Curcumin and inflammatory bowel diseases: From in vitro studies to clinical trials

Molecular Immunology 130 (2021) 20–30

Contents lists available at ScienceDirect

Molecular Immunology journal homepage: www.elsevier.com/locate/molimm

Review

Curcumin and inflammatory bowel diseases: From in vitro studies to clinical trials Farzaneh Fallahi a, Sarina Borran b, Milad Ashrafizadeh c, Ali Zarrabi d, Mohammad Hossein Pourhanifeh e, Mahmood Khaksary Mahabady f, Amirhossein Sahebkar g, h, **, Hamed Mirzaei a, * a

Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Istanbul, Turkey d Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey e Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran f Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran g Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran h School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b c

A R T I C L E I N F O

A B S T R A C T

Keywords: Inflammatory bowel disease Curcumin Herbal compound Anti-inflammation Disease therapy

Inflammatory bowel diseases (IBDs) may result from mutations in genes encoding for innate immunity, which can lead to exacerbated inflammatory response. Although some mono-targeted treatments have developed in recent years, IBDs are caused through several pathway perturbations. Therefore, targeting all these pathways is difficult to be achieved by a single agent. Moreover, those mono-targeted therapies are usually expensive and may cause side-effects. These limitations highlight the significance of an available, inexpensive and multitargeted dietary agents or natural compounds for the treatment and prevention of IBDs. Curcumin is a multi­ functional phenolic compound that is known for its anti-inflammatory and immunomodulatory properties. Over the past decades, mounting experimental investigations have revealed the therapeutic potential of curcumin against a broad spectrum of inflammatory diseases including IBDs. Furthermore, it has been reported that cur­ cumin directly interacts with many signaling mediators implicated in the pathogenesis of IBDs. These preclinical findings have created a solid basis for the assessment of the efficacy of curcumin in clinical practice. In clinical trials, different dosages e.g., 550 mg /three times daily-1month, and 1 g /twice times daily-6month of curcumin were used for patients with IBDs. Taken together, these findings indicated that curcumin could be employed as a therapeutic candidate in the treatment of IBDs. Moreover, it seems that overcome to current limitations of curcumin i.e., poor oral bioavailability, and poor oral absorption with using nanotechnology and others, could improve the efficacy of curcumin both in pre-clinical and clinical studies.

1. Introduction Inflammatory bowel diseases (IBDs) may result from mutations in genes coding for innate immunity which alongside environmental fac­ tors, can lead to exacerbated inflammatory response (Mehta et al., 2017). Crohn’s disease (CD) and ulcerative colitis (UC) represent the same conditions and also present chronic inflammation of the gastro­ intestinal tract (Chan et al., 2017). Gastrointestinal microbiome,

immune system and barrier function contribute effectively to IBDs, although its precise etiology is a mystery (Senhaji et al., 2016). Devel­ oped countries –for instance the United States, United Kingdom and northern Europe- have a higher incidence rate in IBDs compared to developing countries, according to epidemiological studies (Ng et al., 2017; Burisch et al., 2013). However, some developing countries have had a rise in incidence and prevalence of IBDs; with a higher frequency of UC than CD (Cosnes et al., 2011; van der Sloot et al., 2017). Bioactive

* Corresponding author at: Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran. ** Corresponding author at: Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail addresses: [email protected] (A. Sahebkar), [email protected] (H. Mirzaei). https://doi.org/10.1016/j.molimm.2020.11.016 Received 17 July 2020; Accepted 17 November 2020 Available online 19 December 2020 0161-5890/© 2020 Elsevier Ltd. All rights reserved.

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

compounds are suggested to be effective in IBD treatment considering their anti-inflammatory and antioxidant functions (Rajasekaran, 2011; Dulbecco and Savarino, 2013; Kondamudi et al., 2015). One example for such compounds is Indian saffron (Curcuma longa Linnaeus) or turmeric. Curcuminoids consist of Curcumin (known for its typical yellowish color), bisdemethoxycurcumin, and demethoxycurcumin which can be exclusively found in the rhizome of Curcuma longa in amounts of 77 %, 17 %, and 3% respectively (Aggarwal and Harikumar, 2009; Yadav et al., 2013; Chin, 2016). Evidences indicated that curcumin could be used as therapeutic candidate alone or in combination with other ther­ apeutic agents in the treatment of IBDs. Pre-clinical studies suggested that curcumin exerts its pharmacological effects via targeting a variety of cellular and molecular pathways that are involved in IBDs pathogenesis. Clinical studies showed opposed results on the therapeutic impacts of curcumin in IBDs. It seems that large-scale clinical trials with different dosages of curcumin can contribute to more understanding about the real role of curcumin in this group of diseases. Herein, we summarized various pre-clinical and clinical studies on curcumin in IBDs.

mechanism (Sturm and Dignass, 2008; Paclik et al., 2008; Krishnan et al., 2010). It is the distribution of leukocytes – such as dendritic cells (DCs), macrophages, effector CD4+ or CD8+ T cells, and Treg cells - that define mucosal immunity (Fig. 1). More than 100 loci have been reported to play a role in IBD devel­ opment by either being a cause for it or acting as protection (Jostins et al., 2012). It is crucial to take in mind that explanation of IBDs may be burdensome due to how variously they affect different cell types (Lassen et al., 2014; Huttenhower et al., 2014). The intestinal immune system such as the innate immune response, intestinal barrier, microbial de­ fense, reactive oxygen, and antimicrobial activity make up different IBD-associated pathways (Khor et al., 2011). NOD2 gene (located on chromosome 16), as an example, encodes nucleotide-binding oligo­ merization domain-containing protein 2 (NOD2) and regulates immune responses through detecting bacterial peptides Mutation in the NOD2 gene is a predisposing factor in CD (Rubino et al., 2012). In one previous experiment, The NOD2− /− mice had more inflammatory reactions than control group (Barreau et al., 2007). Also, specific types of colitis in normal mice has been shown to be moderated by NOD2 ligand treat­ ments (Fernandez et al., 2011; Watanabe et al., 2008). It has been re­ ported that Lactobacillus peptidoglycan enhances the expression of IL-10 in the colonic mucosa, and Foxp3+ Treg cells and number of CD103+DCs in mesenteric lymph nodes of a TNBS-driven colitis model, indicating that tolerogenic environment can be potentiated by NOD2 activity in the intestinal mucosa (Fernandez et al., 2011). IBD pathogenesis is associated with migration or homing-related receptors, including C-C chemokine receptor (CCR)7, α4β7 integrin, CCR5, αEβ7 integrin, CD62 L, CCR9 and CCR4 (Guo et al., 2008; Kang

2. Inflammatory bowel disease pathogenesis The intestinal microbiome plays a great role in mucosal immunity (Colombo et al., 2015). Different types of cells make up the intestinal epithelium lying on basal lamina: columnar cells, goblet cells, endocrine cells, and leukocytes (McAvoy and Dixon, 1978). There are additional exclusive mucosa-associated lymphoid tissues such as Peyer’s patches, mesenteric lymph nodes, and isolated lymphoid follicles. An equivalent mucosal immunity is vital for a healthy homeostasis and defense

Fig. 1. Inflammatory bowel disease pathogenesis. 21

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

et al., 2007; Yuan et al., 2007; Denning et al., 2005; Suffia et al., 2005; Schneider et al., 2007; Venturi et al., 2007). These receptors –expressed by Treg cells- play an essential role in the intestinal immunological homeostasis. Hence, Treg cells deficient migration into the intestine contributes to defective expression of mentioned receptors, leading to IBD development. For instance, CCR7 deficiency is correlated with loss of Treg functions in a colitis animal model (Schneider et al., 2007).

model. In addition to autophagy, curcumin induces anti-inflammatory effect by decreasing levels of IL-17, IL-6, and tumor necrosis factor-α (TNF-α) (Yue et al., 2019). The inhibitory effects of curcumin on auto­ phagy and inflammation pave the way into effective treatment of colitis. IBD leads to recurrent anemia, poor iron absorption as well as low quality of life. It is recommended to use polyphenolic combined curcu­ min as an anti-inflammatory agent with minimal toxicity. In addition, curcumin is able to modulate iron metabolism proteins and reduce the iron stores. Therefore, its iron reduction property should be considered in IBD by monitoring erythroid parameters (Samba-Mondonga et al., 2019). Studies have shown that use of curcumin ameliorates expression of cyclooxygenase (COX), prostaglandin E-2 (PGE2), and inflammatory cytokines in chondrocytes. In this way, curcumin suppresses nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the chondrocytes by preventing the nuclear translocation of p65 subunit of NF-κB (Chen et al., 2014). It seems that anti-inflammatory and anti-apoptotic features of curcumin are two effective factors in treat­ ment of IBDs. Curcumin alleviates intestinal epithelial damage by in­ hibition of apoptotic cell death and reducing the levels of inflammatory cytokines such as interferon-γ (IFN-γ), (Loganes et al., 2017). Recent studies have shown the anti-apoptotic, anti-inflammatory and antioxidant properties of curcumin by affecting various molecular signaling pathways such as PPARγ, PI3K, TLR-4, Akt, mTOR, ERK5, AP1, TGF-β, PAK1, Wnt, β-catenin, Shh, Rac1, p38MAPK, EBPα, NLRP3 inflammasome, Nrf2, Notch-1, AMPK, STAT3, and MyD-88 (Patel et al., 2019). On the other hand, the aforementioned molecular pathways are able to participate in development of IBDs. For instance, STAT3 is a crucial molecular pathways with pleiotropic effects on cell proliferation, differentiation, migration, and angiogenesis (Lee et al., 2019). The

