAT pathways in IBD, we searched for articles in PubMed with three main key words (phytochemical, IBD, and anti-inflammation). In addition, we limited phytochemicals that regulated JAK–STAT pathways in in vivo animal model

Molecules 2021, 26, 2824 3 of 20

systems. Numerous studies have shown that phytochemicals, including phenolic compounds, terpenoids, alkaloids, and organosulfur compounds, could be used as therapeutic agents as they modulate cellular inﬂammatory mechanisms associated with IBD [24]. In particular, some phytochemicals have been reported to inhibit activation of the JAK– STAT pathway [25]. Considering the advantages of phytochemicals with few side effects, phytochemicals targeting the JAK–STAT pathways would be a good source of new drugs for the treatment of IBD [26]. This review describes the current understanding of the JAK–STAT pathway in IBD and highlights the signiﬁcance of the JAK–STAT pathway as a therapeutic target for IBD. In addition, we discuss the evidence that phytochemicals induce IBD remission by affecting the JAK–STAT pathway in animal models of IBD. Furthermore, we analyzed human- relevant equivalent doses of each phytochemical modulating the JAK–STAT pathway and suggest that phytochemicals have strong potential for the development of new anti-JAK– STAT drugs for IBD.

2. JAK–STAT Signaling Pathway in IBD The JAK–STAT pathway is a well-conserved signaling pathway and is involved in many cellular processes, including cell division, cell death, and regulatory immune function [27]. The JAK–STAT pathway plays a pathogenic role in many diseases, and its hyperactivation is associated with inflammatory and autoimmune diseases such as rheumatoid arthritis, IBD, systemic lupus erythematosus, and psoriasis [28]. Although the etiology of IBD remains unknown, mucosal immune and non-immune cells in the inflamed gut of IBD patients spontaneously release pro-inflammatory cytokines such as TNF-α, interferon gamma (IFN-γ), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, and IL-12, which play a central pathologic role in IBD [29]. These extracellular cytokines in IBD modulate inflammatory responses by activating the JAK–STAT pathway. The binding of cytokines to their cognate receptors triggers the conformational change of the receptors that alter the position of the associated JAK, resulting in phosphorylation of JAK and tyrosine residues on cytokine receptors [30]. Phosphorylated tyrosine residues on cytokine receptors serve as binding sites for STATs, and the recruitment of STAT to the receptor induces the phosphorylation of STAT by JAK [31]. Ultimately, phosphorylated STATs dissociate from their receptor docking sites and form homo- or heterodimers. After that, they translocate from the cytoplasm into the nucleus, where they regulate the transcription of cytokine-responsive genes (Figure1)[ 19]. The JAK–STAT pathway is a significant intracellular downstream signaling mediator used by various inflammatory cytokines that are increased in IBD. Thus, inhibitors targeting the JAK–STAT pathway have the advantage of suppressing multiple cytokine pathways in the treatment of IBD.

2.1. JAK Family of Proteins and JAK Inhibitors The Janus kinase (JAK) protein family is a non-receptor protein tyrosine kinase family that includes four proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK3 is predominantly found in hematopoietic cells, whereas the expression of JAK1, JAK2, and TYK2 is not restricted to specific tissues [32]. JAK is a critical intracellular signaling mediator that transduces signals from cell surface cytokine receptors to the nucleus in IBD [33]. JAK dysregulation can result in pathological processes in IBD [34]. In addition, various cytokines have been widely accepted as crucial inflammatory mediators leading to immunological events in IBD patients [16]. In this regard, we focus on specific cytokines that have been reported to play a key role in IBD pathogenesis and discuss the JAKs activated by these cytokines. JAK differentially associates with diverse cytokine receptors activated by various cytokines and activates different types of STAT members [19]. In other words, the JAK protein functions as a transmitter between cytokine receptors and STATs in multiple combinations, which allows the generation of specific responses to many different cytokines [35]. Each JAK protein associates with different subunits of cytokine receptors facilitating mul- Molecules 2021, 26, x FOR PEER REVIEW 4 of 19

JAK differentially associates with diverse cytokine receptors activated by various cytokines and activates different types of STAT members [19]. In other words, the JAK pro- Molecules 2021, 26, 2824 tein functions as a transmitter between cytokine receptors and STATs in multiple combi-4 of 20 nations, which allows the generation of specific responses to many different cytokines [35]. Each JAK protein associates with different subunits of cytokine receptors facilitating multiple combinations with different JAK proteins, which exhibit intracellular complexity tipleof IBD combinations [33,36]. Depending with different on the JAKactivated proteins, signaling which from exhibit specific intracellular cytokines complexity to their cog- of IBDnate [receptors,33,36]. Depending the pairing on theof JAK activated is determined signaling (Figure from speciﬁc 2). Binding cytokines of IL-2 to their family cognate cyto- receptors,kines (IL-2, the IL-4, pairing IL-7, ofIL-9, JAK IL-15, is determined and IL-21) (Figure to the 2type). Binding I receptor of IL-2 common family γ-chain cytokines (γc) γ γ (IL-2,activates IL-4, JAK1 IL-7, IL-9,and IL-15,JAK3 and[37,38]. IL-21) Granulocyte-macrophage to the type I receptor common colony-stimulating-chain ( c) activates factor JAK1(GM-CSF), and JAK3 which [37 has,38 been]. Granulocyte-macrophage reported to be increased colony-stimulatingin the serum of CD factorpatients, (GM-CSF), binds to which has been reported to be increased in the serum of CD patients, binds to the type I the type I receptor β-chain and is mediated through JAK2 [39,40]. IL-6 has been reported receptor β-chain and is mediated through JAK2 [39,40]. IL-6 has been reported to have to have a direct correlation with disease activity in IBD [41]. Binding of IL-6 to type I re- a direct correlation with disease activity in IBD [41]. Binding of IL-6 to type I receptor ceptor common glycoprotein 130 (gp130) primarily activates JAK1 and TYK2, followed by common glycoprotein 130 (gp130) primarily activates JAK1 and TYK2, followed by JAK2 JAK2 and TYK2 [42,43]. IL-12 and IL-23 signal through the IL-12 receptor leads to the and TYK2 [42,43]. IL-12 and IL-23 signal through the IL-12 receptor leads to the activation activation of JAK2 and TYK2 [44,45]. IL-10 and IL-22 bind to type II cytokine receptors, of JAK2 and TYK2 [44,45]. IL-10 and IL-22 bind to type II cytokine receptors, which activate which activate JAK1 and TYK2 [28]. Signaling between IFN-γ and IFN-γ receptor requires JAK1 and TYK2 [28]. Signaling between IFN-γ and IFN-γ receptor requires JAK1 and JAK1 and JAK2 [46]. JAK2 [46].

Figure 2. JAK-STAT signalingsignaling pathways pathways in in IBD. IBD. Multiple Multiple combinations combinations with with JAK JAK proteins proteins and and STAT proteinsSTAT proteins are determined are determined depending depending on the on cytokines the cytokines and theirand their cognate cognate receptors. receptors. Each Each cytokine cyto- familykine family playing playing a key a rolekey inrole IBD in pathogenesisIBD pathogenesis is divided is divided into twointo classes.two classes. JAK, JAK, janus janus kinase; kinase; STAT, STAT, signal transducer activator and activation of transcription; IL, interleukin; GM-CSF, granu- signal transducer activator and activation of transcription; IL, interleukin; GM-CSF, granulocyte- locyte-macrophage colony-stimulating factor; IFN, interferon. macrophage colony-stimulating factor; IFN, interferon.

Various inflammatoryinflammatory cytokinescytokines areare linkedlinked toto thethe pathologicalpathological effectseffects ofof IBDIBD throughthrough JAKJAK proteinsproteins [[47].47]. Thus, therapy inhibiting JAK may block multiple proinflammatoryproinflammatory cy- tokinetokine signalingsignaling pathwayspathways in in IBD, IBD, unlike unlike therapy therapy targeting targeting cytokines cytokines or cytokineor cytokine receptors. recep- Currently,tors. Currently, several several JAK inhibitorsJAK inhibitors are being are be evaluateding evaluated for the for treatment the treatment of IBD ofpatients, IBD pa- andtients, one andof them,one of tofacitinib, them, tofacitinib, has already has alread been approvedy been approved for active for UC active patients UC [ 48patients] (Table [48]1). Tofacitinib(Table 1). Tofacitinib is a strong is selective a strong inhibitor selective of inhibitor JAK3 and of JAK1JAK3 andand hasJAK1 modest and has selectivity modest forse- JAK2lectivity and for TYK2 JAK2 [ 49and,50 TYK2]. It can [49,50]. mainly It can block mainly proinflammatory block proinflammatory cytokines (IL-2,cytokines IL-4, (IL-2, IL-7, IL-9,IL-4, IL-15,IL-7, IL-9, and IL-15, IL-21) and by inhibiting IL-21) by JAK1/3inhibiting and JAK1/3 modulating and modulating other cytokines other cytokines that use JAK2 that anduse JAK2 TYK2. and Other TYK2. JAK Other inhibitors JAK areinhibitors being developedare being developed in clinical trials,in clinical including trials, peficitinibincluding andpeficitinib TD-1473 and as TD-1473 pan-JAK as inhibitors pan-JAK [inhibitors51,52], and [51,52], filgotinib and and filgotinib upadacitinib and upadacitinib with selectivity with forselectivity JAK1 [53 for,54 JAK1]. Although [53,54]. these Although JAK inhibitors these JAK target inhibitors specific target JAKs, specific higher JAKs, doses higher could leaddoses to could off-target lead bindingto off-target or immunosuppressive binding or immunosuppressive adverse effects adverse [55]. Therefore, effects [55]. we There- could alternativelyfore, we could consider alternatively phytochemicals, consider phytoc whichhemicals, can modulate which can JAK mo pathwaysdulate JAK in IBD,pathways with fewer side effects than synthetic chemical drugs for the management of adverse processes related to JAK inhibition.

