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Curcumin and Intestinal Inflammatory Diseases: Molecular Mechanisms of Protection

Kathryn Burge, Aarthi Gunasekaran, Jeffrey Eckert and 1 more

International Journal of Molecular Sciences · 2019 · Review · CC BY

doi:10.3390/ijms20081912

Abstract

Intestinal inflammatory diseases, such as Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis, are becoming increasingly prevalent. While knowledge of the pathogenesis of these related diseases is currently incomplete, each of these conditions is thought to involve a dysfunctional, or overstated, host immunological response to both bacteria and dietary antigens, resulting in unchecked intestinal inflammation and, often, alterations in the intestinal microbiome. This inflammation can result in an impaired intestinal barrier allowing for bacterial translocation, potentially resulting in systemic inflammation and, in severe cases, sepsis. Chronic inflammation of this nature, in the case of inflammatory bowel disease, can even spur cancer growth in the longer-term. Recent research has indicated certain natural products with anti-inflammatory properties, such as curcumin, can help tame the inflammation involved in intestinal inflammatory diseases, thus improving intestinal barrier function, and potentially, clinical outcomes. In this review, we explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its antimicrobial and immunomodulatory properties, as well as its potential to alter the intestinal microbiome. Curcumin may play a significant role in intestinal inflammatory disease treatment in the future, particularly as an adjuvant therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The incidence of intestinal inflammatory diseases, such as necrotizing enterocolitis (NEC), Crohn’s disease (CD), and ulcerative colitis (UC), is increasing worldwide. NEC is the most common gastrointestinal emergency affecting premature infants, and is associated with a high mortality rate and significant morbidity. The disease is multifactorial with, currently, poorly understood pathogenesis. A number of risk factors have been identified for developing the condition, including prematurity, hypoxic-ischemic injury, altered microbiome, and formula feeding. NEC is largely characterized by intestinal inflammation and necrosis of the gut. To date, limited treatments for NEC are available, consisting of supportive treatment, surgical resection of damaged tissue, antibiotics, and rest of the bowels. Many infants surviving NEC are subsequently subject to additional morbidity in the form of short-gut syndrome and neurodevelopmental impairments.

CD and UC, together referred to as inflammatory bowel disease (IBD), are chronic, relapsing inflammatory diseases with no cure and significant morbidity, most often affecting young adults. Much like NEC, the etiology of IBD is, as yet, unexplained, but is thought to involve an overstimulation and excessive response of the intestinal mucosal immune system to resident luminal microorganisms. In Crohn’s disease, inflammation is discontinuous and manifests as distinct granulomas, with inflammation often permeating transmurally and even affecting adjacent lymph nodes. In contrast, ulcerative colitis, occasionally a milder condition, is characterized by continuous mucosal inflammation localized to the colon. Both CD and UC result in extensive epithelial damage. Treatment options for both diseases, including drugs such as cyclosporine, corticosteroids, 5-aminosalicylic acid (mesalamine), mercaptopurines, anti-tumor necrosis factor-alpha (TNF-α), and azathioprine, are costly, often involve significant side effects, and are limited in effectiveness and specificity.

The intestinal barrier is critical to health and is one of the most metabolically dynamic systems in the body. The intestines must constantly balance allowing molecules in (e.g., water, electrolytes, nutrients) while keeping inflammatory environmental antigens out. Additionally, the intestinal barrier must manage the prevention of invading and translocating luminal bacteria, but also not become hyperreactive to these commensal or symbiotic microorganisms. The intestinal barrier is composed of both an external physical and biochemical barrier and a complementary inner immunological barrier. Wang et al. have described the physical intestinal barrier as a four-layered system, where a strengthening in any one of these layers serves to strengthen the barrier as a whole. The four integral components of the physical barrier consist of (1) a lipopolysaccharide (LPS)-detoxifying alkaline phosphatase layer, (2) a physical mucin barrier that inhibits bacterial interaction with the intestine, (3) tight junctions, and (4) Paneth cell-secreted antimicrobial proteins (AMPs).

The cells comprising the physical intestinal barrier are intestinal epithelial cells (IECs), a group encompassing mucus-secreting goblet cells, AMP-secreting Paneth cells, enteroendocrine cells, and absorptive enterocytes, among others. IECs can not only sense microbes and microbial products, but they can respond by further reinforcement of their own physical barrier and coordination of the response by the intestinal immune system, becoming more or less tolerogenic as dictated by the intestinal luminal contents. Commensal bacteria signal the development of tolerogenic dendritic cells (DCs) and macrophages by spurring IEC-derived production of retinoic acid (RA), transforming growth factor-beta (TGF-β), and thymic stromal lymphopoietin (TSLP). A tolerogenic immune population allows for the production of interleukin (IL)-10 and RA, both immunomodulatory compounds that can suppress pro-inflammatory cytokine production and promote the function of regulatory T cells. Intestinal epithelial cells sense pathogenic microbes and microbial products via transmembrane pattern recognition receptors (PRRs). One class of PRRs expressed in IECs is toll-like receptors (TLRs). TLR4, in particular, a PRR recognizing LPS from gram-negative bacteria, is thought to play an important role in intestinal inflammatory diseases. IECs can also respond to luminal bacteria by producing reactive oxygen species (ROS), which can both eliminate bacteria and signal for cell migration and epithelial repair.

The functional immunological barrier of the intestines lies largely underneath the physical barrier of IECs. The immune system of the intestine is composed of both innate and adaptive arms. As a newborn, adaptive immunity is less effective, so the infant relies primarily on innate immunity. Innate immunity is comprised of primarily physical barriers (e.g., IEC mucus and AMP production), and a reactive component (e.g., resident and patrolling immune cells). Adaptive immunity is reliant upon antigen-presenting cells (APC), largely dendritic cells, which direct T and B cell differentiation and activation. Both goblet cells and specialized IECs, microfold cells (M cells), can present antigens to dendritic cells, priming the adaptive immune system. From here, naïve T helper (Th) cells are differentiated into subsets (e.g., Th1 or Th2) with varying characteristics and cytokine profiles depending upon the local environment.

The pathogenesis of intestinal inflammatory diseases likely involves both IECs and intestinal immune cells. When the highly complex, bilayered intestinal barrier is either underdeveloped or disturbed, intestinal inflammatory diseases may result. The breakdown of the intestinal barrier is most often attributed to overproduction of pro-inflammatory cytokines, such as TNF-α, IL-1β, and interferon-gamma (IFN-γ), triggered by activation of the nuclear factor-kappaB (NF-κB) and activator protein 1/mitogen-activated protein kinase (AP-1/MAPK) pathways.

2.1. Microbiome in NEC

The status of the microbiome in NEC has been widely investigated, but is inherently complex, involving frequent interindividual differences and temporal variability in microbial populations with development and progression of the disease and maturation of the intestine. Intestinal microbes are known to play a role in NEC, as germ-free animal models are protected from development of the disease. Preterm infants are recognized to harbor suppressed bacterial diversity, increased percentage of likely pathogenic flora, and reduced bacterial species compared to term infants. The development of NEC has been correlated to relative increases in Proteobacteria phylum microbiota, while microbes in Firmicutes, Bacteroides, and Negativicutes are found in reduced proportions. The role of microbial species diversity in NEC has been questioned, however, as meta-analyses have failed to find differences in either alpha or beta diversity indices when comparing babies developing NEC to healthy infants. These changes in the NEC preterm infant microbiome may be innate to the maturity of the intestine, but may also be predicated on a number of risk factors for NEC development. For example, antibiotic usage predisposes preterm infants to the development of NEC, likely through increases in Proteobacteria and reductions in Firmicutes and Actinobacteria. Interestingly, the microbial environment of the placenta and amniotic fluid, both previously thought to be sterile environments, clearly impacts the infant, as the meconium of babies developing NEC differs from those not developing the disease. Additionally, higher intestinal luminal pH is associated with the development of NEC, and studies in babies prescribed H2 blockers demonstrated increases in Proteobacteria and a reduction in Firmicutes microbes, mimicking changes seen in NEC babies. Finally, the role of breastfeeding in the development of NEC has been well established, and the microbiome of the milk appears to be highly individualized. Breastmilk is known to reduce the incidence of NEC, potentially through oligosaccharide-associated increases in Bifidobacteria microbial growth.

Functional changes associated with shifts in the microbiome are increasingly recognized to be important, and will likely be a point of emphasis in future research. For example, short chain fatty acids (SCFAs), such as butyrate, are produced by gut bacteria and enhance the barrier function of the intestinal epithelium. Host metabolism of butyrate leads to an environment less conducive to intestinal dysbiosis. Intestinal microbial metabolites are also known to affect gut motility via indirect influences on serotonin production, a process which may influence the development or progression of NEC.

2.2. Microbiome in IBD

As with NEC, the development of IBD is thought to involve intestinal dysbiosis. In IBD, a shift in the intestinal microbiota occurs, resulting in overall decreased diversity, reduced percentages of Firmicutes, and increased percentages of Actinobacteria and Proteobacteria. In particular, pro-inflammatory Escherichia and Fusobacterium species are increased, while anti-inflammatory Roseburia and Faecalibacterium species are decreased. Additionally, the microbial composition of IBD patients in remission compared to those with active disease differs, with those with active disease demonstrating higher levels of Clostridium, Faecalibacterium, and Bifidobacterium species. Despite these general trends, human studies of microbial shifts in the context of IBD show very individualized differences.

Many of the risk factors for developing IBD-associated intestinal dysbiosis are similar to those of NEC, such as a lack of breastfeeding or caesarean instead of vaginal delivery. However, the composition of the diet in IBD patients also appears to be highly relevant. For example, diets low in fiber have been associated with an increase in the development of colitis, while high-fiber diets have been linked to protection from the disease. Increased dietary fiber leads to the production of butyrate by commensal bacteria, known for its beneficial role in immunomodulation of regulatory T cells. Both pre- and probiotics have also been studied in the context of IBD, but clinical trials have shown largely inconsistent results from these supplements.

3.1. NF-κB Signaling

Both NF-κB and AP-1/MAPK pathways (Figure 1) are thought to play a role in intestinal inflammatory diseases. NF-κB and AP-1 are ubiquitous transcription factors that bind DNA to regulate gene expression of inflammatory, differentiating, proliferative, and apoptotic genes. The NF-κB pathway can be stimulated via cytokine receptor ligands, PRRs, ROS, TNF receptor proteins, T cell receptors, and B cell receptors. NF-κB is likely the dominant transcription factor involved in intestinal inflammatory diseases, and involves five subunits: p50, p65 (RelA), p52, cRel, and RelB. These NF-κB components either homo- or heterodimerize to form active NF-κB. In unstimulated cells, NF-κB resides in the cytoplasm, bound to inhibitory molecules of the IκB family that deem the proteins inactive. Once stimulated, however, IκB proteins are degraded by the IκB kinase (IKK) complex. The IKK complex includes the subunits IKKα and IKKβ, as well as the regulatory protein, NEMO (NF-κB essential modulator). IKK activation can be triggered by cytokines, microbial components, generalized cellular stress, and growth factors. Following release into the cytoplasm, NF-κB proteins can translocate to the nucleus to bind to DNA promoters and initiate transcription of inflammatory genes, such as IL-1β, TNF-α, IL-12, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-23, and IL-6, as well as genes related to the function and activation of T cells. Negative regulation of NF-κB signaling largely occurs through IκBα, which is able to translocate to the nucleus and negatively regulate NF-κB activation, interleukin-1 receptor-associated kinase-M (IRAK-M), a negative regulator of TLR signaling upstream of NF-κB, and through TNF receptor-associated factor 1 (TRAF1), which blocks the IKK complex.

Inflammation is a necessary defensive reaction of the host to both microbial infections and tissue damage, and is normally an acute and short-lived process. Dysregulated NF-κB signaling, however, can quickly lead to chronic inflammation and tissue damage. However, NF-κB plays a necessary role in healthy physiology. Interestingly, though NF-κB signaling occurs in both immune and IECs of the intestine, some evidence suggests NF-κB is protective in IECs, where it is necessary for the integrity of the epithelium, but inflammatory in intestinal myeloid cells. For example, studies in NEMO-deficient and gastrointestinally infected mice have indicated that an absence of NF-κB signaling in IECs leads to severe inflammation, indicating NF-κB can also play an anti-inflammatory role, depending on the context. Clearly, however, NF-κB is critical to IEC-driven lymphocyte development and host defense, particularly against pathogenic bacteria.

3.2. AP-1 Signaling

The AP-1 pathway, much like NF-κB, can be stimulated by LPS-activated TLR4, growth factors, ROS, inflammatory cytokines, and generalized cellular stress. AP-1 consists of four DNA-binding families, the Fos, Jun, ATF/cyclic AMP-response element-binding (CREB), and Maf families, which homo- or heterodimerize. The AP-1 pathway is also dependent on activation of MAPKs, which include extracellular signal-regulated kinases (ERK1/2), Jun N-terminal kinases (JNK), c-Fos-regulating kinases, and p38. The regulation of the AP-1 pathway is complex, with dimer composition, transcriptional and translational activity, and various protein interactions playing multiple roles. When activated via pro-inflammatory cytokines and oxidative stress, as is most common in intestinal inflammatory diseases, the MAPK JNK translocates to the nucleus, phosphorylating c-Jun, activating transcription upon dimerization with c-Fos. Target genes include pro-inflamatory mediators such as IL-1β, IL-6, IL-12, IL-23, iNOS, COX-2, and TNF-α, as well as matrix metalloproteinase 9 (MMP9). Adding to the complexity, though NF-κB and AP-1 are often differentiated as two separate signaling pathways, they are capable of modulating each other, with multiple overlapping downstream target genes. For example, Mishra et al. have demonstrated that c-Jun, a member of the DNA-binding families of AP-1, is necessary in NF-κB-dependent LPS signaling for transcription in macrophages.

The AP-1 pathway is active in both IECs and immune cells of the intestine. As with NF-κB, AP-1 signaling is believed to be necessary for healthy intestinal homeostasis and microbiota crosstalk. For example, Wang et al. have demonstrated that c-Jun is important in the resolution of intestinal wounds. However, dysregulated or unabated AP-1 signaling can lead to a number of physiological abnormalities, including excessive inflammation, and is believed to contribute to the development of intestinal inflammatory diseases.

3.3. TLR4 Induction

TLR4 is an upstream regulator of both NF-κB and AP-1, and its induction is critical to intestinal inflammatory diseases. The TLR4 pathways aid in host immunity by allowing the host to distinguish between self and non-self molecules. TLR4 signaling occurs in both IECs and intestinal immune cells, and is unique in that it operates, in both NF-κB and AP-1 signaling, through myeloid differentiation factor 88 (MyD88)-dependent and -independent mechanisms. In both MyD88-dependent and -independent mechanisms, ligand-induced dimerization of TLR4 is necessary to signal downstream. In NF-κB, MyD88-dependent signaling, TLR4 ligand-binding recruits Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP), which then recruits MyD88 to the site. MyD88 interacts with and activates IRAK4, which then phosphorylates IRAK1. These IRAKs then detach from MyD88 and bind with TRAF6. TRAF6 activates transforming growth factor-beta-activated kinase 1 (TAK1), and TAK1, through TAK1-binding proteins, TAB1 and TAB2, activates IKK, initializing the NF-κB pathway. In NF-κB, MyD88-independent signaling, TLR4 recruits the adaptor proteins TIR-domain-containing adaptor protein inducing interferon-β (TRIF) and translocation associated membrane protein (TRAM). Receptor-interacting protein (RIP1) associates with TRIF and TANK-binding kinase (TBK1) to form a signaling complex, which then regulates the downstream IκBα degradation. RIP1 is also capable of signaling through a PI3K-Akt-dependent mechanism, negatively regulating mammalian target of rapamycin (mTOR) through NF-κB.

Alternatively, in AP-1, MyD88-dependent signaling, ligand-binding recruits TIRAP, and subsequently MyD88. Signaling progresses similar to that of NF-κB, MyD88-dependent (above) through the activation of TAK1. While in NF-κB signaling, TAK1 activates IKK, in AP-1 transduction, TAK1 activates MAPK family members (ERK1/2, JNK, and p38), leading to the activation and nuclear translocation of of AP-1 proteins (c-Fos, c-Jun, ETS domain-containing protein 2 (ELK-2), activating transcription factor 2 (ATF-2)) and gene transcription. In AP-1, MyD88-independent signaling, ligand-binding recruits TRAM, and subsequently TRIF. TRIF binds to TRAF6, leading to the activation of TAK1. From here, phosphorylation of MAPKs occurs similarly to the AP-1, MyD88-dependent pathway. TLR4 signaling is generally regulated by vascular endothelial growth factor-C (VEGF-C), nerve growth factor 1B (Nur-77), and selective androgen receptor modulators (SARMs), which negatively feedback to control this inflammatory pathway.