3. Curcumin as a therapeutic agent in inflammatory bowel disease It has been shown that curcumin exerts its therapeutic effects on IBDs via targeting a spectrum of cellular and molecular pathways (Fig. 2). Autophagy is a catabolic process in which additional macromole­ cules and organelles and aged ones undergo degradation after the fusion of autophagosome with lysosome (Yang and Klionsky, 2020; Wen and Klionsky, 2019). The involvement of autophagy in emergence of various disorders has been explored. It seems that autophagy have a role in development of IBDs. As a consequence it has been shown that down-regulation of autophagy attenuates excessive inflammatory response in IBDs. The polysaccharide from pycnoporus sanguineus (PPS) is able to ameliorate colitis via autophagy suppression (Li et al., 2020). As recently shown mutation in autophagy-related genes is associated with development of IBDs (Quach et al., 2019). These studies are in agreement with the fact that imbalance of autophagy is related to IBDs. As curcumin has regulatory properties in autophagy, its administration remarkably reduces the expression of genes regulating autophagy such as Beclin-1, autophagy-related gene 5 (ATG5) and LC3II, leading to improvement in colitis. Besides, curcumin diminishes autophagosome formation in colonic epithelial cells of an animal DSS-induced colitis

Fig. 2. Molecular pathways targeted by curcumin in amelioration of IBDs. 22

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

STAT3 signaling pathway has a role in colitis development and its regulation is of importance in treatment of this disorder (Gu et al., 2020; Dou et al., 2020). Curcumin has been proven to control the severity of DSS-induced colitis by inhibition of NF- ĸB and STAT3, COX-2 expres­ sion and inducible nitric oxide synthase (iNOS). Intragastric adminis­ tration of curcumin- particularly non-electrophilic curcumin analoguesuppresses induced mice colitis by inhibiting pro-inflammatory signals (Yang et al., 2018). In inflamed tissues, curcumin can interact with transient potential vanilloid receptor 1 (TRPV1) which has a protective role in inflamma­ tion of the intestine (Martelli et al., 2007). In an animal model of necrotizing colitis, oral administration of curcumin attenuated visceral hyperalgesia and DSS-induced colitis through TRPV1 receptor phos­ phorylation. In addition, repeated oral administration of curcumin inhibited the increase in DAI and abdominal withdrawal reflex score induced by DSS. In L6-S1 dorsal root ganglion, the expression of TRPV1 was enhanced in the small- to medium-sized calcitonin gene-associated peptide-positive peptidergic and isolectin B4-positive non-peptidergic neurons in rats treated with DSS, and oral curcumin administration alleviated such alterations. Curcumin suppressed membrane TRPV1 upregulation induced by phorbol myristate acetate in the HEK293 cell line which stably expresses hTRPV1. Colonic expression as well as phosphorylation of TRPV1 possesses suppressive effects via the afferent fibers planed by peptidergic and non-peptidergic nociceptive neurons of dorsal root ganglion (Yang et al., 2017). Curcumin is a common inflammasome inhibitor especially for NLRP3 due to disturbing down­ stream events including ASC oligomerization, the efficient spatial arrangement of mitochondria, speckle formation, and preventing K + efflux. Numerous clinical studies have revealed that curcumin is useful for inflammatory disease particularly in disease caused by NLRP3 (Yin and Guo, 2018). Curcumin significantly represses inflammasome acti­ vation of NLRP3 and IL-1β production in DSS-stimulated macrophages.

Various cytokines (IL-1β, IL-6, MCP-1, MPO) and caspase-1 which can cause histopathological damage, were also reduced by the effect of this chemical. The DSS-induced K + efflux, intracellular ROS formation and cathepsin B release were down-regulated by curcumin administration. As a result, curcumin improves symptoms of colitis by improving weight loss, DAI and shortening the length of the colon. Since curcumin has a potent suppressive role in DSS-mediated NLRP3 inflammasome activa­ tion in mice, it can be a promising option in treatment of IBD (Gong et al., 2018). 4. Limitations of curcumin Despite its potential anti-cancer effects, curcumin has not yet been completely proven to be effective in clinical trials. One of its major drawbacks is poor solubility in water, only about 11 ng/mL, which may limit its oral administration (Tønnesen et al., 2002). Also, it is unstable at both alkaline and neutral media; however, it is highly soluble in acidic PH. Moreover, curcumin bioavailability is low due to its rapid elimi­ nation and metabolism (Ravindranath and Chandrasekhara, 1981; Ire­ son et al., 2002). Whether taken intravenously, via peritoneum or orally, it is mainly metabolized into glucuronide derivatives in liver and excreted into gastrointestinal tract through bile. Therefore, it displays reduced anti immunosuppressive effects in cancer patients (Sharma et al., 2001, 2004a). In one study conducted on patients who were diagnosed with metastatic colorectal cancer, after receiving 3600 mg of curcumin daily, the concentration of curcumin in peripheral circulation, was in nanomolar level (Garcea et al., 2004). Similarly in another study, only minor changes were observed in high risk patients’ peripheral blood after taking 8000 mg of curcumin per day (Cheng et al., 2001). Also, in subjects receiving 10,000–12,000 mg, curcumin doses of 500 to 8000 mg were not measurable in the blood of patients and only a small number of its metabolites were detected (Lao et al., 2006; Soni et al.,

Fig. 3. Different strategies for curcumin nanoformulation preparation (B) Schematic illustrations of the polymer-curcumin conjugate micelles. PLA linked with curcumin by tris along with hydrophilic PEG as corona generating the hydrophobic block of micelles; a controlled release system. 23

Molecular Immunology 130 (2021) 20–30

F. Fallahi et al.

2006). Thus, improvements in solubility and bioavailability of curcumin should be considered in order to increase its therapeutic benefits. Fig. 3 illustrates a variety of nanostrategies that can be used to overcome curcumin limitations (Tables 1–3).

2019). As mentioned earlier, poor bioavailability of curcumin signifi­ cantly restricts its therapeutic effects. To date, a number of nanocarriers including lipid nanoparticles, liposomes, niosomes, carbon nanotubes, polymeric nanoparticles have been designed for enhancing bioavail­ ability and therapeutic capability of curcumin (Nasery et al., 2020; Di Natale et al., 2020; Khan et al., 2020; Ban et al., 2020; Jahromi et al., 2020; Obeid et al., 2019). Using lipid nanocarriers loaded with curcumin as a targeted therapy in IBD is suggested to be beneficial. The murine IBD models in vitro and in vivo were applied to test three lipidic nano­ carriers including nanoemulsifying drug delivery systems (SNEDDS),

5. Novel therapeutic approaches for curcumin in targeting inflammatory bowel disease The nanocarriers have been applied in the delivery of naturally occurring compounds for treatment of various disorders (Kashyap et al., Table 1 in vitro and in vivo studies on effects of curcumin in IBDs. Dose (s)

Target gene (s)

Effect (s)

Model (in vitro/ in vivo)

Type of cell line

Ref

10-mmol/L

NF-kB, TLR, IL-1β, NLRP3, caspase-1, MYD88, NLRC4, TXNIP, HSP90AA1, IL12, IL-6, MEFV – p38, JNK-MAPK

Induces pyroptosis

In vivo, In vitro

LP9/TERT-1

(Miller et al., 2014)

Reduces contractions of ileum. Reduces apoptotsis, lipid peroxidation, colon injury and inflammatory reactions. Reduces colonic mucosa damage index Decreases cytokine levels, inflammatory proteins and immunoreactivity of ß-catenin. Reduces histological scores.

In vivo In vivo

– –

In vivo In vivo

– _

(Aldini et al., 2012) (Topcu-Tarladacalisir et al., 2013) (Zeng et al., 2013) (Villegas et al., 2011)

In vivo

_

(Lubbad et al., 2009a)

TNF-α, IL-6, IL-17, IL-10, ATG5, LC-3II, beclin-1 bcl-2

inhibites autophagy, modulates cytokines

In vivo

_

(Yue et al., 2019)

IFN-γ, Stat1

Inhibits IFN-γ

T-84, YAMC

100 mg/kg 0⋅2 % curcumin

MPO, NF-ĸB TLR-4 Pxr, Ppara, Rxr

(Midura-Kiela et al., 2012) (Lubbad et al., 2009b) (Nones et al., 2009)

2%(wt/wt) curcumin 1μM

MyD88, Lipocalin 2

Inhibits TLR-4 and NF- ĸB. Suppresses histological signs of inflammation. Decreases iron stores

In vivo / In vitro In vivo In vivo In vivo

_

In vitro

HT29

(Samba-Mondonga et al., 2019) (Loganes et al., 2017)

0.1 or 0.25 mmol/kg 0.2 %, 0.5 %, and 2.0 % (wt/wt) 0− 20 μM

NF-ĸB, STAT3, COX-2

In vivo

_

(Yang et al., 2018)

Iron-regulatory proteins in the liver (IRR) and hepcidin COX-2

HepG2

(Jiao et al., 2009)

Suppresses COX-2

In vivo, In vitro In vitro

(Zhang et al., 1999)

20, 60 mg/kg

TRPV1, pTRPV1

Attenuates visceral hyperalgesia.

SK-GT-4, SCC450, IEC-18 and HCA-7 HEK293

100 μg/g, 10–50 μM 25, 50 and 100 mg/kg 10, 25, and 50 μM 100 mg/ kg/day 100 mg/kg

MIP-2, KC, IL-1β, MIP-1α, IL-8, PI3K

Suppresses neutrophil chemotaxis and chemokines. Attenuates colonic damage, oxidative stress and represses NFκ-B and iNOS. Ameliorates inflammsome activation.

YAMC

(Larmonier et al., 2011)

–

(Venkataranganna et al., 2007) (Gong et al., 2018)

200 mg/kg/day 100 mg/kg/day 100 mg/kg 18 mg/day 100 mg/Kg, 200 mg/kg 15 mg/kg, 30 mg/kg, 60 mg/ kg 0− 75 μM

200 mg/kg 20mM 200 mg/kg 28.6μM 8 mg/kg/day – 162 mg/kg/ day 0.2 % curcumin 0.1–1% curcumin 0.25 % curcumin 2 g/L 200 mg/kg

TLR4, NF-κB and IL-27 IL-6, TNF-α, IFN-γ, p53, ß-catenin, COX2, iNOS NF-kB

IFNγ, IL7

NFκ-B and iNOS NLRP3, IL-1β, IL-6, MCP-1

Prevents intestinal cells from inflammatory damage. Alleviates NOS, COX-2, STAT3, NF-ĸB and sverity of colitis. Inhibits the production of hepcidin.