2.2. STAT Family of Proteins and STAT Inhibitors The signal transducer and activator of transcription (STAT) family, which is a critical transcription factor that mediates cytokine-driven signaling, has been actively investigated Molecules 2021, 26, 2824 5 of 20

in IBD pathology [56]. The STAT protein family is composed of seven proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 [57]. Increased expression and activation of STAT1 has been reported in active IBD patients [56,58]. However, the function of STAT1 depends on the cell type in IBD; it is pro-inflammatory in lymphocytes and anti-inflammatory in macrophages/intestinal epithelial cells [59,60]. The phosphorylation of STAT1 is mediated by JAK1/JAK2 or JAK1/TYK2 and has fundamental relevance to signaling via the IFN-γ and related family of receptors [46,61]. STAT1 is also known to be activated by gp130 and γC family receptors [62]. STAT2 is mostly involved in type I interferon (IFN-α and IFN-β)[63]. Although STAT2 has been less studied in IBD pathology compared to other STAT proteins, STAT2 has been suggested to be downregulated in IBD [56]. STAT3 has been well studied to have a fundamental role in IBD. STAT3 is phosphorylated by JAK1, JAK2, or TYK2 activated via signaling of the gp130 family of cytokines (IL-6 and IL-11) or IL-10 family members such as IL-10 and IL-22 [64]. Several studies have reported that the expression and phosphorylation of STAT3 are increased in IBD [65,66]. In addition, downregulation of STAT3 has been shown to improve disease severity in a murine model of colitis [67,68]. The IL-6-STAT3 signaling is involved in the proliferation of lamina propria T cells and blocking of these attenuates chronic intestinal inflammation in experimental colitis [69]. However, similar to STAT1, STAT3 is known to play a role in both pro- and anti-inflammatory effects. STAT3, which is activated by cytokines such as IL-22 and IL-10, plays a protective role in IBD. IL-22 has been reported to induce wound healing, resulting in epithelial regeneration [70–72]. STAT3 phosphorylation by IL-10, which is produced in a wide range of innate leukocytes (macrophages, neutrophils, and dendritic cells), might play a role in preventing the disease in experimental colitis models [73,74]. Taken together, STAT3 promotes pro-inflammatory signals in acquired immune cells in IBD, whereas its role in innate immune cells is the suppression of colitis by enhancing mucosal protection. STAT4 is phosphorylated by JAK2 and TYK2 in response to IL-12- or IL-23-dependent signaling [44,75]. STAT4 is thought to be linked to IBD based on its essential role in the function of T helper type 1 (Th1) cells, which are thought to be important for CD pathogenesis [76]. STAT4 signaling in response to IL-12 is involved in promoting inflammatory reactions by inducing the expression of the Th1-secreted cytokine, IFN-γ [77]. Increased expression of STAT4 in IBD patients has been shown to be involved in chronic inflammation [78,79]. Indeed, STAT4 knock out mice showed protective effects against experimental colitis [80,81]. Thus, targeting STAT4 may have therapeutic potential against IBD. STAT5 is predominantly activated through JAK1 and JAK3 in response to the γC family of receptors by IL-2, -7, -9, -15, and -21, and is also activated by JAK2 in response to the type I receptor β-chain by the IL-3 family [38,82]. Several studies have shown that STAT5 plays a protective role in colitis. As a protective mechanism, STAT5 has been shown to be essential for the proliferation of intestinal epithelial stem cells, leading to the regeneration of crypt epithelium [83]. STAT5 also plays a crucial role in IL-2 dependent forkhead box P3 (FOXP3) induction in Treg cells that can prevent intestinal inflammation in experimental colitis [84,85]. Thus, STAT5 may not be an appropriate therapeutic target for the treatment of IBD. STAT6 phosphorylation arises from JAK1 and JAK3, similar to STAT5; however, it is only induced by the γC family of receptors such as IL-4R and IL-13R [62]. STAT6 has been shown to be involved in T helper cell type 2 (Th2)-dependent IBD pathology and to have pro-inflammatory properties via the regulation of Th2 cytokines [86,87]. The phosphorylation of STAT6 was observably increased in the tissue of UC patients [88,89]. As shown above, STAT proteins could be attractive targets for the regulation of intestinal inflammation in addition to JAK for the treatment of IBD. Indeed, direct inhibitors that block STAT proteins have long been studied for treating inflammatory and autoimmune diseases, including IBD [90]. Small molecule compounds inhibiting STAT1 signaling have been shown to improve disease in experimental colitis by selective sequestering of STAT1 Molecules 2021, 26, 2824 6 of 20

from the receptor [91]. STAT3 inhibitors reduce DNA binding of STAT3, thus blocking cell transformation [92]. In particular, drug discovery targeting STAT3 has been extensively undertaken in various diseases, and a large amount of evidence has supported the therapeutic potential of STAT3 inhibitors [93–96]. Nevertheless, to date, there have been no direct STAT inhibitors in clinics for the treatment of IBD. It has been reported that C188-9 has preventive effects in murine IBD models [22] (Table1). Thus, the identiﬁcation and development of phytochemicals targeting STAT proteins could have a signiﬁcant role in the development of therapeutic drugs for IBD.

Table 1. Targeting the JAK–STAT pathway for IBD treatment.

Compound Target Preclinical/Clinical Model Dose/Daily Ref. Tofacitinib JAK1, JAK3 Approved 10, 20 mg [97] Filgotinib JAK1 PhaseII, III 200 mg [98] JAK inhibitor Upadacitinib JAK1 PhaseIII 24 mg [99] Peﬁcitinib JAK1, JAK2, JAK3, TYK2 PhaseII 25, 75, 150 mg [100] TD-1473 JAK1, JAK2, JAK3 PhaseII, III 20, 80, 270 mg [52] DSS- or TNBS induced STAT inhibitor C188-9 STAT3 Not designated [22] IBDmurine model

3. Phytochemicals Targeting the JAK–STAT Pathway Recently, phytochemicals have been highlighted as alternative/potent candidates for the management of IBD. Many studies have reported that plant-derived natural compounds are considered to have protective and therapeutic effects as dietary supplements for IBD [24]. It has also been suggested that phytochemicals can improve the intestinal barrier through various action mechanisms, including cytokine regulation and reduction of oxidative stress [25,101]. So far, it has been mainly focused on the ability of phytochemicals to downregulate the production of cytokines in IBD [23]. As discussed in the previous section, inhibition of JAK–STAT pathways prevents multiple pro-inﬂammatory cytokine signaling pathways, which can be considered a new therapy in IBD. Herein, we discuss the present evidence that phytochemicals could induce IBD remission by affecting the JAK–STAT pathway in animal model systems of IBD (Table2). In addition, we analyzed human- relevant equivalent doses of each phytochemicals modulating JAK–STAT pathways, which suggests that these phytochemicals could be considered as candidates for new JAK–STAT inhibitors and have the potential for combinatorial use with current JAK inhibitors or other therapeutic drugs in IBD.

3.1. Phenolics Phenolic compounds are secondary metabolites produced by plant cells, which possess a variety of bioactivities such as anti-inflammatory, antioxidant, antibacterial, and antiviral [102]. In particular, phenolic compounds have been well known to play anti- inflammatory roles by modulating diverse intracellular signaling pathways of inflammation and to have beneficial effects in various chronic inflammatory diseases [103].