TLR4 signaling is important in that it primes the immune system, leading to the maturation of DCs and differentiation of Th1 and Th2 T cell subsets. Additionally, TLR4 signaling promotes the differentiation of macrophages to an M1 phenotype, characterized by the production of pro-inflammatory cytokines. Because TLR4 is upstream of both NF-κB and AP-1, however, denotes that a disproportionate TLR4 induction begets excessive inflammation.

4.1. Pathogenesis of NEC

The pathogenesis of NEC is thought to involve the underdeveloped intestinal motility and barrier functions of the infant, an altered microbiome, and an immature, but hypersensitive, immune system. Both innate and adaptive immune factors contribute to susceptibility to NEC, but the exact sequence of events in development of the disease is poorly understood.

In NEC, induction of the TLR4 pathway is not only implicated in the disease, but is thought to potentially be required for its development. In normal physiology, IECs express very low levels of TLR4. However, in both mice and humans, prematurity is denoted by an unusually high expression of TLR4. Activation of TLR4 signaling in this environment not only leads to excessive inflammation, but also increased apoptosis of IECs, reduced migration and proliferation of IECs to replace those lost to apoptotic events, and the destruction of the intestinal epithelium. The impaired intestinal barrier now allows the immature immune system greater and more frequent access to microbial antigens. Dendritic cells residing in the intestine begin presenting antigens, and T cells, monocytes, and macrophages activate and initiate the production of a wealth of pro-inflammatory cytokines and chemokines. This inflammatory cascade leads to recruitment of neutrophils, release of ROS, and further intestinal inflammation and necrosis. Endothelial nitric oxide synthase (eNOS) is also reduced by TLR4 activation, potentially resulting in intestinal ischemia and necrosis. A vicious cycle ensues, where inflammation begets more inflammation, overriding any attempts by the host of counterregulation. This inflammation spreads systemically, affecting organs as remote as the brain.

Evidence of the upregulation of TLR4/NF-κB/AP-1 signaling in NEC is robust. Preterm infants are likely developmentally predisposed to excessive NF-κB activation. In vitro and fetal cell explant studies of IECs have revealed that immature enterocytes display lower levels of the NF-κB-inhibiting IκBα compared to mature cells, resulting in elevated IL-8 production in response to LPS. De Plaen et al. demonstrated persistent NF-κB activation in intestinal epithelial cells in a rat model of NEC, while additional animal models have established that levels of NF-κB positively correlate with disease severity. Managlia et al. demonstrated that NF-κB activation occurs before the onset of intestinal injury, and that monocytes are differentiated into inflammatory intestinal macrophages during the very early stages of NEC via IKKβ. Fusunyan et al. examined small intestinal histology from preterm infants with NEC and denoted both increased TLR4 and reduced IκB expression. Additionally, the neonatal intestine is also characterized by higher levels of c-Jun and c-Fos, important mediators in the AP-1 pathway. Thus, the immature intestinal environment of the premature infant predisposes it to chronic inflammatory signaling.

A number of differences beyond the hyperinduction of TLR4/NF-κB/AP-1 have been noted between normal physiology and NEC, in both animal models and humans. IECs not only express PRRs, such as TLR4, but also present major histocompatibility class (MHC) I and II molecules, information presented to the adaptive immune system for future identification of foreign compounds. In NEC, infants generally show a lower expression of MHC II molecules, potentially allowing pathogenic bacteria to more easily translocate the intestinal epithelium. Goblet cells in the epithelium, characterized by protective mucin 2 (MUC2) production, are reduced in number and show decreased MUC2 production in both mice and humans.

The importance of neutrophils in the development of NEC is still unclear. Neutrophils, among the first cells recruited to the site of injury, release bactericidal compounds and ROS, and attract further immune cell recruitment. Some animal studies have demonstrated a protective effect of neutrophil recruitment in NEC, while others have shown the oxidative metabolites from neutrophils may further degrade tissue impacted by NEC. However, limited studies in humans have indicated that neutropenia is a significant risk factor for NEC, and immature human neutrophils show a reduced ability to phagocytize. Meanwhile, macrophages in the immature intestine are hyperactive, demonstrating an increased sensitivity to microbial products, but the presence of TGF-β can suppress this immune activity. Patients with NEC show increased tissue macrophage infiltration and suppressed levels of TGF-β2, an embryonic isoform. Additionally, these macrophages may not be fully functional, as they, like immature neutrophils, show a reduced ability to phagocytize. Dendritic cells, while not studied much in the context of NEC, may also contribute to the breakdown of the intestinal barrier.

Though adaptive immunity is less pronounced in neonates, T cells are still believed to contribute to NEC pathogenesis in a number of ways. For example, neonatal γδ intraepithelial lymphocytes (IELs), the first subset of intestinal T cells present during embryogenesis, produce higher levels of the cytokines IFN-γ and IL-10 compared to adult populations. γδ IELs are thought to protect against bacterial invasion if mucosal injury occurs. However, these γδ IELs are significantly less abundant in preterm infants with NEC compared to age-matched controls. Tregs, T cells that regulate immune responses and promote tolerance, in both mice and humans, are found in lower levels in NEC infants compared to controls. Th17 cells, a pro-inflammatory subset of T helper cells credited with tissue inflammation and destruction, are present in higher concentrations in the context of NEC. The primary cytokine produced by Th17 cells, IL-17A, is believed to contribute significantly to NEC development by disrupting tight junctions, reducing IEC proliferation, and increasing IEC apoptosis. Another subset of T helper cells, Th1, mediate, in large part, the cellular response to intracellular pathogens and microbial products. In NEC, there is some evidence these inflammatory mediators have a reduced ability to respond to pathogens and produce their signature cytokine, IFN-γ.

As expected given the upregulation of TLR4/NF-κB/AP-1 signaling in NEC, cytokine and pro-inflammatory ROS-associated enzyme levels drastically differ compared to age-matched controls. For example, levels of inducible nitric oxide synthase (iNOS), an enzyme responsible for the production of nitric oxide (NO) and involved in inflammatory immune defense and oxidative tissue damage, are upregulated in NEC, both in tissue and serum. TNF-α, a pro-inflammatory cytokine known to increase IL-1, provoke leukocyte migration, spur angiogenesis, and associated with shock, is increased in NEC. TNF-α also increases levels of matrix metalloproteinases, such as MMP9, MMP12, and MMP19, destructive proteins which serve in the breakdown of the intestinal extracellular matrix. Interestingly, the inhibitor of MMPs, tissue inhibitor of metalloproteinases (TIMPs), is also upregulated in NEC, likely indicating an attempt by the body at repair.

IL-1, a pro-inflammatory cytokine stimulated by TNF-α, is associated with leukocyte adhesion, macrophage and neutrophil activation, and the upregulation of IL-8. Levels of both IL-1α and IL-1β are upregulated in the NEC intestine. Additionally, evidence suggests the neonatal intestine has enhanced sensitivity to IL-1β compared to more mature enterocytes. IL-1 receptor antagonist (IL-1Ra), an anti-inflammatory protein competitively inhibiting both IL-1 isoforms, is also upregulated in NEC, though this upregulation is clearly not enough to counteract the rampant inflammation induced by IL-1.

IL-6, a cytokine stimulated by a variety of pro-inflammatory cytokines including IL-1 and TNF-α, can act in both pro-inflammatory and anti-inflammatory means, and is an activator of lymphocytes in the adaptive immune system. Levels of IL-6 are elevated in NEC. Plasma IL-6, in particular, is significantly associated with higher NEC morbidity and mortality. IL-8, a neutrophil and monocyte chemokine, is found in greater abundance in premature infants, but levels are upregulated further still in NEC, though often with a temporal delay. IL-12, IL-18, and IFN-γ, which work simultaneously to increase inflammation via ROS, are upregulated in NEC. Serum levels of IL-2 and IL-5 are also increased in the disease. Finally, levels of IL-4 and IL-10, counterregulatory anti-inflammatory cytokines, are increased in NEC, while serum and tissue levels of the immune suppressor TGF-β are reduced. The upregulation of IL-10, again, may demonstrate an attempt by the host at repair.

4.2. Pathogenesis of IBD

Whereas in NEC, pathogenesis of the disease is strongly predicated on prematurity, the development of IBD is thought to be dependent upon genetic susceptibility, lifestyle factors, such as diet and antibiotic use, intestinal barrier dysfunction, and, potentially, altered microbiome. These factors, altogether, result in a heightened mucosal inflammatory response to luminal microbiota and breakdown of the intestinal barrier, likely through disruption of tight junctions. Interestingly, increased intestinal permeability is often used clinically to predict relapse of Crohn’s disease, in particular, but intestinal permeability is, itself, not enough to initiate CD development, as first-degree relatives of CD patients, though asymptomatic, also demonstrate increased intestinal permeability. As with NEC, the succession of events leading to development of IBD is not known.

Both the innate and adaptive immune systems contribute to IBD pathology. In a genetically susceptible individual, a small break in the intestinal epithelium, such as through bacterial translocation, activates the innate immune system, most likely through upregulated TLR4 activity. Activation of TLR4, and subsequently NF-κB and AP-1, promotes the enlistment of monocyte-derived macrophages, initializing production of pro-inflammatory cytokines, leukocyte-attracting chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1) and MCP-3, and macrophage inflammatory proteins (MIP). When inflammation is not constrained, APCs then enter mesenteric lymph nodes and drive T helper cell differentiation and the proliferation of macrophages, resulting in heightened sensitivity to luminal commensal bacteria. Neutrophils then infiltrate damaged tissue and excessive pro-inflammatory cytokine release ensues, as well as the release of additional pro-inflammatory mediators, such as eicosanoids, MMPs, platelet-activating factor (PAF), reactive nitrogen species (RNS), and ROS. MAPK activation in IECs spurs the upregulation of both COX-2 and iNOS, which can cause additional damage to the intestinal epithelium. Furthermore, levels of vascular cell adhesion molecule 1 (VCAM-1), E-selectins, very late antigen 4 (VLA-4), macrophage 1 antigen (Mac-1), lymphocyte function-associated antigen 1 (LFA-1), and intercellular adhesion molecule 1 (ICAM-1) increase, attracting further recruitment and activation of lymphocytes. Levels of counterregulatory mediators, meanwhile, such as TGF-β1 and IL-10, are reduced. Thus, a vicious cycle of chronic inflammation ensues, resulting in the apoptosis of IECs, the prevention of apoptosis in, and accumulation of, T cells, and further compromise of intestinal barrier function. In the long-term, excessive signaling and inflammation resulting from microbial recognition by IECs has also been shown to drive colorectal cancer development in individuals suffering from IBD.

There is significant evidence of the upregulation of TLR4/NF-κB/AP-1 signaling in IBD. Levels of TLR4 are upregulated in the intestinal tissue of both humans and animal models of IBD. In both CD and UC, levels of tissue NF-κB are positively correlated with intestinal inflammation severity. Intestinal mucosal macrophages of both UC and CD patients demonstrate increased levels of NF-κB, resulting in increased capacity for inflammatory TNF-α, IL-1 and IL-6 cytokine production. In IBD, the p65 subunit of NF-κB is increased, particularly in Crohn’s disease. Additionally, in an extensively utilized mouse model of IBD, trinitrobenzene sulfonic acid (TNBS)/ethanol-induced colitis, activation of the p65 subunit is a requisite step in the pathogenesis of the disease model. AP-1 signaling has been deemed dysfunctional in IBD through increased JNK activity in both macrophages and IECs. Several studies have also indicated increased JNK activity in the inflamed mucosa of IBD patients.

IBD intestinal physiology vastly differs from that of healthy individuals, in both humans and animal models. For example, Paneth cells in IBD are known to release fewer AMPs, potentially allowing more bacteria to translocate the intestinal epithelium. Recent research has also pointed to potential differences in autophagy in IBD, both of pathogens (xenophagy), as well as damaged mitochondria (mitophagy), leading to more microbial invasion and reduced clearance of damaged tissue. Monocytes in IBD also show reduced MHC II expression, which has been shown to correlate with disease activity.

T cells contribute significantly to inflammatory bowel disease, and therapy aimed at T cell reduction has been shown to abrogate the disease. In Crohn’s disease, in particular, T cells are extremely prevalent, and often form distinctive granulomas. These T cells, primarily naïve, are recruited via the blood to the intestinal mucosa, largely through the production of adhesion molecules and pro-inflammatory cytokines. An upregulation of IL-6 during IBD development leads to activation of the STAT3 pathway, preventing T cell apoptosis, and allowing for the abnormal accumulation of these cells in the intestine. These T cells secrete large amounts of pro-inflammatory cytokines, permitting IBD disease progression.

In IBD, T helper cell profiles differ by disease. In CD, the profile of T helper cells is strongly skewed toward that of the Th1 and Th17 phenotypes, driven by LPS-associated IL-12 production. Th1 cells, important in pathogen clearance, produce large amounts of IFN-γ, TNF-α, and IL-2, and active CD lesions show high levels of these cytokines and their associated T cells. Th1 cells, much like naïve T cells in IBD, appear to be protected from apoptosis. Th17 cells, the differentiation of which is spurred by IL-6 and TGF-β, are maintained via IL-12-associated release of IL-23. Th17 cells, native to the intestinal barrier and important in the elimination of extracellular pathogens, produce IL-17, an inflammatory cytokine aiding in neutrophil and monocyte recruitment. Unlike in NEC, the role of IL-17 in IBD is not clear, as it plays a protective and pathogenic role, depending upon the model. In UC, however, the T helper cell profile leans towards Th2, Th9, and Th17 phenotypes, producing large amounts of IL-5 and IL-13. Th2 cell differentiation is driven by IL-4, and when this pathway becomes dysregulated, upregulated Th2-associated production of IL-13 contributes to tissue destruction, as it induces apoptosis in IECs. Th9 cells, meanwhile, driven simultaneously by IL-4 and TGF-β, produce IL-9, a pleotropic cytokine thought to impair the intestinal barrier function and exacerbate UC-associated tissue damage. Additionally, the production of IL-21 may also play a role in IBD by driving both Th1 and Th17 responses.

T regulatory cells (Tregs) also play an important role in intestinal inflammatory disease pathogenesis, as they can inhibit effector T cells from functioning, promoting a more tolerogenic immune phenotype. There is some indication the balance between effector T cells and Tregs is altered in intestinal inflammatory diseases, allowing for disease progression via inflammatory cytokine production and T cell activation positive feedback loops. Further evidence of this imbalance is provided by studies denoting transfusions of Tregs into animal models of experimental colitis ameliorate the disease. Treg function and Th17 differentiation is, in part, due to regulation by IL-18, a cytokine found in higher levels in IBD patients.

Another group of lymphocytes thought to be important in IBD are the innate lymphoid cells, a population of lymphocytes which lack typical adaptive lymphocyte markers. Patients with IBD, particularly CD, show significant mucosal infiltration of innate lymphoid cells, group 1 (ILC1), demarcated by production of IFN-γ and TNF, and mouse studies mirror this finding. Type 3 innate lymphoid cells (ILC3s) also play a role, producing both IL-22 and IL-17. IL-22 is important in intestinal repair, and in mouse models, blocking this pathway leads directly to colitis. IBD patients are known to have an increase in the IL-22 binding protein, an antagonist to IL-22.

With increased TLR4/NF-κB/AP-1 signaling comes excessive production of inflammatory cytokines and oxidative molecules, some of which have already been discussed. Both CD and UC are characterized by increased synthesis of IL-1β, IL-6, IL-8, TNF-α, and IL-16, a T cell chemoattractant. In the context of IBD, TNF-α and IL-1β are particularly important. TNF-α can activate resident tissue macrophages, spur further proinflammatory cytokine and oxidative inflammatory mediator release, as well as induce adhesion molecule expression, further driving leukocyte recruitment to areas of inflammation. IL-1β, a pro-inflammatory cytokine associated with the innate immune response, has been found in high levels in the tissues of patients with IBD, as well as in monocytes from these patients. In both humans and animal models, the balance of IL-1 and IL-1Ra plays a determinative role in IBD. The IL-1Ra/IL-1 ratio is decreased in IBD, and this ratio correlates negatively with clinical severity of the disease. In Crohn’s disease, the activity of inositol polyphosphate 5′-phosphatase D (SHIP), a negative regulator of IL-1β expression, is reduced, furthering the imbalance of IL-1Ra/IL-1. Both IL-1β and TNF-α can induce production of MMPs, further destroying the intestinal scaffolding. MMP3, in particular, has been found in high levels in the tissues of IBD patients. Overproduction of IL-6 is also thought to be important in IBD, where in mouse models, elevated IL-6 levels are directly involved in disease pathogenesis and can result in the abnormal accumulation of T cells in the intestine. IFN-γ production, in the context of CD, is important in driving further production of IL-1, IL-6, and TNF-α. Finally, the negative regulator of the immune-calming TGF-β, mothers against decapentaplegic homolog 7 (SMAD7), is increased in IBD, thereby blocking one counterregulatory measure to the excessive inflammation induced by these cytokines.