In vivo, In vitro In vivo, In vitro In vivo

(Yang et al., 2017)

Regulates the JAK/STAT/SOCS signals and inhibited the activation of Dendritic cells. Regulates activation of dendritic cells and ameliorates damaged colonic mucosa.

In vivo

BMDMs and Peritoneal macrophages –

In vivo

–

(Zhao et al., 2016b)

Regulates the MMP-3 production. Represses the CD8+ and CD11c + cells. Up regulates anti-inflammatory cytokine gene and Represses improper transportation of epithelial cells. Eliminates tumorigenesis, Preserves colonic microbial ecology

In vitro In vivo In vitro

18co, ISEMFs _ HEK293, Flp293, 293TLR4 cells

(Fontani et al., 2014) (Zhao et al., 2017) (McCann et al., 2014)

In vivo

–

(McFadden et al., 2015)

ERK, FN1, TNFSF12, PI3K complex, p38 and ERK MAPKs. NF-ĸB, IL-12/23p40 and IFN-γ

Reduces activation of inflamatory transcription factors.

In vivo

–

(Cooney et al., 2016)

MLN

(Larmonier et al., 2008)

IL-1β, p38 MAPK D-lactate, DAO, MPO, ICAM-1, IL-1β and TNF-α NOS and terminal-deoxynucleotidyltransferase

Suppresses NF-ĸB and p38 MAPK activity. Ameliorates MKP-1, p38 and NF-kB activation Represses oxidative stress and inactivated endothelial dysfunction

In vivo, In vitro in vivo In vivo, In vitro In vivo

_ IEC-6

(Salh et al., 2003) (Song et al., 2010)

_

(Sagiroglu et al., 2014)

IL-4, IL-10, and IFN-γ, GM-CSF, IL12p70, IL-15, IL-23, and TGF-β1 TNF-α, IL-2, IL-6, IL-12, p40, IL-17, IL-21, CD205, CD54, TLR4, CD252, CD256 and CD254 MMP-3, (TNF)α, TIMP-1 IL-10, IFN-γ and (TGF)-β1 IL-10− 1082 A IL-6, IL-1β, IL-17A, and IL-23p19

24

In vivo, In vitro

_ _

(Zhao et al., 2016a)

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

Table 2 Novel formulations for targeting curcumin. Type of Curcumin

Dose (s)

Effect (s)

Model

C142, C150

40 mg/kg

Represses inflammatory cytokines, TNF-α, IL-6 and IL-4.

C-SBLNs

25mg

–

Coltect

500 mg

Inhibits the pro-inflammatory cytokine, leucocyte infiltration, oxidative stress and maintenance the structure of colon. Ameliorates DAI

In vivo, In vitro In vivo In vivo

–

Curcumin-PAAm-gXG-NPs PF127-NPs

100 mg/kg

In vivo/ in vitro In vivo In vitro, in vivo In vitro In vivo

HCT116 cell lines

CC-NPs Oral curcumin-S

5 mg/kg 100 μL 10mg 5mg 15mg

Improvement in weight loss and colonic inflammation and signs of colitis. Suppresses myeloperoxidase and nitrite level. Suppresses IL-6, IL-12 and TNF-α. Inhibited TNF-a. Inhibits Monophosphoryl Lipid-A and TLR-4.

Cell line (s)

Ref

HEK-TLR-4 YFP – MD2 cell line (NR-9315), HCT116 and HT-29

(Szebeni et al., 2019) (Sharma et al., 2019) (Shapira et al., 2018) (Mutalik et al., 2016) (Chen et al., 2019) (Beloqui et al., 2014) (Kesharwani et al., 2018)

In vivo

–

(Li et al., 2015)

– J774 and Caco-2 cells

CUR-PIP-SMEDDS

25mg

Reduces MPO, MDA, DAI, histopathological lesion, TNF-α and IL-6 levels.

ZN/PVMMA_CRM

–

lowered TNFa, IL-1b, NOS2 and COX-2 levels.

In vitro

RAW 264.7 cell lines

CC SNEDDS CC NLC CC NC

50 μL 50 μL 50 μL In vivo: 1000 μL CC, NC: 200 μL 5, 25 or 50 mg/kg 100 μM 6 mg

(Blanco-Garcia et al., 2017)

Downregulation of neutrophil infiltration and TNF- a.

In vivo/ in vitro

J774 cells Caco-2 cells

(Beloqui et al., 2016)

Increases IL-10, IL-11 and FOXP3. Ameliorates DAI score.

In vivo

–

(Toden et al., 2017)

Attenuates inflammation and protected the layer of mucos.

In vitro / in vivo

Caco2-BBE, Colon-26 cell Raw 264.7

(Xiao et al., 2016)

In vivo

–

(Xiao et al., 2015)

Reduces necrosis, edema and hemorrhage of colon.

in vitro

_

(Sareen et al., 2014)

Improves absorption and bioavailability of curcumin. Also increases the serum concentration.

In vivo

–

(Shoba et al., 1998)

Improves solubility and inactivating NF-κB.

In vitro

RAW 264.7

(Nahar et al., 2015)

Regulating the gut microbes.

In vivo, in vitro

HT-29

(Ohno and Nishida, 2017)

In vivo

_

(Zhang et al., 2006)

ETO-curcumin HA-siCD98/CUR-NPs Curcumin-loaded MPs curcumin loaded microsponges Curcumin + piperine SLCP

6 mg 100 mg 20 mg/kg 2g/kg 10 to 50

μg/mL

Theracurmin

0.2 %(w/ w)

Cur+Dex

30 mg/kg

Inactivating of Th1 cytokines, enhancing Th2 cytokines and the proportion of IFN-γ/IL-4.

nanostructured lipid carriers (NLC) and lipid core-shell protamine nanocapsules (NC), as anti-inflammatory drugs. in vitro studies in Caco-2 cell monolayers revealed that curcumin containing (CC)-NC perme­ ability was 30-fold higher than that of CC-SNEDDS (NC > SNEDDS > NLC and CC suspension). In contrast to the CC-NC and CC suspension, the CC-SNEDDS and CC-NLC caused a convincing fall in TNF-α secretion by LPS-activated macrophages (J774 cells). On the other hand, in vivo studies showed a reduction in TNF-α secretion and, thus, making inflammation feasible by only CC-NLC. It was discovered that success rate in IBD treatment is not related to high CC permeability, but to CC retention due to lipid-based nanocarriers at the intestinal site (Beloqui et al., 2016). TNF-α can lead to neuron inflammation and neurologic pain via raising prostanoid production, neurological hyper-excitability, and no­ ciceptor (pain receptor) activation. Therefore, by ceasing TNF-α pro­ duction and reducing its serum levels, anti-inflammatory conditions may be exerted (Abdolahi et al., 2017). Sharma et al. examined bioavailability of oral curcumin via curcumin loaded solid binary lipid nanoparticles (C-SBLNs) and tested its therapeutic potential in IBD. They used solvent emulsification evaporation method to produce nano-sized C-SBLNs (210.56 ± 41.22 nm) with high rate of entrapment (83.12 ± 6.57 %) using binary lipids i.e. stearic acid and tristearin. Also, high entrapment of C-SBLN was confirmed by ATR-FTIR method and, on the contrary, thermal and pXRD techniques proved its loss of crystallinity. The 24 -h stability of such drug was achieved by cryodesiccation of C-SBLNs, which extended its releasing duration. In addition, localized cellular uptake in inflamed IBD tissue was improved via enhancement of

C-SBLNs. And, inflammatory responses, such as leukocyte infiltration, oxidative stress and cytokine secretion, underwent a sharp reduction by means of oral C-SBLNs in DSS induced colitis models. Therefore, this research adopts in vitro and pre-clinical assessments to suggest that C-SBLNs are a more effective alternative in IBD treatment (Sharma et al., 2019). Supplementary medicines such as piperine, liposomal curcumin, curcumin nanoparticles and phospholipid complexes are efficient in terms of bioavailability rates and therapeutic potential (Patel et al., 2019). BoXiao et al. adopted a new method for treating ulcerative colitis, by oral administration of functionalized porous nanoparticles which was more likely to accumulate in intestinal tissue. Curcumin was loaded into pluronic F127 (PF127) functionalized porous poly (lactic-co-glycolic acid) nanoparticles to obtain porous PF127-functionalized CUR-loaded NPs (porous PF127-NPs). The features of resulted NPs were about 270 nm of hydrodynamic diameter and a high size-distribution with some­ what negative surface and a manageable curcumin release. The PF127 modified NPs showed higher biocompatibility and cellular uptake rate than those without PF127. Additionally, they were relatively more successful in limiting inflammation by hindering pro-inflammatory cy­ tokines such as IL-6,12 and TNF- α of that in porous NPs and non-12 porous PF127-NPs. Also, according to in vivo studies, porous PF127-NPs reached higher therapeutic success rate in comparison to porous NPs and non-porous PF127-NPs. Thus, porous PF127-NPs seem more likely to be advantageous in ulcerative colitis therapy (Chen et al., 2019). Toll-like receptors (TLRs) play important roles against infections, 25

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

Table 3 Clinical trials regarding efficacy of curcumin in treatment of IBDs. Curcumin

Dose(s)

Duration

Outcome(s)

Ref

Curcumin

4, 6 and 8 g daily

3 months

(Hsieh, 2001)

Curcumin

0.45 and 3.6 g daily

4 months

Curcumin

500 mg twice daily 1 g twice daily 2 g twice daily

3 weeks 3 weeks 3 weeks

Curcumin

150 mg 3 time a day

8 weeks

SMEDDS

50 mg increased to 100 mg after 2 weeks Results: 50 mg

Registry: 1 year Results: 3 months

Curcumin is poorly absorbed and may have limited systemic bioavailability. Serum levels peaked between one and two hours after administration and declined rapidly thereafter The mean plasma curcumin measured after one hour on day 1 was 11.1 ± 0.6 nmol/L. This measurement remained relatively consistent at all-time points measured during the first month of curcumin therapy. The molecule was not detected in the plasma of patients taking lower doses. Three patients saw improvement in PUCAI/PCDAI score. Curcumin may be used as an adjunctive therapy for individuals seeking a combination of conventional and alternative medicine without clinically significant side effects. Low dose was ineffective in inducing remission in mild to moderate cases of ulcerative colitis.

