phytochemicals enhance antioxidant enzyme expression to

Mol. Nutr. Food Res. 61, 6, 2017, 1600659 (1 of 19) 1600659DOI 10.1002/mnfr.201600659

REVIEW

Phytochemicals enhance antioxidant enzyme expression

to protect against NSAID-induced oxidative damage of

the gastrointestinal mucosa

Yu-Ting Cheng, Chi-Cheng Lu and Gow-Chin Yen

Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan

Received: July 29, 2016Revised: November 15, 2016

Accepted: November 17, 2016

The gastrointestinal (GI) mucosa provides the first protective barrier for digested food andxenobiotics, which are easily attacked by toxic substances. Nonsteroidal anti-inflammatorydrugs, including aspirin, diclofenac, indomethacin, and ketoprofen, are widely used in clinicalmedicine, but these drugs may cause oxidative stress, leading to GI damage such as ulcers.Lansoprazol, omeprazole, and other clinical drugs are widely used to treat duodenal and gas-tric ulcers and have been shown to have multiple biological functions, such as antioxidantactivity and the ability to upregulate antioxidant enzymes in vivo. Therefore, the reduction ofoxidative stress may be an effective curative strategy for preventing and treating nonsteroidalanti-inflammatory drug induced ulcers of the GI mucosa. Phytochemicals, such as dietary phe-nolic compounds, phenolic acids, flavan-3-ols, flavonols, flavonoids, gingerols, carotenes, andorganosulfur, are common antioxidants in fruits, vegetables, and beverages. A large amountof evidence has demonstrated that natural phytochemicals possess bioactivity and potentialhealth benefits, such as antioxidant, anti-inflammatory, and antibacterial benefits, and they canprevent digestive disease processes. In this review, we summarize the literature on phytochem-icals with biological effects, such as angiogenic, antioxidant, antiapoptotic, anti-inflammatory,and antiulceration effects, and their related mechanisms are also discussed.

Keywords:

Antioxidant enzymes / NSAIDs / Oxidative stress / Phytochemicals / Ulcer

1 Introduction: prevalence

Peptic ulcers induced by mucosal damage are a prevalentdigestive disease in the United States, and approximately500,000 individuals with gastrointestinal (GI) ulcers are diag-nosed each year [1–4]. The GI mucosa provides the first pro-tective barrier against xenobiotics, but it is easily damaged bytoxic substances. Serious ulceration may lead to GI bleedingor even perforation. The pathophysiology of peptic ulcers is of-

Correspondence: Dr. Gow-Chin YenE-mail: [email protected]

Abbreviations: COX, cyclooxygenase; EGCG, (−)-epigallocatech-in-3-gallate; GI, gastrointestinal; GSH, glutathione; GSSG, ox-idized GSH; GPx, glutathione peroxidase; GR, glutathione re-ductase; HO-1, heme oxygenase-1; HSP70, heat shock protein-70; iNOS, inducible nitric oxide synthase; LPO, lipid peroxida-tion; MDA, malondialdehyde; MPO, myeloperoxidase; Nrf2, nu-clear factor erythroid 2 related factor 2; NSAID, nonsteroidal anti-inflammatory drug; PCA, protocatechuic acid; PG, prostaglandin;RCS, reactive carbonyl species; ROS, reactive oxygen species;SOD, superoxide dismutase; TGF, transforming growth factor

ten depicted as an imbalance between aggressive and protec-tive factors (Fig. 1). Common endogenous aggressive factorsinclude bile salts, gastric acid, and pepsin, whereas exoge-nous aggressive factors include the consumption of alco-hol, infection by Helicobacter pylori, and nonsteroidal anti-inflammatory drugs (NSAIDs). Relevant protective factorsinclude mucosal blood flow, mucosal cellular proliferationand restitution, and prostaglandin (PG) [4–7].

NSAIDs, including aspirin, diclofenac, indomethacin,naproxen, and ketoprofen, are all available to control acuteand chronic pain from rheumatoid arthritis and to alleviateswelling as anti-inflammatory medications. However, theiruse can cause oxidative damage to the GI mucosa in the clini-cal stage [5]. It has been reported that intestinal diseases, suchas ulcers, are related to lipid peroxidation (LPO) and oxidativedamage in the mucosa [8]. It is important to reduce the levelsof reactive oxygen species (ROS) in GI ulcers because ROS cancause oxidative damage to biological macromolecules such aslipids, DNA, and proteins.

Colour online: See the article online to view Fig. 1 in colour.

C© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com

1600659 (2 of 19) Y.-T. Cheng et al. Mol. Nutr. Food Res. 61, 6, 2017, 1600659

Figure 1. The defensive and aggres-sive factors related to peptic ulcer dis-eases. The pathophysiology of a gas-trointestinal ulcer is often depictedas an imbalance between aggressivefactors and protective factors. Com-mon endogenous aggressive factorsinclude bile salts, gastric acid, andpepsin, whereas exogenous aggres-sive factors include the consumption ofalcohol, Helicobacter pylori infection,and NSAIDs. The relevant protectivefactors include prostaglandin (PG), mu-cosal blood flow, mucosal cellular pro-liferation, and restitution.

The appearance of LPO and oxidative damage in the GImucosa is correlated with intestinal diseases, chronic intesti-nal inflammation, or peptic ulcers [9–11]. Phytochemicalspossess multiple biofunctional activities, including scaveng-ing of ROS, trapping of reactive carbonyl species (RCS), andchelation of metal ions [12]. The dietary intake of natural an-tioxidants could decrease the risk of oxidative stress relateddiseases in living systems. Hence, the use of oxygen rad-ical scavengers and antioxidant supplements from naturalfoods might be an effective and potential therapeutic strat-egy for preventing tissue damage under oxidative stress. Inthis review, we summarize and characterize the beneficialhealth effects of recent experimental and clinical studies de-scribing the major antioxidant compounds of vegetables and

fruits that upregulate antioxidant enzymes to protect againstNSAID-induced oxidative damage of the GI mucosa.

2 Relationship between NSAID-inducedoxidative injury of the GI mucosa andrelated effects such as apoptosis,angiogenesis, antioxidant enzymes,and inflammation

Peptic ulcers are a multifactorial and complex dis-ease involved in duodenal and gastric ulcers. Althoughthere have been medical advances, the managementof peptic ulcers and their complications remain a

Figure 2. Mechanisms of NSAID-induced gastrointestinal ulcers.There are several mechanisms forNSAID-induced gastrointestinal ul-cers, including the upregulation ofoxidative stress, cyclooxygenase-2(COX-2), and apoptosis, and thedownregulation of cyclooxygenase-1 (COX-1), prostaglandin (PG),endothelin-converting enzyme-1 (ECE-1), angiogenesis, mucosal cellularproliferation, and restitution.


Mol. Nutr. Food Res. 61, 6, 2017, 1600659 (3 of 19) 1600659

challenge, including high morbidity and death ratesfor the disease [13, 14]. NSAIDs are widely used tolessen inflammation, fevers, and pain in clinical medicineand can be divided into non-cyclooxygenase (non-COX)selective (COX-1 and COX-2) inhibitors and COX-2selective inhibitors [15]. Epidemiologic studies indicate thatpatients with non-COX selective NSAIDs have a higher riskof ulcers in the GI tract [6, 13, 15]. The major non-COX se-lective inhibitors include aspirin, diclofenac, indomethacin,piroxicam, naproxen, and ketoprofen [5, 16, 17].