Pro-inflammatory cytokine release may result in tight junction disruption in IBD, further damaging the intestinal barrier. For example, claudin-2, a pore-forming protein, is known to be upregulated in IBD, particularly in crypts where the protein is not normally present. Additionally, the loss of tight junction strands and physical severing of these strands is associated with IBD-associated intestinal barrier defects. Alterations in tight junctions, however, are thought to be a consequence of upregulated cytokine production, rather than a causative factor in IBD.

5. The Effects of Curcumin on Intestinal Inflammatory Diseases

Curcumin, the biologically active, hydrophobic, phenolic component of turmeric (Curcuma longa), is a natural product commonly utilized in Ayurdevic and traditional medicine, both topically and orally, for its potent effects on multiple body systems. Four compounds, collectively termed curcuminoids and imparting a yellow color, are derived from turmeric, including curcumin, bisdemethoxycurcumin, demethoxycurcumin, and cyclocurcumin, with curcumin found in the highest concentration by weight. Commercially purchased curcumin is often an impure mixture of approximately three-quarters curcumin, 17% demethoxycurcumin, 3% bisdemethyoxycurcumin, and little to no cyclocurcumin, and human curcumin clinical trial results have been complicated by the fact that multiple, heterogeneous mixtures of curcuminoids have been used in these studies. Curcumin is characterized by the inclusion of two aromatic rings, and its phenolic hydrogens are believed to impart antioxidant activity to the molecule. Curcumin, also known as diferuloylmethane, has been a popular supplement largely because of its affordability and safety, with no known toxic side effects in humans up to doses of 12 g/day.

5.1. Antibacterial and Microbiome Effects

Curcumin demonstrates a wide range of effects on the gastrointestinal system. In in vitro and in vivo models of Helicobacter pylori infection, curcumin inhibited bacterial growth on agar plates, and eradicated the bacteria from mice, respectively. The bactericidal effect of curcumin appears to occur through an inhibition of bacterial cell division, resulting in the inappropriate assembly of the bacterial protofilament. Further, Niamsa and Sittiwet demonstrated the antimicrobial activity of curcumin against a number of commonly encountered pathogenic Gram-negative and Gram-positive bacteria.

Curcumin is also capable of regulating the gut microbiota, as a whole. Intestinal inflammatory diseases are defined, in part, by an altered, frequently pathogenic, microbiome. In IBD, the microbiome is often enriched by a population of adherent invasive E. coli (AIEC), which can promote inflammation in the gut. Studies investigating the effects of curcumin on the microbiome have attained different results depending upon the disease characteristics of the studied population. For example, in mice living in specific-pathogen-free conditions, curcumin supplementation decreased the microbial richness and diversity. In a rat model of hepatic steatosis, curcumin administration reduced species richness and diversity, shifted the structure of the gut microbiota, and induced significant microbiota compositional changes compared to both high-fat diet and control groups, reversing the buildup of fat in the liver. Importantly, curcumin favored the maintenance of short-chain fatty acid-producing bacteria, which are known to provide intestinal mucosal protection and inhibit intestinal inflammation.

In rats that have been ovariectomized, estrogen-deficiency-associated gut microbial shift is partially reversed by supplementation with curcumin. Ohno et al. showed, in a mouse model of colitis, an immunological and microbiological shift towards improved intestinal barrier function and reduced intestinal inflammation with nanoparticle curcumin supplementation. Curcumin administration in these mice significantly increased butyrate-producing microbiota, which are associated with colonic induction of Tregs, tolerance-promoting T cells. McFadden et al. utilized an IL-10-deficient model of murine colitis to demonstrate that curcumin supplementation prevented age-associated decreases in bacterial alpha diversity, increased bacterial richness, decreased Coriobacterales, increased Lactobacillales, and prevented development of colorectal cancer.

Studies on the effects of curcumin on the human gut microbiota are generally lacking, potentially due to the widely acknowledged absorption issues of the compound. Peterson et al., in a pilot study, compared whole turmeric or curcumin extracts to placebo, and showed an increase in species and a trend toward increased alpha diversity with turmeric or curcumin supplementation. While individual responses to treatment varied, the patterns within the groups were very similar in both turmeric and curcumin, suggesting that curcumin, the most significant bioactive component of turmeric, was driving the observed changes. Interestingly, in subjects supplementing with turmeric or curcumin, the relative abundance of Blautia spp., believed to be the major metabolizers of curcumin, was reduced compared to controls. While more complete studies on the effects of curcumin on the human microbiota are warranted, curcumin may be able to both simultaneously eradicate some pathogenic bacteria while globally shifting the composition of the intestinal microbiome.

5.2. Effects on Signal Transduction

Inflammation in intestinal inflammatory diseases is largely driven through upregulated TLR4/NF-κB/AP-1 signaling. Activation of TLR4 initiates an innate immune response and subsequent inflammation, in both NEC and IBD. Treatments abrogating TLR4-dependent signal transduction have been shown to lead to an amelioration of intestinal inflammatory disease. Curcumin has been shown to inhibit both MyD88-dependent and -independent signaling mechanisms. Additionally, curcumin can bind to myeloid differentiation protein 2 (MD-2), a protein bound to the extracellular TLR4 domain, thereby suppressing the innate immune response to LPS. Additionally, should this initial inhibition not occur, curcumin can inhibit TLR4 signaling at a number of downstream steps, including TRAF6 and IRAK1, as well as through immune-modulating (e.g., MCP-1, MIP-2) and signaling-associated cytokine blockades. In a Caco-2 model of the intestinal epithelium, treatment with curcumin resulted in diminished LPS-induced pro-inflammatory cytokine release and tight junction protein disruption, likely through a TLR4-dependent reduction in signaling. In TNBS-induced colitis rodent models, curcumin has been shown to ameliorate the disease through a reduction in TLR4 signal transduction.

Eckert et al. treated T84 intestinal epithelial monolayers with FLLL32, an analog of curcumin with greater solubility and potency. FLLL32 treatment reduced paracellular permeability associated with IL-6-induced inflammation, denoted as an alleviation of the IL-6-induced drop in transepithelial electrical resistance (TEER) (Figure 2). This same group, in a dithizone/Klebsiella Paneth cell ablation animal model of NEC, showed mouse pups treated with 25 mg/kg FLLL32 developed NEC less frequently, and at a significantly reduced severity, compared to pups with untreated NEC (Figure 3A–D; 20× magnification). Additionally, a fluorescein isothiocyanate (FITC)-dextran in vivo intestinal barrier assay demonstrated enhanced preservation of the intestinal barrier in FLLL32-treated animals compared to those with untreated NEC (Figure 3E). Finally, FLLL32 treatment decreased levels of the inflammatory cytokines IL-1β, IL-6, TNF-α, and growth-regulated oncogene-alpha (GRO-α) compared to levels in pups with untreated NEC, thereby inhibiting NEC-associated inflammation, likely through a TLR4/NF-κB-dependent reduction in signaling (Figure 3F–I).

Downstream of TLR4, signaling continues through either NF-κB or AP-1, both of which are upregulated in, and critical to, intestinal inflammatory diseases. In both NEC and IBD, inhibition of NF-κB signaling has been shown to reduce injuries to the bowel. Additionally, p38 MAPK inhibitors have established some success against colitis, including potentially in human IBD. Curcumin inhibition of NF-κB activation appears to be through inhibition of IKKβ, thus reducing IκB kinase activity, and preventing NF-κB subunit movement to the nucleus. The mechanism of curcumin therapy in intestinal inflammatory diseases mimics that of steroids, blocking IκBα degradation in the cytoplasm and inhibiting nuclear translocation of the p65 subunit, in particular. In AP-1 signaling, curcumin can inhibit MAPK, ERK1/2, JNK, and p38, both directly and indirectly, thereby limiting transcription of inflammatory target genes.

Numerous studies, in both animal models and humans, have documented curcumin inhibition of NF-κB and AP-1 signaling. For example, in a variety of IEC lines, Jobin et al. showed curcumin can inhibit NF-κB-binding to DNA, degradation of IκBα, translocation to the nucleus of RelA, serine phosphorylation of IκB, and activity of IKK. In HT29 IECs, in vitro treatment with curcumin inhibited TNF-α- and IL-1β-induced activation of p38 and JNK, while also inhibiting IκB degradation. In a rat model of TNBS-colitis, curcumin treatment significantly reduced protein expression of MyD88 and NF-κB, prevented the degradation of IκB, and also alleviated symptoms of colitis via a reduction in p38 MAPK. Sugimoto et al. showed an amelioration of experimental TNBS-colitis in mice via a reduction in NF-κB activity. Additionally, curcumin pretreatment of mouse dendritic cells suppressed NF-κB translocation to the nucleus, as well as decreased phosphorylation of ERK, p38, and JNK.

5.3. Effects on Inflammation and Immunomodulation

The effects of curcumin on inflammation and immunomodulation are widely touted. Curcumin affects the function, differentiation, and maturation of a number of immune cells actively engaged in the pathogenesis or progression of intestinal inflammatory diseases. Dendritic cells treated with curcumin tend to promote the induction of intestinal T cells with a hyporesponsive phenotype, and these dendritic cells also demonstrate inhibited antigen presenting ability, leading to reduced stimulation of the adaptive immune system. Curcumin-treated DCs also stimulate the differentiation of intestinal Tregs, and in a mouse model of colitis, these Tregs prevented the development of the disease. Other studies have indicated that curcumin pretreatment suppresses LPS-induced NF-κB p65 translocation and MAPK phosphorylation in dendritic cells, leading to a reduction in inflammation. Curcumin treatment of DCs reduces pro-inflammatory cytokine expression (IL-1, IL-6, TNF-α), and importantly that of IL-12, inhibiting the ability of these DCs to induce Th1-type responses. Additionally, curcumin can reduce the dendritic cell expression of ICAM-1 (intercellular adhesion molecule-1) and CD11c, proteins related to both cellular adhesion and T cell activation, likely through an AP-1-dependent pathway. However, potentially the most important effect of curcumin on dendritic cells is to prevent their maturation via a suppression of indoleamine 2,3-dioxygenase (IDO), with an anti-inflammatory effect similar to that of corticosteroids.

Curcumin has been demonstrated to inhibit T cell-mediated immune functions playing a significant role in chronic intestinal inflammatory diseases, such as the ability to reduce the proliferative response of lymphocytes. This reduction in proliferation may occur due to both the antioxidant properties of curcumin, reducing ROS-related proliferation, and inhibition of ribonucleotide reductase and DNA polymerase activation, important in the cell cycle. In addition, curcumin has been shown to reduce NF-κB-induced, T cell-initiated cytokine production, including the Th1-type cytokines, IL-2 and IFN-γ, further inhibiting lymphocyte proliferation. In CD, Th1 cells predominate and are thought to drive much of the adaptive immune-related inflammation. Curcumin can block production of the Th1 subset by suppressing macrophage production of IL-12, while also enhancing proliferation of the Th2 subclass, characterized by a more anti-inflammatory cytokine profile. For example, in a rat model of TNBS-induced colitis, curcumin at a dose of 30 mg/kg enhanced Th2 synthesis and suppressed Th1 proliferation, leading to a less inflammatory T helper profile. Curcumin may also inhibit Th17 development, important in NEC, reducing production of the pro-inflammatory cytokines IL-6, IL-21, and IL-17.

Dysregulation or hyperstimulation of the macrophage response, and alterations in function (e.g., decreased phagocytic ability in premature infant macrophages) are critical in intestinal inflammatory diseases. Both monocytes and monocyte-derived macrophages in NEC infants exhibit an elevated expression of TLR4, TNF-α, and IL-6 compared to age-, sex-, and weight-matched controls, as well as lower levels of TGF-β1. Curcumin has been shown to inhibit TLR4 activation and enhance production of TGF-β1, particularly in areas of active inflammation, such as the disrupted intestinal barrier. In rat macrophages, curcumin treatment at 30 mg/kg reduces the ability of cells to generate ROS and secrete lysosomal breakdown enzymes, leading to a potential reduction in mucosal inflammation. Curcumin can also inhibit NF-κB-induced macrophage and monocyte production of IL-12, IFN-γ, iNOS, MIP-2, IL-1β, IL-8, MCP-1, MIP-1α, and TNF-α. Inhibition of IL-12 is particularly important in the context of adaptive immune cell differentiation and further progression of intestinal inflammation. In addition, several studies have indicated treatment with curcumin enhances the phagocytic activity of macrophages.

Intestinal inflammatory diseases are characterized by neutrophil recruitment and activation to the site(s) of injury, an early step providing a major source of ROS for further mucosal and epithelial degradation. Curcumin is known to prevent neutrophil recruitment, largely accomplished through downregulation of NF-κB- and PI3K-Akt-induced chemotaxis, as well as a reduction in superoxide release. Curcumin also inhibits neutrophils from aggregating, degranulating, and producing superoxide radicals. In both B cells and natural killer cells, curcumin has been shown to enhance activity or suppress activation, depending upon the dose and context. Both B cells and natural killer cells have been identified as a potential general source of inflammation in the intestine, particularly in the context of microbial infection.

In addition to the effects on specific immune cells, curcumin alters the generalized production of cytokines across the entire intestinal immune system. Curcumin inhibits production of TNF-α, IFN-γ, IL-1, IL-2, IL-6, and IL-8, while elevating that of IL-10 and TGF-β. For instance, in both rat methotrexate-colitis and LPS-treated IEC-6 models, curcumin decreases levels of TNF-α and IL-1β, as well as increases levels of the anti-inflammatory cytokine, IL-10. In HT29 IECs, in vitro treatment with curcumin inhibited TNF-α- and IL-1β-induced IL-8 release. In mice, curcumin has also been shown to suppress LPS-induced IL-12, IL-1β, IL-6, and TNF-α production.

Finally, COX-2, an inflammatory enzyme induced by NF-κB and AP-1 signaling, is an important mediator in prostaglandin synthesis. Levels of COX-2 are known to be upregulated in the context of intestinal inflammatory diseases. In BV2 microglial cells, curcumin treatment abrogated COX-2 gene expression through reduction of both AP-1 and NF-κB signaling. In addition to inhibiting the production of COX-2, curcumin can inhibit the receptors for COX-2. In a rat model of TNBS-induced colitis, curcumin reduced COX-2 expression, as well as the expression of several inflammatory cytokines, but increased levels of prostaglandin E2 (PGE2). In human colon epithelial cells, as well as HT-29 colonocytes, COX-2 has also been shown to be blocked by curcumin, likely through inhibition of NF-κB and IKK activity. Clinical trials with curcumin treatment have been largely successful, but the mechanisms of action have not been well-studied in these trials. For example, in quiescent ulcerative colitis patients, 2 g curcumin effectively maintainted remission. In UC patients with mild-to-moderate disease, 3 g curcumin, in combination with the anti-inflammatory drug, mesalamine, induced remission in over 50% of the study population. Both clinical trials likely depend on the anti-inflammatory effects of curcumin.

5.4. Antioxidant Effects

Curcumin is characterized by extensive antioxidant activity. Profligate oxidative stress plays a pathogenic role in intestinal inflammatory diseases, primarily through the breakdown of intact tight junctions. Physiological levels of nitric oxide protect the intestinal mucosa, but the large amounts of NO released via iNOS, and potentially eNOS, during intestinal inflammatory disease progression can lead to tissue injury and necrosis. Unabated generation of ROS and RNS can result in the peroxidation of membrane lipids, DNA damage, and the denaturing of cellular proteins. In the intestinal mucosa, curcumin reduces levels of ROS, such as NO, superoxide anions, and malondialdehyde (MDA).

During inflammatory events, iNOS produces nitric oxide in pathogenic amounts. In intestinal inflammatory diseases, chronic iNOS stimulation likely leads to the breakdown of the intestinal integrity due to this generation of RNS. In vitro experiments have demonstrated iNOS works in tandem with COX-2 through MAPK-dependent signaling, resulting in synergistic levels of inflammation and tissue destruction. In human tissues, increased levels of NO and iNOS expression have been demonstrated in intestinal inflammatory diseases. iNOS expression appears to be a critical step in experimental colitis models, as iNOS-deficient mice do not develop the disease. iNOS production is inhibited by curcumin. In vitro studies have demonstrated curcumin can scavenge excess NO effectively, and in rat colitis models, curcumin can downregulate iNOS expression and decrease tissue levels of nitrite. Finally, in a mouse model of TNBS-colitis, curcumin inhibits production of iNOS and peroxidation of lipids via reducing the Th1 cytokine response, leading to diminished tissue damage.

Myeloperoxidase (MPO), a component of monocyte and neutrophil granules, produces high levels of ROS. MPO is often used clinically as a marker of neutrophil infiltration into the intestinal mucosa. Curcumin has been shown to decrease intestinal inflammatory disease-associated MPO activity in animal models of colitis, thereby limiting oxidative tissue damage. For example, in an immune-mediated model of mouse colitis, Mouzaoui et al. demonstrated curcumin is capable of reducing neutrophil intestinal infiltration, thereby reducing MPO activity, as well as returning NO levels to baseline via inhibition of iNOS and reduced inflammatory cell infiltration. In a rat model of TNBS-colitis, treatment with curcumin significantly reduced activity of MPO. Additionally, in a rat methotrexate-colitis model, curcumin decreased intestinal MPO and increased levels of free radical-scavenging superoxide dismutase (SOD). These effects appeared to occur via a mitogen-activated protein kinase phosphatase 1 (MKP1)-induced reduction in p38 phosphorylation, as well as inhibition of IκB cytoplasmic degradation.

