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World Journal of
Gastroenterology
World J Gastroenterol 2020 June 28; 26(24): 3318-3516
ISSN 1007-9327 (print)
ISSN 2219-2840 (online)
Published by Baishideng Publishing Group Inc
W J G World Journal of
Gastroenterology
Contents Weekly Volume 26 Number 24 June 28, 2020
OPINION REVIEW
3318 Extended lymphadenectomy in hilar cholangiocarcinoma: What it will bring?
Li J, Zhou MH, Ma WJ, Li FY, Deng YL
REVIEW
3326 Non-invasive tests for the prediction of primary hepatocellular carcinoma
Marasco G, Colecchia A, Silva G, Rossini B, Eusebi LH, Ravaioli F, Dajti E, Alemanni LV, Colecchia L, Renzulli M,
Golfieri R, Festi D
3344 Intestinal Ca2+ absorption revisited: A molecular and clinical approach
Areco VA, Kohan R, Talamoni G, Tolosa de Talamoni NG, Peralta López ME
3365 Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide
pathways
Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N, Momtaz S, Rahimi R, Abdollahi M,
Abdolghaffari AH
3401 Long noncoding RNAs in gastric cancer: From molecular dissection to clinical application
Gao Y, Wang JW, Ren JY, Guo M, Guo CW, Ning SW, Yu S
MINIREVIEWS
3413 Ultrasound liver elastography beyond liver fibrosis assessment
Ferraioli G, Barr RG
3421 Recent progress in pulsed electric field ablation for liver cancer
Liu ZG, Chen XH, Yu ZJ, Lv J, Ren ZG
ORIGINAL ARTICLE
Basic Study
3432 Hepatoprotective effects of Hovenia dulcis seeds against alcoholic liver injury and related mechanisms
investigated via network pharmacology
Meng X, Tang GY, Zhao CN, Liu Q, Xu XY, Cao SY
Retrospective Cohort Study
3447 Comparison of operative link for gastritis assessment, operative link on gastric intestinal metaplasia
assessment, and TAIM stagings among men with atrophic gastritis
Nieminen AA, Kontto J, Puolakkainen P, Virtamo J, Kokkola A
WJG https://www.wjgnet.com
June 28, 2020 Volume 26 Issue 24
I
Contents World Journal of Gastroenterology
Volume 26 Number 24 June 28, 2020
3458 Multiphase computed tomography radiomics of pancreatic intraductal papillary mucinous neoplasms to
predict malignancy
Polk SL, Choi JW, McGettigan MJ, Rose T, Ahmed A, Kim J, Jiang K, Balagurunathan Y, Qi J, Farah PT, Rathi A,
Permuth JB, Jeong D
Retrospective Study
3472 Transjugular intrahepatic portosystemic shunt for pyrrolizidine alkaloid-related hepatic sinusoidal
obstruction syndrome
Zhou CZ, Wang RF, Lv WF, Fu YQ, Cheng DL, Zhu YJ, Hou CL, Ye XJ
Observational Study
3484 Evaluation of characteristics of left-sided colorectal perfusion in elderly patients by angiography
Zhang C, Li A, Luo T, Li Y, Li F, Li J
SYSTEMATIC REVIEWS
3495 Clinical efficacy of the over-the-scope clip device: A systematic review
Bartell N, Bittner K, Kaul V, Kothari TH, Kothari S
WJG https://www.wjgnet.com
June 28, 2020 Volume 26 Issue 24
II
WJG https://www.wjgnet.com III June 28, 2020 Volume 26 Issue 24
World Journal of Gastroenterology
Contents Weekly Volume 26 Number 24 June 28, 2020
ABOUT COVER
Editorial board member of World Journal of Gastroenterology, Dr. Ji is a Distinguished Professor in Shanghai
University of Traditional Chinese medicine, Shanghai, China. Having received his Bachelor degree from Yangzhou
College of medicine in 1991, Dr. Ji undertook his postgraduate training first at Hubei College of Traditional
Chinese medicine, received his Master degree in 1994, and then at Shanghai University of Traditional Chinese
medicine, received his PhD in 1997. He became Chief Physician in the Gastroenterology Division, Longhua
Hospital affiliated to Shanghai University of Traditional Chinese medicine since 2004. His ongoing research
interests are applicating Evidence-based medicine methods to study the effects, and managing the disease-
syndrome pattern establishment of integrative medicine on digestive diseases. Currently, he is the President of the
Shanghai Association for the Study of the Liver with integrative medicine.