3.1.1. Curcumin Curcumin is the most well studied phenolic compound derived from Curcuma longa and is known to have anti-mutagenic and anti-tumorigenic effects [104]. Several studies have shown that curcumin has anti-inflammatory effects against IBD. Accumulating evidence has revealed that curcumin has an anti-inflammatory effect on chronic inflammatory diseases by modulating JAK–STAT pathways [105]. In particular, some studies have shown that curcumin has beneficial effects in murine models of IBD. It reduces the severity of dextran sulfate sodium (DSS)-induced colitis by blocking the DNA binding of STAT3 and suppressing STAT3 phosphorylation in the mouse colon [106]. STAT3 has been reported to be highly phosphorylated in IBD patients and to be further involved in colitis-associated Molecules 2021, 26, 2824 7 of 20

cancer as well as colonic inflammation [107]. Another study reported that curcumin can ameliorate trinitrobenzene sulfonic acid (TNBS)-induced severe colitis by downregulating the phosphorylation of JAK2, STAT3, and STAT6 in colonic tissues [108]. It was also found that pretreatment with curcumin in TNBS-induced IBD reduced inflammatory tissue damage by inhibiting the phosphorylation of STAT1 [108]. This suggests that curcumin could be used as a therapeutic intervention for human intestinal inflammation. Although further clinical studies are needed, such as precise dose of administration, curcumin could reduce clinical symptoms of IBD patients and be an effective therapy in humans [109].

3.1.2. EGCG Epigallocatechin-3-gallate (EGCG), a major bioactive polyphenol in green tea, is known to suppress inflammation and oxidative stress [110]. Many studies have shown that EGCG has anti-inflammatory effects on chronic inflammatory diseases, such as neurodegenerative diseases and cancers, in a multifactorial manner [111,112]. It improves acetic acid-induced colitis by reducing oxidative stress by decreasing nitric oxide (NO) production, increasing superoxide dismutase (SOD) expression, and inhibiting the production of TNF-α and IFN-γ in rats [113]. Treatment of DSS-induced colitis mice with EGCG ameliorated colitis by reducing malondialdehyde (MDA) caused by reactive oxygen species (ROS), which is one of the effector mechanisms of inflammation [114]. A recent study showed that EGCG downregulated cytokine IL-6 and reduced the expression of STAT3 protein in the colon tissue of colitis-induced mice. Therefore, EGCG reduced UC-like disease activity [115].

3.1.3. Ellagic Acid Ellagic acid, found in a wide range of fruits and vegetables, including Punica granatum (pomegranate), is known to have various biological activities [116]. In particular, many experimental studies have reported that ellagic acid has significant anti-inflammatory activities in the GI tract [117]. The ellagic acid and ellagic acid-rich fraction of pomegranate have antiulcerative effects in DSS-induced mice and rats [118,119]. Regarding specific anti- IBD molecular mechanisms, ellagic acid decreased inflammatory cytokines (IL-6, TNF-α, and IFN-γ) and crucial inflammatory mediators such as cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS), and blocked the expression and activation of STAT3 signaling pathways along with mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), resulting in a decrease in disease severity in both acute and chronic colitis [120,121].

3.1.4. Gallic Acid Gallic acid, also known as 3,4,5-trihydroxybenzoic acid, is a naturally occurring phenolic compound found in fruits, nuts, and vegetables, and has been shown to have anti- inﬂammatory properties in a variety of chronic inﬂammatory disorders [122,123]. Gallic acid ameliorated UC-like clinical symptoms by reducing the phosphorylation of STAT3 and decreasing p65-NF-κB expression in the colon of DSS-induced mice [124]. Another study showed that gallic acid improved disease severity in DSS-induced mice by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and downregulating the production of IL-21 and IL-23 [125].

3.1.5. Paeonol Paeonol, 2-hydroxy-4-methoxy acetophenone, is a major phenolic compound found in Paeonia suffruticosa, which has been used in traditional medicine and has been reported to have various bioactivities [126]. In particular, several studies have shown that paeonol exhibits anti-inﬂammatory effects in many inﬂammation-related diseases [127]. It reduced TNBS-induced colitis and suppressed IFN-γ-induced STAT1 activation in colon cancer- derived CW-2 cells and T cell leukemia-derived Jurkat cells [128]. Oral administration of paeonol in colitis animal models (mice or rats) reduced colitis symptoms, suggesting that paeonol could be a therapeutic intervention for the treatment of IBD [129,130]. Molecules 2021, 26, 2824 8 of 20

3.1.6. Piceatannol Piceatannol is a hydroxylated derivative of resveratrol, which is a natural stilbene of phenolic compounds in grapes, berries, and passion fruits [131]. It is well known to have anti- inflammatory and suppressive effects on tumors [132,133]. Its anti-inflammatory activities target various inflammatory mediators such as iNOS, COX2, and NK-κB in vivo [134,135]. In DSS-induced colitis mice, piceatannol has been reported to ameliorate clinical signs in colonic tissue [136]. In this case, it exerted anti-inflammatory effects in the colon by decreasing the phosphorylation of STAT3, in addition to reducing the expression of iNOS, COX2, and crucial inflammatory cytokines such as TNF-α and IL-6.

3.1.7. Shikonin Shikonin is a major component extracted from the root of Lithospermum erythrorhizon and has been studied as a potential anticancer and anti-inflammatory drug [137]. The anti- inflammatory effect of shikonin was verified in several in vivo model systems, which attenuated the pathological symptoms by reducing inflammation by inhibiting NF-κB pathways [138–140]. Furthermore, shikonin reduced disease symptoms by blocking the activation of STAT3 and reducing colonic inflammatory cytokines, including IL-1β, IL-6, and TNF-α in a DSS-induced UC model [141]. This suggests that shikonin can be used as a therapeutic agent for treating IBD.

3.2. Terpenoid Terpenoids are secondary metabolites widely distributed in plants and are known to have significant therapeutic potential against inflammatory diseases [142]. Many studies have verified that terpenoids exert anti-inflammatory effects by targeting various inflammatory mediators in in vivo inflammatory disease model systems [143].

Triptolide Triptolide is a bioactive diterpenoid extracted from Tripterygium wilfordii [144]. It suppresses colitis symptoms by inhibiting the IL-6/STAT3 signaling pathway in IL-10 deﬁcient mice as well as in an in vitro culture of colonic explants of patients with CD [145]. It also inhibits the progression from colitis to colon cancer in a 1, 2-dimethylhydrazine (DMH)/DSS- induced mouse model and downregulates the JAK–STAT3 pathway by the phosphorylation of STAT3 in colorectal cancer cells [146].

3.3. Nitrogen-Containing Alkaloids and Sulfur-Containing Compounds 3.3.1. Boldine Boldine, an aporphine alkaloid found in the boldo tree, has been used as a traditional remedy in several diseases and is well known for its anti-tumor, anti-atherogenic, and anti- diabetic effects [147–149]. In terms of anti-inﬂammatory activity, boldin has been reported to attenuate DSS-induced colon damage in mice by inhibiting inﬂammatory processes by increasing antioxidant enzymes SOD and catalase (CAT) and decreasing the expression and activation of STAT3 protein as well as p65 NF-κB in the colon [150].

3.3.2. Berberine Berberine, a benzylisoquinoline alkaloid found in the Berberis species, has been reported to have beneﬁcial effects on DSS- or TNBS-induced colitis mouse models through various molecular mechanisms [151]. Berberine showed anti-colitic activity in TNBS- treated mice by blocking the expansion of Th1 and T helper type 17 (Th17) cells by reducing the phosphorylation of STAT1 and STAT3 in CD4+ T cells isolated from mice [152]. In addition, it ameliorated clinical severity in DSS-induced chronic relapsing mice by inhibiting the differentiation of Th17 cells by downregulating the phosphorylation of STAT3 [153]. Another study reported that berberine is involved in the protection of the intestinal barrier, not only by reducing pro-inﬂammatory cytokines and oxidative stress mediators such as myeloperoxidase (MPO), but also by increasing the expression of tight junction Molecules 2021, 26, 2824 9 of 20

proteins such as zonula occludin-1 (ZO-1), resulting in relieving colitic symptoms in DSS- induced colitis mice [154]. In addition, a recent study demonstrated that berberine inhibited the phosphorylation of JAK1/2 and STAT1/3/4/5/6 through oncostatin M, belonging to the IL-6 cytokine family, leading to the attenuation of gut inﬂammation in DSS-induced mice [155].

3.3.3. Garlic Organosulfur Compounds (Allicin, Diallyl Trisulfide, and Alliin) Garlic has long been used as food or traditional medicine for many diseases, and many studies have verified through in vitro and in vivo model systems that garlic organosulfur compounds have various biological activities, including anti-inflammatory, anti-oxidative, anti-diabetic, and anticancer properties [156]. Garlic is composed of several major organosulfur compounds, some of which have been reported to have anti-inflammatory activity in vivo [157]. Allicin is a sulfur-containing natural compound obtained from garlic, Allium sativum, which has various biological activities [158]. In DSS-induced colitis mice, allicin reduced colon damage by suppressing the phosphorylation of STAT3 and inhibiting the expression of NF-κB[159]. Diallyl trisulfide (DATS) is an organic polysulfide from garlic that has been reported to ameliorate disease symptoms in DSS-induced colitis mice by blocking the DNA binding and phosphorylation of STAT3 [160]. Alliin is a well-known sulfur-containing compound in garlic. Treatment with alliin in DSS-induced colitis mice reduced colon damage, showing a decrease in pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in colonic tissue [161]. In addition, alliin downregulated the activation of STAT1, MAPK, and NF-κB in lipopolysaccharide (LPS)-stimulated macrophages.