Matrix metalloproteinases (MMPs) are enzymes required in the degradation of the extracellular matrix. MMPs are upregulated in intestinal inflammatory diseases largely due to pro-inflammatory cytokine production. Research in humans suffering from IBD has established the intestinal epithelium overexpresses levels of MMP1, MMP3, MMP7, MMP9, MMP10, and MMP12. Infiltrating leukocytes and vascular endothelial cells were determined to be the source of MMP7 and MMP13, while macrophages produced MMP8, MMP9, and MMP10. Neutrophils were largely responsible for MMP9. Matrix metalloproteinases have not been well studied in NEC; however, MMP3 is known to be upregulated in the disease. Curcumin is known to inhibit the large majority of these matrix metalloproteinases, though their inhibition has not been extensively investigated in the context of intestinal inflammatory diseases. For example, in human umbilical vein endothelial cells (HUVEC), curcumin inhibits the expression of MMP9, while, in cartilage explants, curcumin reduces MMP3. In human fibroblasts, curcumin downregulates MMP1 and MMP3 expression through a MAPK-dependent pathway, and in HT29 cells, curcumin reduced production of MMP7.

Finally, curcumin can upregulate phase II enzymes related to the metabolism and detoxification of xenobiotics, as well as additional antioxidant proteins, such as nuclear factor (erythroid-derived 2)-related factor (Nrf2), a transcription factor functioning as a master regulator of antioxidant proteins, and heme oxygenase-1 (HO-1), a redox-sensitive, stress-induced protein capable of degrading heme to iron, biliverdin, and carbon monoxide (CO). In an in vitro model of rat hepatic stellate cells, Liu et al. showed curcumin upregulates the nuclear translocation of Nrf2, thereby protecting the cells from oxidative stress. HO-1 can be induced by a variety of ROS, including H2O2. In a Caco-2 model of the intestinal epithelium, Wang et al. indicated curcumin reduced the oxidative stress and cytotoxicity induced by H2O2 production. Additionally, curcumin was protective against H2O2-induced tight junction disruption, and its associated increase in paracellular permeability.

6. Conclusions

In this review, we discussed the potential protective effects of curcumin on intestinal inflammatory diseases. IBD and NEC are characterized by hyperstimulation of the immune system to luminal bacteria and dietary antigens, resulting in rampant intestinal inflammation. This inflammation impairs the functioning of the intestinal barrier, allowing for increased bacterial translocation, systemic inflammation, and in very severe cases, sepsis. Recent research has focused on the effects of natural anti-inflammatories, such as curcumin, on intestinal inflammatory diseases, largely due to their safety profile and affordability. Curcumin is characterized by beneficial effects on the microbiome, antimicrobial properties, inhibition of TLR4/NF-κB/AP-1 signal transduction, changes in cytokine profiles, and alterations to immune cell maturation and differentiation. The culmination of the vast number of effects of curcumin on the intestinal epithelium and immune system is to strengthen the intestinal barrier through a reduction in bacterial translocation and inflammation. While curcumin looks promising in the treatment of intestinal inflammatory diseases, further controlled clinical trials are needed.

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    Sela D.A. Bifidobacterial utilization of human milk oligosaccharides. Int. J. Food Microbiol. 2011;149:58-64.

    Not in our library10.1016/j.ijfoodmicro.2011.01.025

  35. 35.

    Niemarkt H.J., De Meij T.G., van Ganzewinkel C.-J., de Boer N.K.H., Andriessen P., Hutten M.C., Kramer B.W. Necrotizing enterocolitis, gut microbiota, and brain development: Role of the brain-gut axis. Neonatology. 2019;115:423-431.

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    Byndloss M.X., Olsan E.E., Rivera-Chavez F., Tiffany C.R., Cevallos S.A., Lokken K.L., Torres T.P., Byndloss A.J., Faber F., Gao Y., et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science. 2017;357:570-575.

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  37. 37.

    Ge X., Pan J., Liu Y., Wang H., Zhou W., Wang X. Intestinal crosstalk between microbiota and serotonin and its impact on gut motility. Curr. Pharm. Biotechnol. 2018;19:190-195.

    Not in our library10.2174/1389201019666180528094202

  38. 38.
    Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention · 2017
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  39. 39.

    Kostic A.D., Xavier R.J., Gevers D. The microbiome in inflammatory bowel disease: Current status and the future ahead. Gastroenterology. 2014;146:1489-1499.

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    Prosberg M., Bendtsen F., Vind I., Petersen A.M., Gluud L.L. The association between the gut microbiota and the inflammatory bowel disease activity: A systematic review and meta-analysis. Scand. J. Gastroenterol. 2016;51:1407-1415.

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    Wills E.S., Jonkers D.M.A.E., Savelkoul P.H., Masclee A.A., Pierik M.J., Penders J. Fecal microbial composition of ulcerative colitis and Crohn’s disease patients in remission and subsequent exacerbation. PLoS ONE. 2014;9:e90981.

    Not in our library10.1371/journal.pone.0090981

  42. 42.

    Malavia D., Crawford A., Wilson D. Nutritional immunity and fungal pathogenesis: The struggle for micronutrients and the host-pathogen interface. Adv. Microb. Phys. 2017;70:85-103.

    Not in our library10.1016/bs.ampbs.2017.01.006

  43. 43.

    Macia L., Tan J., Vieira A.T., Leach K., Stanley D., Luong S., Maruya M., Ian McKenzie C., Hijikata A., Wong C., et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 2015;6:6734.

    Not in our library10.1038/ncomms7734

  44. 44.

    Koh A., De Vadder F., Kovatcheva-Datchary P., Backhed F. From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites. Cell. 2016;165:1332-1345.

    Not in our library10.1016/j.cell.2016.05.041

  45. 45.

    Atarashi K., Tanoue T., Oshima K., Suda W., Nagano Y., Nishikawa H., Fukuda S., Saito T., Narushima S., Hase K., et al. Treg induction by a rationally selected mixture of Clostridia stains from the human microbiota. Nature. 2013;500:232-236.

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  46. 46.

    Gao Y., Huang Y., Zhao Y., Hu Y., Li Z., Guo Q., Zhao K., Lu N. LL202 protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting MAPK/AP-1 signaling. Oncotarget. 2016;7:63981-63994.

    Not in our library10.18632/oncotarget.11742

  47. 47.

    Grishin A.V., Wang J., Potoka D.A., Hackam D.J., Upperman J.S., Boyle P., Zamora R., Ford H.R. Lipopolysaccharide induces cyclooxygenase-2 in intestinal epithelium via a noncanonical p38 MAPK pathway. J. Immunol. 2006;176:580-588.

    Not in our library10.4049/jimmunol.176.1.580

  48. 48.

    Nanthakumar N.N., Young C., Ko J.S., Meng D., Chen J., Buie T., Walker W.A. Glucocorticoid responsiveness in developing human intestine: Possible role in prevention of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2005;288:G85-G92.

    Not in our library10.1152/ajpgi.00169.2004

  49. 49.
    NF-κB signaling in inflammation · 2017
    No notice
  50. 50.

    Baldwin A.S. The NF-KB and I-KB proteins: New discoveries and insights. Annu. Rev. Immunol. 1996;14:649-681.

    Not in our library10.1146/annurev.immunol.14.1.649

  51. 51.

    Schreiber S., Nikolaus S., Hampe J. Activation of nuclear factor κB in inflammatory bowel disease. Gut. 1998;42:477-484.

    Not in our library10.1136/gut.42.4.477

  52. 52.

    De Plaen I.G., Liu S.X., Tian R., Neequaye I., May M.J., Han X.B., Hsueh W., Jilling T., Lu J., Caplan M.S. Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr. Res. 2007;62:716-721.

    Not in our library10.1203/pdr.0b013e3180534219

  53. 53.

    Atreya I., Atreya R., Neurath M.F. NF-κB in inflammatory bowel disease. J. Intern. Med. 2008;263:591-596.

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  54. 54.

    Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U. Control of IκB-α proteolysis by site-specific signal induced phosphorylation. Science. 1995;267:1485-1487.

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  55. 55.

    Siebenlist U., Brown K., Claudio E. Control of lymphocyte development by nuclear factor-κB. Nat. Rev. Immunol. 2005;5:435-445.

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  56. 56.

    Afonina I.S., Zhong Z., Karin M., Beyaert R. Limiting inflammation—the negative regulation of NF_κB and NLRP3 inflammasome. Nat. Immunol. 2017;18:861-869.

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    Abreu M.T. Toll-like receptor signaling in the intestinal epithelium: How bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 2010;10:131-144.

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    Wullaert A., Bonnet M.C., Pasparakis M. NF-κB in the regulation of epithelial homeostasis and inflammation. Cell Res. 2011;21:146-158.

    Not in our library10.1038/cr.2010.175

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    Nenci A., Becker C., Wullaert A., Gareus R., van Loo G., Danese S., Huth M., Nikolaev A., Neufert C., Madison B., et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 2007;446:557-561.

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  60. 60.

    Zaph C., Troy A.E., Taylor B.C., Berman-Booty L.D., Guild K.J., Du Y., Yost E.A., Gruber A.D., May M.J., Greten F.R., et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature. 2007;446:552-556.

    Not in our library10.1038/nature05590

  61. 61.

    Guha M., Mackman N. LPS induction of gene expression in human monocytes. Cell. Signal. 2001;13:85-94.

    Not in our library10.1016/s0898-6568(00)00149-2

  62. 62.

    Granet C., Miossec P. Combination of the pro-inflammatory cytokines IL-1, TNF-alpha and IL-17 leads to enhanced expression and additional recruitment of AP-1 family members, Egr-1 and NF-κB in osteoblast-like cells. Cytokine. 2004;26:169-177.

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  63. 63.

    Dokter W.H.A., Koopmans S.B., Vellenga E. Effects of IL-10 and IL-4 on LPS-induced transcription factors (AP-1, NF-IL6 and NF-kappaB) which are involved in IL-6 regulation. Leukemia. 1996;10:1038-1316.

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  64. 64.

    Eferl R., Wagner E.F. AP-1: A double-edged sword in tumorigenesis. Nat. Rev. Cancer. 2003;3:859-868.

    Not in our library10.1038/nrc1209

  65. 65.

    Karin M., Takahashi T., Kapahi P., Delhase M., Chen Y., Makris C., Rothwarf D., Baud V., Natoli G., Guido F., et al. Oxidative stress and gene expression: The AP-1 and NF-κB connections. Biofactors. 2001;15:87-89.

    Not in our library10.1002/biof.5520150207

  66. 66.

    Verma I.M., Stevenson J.K., Schwarz E.M., Van Antwerp D., Miyamoto S. Rel/NF-kappa B/I kappa B family: Intimate tales of association and dissociation. Genes Dev. 1995;9:2723-2735.

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    Fujioka S., Niu J., Schmidt C., Sclabas G.M., Peng B., Uwagawa T., Li Z., Evans D.B., Abbruzzese J.L., Chiao P.J. NF-κB and AP-1 connection: Mechanism of NF-κB-dependent regulation of AP-1 activity. Mol. Cell Biol. 2004;24:7806-7819.

    Not in our library10.1128/mcb.24.17.7806-7819.2004

  68. 68.

    Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim. Biophys. Acta. 1991;1072:129-157.

    Not in our library10.1016/0304-419x(91)90011-9

  69. 69.

    Chang L., Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37-40.

    Not in our library10.1038/35065000

  70. 70.

    Johnson G.L., Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911-1912.

    Not in our library10.1126/science.1072682

  71. 71.
    Hijacking of the AP-1 Signaling Pathway during Development of ATL · 2018
    No notice
  72. 72.

    Chen Y., Currie R.W. Small interfering RNA knocks down heat shock factor-1 (HSF-1) and exacerbates pro-inflammatory activation of NF-kappa B and AP-1 in vascular smooth muscle cells. Cardiovasc. Res. 2006;69:66-75.

    Not in our library10.1016/j.cardiores.2005.07.004

  73. 73.
    MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment · 2015
    No notice
  74. 74.

    Tremblay L., Valenza F., Ribeiro S.P., Li J.F., Slutsky A.S. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J. Clin. Investig. 1997;99:944-952.

    Not in our library10.1172/jci119259

  75. 75.

    Roy A., Srivastava M., Saqib U., Liu D., Faisal S.M., Sugathan S., Bishnoi S., Baig M.S. Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways. Int. Immunopharmacol. 2016;40:79-89.

    Not in our library10.1016/j.intimp.2016.08.026

  76. 76.

    Fanjul-Fernández M., Folgueras A.R., Cabrera S., López-Otín C. Matrix metalloproteinases: Evolution, gene regulation and functional analysis in mouse models. Cell Res. 2010;1803:3-19.

    Not in our library10.1016/j.bbamcr.2009.07.004

  77. 77.

    Mishra R.K., Potteti H.R., Tamatam C.R., Elangovan I., Reddy S.P. c-Jun is required for nuclear factor-κB-dependent, LPS-stimulated Fos-related Antigen-1 transcription in alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 2016;55:667-674.

    Not in our library10.1165/rcmb.2016-0028oc

  78. 78.

    Cahill C.M., Zhu W., Oziolor E., Yang Y.-J., Tam B., Rajanala S., Rogers J.T., Walker W.A. Differential expression of the activator protein 1 transcription factor regulates interleukin-1β induction of interleukin 6 in the developing enterocyte. PLoS ONE. 2016;11:e0145184.

    Not in our library10.1371/journal.pone.0145184

  79. 79.

    Kwon D.-J., Ju S.M., Youn G.S., Choi S.Y., Park J. Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF-κB and AP-1 activation in RAW 264.7 macrophages. Food Chem. Toxicol. 2013;58:479-486.

    Not in our library10.1016/j.fct.2013.05.031

  80. 80.
    Butyrate produced by commensal bacteria potentiates phorbol esters induced AP-1 response in human intestinal epithelial cells. · 2012
    Not checked
  81. 81.

    Wang P.-Y., Wang S.R., Xiao L., Chen J., Wang J.-Y., Rao J.N. c-Jun enhances intestinal epithelial restitution after wounding by increasing phospholipase C-γ1 transcription. Am. J. Physiol. Cell Physiol. 2017;312:C367-C375.

    Not in our library10.1152/ajpcell.00330.2016

  82. 82.

    Ishiguro Y., Yamagata K., Sakuraba H., Munakata A., Nakane A., Morita T., Nishihira J. Macrophage migration inhibitory factor and activator protein-1 in ulcerative colitis. Ann. N. Y. Acad. Sci. 2006;1029:348-349.

    Not in our library10.1196/annals.1309.040

  83. 83.

    Zingarelli B., Yang Z., Hake P.W., Denenberg A., Wong H.R. Absence of endogenous interleukin-10 enhances early stress response during postischemic injury in mice intestine. Gut. 2001;5:610-622.

    Not in our library10.1136/gut.48.5.610

  84. 84.

    Nicolaou F., Teodoridis J.M., Park H., Georgakis A., Farokhzad O.C., Böttinger E.P., Da Silva N., Rousselot P., Chomienne C., Ferenczi K., et al. CD11c gene expression in hairy cell leukemia is dependent upon activation of the proto-oncogenes ras and junD. Blood. 2003;101:4033-4041.

    Not in our library10.1182/blood-2002-01-0324

  85. 85.

    Moriyama I., Ishihara S., Rumi M.A., Aziz M.D., Mishima Y., Oshima N., Kadota C., Kadowaki Y., Amano Y., Kinoshita Y. Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis. Lab. Investig. 2008;88:652-663.

    Not in our library10.1038/labinvest.2008.38

  86. 86.

    Boone D.L., Ma A. Connecting the dots from Toll-like receptors to innate immune cells and inflammatory bowel disease. J. Clin. Investig. 2003;111:1284-1286.

    Not in our library10.1172/jci18545

  87. 87.

    Sodhi C.P., Neal M.D., Siggers R., Sho S., Ma C., Branca M.F., Prindle T., Russo A.M., Afrazi A., Good M., et al. Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology. 2012;143:708-718.

    Not in our library10.1053/j.gastro.2012.05.053

  88. 88.

    Youn H.S., Saitoh S.I., Miyake K., Hwang D.H. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol. 2006;72:62-69.

    Not in our library10.1016/j.bcp.2006.03.022

  89. 89.

    Park H.H., Lo Y.C., Lin S.C., Wang L., Yang J.K., Wu H. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu. Rev. Immunol. 2007;25:561-586.

    Not in our library10.1146/annurev.immunol.25.022106.141656

  90. 90.