Nonselective NSAID induction of peptic ulcers is a mul-tifaceted process that includes the generation of ROS, induc-ing inflammatory molecules of the COX-2, cytosolic phos-pholipases A2, leukotriene B4, 5-lipoxygenase, PGE2, TNF-�,IL-1�, and IL-6 production [18–21], increasing LPO, xanthineoxidase, and DNA damage (8-OHdG production) [3, 22], andthe inhibition of antioxidant enzymes including glutathioneperoxidase (GPx), glutathione reductase (GR), glutathioneS-transferase, catalase, superoxide dismutase (SOD), andheme oxygenase-1 (HO-1) as well as glutathione (GSH)/ oxi-dized GSH (GSSG) ratio in vivo [23,24]. Moreover, ROS mayalso cause oxidative damage to biological macromoleculesand react with proteins, lipids, and mitochondrial DNA, lead-ing to cells death by affecting various apoptotic pathways inthe GI tract [3,5,22]. Furthermore, taking NSAIDs also down-regulates angiogenesis, inhibits mucosal cellular restitution,and promotes extracellular matrix degradation [25, 26], as il-lustrated in Fig. 2 and Table 1. Thus, it is important to regulatethe levels of ROS in the GI tract. In this study, we summarizethe literature on multi-NSAIDs with varying degrees of ul-cerogenic activity associated with different biological effectsincluding oxidative stress, inflammation, and GI protection.

2.1 The role of oxidative stress and antioxidant

enzymes in ulceration

NSAID-induced LPO and oxidative stress might also causeulcers in the GI mucosa [27]. Some reports have indicatedthat oral administration of NSAIDs causes GI oxidative injurythrough increased lactate dehydrogenase leakage, mucosalLPO (malondialdehyde, MDA), DNA damage, and decreasedgastric mucus secretion in vivo [3, 27]. Thus, upregulationof antioxidant enzymes, such as GPx, GR, SOD, and HO-1, might be a major mechanism of action against oxidativestress associated GI ulcers.

The selenium-dependent enzyme GPx is thought to actas a barrier against hydroperoxide attack [28]. Brigelius-Flohe[29] indicated that GI isoenzyme (GI-GPx) is the most re-lated to a classical enzyme and might provide a barrieragainst hydroperoxides from the metabolism of xenobiotics.GR is responsible for maintaining a balance of reduced GSHand GSSG. The activation of GR plays an important rolein increasing the concentration of GSH, which maintainsthe redox status of the organism [30]. Thus, the ratio ofGSH/GSSG is an index for oxidative stress. The levels of

the total sulfhydryl groups are important in maintaining an-tioxidation or detoxification of ROS and intracellular redoxstatus [31]. Cheng et al. [3] reported that ketoprofen not onlyincreased the levels of LPO and ROS but also decreased thelevels of intracellular antioxidants in vitro, such as GPx, GR,and total sulfhydryl groups. In addition, HO-1 and SOD areimportant antioxidant enzymes for the elimination of ROSand RCS, and they can act as metal ion chelators in the hu-man body [32–34]. HO-1 protects GI cells against oxidativedamage through the breakdown of heme to biliverdin andcarbon monoxide [32] and suppresses inflammation and tis-sue damage after ROS induction in the intestine and stom-ach [33]. Some reports also indicate that administration ofNSAIDs such as indomethacin, diclofenac, piroxicam, andketoprofen reduced the levels of GPx, GR, SOD, catalase ac-tivities, and the GSH and GSH/GSSG ratio in the GI mucosa[3,19,35]. These updated data confirm the well-established di-verse benefits of pharmacological actions and might supportthe standpoint for nutraceutical applications.

2.2 Inhibition of PGs by COX in ulceration

Inflammatory diseases such as asthma, rheumatoid arthri-tis, and hepatitis are a major cause of morbidity in humans.Reports on chronic inflammation indicate that it can lead tothe development of cancer as well as cardiovascular and neu-rodegenerative diseases [36–38]. The rate of conversion ofarachidonic acid into prostanoids depends on the availabilityof two COX enzymes, COX-1 and COX-2 [39]. COX-1 con-verts arachidonic acid into PGs. PGs are potent vasodilatorsthat control almost all aspects of the gastric mucosal defenseand healing. Inhibition of COX-1 and PG synthesis has beenshown to cause serious GI damage [15]. It has been previ-ously reported that the GI toxicity of NSAIDs in rats resultsfrom a combination of the inhibition of COX-1 and the stim-ulation of COX-2 production in gastric mucosal lesions [40].Furthermore, increased COX-2 gene expression is commonlyassociated with inflammatory responses [41].

2.3 NSAIDs induce apoptosis in the GI mucosa

GI ulcer formation is a multifaceted process that includesROS generation, extracellular matrix degradation, and mito-chondrial damage. Mitochondria play a crucial role in ROShomeostasis and cell survival [42]. Musumba et al. [5] alsoreported that NSAID-induced ROS might also cause GImucosal cell apoptosis by affecting various signaling cas-cades such as those involving Bax, caspase-8, caspase-9, andcaspase-3 activities. Hence, the downregulation of ROS lev-els may be the most important cytoprotective mechanismagainst NSAID-induced GI tissue/cell apoptosis. Therapiesthat effectively target NSAID-induced apoptosis likely re-quire inhibition of both mitochondria- and caspase-mediatedpathways.



Table 1. Models of NSAIDs-caused gastrointestinal ulcers

NSAIDs Animals Dose/inducedmodel

Biological effects Reference

Aspirin SD rats 200 mg/kgb.w./intragastric

COX-2 (↑)cPLA2 (↑)IL-1� (↑)LTB4 (↑)MPO (↑)PGE2 (↓)TNF-� (↑)

[18]

Diclofenac SD rats 80 mg/kgb.w./intragastric

5-LOX (↑)COX-1 mRNA (↓)COX-2 protein (↑)cPLA2 (↑)MPO (↑)

[20]

Indomethacin SD rats 18 and 48 mg/kgb.w./intragastric

Catalase (↓)COX-2 (↑)GST (↓)IL-1� (↑)IL-6 (↑)MDA (↑)MPO (↑)Mucin (↓)PGE2 (↓)SOD (↓)TNF-� (↑)TSH (↓)

[19,35]

Piroxicam Wistar rats 30 mg/kgb.w./intragastric

Catalase (↓)Gastric tissue PGE2 (↓)GSH (↓)Hydroxyl radical (↑)MDA (↑)Serum PGE2 (↓)SOD (↓)TSH (↓)Xanthine oxidase (↑)

[23,24]

Piroxicam Swiss mice 100 mg/kgb.w./intragastric

LTB4 (↑)Mucin content (↓)PGE2 (↓)TNF-� (↑)

[21]

Naproxen SD rats 80 mg/kgb.w./intragastric

Catalase (↓)GPx (↓)MDA (↑)MMP2 (↓)SOD (↓)TNF-� (↑)

[124]

Ketoprofen SD rats 50 mg/kgb.w./intragastric

8-OHdG (↑)Caspase-3 (↑)COX-2 (↑)GPx (↓)GR (↓)GSH (↓)GSH/GSSG (↓)MDA (↑)

[3,22]

cPLA2, cytosolic phospholipases A2; LTB4, leukotriene B4; 5-LOX, 5-lipoxygenase; GST, glutathione S-transferase; TSH, total sulfhydrylgroup; MMP, metalloproteinase.