3.3.4. Phenethylisothiocyanate Phenethylisothiocyanate (PEITC) is enriched in many cruciferous vegetables and is well known for its anti-cancer activity [162]. Relatively few studies have investigated the anti-inﬂammatory effects of PEITC. PEITC has been reported to alleviate histopatho- logical signs in the acute and chronic inﬂammatory colon induced by DSS and attenuate the activation of STAT1 in LPS-activated macrophages. Therefore, blocking the activation of STAT1 by PEITC is associated with a reduction in IBD [163]. Molecules 2021, 26, x FOR PEER REVIEW 10 of 19

Molecules 2021, 26, x FOR PEER REVIEW 10 of 19

Molecules 2021, 26, x FOR PEER REVIEW 10 of 19 Molecules 2021, 26, x FOR PEER REVIEW 10 of 19 Table 2. Phytochemicals targeting JAK–STAT pathways in inflammatory bowel disease models. Molecules 2021, 26, x FOR PEER REVIEW 10 of 19 Table 2. Phytochemicals targeting JAK–STATEffective pathways Doses in inflammatoryTranslated into bowelHu- diseaseTarget of models. Molecules 2021, 26, x FOR PEER REVIEW Experimental 10 of 19 Class of PhytochemicalsTable 2.Phytochemical Phytochemicals Name targeting JAK–STAT(mg/kg pathways Body inman-Relevant inflammatory Equiva- bowel JAK–STATdisease models. Main Source Ref. Molecules 2021, 26, xTable FOR PEER 2. Phytochemicals REVIEW targetingSystem JAK–STAT Effective pathways Doses in Translatedinflammatory into bowelHu- diseaseTarget of models. 10 of 19 Experimental Weight, Daily) lent (mg/kg) Pathway Molecules Class of2021 Phytochemicals, 26, 2824 Phytochemical Name (mg/kg Body man-Relevant Equiva- JAK–STAT Main Source Ref. 10 of 20 System Effective Doses Translated into Hu- Target of Table 2. PhytochemicalsCurcumin targetingExperimental JAK–STAT EffectiveWeight, pathways Daily) Doses in Translatedinflammatorylent (mg/kg) into Hu-bowel TargetdiseasePathway of models. Class of Phytochemicals Phytochemical Name Experimental (mg/kg Body man-Relevant Equiva- JAK–STAT Main Source Ref. Class of PhytochemicalsTable 2.Phytochemical PhytochemicalsCurcumin Name targeting DSS-inducedSystem JAK–STAT (mg/kg pathways36.8, Body 92 inman-Relevant inflammatory2.9, 7.4 Equiva- bowelJAK–STAT diseaseJAK2, models. CurcumaMain Source longa Ref.[106] Phenolic System EffectiveWeight, Daily) Doses Translatedlent (mg/kg) into Hu- PathwayTarget of Table 2. Phytochemicals targetingTNBS-inducedExperimental JAK–STAT Weight, pathways100 Daily) in inflammatorylent (mg/kg)8.1 bowelSTAT1, Pathwaydisease 3, models.6 Linn (turmeric) [108] Class of Phytochemicals PhytochemicalCurcumin Name DSS-inducedTable 2. Phytochemicals Effective(mg/kg36.8, 92BodyDoses targeting man-RelevantTranslated JAK–STAT2.9, 7.4 into Equiva- Hu- pathwaysJAK–STATTargetJAK2, inof inﬂammatory CurcumaMain Source longa bowel [106] Ref. disease models. Phenolic Curcumin ExperimentalSystem Class of Phytochemicals Phytochemical Name TNBS-induced EffectiveWeight,(mg/kg100 Daily)Body Doses man-RelevantTranslatedlent (mg/kg)8.1 into Equiva- Hu- STAT1,JAK–STATPathwayTarget 3, of 6 LinnMain (turmeric) Source [108] Ref. DSS-inducedExperimentalSystem 36.8, 92 Effective2.9, 7.4 Doses JAK2, TranslatedCurcuma intolonga [106] Class ClassofPhenolic Phytochemicals of PhytochemicalPhytochemicalCurcuminEGCG Name DSS-inducedExperimental Weight,(mg/kg36.8, Daily)92Body man-Relevantlent2.9, (mg/kg) 7.4 Equiva- JAK–STATPathwayJAK2, CurcumaMain Source longa [106] Ref. Target of JAK–STAT Phenolic TNBS-inducedSystem 100 (mg/kg8.1 Body STAT1, 3, 6Human-Relevant Linn (turmeric) [108] Main Source Ref. Curcumin TNBS-induced 100 8.1 STAT1, 3, 6 Linn (turmeric) [108] Phytochemicals NameEGCG DSS-inducedSystem Weight,36.8, Daily)92 lent2.9, (mg/kg) 7.4 PathwayJAK2, Curcuma longa [106] Pathway Phenolic Weight, Daily) Equivalent (mg/kg) Curcumin TNBS-induced 100 8.1 STAT1, 3, 6 Linn (turmeric) [108] EGCG DSS-induced 36.8, 92 2.9, 7.4 JAK2, Curcuma longa [106] Phenolic CurcuminEGCG DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115] TNBS-inducedDSS-inducedDSS-induced 36.8,100 92 36.8,2.9,8.1 7.4 92 STAT1,JAK2, 3, 6 LinnCurcuma2.9, (turmeric) 7.4 longa [108][106] Curcuma longa [106] PhenolicPhenolic JAK2, STAT1, 3, 6 EGCG TNBS-inducedDSS-inducedTNBS-induced 50,100 100 4.0,1008.1 8.1 STAT1, STAT3 3, 6 Linn green8.1 (turmeric) tea [115][108] Linn (turmeric) [108]

EGCG DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115] DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115] EGCGEGCG Ellagic acid DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115]