1000 mg

8 weeks

Curcumin altered the gut microbiota in a highly similar manner

Curcumin

2 g/day

6 months

Improved endoscopic and clinical activity index

Curcumin

3 g/day

1 month

curcumin

550 550 360 360

Addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients. producing no apparent adverse effects.

1 month, 1 month, 1 month, 2 monthes

All proctitis patients improved, with reductions in concomitant medications in four, and four of five Crohn’s disease patients had lowered CDAI scores and sedimentation rates.

(Holt et al., 2005)

Coltect

500 mg

8 weeks

The patients’ symptoms had improved, with a decrease in abdominal pain, amount of blood in stool and the number of weekly stools. The CAI scores were significantly reduced.

(Shapira et al., 2018)

NCB-02

140 mg

8 weeks

Improvements in disease activity.

Curcumin

360 mg

3 months

The inhibitory effects of curcumin on inflammatory mechanisms like COX-2, LOX, TNF-alpha, IFN-gamma, NF-kappaB and its unrivalled safety profile suggest that it has bright prospects in the treatment of IBD

Curcumin + Bioperine

mg mg mg mg

Clinical remission, Clinical response and Endoscopic remission was observed.

prolonged presence of their signals may have conflicting effects via overactivation of inflammation though, leading to exacerbation of infection. Influenza A virus can activate TLR pathways such as TLR2/4, p38/JNK MAPK and NF-κB which could be suppressed by curcumin (Dai et al., 2018). Tummala et al., assessed polymer-drug complexes for IBD treatment in various aspects such as formulation, characterization and pharmacology. Ora-Curcumin-S is one of the anti-inflammatory poly-­ drug based complexes that targets epithelium of colon. This drug is a result of curcumin and Eudragit®S100 –a hydrophilic polymer sub­ stance- combination by non-covalence bonds. Based on physiochemical tests, this complex shows an amorphous characteristic. Ora-Curcumin-S – a polymer drug complex – unlike solid dispersions, sustains when it is dissolved in aqueous buffers. It shows more solubility characteristics than curcumin depending on the pH levels, specifically observed at pH > 6.8. Moreover, 10–20 % of unformulated curcumin did not resist in pH 7.4, triggered intestinal fluid as well as phosphate buffer after 24 h; however, about 90 % of Ora-Curcumin-S was stable in these conditions. Ora-Curcumin-S inhibits monophosphoryl lipid-A. Ora-Curcumin-S in­ hibits monophosphoryl lipid-A and E. Coli induced inflammatory re­ sponses in dendritic cells and cells over expressing TLR-4, suggesting that Ora-Curcumin-S is a novel polymer-based TLR-4 antagonist. Pre­ liminary pharmacokinetics illustrated targeted soluble curcumin trans­ ference into the colonic lumen bypassing the systemic circulation in vivo. In addition, in an animal model of ulcerative colitis, Ora-Curcumin-S possesses remarkable preventive impacts on colitis-associated injuries through multiple preclinical factors, such as spleen weight, colon edema, body weight, colon length, colonoscopy pictures, pro-inflammatory signaling, and independent pathological scoring (Kesharwani et al., 2018). Curcumin also shows anti-inflammatory features by reducing mRNA expressions of major inflammatory cyto­ kines such as IL-4, IL-5, TNF-α and TGF-β (Shahid et al., 2019). Adjuvant therapy with piperine and various curcumin compounds is closely associated with higher bioavailability and better survival rate

(Sharma et al., 2004b)

(Suskind et al., 2013) (Kedia et al., 2017) (Banerjee et al., 2017) (Peterson et al., 2018) (Hanai et al., 2006) (Lang et al., 2015)

(Singla et al., 2014) (Hanai and Sugimoto, 2009)

(Patel et al., 2019). As it will be explained in following sentences, nanoparticle curcumin complexes attribute to inhibiting weight loss, colitis, and severity of IBDs and enhance epithelial absorption. For example, NF-κB was found significantly reduced after treatment with these compounds based on immunoblot analysis. It also hindered cyto­ kine production therefore, suppressing inflammation. Curcumin, alongside stimulating butyrate producing bacteria which play an important role in reducing chances of IBDs, activated regulatory T cell and regulatory dendritic cells in colon. The modulated colonic micro­ biota reduces severity of DSS-induced colitis. Thus, curcumin shows a great promise in future treatment of IBDs (Ohno and Nishida, 2017). Curcumin biological analogues were synthesized to enhance poor bioavailability and solubility of natural curcumin (58). Therefore, the anti-inflammatory characteristic of Mannich curcuminoids was studied ´s et al. After inducing colitis in a rat model by TNBS, syn­ by G. Puska thesized C142 or C150 were tested for their anti-inflammatory action. These curcuminoids prevented infiltration of leukocytes into the sub­ mucosa and muscular layer of inflamed intestine. They both attributed to less body weight loss and C150 helped with 20 % less tissue edema, decreasing the weight of standard colon preparation. They both also successfully reduced the size of hemorrhages, thus, making it less severe. Additionally, C142 and C150 decreased colonic MPO (myeloperoxidase) activity by 50 %, meaning that it resulted in lower neutrophil infiltra­ tion. Lipopolysaccharide (LPS) when used with curcuminoids as a cotreatment strategy, constrains NF-ĸB (nuclear factor kappa B) activity, depending on their concentration. By the stimulation of LPS, C150 significantly reduced cytokine production such as tumor necrosis fac­ tors, IL-6 and IL-4 in human PBMCs (peripheral blood mononuclear cells) (46). 6. Curcumin and clinical trials in inflammatory bowel disease Regarding the published clinical trials, several researchers have 26

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

yielded data on beneficial effects of curcumin in the therapy of multiple types of diseases. Curcumin has been utilized as combined therapy with routine cancer treatments, but an absence of groups in the study design, problems with placebo composition, and a lack of comparator groups have usually been seen (Elad et al., 2013; Cruz-Correa et al., 2006; Dhillon et al., 2008; Bayet-Robert et al., 2010). Also, curcumin has been utilized as a preventive therapy in healthy individuals and has been revealed to inhibit diverse molecular and cellular pathways in various diseases, including IBDs (Ide et al., 2010). Moreover, curcumin has been indicated to protect against oxidative stress in healthy cases (Dominiak et al., 2010). Overall, no side effects or problems have been reported in patients received curcumin as a prevention therapy, hence it can be considered as a well-tolerated agent (Carroll et al., 2011). Salomon et al., explored whether curcumin treatment was efficient for induction of remission among mild-to moderate UC patients who didn’t respond well to maximal 5ASA therapy (Salomon et al., 2015) in a placebo-controlled double-blind study. Fifty 5ASAtreatment-resistant UC patients scoring between 5–12 in the Simple Clinical Colitis Activ­ ity Index (SCCAI) were selected and treated randomly with 3 g curcumin or placebo everyday for 30 days beside the maximal (oral + topical) 5ASA treatment. In addition to Clinical index (SCCAI), endoscopic index (partial Mayo) and serological parameters were defined at the beginning and at the end of the study. After 4 weeks, clinical remission was induced in 54 % (14/26) of curcumin-treated patients scoring 2 or less in SCCAI whereas none of the 24 cases in placebo group was reported with the same result, indicated by the intention-to-treat analysis (P = 0.01, OR 42.2, 95CI 2.3–760). Three or more points decrease in SCCAI was defined as successful clinical response, which was reached by 17/26 patients in curcumin group and 3/24 patients in placebo one (P < 0.001, OR 13.2, 95CI 3.1–56.6). Endoscopic remission was introduced as par­ tial Mayo score equal or below one, which was reported in 36 % (8/22) of curcumin-treated patients and in 0% (0/16) of the placebo-treated patients (P = 0.035, OR 23.5, 95CI 1.2–445). The mean change in par­ tial Mayo score equaled -0.55 ± 0.79 in the curcumin arm comparing with +015 ± 0.49 for the placebo arm (P = 0.04). Curcumin proved to be an effective adjuvant therapy that promotes remission in mild-to-moderate active UC clinically and endoscopically without raising any significant side effect. Thus, Curcumin would be regarded as a potential therapeutic agent for inflammatory bowel diseases with a natural safe origin (Salomon et al., 2015). Kedia and colleagues assessed the role of oral curcumin therapy in clinical remission of mild-to-moderate ulcerative colitis. An 8-week randomized clinical trial was carried out comparing the clinical remis­ sion in mesalamine (2.4 g) and curcumin (150 mg; thrice a day) treat­ ment with mesalamine and placebo in affected subjects. There was no significant difference in the treatment failure rates, mucosal healing, clinical response, and clinical remission between placebo and curcumin groups at the end of trial. Taken together, 450 mg/d curcumin was ineffective in remission induction in mild-to-moderate ulcerative colitis patients (Kedia et al., 2017). Bommelaer et al., examined whether curcumin is endoscopically or clinically effective as an add-on therapy with thiopurine in avoiding Crohn’s disease (CD) relapse after surgery (Bommelaer et al., 2020). They designed a double-blinded controlled experiment carried out at 8 referral centers in France, randomly selecting 62 CD patients with un­ dergoing bowel resection. Within six months, half of the patients (n = 31) receiving azathioprine (2.5 mg/kg) were orally given curcumin 3 g per day and the other half were administered with the placebo beside the main therapy. In addition to colonoscopic examinations, CD activity index, laboratory tests and QoL questionnaires were used to evaluate the results within this period. CD postoperative recurrence in each group (Rutgeerts’ index score ≥ i2) at month 6 was set as the primary endpoint, defined by central reading). Once half of the patients were registered in the experiment, an interim examination was performed. At month 6, the results indicated no appreciable difference neither in severe adverse effect (6% among placebo group and 16 % among curcumin group) nor