    Zhang Y., Lu Y., Ma L., Cao X., Xiao J., Chen J., Jiao S., Gao Y., Liu C., Duan Z., et al. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock. Immunity. 2014;40:501-514.

    Not in our library10.1016/j.immuni.2014.01.013

  91. 91.

    Li L., Liu Y., Chen H.Z., Li F.W., Wu J.F., Zhang H.K., He J.P., Xing Y.Z., Chen Y., Wang W.J., et al. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat. Chem. Biol. 2015;11:339-346.

    Not in our library10.1038/nchembio.1788

  92. 92.

    Gohda J., Matsumura T., Inoue J. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J. Immunol. 2004;173:2913-2917.

    Not in our library10.4049/jimmunol.173.5.2913

  93. 93.

    Neu J. Gastrointestinal development and meeting the nutritional needs to premature infants. Am. J. Clin. Nutr. 2007;85:629S-634S.

    Not in our library10.1093/ajcn/85.2.629s

  94. 94.

    Papillon S., Castle S.L., Gayer C.P., Ford H.R. Necrotizing enterocolitis: Contemporary management and outcomes. Adv. Pediatr. 2013;60:263-279.

    Not in our library10.1016/j.yapd.2013.04.011

  95. 95.

    Niño D.F., Sodhi C.P., Hackam D.J. Necrotizing enterocolitis: New insights into pathogenesis and mechanisms. Nat. Rev. Gastroenterol. Hepatol. 2016;13:590-600.

    Not in our library10.1038/nrgastro.2016.119

  96. 96.

    Battersby A.J., Gibbons D.L. The gut mucosal immune system in the neonatal period. Ped. Allergy Immunol. 2013;24:414-421.

    Not in our library10.1111/pai.12079

  97. 97.

    Leaphart C.L., Cavallo J.C., Gribar S.C., Cetin S., Li J., Branca M.F., Dubowski T.D., Sodhi C.P., Hackam D.J. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol. 2007;179:4808-4820.

    Not in our library10.4049/jimmunol.179.7.4808

  98. 98.

    Egan C.E., Sodhi C.P., Good M., Lin J., Jia H., Yamaguchi Y., Lu P., Ma C., Branca M.F., Weyandt S., et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J. Clin. Investig. 2016;126:495-508.

    Not in our library10.1172/jci83356

  99. 99.

    Good M., Siggers R.H., Sodhi C.P., Afrazi A., Alkhudari F., Egan C.E., Neal M.D., Yazji I., Jia H., Lin J., et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc. Natl. Acad. Sci. USA. 2012;109:11330-11335.

    Not in our library10.1073/pnas.1200856109

  100. 100.

    Good M., Sodhi C.P., Egan C.E., Afrazi A., Jia H., Yamaguchi Y., Lu P., Branca M.F., Ma C., Prindle T., et al. Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor. Mucosal Immunol. 2015;8:1166-1179.

    Not in our library10.1038/mi.2015.30

  101. 101.

    Neal M.D., Sodhi C.P., Dyer M., Craig B.T., Good M., Jia H., Yazji I., Afrazi A., Richardson W.M., Beer-Stolz D., et al. A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J. Immunol. 2013;190:3541-3551.

    Not in our library10.4049/jimmunol.1202264

  102. 102.

    Good M., Sodhi C.P., Yamaguchi Y., Jia H., Lu P., Fulton W.B., Martin L.Y., Prindle T., Nino D.F., Zhou Q., et al. The human milk oligosaccharide 2′-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine. Br. J. Nutr. 2016;116:1175-1187.

    Not in our library10.1017/s0007114516002944

  103. 103.

    Toiyama Y., Araki T., Yoshiyama S., Hiro J., Miki C., Kusonoki M. The expression patterns of toll-like receptors in the ileal pouch mucosa of postoperative ulcerative colitis patients. Surg. Today. 2006;36:287-290.

    Not in our library10.1007/s00595-005-3144-y

  104. 104.

    Lu P., Sodhi C.P., Hackam D.J. Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis. Pathophysiology. 2014;21:81-93.

    Not in our library10.1016/j.pathophys.2013.11.007

  105. 105.
    The Mechanism of Excessive Intestinal Inflammation in Necrotizing Enterocolitis: An Immature Innate Immune Response · 2011
    No notice
  106. 106.

    Fusunyan R.D., Nanthakumar N.N., Baldeon M.E., Walker W.A. Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatr. Res. 2001;49:589-593.

    Not in our library10.1203/00006450-200104000-00023

  107. 107.

    Managlia E., Liu S.X.L., Yan X., Tan X.-D., Chou P.M., Barrett T.A., De Plaen I.G. Blocking NF-κB activation in Ly6c+ monocytes attenuates necrotizing enterocolitis. Am. J. Pathol. 2019;189:604-618.

    Not in our library10.1016/j.ajpath.2018.11.015

  108. 108.

    Martinez F.O., Gordon S., Locati M., Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: New molecules and patterns of gene expression. J. Immunol. 2006;177:7303-7311.

    Not in our library10.4049/jimmunol.177.10.7303

  109. 109.

    Yazji I., Sodhi C.P., Lee E.K., Good M., Egan C.E., Afrazi A., Neal M.D., Jia H., Lin J., Ma C., et al. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc. Natl. Acad. Sci. USA. 2013;110:9451-9456.

    Not in our library10.1073/pnas.1219997110

  110. 110.

    Claud E.C., Lu L., Anton P.M., Savidge T., Walker W.A., Cherayil B.J. Developmentallly regulated IkappaB expression in intestinal epithelium and susceptibility to flagellin-induced inflammation. Proc. Natl. Acad. Sci. USA. 2004;101:7404-7408.

    Not in our library10.1073/pnas.0401710101

  111. 111.
    Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis · 2000
    Not checked
  112. 112.

    Rentea R.M., Welak S.R., Fredrich K., Donohoe D., Pritchard K.A., Oldham K.T., Gourlay D.M., Liedel J.L. Early enteral stressors in newborns increase inflammatory cytokine expression in a neonatal necrotizing enterocolitis rat model. Eur. J. Ped. Surg. 2013;23:39-47.

    Not in our library10.1055/s-0032-1329704

  113. 113.

    Jones C.A., Holloway J.A., Warner J.O. Phenotype of fetal monocytes and B lymphocytes during the third trimester of pregnancy. J. Reprod. Immunol. 2002;56:45-60.

    Not in our library10.1016/s0165-0378(02)00022-0

  114. 114.

    Hackam D.J., Upperman J.S., Grishin A., Ford H.R. Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis. Semin. Pediatr. Surg. 2005;14:49-57.

    Not in our library10.1053/j.sempedsurg.2004.10.025

  115. 115.

    Clark J.A., Doelle S.M., Halpern M.D., Saunders T.A., Holubee H., Dvorak D., Boitano S.A., Dvorak B. Intestinal barrier failure during experimental necrotizing enterocolitis: Protective effect of EGF treatment. Am. J. Physiol. 2006;291:G938-G949.

    Not in our library10.1152/ajpgi.00090.2006

  116. 116.

    Martin N.A., Mount Patrick S.K., Estrada T.E., Frisk H.A., Rogan D.T., Dvorak B., Halpern M.D. Active transport of bile acids decreases mucin 2 in neonatal ileum: Implications for development of necrotizing enterocolitis. PLoS ONE. 2011;6:e27191.

    Not in our library10.1371/journal.pone.0027191

  117. 117.

    Nathan C. Neutrophils and immunity: Challenges and opportunities. Nat. Rev. Immunol. 2006;6:173-182.

    Not in our library10.1038/nri1785

  118. 118.

    Emami C.N., Mittal R., Wang L., Ford H.R., Prasadarao N.V. Role of neutrophils and macrophages in the pathogenesis of necrotizing enterocolitis caused by Cronobacter sakazakii. J. Surg. Res. 2012;172:18-28.

    Not in our library10.1016/j.jss.2011.04.019

  119. 119.

    Musemeche C., Caplan M., Hsueh W., Sun X., Kelly A. Experimental necrotizing enterocolitis: The role of polymorphonuclear neutrophils. J. Pediatr. Surg. 1991;26:1047-1049.

    Not in our library10.1016/0022-3468(91)90671-f

  120. 120.

    Christensen R.D., Yoder B.A., Baer V.L., Snow G.L., Butler A. Early-onset neutropenia in small-for-gestational-age infants. Pediatrics. 2015;136:e1259-e1267.

    Not in our library10.1542/peds.2015-1638

  121. 121.

    Strunk T., Temming P., Gembruch U., Reiss I., Bucsky P., Schultz C. Differential maturation of the innate immune response in human fetuses. Ped. Res. 2004;56:219-226.

    Not in our library10.1203/01.pdr.0000132664.66975.79

  122. 122.

    Maheshwari A., Kelly D.R., Nicola T., Ambalavanan N., Jain S.K., Murphy-Ullrich J., Athar M., Shimamura M., Bhandari V., Aprahamian C., et al. TFG-beta2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology. 2011;140:242-253.

    Not in our library10.1053/j.gastro.2010.09.043

  123. 123.

    MohanKumar K., Namachivayam K., Chapalamadugu K.C., Garzon S.A., Premkumar M.H., Tipparaju S.M., Maheshwari A. Smad7 interrupts TGF-beta signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis. Pediatr. Res. 2016;79:951-961.

    Not in our library10.1038/pr.2016.18

  124. 124.

    Namachivayam K., Blanco C.L., MohanKumar K., Jagadeeswaran R., Vasquez M., McGill-Vargas L., Garzon S.A., Jain S.K., Gill R.K., Freitag N.E., et al. Smad7 inhibits autocrine expression of TGF-beta2 in intestinal epithelial cells in baboon necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2013;304:G167-G180.

    Not in our library10.1152/ajpgi.00141.2012

  125. 125.

    MohanKumar K., Kaza N., Jagadeeswaran R., Garzon S.A., Bansal A., Kurundkar A.R., Namachivayam K., Remon J.I., Bandepalli C.R., Feng X., et al. Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: Evidence from an animal model. Am. J. Physiol. Gastrointest. Liver Physiol. 2012;303:G93-G102.

    Not in our library10.1152/ajpgi.00016.2012

  126. 126.

    Emami C.N., Mittal R., Wang L., Ford H.R., Prasadarao N.V. Recruitment of dendritic cells is responsible for intestinal epithelial damage in the pathogenesis of necrotizing enterocolitis by Cronobacter sakazakii. J. Immunol. 2011;186:7067-7079.

    Not in our library10.4049/jimmunol.1100108

  127. 127.

    Weitkamp J.H., Rosen M.J., Zhao Z., Koyama T., Geem D., Denning T.L., Rock M.T., Moore D.J., Halpern M.D., Matta P., et al. Small intestinal intraepithelial TCRgammadelta+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis. PLoS ONE. 2014;9:e99042.

    Not in our library10.1371/journal.pone.0099042

  128. 128.

    Gibbons D.L., Haque S.F., Silberzahn T., Hamilton K., Langford C., Ellis P., Carr R., Hayday A.C. Neonates harbour highly active gammadelta T cells with selective impairments in preterm infants. Eur. J. Immunol. 2009;39:1794-1806.

    Not in our library10.1002/eji.200939222

  129. 129.

    Ismail A.S., Behrendt C.L., Hooper L.V. Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J. Immunol. 2009;182:3047-3054.

    Not in our library10.4049/jimmunol.0802705

  130. 130.

    Weitkamp J.H., Koyama T., Rock M.T., Correa H., Goettel J.A., Matta P., Oswald-Richter K., Rosen M.J., Engelhardt B.G., Moore D.J., et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut. 2013;62:73-82.

    Not in our library10.1136/gutjnl-2011-301551

  131. 131.

    Basha S., Surendran N., Pichichero M. Immune responses in neonates. Exp. Rev. Clin. Immunol. 2014;10:1171-1184.

    Not in our library10.1586/1744666x.2014.942288

  132. 132.

    Markel T.A., Crisostomo P.R., Wairiuko G.M., Pitcher J., Tsai B.M., Meldrum D.R. Cytokines in necrotizing enterocolitis. Shock. 2006;25:329-337.

    Not in our library10.1097/01.shk.0000192126.33823.87

  133. 133.

    Kling K.M., Kirby L., Kwan K.Y., Kim F., McFadden D.W. Interleukin-10 inhibits inducible nitric oxide synthase in an animal model of necrotizing enterocolitis. Int. J. Surg. Investig. 1999;1:337-342.

    Not in our library

  134. 134.

    Baud V., Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol. 2001;11:372-377.

    Not in our library10.1016/s0962-8924(01)02064-5

  135. 135.

    Tracey K.J., Fong Y., Hesse D.G., Manogue K.R., Lee A.T., Kuo G.C., Lowry S.F., Cerami A. Anti-cachectin/THF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature. 1987;330:662-664.

    Not in our library10.1038/330662a0

  136. 136.

    Baregamian N., Song J., Bailey C.E., Papaconstantinou J., Evers B.M., Chung D.H. Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and C-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxid. Med. Cell. Longev. 2009;2:297-306.

    Not in our library10.4161/oxim.2.5.9541

  137. 137.

    Caplan M.S., Hsueh W. Necrotizing enterocolitis: Role of platelet activating factor, endotoxin, and tumor necrosis factor. J. Pediatr. 1990;117:S47-S51.

    Not in our library10.1016/s0022-3476(05)81130-8

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    Harris M.C., Costarino A.T., Sullivan J.S., Dulkerian S., McCawley L., Corcoran L., Butler S., Kilpatrick L. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J. Pediatr. 1994;124:105-111.

    Not in our library10.1016/s0022-3476(94)70264-0

  139. 139.

    Morecroft J.A., Spitz L., Hamilton P.A., Holmes S.J. Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatr. Suppl. 1994;396:18-20.

    Not in our library10.1111/j.1651-2227.1994.tb13235.x

  140. 140.

    Churg A., Wang R.D., Tai H., Wang X., Xie C., Dai J., Shapiro S.D., Wright J.L. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. Am. J. Respir. Crit. Care Med. 2003;167:1083-1089.

    Not in our library10.1164/rccm.200212-1396oc

  141. 141.

    Saren P., Welgus H.G., Kovanen P.T. TNF-α and IL-1β selectively induce expression of 92 kDa gelatinase by human macrophages. J. Immunol. 1996;157:4159-4165.

    Not in our library

  142. 142.

    Impola U., Toriseva M., Suomela S., Jeskanen L., Hieta N., Jahkola T., Grenman R., Kähäri V., Saarialho-Kere U. Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation. Int. J. Cancer. 2003;103:709-716.

    Not in our library10.1002/ijc.10902

  143. 143.

    Pender S.L., Braegger C., Gunther C., Monteleone G., Meuli M., Schuppan D., MacDonald T.T. Matrix metalloproteinases in necrotising enterocolitis. Pediatr. Res. 2003;54:160-164.

    Not in our library10.1203/01.pdr.0000072326.23442.c3

  144. 144.

    Birkedal-Hansen H., Moore W.G., Bodden M.K., Windsor L.J., Birkedal-Hansen B., DeCarlo A., Engler J.A. Matrix metalloproteinases: A review. Crit. Rev. Oral Biol. Med. 1993;4:197-250.

    Not in our library10.1177/10454411930040020401

  145. 145.

    Male D. Immunology: An Illustrated Outline. 1998;1-146.

    Not in our library

  146. 146.

    Minekawa R., Takeda T., Sakata M., Hayashi M., Isobe A., Yamamoto T., Tasaka K., Murata Y. Human breast milk suppresses the transcriptional regulation of IL-1β induced NF-κB signaling in human intestinal cells. Am. J. Physiol. Cell Physiol. 2004;287:C1401-C1411.

    Not in our library10.1152/ajpcell.00471.2003

  147. 147.

    Viscardi R.M., Lyon N.H., Sun C.C., Hebel J.R., Hasday J.D. Inflammatory cytokine mRNAs in surgical specimens of necrotizing enterocolitis and normal newborn intestine. Pediatr. Pathol. Lab. Med. 1997;17:547-559.

    Not in our library10.1080/15513819709168731

  148. 148.

    Edelson M.B., Bagwell C.E., Rozycki H.J. Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics. 1999;103:766-771.

    Not in our library10.1542/peds.103.4.766

  149. 149.

    Romagnoli C., Freeza S., Cingolani A., De Luca A., Puopolo M., De Carolis M.P., Vento G., Antinori A., Tortorolo G. Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis. Eur. J. Pediatr. 2001;160:345-350.

    Not in our library10.1007/pl00008445

  150. 150.

    Ren Y., Lin C.L., Chen X.Y., Huang X., Lui V., Nicholls J., Lan H.Y., Tam P.K. Up-regulation of macrophage migration inhibitory factor in infants with acute neonatal necrotizing enterocolitis. Histopathology. 2005;46:659-667.

    Not in our library10.1111/j.1365-2559.2005.02159.x

  151. 151.