Ellagic acid DSS-inducedDSS-induced 50, 100 50, 4.0, 100 8.1 STAT3 4.0, green 8.1 tea [115] STAT3 green tea [115] Pomegranate Ellagic acid DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115] Ellagic acid DSS-induced 100 8.1 STAT3 (Punica granatum L., [120] Pomegranate DSS-induced 100 8.1 STAT3 (PunicaLythraceae granatum) L., [120] Ellagic acid Pomegranate PomegranateLythraceae) Ellagic acid DSS-induced 100 8.1 STAT3 (Punica granatum L., [120] Ellagic acid DSS-induced 100 8.1 STAT3 (Punica granatum L., [120] PomegranateLythraceae) Pomegranate (Punica EllagicGallic acidacid Lythraceae) DSS-inducedDSS-induced 100 100 8.1 STAT3 (PunicaPomegranate 8.1 granatum L., [120] STAT3 granatum L., [120] Gallic acid Green tea, strawber- DSS-induced 100 8.1 STAT3 (PunicaLythraceae granatum) L., [120] Lythraceae) ries,Pomegranate grapes, bana- Gallic acid DSS-induced 10 0.8 STAT3 GreenLythraceae tea, strawber-) [124] Gallic acid DSS-induced 100 8.1 STAT3 (Punicanas, and granatum many L., [120] ries, grapes, bana- Gallic acid DSS-induced 10 0.8 STAT3 GreenotherLythraceae tea, strawber-fruits) [124] Gallic acid Greennas, tea, and strawber- many Green tea, ries, grapes, bana- DSS-induced 10 0.8 STAT3 ries,other grapes, fruits bana- [124] strawberries, grapes, Gallic acid DSS-induced 10 0.8 STAT3 Greennas, tea,and strawber- many [124] DSS-induced 10nas, 0.8 and many STAT3 [124] GallicPaeonol acid ries,other grapes, fruits bana- bananas, and many DSS-induced 0.5 mg/kg10 treated 0.8 STAT3 Greenother tea, fruitsstrawber- [124] other fruits Paeonol TNBS-induced 0.04 STAT1 Moutannas, and Cortexmany [128] intrarectally Greenries, grapes, tea, strawber- bana- DSS-induced 0.5 mg/kg10 treated 0.8 STAT3 other fruits [124] Paeonol TNBS-induced 0.04 STAT1 ries,Moutannas, grapes, and Cortex many bana- [128] Paeonol DSS-induced intrarectally10 0.8 STAT3 [124] Piceatannol 0.5 mg/kg treated 0.5 mg/kg treated nas,other and fruits many TNBS-inducedTNBS-induced 0.5 mg/kg treated 0.04 STAT1 Moutan0.04 Cortex [128] STAT1 Moutan Cortex [128] Paeonol TNBS-induced intrarectally intrarectally0.04 STAT1 Moutanother fruitsCortex [128] Piceatannol intrarectally 0.5 mg/kg treated Paeonol TNBS-induced 0.04 STAT1 Grapes,Moutan rheum Cortex un- [128] Piceatannol intrarectally PiceatannolPiceatannolPaeonol 0.5 mg/kg10 treated 0.8 STAT3 dulatum, rhubarb, [136] TNBS-inducedDSS-induced 0.04 STAT1 Grapes,Moutan rheum Cortex un- [128] 0.5intrarectally mg/kg treated and sugar cane Grapes, rheum Piceatannol TNBS-induced 10 0.040.8 STAT3STAT1 dulatum,Moutan rhubarb, Cortex [136][128] DSS-inducedDSS-induced intrarectally 10Grapes, 0.8 rheum un- STAT3 undulatum, rhubarb, [136] Grapes,and sugar rheum cane un- Piceatannol 10 0.8 STAT3 dulatum, rhubarb, [136] DSS-induced 10 0.8 STAT3 dulatum, rhubarb, [136] and sugar cane Piceatannol DSS-induced Grapes,and sugar rheum cane un- Shikonin and sugar cane 10 0.8 STAT3 dulatum, rhubarb, [136] Shikonin DSS-induced Grapes, rheum un- Shikonin and sugar cane 10 0.8 STAT3 dulatum,Grapes,Lithospermum rheum rhubarb, un- [136] Lithospermum DSS-induced 25 2.0 STAT3 [141] Shikonin DSS-induced10 250.8 STAT3 dulatum,and 2.0 sugar rhubarb, cane [136] STAT3 [141] Shikonin DSS-induced Lithospermumerythrorhizon erythrorhizon DSS-induced 25 2.0 STAT3 and sugar cane [141] erythrorhizon Shikonin Lithospermum DSS-induced 25 2.0 STAT3 Lithospermum [141] DSS-induced 25 2.0 STAT3 erythrorhizon [141] TriptolideShikonin erythrorhizon Lithospermum TriptolideShikonin DSS-induced 25 2.0 STAT3 [141] 0.07 mg/kg erythrorhizon IL-10 deficient TripterygiumLithospermum Wil- Terpenoid Triptolide DSS-induced treated 25intraperi- 0.005 2.0 STAT3 [141][146] Triptolide colitis mice 0.07 mg/kg Lithospermumerythrorhizonfordii Hook. f IL-10DSS-induced deficient toneally25 2.0 STAT3 Tripterygium Wil- [141] Terpenoid treated intraperi- 0.005 STAT3 erythrorhizon [146] colitis mice 0.07 mg/kg fordii Hook. f Triptolide IL-10 deficient 0.07toneally mg/kg Tripterygium Wil- Terpenoid IL-10 deficient treated intraperi- 0.005 STAT3 Tripterygium Wil- [146] Terpenoid Triptolide colitis mice treated intraperi- 0.005 STAT3 fordii Hook. f [146] Boldin colitis mice 0.07toneally mg/kg fordii Hook. f Triptolide IL-10 deficient toneally Tripterygium Wil- Terpenoid treated0.07 mg/kgintraperi- 0.005 STAT3 [146] Boldin colitis mice fordii Hook. f IL-10 deficient toneally Tripterygium Wil- NitrogenTerpenoid containing alka- treated0.07 intraperi-mg/kg 0.005 STAT3 [146] Boldin IL-10DSS-inducedcolitis deficient mice 50 4.0 STAT3 TripterygiumfordiiBoldo Hook. tree Wil- f [150] Terpenoidloid Boldin treatedtoneally intraperi- 0.005 STAT3 [146] Nitrogen containing alka- colitis mice fordii Hook. f DSS-induced toneally50 4.0 STAT3 Boldo tree [150] loid Boldin Nitrogen containing alka- Nitrogen containing alka- Boldin DSS-induced 50 4.0 STAT3 Boldo tree [150] loid DSS-induced 50 4.0 STAT3 Boldo tree [150] loid Berberine 20 1.6 [153] Nitrogen containing alka- Boldin DSS-induced STAT3 Berberis species DSS-induced 50 4.0 STAT3 Boldo tree [150][155] loid Berberine 20 1.6 [153] Nitrogen containing alka- DSS-induced STAT3 Berberis species DSS-induced 50 4.0 STAT3 Boldo tree [155][150] Nitrogen containingloid alka- Berberine 20 1.6 [153] Berberine DSS-inducedDSS-induced 2050 1.6 4.0 STAT3 STAT3 BerberisBoldo species tree [153][150] loid DSS-induced 50 4.0 STAT3 Berberis species [155] 50 4.0 [155] Berberine 20 1.6 [153] DSS-induced STAT3 Berberis species Berberine 2050 1.64.0 [153][155] DSS-induced STAT3 Berberis species Berberine 5020 4.01.6 [155][153] DSS-induced STAT3 Berberis species 50 4.0 [155]

Molecules 2021, 26, x FOR PEER REVIEW 10 of 19

Table 2. Phytochemicals targeting JAK–STAT pathways in inflammatory bowel disease models.

Table 2. Phytochemicals targeting JAK–STATEffective pathways Doses in inflammatoryTranslated into bowel Hu- diseaseTarget of models. Experimental Class of Phytochemicals Phytochemical Name Effective(mg/kg DosesBody man-RelevantTranslated into Equiva- Hu- JAK–STATTarget of Main Source Ref. ExperimentalSystem Class of Phytochemicals Phytochemical Name Weight,(mg/kg BodyDaily) man-Relevantlent (mg/kg) Equiva- JAK–STATPathway Main Source Ref. System Curcumin Weight, Daily) lent (mg/kg) Pathway

Curcumin DSS-induced 36.8, 92 2.9, 7.4 JAK2, Curcuma longa [106] Phenolic TNBS-inducedDSS-induced 36.8,100 92 2.9,8.1 7.4 STAT1,JAK2, 3, 6 LinnCurcuma (turmeric) longa [106][108] Phenolic TNBS-induced 100 8.1 STAT1, 3, 6 Linn (turmeric) [108]

EGCG EGCG

DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115] DSS-induced 50, 100 4.0, 8.1 STAT3 green tea [115]

Ellagic acid Ellagic acid Pomegranate DSS-induced 100 8.1 STAT3 (PunicaPomegranate granatum L., [120] DSS-induced 100 8.1 STAT3 (PunicaLythraceae granatum) L., [120] Lythraceae)

Gallic acid Gallic acid Green tea, strawberries, grapes, bana- DSS-induced 10 0.8 STAT3 Green tea, strawber- [124] ries,nas, grapes, and many bana- DSS-induced 10 0.8 STAT3 other fruits [124] nas, and many other fruits

Paeonol 0.5 mg/kg treated Paeonol TNBS-induced 0.04 STAT1 Moutan Cortex [128] 0.5 intrarectallymg/kg treated TNBS-induced 0.04 STAT1 Moutan Cortex [128] intrarectally Piceatannol

Piceatannol Grapes, rheum un-

10 0.8 STAT3 Grapes,dulatum, rheum rhubarb, un- [136] DSS-induced 10 0.8 STAT3 dulatum,and sugar rhubarb, cane [136] DSS-induced and sugar cane Molecules 2021, 26, 2824 11 of 20

Shikonin Shikonin Lithospermum DSS-induced 25 2.0 Table 2. Cont. STAT3 [141] Lithospermumerythrorhizon DSS-induced 25 2.0 STAT3 [141] Effective Doses Translatederythrorhizon into Class of Phytochemical Experimental Target of JAK–STAT (mg/kg Body Human-Relevant Main Source Ref. Phytochemicals TriptolideName System Pathway Weight, Daily) Equivalent (mg/kg) Triptolide 0.07 mg/kg Triptolide IL-10 deficient Tripterygium Wil- Terpenoid treated0.07 mg/kg intraperi- 0.005 STAT3 [146] IL-10colitisIL-10 deficient mice deﬁcient colitis 0.07 mg/kg treated Tripterygiumfordii Hook. Wil- f Tripterygium Wilfordii TerpenoidTerpenoid treatedtoneally intraperi- 0.005 STAT3 0.005[146] STAT3 [146] Molecules 2021, 26, x FOR PEER REVIEW colitis micemice intraperitoneally fordii Hook. f 11 of 19 Hook. f toneally