2.4 Role of angiogenesis in GI mucosal repair

Another method for protecting against NSAID-induced dam-age of the mucosa may be involved in the upregulation of neo-vascularization in the GI tract [25,26,43]. Neovascularization,which is the generation of new capillaries, is tightly controlledand normally occurs during embryonic and postembryonicdevelopment, the reproductive cycle, and wound repair [43].Reports indicate that against NSAID-induced damage of pep-tic ulcers may involve the upregulation of neovasculariza-tion in the GI mucosa [25, 26]. An effective approach for theremedy of stomach ulcers might be through enhancement ofstomach epithelial cell migration [44]. Angiogenic growth fac-tors, such as fibroblast growth factors , transforming growthfactor-alpha (TGF-�), trefoil factors, hepatocyte growth factor,basic fibroblast growth factor, platelet-derived growth factor,TGF-�, and vascular endothelial growth are the most impor-tant factors in GI mucosal reconstruction, mucosal defense,and ulcer healing [43–45]. Deng et al. [43] indicated that anincrease in angiostatin or endostatin (an endogenous angio-genesis inhibitor) plays a pathologic role in impaired anddelayed healing of intestinal mucosal ulcers. These resultssuggest that angiogenesis serves as a barrier against NSAID-induced GI mucosal damage and can help mucosal repair.

3 Gastroprotective effects ofphytochemicals and their underlyingmechanisms

NSAIDs, including aspirin, diclofenac, indomethacin,naproxen, and ketoprofen, are all available to control theacute and chronic pain of rheumatoid arthritis, and theiranti-inflammatory effects alleviate swelling; however, theiruse could cause oxidative injury of the GI mucosa in clinicalmedicine [6,41]. Reports indicate that NSAID-induced pepticulcers are associated with oxidative stress and apoptosis. Theappearance of LPO and oxidative damage in the GI mucosa iscorrelated with intestinal diseases, chronic intestinal inflam-mation, or ulcers [8]. These results suggest that GI ulcersinduced by NSAIDs result from the induction of oxidativestress and/or the reduction of antioxidant enzymes.

Nuclear factor erythroid 2 related factor 2 (Nrf2), which isa vital transcription factor, binds to an antioxidant responseelement in the promoter regions of genes encoding sev-eral antioxidant and detoxifying enzymes and related stress-responsive proteins [46]. Nrf2 elicits rescue pathways thatprotect cells against oxidative damage, abnormal immune re-sponses, abnormal inflammation, apoptosis, and carcinogen-esis [47, 48]. Under normal conditions, Nrf2 is inactive andis bound in the cytosol by Kelch-like ECH-associated protein1 (Keap1). Stimuli of the cytoplasmic Keap1 protein, includ-ing antioxidants, oxidants, chemopreventive agents, and elec-trophilic agents, that possess the ability to modify thiol groupsand release Nrf2 from Keap1 allow Nrf2 to translocate intothe nucleus and bind to the antioxidant response element.

Nrf2 regulates antioxidant and phase II detoxification en-zymes such as NAD(P)H:quinone acceptor oxidoreductase 1,SOD, catalase, GPx, GR, and HO-1 [49].

GPx, HO-1, and SOD are important antioxidant enzymesfor the elimination of ROS and RCS, and they can act as metalion chelators in the human body [32–34]. The GI isoenzyme-GPx is the main gastric enzyme, which serves as a barrieragainst hydroperoxide [29]. HO-1 protects GI cells against ox-idative damage through the breakdown of heme to biliverdinand carbon monoxide [32] and suppresses inflammation andtissue damage by ROS induction in the stomach and intes-tine [33]. Hence, the upregulation of antioxidant enzymesby Nrf2 may be related to the prevention of NSAID-inducedGI ulcers. Phytochemicals, such as sulforaphane, catechin,and caffeic acid, effectively prevent the NSAID-induced in-jury of intestinal epithelial cells by upregulating Nrf2/HO-1signaling pathways [3,22,50]. Hence, the upregulation of an-tioxidant enzymes by Nrf2 may be related to the preventionof NSAID-induced GI ulcers.

Recent reports have suggested that cytosolic Nrf2 becomesunstable without DJ-1 (also referred to as PARK7), and the re-sponses of Nrf2-regulated downstream antioxidant enzymesare attenuated [51, 52]. Early-onset Parkinson’s disease andneurodegenerative disorders have been linked to pathogenicmutations in DJ-1 [53]. Taira et al. [54] indicated that upreg-ulation of DJ-1 prevented neuroblastoma cell death due tooxidative stress in Parkinson’s disease. Previous reports indi-cated that catechin effectively prevented ketoprofen-inducedoxidative damage by the upregulation of HO-1 in Int-407 cells,which might play a key role in the prevention of NSAID-induced mucosal damage [3]. Cheng et al. [22] also showedthat caffeic acid effectively prevented ketoprofen-induced ox-idative damage to the GI cells by inducing the expressionof antioxidant enzymes and through the DJ-1/Nrf2-mediatedprocess. These results indicate that increasing antioxidant en-zyme expression by Nrf2 might represent a potential curativeapproach to protect patients against oxidative stress relateddevelopment of GI mucosal ulcers. Importantly, it is docu-mented that dietary foods may be effective against GI ulcersby the upregulation of antioxidant enzymes and the down-regulation of oxidative stress [55].

Aspirin and other NSAIDs, such as indomethacin anddiclofenac, are commonly used for treating pain and in-flammation [56, 57]. Leung et al. [56] indicated that aspirinwith caspase inhibitors causes gastric mucosal cell deaththrough a caspase-independent pathway that is indicativeof apoptosis-like programmed cell death. Liu et al. [58]also showed that indomethacin induced oxidative damageto the GI mucosa by downregulating heat shock protein-70 (HSP70) and Bax protein expression instead of sup-pressing the Bcl-2 level in gastric tissue. Epidemiologicstudies indicate that 75 mg/day body weight (b.w.) of di-clofenac treatment increased DNA damage (8-OHdG pro-duction) and decreased HSP70 and caspase-3 expression inthe gastric mucosa of humans [58]. It was suggested thatthe gastroprotective effects of natural antioxidants were due



to the improvement of antioxidative status, activation ofCOX-mediated PGE2 synthesis, and downregulation of theBax level, as well as upregulation of Bcl-2 and HSP70 pro-teins [58]. Proton pump inhibitors, including lansoprazole,are widely used to treat duodenal and gastric ulcers [59].Some studies have indicated that lansoprazole can reversethe effects of NSAIDs (diclofenac, indomethacin, ketopro-fen, and piroxicam) on the mucosal content of LPO prod-ucts (MDA) and myeloperoxidase (MPO) via upregulationof antioxidant enzymes [59–61]. In addition, the heat shockresponse exhibits defense machinery, and its associated reg-ulatory signals or heat shock proteins are involved in GI pro-tection. HO-1 is known as HSP32 and can be stimulatedduring pathological conditions and oxidative stress [62, 63].Recent evidence indicates that HO-1 breaks down heme tobiliverdin and carbon monoxide, has antioxidant effects, andcan mitigate inflammation, control cell growth, and elimi-nate cell death [32]. The upregulation of HO-1 expressionreduces inflammation and tissue damage caused by ROS inthe GI tract [41]. Megias et al. [64] indicated that HO-1 mod-ulated PGE2 production in osteoarthritic chondrocytes. PGscan maintain GI mucosal integrity, control most gastric mu-cosal defenses, and resolve inflammation [25,65]. Hence, up-regulation of antioxidant enzymes, especially HO-1, shouldbe an effective prevention or curative intervention strategyagainst oxidative stress induced GI damage leading to an ulcerdisease.