    Goepfert A.R., Andrews W.W., Waldemar C., Ramsey P.S., Cliver S.P., Goldenber R.L., Hauth J.C. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am. J. Obstet. Gynecol. 2004;191:1375-1381.

    Not in our library10.1016/j.ajog.2004.06.086

  152. 152.

    Luster A.D. Chemokines—Chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 1998;338:436-445.

    Not in our library10.1056/nejm199802123380706

  153. 153.

    Chikano S., Sawada K., Shimoyama T., Kashiwamura S.I., Sugihara A., Sekikawa K., Terada N., Nakanishi K., Okamura H. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut. 2000;47:779-786.

    Not in our library10.1136/gut.47.6.779

  154. 154.

    Kashiwamura S., Ueda H., Okamura H. Roles of interleukin-18 in tissue destruction and compensatory reactions. J. Immunol. 2002;25(Suppl. 1):S4-S11.

    Not in our library10.1097/00002371-200203001-00002

  155. 155.

    Halpern M.D., Holubec H., Dominguez J.A., Williams C.S., Meza Y.G., McWilliam D.L., Payne C.M., McCuskey R.S., Besselsen D.G., Dvorak B. Upregulation of IL-18 and Il-12 in the ileum of neonatal rats with necrotizing enterocolitis. Pediatr. Res. 2002;51:733-739.

    Not in our library10.1203/00006450-200206000-00012

  156. 156.

    Nadler E.P., Dickinson E., Knisely A., Zhang X.R., Boyle P., Beer-Stolz D., Watkins S.C., Ford H.R. Expression of inducible nitric oxide synthase and interleukin 12 in experimental necrotizing enterocolitis. J. Surg. Res. 2000;92:71-77.

    Not in our library10.1006/jsre.2000.5877

  157. 157.

    Ford H.R., Sorrells D.L., Knisely A.S. Inflammatory cytokines, nitric oxide, and necrotizing enterocolitis. Semin. Pediatr. Surg. 1996;5:155-159.

    Not in our library

  158. 158.

    Benkoe T., Baumann S., Weninger M., Pones M., Reck C., Rebhandl W., Oehler R. Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis. PLoS ONE. 2013;8:e58720.

    Not in our library10.1371/journal.pone.0058720

  159. 159.

    Maheshwari A., Schelonka R.L., Dimmitt R.A., Carlo W.A., Munoz-Hernandez B., Das A., McDonald S.A., Thorsen P., Skogstrand K., Hougaard D.M., et al. Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants. Pediatr. Res. 2014;76:100-108.

    Not in our library10.1038/pr.2014.48

  160. 160.

    Fiocchi C. Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology. 1998;115:182-205.

    Not in our library10.1016/s0016-5085(98)70381-6

  161. 161.

    Uhlig H.H., Powrie F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 2018;36:755-781.

    Not in our library10.1146/annurev-immunol-042617-053055

  162. 162.

    Zeissig S., Bürgel N., Günzel D., Richter J., Mankertz J., Wahnschaffe U., Kroesen A.J., Zeitz M., Fromm M., Schulzke J.D. Changes in expression and distribution of claudins 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007;56:61-72.

    Not in our library10.1136/gut.2006.094375

  163. 163.
    Flavonoids in Inflammatory Bowel Disease: A Review · 2016
    No notice
  164. 164.
    Association between Faecalibacterium prausnitzii Reduction and Inflammatory Bowel Disease: A Meta-Analysis and Systematic Review of the Literature · 2014
    No notice
  165. 165.

    Levy M., Kolodziejezyk A.A., Thaiss C.A., Elinav E. Dysbiosis and the immune system. Nat. Rev. Immunol. 2017;17:219-232.

    Not in our library10.1038/nri.2017.7

  166. 166.

    Weber C.R., Turner J.R. Inflammatory bowel disease: Is it really just another break in the wall? Gut. 2007;56:6-8.

    Not in our library10.1136/gut.2006.104182

  167. 167.

    Hollander D. Crohn’s disease—A permeability disorder of the tight junction? Gut. 1988;29:1621-1624.

    Not in our library10.1136/gut.29.12.1621

  168. 168.

    Xavier R.J., Podolsky D.K. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427-434.

    Not in our library10.1038/nature06005

  169. 169.

    Arnott I.D., Kingstone K., Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand. J. Gastroenterol. 2000;35:1163-1170.

    Not in our library10.1080/003655200750056637

  170. 170.

    Wyatt J., Vogelsang H., Hubl W., Waldhoer T., Lochs H. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet. 1993;341:1437-1439.

    Not in our library10.1016/0140-6736(93)90882-h

  171. 171.

    Katz K.D., Hollander D., Vadheim C.M., McElree C., Delahunty T., Dadufalza V.D., Krugliak P., Rotter J.I. Intestinal permeability in patients with Crohn’s disease and their healthy relatives. Gastroenterology. 1989;97:927-931.

    Not in our library10.1016/0016-5085(89)91499-6

  172. 172.

    Peeters M., Geypens B., Claus D., Nevens H., Ghoos Y., Verbeke G., Baert F., Vermeire S., Vlietinck R., Rutgeerts P. Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology. 1997;113:802-807.

    Not in our library10.1016/s0016-5085(97)70174-4

  173. 173.

    Smith P.D., Smythies L.E., Shen R., Greenwell-Wild T., Gliozzi M., Wahl S.M. Intestinal macrophages and response to microbial environment. Mucosal Immunol. 2011;4:31-42.

    Not in our library10.1038/mi.2010.66

  174. 174.

    Schreiber S., Heinig T., Panzer U., Reinking R., Bouchard A., Stahl P.D., Raedler A. Impaired response of activated mononuclear phagocytes to interleukin-4 in inflammatory bowel disease. Gastroenterology. 1995;108:21-33.

    Not in our library10.1016/0016-5085(95)90004-7

  175. 175.

    Podolsky D.K. Inflammatory bowel disease. N. Engl. J. Med. 2002;347:417-429.

    Not in our library10.1056/nejmra020831

  176. 176.

    Holtmann M.H., Neurath M.F. Differential TNF-signaling in chronic inflammatory disorders. Curr. Mol. Med. 2004;4:439-444.

    Not in our library10.2174/1566524043360636

  177. 177.

    Sartor R.B. Mechanisms of disease: Pathogenesis of Crohn’s disease and ulcerative colitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006;3:390-407.

    Not in our library10.1038/ncpgasthep0528

  178. 178.

    Shih D.Q., Targan S.R. Insights into IBD pathogenesis. Curr. Gastroenterol. Rep. 2009;11:473-480.

    Not in our library10.1007/s11894-009-0072-9

  179. 179.

    Strober W., Fuss I., Mannon P. The fundamental basis of inflammatory bowel disease. J. Clin. Investig. 2007;117:514-521.

    Not in our library10.1172/jci30587

  180. 180.

    Cerovic V., Houston S.A., Scott C.L., Aumeunier A., Yrlid U., Mowat A.M., Milling S.W. Intestinal cd103(-) dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunol. 2013;6:104-113.

    Not in our library10.1038/mi.2012.53

  181. 181.

    Laing K.J., Secombes C.J. Chemokines. Dev. Comp. Immunol. 2004;28:443-460.

    Not in our library10.1016/j.dci.2003.09.006

  182. 182.

    Kim J.M., Jung H.Y., Lee J.Y., Youn J., Lee C.H., Kim K.H. Mitogen-activated protein kinase and activator protein-1 dependent signals are essential for Bacteroides fragilis enterotoxin-induced enteritis. Eur. J. Immunol. 2005;35:2648-2657.

    Not in our library10.1002/eji.200526321

  183. 183.

    Vainer B. Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: Presence, visualization, and significance. APMIS Suppl. 2010;129:1-43.

    Not in our library10.1111/j.1600-0463.2010.02647.x

  184. 184.

    Steidler L., Hans W., Schotte L., Neirynck S., Obermeier F., Falk W., Fiers W., Remaut E. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352-1355.

    Not in our library10.1126/science.289.5483.1352

  185. 185.

    Kitani A., Fuss U., Nakamura K., Schwartz O.M., Usui T., Strober W. Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-β1 plasmid: TGF-β1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor β2 chain downregulation. J. Exp. Med. 2000;192:41-52.

    Not in our library10.1084/jem.192.1.41

  186. 186.

    Fukata M., Chen A., Vamadevan A.S., Cohen J., Breglio K., Krishnareddy S., Hsu D., Xu R., Harpaz N., Dannenberg A.J., et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133:1869-1881.

    Not in our library10.1053/j.gastro.2007.09.008

  187. 187.

    Vlantis K., Wullaert A., Sasaki Y., Schmidt-Supprian M., Rajewsky K., Roskams T., Pasparakis M. Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J. Clin. Investig. 2011;121:2781-2793.

    Not in our library10.1172/jci45349

  188. 188.

    Cario E., Podolsky D.K. Differential alteration in intestinal epithelial cells expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 2000;68:7010-7017.

    Not in our library10.1128/iai.68.12.7010-7017.2000

  189. 189.

    Ortegea-Cava C.F., Ishihara S., Rumi M.A., Kawashima K., Ishimura N., Kazumori H., Udagawa J., Kadowaki Y., Kinoshita Y. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 2003;170:3977-3985.

    Not in our library10.4049/jimmunol.170.8.3977

  190. 190.

    Rogler G., Brand K., Vogl D., Page S., Hofmeister R., Andus T., Knuechel R., Baeuerle P.A., Scholmerich J., Gross V. Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology. 1998;115:357-369.

    Not in our library10.1016/s0016-5085(98)70202-1

  191. 191.

    Neurath M.F., Petterson S., Meyer zum Büschenfelde K.H., Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κB abrogates established experimental colitis in mice. Nat. Med. 1996;2:998-1004.

    Not in our library10.1038/nm0996-998

  192. 192.

    Waetzig G.H., Seegert D., Rosenstiel P., Nikolaus S., Schreiber S. p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J. Immunol. 2002;168:5342-5351.

    Not in our library10.4049/jimmunol.168.10.5342

  193. 193.

    Abreu-Martin M.T., Palladino A.A., Faris M., Carramanzana N.M., Nel A.E., Targan S.R. Fas activates the JNK pathway in human colonic epithelial cells: Lack of a direct role in apoptosis. Am. J. Physiol. 1999;276:G599-G605.

    Not in our library10.1152/ajpgi.1999.276.3.g599

  194. 194.

    Bantel H., Schmitz M.L., Raible A., Gregor M., Schulze-Osthoff K. Critical role of NF-κB and stress-activated protein kinases in steroid unresponsiveness. FASEB J. 2002;16:1832-1834.

    Not in our library10.1096/fj.02-0223fje

  195. 195.

    Salzman N.H., Underwood M.A., Bevins C.L. Paneth cells, defensins, and the commensal microbiota: A hypothesis on intimate interplay at the intestinal mucosa. Semin. Immunol. 2007;19:70-83.

    Not in our library10.1016/j.smim.2007.04.002

  196. 196.

    Iida T., Onodera K., Nakase H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J. Gastroenterol. 2017;23:1944-1953.

    Not in our library10.3748/wjg.v23.i11.1944

  197. 197.

    Gardiner K.R., Crockard A.D., Halliday M.I., Rowlands B.J. Class II major histocompatibility complex antigen expression on peripheral blood monocytes in patients with inflammatory bowel disease. Gut. 1994;35:511-516.

    Not in our library10.1136/gut.35.4.511

  198. 198.

    MacDonald T.T., Monteleone G., Pender S.L.F. Recent developments in the immunology of inflammatory bowel disease. Scand. J. Immunol. 2000;51:2-9.

    Not in our library10.1046/j.1365-3083.2000.00658.x

  199. 199.

    Atreya R., Mudter J., Finotto S., Müllberg J., Jostock T., Wirtz S., Schütz M., Bartsch B., Holtmann M., Becker C., et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn’s disease and experimental colitis in vivo. Nat. Med. 2000;6:583-588.

    Not in our library10.1038/75068

  200. 200.

    Fuss I.J., Neurath M., Boirivant M., Klein J.S., de la Motte C., Strong S.A., Fiocchi C., Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 1996;157:1261-1270.

    Not in our library

  201. 201.

    Parronchi P., Romagnani P., Annunziato F., Sampognaro S., Becchio A., Giannarini L., Maggi E., Pupilli C., Tonelli F., Romagnani S. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am. J. Pathol. 1997;150:823-832.

    Not in our library

  202. 202.

    Romagnani S. Lymphokine production by human T cells in disease states. Annu. Rev. Immunol. 1994;12:227-257.

    Not in our library10.1146/annurev.iy.12.040194.001303

  203. 203.

    Ebrahimpour S., Shahbazi M., Khalili A., Tahoori M.T., Zavaran Hosseini A., Amari A., Aghili B., Abediankenari S., Mohammadizad H., Mohammadnia-Afrouzi M. Elevated levels of IL-2 and IL-21 produced by CD4+ T cells in inflammatory bowel disease. J. Biol. Regul. Homeost. Agents. 2017;31:279-287.

    Not in our library

  204. 204.

    Breese E., Braegger C.P., Corrigan C.J., Walker-Smith J.A., MacDonald T.T. Interleukin-2 and interferon-γ secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993;78:127-131.

    Not in our library

  205. 205.

    Mariani P., Bachetoni A., D’Alessandro M., Lomanto D., Mazzocchi P., Speranza V. Effector Th-1 cells with cytotoxic function in the intestinal lamina propria of patients with Crohn’s disease. Dig. Dis. Sci. 2000;45:2029-2035.

    Not in our library10.1023/a:1005516730754

  206. 206.

    Fuss I.J., Marth T., Neurath M.F., Pearlstein G.R., Jain A., Strober W. Anti-interleukin 12 treatment regulates apoptosis of Th1 cells in experimental colitis in mice. Gastroenterology. 1999;117:1078-1088.

    Not in our library10.1016/s0016-5085(99)70392-6

  207. 207.

    Stockinger B., Veldhoen M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 2007;19:281-286.

    Not in our library10.1016/j.coi.2007.04.005

  208. 208.

    Schmidt C., Giese T., Ludwig B., Mueller-Molaian I., Marth T., Zeuzem S., Meuer S.C., Stallmach A. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: Elevated interleukin-23p19 and interleukin-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm. Bowel Dis. 2005;11:16-23.

    Not in our library10.1097/00054725-200501000-00003

  209. 209.

    Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 2009;27:485-517.

    Not in our library10.1146/annurev.immunol.021908.132710

  210. 210.

    O’Connor W., Kamanaka M., Booth C.J., Town T., Nakae S., Iwakura Y., Kolls J.K., Flavell R.A. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat. Immunol. 2009;10:603-609.

    Not in our library10.1038/ni.1736

  211. 211.

    Song X., Dai D., He X., Zhu S., Yao Y., Gao H., Wang J., Qu F., Qiu J., Wang H., et al. Growth factor FGF2 cooperates with interleukin-17 to repair intestinal epithelial damage. Immunity. 2015;43:488-501.

    Not in our library10.1016/j.immuni.2015.06.024

  212. 212.

    Yen D., Cheung J., Scheerens H., Poulet F., McClanahan T., McKenzie B., Kleinschek M.A., Owyang A., Mattson J., Blumenschein W., et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Investig. 2006;116:1310-1316.

    Not in our library10.1172/jci21404

  213. 213.

    Khor B., Gardet A., Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307-317.

    Not in our library10.1038/nature10209

  214. 214.

    Mazieiro R., Frizon R.R., Barbalho S.M., de Alvares Goulart R. Is curcumin a possibility to treat inflammatory bowel diseases? J. Med. Food. 2018;21:1077-1085.

    Not in our library10.1089/jmf.2017.0146

  215. 215.

    Bamias G., Cominelli F. Role of Th2 immunity in intestinal inflammation. Curr. Opin. Gastroenterol. 2015;31:471-476.

    Not in our library10.1097/mog.0000000000000212

  216. 216.

    Shohan M., Elahi S., Shirzad H., Rafieian-Kopaei M., Bagheri N., Soltani E. Th9 cells: Probably players in ulcerative colitis pathogenesis. Int. Rev. Immunol. 2018;37:192-205.

    Not in our library10.1080/08830185.2018.1457659

  217. 217.

    Fina D., Caruso R., Pallone F., Monteleone G. Interleukin-21 (IL-21) controls inflammatory pathways in the gut. Endocr. Metab. Immune Disord. Drug Targets. 2007;7:288-291.

    Not in our library10.2174/187153007782794308

  218. 218.

    Rivas M.N., Koh Y.T., Chen A., Nguyen A., Lee Y.H., Lawson G., Chatila T.A. MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice. J. Clin. Investig. 2012;122:1933-1947.

    Not in our library10.1172/jci40591

  219. 219.

    Mayne C.G., Williams C.B. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm. Bowel Dis. 2013;19:1772-1788.

    Not in our library10.1097/mib.0b013e318281f5a3

  220. 220.

    De Souza H.S., Fiocchi C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016;13:13-27.

    Not in our library10.1038/nrgastro.2015.186

  221. 221.