Molecules 2021, 26, x FOR PEER REVIEW 11 of 19 Boldin Molecules 2021, 26, x FOR PEER REVIEWBoldin 11 of 19 Boldin Molecules 2021, 26, x FOR PEER REVIEW JAK1, 2 and 11 of 20 Molecules Nitrogen 2021 containing containing, 26, x FOR alka- PEER REVIEW 11 of 19 DSS-induced 50 4.0 STAT3 Boldo tree [150] DSS-induced 50JAK1,STAT1, 2 and 3, 4, 4.0 STAT3 Boldo tree [150] Nitrogenalkaloid containingloid alka- DSS-induced 50 4.0 STAT1, STAT35, 63, 4, Boldo tree [150] loid JAK1, 2 and 5, 6 JAK1,STAT1, 2 and3, 4, JAK1, 2 and BerberineBerberineAllicin 20 1.6 STAT1,5, 6 3, 4, [153] DSS-induced STAT1,STAT3 3, 4, Berberis species STAT3 Allicin 50 204.0 5, 6 1.6 [155] [153] Berberine DSS-induced 20 1.6 5, 6 [153] JAK1, 2 and STAT1, 3, Berberis species Organosulfur compounds DSS-inducedDSS-induced 10 50 0.8 STAT3 STAT3 Berberis4.0Garlic species [159] [155] Allicin 50 4.0 [155] 4, 5, 6 Organosulfur compounds DSS-induced 10 0.8 STAT3 Garlic [159] Allicin

Organosulfur compounds Diallyl trisulfide DSS-induced 10 0.8 STAT3 Garlic [159] AllicinAllicin OrganosulfurOrganosulfur compounds DSS-induced 10 0.8 STAT3 Garlic [159] Diallyl trisulfide DSS-induced 10 0.8 STAT3 Garlic [159] compounds DSS-induced 45, 90 3.6, 7.2 STAT3 Garlic [160]

Organosulfur compounds DSS-induced 10 0.8 STAT3 Garlic [159] Diallyl trisulfide DSS-induced 45, 90 3.6, 7.2 STAT3 Garlic [160] Diallyl trisulﬁde Diallyl trisulfide Alliin DSS-inducedDSS-induced 45, 90 45, 3.6, 907.2 STAT3 3.6,Garlic 7.2 [160] STAT3 Garlic [160]

DiallylAlliin trisulfide DSS-induced 45, 90 3.6, 7.2 STAT3 Garlic [160]

Alliin DSS-induced 500 40.5 STAT1 Garlic [161] Alliin DSS-induced 45, 90 3.6, 7.2 STAT3 Garlic [160] DSS-induced 500 40.5 STAT1 Garlic [161] DSS-induced 500 40.5 STAT1 Garlic [161] Alliin