A recently published report indicates that dairy prod-ucts with certain probiotics, such as Lactobacillus and Bifi-dobacterium, exhibit prevention against NSAIDs, alcohol, andH. pylori induced GI ulcers and possess antioxidant, anti-apoptotic, anti-inflammatory, and antibacterial activity [66].Moreover, probiotics can accelerate mucosa repair and help tomaintain mucosal health via induction of angiogenic growthfactors by H. pylori [66]. Similarly, a large amount of evi-dence has demonstrated that phytochemicals possess bioac-tivity and potential health benefits. Some reports indicatedthat dietary phenolic compounds (curcumin, mangiferin,and �-myrcene), phenolic acids (caffeic acid and ellagicacid), flavan-3-ols (catechin and (−)-epigallocatechin-3-gallate[EGCG]), flavonols (quercetin and morin), flavonoids (resver-atrol and pogostone), gingerols (6-gingerol and 6-shogaol),carotenes (lycopene and �-carotene), and organosulfur(s-allyl cysteine) possess multiple bioactivity and potentialhealth benefits, such as antioxidant, anti-inflammatory, andantibacterial benefits, and they can prevent digestive diseaseprocesses [35,47,67–70]. In addition, some of the most bene-ficial phytochemicals also appear to increase antioxidant en-zymes, mucosal defense, and the capacity to heal ulcers viaupregulation of the Nrf2 signaling pathway, which may aidmucosal repair [3,22,46,47,71–75]. These results suggest thatNrf2 expression induced by phytochemicals/pharmacologicalmodulators may be a novel means of increasing GI protec-tion. In this review, we summarize the actions of phyto-chemicals and their related mechanisms are also discussed inTable 2.

3.1 Phenolic compounds (curcumin, mangiferin, and

�-myrcene)

3.1.1 Curcumin

Curcumin is a dietary pigment in turmeric (popularly called“curry powder”) and is widely used as a spice and color-ing agent in food [76]. Curcumin possesses multiple healthbenefits and might be a highly efficient antioxidant forthe GI tract [77, 78]. He et al. [79] indicated that orallyadministrated (p.o.) with 20 mg/kg b.w. curcumin for 7days downregulated the acetylation of histone H3 at thesite of the H+ and K+–ATPase gene promoters inducedby water immersion-restraint stress for 4 h. Thong-Ngamet al. [67] indicated that oral administration of curcumin at200 mg/kg b.w. for 30 min decreased the oxidative dam-age to the gastric mucosa, the inflammatory cytokine TNF-�,and leukocyte adhesion of ICAM-1 that were induced by in-domethacin (150 mg/kg b.w. for 8 h, p.o.) in rats. Theseresults suggest that curcumin has preventive and therapeu-tic effects on gastric ulcers by the modulation of gastric acidsecretions and through its antioxidant and anti-inflammatorycapabilities.

3.1.2 Mangiferin

Mangiferin is a natural phenolic glucosylxanthone fromMangifera indica L. (Anacardiaceae) [46, 80]. Reports indi-cate that mangiferin might have highly efficient antioxidant,antimicrobial, antidiabetes, anti-inflammatory, antitumori-genic, and antiulcer activities [80, 81]. Sahoo et al. [81] in-dicated that mangiferin (10 �g/mL) can inhibit TNF-inducedLPO and increase catalase activity, which thereby inhib-ited apoptosis in U937 and HepG2 cell lines. Mangiferin(30 mg/kg b.w. for 3 days, p.o.) has proven to have antigastricacid secretory and antioxidant gastroprotective effects againstabsolute ethanol (96%, 0.2 mL for 30 min) or indomethacin(30 mg/kg b.w. for 8 h) induced gastric ulcers [2, 46]. Mech-anistic studies revealed that mangiferin (10 mg/kg b.w. for3 days, p.o.) stimulation increased PPAR�, nuclear Nrf2, andtotal HO-1 protein expression but decreased the inductionof nuclear NF-�B in the gastric mucosa of rats treated withischemia/reperfusion [46]. These results imply a protectiveeffect of mangiferin on GI ulcers.

3.1.3 �-Myrcene

�-Myrcene (7-methyl-3-methylene-1,6-octadiene) is a com-mon antioxidant found in lemongrass, hops, and verbena andis widely used in cosmetics [82]. Moraes et al. [82] indicatedthat Citrus aurantium and its major compound, �-myrcene,provided significant gastric protection against absolute al-cohol and indomethacin-induced mucosal oxidative injury.Bonamin et al. [83] showed that intragastrically administrated


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g/k

gb

.w.f

or

30m

in,f

ollo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

(50

mg

/kg

b.w

.fo

r6

h,

i.g.)

.

�-M

yrce

ne

cou

ldd

ecre

ase

ind

om

eth

acin

(50

mg

/kg

b.w

.)in

du

ced

-oxi

dat

ive

dam

age

toth

ega

stri

cm

uco

saan

dp

reve

nt

the

dep

leti

on

of

GP

x,G

R,G

SH

,an

dN

Ole

vels

,an

dsu

lfhy

dry

lgro

up

s.

[83]

Ph

en

olic

acid

s

Caf

feic

acid

Hu

man

inte

stin

alIn

t-40

7ce

llsw

ere

trea

ted

wit

hca

ffei

cac

idat

50�

Mfo

r1–

4h

.S

Dra

tsw

aso

rally

adm

inis

trat

edw

ith

caff

eic

acid

at12

0m

g/k

gb

.w.f

or

21d

ays,

follo

wed

by

trea

tmen

tw

ith

keto

pro

fen

(50

mg

/kg

b.w

.fo

r1

day

,i.g

.).

Up

reg

ula

tio

no

fG

Px,

GR

,an

d�-G

CS

anti

oxid

ant

enzy

me

mR

NA

exp

ress

ion

by

DJ-

1/N

rf2

sig

nal

ing

pat

hw

ayin

Int-

407

cells

.D

ow

nre

gu

lati

on

of

MD

A,L

DH

leak

age,

CO

X-2

,NO

,an

d8-

OH

dG

inS

Dra

tsin

du

ced

by

keto

pro

fen

.

[22]


1600659 (8 of 19) Y.-T. Cheng et al. Mol. Nutr. Food Res. 61, 6, 2017, 1600659Ta

ble

2.

Co

nti

nu

ed

Str

uct

ure

Trea

tmen

tM

ech

anis

mR

efer

ence

Ella

gic

acid

Sw

iss

alb

ino

mic

ew

ere

ora

llyad

min

istr

ated

wit

hin

do

met

hac

in(1

8m

g/k

gb

.w,s

ing

led

ose

),fo

llow

edb

ytr

eatm

ent

wit

hel

lag

icac

idat

7m

g/k

gb

.w.f

or

3d

ays.

Ella

gic

acid

cou

ldin

hib

itlip

idp

erox

idat

ion

,TN

F-�

,an

dIL

-1�

exp

ress

ion

and

incr

ease

the

exp

ress

ion

of

IL-4

,EG

F,an

dH

GF

inth

ega

stri

cti

ssu

ein

du

ced

by

ind

om

eth

acin

.

[91]

Bal

b/C

mic

ew

ere

trea

ted

wit

h5%

dex

tran

sulf

ate

sod

ium

and

2%el

lag

icac

id(i

nd

rin

kin

gw

ater

)fo

r7

day

s.

Ella

gic

acid

sho

wed

sig

nifi

can

tp

rote

ctio

no

fth

eco

lon

icm

uco

sain

dex

tran

sulf

ate

sod

ium

ind

uce

du

lcer

ativ

eco

litis

inm

ice

and

red

uce

dth

eg

ross

mu

cosa

ldam

age

by

do

wn

reg

ula

tin

gC

OX

-2,i

NO

S,

and

thei

rre

late

dsi

gn

alin

gp

ath

way

s,su

chas

p38

MA

PK

,N

F-�B

,an

dth

esi

gn

altr

ansd

uce

rS

TAT

3w

asal

sob

lock

ed.

[94]

Fla

van

-3-o

l

Cat

ech

inH

um

anin

test

inal

Int-

407

cells

wer

etr

eate

dw

ith

caff

eic

acid

at10

0�

Mfo

r1–

4h

.S

Dra

tsw

ere

ora

llyad

min

istr

ated

wit

hca

tech

inat

35m

g/k

gb

.w.f

or

21d

ays,

follo

wed

by

trea

tmen

tw

ith

keto

pro

fen

(50

mg

/kg

b.w

.fo

r1

day

,i.g

.).