in quality of life (QoL) between two groups. Although postoperative recurrence, defined as Rutgeerts’ index score ≥ i2, was reported to be slightly higher in placebo group than curcumin group (68 % vs 58 %), severe recurrence of CD (determined as Rutgeerts’ index score ≥ i3) was significantly higher among curcumin-treated patients (55 %) compared to the placebo-treated patients (26 %). At month 6, a clinical recurrence of CD (CD activity index score >150) was diagnosed in 45 % of patients in placebo group and 30 % of patients in curcumin group. Finally, cur­ cumin did not lead to any improvement in minimizing postoperative CD recurrence among patients treated with thiopurine after surgery. As no positive effect was observed, the experiment was not continued any further (Bommelaer et al., 2020). Hanai et al. evaluated the curcumin efficiency as maintenance treatment in quiescent ulcerative colitis subjects (Hanai et al., 2006). In this 6-month investigation, preventive effects of curcumin on disease relapse was assessed. Forty-four participants received placebo plus mesalamine or sulfasalazine, and 45 participants received curcumin, 1 g after breakfast and 1 g after the evening meal, plus mesalamine or sul­ fasalazine. Endoscopic index and clinical activity index were examined. Among curcumin subjects, 2 relapses occurred during intervention (4.65 %), while 8 of 39 placebo subjects (20.51 %) relapsed. The rate of recurrence revealed considerable difference between placebo and cur­ cumin. In addition, curcumin ameliorated both endoscopic index and clinical activity index, thereby inhibiting the morbidity related to ul­ cerative colitis. In conclusion, curcumin was shown a safe and promising therapeutic agent for maintaining remission in quiescent ulcerative co­ litis patients. More investigations on curcumin should confirm their results (Hanai et al., 2006). In another study, Lang et al., studied the efficacy of curcumin in remission induction in active mild-to-moderate ulcerative colitis pa­ tients. Randomly, patients were recruited to groups administered 3 g/ day curcumin capsules (n = 26) or placebo (n = 24) for 1 month, in combination with mesalamine. Fourteen cases of curcumin group ach­ ieved clinical remission in comparison to none of the patients who received placebo. By seventeen cases in curcumin group, clinical response (decrease of ≥3 points in Simple Clinical Colitis Activity Index) was achieved, compared to three subjects in the placebo group. In eight out of the 22 patients of curcumin group, endoscopic remission (partial Mayo score ≤1) was seen, in comparison to none of 16 patients of pla­ cebo group. Combination therapy of mesalamine and curcumin was more potent than mesalamine alone and placebo combination in endo­ scopic and clinical remission induction in mild-to-moderate active ul­ cerative colitis patients, contributing to no obvious side-effects. Therefore, curcumin may be a promising and safe compound for ulcer­ ative colitis treatment (Lang et al., 2015). 7. Conclusion IBD etiology is not obviously clarified yet; however, it seems to be driven by inflammatory mediators including TNF-α. CD and UC are two main types of IBD. Although UC is restricted to the colon, CD is able to impact all over the gastrointestinal tract from the mouth to the anus. Notably, another mild-to-moderate ulcerative colitis form is named ul­ cerative proctitis, involving rectum inflammation. IBD patients have a higher risk of development of colorectal malignancies compared to healthy population. In general, TNF blockers, immunosuppressants and anti-inflammatory medications are utilized in IBD management. Insuf­ ficient response in a considerable number of patients as well as the adverse events and costs of current biological approaches encourage complementary and alternative management strategies utilization. In recent decades, accumulating evidence has revealed that curcumin as a multifunctional nutraceutical compound, is capable of regulating numerous cellular signaling pathways. Mounting clinical studies have recently indicated the efficacy, safety, and pharmacokinetics of this natural compound against multiple human diseases. Beside some studies that showed no impact of curcumin on IBS, some hopeful impacts have 27

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

been seen in individuals suffering from diverse pro-inflammatory dis­ eases, such as irritable bowel disease, UC, and CD. Curcumin shows its pharmacological effects through targeting a broad spectrum of molec­ ular mechanisms involved in IBDs. In human investigations, curcumin has been utilized either as single therapeutic agent or in combination with other drugs. Altogether, these results indicated that curcumin alone or in combination with other medicines could be effective in the treat­ ment of IBDs. In other hand, there are some limitations and challenges regarding dosing, lack of enough large-scale and long-term trials that should be solved in the future studies.

Cooney, J.M., Barnett, M.P., Dommels, Y.E., Brewster, D., Butts, C.A., McNabb, W.C., Laing, W.A., Roy, N.C., 2016. A combined omics approach to evaluate the effects of dietary curcumin on colon inflammation in the Mdr1a(-/-) mouse model of inflammatory bowel disease. J. Nutr. Biochem. 27, 181–192. Cosnes, J., Gower–Rousseau, C., Seksik, P., Cortot, A., 2011. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140 (6), 1785–1794 e4. Cruz-Correa, M., Shoskes, D.A., Sanchez, P., Zhao, R., Hylind, L.M., Wexner, S.D., Giardiello, F.M., 2006. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 4 (8), 1035–1038. Dai, J., Gu, L., Su, Y., Wang, Q., Zhao, Y., Chen, X., Deng, H., Li, W., Wang, G., Li, K., 2018. Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-kappaB pathways. Int. Immunopharmacol. 54, 177–187. Denning, T.L., Kim, G., Kronenberg, M., 2005. Cutting edge: CD4+ CD25+ regulatory T cells impaired for intestinal homing can prevent colitis. J. Immunol. 174 (12), 7487–7491. Dhillon, N., Aggarwal, B.B., Newman, R.A., Wolff, R.A., Kunnumakkara, A.B., Abbruzzese, J.L., Ng, C.S., Badmaev, V., Kurzrock, R., 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14 (14), 4491–4499. Di Natale, C., Onesto, V., Lagreca, E., Vecchione, R., Netti, P.A., 2020. Tunable release of curcumin with an in silico-supported approach from mixtures of highly porous PLGA microparticles. Materials Basel (Basel) 13 (8). Dominiak, K., McKinney, J., Heilbrun, L.K., Sarkar, F.H., 2010. Critical need for clinical trials: an example of a pilot human intervention trial of a mixture of natural agents protecting lymphocytes against TNF-alpha induced activation of NF-kappaB. Pharm. Res. 27 (6), 1061–1065. Dou, B., Hu, W., Song, M., Lee, R.J., Zhang, X., Wang, D., 2020. Anti-inflammation of Erianin in dextran sulphate sodium-induced ulcerative colitis mice model via collaborative regulation of TLR4 and STAT3. Chem. Biol. Interact. 324, 109089. Dulbecco, P., Savarino, V., 2013. Therapeutic potential of curcumin in digestive diseases. World journal of gastroenterology: WJG 19 (48), 9256. Elad, S., Meidan, I., Sellam, G., Simaan, S., Zeevi, I., Waldman, E., Weintraub, M., RevelVilk, S., 2013. Topical curcumin for the prevention of oral mucositis in pediatric patients: case series. Altern. Ther. Health Med. 19 (3), 21–24. Fernandez, E.M., Valenti, V., Rockel, C., Hermann, C., Pot, B., Boneca, I.G., Grangette, C., 2011. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut 60 (8), 1050–1059. Fontani, F., Marcucci, T., Picariello, L., Tonelli, F., Vincenzini, M.T., Iantomasi, T., 2014. Redox regulation of MMP-3/TIMP-1 ratio in intestinal myofibroblasts: effect of Nacetylcysteine and curcumin. Exp. Cell Res. 323 (1), 77–86. Garcea, G., Jones, D., Singh, R., Dennison, A., Farmer, P., Sharma, R., Steward, W., Gescher, A., Berry, D., 2004. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br. J. Cancer 90 (5), 1011–1015. Gong, Z., Zhao, S., Zhou, J., Yan, J., Wang, L., Du, X., Li, H., Chen, Y., Cai, W., Wu, J., 2018. Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1beta production. Mol. Immunol. 104, 11–19. Gu, X., Jiang, Y.N., Wang, W.J., Zhang, J., Shang, D.S., Sun, C.B., Tian, J.T., Tian, J.W., Yu, B., Zhang, Y., 2020. Comprehensive circRNA expression profile and construction of circRNA-related ceRNA network in cardiac fibrosis. Biomed. Pharmacother. 125, 109944. Guo, Z., Jang, M.H., Otani, K., Bai, Z., Umemoto, E., Matsumoto, M., Nishiyama, M., Yamasaki, M., Ueha, S., Matsushima, K., 2008. CD4+ CD25+ regulatory T cells in the small intestinal lamina propria show an effector/memory phenotype. Int. Immunol. 20 (3), 307–315. Hanai, H., Sugimoto, K., 2009. Curcumin has bright prospects for the treatment of inflammatory bowel disease. Curr. Pharm. Des. 15 (18), 2087–2094. Hanai, H., Iida, T., Takeuchi, K., Watanabe, F., Maruyama, Y., Andoh, A., Tsujikawa, T., Fujiyama, Y., Mitsuyama, K., Sata, M., Yamada, M., Iwaoka, Y., Kanke, K., Hiraishi, H., Hirayama, K., Arai, H., Yoshii, S., Uchijima, M., Nagata, T., Koide, Y., 2006. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 4 (12), 1502–1506. Holt, P.R., Katz, S., Kirshoff, R., 2005. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig. Dis. Sci. 50 (11), 2191–2193. Hsieh, C., 2001. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21 (2895), e2900. Huttenhower, C., Kostic, A.D., Xavier, R.J., 2014. Inflammatory bowel disease as a model for translating the microbiome. Immunity 40 (6), 843–854. Ide, H., Tokiwa, S., Sakamaki, K., Nishio, K., Isotani, S., Muto, S., Hama, T., Masuda, H., Horie, S., 2010. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 70 (10), 1127–1133. Ireson, C.R., Jones, D.J., Orr, S., Coughtrie, M.W., Boocock, D.J., Williams, M.L., Farmer, P.B., Steward, W.P., Gescher, A.J., 2002. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol. Biomarkers Prev. 11 (1), 105–111. Jahromi, H.K., Farzin, A., Hasanzadeh, E., Barough, S.E., Mahmoodi, N., Najafabadi, M. R.H., Farahani, M.S., Mansoori, K., Shirian, S., Ai, J., 2020. Enhanced sciatic nerve regeneration by poly-L-lactic acid/multi-wall carbon nanotube neural guidance conduit containing Schwann cells and curcumin encapsulated chitosan nanoparticles in rat. Mater. Sci. Eng. C Mater. Biol. Appl. 109, 110564. Jiao, Y., Wilkinson, J.T., Di, X., Wang, W., Hatcher, H., Kock, N.D., D’Agostino Jr., R., Knovich, M.A., Torti, F.M., Torti, S.V., 2009. Curcumin, a cancer chemopreventive