Phenethylisothiocya- DSS-induced 500 40.5 STAT1 Garlic [161] Alliin Phenethylisothiocyanatenate (PEITC) DSS-induced 500 40.5 STAT1 Garlic [161] Phenethylisothiocya- (PEITC) cruciferous vegeta- nate (PEITC) DSS-inducedDSS-induced 50075 40.5 6.0 STAT1 STAT1 Garlic [161][163] cruciferous Phenethylisothiocya- DSS-induced 75 6.0 STAT1 [163] cruciferousbles vegeta- vegetables DSS-induced 75 6.0 STAT1 [163] Phenethylisothiocya-nate (PEITC) bles cruciferous vegeta- nate (PEITC) DSS-induced 75 6.0 STAT1 [163] Phenethylisothiocya-All phytochemicals orally administered, except paeonol (intrarectal administration) andbles triptolide (intraperitoneal administration). All phytochemicals orally administered, except paeonol (intrarectal administration) and triptolide (intraperitonealcruciferous vegeta- admin- nate (PEITC) DSS-induced 75 6.0 STAT1 [163] istration). bles All phytochemicals orally administered, except paeonol (intrarectal administration) and triptolide (intraperitonealcruciferous admin- vegeta- DSS-induced 75 6.0 STAT1 [163] istration). bles All phytochemicals orally administered, except paeonol (intrarectal administration) and triptolide (intraperitoneal admin- 4. Challenges of Phytochemicals Targeting JAK–STAT Pathways for IBD Treatment Allistration). phytochemicals orally administered, except paeonol (intrarectal administration) and triptolide (intraperitoneal admin- 4. Challenges In this section, of Phytochemicals we discuss our Target currenting kn JAK–STATowledge and Pathways significance for IBD of phytochemicals Treatment istration).All phytochemicals orally administered, except paeonol (intrarectal administration) and triptolide (intraperitoneal admin- 4.as Challenges naturalIn this section,resources of Phytochemicals we in discuss the discovery our Target current of ingJAK kn JAK–STATowledge inhibitors and orPathways significance STAT inhibitors. for ofIBD phytochemicals Treatment A total of 14 istration). phytochemicals have been confirmed to have anti-IBD effects by inhibiting JAK, STAT, or 4.as ChallengesnaturalIn this resources section, of Phytochemicals we in discussthe discovery our Target current of ingJAK kn JAK–STAT owledgeinhibitors and or Pathways significanceSTAT inhibitors. for IBDof phytochemicals TreatmentA total of 14 phytochemicalsboth in in vivo murinehave been model confirmed systems to (Fig haveure anti-IBD 3). Phytochemicals effects by inhibiting modulating JAK, JAK–STAT STAT, or 4.as ChallengesnaturalIn this resourcessection, of Phytochemicals we in discuss the discovery our Target current of ingJAK kn JAK–STATowledge inhibitors and or Pathways significance STAT inhibitors. for ofIBD phytochemicals TreatmentA total of 14 bothpathways in in vivo can havemurine several model strengths systems as (Fig potenture 3).ial Phytochemicalsinhibitors against modulating IBD. Currently, JAK–STAT devel- asphytochemicals natural resources have in been the confirmeddiscovery ofto haveJAK inhibitorsanti-IBD effects or STAT by inhibitinginhibitors. JAK, A total STAT, of 14or pathwaysopingIn orthis candeveloped section, have severalwe JAK discuss inhibitors strengths our current ashave potent beenknowledgeial reported inhibitors and to significance against have various IBD. of Currently, phytochemicals adverse devel-effects, phytochemicalsboth in in vivo murine have been model confirmed systems to (Fig haveure anti-IBD 3). Phytochemicals effects by inhibiting modulating JAK, JAK–STAT STAT, or opingasincluding natural or developed resourceshigher rates JAKin theof inhibitors discoveryinfluenza, have ofherpes JAK been inhibitors zosterreported infection, orto STAThave arthralgia, variousinhibitors. adverse and A total headache effects, of 14 bothpathways in in vivocan have murine several model strengths systems as (Fig potenture 3).ial inhibitorsPhytochemicals against modulating IBD. Currently, JAK–STAT devel- includingphytochemicals[55,97,164]. higher In this have rates regard, been of phytochemicalsconfirmedinfluenza, toherpes have targeting anti-IBDzoster theinfection, effects JAK–STAT by arthralgia, inhibiting pathway andJAK, having headache STAT, fewer or pathwaysoping or developedcan have several JAK inhibitors strengths haveas potent beenial reported inhibitors to againsthave various IBD. Currently, adverse effects,devel- [55,97,164].bothside ineffects in vivo In could this murine regard, be advantageous model phytochemicals systems for (Fig IBD targetingure treatment 3). Phytochemicals the JAK–STAT [26]. In addition, modulating pathway phytochemicals having JAK–STAT fewer opingincluding or developed higher rates JAK of inhibitors influenza, have herpes been zoster reported infection, to have arthralgia, various adverse and headache effects, sidepathwayshave effects been can foundcould have tobe several have advantageous a widestrengths array for as of potentIBD anti treatment-inflammatoryial inhibitors [26]. against activitiesIn addition, IBD. in IBDCurrently, phytochemicals [165]. Indeed, devel- including[55,97,164]. higher In this ratesregard, of phytochemicalsinfluenza, herpes targeting zoster theinfection, JAK–STAT arthralgia, pathway and having headache fewer haveopingas shown been or developed foundin Section to have JAK3, the a inhibitors wide majority array haveof of phytochemicals anti been-inflammatory reported have to activitieshave been various reported in IBD adverse [165]. to simultane- Indeed, effects, [55,97,164].side effects In could this regard,be advantageous phytochemicals for IBD targeting treatment the JAK–STAT[26]. In addition, pathway phytochemicals having fewer asincludingously shown have inhigher otherSection ratesanti-inflammatory 3, the of majorityinfluenza, of effects herpesphytochemicals togetherzoster infection, with have modulation been arthralgia, reported of andthe to simultane- JAK–STATheadache sidehave effects been found could to be have advantageous a wide array for of IBD anti -inflammatorytreatment [26]. activities In addition, in IBD phytochemicals [165]. Indeed, ously[55,97,164].pathway. have Accordingly, Inother this anti-inflammatory regard, phytochemicals phytochemicals effects might targeting together be able the with to JAK–STAT provide modulation resources pathway of the forhaving JAK–STAT new fewerdrugs haveas shown been foundin Section to have 3, the a wide majority array of of phytochemicals anti-inflammatory have activities been reported in IBD [165].to simultane- Indeed, pathway.sidetargeting effects Accordingly,JAK–STAT could be advantageouspathways phytochemicals and forcould mightIBD be treatment an be alternativeable to [26]. provide andIn addition, complementaryresources phytochemicals for new medicine drugs asously shown have in otherSection anti-inflammatory 3, the majority of effects phytochemicals together with have modulation been reported of the to simultane-JAK–STAT targetinghavefor treating been JAK–STAT found IBD topatients. have pathways a Inwide addition, and array could of there anti be -inflammatory couldan alternative be combinatorial andactivities complementary availabilityin IBD [165]. medicine of Indeed, phyto- ouslypathway. have Accordingly, other anti-inflammatory phytochemicals effects might together be able with to provide modulation resources of the for JAK–STAT new drugs foraschemicals showntreating in along IBD Section patients. with 3, current the In majority addition, therapies of there phytochemicals for IBD. could A combinationbe combinatorial have been of diverse reported availability biological to simultane- of phyto- agents pathway.targeting Accordingly,JAK–STAT pathways phytochemicals and could might be an be alternative able to provide and complementary resources for new medicine drugs chemicalsouslyhas been have typicallyalong other with anti-inflammatory used current in IBD, therapies but clinicaleffects for IBD. datatogether A combinationfor safety with modulationand of efficacy diverse ofhave biological the been JAK–STAT agentslimited targetingfor treating JAK–STAT IBD patients. pathways In addition, and could there be could an alternative be combinatorial and complementary availability medicineof phyto- haspathway.[166]. been Although typically Accordingly, there used are phytochemicalsin noIBD, current but clinical data might on data the be for combinationable safety to provide and of efficacy phytochemicalsresources have for been new targeting limited drugs forchemicals treating along IBD patients.with current In addition, therapies there for IBD. could A combination be combinatorial of diverse availability biological of phyto- agents [166].targetingJAK–STAT Although JAK–STAT pathways there pathwaysare and no existing current and IBD coulddata therapies, on be the an combinationalternative they could and of have phytochemicalscomplementary attractive potential targetingmedicine for chemicalshas been typically along with used current in IBD, therapies but clinical for IBD. data A for combination safety and of efficacy diverse have biological been limitedagents JAK–STATforIBD treating treatment pathwaysIBD because patients. and of Intheexisting addition, fewer IBD side there therapies, effect coulds of theyphytochemicals.be combinatorial could have attractiveFu availabilityrthermore, potential of intestinal phyto- for has[166]. been Although typically there used are in no IBD, current but clinical data on data the forcombination safety and of efficacy phytochemicals have been targeting limited IBDchemicalsenteroid/organoid treatment along because with culture current of the from fewertherapies intestinal side for effect IBD.stems of A cells phytochemicals.combination (ISCs) have of diversebeen Furthermore, recently biological considered intestinal agents [166].JAK–STAT Although pathways there areand no existing current IBD data therapies, on the combination they could ofhave phytochemicals attractive potential targeting for enteroid/organoidhasas new been therapeutic typically cultureused strategies in fromIBD, for butintestinal the clinical treatmen stem datat ofcells for refractory safety(ISCs) andhave IBD efficacy [167,168].been recently have Transplantation been considered limited JAK–STATIBD treatment pathways because and of the existing fewer IBD side therapies, effects of phytochemicals.they could have Fuattractiverthermore, potential intestinal for as[166].of new intestinal Although therapeutic organoid there strategies are in noIBD currentfor patients the treatmen data coul ond thet beof combination refractoryused to promote IBD of [167,168]. phytochemicals the regeneration Transplantation targeting of the IBDenteroid/organoid treatment because culture of the from fewer intestinal side effect stems of cells phytochemicals. (ISCs) have been Furthermore, recently considered intestinal ofJAK–STATdamaged intestinal intestinal pathways organoid tissue andin IBD existing and patients also IBD provide coul therapies,d be new used they scaffolding to could promote have for the attractivethe regeneration discovery potential of of novel thefor enteroid/organoidas new therapeutic culture strategies from for intestinal the treatmen stemt of cells refractory (ISCs) have IBD [167,168].been recently Transplantation considered damagedIBDdrugs treatment for intestinalIBD becausetreatment. tissue of theTherefore, and fewer also side provideanti-colit effect newsic of activity phytochemicals. scaffolding of phytochemicals for theFurthermore, discovery targeting intestinalof novel JAK– asof newintestinal therapeutic organoid strategies in IBD for patients the treatmen could tbe of refractoryused to promote IBD [167,168]. the regeneration Transplantation of the drugsenteroid/organoidSTAT for pathways IBD treatment. could culture be Therefore, frominvestigated intestinal anti-colit in stem intestinalic activitycells (ISCs)organoid of phytochemicals have cultures been recently mimicking targeting considered in JAK– vivo ofdamaged intestinal intestinal organoid tissue in IBD and patients also provide could benew used scaffolding to promote for thethe regenerationdiscovery of ofnovel the STATasphysiology new pathways therapeutic of IBD. could strategies In beaddition, investigated for the the treatmen combination in intestinalt of refractory of organoid these IBDphytochemicals cultures [167,168]. mimicking Transplantation and the in trans-vivo damageddrugs for IBDintestinal treatment. tissue Therefore, and also anti-colitprovide newic activity scaffolding of phytochemicals for the discovery targeting of novel JAK– physiologyofplantation intestinal ofof organoid intestinalIBD. In addition,in organoid IBD patients the could combination coul be thed be advanced used of these to promotestrategy phytochemicals forthe IBD regeneration treatment. and the trans-of the drugsSTAT forpathways IBD treatment. could be Therefore, investigated anti-colit in intestinalic activity organoid of phytochemicals cultures mimicking targeting in JAK– vivo plantationdamaged intestinalof intestinal tissue organoid and also could provide be the newadvanced scaffolding strategy for for the IBD discovery treatment. of novel STATdrugsphysiology pathwaysfor IBD of treatment.IBD. could In addition,be Therefore, investigated the anti-colitcombination in intestinalic activity of organoid these of phytochemicalsphytochemicals cultures mimicking targeting and the in trans- JAK–vivo physiologySTATplantation pathways ofof intestinal IBD. could In addition, beorganoid investigated the could combination inbe intestinalthe advanced of organoidthese strategy phytochemicals cultures for IBD mimicking treatment. and the in trans- vivo plantation of intestinal organoid could be the advanced strategy for IBD treatment.

Molecules 2021, 26, 2824 12 of 20

4. Challenges of Phytochemicals Targeting JAK–STAT Pathways for IBD Treatment In this section, we discuss our current knowledge and significance of phytochemicals as natural resources in the discovery of JAK inhibitors or STAT inhibitors. A total of 14 phytochemicals have been confirmed to have anti-IBD effects by inhibiting JAK, STAT, or both in in vivo murine model systems (Figure3). Phytochemicals modulating JAK–STAT pathways can have several strengths as potential inhibitors against IBD. Currently, developing or developed JAK inhibitors have been reported to have various adverse effects, including higher rates of influenza, herpes zoster infection, arthralgia, and headache [55,97,164]. In this regard, phytochemicals targeting the JAK–STAT pathway having fewer side effects could be advantageous for IBD treatment [26]. In addition, phytochemicals have been found to have a wide array of anti-inflammatory activities in IBD [165]. Indeed, as shown in Section3, the majority of phytochemicals have been reported to simultaneously have other anti-inflammatory effects together with modulation of the JAK–STAT pathway. Accordingly, phytochemicals might be able to provide resources for new drugs targeting JAK–STAT pathways and could be an alternative and complementary medicine for treating IBD patients. In addition, there could be combinatorial availability of phytochemicals along with current therapies for IBD. A combination of diverse biological agents has been typically used in IBD, but clinical data for safety and efficacy have been limited [166]. Although there are no current data on the combination of phytochemicals targeting JAK–STAT pathways and existing IBD therapies, they could have attractive potential for IBD treatment because of the fewer side effects of phytochemicals. Furthermore, intestinal enteroid/organoid culture from intestinal stem cells (ISCs) have been recently considered as new therapeutic strategies for the treatment of refractory IBD [167,168]. Transplantation of intestinal organoid in IBD patients could be used to promote the regeneration of the damaged intestinal tissue and also provide new scaffolding for the discovery of novel drugs for IBD treatment. Therefore, anti-colitic activity of phytochemicals targeting JAK–STAT pathways could be investigated in intestinal organoid cultures mim- Molecules 2021, 26, x FOR PEER REVIEW 12 of 19 icking in vivo physiology of IBD. In addition, the combination of these phytochemicals and the transplantation of intestinal organoid could be the advanced strategy for IBD treatment.