Up

reg

ula

tio

no

fG

Px,

GR

,an

dH

O-1

anti

oxid

ant

enzy

me

by

Nrf

2in

Int-

407

cells

.D

ow

nre

gu

lati

on

of

MD

A,L

DH

leak

age,

and

8-O

Hd

Gin

SD

rats

ind

uce

db

yke

top

rofe

n.

[3]

BA

LB/c

mic

ew

ere

trea

ted

wit

h0.

5m

LH

.p

ylo

rib

acte

rial

susp

ensi

on

(1011

bac

teri

a/L,

i.g.f

or

7d

ays)

,fo

llow

edb

ytr

eatm

ent

wit

hca

tech

inat

320

�g

/0.5

mL

for

7–14

day

s(p

.o.)

.

Cat

ech

ins

hav

esh

ow

np

ote

nti

alan

ti-H

.pyl

ori

acti

vati

on

and

red

uce

du

lcer

atio

nb

yd

ow

nre

gu

lati

ng

the

infl

amm

aso

me/

casp

ase-

1p

ath

way

inm

ice.

[97]

SD

rats

wer

eo

rally

adm

inis

trat

edw

ith

cate

chin

at10

0m

g/k

gb

.w.f

or

30m

in,

follo

wed

by

trea

tmen

tw

ith

1m

LH

Cl-

eth

ano

lso

luti

on

for

1h

(i.g

.).

Cat

ech

insi

gn

ifica

ntl

yin

crea

sed

the

mu

cus

con

ten

tin

SD

rats

.[9

5]

SD

rats

wer

etr

eate

dis

chem

ia/r

eper

fusi

on

(I/R

)fo

r1

h,

follo

wed

by

trea

tmen

tw

ith

cate

chin

at50

mg

/kg

b.w

.fo

r3

day

s(p

.o.)

.

Cat

ech

insi

gn

ifica

ntl

yin

crea

sed

the

leve

lof

cata

lase

and

dec

reas

edth

eox

idat

ive

stre

ssin

rats

that

was

ind

uce

db

yp

ylo

rus

ligat

ure

.

[98]

Fou

rca

tech

ins,

(+)-

cate

chin

,(–

)-ep

icat

ech

in,(

–)-e

pic

atec

hin

galla

te,

and

(–)-

epig

allo

cate

chin

wer

ed

isso

lved

ind

imet

hyls

ulf

oxid

e,an

dth

ein

hib

itio

no

fga

stri

cen

zym

eac

tive

sw

ere

anal

yzed

by

H+

and

K+ -

AT

Pase

,wh

ich

wer

ep

rep

ared

fro

mh

og

sst

om

ach

.

Cat

ech

in(1

70�

M),

epic

atec

hin

(47

�M

),E

CG

(93

�M

),an

dEG

C(0

.11

�M

)co

uld

inh

ibit

50%

acti

vity

of

gast

ric

H+

and

K+ -

AT

Pase

.

[101

]



Ta

ble

2.

Co

nti

nu

ed

Str

uct

ure

Trea

tmen

tM

ech

anis

mR

efer

ence

EGC

GS

wis

sal

bin

om

ice

wer

eo

rally

adm

inis

trat

edw

ith

EGC

Gat

2m

g/k

gb

.w.f

or

3d

ays,

follo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

(18

mg

/kg

b.w

.fo

r4

h,p

.o.)

.

EGC

Gco

uld

dec

reas

ein

do

met

hac

in-i

nd

uce

dga

stri

cm

uco

salo

xid

ativ

ed

amag

ean

dp

reve

nt

the

red

uct

ion

of

PG

syn

thes

isin

the

gast

ric

tiss

ues

of

mic

e.

[99]

EGC

Gw

asd

isso

lved

ind

imet

hyls

ulf

oxid

e,an

dth

ein

hib

itio

no

fga

stri

cen

zym

eac

tive

sw

asan

alyz

edb

yH

+an

dK

+ -A

TPa

se,w

hic

hw

ere

pre

par

edfr

om

ho

gs

sto

mac

h.

EGC

G(0

.069

�M

)co

uld

inh

ibit

50%

acti

vity

of

gast

ric

H+

and

K+ -

AT

Pase

.

[101

]

Fla

vo

no

ls

Qu

erce

tin

Alb

ino

rats

wer

etr

eate

dw

ith

ind

om

eth

acin

50m

g/k

gb

.w.f

or

2d

ays

(p.o

.),f

ollo

wed

by

ora

lad

min

istr

atio

no

fq

uer

ceti

nat

50m

g/k

gb

.w.f

or

15d

ays.

Do

wn

reg

ula

tio

no

fLP

Oan

dM

PO

,an

du

pre

gu

lati

on

of

GS

H,S

OD

,an

dca

tala

sein

Alb

ino

rats

ind

uce

db

yin

do

met

hac

in.

[73]

Qu

erce

tin

was

dis

solv

edin

dim

ethy

lsu

lfox

ide,

and

the

inh

ibit

ion

of

gast

ric

enzy

me

acti

ves

was

anal

yzed

by

H+

and

K+ -

AT

Pase

,wh

ich

wer

ep

rep

ared

fro

mh

og

sst

om

ach

.

Qu

erce

tin

(IC

50va

lue

of

2.3

�M

)in

hib

ited

the

leve

lof

ph

osp

ho

-ry

late

den

zym

eb

yco

mp

etit

ion

wit

hA

TP,

wh

ich

cou

ldin

hib

itth

eH

+an

dK

+ -A

TPa

seac

tivi

ty.

[104

]

Hu

man

Co

co-2

cells

wer

etr

eate

dw

ith

ind

om

eth

acin

(250

or

500

�M

)al

on

eo

rin

the

pre

sen

ceo

fq

uer

ceti

nat

10�

g/m

L.

Qu

erce

tin

agai

nst

ind

om

eth

acin

-in

du

ced

NF-

�B

and

IL-8

exp

ress

ion

sin

Co

ca-2

cells

thro

ug

hm

od

ula

tin

go

fN

rf2

tran

slo

cati

on

.

[105

]

SD

rats

wer

eo

rally

adm

inis

trat

edw

ith

qu

erce

tin

at50

mg

/kg

b.w

.fo

r30

min

,fo

llow

edb

ytr

eatm

ent

wit

hin

do

met

hac

inat

40m

g/k

gb

.w.f

or

4h

(p.o

.).

Inh

ibit

ion

of

ind

om

eth

acin

-cau

sed

ICA

M-1

and

P-s

elec

tin

exp

ress

ion

san

dth

ein

crea

sein

MP

Oac

tivi

tyin

gast

ric

and

ileal

tiss

ues

.

[105

]

Mo

rin

Fem

ale

Wis

tar

rats

wer

eo

rally

adm

inis

trat

edw

ith

mo

rin

(25

mg

/kg

b.w

.)o

rtr

init

rob

enze

nes

ulp

ho

nic

acid

(48

mg

/kg

b.w

.)fo

r1–

4w

eeks

.

Mo

rin

sig

nifi

can

tly

red

uce

dth

ele

vels

of

leu

kotr

ien

eB

4an

dIL

-1�

,ox

idat

ive

stre

ss,a

nd

NO

exp

ress

ion

inra

tsw

ith

chro

nic

exp

erim

enta

lco

litis

.

[112

]



Ta

ble

2.

Co

nti

nu

ed

Str

uct

ure

Trea

tmen

tM

ech

anis

mR

efer

ence

SD

rats

wer

etr

eate

dw

ith

mo

rin

at50

mg

/kg

b.w

.fo

r30

min

(p.o

.),f

ollo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

at48

mg

/kg

b.w

.fo

r4

h(p

.o.)