    Veltkamp C., Anstaett M., Wahl K., Möller S., Gangl S., Bachmann O., Hardtke-Wolenski M., Länger F., Stremmel W., Manns M.P., et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNFα treatment. Gut. 2011;60:1345-1353.

    Not in our library10.1136/gut.2010.217117

  222. 222.

    Liu Z., Geboes K., Colpaert S., Overbergh L., Mathieu C., Heremans H., de Boer M., Boon L., D’Haens G., Rutgeerts P., et al. Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions. J. Immunol. 2000;164:6005-6014.

    Not in our library10.4049/jimmunol.164.11.6005

  223. 223.

    Harrison O.J., Srinivasan N., Pott J., Schiering C., Krausgruber T., Ilott N.E., Maloy K.J. Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine. Mucosal Immunol. 2015;8:1226-12236.

    Not in our library10.1038/mi.2015.13

  224. 224.

    Nowarski R., Jackson R., Gagliani N., de Zoete M.R., Palm N.W., Bailis W., Low J.S., Harman C.C., Graham M., Elinav E., et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell. 2015;163:1444-14456.

    Not in our library10.1016/j.cell.2015.10.072

  225. 225.

    Ludwiczek O., Kaser A., Novick D., Dinarello C.A., Rubinstein M., Tilg H. Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn’s disease. Eur. Cytokine Netw. 2005;16:27-33.

    Not in our library

  226. 226.

    Artis D., Spits H. The biology of innate lymphoid cells. Nature. 2015;517:293-301.

    Not in our library10.1038/nature14189

  227. 227.

    Elemam N.M., Hannawi S., Maghazachi A.A. Innate lymphoid cells (ILCs) as mediators of inflammation, release of cytokines and lytic molecules. Toxins. 2017;9:398.

    Not in our library10.3390/toxins9120398

  228. 228.

    Bernink J.H., Peters C.P., Munneke M., te Velde A.A., Meijer S.L., Weijer K., Hreggvidsdottir H.S., Heinsbroek S.E., Legrand N., Buskens C.J., et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 2013;14:221-229.

    Not in our library10.1038/ni.2534

  229. 229.

    Fuchs A., Vermi W., Lee J.S., Lonardi S., Gilfillan S., Newberry R.D., Cella M., Colonna M. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013;38:769-781.

    Not in our library10.1016/j.immuni.2013.02.010

  230. 230.

    Sugimoto K., Ogawa A., Mizoguchi E., Shimomura Y., Andoh A., Bhan A.K., Blumberg R.S., Xavier R.J., Mizoguchi A. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Investig. 2008;118:534-544.

    Not in our library10.1172/jci33194

  231. 231.

    Zenewicz L.A., Yancopoulos G.D., Valenzuela D.M., Murphy A.J., Stevens S., Flavell R.A. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29:947-957.

    Not in our library10.1016/j.immuni.2008.11.003

  232. 232.

    Pelczar P., Witkowski M., Perez L.G., Kempski J., Hammel A.G., Brockmann L., Kleinschmidt D., Wende S., Haueis C., Bedke T., et al. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science. 2016;354:358-362.

    Not in our library10.1126/science.aah5903

  233. 233.

    Van Deventer S.J.H. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40:443-448.

    Not in our library10.1136/gut.40.4.443

  234. 234.

    Keates A.C., Castagnuolo I., Crickshank W.W., Qiu B., Arseneau K.O., Brazer W., Kelly C.P. Interleukin 16 is upregulated in Crohn’s disease and participates in TNBS colitis in mice. Gastroenterology. 2000;119:972-982.

    Not in our library10.1053/gast.2000.18164

  235. 235.

    Prasad S., Mingrino R., Kaukinen K., Hayes K.L., Powell R.M., MacDonald T.T., Collins J.E. Inflammatory processes have differential effects on claudins 2, 3 and 4 in colonic epithelial cells. Lab. Investig. 2005;85:1139-1162.

    Not in our library10.1038/labinvest.3700316

  236. 236.

    McCabe R.P., Secrist H., Botney M., Egan M., Peters M.G. Cytokine mRNA expression in intestine from normal and inflammatory bowel disease patients. Clin. Immunol. Immunopathol. 1993;66:52-58.

    Not in our library10.1006/clin.1993.1007

  237. 237.

    Nakamura M., Saito H., Kasanuki J., Tamura Y., Yoshida S. Cytokine production in patients with inflammatory bowel disease. Gut. 1992;33:55-58.

    Not in our library10.1136/gut.33.7.933

  238. 238.

    Arend W.P. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 2002;13:323-340.

    Not in our library10.1016/s1359-6101(02)00020-5

  239. 239.

    Maeda S., Ohno K., Nakamura K., Uchida K., Nakashima K., Fukushima K., Tsukamoto A., Goto-Koshino Y., Fujino Y., Tsujimoto H. Mucosal imbalance of interleukin-1β and interleukin-1 receptor antagonist in canine inflammatory bowel disease. Vet. J. 2012;194:66-70.

    Not in our library10.1016/j.tvjl.2012.02.026

  240. 240.

    Casini-Raggi V., Kam L., Chong Y.J.T., Fiocchi C., Pizarro T.T., Cominelli F. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J. Immunol. 1995;154:2434-2440.

    Not in our library

  241. 241.

    Ngoh E.N., Weisser S.B., Lo Y., Kozicky L.K., Jen R., Brugger H.K., Menzies S.C., McLarren K.W., Nackiewicz D., van Rooijen N., et al. Activity of SHIP, which prevents expression of interleukin Iβ, is reduced in patients with Crohn’s disease. Gastroenterology. 2016;150:465-476.

    Not in our library10.1053/j.gastro.2015.09.049

  242. 242.

    MacDonald T.T., Bajaj-Elliott M., Pender S.L.F. T cells orchestrate intestinal mucosal shape and integrity. Immunol. Today. 1999;20:505-510.

    Not in our library10.1016/s0167-5699(99)01536-4

  243. 243.

    Louis E., Ribberns C., Godon A., I Franchimont D., De Groote D., Hardy N., Boniver J., Belaiche J., Malaise M. Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. Clin. Exp. Immunol. 2000;120:241-246.

    Not in our library10.1046/j.1365-2249.2000.01227.x

  244. 244.

    Heuschkel R.B., MacDonald T.T., Monteleone G., Bajaj-Elliott M., Smith J.A., Pender S.L. Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease. Gut. 2000;47:57-62.

    Not in our library10.1136/gut.47.1.57

  245. 245.

    Saarialho-Kere U., Vaalamo M., Puolakkainen P., Airola K., Parks W.C., Karjalainen-Lindsberg M.L. Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am. J. Pathol. 1996;148:519-526.

    Not in our library

  246. 246.

    Monteleone G., Kumberova A., Croft N.M., McKenzie C., Steer H.W., MacDonald T.T. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J. Clin. Investig. 2001;108:601-609.

    Not in our library10.1172/jci12821

  247. 247.

    Heller F., Florian P., Bojarski C., Richter J., Christ M., Hillenbrand B., Mankertz J., Gitter A.H., Bürgel N., Fromm M., et al. Interleukin-13 is the key effector th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129:550-564.

    Not in our library10.1016/j.gastro.2005.05.002

  248. 248.

    Pari L., Tewas D., Eckel J. Role of curcumin in health and disease. Arch. Physiol. Biochem. 2008;114:127-149.

    Not in our library10.1080/13813450802033958

  249. 249.

    Gupta S.C., Patchva S., Aggarwal B.B. Therapeutic roles of curcumin: Lessons learned from clinical trials. AAPS J. 2013;15:195-218.

    Not in our library10.1208/s12248-012-9432-8

  250. 250.

    Peterson C.T., Vaughn A.R., Sharma V., Chopra D., Mills P.J., Peterson S.N., Sivamani R.K. Effects of turmeric and curcumin dietary supplementation on human gut microbiota: A double-blind, randomized, placebo-controlled pilot study. J. Evid. Based Integr. Med. 2018;23:1-8.

    Not in our library10.1177/2515690x18790725

  251. 251.
    Dose escalation of a curcuminoid formulation · 2006
    No notice
  252. 252.

    De R., Kundu P., Swarnakar S., Ramamurthy T., Chowdhury A., Nair G.B., Mukhopadhyay A.K. Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob. Agents Chemother. 2009;53:1592-1597.

    Not in our library10.1128/aac.01242-08

  253. 253.

    Rai D., Singh J.K., Roy N., Panda D. Curcumin inhibits FtsZ assembly: An attractive mechanism for its antibacterial activity. Biochem. J. 2008;410:147-155.

    Not in our library10.1042/bj20070891

  254. 254.

    Niamsa N., Sittiwet C. Antimicrobial activity of Curcuma longa aqueous extract. J. Pharmacol. Toxicol. 2009;4:173-177.

    Not in our library

  255. 255.

    Patole S. Microbiota and necrotizing enterocolitis. Nestle Nutr. Inst. Workshop Ser. 2017;88:81-94.

    Not in our library10.1159/000455989

  256. 256.

    Chassaing B., Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1720-1728.

    Not in our library10.1053/j.gastro.2011.01.054

  257. 257.

    Chow J., Tang H., Mazmanian S.K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr. Opin. Immunol. 2011;23:473-480.

    Not in our library10.1016/j.coi.2011.07.010

  258. 258.
    Regulative effects of curcumin spice administration on gut microbiota and its pharmacological implications · 2017
    No notice
  259. 259.

    Feng W., Wang H., Zhang P., Gao C., Tao J., Ge Z., Zhu D., Bi Y. Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats. Biochim. Biophys. Acta. 2017;1861:1801-1812.

    Not in our library10.1016/j.bbagen.2017.03.017

  260. 260.

    Maslowski K.M., Vieira A.T., Ng A., Kranich J., Sierro F., Yu D., Schilter H.C., Rolph M.S., Mackay F., Artis D., et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461:1282-1286.

    Not in our library10.1038/nature08530

  261. 261.

    De Filippo C., Cavalieri D., Di Paola M., Ramazzotti M., Poullet J.B., Massart S., Collini S., Pieraccini G., Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. USA. 2010;107:14691-14696.

    Not in our library10.1073/pnas.1005963107

  262. 262.

    Zhang Z., Chen Y., Xiang L., Wang Z., Xiao G.C., Hu J. Effect of curcumin on the diversity of gut microbiota in ovariectomized rats. Nutrients. 2017;9:1146.

    Not in our library10.3390/nu9101146

  263. 263.
    Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells · 2017
    Expression of concern
  264. 264.

    Law I.K., Bakirtzi K., Polytarchou C., Oikonomopoulos A., Hommes D., Iliopoulos D., Pothoulakis C. Neurotensin—regulated miR-133alpha is involved in proinflammatory signaling in human colonic epithelial cells and in experimental colitis. Gut. 2015;64:1095-1104.

    Not in our library10.1136/gutjnl-2014-307329

  265. 265.

    Narushima S., Sugiura Y., Oshima K., Atarashi K., Hattori M., Suematsu M., Honda K. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes. 2014;5:333-339.

    Not in our library10.4161/gmic.28572

  266. 266.

    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., et al. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflamm. Bowel Dis. 2015;21:2483-2494.

    Not in our library10.1097/mib.0000000000000522

  267. 267.

    Burapan S., Kim M., Han J. Curcuminoid demethylation as an alternative metabolism by human intestinal microbiota. J. Agric. Food Chem. 2017;65:3305-3310.

    Not in our library10.1021/acs.jafc.7b00943

  268. 268.

    Hwang S.W., Kim J.H., Lee C., Im I.P., Kim J.S. Intestinal alkaline phosphatase ameliorates experimental colitis via toll-like receptor 4-dependent pathway. Eur. J. Pharmacol. 2018;820:156-166.

    Not in our library10.1016/j.ejphar.2017.12.026

  269. 269.

    Boozari M., Butler A.E., Sahebkar A. Impact of curcumin on toll-like receptors. J. Cell. Physiol. 2019.

    Not in our library10.1002/jcp.28103

  270. 270.

    Gradišar H., Keber M.M., Pristovšek P., Jerala R. MD-2 as the target of curcumin in the inhibition of response to LPS. J. Leukoc. Biol. 2007;82:968-974.

    Not in our library10.1189/jlb.1206727

  271. 271.

    Peng L., Li X., Song S., Wang Y., Xu L. Effects of curcumin on mRNA expression of cytokines related to toll-like receptor 4 signaling in THP-1 cells. Chin. J. Dermatol. 2010;43:493-496.

    Not in our library

  272. 272.

    Baliga M.S., Joseph N., Venkataranganna M.V., Saxena A., Ponemone V., Fayad R. Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: Preclinical and clinical observations. Food Funct. 2012;3:1109-1117.

    Not in our library10.1039/c2fo30097d

  273. 273.

    Eckert J., Scott B., Lawrence S.M., Ihnat M., Chaaban H. FLLL32, a curcumin analog, ameliorates intestinal injury in necrotizing enterocolitis. J. Inflamm. Res. 2017;10:75-81.

    Not in our library10.2147/jir.s131051

  274. 274.

    Murano M., Maemura K., Hirata I., Toshina K., Nishikawa T., Hamamoto N., Sasaki S., Saitoh O., Katsu K. Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis. Clin. Exp. Immunol. 2000;120:51-58.

    Not in our library10.1046/j.1365-2249.2000.01183.x

  275. 275.

    Gan H.T., Chen Y.Q., Ouyang Q. Sulfasalazine inhibits activation of nuclear factor-kappaB in patients with ulcerative colitis. J. Gastroenterol. Hepatol. 2005;20:1016-1024.

    Not in our library10.1111/j.1440-1746.2005.03862.x

  276. 276.

    Hommes D., van den Blink B., Plasse T., Bartelsman J., Xu C., Macpherson B., Tytgat G., Peppelenbosch M., Van Deventer S. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease. Gastroenterology. 2002;122:7-14.

    Not in our library10.1053/gast.2002.30770

  277. 277.

    Pan M.H., Lin-Shiau S.Y., Lin J.K. Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem. Pharmacol. 2000;60:1665-1676.

    Not in our library10.1016/s0006-2952(00)00489-5

  278. 278.

    Jobin C., Bradham C.A., Russo M.P., Juma B., Narula A.S., Brenner D.A., Sartor R.B. Curcumin blocks cytokine-mediated NF-κB activation and proinflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. J. Immunol. 1999;163:3474-3483.

    Not in our library

  279. 279.

    Shishodia S., Singh T., Chaturvedi M.M. Modulation of transcription factors by curcumin. Adv. Exp. Med. Biol. 2007;595:127-148.

    Not in our library10.1007/978-0-387-46401-5_4

  280. 280.

    Hahm E.R., Cheon G., Lee J., Kim B., Park C., Yang C.H. New and known symmetrical curcumin derivatives inhibit the formation of Fos-Jun-DNA complex. Cancer Lett. 2002;184:89-96.

    Not in our library10.1016/s0304-3835(02)00170-2

  281. 281.

    Huang T.S., Lee S.C., Lin J.K. Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl. Acad. Sci. USA. 1991;88:5292-5296.

    Not in our library10.1073/pnas.88.12.5292

  282. 282.

    Huang M.T., Smart R.C., Wong C.Q., Conney A.H. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 1988;48:5941-5946.

    Not in our library

  283. 283.

    Ukil A., Maity S., Karmakar S., Datta N., Vedasiromoni J.R., Das P.K. Curcumin, the major component of food flavour turmeric, reduces mucosal injury in trinitrobenzene sulphonic acid-induced colitis. Br. J. Pharmacol. 2003;139:209-2018.

    Not in our library10.1038/sj.bjp.0705241

  284. 284.

    Salh B., Assi K., Templeman V., Parhar K., Owen D., Gomez-Munoz A., Jacobson K. Curcumin attenuates DNB-induced murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2003;285:G235-G243.

    Not in our library10.1152/ajpgi.00449.2002

  285. 285.

    Holt P.R., Katz S., Kirshoff R. Curcumin therapy in inflammatory bowel disease: A pilot study. Dig. Dis. Sci. 2005;50:2191-2193.

    Not in our library10.1007/s10620-005-3032-8

  286. 286.

    Moon D.O., Jin C.Y., Lee J.D., Choi Y.H., Ahn S.C., Lee C.M., Jeong S.C., Park Y.M., Kim G.Y. Curcumin decreases binding of Shiga-like toxin-1B on human intestinal epithelial cell line HT29 stimulated with TNF-alpha and Il-1beta: Suppression of p38, JNK and NF-kappaB p65 as potential targets. Biol. Pharm. Bull. 2006;29:1470-1475.

    Not in our library10.1248/bpb.29.1470

  287. 287.

    Jian Y.T., Mai G.F., Wang J.D., Zhang Y.L., Luo R.C., Fang Y.X. Preventive and therapeutic effects of NF-κB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid. World J. Gastroenterol. 2005;11:1747-1752.

    Not in our library10.3748/wjg.v11.i12.1747

  288. 288.