FigureFigure 3. 3.Phytochemicals Phytochemicals targeting targeting JAK–STATJAK–STAT pathways. pathways. ((AA)) PhytochemicalsPhytochemicals targetingtargeting STATSTAT pro-proteins.teins. Phytochemicals Phytochemicals in in green green box box (paeonol, (paeonol, alliin, alliin, and and phenethylisothiocyanate) phenethylisothiocyanate) inhibit inhibit the the activa- acti- tionvation of STAT1. of STAT1. Phytochemicals Phytochemicals in yellow in yellow box box (EGCG, (EGCG, ellagic ellagic acid, acid, gallic gallic acid, acid, piceatannol, piceatannol, shikonin, shikonin, triptolide, boldin, allicin, and diallyl trisulfide) inhibit the activation of STAT3. Berberine triptolide, boldin, allicin, and diallyl trisulfide) inhibit the activation of STAT3. Berberine inhibits inhibits the phosphorylation of STAT1/3/4/5/6. Curcumin inhibits the activation of STAT1/3/6. (B) the phosphorylation of STAT1/3/4/5/6. Curcumin inhibits the activation of STAT1/3/6. (B) Phy- Phytochemicals targeting JAK proteins. Berberine inhibits the phosphorylation of JAK1/2. Curcu- tochemicalsmin downregulates targeting the JAK phosphorylation proteins. Berberine of JAK2. inhibits the phosphorylation of JAK1/2. Curcumin downregulates the phosphorylation of JAK2. Although phytochemicals have potential for developing new anti-JAK–STAT drugs Although phytochemicals have potential for developing new anti-JAK–STAT drugs for for IBD, there are some obstacles. Phytochemicals targeting JAK–STAT signaling in the IBD, there are some obstacles. Phytochemicals targeting JAK–STAT signaling in the previ- previous section have only been shown to ameliorate disease symptoms in experimental ous section have only been shown to ameliorate disease symptoms in experimental rodent models.rodent models. Thus, the Thus, safety the and safety efficacy and identifiedefficacy identified in animal in studies animal must studies be translated must be trans- into lated into human trials. In this regard, we summarized anti-colitic phytochemicals based on structural classification [169,170] and analyzed the effective doses in each experimental system (Table 2). A large portion of effective compounds are phenolic compounds, and the second most dominant class is organosulfur compounds. Furthermore, we translated the effective doses of phytochemicals in rodent model systems into human-relevant equivalent doses [171]. Given the orally administered phytochemicals, translated doses of these phytochemicals ranged from a minimum of 0.8 mg/kg to a maximum of 40.5 mg/kg. The most effective phytochemicals against IBD are gallic acid, piceatannol, and allicin, with a human-relevant equivalent dose of 0.8 mg/kg. These three phytochemicals seem to have anti-colitic activity at a much lesser dose than the effective dose of JAK inhibitors (filgotinib: 200 mg once daily → 3.3 mg/kg in case body mass weighs 60 kg) that have been used for treating IBD patients as shown in Table 1. In addition, as shown in Table 2, a majority of phytochemicals targeting JAK–STAT pathways seem to be involved in the inhibition of STAT3 activity. STAT3 has been considered the most crucial factor among STAT family members in colitis-associated colorectal cancer due to its crosstalk with cytokine-mediated chronic inflammation in the intestine [172]. Although several small-molecule STAT3 inhibitors have been clinically investigated for treating advanced solid tumors, including colorectal cancer, and have also been preclinically studied in murine arthritis and athema models [93,94,96], there have been no direct STAT inhibitors for clinical application against IBD. Thus, phytochemicals modulating STAT3 could be a good resource for the discovery of new STAT3 inhibitors for the treatment of IBD. A large number of studies have shown that functional nutraceuticals can reduce inflammation of the GI tract by regulating proinflammatory cytokines in IBD [173]. Nutraceutical combines two words, ‘nutrient’ and ‘pharmaceutical’. Phytochemicals have been considered nutraceutical agents against autoimmune disorders [174]. In this respect, phytochemicals targeting JAK–STAT pathways could be significant resources for developing new nutraceutical agents with potentially strong medicinal properties against IBD.

5. Conclusions and Perspective

Molecules 2021, 26, 2824 13 of 20

human trials. In this regard, we summarized anti-colitic phytochemicals based on structural classification [169,170] and analyzed the effective doses in each experimental system (Table2). A large portion of effective compounds are phenolic compounds, and the second most dominant class is organosulfur compounds. Furthermore, we translated the effective doses of phytochemicals in rodent model systems into human-relevant equivalent doses [171]. Given the orally administered phytochemicals, translated doses of these phytochemicals ranged from a minimum of 0.8 mg/kg to a maximum of 40.5 mg/kg. The most effective phytochemicals against IBD are gallic acid, piceatannol, and allicin, with a human-relevant equivalent dose of 0.8 mg/kg. These three phytochemicals seem to have anti-colitic activity at a much lesser dose than the effective dose of JAK inhibitors (filgotinib: 200 mg once daily → 3.3 mg/kg in case body mass weighs 60 kg) that have been used for treating IBD patients as shown in Table1. In addition, as shown in Table2, a majority of phytochemicals targeting JAK–STAT pathways seem to be involved in the inhibition of STAT3 activity. STAT3 has been considered the most crucial factor among STAT family members in colitis-associated colorectal cancer due to its crosstalk with cytokine-mediated chronic inflammation in the intestine [172]. Although several small-molecule STAT3 inhibitors have been clinically investigated for treating advanced solid tumors, including colorectal cancer, and have also been preclinically studied in murine arthritis and athema models [93,94,96], there have been no direct STAT inhibitors for clinical application against IBD. Thus, phytochemicals modulating STAT3 could be a good resource for the discovery of new STAT3 inhibitors for the treatment of IBD. A large number of studies have shown that functional nutraceuticals can reduce inflammation of the GI tract by regulating proinflammatory cytokines in IBD [173]. Nu- traceutical combines two words, ‘nutrient’ and ‘pharmaceutical’. Phytochemicals have been considered nutraceutical agents against autoimmune disorders [174]. In this respect, phytochemicals targeting JAK–STAT pathways could be significant resources for developing new nutraceutical agents with potentially strong medicinal properties against IBD.

5. Conclusions and Perspective JAK–STAT-mediated cellular signaling responses play an essential role in both enteric homeostasis and IBD pathology, which is characterized by uncontrolled chronic inflammation in the GI tract. Numerous inflammatory cytokines are chronically produced and released in the GI tract and regulate the JAK–STAT signaling pathway in IBD. In addition to targeting particular cytokines such as TNF-α, the clinical significance of the JAK–STAT pathway in IBD has been emphasized by an ongoing preclinical and clinical study using JAK and STAT inhibitors for the treatment of IBD patients. Targeting the JAK–STAT pathway can prevent multiple pro-inflammatory cytokine signaling pathways in IBD. The orally available JAK inhibitor, tofacitinib, approved by the FDA, has been clinically confirmed to have beneficial effects in patients with moderate to severe UC, but considering safety issues, tofacitinib-treated patients have shown various adverse effects, including a high rate of infection [175]. It is imperative to consider phytochemicals that can modulate JAK–STAT pathways as potential candidates for IBD treatment. In this respect, this review has focused on particular phytochemicals that inhibit JAK–STAT pathways and suppress IBD pathology in vivo in animal model systems, among many phytochemicals with anti-inflammatory effects against IBD. The phytochemicals are shown in Table2 have been shown to protect against colonic inflammation and ameliorate disease symptoms by downregulating JAK– STAT signaling in murine IBD models. The effective dose of phytochemicals in the IBD murine model was translated into a human-relevant equivalent dose, and the phytochemicals were considered to have competitive power as potential candidates for the treatment of IBD. However, more studies focusing on the precise mechanism of suppressing JAK–STAT pathways are required to understand the relationship between its structural character- istics and anti-JAK–STAT activity or cell type specificity of each phytochemical in IBD. Furthermore, to verify the beneficial effects of these phytochemicals in managing IBD, their therapeutic utilization requires safety and efficacy data through both pre-clinical Molecules 2021, 26, 2824 14 of 20

and clinical studies in IBD. Taken together, we provide a fundamental understanding of phytochemicals modulating JAK–STAT pathways to develop new therapeutic drugs, alternative medicines, and nutraceutical agents for treating IBD.

Author Contributions: Conceptualization: S.Y.M. and C.H.; investigation: S.Y.M., K.D.K., J.Y., J.-H.L., S.Y.M. and C.H.; writing—review and editing: S.Y.M.; supervision: C.H.; funding acquisition: C.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was supported by the grants from the National Research Foundation (NRF) of Korea (NRF-2018R1C1B6007728 and NRF-2021R1C1C1006516). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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