.

Mo

rin

pro

tect

sag

ain

stin

do

met

hac

inin

du

ced

-gas

tric

mu

cosa

dam

age

by

do

wn

reg

ula

tio

no

fM

PO

,NF-

�B

,T

NF-

�,M

CP

-1,i

NO

S,I

CA

M-1

,IL-

6,ca

spas

e-3,

and

up

reg

ula

tio

no

fP

GE

2,S

OD

,GS

Tin

the

gast

ric

mu

cosa

.

[35]

Fla

vo

no

ids

Res

vera

tro

lS

Dra

tsw

ere

trea

ted

wit

hre

sver

atro

l(1

00�

mo

l/Lfo

r15

min

,p.o

.),f

ollo

wed

ulc

erin

du

ced

by

isch

emia

for

2h

,an

dre

per

fusi

on

for

4h

.

Res

vera

tro

lco

uld

incr

ease

Na+

-K+ -

AT

Pase

and

Ca2+

-AT

Pase

acti

vity

,an

dth

ele

vels

of

Bcl

-2an

dS

OD

exp

ress

ion

,bu

tit

do

wn

reg

ula

ted

MD

Aan

dLD

Hle

vels

,cas

pas

e-3

acti

vity

,an

dB

axex

pre

ssio

nin

the

gast

ric

mu

cosa

ind

uce

db

yis

chem

ia/r

eper

fusi

on

.

[115

]

Sw

iss

alb

ino

mic

ew

ere

trea

ted

wit

hre

sver

atro

lat2

mg

/kg

b.w

.fo

r4–

7d

ays

(p.o

.),f

ollo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

(18

mg

/kg

b.w

.,si

ng

leo

rald

ose

).

Trea

tmen

tw

ith

resv

erat

rolc

ou

ldin

hib

iteN

OS

exp

ress

ion

inth

ega

stri

cti

ssu

ein

du

ced

by

ind

om

eth

acin

.

[71]

Ku

nm

ing

mic

ew

ere

ora

llyin

ocu

late

d10

8

CFU

H.p

ylo

rifo

r1

wee

k,fo

llow

edtr

eate

dw

ith

resv

erat

rola

t10

0m

g/k

gb

.w.f

or

6w

eeks

(p.o

.).

Trea

tmen

tw

ith

resv

erat

rolc

ou

ldag

ain

stH

.pyl

ori

ind

uce

dIL

-8,i

NO

S,

and

NF-

�B

exp

ress

ion

by

acti

vati

on

of

the

Nrf

2/H

O-1

pat

hw

ay.

[75]

Pog

ost

on

eS

Dra

tsw

ere

trea

ted

wit

hp

og

ost

on

eat

40m

g/k

gb

.w.f

or

7d

ays

(i.g

.),f

ollo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

(50

mg

/kg

b.w

.,fo

r1

h,i

.g.)

.

Th

ep

rom

oti

on

of

CO

X-m

edia

ted

PG

E2

and

cellu

lar

anti

oxid

ant

mec

han

ism

by

incr

easi

ng

gast

ric

SO

D,C

AT,

and

GS

Hle

vels

asw

ell

asd

ecre

asin

glip

idp

erox

idat

ion

and

mu

cosa

lap

op

tosi

so

fH

SP

70ac

tiva

tio

naf

ter

ind

uce

db

yin

do

met

hac

in.

[72]

Gin

gero

ls

6-G

ing

ero

lW

ista

rra

tsw

ere

ora

lad

min

istr

atio

no

f6-

gin

ger

ol(

2m

g/k

gb

.w.)

wit

has

pir

in(2

00m

g/k

gb

.w)

for

4h

.

Trea

tmen

to

f6-

gin

ger

olc

ou

ldre

du

ceth

ein

cid

ence

of

mu

cosa

lesi

on

san

dle

vels

of

infl

amm

ato

rycy

toki

ne,

such

asiN

OS

,TN

F-�

,an

dIL

-1�

inth

ega

stri

cm

uco

sa.

[69]



Ta

ble

2.

Co

nti

nu

ed

Str

uct

ure

Trea

tmen

tM

ech

anis

mR

efer

ence

6-S

ho

gao

lW

ista

rra

tsw

ere

ora

lad

min

istr

atio

no

f6-

sho

gao

l(1

mg

/kg

b.w

.)w

ith

asp

irin

(200

mg

/kg

b.w

)fo

r4

h.

6-S

ho

gao

lco

uld

inh

ibit

iNO

S,T

NF-

�,

and

IL-1

�ex

pre

ssio

nin

the

gast

ric

mu

cosa

ind

uce

db

yas

pir

in(2

00m

g/k

gb

.w.)

.

[69]

Caro

ten

es

Lyco

pen

eW

ista

rra

tsw

ere

trea

ted

wit

hly

cop

ene

(100

mg

/kg

b.w

.fo

r5

min

,p.o

.),

follo

wed

by

trea

tmen

tw

ith

ind

om

eth

acin

(25

mg

/kg

b.w

.fo

r6

h,

p.o

.).

Trea

tmen

to

fly

cop

ene

pri

or

toth

ead

min

istr

atio

no

fin

do

met

hac

in(2

5m

g/k

gb

.w.)

red

uce

dth

ein

cid

ence

of

mu

cosa

lesi

on

san

dle

vels

of

oxid

ativ

est

ress

,su

chas

MD

Aan

dM

PO

inga

stri

cm

uco

sal.

Lyco

pen

eco

uld

enh

ance

SO

D,c

atal

ase,

and

GS

Hex

pre

ssio

nin

the

gast

ric

tiss

ue

ind

uce

db

yin

do

met

hac

in.

[70]

�-C

aro

ten

eW

ista

rra

tsw

ere

trea

ted

wit

h�

-car

ote

ne

(30

or

60m

g/k

gb

.w.f

or

5d

ays,

i.p),

follo

wed

ulc

erin

du

ced

by

isch

emia

for

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(i.g.) with 7.5 mg/kg b.w. �-myrcene for 30 min could reduceindomethacin-induced (50 mg/kg b.w. for 6 h, i.g.) oxidativedamage to the gastric mucosa and prevent the depletion ofGPx, GR, GSH, NO, and sulfhydryl groups.

3.2 Phenolic acids (caffeic acid and ellagic acid)

3.2.1 Caffeic acid

Caffeic acid and protocatechuic acid (PCA) are common phy-tochemical compounds found in fruits, vegetables, grains,and traditional Chinese herbs that possess many beneficialeffects, including anticancer, antioxidant, antihypertension,and anti-inflammatory effects [84–87]. Vitaglione et al. [85]indicated that in humans, PCA is primarily produced as ametabolite of anthocyanins. The report indicated that the fateof anthocyanins in humans was that less than 1% of intakewas absorbed. Oral administration of PCA has shown highbioavailability and bioefficacy in rats [85], which might mod-erately decrease the oxidative stress in the GI tract. However,this hypothesis may require more evidence. Similarly, caffeicacid was distributed to the plasma in an intact form becauseof its easy absorption in the small intestinal mucosa [88, 89].Therefore, it is more suitable for investigating GI protection.Cheng et al. [22] reported that caffeic acid at 50 �M for 1–4 hstrongly induced GPx activity in Int-407 cells, which sug-gests that caffeic acid is important in preventing GI oxida-tive damage. Caffeic acid also attenuated excessive COX-2protein expression and NO generation in lipopolysaccharide-induced RAW 264.7 cells, which suggests that caffeic acidprevents a form of inflammation-associated GI damage [90].Moreover, the pretreatment of caffeic acid at 120 mg/kg b.w.for 21 days (p.o.) effectively inhibited ketoprofen-induced(50 mg/kg b.w. for 1 day, p.o.) oxidative damage of theGI mucosa by inducing the expression of antioxidant en-zymes and modulating the DJ-1/Nrf2 pathway [22]. There-fore, caffeic acid is a potential curative compound that canbe used for treating GI mucosal injuries caused by oxidativestress.