Declaration of Competing Interest The authors declare no conflict of interest. References Abdolahi, M., Tafakhori, A., Togha, M., Okhovat, A.A., Siassi, F., Eshraghian, M.R., Sedighiyan, M., Djalali, M., Mohammadzadeh Honarvar, N., Djalali, M., 2017. The synergistic effects of omega-3 fatty acids and nano-curcumin supplementation on tumor necrosis factor (TNF)-alpha gene expression and serum level in migraine patients. Immunogenetics 69 (6), 371–378. Aggarwal, B.B., Harikumar, K.B., 2009. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int. J. Biochem. Cell Biol. 41 (1), 40–59. Aldini, R., Budriesi, R., Roda, G., Micucci, M., Ioan, P., D’Errico-Grigioni, A., Sartini, A., Guidetti, E., Marocchi, M., Cevenini, M., Rosini, F., Montagnani, M., Chiarini, A., Mazzella, G., 2012. Curcuma longa extract exerts a myorelaxant effect on the ileum and colon in a mouse experimental colitis model, independent of the antiinflammatory effect. PLoS One 7 (9), e44650. Ban, C., Jo, M., Park, Y.H., Kim, J.H., Han, J.Y., Lee, K.W., Kweon, D.H., Choi, Y.J., 2020. Enhancing the oral bioavailability of curcumin using solid lipid nanoparticles. Food Chem. 302, 125328. Banerjee, R., Medaboina, K., Boramma, G.G., Amsrala, S., Reddy, D.N., 2017. Novel bioenhanced curcumin with mesalamine for induction of remission in mild to moderate ulcerative colitis. Gastroenterology 152 (5), S587. Barreau, F., Meinzer, U., Chareyre, F., Berrebi, D., Niwa-Kawakita, M., Dussaillant, M., Foligne, B., Ollendorff, V., Heyman, M., Bonacorsi, S., 2007. CARD15/NOD2 is required for Peyer’s patches homeostasis in mice. PLoS One 2 (6), e523. Bayet-Robert, M., Kwiatkowski, F., Leheurteur, M., Gachon, F., Planchat, E., Abrial, C., Mouret-Reynier, M.A., Durando, X., Barthomeuf, C., Chollet, P., 2010. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol. Ther. 9 (1), 8–14. Beloqui, A., Coco, R., Memvanga, P.B., Ucakar, B., des Rieux, A., Preat, V., 2014. pHsensitive nanoparticles for colonic delivery of curcumin in inflammatory bowel disease. Int. J. Pharm. 473 (1–2), 203–212. Beloqui, A., Memvanga, P.B., Coco, R., Reimondez-Troitino, S., Alhouayek, M., Muccioli, G.G., Alonso, M.J., Csaba, N., de la Fuente, M., Preat, V., 2016. A comparative study of curcumin-loaded lipid-based nanocarriers in the treatment of inflammatory bowel disease. Colloids Surf. B Biointerfaces 143, 327–335. Blanco-Garcia, E., Otero-Espinar, F.J., Blanco-Mendez, J., Leiro-Vidal, J.M., LuzardoAlvarez, A., 2017. Development and characterization of anti-inflammatory activity of curcumin-loaded biodegradable microspheres with potential use in intestinal inflammatory disorders. Int. J. Pharm. 518 (1–2), 86–104. Bommelaer, G., Laharie, D., Nancey, S., Hebuterne, X., Roblin, X., Nachury, M., PeyrinBiroulet, L., Fumery, M., Richard, D., Pereira, B., 2020. Oral curcumin no more effective than placebo in preventing recurrence of Crohn’s Disease after surgery in a randomized controlled trial. Clin. Gastroenterol. Hepatol. 18 (7), 1553–1560 e1. Burisch, J., Jess, T., Martinato, M., Lakatos, P.L., 2013. ECCO-EpiCom, The burden of inflammatory bowel disease in Europe. J. Crohns Colitis 7 (4), 322–337. Carroll, R.E., Benya, R.V., Turgeon, D.K., Vareed, S., Neuman, M., Rodriguez, L., Kakarala, M., Carpenter, P.M., McLaren, C., Meyskens Jr., F.L., Brenner, D.E., 2011. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev. Res. Phila. (Phila) 4 (3), 354–364. Chan, W., Chen, A., Tiao, D., Selinger, C., Leong, R., 2017. Medication adherence in inflammatory bowel disease. Intest. Res. 15 (4), 434. Chen, J., Wang, F.L., Chen, W.D., 2014. Modulation of apoptosis-related cell signalling pathways by curcumin as a strategy to inhibit tumor progression. Mol. Biol. Rep. 41 (7), 4583–4594. Chen, Q., Gou, S., Ma, P., Song, H., Zhou, X., Huang, Y., Kwon Han, M., Wan, Y., Kang, Y., Xiao, B., 2019. Oral administration of colitis tissue-accumulating porous nanoparticles for ulcerative colitis therapy. Int. J. Pharm. 557, 135–144. Cheng, A., Hsu, C., Lin, J., Hsu, M., Ho, Y., Shen, T., Ko, J., Lin, J., Lin, B., Wu, M., 2001. Phase 1 clinical trial of curcumin, a chemopreventive agent, patients with high-risk of pre-malignant lesions. Anticancer Res. 21, 2895. Chin, K.-Y., 2016. The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis, Drug design. development and therapy 10, 3029. Colombo, B.M., Scalvenzi, T., Benlamara, S., Pollet, N., 2015. Microbiota and mucosal immunity in amphibians. Front. Immunol. 6, 111.

28

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30

and chemotherapeutic agent, is a biologically active iron chelator. Blood 113 (2), 462–469. Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., 2012. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491 (7422), 119. Kang, S.G., Piniecki, R.J., Hogenesch, H., Lim, H.W., Wiebke, E., Braun, S.E., Matsumoto, S., Kim, C.H., 2007. Identification of a chemokine network that recruits FoxP3+ regulatory T cells into chronically inflamed intestine. Gastroenterology 132 (3), 966–981. Kashyap, D., Tuli, H.S., Yerer, M.B., Sharma, A., Sak, K., Srivastava, S., Pandey, A., Garg, V.K., Sethi, G., Bishayee, A., 2019. Natural product-based nanoformulations for cancer therapy: opportunities and challenges. Semin. Cancer Biol. Kedia, S., Bhatia, V., Thareja, S., Garg, S., Mouli, V.P., Bopanna, S., Tiwari, V., Makharia, G., Ahuja, V., 2017. Low dose oral curcumin is not effective in induction of remission in mild to moderate ulcerative colitis: results from a randomized double blind placebo controlled trial. World J. Gastrointest. Pharmacol. Ther. 8 (2), 147. Kesharwani, S.S., Ahmad, R., Bakkari, M.A., Rajput, M.K.S., Dachineni, R., Valiveti, C.K., Kapur, S., Jayarama Bhat, G., Singh, A.B., Tummala, H., 2018. Site-directed noncovalent polymer-drug complexes for inflammatory bowel disease (IBD): formulation development, characterization and pharmacological evaluation. J. Control. Release 290, 165–179. Khan, M.M., Madni, A., Tahir, N., Parveen, F., Khan, S., Jan, N., Ali, A., Abdurrahim, M., Farooq, U., Khan, M.I., 2020. Co-delivery of curcumin and cisplatin to enhance cytotoxicity of cisplatin using lipid-chitosan hybrid nanoparticles. Int. J. Nanomedicine 15, 2207–2217. Khor, B., Gardet, A., Xavier, R.J., 2011. Genetics and pathogenesis of inflammatory bowel disease. Nature 474 (7351), 307. Kondamudi, P.K., Kovelamudi, H., Nayak, P.G., Rao, M.C., Shenoy, R.R., 2015. Curcumin half analog modulates interleukin-6 and tumor necrosis factor-alpha in inflammatory bowel disease. Pharmacogn. Mag. 11 (Suppl. 2), S296. Krishnan, K., Arnone, B., Buchman, A., 2010. Intestinal growth factors: potential use in the treatment of inflammatory bowel disease and their role in mucosal healing. Inflamm. Bowel Dis. 17 (1), 410–422. Lang, A., Salomon, N., Wu, J.C., Kopylov, U., Lahat, A., Har-Noy, O., Ching, J.Y., Cheong, P.K., Avidan, B., Gamus, D., Kaimakliotis, I., Eliakim, R., Ng, S.C., BenHorin, S., 2015. Curcumin in combination with mesalamine induces remission in patients with mild-to-Moderate ulcerative colitis in a randomized controlled trial. Clin. Gastroenterol. Hepatol. 13 (8), 1444–1449 e1. Lao, C.D., Ruffin, M.T., Normolle, D., Heath, D.D., Murray, S.I., Bailey, J.M., Boggs, M.E., Crowell, J., Rock, C.L., Brenner, D.E., 2006. Dose escalation of a curcuminoid formulation. BMC Complement. Altern. Med. 6 (1), 1–4. Larmonier, C.B., Uno, J.K., Lee, K.M., Karrasch, T., Laubitz, D., Thurston, R., MiduraKiela, M.T., Ghishan, F.K., Sartor, R.B., Jobin, C., Kiela, P.R., 2008. Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10dependent mechanism of protection, American journal of physiology. Gastrointestinal Liver Physiol. 295 (5), G1079–91. Larmonier, C.B., Midura-Kiela, M.T., Ramalingam, R., Laubitz, D., Janikashvili, N., Larmonier, N., Ghishan, F.K., Kiela, P.R., 2011. Modulation of neutrophil motility by curcumin: implications for inflammatory bowel disease. Inflamm. Bowel Dis. 17 (2), 503–515. Lassen, K.G., Kuballa, P., Conway, K.L., Patel, K.K., Becker, C.E., Peloquin, J.M., Villablanca, E.J., Norman, J.M., Liu, T.-C., Heath, R.J., 2014. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl. Acad. Sci. U. S. A. 111 (21), 7741–7746. Lee, J.H., Mohan, C.D., Basappa, S., Rangappa, S., Chinnathambi, A., Alahmadi, T.A., Alharbi, S.A., Kumar, A.P., Sethi, G., Ahn, K.S., Rangappa, K.S., 2019. The IκB kinase inhibitor ACHP targets the STAT3 signaling pathway in human non-small cell lung carcinoma cells. Biomolecules 9 (12), 875. Li, Q., Zhai, W., Jiang, Q., Huang, R., Liu, L., Dai, J., Gong, W., Du, S., Wu, Q., 2015. Curcumin-piperine mixtures in self-microemulsifying drug delivery system for ulcerative colitis therapy. Int. J. Pharm. 490 (1–2), 22–31. Li, M., Luo, T., Huang, Y., Su, J., Li, D., Chen, X., Zhang, Y., Huang, L., Li, S., Jiao, C., Li, W., Xie, Y., Li, W., 2020. Polysaccharide from Pycnoporus sanguineus ameliorates dextran sulfate sodium-induced colitis via helper T cells repertoire modulation and autophagy suppression. Phytother. Res. Loganes, C., Lega, S., Bramuzzo, M., Vecchi Brumatti, L., Piscianz, E., Valencic, E., Tommasini, A., Marcuzzi, A., 2017. Curcumin anti-apoptotic action in a model of intestinal epithelial inflammatory damage. Nutrients 9 (6). Lubbad, A.S., Oriowo, M.A., Khan, I., 2009a. Curcumin reverses attenuated carbacholinduced contraction of the colon in a rat model of colitis. Scand. J. Gastroenterol. 44 (2), 187–194. Lubbad, A., Oriowo, M.A., Khan, I., 2009b. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol. Cell. Biochem. 322 (1–2), 127–135. Martelli, L., Ragazzi, E., di Mario, F., Martelli, M., Castagliuolo, I., Dal Maschio, M., Palu, G., Maschietto, M., Scorzeto, M., Vassanelli, S., Brun, P., 2007. A potential role for the vanilloid receptor TRPV1 in the therapeutic effect of curcumin in dinitrobenzene sulphonic acid-induced colitis in mice. Neurogastroenterol. Motil. 19 (8), 668–674. McAvoy, J., Dixon, K., 1978. Cell specialization in the small intestinal epithelium of adult Xenopus laevis: structural aspects. J. Anat. 125 (Pt 1), 155. McCann, M.J., Johnston, S., Reilly, K., Men, X., Burgess, E.J., Perry, N.B., Roy, N.C., 2014. The effect of turmeric (Curcuma longa) extract on the functionality of the solute carrier protein 22 A4 (SLC22A4) and interleukin-10 (IL-10) variants associated with inflammatory bowel disease. Nutrients 6 (10), 4178–4190.