    Camacho-Barquero L., Villegas I., Sánchez-Fidalgo S., Motilva V., de la Lastra C.A. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int. Immunopharmacol. 2007;7:333-342.

    Not in our library10.1016/j.intimp.2006.11.006

  289. 289.

    Sugimoto K., Hanai H., Tozawa K., Aoshi T., Uchijima M., Nagata T., Koide Y. Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice. Gastroenterology. 2002;123:1912-1922.

    Not in our library10.1053/gast.2002.37050

  290. 290.

    Kim G.Y., Kim K.H., Lee S.H., Yoon M.S., Lee H.J., Moon D.O., Lee C.M., Ahn S.C., Park Y.C., Park Y.M. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J. Immunol. 2005;174:8116-8124.

    Not in our library10.4049/jimmunol.174.12.8116

  291. 291.

    Cong Y., Wang L., Konrad A., Schoeb T., Elson C.O. Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cells. Eur. J. Immunol. 2009;39:3134-3146.

    Not in our library10.1002/eji.200939052

  292. 292.

    Abdollahi E., Momtazi A.A., Johnston T.P., Sahebkar A. Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: A nature-made jack-of-all-trades? J. Cell Physiol. 2018;233:830-848.

    Not in our library10.1002/jcp.25778

  293. 293.

    Jung I.D., Jeong Y.-I., Lee C.-M., Noh K.T., Jeong S.K., Chun S.H., Choi O.H., Park W.S., Han J., Shin Y.K., et al. COX-2 and PGE2 signaling is essential for the regulation of IDO expression by curcumin in murine bone marrow-derived dendritic cells. Int. Immunopharmacol. 2010;10:760-768.

    Not in our library10.1016/j.intimp.2010.04.006

  294. 294.

    Gao X., Kuo J., Jiang H., Deeb D., Liu Y., Divine G., Chapman R.A., Dulchavsky S.A., Gautam S.C. Immunomodulatory activity of curcumin: Suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. Biochem. Pharmacol. 2004;68:51-61.

    Not in our library10.1016/j.bcp.2004.03.015

  295. 295.

    Yadav V.S., Mishra K.P., Singh D.P., Mehrota S., Singh V.K. Immunomodulatory effects of curcumin. Immunopharmacol. Immunotoxicol. 2005;27:485-497.

    Not in our library10.1080/08923970500242244

  296. 296.

    Jagetia G.C., Aggarwal B.B. “Spicing up” of the immune system by curcumin. J. Clin. Immunol. 2007;27:19-35.

    Not in our library10.1007/s10875-006-9066-7

  297. 297.

    Kang B.Y., Chung S.W., Chung W.-J., Im S.-Y., Hwang S.Y., Kim T.S. Inhibition of interleukin-12 production in lipopolysaccharide-activated macrophages by curcumin. Eur. J. Pharmacol. 1999;384:191-195.

    Not in our library10.1016/s0014-2999(99)00690-1

  298. 298.

    Zhang M., Deng C.S., Zheng J.J., Xia J. Curcumin regulated shift from Th1 to Th2 in trinitrobenzene sulphonic acid-induced chronic colitis. Acta Pharmacol. 2006;27:1071-1077.

    Not in our library10.1111/j.1745-7254.2006.00322.x

  299. 299.

    Bakır B., Yetkin Ay Z., Büyükbayram H.İ., Kumbul Doğuç D., Bayram D., Candan I.A., Uskun E. Effect of curcumin on systemic T helper 17 cell response: Gingival expression of interleukin-17 and retinoic acid receptor-related orphan receptor γt and alveolar bone loss in experimental periodontitis. J. Periodontol. 2016;87:e183-e191.

    Not in our library10.1902/jop.2016.150722

  300. 300.

    Brouet I., Ohshima H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem. Biophys. Res. Commun. 1995;206:533-540.

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    Mani H., Sidhu G.S., Kumari R., Gaddipati J.P., Seth P., Maheshwari R.K. Curcumin differentially regulates TGF-β1, its receptors and nitrix oxide synthase during impaired wound healing. BioFactors. 2002;16:29-43.

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    Joe B., Lokesh B.R. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages. Biochim. Biophys. Acta. 1994;1224:255-263.

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    Joe B., Lokesh B.R. Dietary n-3 fatty acids, curcumin and capsaicin lower the release of lysosomal enzymes and eicosanoids in rat peritoneal macrophages. Mol. Cell. Biochem. 2000;203:153-161.

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    Billerey-Larmonier C., Uno J.K., Larmonier N., Midura A.J., Timmermann B., Ghishan F.K., Kiela P.R. Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent. Inflamm. Bowel Dis. 2008;14:780-793.

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    Chan M.M., Huang H.I., Fenton M.R., Fong D. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural produce with anti-inflammatory properties. Biochem. Pharmacol. 1998;55:1955-1962.

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    Bai X., Oberley-Deegan R.E., Bai A., Ovrutsky A.R., Kinney W.H., Weaver M., Zhang G., Honda J.R., Chan E.D. Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection. Respirology. 2016;21:951-957.

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    Mimche P.N., Thompson E., Taramelli D., Vivas L. Curcumin enhances non-opsonic phagocytosis of Plasmodium falciparum through up-regulation of CD36 surface expression on monocytes/macrophages. J. Antimicrob. Chemother. 2012;67:1895-1904.

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    Martin A.R., Villegas I., La Casa C., de la Lastra C.A. Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochem. Pharmacol. 2004;67:1399-1410.

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    Jiang H., Deng C.S., Zhang M., Xia J. Curcumin-attenuated trinitrobenzene sulphonic acid induces chronic colitis by inhibiting expression of cyclooxygenase-2. World J. Gastrolenterol. 2006;12:3848-3853.

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    Zhang M., Denc C., Zheng J., Xia J., Sheng D. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma. Int. Immunopharmacol. 2006;6:1233-1242.

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    Larmonier C.B., Midura-Kiela M.T., Ramalingam R., Laubitz D., Janikashvili N., Larmonier N., Ghishan F.K., Kiela P.R. Modulation of neutrophil motility by curcumin: Implications for inflammatory bowel disease. Inflamm. Bowel Dis. 2011;17:503-515.

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    Larmonier C.B., Uno J.K., Lee K.M., Karrasch T., Laubitz D., Thurston R., Midura-Kiela M.T., Ghishan F.K., Sartor R.B., Jobin C., et al. Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection. Am. J. Physiol. Gastrointest. Liver Physiol. 2008;295:G1079-G1091.

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    Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions. 1989;28:298-303.

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    Okazaki Y., Han Y., Kayahara M., Watanabe T., Arishige H., Kato N. Consumption of curcumin elevates fecal immunoglobulin A, an index of intestinal immune function, in rats fed a high-fat diet. J. Nutr. Sci. Vitaminol. 2010;56:68-71.

    Not in our library10.3177/jnsv.56.68

  317. 317.

    Churchill M., Chadburn A., Bilinski R.T., Bertagnolli M.M. Inhibition of intestinal tumors by curcumin is associated with changes in the intestinal immune cell profile. J. Surg. Res. 2000;89:169-175.

    Not in our library10.1006/jsre.2000.5826

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    Decoté-Ricardo D., Chagas K., Rocha J., Redner P., Lopes U., Cambier J., Pecanha L. Modulation of in vitro murine B-lymphocyte response by curcumin. Phytomedicine. 2009;16:982-988.

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    Timmermans W.M.C., van Laar J.A.M., van der Houwen T.B., Kamphuis L.S.J., Bartol S.J.W., Lam K.H., Ouwendijk R.J., Sparrow M.P., Gibson P.R., van Hagen P.M., et al. B-cell dysregulation in Crohn’s disease is partially restored with infliximab therapy. PLoS ONE. 2016;11:e0160103.

    Not in our library10.1371/journal.pone.0160103

  320. 320.

    Harrington L., Srikanth C.V., Antony R., Shi H.N., Cherayil B.J. A role for natural killer cells in intestinal inflammation caused by infection with Salmonella enterica serovar Typhimurium. FEMS Immunol. Med. Microbiol. 2007;51:372-380.

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  321. 321.

    Mouzaoui S., Rahim I., Djerdjouri B. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-alpha induced oxidative stress, colitis and hepatotoxicity in mice. Int. Immunopharmacol. 2012;12:302-311.

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  322. 322.

    Midura-Kiela M.T., Radhakrishnan V.M., Larmonier C.B., Laubitz D., Ghishan F.K., Kiela P.R. Curcumin inhibits interferon-γ signaling in colonic epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2012;302:G85-G96.

    Not in our library10.1152/ajpgi.00275.2011

  323. 323.

    Kim Y.S., Young M.R., Bobe G., Colburn N.H., Milner J.A. Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev. Res. 2009;2:200-208.

    Not in our library10.1158/1940-6207.capr-08-0141

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    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., et al. Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-κB activation. PLoS ONE. 2010;5:e12969.

    Not in our library10.1371/journal.pone.0012969

  325. 325.

    Zhang X., Wu J., Ye B., Wang Q., Xie X., Shen H. Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway. BMC Complement. Altern. Med. 2016;16:299.

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    Kang G., Kong P.J., Yuh Y.J., Lim S.Y., Yim S.V., Chun W., Kim S.S. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappaB bindings in BV2 microglial cells. J. Pharmacol. Sci. 2004;94:325-328.

    Not in our library10.1254/jphs.94.325

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    Plummer S.M., Holloway K.A., Manson M.M., Munks R.J., Kaptein A., Farrow S., Howells L. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemoprotective agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signaling complex. Oncogene. 1999;18:6013-6020.

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    Goel A., Boland C.R., Chauhan D.P. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett. 2001;172:111-118.

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    Hanai H., Iida T., Takeuchi K., Watanabe F., Maruyama Y., Andoh A., Tsujikawa T., Fujiyama Y., Mitsuyama K., Sata M., et al. Curcumin maintenance therapy for ulcerative colitis: Randomized, multicenter, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 2006;4:1502-1506.

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    Lang A., Salomon N., Wu J.C.Y., Kopylov U., Lahat A., Har-Noy O., Ching J.Y.L., Cheong P.K., Avidan B., Gamus D., et al. Curcumin in combination with mesalamine induces remission in patients with mild-to-moderate ulcerative colitis in randomized controlled trial. Clin. Gastroenterol. Hepatol. 2015;13:1444-1449.

    Not in our library10.1016/j.cgh.2015.02.019

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    Babbs C.F. Oxygen radicals in ulcerative colitis. Free Radic. Biol. Med. 1992;13:169-181.

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    Grisham M.B. Oxidants and free radicals in inflammatory bowel disease. Lancet. 1994;344:859-861.

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    Aceti A., Beghetti I., Martini S., Faldella G., Corvaglia L. Oxidative stress and necrotizing enterocolitis: Pathogenetic mechanisms, opportunities for intervention, and the role of human milk. Oxid. Med. Cell. Longev. 2018;2018:7397659.

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    Chen M.L., Ge Z., Fox J.G., Schauer D.B. Disruption of tight junctions and induction of proinflammatory cytokine responses in colonic epithelial cells by Campylobacter jejuni. Infect. Immun. 2006;74:6581-6589.

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    Tanida S., Mizoshita T., Mizushima T., Sasaki M., Shimura T., Kamiya T., Kataoka H., Joh T. Involvement of oxidative stress and mucosal address in cell adhesion molecule-1 (MAdCAM-1) in inflammatory bowel disease. J. Clin. Biochem. Nutr. 2011;48:112-116.

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    Basuroy S., Seth A., Elias B., Naren A.P., Rao R. MAPK interacts with occluding and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide. Biochem. J. 2006;393:69-77.

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    Grisham M.B., Yamada T. Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann. N. Y. Acad. Sci. 1992;664:103-115.

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    Lundberg J.O., Hellstrom P.M., Lundberg J.M., Alving K. Greatly increased luminal nitric oxide in ulcerative colitis. Lancet. 1994;344:1673-1674.

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    Wallace J.L., Miller M.J.S. Nitric oxide in mucosal defense: A little goes a long way. Gastroenterology. 2000;119:512-520.

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    Stroes E., Hijmering M., van Zandvoort M., Wever R., Rabelink T.J., Van Faassen E.E. Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett. 1998;438:161-164.

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    Cross R.K., Wilson K.T. Nitric oxide in inflammatory bowel disease. Inflamm. Bowel Dis. 2003;9:179-189.

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    Sreejayan, Rao M.N. Curcuminoids as potent inhibitors of lipid peroxidation. J. Pharm. Pharmacol. 1994;46:1013-1016.

    Not in our library10.1111/j.2042-7158.1994.tb03258.x

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    Onoda M., Inano H. Effect of curcumin on the production of nitric oxide by cultured rat mammary gland. Nitric Oxide. 2000;4:505-515.

    Not in our library10.1006/niox.2000.0305

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    Venkataranganna M.V., Rafiq M., Gopumadhavan S., Peer G., Babu U.V., Mitra S.K. NCB-02 (standardized Curcumin preparation) protects dinitrochlorobenzene-induced colitis through down-regulation of NFkappa-B and iNOS. World J. Gastroenterol. 2007;13:1103-1107.

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    Sanchez-Munoz F., Dominguez-Lopez A., Yamamoto-Furusho J.K. Role of cytokines in inflammatory bowel disease. World J. Gastroenterol. 2008;14:4280-4288.

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    Pedersen G., Saermark T., Kirkegaard T., Brynskov J. Spontaneous and cytokine induced expression and activity of matrix metalloproteinases in human colonic epithelium. Clin. Exp. Immunol. 2009;155:257-265.

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    Rath T., Roderfeld M., Halwe J.M., Tschuschner A., Roeb E., Graf J. Cellular sources of MMP-7, MMP-13 and MMP-28 in ulcerative colitis. Scand. J. Gastroenterol. 2010;45:1186-1196.

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    Koelink P.J., Overbeek S.A., Braber S., Morgan M.E., Henricks P.A., Abdul Roda M., Verspaget H.W., Wolfkamp S.C., te Velde A.A., Jones C.W., et al. Collagen degradation and neutrophilic infiltration: A vicious circle in inflammatory bowel disease. Gut. 2014;63:578-587.

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    Vandooren J., van den Steen P.E., Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade. Crit. Rev. Biochem. Mol. Biol. 2013;48:222-272.

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    Thaloor D., Singh A.K., Sidhu G.S., Prasad P.V., Kleinman H.K., Maheshwari R.K. Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin. Cell Growth Differ. 1998;9:305-312.

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    Clutterbuck A.L., Allaway D., Harris P., Mobasheri A. Curcumin reduces prostaglandin E2, matrix metalloproteinase-3 and proteoglycan release in the secretome of interleukin 1β-treated articular cartilage. F1000 Res. 2013;2:147.

    Not in our library10.12688/f1000research.2-147.v1

  352. 352.

    Hwang B.M., Noh E.M., Kim J.S., Kim J.M., You Y.O., Hwang J.K., Kwon K.B., Lee Y.R. Curcumin inhibits UVB-induced matrix metalloproteinase-1/3 expression by suppressing the MAPK-p38/JNK pathways in human dermal fibroblasts. Exp. Dermatol. 2013;22:371-374.

    Not in our library10.1111/exd.12137

  353. 353.

    Kim M., Murakami A., Ohigashi H. Modifying effects of dietary factors on (-)-epigallocatechin-3-galalte-induced pro-matrix metalloproteinase-7 production in HT-29 human colorectal cancer cells. Biosci. Biotechnol. Biochem. 2007;71:2442-2450.

    Not in our library10.1271/bbb.70213

  354. 354.

    Li W., Kong A.N. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol. Carcinog. 2009;48:91-104.

    Not in our library10.1002/mc.20465

  355. 355.

    Motterlini R., Foresti R., Bassi R., Green C.J. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic. Biol. Med. 2000;28:1303-1312.

    Not in our library10.1016/s0891-5849(00)00294-x

  356. 356.

    McNally S.J., Harrison E.M., Ross J.A., Garden O.J., Wigmore S.J. Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int. J. Mol. Med. 2007;19:165-172.

    Not in our library10.3892/ijmm.19.1.165

  357. 357.

    Pedersen C.B., Gregersen N. Stress response profiles in human fibroblasts exposed to heat shock or oxidative stress. Methods Mol. Biol. 2010;648:161-173.

    Not in our library10.1007/978-1-60761-756-3_10

  358. 358.

    Liu Z., Dou W., Zheng Y., Wen Q., Qin M., Wang X., Tang H., Zhang R., Lv D., Wang J., Zhao S. Curcumin upregulates Nrf2 translocation and protects rat hepatic stellate cells against oxidative stress. Mol. Med. Rep. 2016;13:1717-1724.

    Not in our library10.3892/mmr.2015.4690

  359. 359.

    Wang N., Wang G., Hao J., Ma J., Wang Y., Jiang X., Jiang H. Curcumin ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells. Dig. Dis. Sci. 2012;57:1792-1801.

    Not in our library10.1007/s10620-012-2094-7

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