3.2.2 Ellagic acid

Ellagic acid (2,3,7,8-tetrahydroxy[1] benzopyrano[5,4,3-cde][1]benzopyran-5,10-dione) is one of the naturally occurringpolyphenols found in cranberries, Indian gooseberries,pecans, pomegranates, raspberries, strawberries, walnuts,and other plant foods and is found mainly in the form ofellagitannins [91]. Some reports have indicated the antipro-liferative and antioxidant activities of ellagic acid in vitro andin vivo [92]. Ellagic acid has been shown to exert a potentscavenging effect on both hydroxy anions and superoxideanions. Moreover, the rats were orally administrated withellagic acid (7 mg/kg b.w., p.o.) for 3 days could inhibitLPO, TNF-�, and IL-1� expression, and increased the ex-

pression of IL-4, EGF, and hepatocyte growth factor in gas-tric tissue induced by indomethacin (18 mg/kg b.w., singledose, p.o.) [91, 93]. Moreover, diets supplemented with 2%ellagic acid for 7 days showed significant protection of thecolonic mucosa in dextran sulfate sodium induced (1 and5% DSS) ulcerative colitis in mice and reduced the grossmucosal damage by downregulating COX-2, inducible ni-tric oxide synthase (iNOS), and their related signaling path-ways, such as p38 MAPK, NF-�B, and the signal transducerand activator of transcription 3 (STAT3) was also blocked[94].

3.3 Flavan-3-ol (catechin and EGCG)

Catechin derivatives, such as EGCG, (−)-epigallocatechin,(−)-epicatechin-3-gallate, and (−)-epicatechin, have beenwidely investigated and provide a potential therapeutic ap-proach for oxidative stress associated GI ulcer diseases [3,95].EGCG and catechins are stable under acidic conditions andmay be more suitable for studying GI protection [96]. More-over, these catechins at 320 �g/0.5 mL for 7 days (p.o.) haveshown potential anti-H. pylori activation and reduced ulcer-ation by downregulating the inflammasome/caspase-1 path-way in mice [97]. Jung et al. [95] indicated that pretreatmentwith catechin at 100 mg/kg b.w. for 30 min followed by HCl-ethanol for 1 h significantly increased the mucus content inrats. Rao et al. [98] demonstrated that catechin at 50 mg/kgb.w. for 3 days significantly increased the level of catalase anddecreased the oxidative stress in rats that was induced by py-lorus ligature. Cheng et al. [3] showed that supplementationwith catechin (100 �M for 1–4 h) appeared to increase theantioxidant capacity of Int-407 cells, not only through its ownnatural antioxidant activity, but also by stimulating the expres-sion of antioxidants and detoxifying enzymes such as HO-1[3]. Pretreatment of SD rats with catechin (35 mg/kg b.w. for21 days) could decrease ketoprofen-induced (50 mg/kg b.w.for 1 day) gastric mucosal oxidative damage and could pre-vent the reduction of GPx, GRd antioxidant enzymes, and theGSH/GSSG ratio in the intestinal mucosa [3]. Similarly, oraladministration of EGCG (2 mg/kg b.w. for 3 days) could de-crease indomethacin-induced (18 mg/kg b.w. for 4 h) gastricmucosal oxidative damage and prevented the reduction of PGsynthesis in the gastric tissues of mice [99]. The administra-tion of EGCG at 40 and 80 mg/kg/day for 6 days reducedthe formation of cholesterol gallstones in a dose-dependentmanner in a C57BL/6 mouse model by downregulating theactivity of NF-�B and upregulating the activity of PPAR�

[100]. Furthermore, catechin (170 �M), epicatechin (47�M), (−)-epicatechin-3-gallate (93 �M), (−)-epigallocatechin(0.11 �M), and EGCG (0.069 �M) could inhibit 50% activ-ity of gastric H+, K+-ATPase, and EGCG and showed themost inhibitory activity in vitro [101]. These findings suggestthat the antisecretory and antiulcerogenic effects of catechinsare due to their inhibitory activity on gastric H+ and K+−

ATPase.



3.4 Flavonols (quercetin and morin)

3.4.1 Quercetin

Quercetin (3,5,7,3′,4′-pentahydroxy flavone) is a flavonewidely found in fruits and vegetables that has health-promoting and disease-preventing activity [13]. The dailyintake of this phenolic compound is approximately 5–40mg/day in a healthy diet [102]. Quercetin is one of the mostpotent scavengers of free radicals and is more active thanthe well-known antioxidant vitamins C and E. Its antioxi-dant and anti-inflammatory activities are contributing fac-tors to its therapeutic efficacy for peptic ulcers [102, 103].Abourehab et al. [73] indicated that the oral administration ofquercetin at 50 mg/kg b.w for 15 days significantly downreg-ulated the levels of LPO and MPO but upregulated the levelsof GSH, SOD, and catalase in Albino rats treated with in-domethacin (30 mg/kg b.w. for 2 days, p.o.). Murakami et al.[104] indicated that quercetin (IC50 value of 2.3 �M) inhib-ited the levels of phosphorylated enzyme by competition withATP, which could inhibit the H+ and K+–ATPase activity invitro. Carrasco-Pozo et al. [105] demonstrated that quercetin(10 �g/mL) against indomethacin (250 or 500 �M) inducedinflammation of NF-�B and IL-8 expressions in Coca-2cells through modulating of Nrf2 translocation. Moreover,quercetin (50 mg/kg b.w. for 30 min, p.o.) could inhibit in-domethacin (40 mg/kg b.w. for 4 h, p.o.)-induced ICAM-1and P-selectin expressions and MPO activity in gastric andileal tissue [105].

3.4.2 Morin

Morin (2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one) is found in guava (Psidium guajava), almond(Prunus dulcis), old fustic (Maclura tinctoria), and osage or-ange (Maclura pomifera) [106, 107]. It possesses many ben-eficial characteristics and might be a highly efficient an-tioxidant, anti-inflammatory, and xanthine oxidase inhibitoryagent [108–111]. Galvez et al. [112] indicated that oral ad-ministration of morin (25 mg/kg b.w.) for 4 weeks signif-icantly reduced the levels of leukotriene B4 and IL-1�, ox-idative stress, and NO expression in rats with chronic ex-perimental colitis. Sinha et al. [35] also indicated that ratpretreatment with morin (50 mg/kg b.w. for 30 min, p.o.)protected against indomethacin-induced (48 mg/kg b.w. for4 h) gastric mucosal damage by downregulating MPO, NF-�B,TNF-�, MCP-1, iNOS, ICAM-1, IL-6, and caspase-3, as wellas upregulating PGE2, SOD, and glutathione S-transferasein the gastric mucosa. These findings suggest that morinhas a beneficial anti-inflammatory effect on the intestinalmucosa.