McFadden, R.M., Larmonier, C.B., Shehab, K.W., Midura-Kiela, M., Ramalingam, R., Harrison, C.A., Besselsen, D.G., Chase, J.H., Caporaso, J.G., Jobin, C., Ghishan, F.K., Kiela, P.R., 2015. The role of curcumin in modulating colonic microbiota during colitis and Colon Cancer prevention. Inflamm. Bowel Dis. 21 (11), 2483–2494. Mehta, M., Ahmed, S., Dryden, G., 2017. Immunopathophysiology of inflammatory bowel disease: how genetics link barrier dysfunction and innate immunity to inflammation. Innate Immun. 23 (6), 497–505. Midura-Kiela, M.T., Radhakrishnan, V.M., Larmonier, C.B., Laubitz, D., Ghishan, F.K., Kiela, P.R., 2012. Curcumin inhibits interferon-gamma signaling in colonic epithelial cells, American journal of physiology. Gastrointestinal Liver Physiol. 302 (1), G85–96. Miller, J.M., Thompson, J.K., MacPherson, M.B., Beuschel, S.L., Westbom, C.M., Sayan, M., Shukla, A., 2014. Curcumin: a double hit on malignant mesothelioma. Cancer Prev. Res. Phila. (Phila) 7 (3), 330–340. Mutalik, S., Suthar, N.A., Managuli, R.S., Shetty, P.K., Avadhani, K., Kalthur, G., Kulkarni, R.V., Thomas, R., 2016. Development and performance evaluation of novel nanoparticles of a grafted copolymer loaded with curcumin. Int. J. Biol. Macromol. 86, 709–720. Nahar, P.P., Slitt, A.L., Seeram, N.P., 2015. Anti-inflammatory effects of novel standardized solid lipid curcumin formulations. J. Med. Food 18 (7), 786–792. Nasery, M.M., Eslaminejad, T., Mandeghary, A., Zeinali, M., Pardakhti, A., Behnam, B., Mohammadi, M., 2020. Cytotoxicity evaluation of curcumin-loaded affibodydecorated liposomes against breast cancerous cell lines. J. Liposome Res. 1–20. Ng, S.C., Shi, H.Y., Hamidi, N., Underwood, F.E., Tang, W., Benchimol, E.I., Panaccione, R., Ghosh, S., Wu, J.C., Chan, F.K., 2017. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390 (10114), 2769–2778. Nones, K., Dommels, Y.E., Martell, S., Butts, C., McNabb, W.C., Park, Z.A., Zhu, S., Hedderley, D., Barnett, M.P., Roy, N.C., 2009. The effects of dietary curcumin and rutin on colonic inflammation and gene expression in multidrug resistance genedeficient (mdr1a-/-) mice, a model of inflammatory bowel diseases. Br. J. Nutr. 101 (2), 169–181. Obeid, M.A., Khadra, I., Albaloushi, A., Mullin, M., Alyamani, H., Ferro, V.A., 2019. Microfluidic manufacturing of different niosomes nanoparticles for curcumin encapsulation: physical characteristics, encapsulation efficacy, and drug release. Beilstein J. Nanotechnol. 10, 1826–1832. Ohno, M., Nishida, A., 2017. Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells. PLoS One 12 (10), e0185999. Paclik, D., Lohse, K., Wiedenmann, B., Dignass, A.U., Sturm, A., 2008. Galectin-2 and-4, but not galectin-1, promote intestinal epithelial wound healing in vitro through a TGF-beta-independent mechanism. Inflamm. Bowel Dis. 14 (10), 1366–1372. Patel, S.S., Acharya, A., Ray, R.S., Agrawal, R., Raghuwanshi, R., Jain, P., 2019. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit. Rev. Food Sci. Nutr. 1–53. Peterson, C.T., Vaughn, A.R., Sharma, V., Chopra, D., Mills, P.J., Peterson, S.N., Sivamani, R.K., 2018. Effects of turmeric and curcumin dietary supplementation on human gut microbiota: a double-blind, randomized, placebo-controlled pilot study. J. Evid. Integr. Med. 23, 2515690x18790725. Quach, C., Song, Y., Guo, H., Li, S., Maazi, H., Fung, M., Sands, N., O’Connell, D., Restrepo-Vassalli, S., Chai, B., Nemecio, D., Punj, V., Akbari, O., Idos, G.E., Mumenthaler, S.M., Wu, N., Martin, S.E., Hagiya, A., Hicks, J., Cui, H., Liang, C., 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat. Commun. 10 (1), 5681. Rajasekaran, S.A., 2011. Therapeutic potential of curcumin in gastrointestinal diseases. World J. Gastrointest. Pathophysiol. 2 (1), 1. Ravindranath, V., Chandrasekhara, N., 1981. In vitro studies on the intestinal absorption of curcumin in rats. Toxicology 20 (2–3), 251–257. Rubino, S.J., Selvanantham, T., Girardin, S.E., Philpott, D.J., 2012. Nod-like receptors in the control of intestinal inflammation. Curr. Opin. Immunol. 24 (4), 398–404. Sagiroglu, T., Kanter, M., Yagci, M.A., Sezer, A., Erboga, M., 2014. Protective effect of curcumin on cyclosporin A-induced endothelial dysfunction, antioxidant capacity, and oxidative damage. Toxicol. Ind. Health 30 (4), 316–327. Salh, B., Assi, K., Templeman, V., Parhar, K., Owen, D., Gomez-Munoz, A., Jacobson, K., 2003. Curcumin attenuates DNB-induced murine colitis, American journal of physiology. Gastrointestinal Liver Physiol. 285 (1), G235–43. Salomon, N., Lang, A., Kopylov, U., Lahat, A., Har-Noy, O., Wu, J., Ching, J., Cheong, P., Avidan, B., Gamus, D., 2015. Curcumin add-on therapy for remission induction in mild-moderate active ulcerative colitis: a multi-center, randomized, placebocontrolled trial. Clin. Gastroenterol. Hepatol. 13 (7), 1381–1382. Samba-Mondonga, M., Constante, M., Fragoso, G., Calve, A., Santos, M.M., 2019. Curcumin induces mild anemia in a DSS-induced colitis mouse model maintained on an iron-sufficient diet. PLoS One 14 (4), e0208677. Sareen, R., Nath, K., Jain, N., 2014. Curcumin loaded microsponges for colon targeting in inflammatory bowel disease: fabrication, optimization, and in vitro and pharmacodynamic evaluation. J. Biomed. Biotechnol. 2014, 340701. Schneider, M.A., Meingassner, J.G., Lipp, M., Moore, H.D., Rot, A., 2007. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J. Exp. Med. 204 (4), 735–745. Senhaji, N., Serrano, A., Badre, W., Serbati, N., Karkouri, M., Zaid, Y., Nadifi, S., Martin, J., 2016. Association of inflammatory cytokine gene polymorphisms with inflammatory bowel disease in a Moroccan cohort. Genes Immun. 17 (1), 60. Shahid, H., Shahzad, M., Shabbir, A., Saghir, G., 2019. Immunomodulatory and antiinflammatory potential of curcumin for the treatment of allergic asthma: effects on expression levels of pro-inflammatory cytokines and aquaporins. Inflammation.