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W J G World Journal of
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Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2020 June 28; 26(24): 3365-3400
DOI: 10.3748/wjg.v26.i24.3365 ISSN 1007-9327 (print) ISSN 2219-2840 (online)
REVIEW
Interventions of natural and synthetic agents in inflammatory bowel
disease, modulation of nitric oxide pathways
Aida Kamalian, Masoud Sohrabi Asl, Mahsa Dolatshahi, Khashayar Afshari, Shiva Shamshiri,
Nazanin Momeni Roudsari, Saeideh Momtaz, Roja Rahimi, Mohammad Abdollahi, Amir Hossein Abdolghaffari
ORCID number: Aida Kamalian
(0000-0002-6589-9083); Masoud
Sohrabi Asl (0000-0003-3195-3552);
Mahsa Dolatshahi
(0000-0002-4524-9462); Khashayar
Afshari (0000-0001-9099-7948);
Shiva Shamshiri
(0000-0002-5040-2839); Nazanin
Momeni Roudsari
(0000-0003-1230-7969); Saeideh
Momtaz (0000-0003-3957-3300); Roja
Rahimi (0000-0001-8637-4350);
Mohammad Abdollahi
(0000-0003-0123-1209); Amir
Hossein Abdolghaffari
(0000-0001-9961-9097).
Author contributions: Kamalian A,
Sohrabi Asl M and Afshari K were
involved in the conceptualization,
data collection; Dolatshahi M and
Shamshiri SH performed the data
collection and resources; Momeni
Roudsari N was involved in data
collection, figures design;
Kamalian A, Sohrabi Asl M,
Afshari K, Dolatshahi M,
Shamshiri SH, Momeni Roudsari N
contributed to writing the original
draft; Momtaz S and Abdollahi M
were involved in supervision,
writing review, editing and final
approval of the manuscript;
Momtaz S was also involved in
validation and table design;
Rahimi R was involved in
provision of study material,
conception and design, and final
approval of the manuscript;
Abdolghaffari AH was involved in
the conceptualization, supervision,
writing review, editing and final
approval of the manuscript; all
authors have read and approved
the final manuscript.
Aida Kamalian, Masoud Sohrabi Asl, Mahsa Dolatshahi, Khashayar Afshari, Department of
Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Mahsa Dolatshahi, Students' Scientific Research Center, Tehran University of Medical
Sciences, Tehran 1417614411, Iran
Shiva Shamshiri, Roja Rahimi, Department of Traditional Pharmacy, School of Persian
Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Nazanin Momeni Roudsari, Amir Hossein Abdolghaffari, Department of Toxicology and
Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University,
Tehran 1941933111, Iran
Saeideh Momtaz, Amir Hossein Abdolghaffari, Medicinal Plants Research Center, Institute of
Medicinal Plants, ACECR, Tehran 1417614411, Iran
Saeideh Momtaz, Mohammad Abdollahi, Amir Hossein Abdolghaffari, Toxicology and Diseases
Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of
Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of
Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Saeideh Momtaz, Amir Hossein Abdolghaffari, Gastrointestinal Pharmacology Interest Group,
Universal Scientific Education and Research Network, Tehran 1417614411, Iran
Amir Hossein Abdolghaffari, Department of Toxicology and Pharmacology, Faculty of
Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
Corresponding author: Amir Hossein Abdolghaffari, PhD, Assistant Professor, Department of
Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad
University, No. 99, Yakhchal, Gholhak, Shariati St., P. O. Box: 19419-33111, Tehran
1417614411, Iran. amirhosein172@hotmail.com
Abstract
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by
chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of
nitric oxide (NO) in serum and affected tissues; mainly synthesized by the
inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation
and is one of the major biomarkers of GI inflammation. Various natural and
synthetic agents are able to ameliorate GI inflammation and decrease iNOS
expression to the extent comparable with some IBD drugs. Thereby, the purpose
of this study was to gather a list of natural or synthetic mediators capable of
WJG https://www.wjgnet.com
June 28, 2020 Volume 26 Issue 24
3365
Conflict-of-interest statement: The
authors have no conflicts of
interest to disclose.