3.5 Flavonoids (resveratrol and pogostone)

3.5.1 Resveratrol

Resveratrol (3,5,4′-trihydroxystilbene), which belongs to thegroup of stilbenes, is a natural polyphenol originally iso-lated from white hellebore and is present in berries, grapes,and peanuts [113, 114]. There are various natural resveratrol-related analogs in plants. The compound 3,5,4′-trimethoxy-trans-stilbene (MR-3) is methoxylated instead of hydroxy-lated at positions 3, 5, and 4′ in resveratrol. The compound3,5,3′,4′,5′-pentamethoxystilbene (MR-5), a methoxy deriva-tive of resveratrol, can be synthesized by artificial methods[114]. Shen et al. [115] indicated that oral administration ofresveratrol at 100 �mol/L for 15 min could increase Na+-K+-ATPase and Ca2+-ATPase activity and the levels of Bcl-2 andSOD expression, but it downregulated MDA and lactate dehy-drogenase levels, caspase-3 activity, and Bax expression in thegastric mucosa induced by ischemia/reperfusion. Dey et al.[71] indicated that rat treatment with resveratrol (2 mg/kgb.w. for 4–7 days, p.o.) inhibited eNOS expression in the gas-tric tissue induced by indomethacin (18 mg/kg b.w., singleoral dose). Zhang et al. [75] also indicated that mice treatedwith resveratrol (100 mg/kg b.w. for 6 weeks) could againstH. pylori (108 CFU)-induced IL-8, iNOS, and NF-�B expres-sions through activation of the Nrf2/HO-1 pathway in gastrictissue.

3.5.2 Pogostone

Pogostemonis Herba is widely used to treat GI diseases withtraditional Chinese herbs, and the major constituent of pogo-stone indicates the occurrence of multiple biological activ-ities such as antioxidant and anti-inflammatory activities[116, 117]. Some reports also indicate that the oral adminis-tration of pogostone was highly absorbed and bioavailable invivo. The mechanisms of pogostone are potentially associatedwith the increase in COX-mediated PGE2 and cellular antiox-idant mechanisms by increasing gastric SOD, catalase, andGSH levels as well as decreasing LPO and mucosal apoptosisand upregulation of HSP70 activation in vivo [72]. Moreover,Chen et al. showed that pogostone (40 mg/kg b.w. for 7 day,i.g.) exerted a gastroprotective effect against indomethacin-induced (50 mg/kg b.w. for 1 h, i.g.) gastric injury in SD rats[72]. These findings suggest that the upregulation of HSPmight work against oxidative stress associated GI ulcers.

3.6 Gingerols (6-gingerol and 6-shogaol)

Ginger (Zingiber officinale), a natural dietary rhizome, iswidely used as a flavoring agent, as a traditional medic-inal herb, and is shown to have multibiological func-tions [118, 119]. Shogaols are dehydrated products of thestructurally related gingerols and are rich in fresh and



Figure 3. The gastroprotectiveeffects of phytochemicals andtheir underlying mechanisms.Phytochemicals, such as phe-nolic compounds (curcumin,mangiferin, and �-myrcene),phenolic acids (caffeic acidand ellagic acid), flavan-3-ols(catechin and EGCG), flavonols(quercetin and morin), flavo-noids (resveratrol and pogo-stone), gingerols (6-gingeroland 6-shogaol), carotenes(lycopene, �-carotene), andorganosulfur (s-allyl cysteine),have been shown to havemultiple biological functions,including antioxidant, anti-inflammatory, antiapoptotic,and angiogenic roles in thegastrointestinal mucosa andagainst NSAID-induced oxida-tive damage.

thermally dried ginger [119,120]. Several potent components,such as gingerols, gingerdiols, shogaols, and paradols, havebeen identified in ginger [120]. Among these, gingerols andshogaols are phenolic compounds with a volatile oil that canbe extracted from ginger root and provide the characteris-tic odor and flavor of ginger [119, 120]. Daily intake of gin-ger (0.25–1 g) contains approximately 1–3% of 6-gingeroland its derivatives in a healthy diet [120]. Moreover, gin-gerols and shogaols have been shown to possess antiox-idative, anti-inflammatory, and anti-carcinogenic properties[119, 120]. Wang et al. [69] reported that the administrationof 6-gingerol (2 mg/kg b.w.) and 6-shogaol (1 mg/kg b.w.) inrats treated with aspirin (200 mg/kg b.w. for 4 h) protectedagainst aspirin-induced peptic ulcers by downregulating in-flammatory cytokines such as iNOS, TNF-�, and IL-1� in thegastric mucosa.

3.7 Carotenes (lycopene and �-carotene)

Lycopene and �-carotene are naturally occurring carotenoidsfound in apricots, guava, papaya, pink grapefruit, tomatoes,and watermelons, and is a highly efficient antioxidant witha singlet oxygen (1O2) and free radical scavenging capacity[121]. Carotenes (lycopene and �-carotene) are the commonphytochemicals that have abundant biological actions andmight be a highly efficient antioxidant for GI tract [78, 122].Boyacioglu et al. [70] indicated that oral administration oflycopene (100 mg/kg b.w. for 5 min, p.o.) significantly de-creased gastric cell apoptosis and the levels of MDA and MPOinduced by indomethacin (25 mg/kg b.w. for 6 h, p.o.). Fur-ther, pretreatment of �-carotene (30 or 60 mg/kg b.w. for5 days, i.p) protected the gastric mucosa against ischemia-reperfusion injury by reducing IL-1�, TNF-�, and TGF-� in



rats [123]. These findings suggest that protective roles of ly-copene and carotene are performed by regulating antioxidantand anti-inflammatory effects in the gastric mucosa.

3.8 Organosulfur (s-allyl cysteine)

S-Allyl cysteine enriched in garlic is one of the naturalorganosulfuric compounds that are beneficial to humanhealth. Recently, s-allyl cysteine has been reported to pos-sess antioxidant and anti-inflammatory effects in vitro andin vivo. Park et al. [68] indicated that s-allyl cysteine (30mg/kg b.w. for 1 h, i.g.) alleviated indomethacin (20 mg/kgb.w. for 24 h) induced gastric mucosal damage by inhibi-tion of COX-2 and upregulation of HO-1 expression. More-over, s-allyl cysteine decreased macrophage infiltration butincreased the mucus secretion and total antioxidant activityin C57BL/6 mice [68]. Choi et al. [18] also indicated that oraladministration of PMK-S005 (a synthetic s-allyl-L-cysteine) at5 mg/kg b.w. for 1 h against NSAIDs, such as aspirin (200mg/kg b.w. for 4 h, i.g.), diclofenac (80 mg/kg b.w. for 4 h,i.g.), and indomethacin (40 mg/kg b.w. for 4 h, i.g.), inducedacute gastric damage by downregulating proinflammatory cy-tokines (cytosolic phospholipases A2, COX-2, and leukotrieneB4) expression, and increasing the synthesis of mucus inrats.

4 Conclusions

Epidemiological reports have shown that increased dietary in-take of phytochemicals are beneficial for GI health. In this re-view, we summarized the protective effects of phytochemicalsand their underlying mechanisms against NSAID-inducedGI ulcers following oxidative stress. The current review con-firms that dietary phytochemicals possess protective effectsand curative potential for peptic ulcers by improving angio-genesis, cytoprotection and re-epithelialization, upregulatingtissue growth factors and PGs, suppressing oxidative damageof the mucosa, increasing endogenous mucosal defensiveagents, and blocking oxidative stress associated gastroduo-denal inflammation and ulceration, as illustrated in Fig. 3.Notably, some of the most beneficial phytochemicals, suchas catechins, caffeic acid, mangiferin, pogostone, quercetin,and resveratrol appear to antiulcer properties through upreg-ulation of Nrf2 signaling pathways, which might play a keyrole to control oxidative stress and prevent cell death for GItract. These results suggest the Nrf2-mediated antioxidant en-zymes expression by phytochemicals/pharmacological mod-ulators, which may be a novel means of increasing GI pro-tection. These updated data confirm the well-established di-verse beneficial biological actions of these phytochemicalsand might support their therapeutic use, as illustrated inTable 2.

This research work was supported in part by the Ministry ofEducation, Taiwan under the ATU plan.

The authors have declared no conflict of interest.

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