29

F. Fallahi et al.

Molecular Immunology 130 (2021) 20–30 Venkataranganna, M.V., Rafiq, M., Gopumadhavan, S., Peer, G., Babu, U.V., Mitra, S.K., 2007. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzeneinduced colitis through down-regulation of NFkappa-B and iNOS. World J. Gastroenterol. 13 (7), 1103–1107. Venturi, G.M., Conway, R.M., Steeber, D.A., Tedder, T.F., 2007. CD25+ CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover. J. Immunol. 178 (1), 291–300. Villegas, I., Sanchez-Fidalgo, S., de la Lastra, C.A., 2011. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Mol. Nutr. Food Res. 55 (2), 259–267. Watanabe, T., Asano, N., Murray, P.J., Ozato, K., Tailor, P., Fuss, I.J., Kitani, A., Strober, W., 2008. Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. J. Clin. Invest. 118 (2), 545–559. Wen, X., Klionsky, D.J., 2019. At a glance: A history of autophagy and cancer. Semin. Cancer Biol. Xiao, B., Si, X., Zhang, M., Merlin, D., 2015. Oral administration of pH-sensitive curcumin-loaded microparticles for ulcerative colitis therapy, Colloids and surfaces. B, Biointerfaces 135, 379–385. Xiao, B., Zhang, Z., Viennois, E., Kang, Y., Zhang, M., Han, M.K., Chen, J., Merlin, D., 2016. Combination therapy for ulcerative colitis: orally targeted nanoparticles prevent mucosal damage and relieve inflammation. Theranostics 6 (12), 2250–2266. Yadav, S.K., Sah, A.K., Jha, R.K., Sah, P., Shah, D.K., 2013. Turmeric (curcumin) remedies gastroprotective action. Pharmacogn. Rev. 7 (13), 42. Yang, Y., Klionsky, D.J., 2020. Autophagy and disease: unanswered questions. Cell Death Differ. 27 (3), 858–871. Yang, M., Wang, J., Yang, C., Han, H., Rong, W., Zhang, G., 2017. Oral administration of curcumin attenuates visceral hyperalgesia through inhibiting phosphorylation of TRPV1 in rat model of ulcerative colitis. Mol. Pain 13, 1744806917726416. Yang, J.Y., Zhong, X., Kim, S.J., Kim, D.H., Kim, H.S., Lee, J.S., Yum, H.W., Lee, J., Na, H. K., Surh, Y.J., 2018. Comparative effects of curcumin and tetrahydrocurcumin on dextran sulfate sodium-induced colitis and inflammatory signaling in mice. J. Cancer Prev. 23 (1), 18–24. Yin, H., Guo, Q., 2018. Curcumin suppresses IL-1beta secretion and prevents inflammation through inhibition of the NLRP3 inflammasome. J. Immunol. 200 (8), 2835–2846. Yuan, Q., Bromley, S.K., Means, T.K., Jones, K.J., Hayashi, F., Bhan, A.K., Luster, A.D., 2007. CCR4-dependent regulatory T cell function in inflammatory bowel disease. J. Exp. Med. 204 (6), 1327–1334. Yue, W., Liu, Y., Li, X., Lv, L., Huang, J., Liu, J., 2019. Curcumin ameliorates dextran sulfate sodium-induced colitis in mice via regulation of autophagy and intestinal immunity. Turk. J. Gastroenterol. 30 (3), 290–298. Zeng, Z., Zhan, L., Liao, H., Chen, L., Lv, X., 2013. Curcumin improves TNBS-induced colitis in rats by inhibiting IL-27 expression via the TLR4/NF-kappaB signaling pathway. Planta Med. 79 (2), 102–109. Zhang, F., Altorki, N.K., Mestre, J.R., Subbaramaiah, K., Dannenberg, A.J., 1999. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol estertreated human gastrointestinal epithelial cells. Carcinogenesis 20 (3), 445–451. Zhang, M., Deng, C.S., Zheng, J.J., Xia, J., 2006. Curcumin regulated shift from Th1 to Th2 in trinitrobenzene sulphonic acid-induced chronic colitis. Acta Pharmacol. Sin. 27 (8), 1071–1077. Zhao, H.M., Xu, R., Huang, X.Y., Cheng, S.M., Huang, M.F., Yue, H.Y., Wang, X., Zou, Y., Lu, A.P., Liu, D.Y., 2016a. Curcumin suppressed activation of dendritic cells via JAK/ STAT/SOCS signal in mice with experimental colitis. Front. Pharmacol. 7, 455. Zhao, H.M., Xu, R., Huang, X.Y., Cheng, S.M., Huang, M.F., Yue, H.Y., Wang, X., Zou, Y., Lu, A.P., Liu, D.Y., 2016b. Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice. World J. Gastroenterol. 22 (23), 5374–5383. Zhao, H.M., Han, F., Xu, R., Huang, X.Y., Cheng, S.M., Huang, M.F., Yue, H.Y., Wang, X., Zou, Y., Xu, H.L., Liu, D.Y., 2017. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8(+)CD11c(+) cells. World J. Gastroenterol. 23 (10), 1804–1815.

Shapira, S., Leshno, A., Katz, D., Maharshak, N., Hevroni, G., Jean-David, M., Kraus, S., Galazan, L., Aroch, I., Kazanov, D., Hallack, A., Becker, S., Umanski, M., Moshkowitz, M., Dotan, I., Arber, N., 2018. Of mice and men: a novel dietary supplement for the treatment of ulcerative colitis. Therap. Adv. Gastroenterol. 11, 1756283x17741864. Sharma, R.A., McLelland, H.R., Hill, K.A., Ireson, C.R., Euden, S.A., Manson, M.M., Pirmohamed, M., Marnett, L.J., Gescher, A.J., Steward, W.P., 2001. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 7 (7), 1894–1900. Sharma, R.A., Euden, S.A., Platton, S.L., Cooke, D.N., Shafayat, A., Hewitt, H.R., Marczylo, T.H., Morgan, B., Hemingway, D., Plummer, S.M., 2004a. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10 (20), 6847–6854. Sharma, R.A., Euden, S.A., Platton, S.L., Cooke, D.N., Shafayat, A., Hewitt, H.R., Marczylo, T.H., Morgan, B., Hemingway, D., Plummer, S.M., Pirmohamed, M., Gescher, A.J., Steward, W.P., 2004b. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10 (20), 6847–6854. Sharma, M., Sharma, S., Wadhwa, J., 2019. Improved uptake and therapeutic intervention of curcumin via designing binary lipid nanoparticulate formulation for oral delivery in inflammatory bowel disorder. Artif. Cells Nanomed. Biotechnol. 47 (1), 45–55. Shoba, G., Joy, D., Joseph, T., Majeed, M., Rajendran, R., Srinivas, P.S., 1998. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 64 (4), 353–356. Singla, V., Pratap Mouli, V., Garg, S.K., Rai, T., Choudhury, B.N., Verma, P., Deb, R., Tiwari, V., Rohatgi, S., Dhingra, R., Kedia, S., Sharma, P.K., Makharia, G., Ahuja, V., 2014. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis - a randomized, placebo-controlled, pilot study. J. Crohns Colitis 8 (3), 208–214. Song, W.B., Wang, Y.Y., Meng, F.S., Zhang, Q.H., Zeng, J.Y., Xiao, L.P., Yu, X.P., Peng, D. D., Su, L., Xiao, B., Zhang, Z.S., 2010. Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NFkappaB activation. PLoS One 5 (9), e12969. Soni, S., Babbar, A.K., Sharma, R.K., Maitra, A., 2006. Delivery of hydrophobised 5fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels. J. Drug Target. 14 (2), 87–95. Sturm, A., Dignass, A.U., 2008. Epithelial restitution and wound healing in inflammatory bowel disease. World J. Gastroenterol. 14 (3), 348. Suffia, I., Reckling, S.K., Salay, G., Belkaid, Y., 2005. A role for CD103 in the retention of CD4+ CD25+ Treg and control of Leishmania major infection. J. Immunol. 174 (9), 5444–5455. Suskind, D.L., Wahbeh, G., Burpee, T., Cohen, M., Christie, D., Weber, W., 2013. Tolerability of curcumin in pediatric inflammatory bowel disease: a forced-dose titration study. J. Pediatr. Gastroenterol. Nutr. 56 (3), 277–279. Szebeni, G.J., Nagy, L.I., Berko, A., Hoffmann, A., Feher, L.Z., Bagyanszki, M., 2019. The anti-inflammatory role of mannich curcuminoids; special focus on colitis. Molecules 24 (8). Toden, S., Theiss, A.L., Wang, X., Goel, A., 2017. Essential turmeric oils enhance antiinflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. Sci. Rep. 7 (1), 814. Tønnesen, H.H., M´ asson, M., Loftsson, T., 2002. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int. J. Pharm. 244 (1–2), 127–135. Topcu-Tarladacalisir, Y., Akpolat, M., Uz, Y.H., Kizilay, G., Sapmaz-Metin, M., Cerkezkayabekir, A., Omurlu, I.K., 2013. Effects of curcumin on apoptosis and oxidoinflammatory regulation in a rat model of acetic acid-induced colitis: the roles of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. J. Med. Food 16 (4), 296–305. van der Sloot, K.W., Amini, M., Peters, V., Dijkstra, G., Alizadeh, B.Z., 2017. Inflammatory bowel diseases: review of known environmental protective and risk factors involved. Inflamm. Bowel Dis. 23 (9), 1499–1509.

30