Open-Access: This article is an
open-access article that was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution
NonCommercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See:
http://creativecommons.org/licen
ses/by-nc/4.0/
Manuscript source: Invited
manuscript
Received: February 24, 2020
Peer-review started: February 24,
2020
First decision: April 22, 2020
Revised: May 9, 2020
Accepted: June 4, 2020
Article in press: June 4, 2020
Published online: June 28, 2020
P-Reviewer: Farhat S, Gazouli M,
Vradelis S
S-Editor: Gong ZM
L-Editor: Webster JR
E-Editor: Ma YJ
modulating IBD through the NO pathway. Electronic databases including Google
Scholar and PubMed were searched from 1980 to May 2018. We found that
polyphenols and particularly flavonoids are able to markedly attenuate NO
production and iNOS expression through the nuclear factor κB (NF-κB) and
JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI
microbiota and reduce NO expression in IBD models through a broad array of
mechanisms. A number of synthetic molecules have been found to suppress NO
expression either dependent on the NF-κB signaling pathway (i.e.,
dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e.,
nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration
of natural and synthetic agents can affect the tissue level of NO and may improve
IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB
signaling pathways.
Key words: Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Nitric oxide;
Nuclear factor-κB; Natural or synthetic mediators
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: The present study aimed to investigate the correlation between the level of nitric
oxide (NO), and inflammatory bowel disease (IBD). Collected data showed that elevated
NO can induce gastrointestinal tract inflammation. Many natural and synthetic agents are
able to decrease NO production through different pathways, thereby, improving
inflammation and IBD symptoms. This study also determined the pharmacological
effects of these agents in suppression of the NO pathway.
Citation: Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni
Roudsari N, Momtaz S, Rahimi R, Abdollahi M, Abdolghaffari AH. Interventions of natural
and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways.
World J Gastroenterol 2020; 26(24): 3365-3400
URL: https://www.wjgnet.com/1007-9327/full/v26/i24/3365.htm
DOI: https://dx.doi.org/10.3748/wjg.v26.i24.3365
INTRODUCTION
Inflammatory bowel disease (IBD) is commonly comprised of Crohn's disease (CD)
and ulcerative colitis (UC), and is a worldwide health issue, afflicting a continually
increasing number of people[1]. Generally, IBD is characterized by chronic or relapsing
inflammation of the gastrointestinal (GI) tract[2]. CD is associated with the transmural
inflammation of potentially any part of the GI tract (mainly the terminal ileum and
colon), usually without bleeding and concomitant complications including strictures,
abscesses, and fistulas. However, UC only affects the mucosal layer of the colon
(especially the rectum) and leads to rectal bleeding[3]. In spite of apparent differences
in histological aspects and clinical manifestations of UC and CD, they share noticeable
similarities from a pathophysiological point of view. In this regard, aberrant immune
response to the microbial and environmental stimuli precipitated by genetic
predispositions is assumed to result in IBD[4-6]. Notably, many factors involved in IBD
converge within the intestinal inflammation, representing inflammatory cells
infiltration and accelerating the inflammatory cytokines and nitric oxide (NO) release.
NO AND THE PATHOPHYSIOLOGY OF IBD
NO is an essential inorganic molecule with various physiological and pathological
implications. NO is a free radical synthesized from the amino acid L-arginine (L-Arg)
in a reaction catalyzed by the nitric oxide synthases (NOS) enzyme group. A number
of NOS such as neuronal NOS (nNOS) and endothelial NOS (eNOS), also called
constitutive NOS, are minimally expressed within the inflamed sites. However,
inducible NOS (iNOS) is highly expressed in inflammatory cells in response to
immunogenic stimuli, majorly in association with a different CD4+ helper T cell
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June 28, 2020 Volume 26 Issue 24
Kamalian A et al. Pharmacological interventions for IBD, targeting NO
3366
profile based on the Th2/Th1 paradigm and pro-inflammatory cytokines through the
activation of mitogen-activated protein kinases (MAPK) and NF-κB[7-9]. Thus, CD was
described as a Th1 type immune response promoted by signal transducer and
activator of transcription (STAT)-4 and T-bet; which are able to produce interferon
gamma (IFN-γ), interleukin (IL)-12, and tumor necrosis factor (TNF)-α. It has been
shown that both IL-12 and IL-18 induce a high level of IFN-γ production, leading to
reinforcement of the Th1 immune response. In contrast, UC is recognized as a Th2
type immune response prompted by the expression of transcription factor STAT-6
and GATA-3, as well as the secretion of IL-5, IL-4, and IL-13[9]. Obviously, an adequate
amount of this immune response in the intestines is necessary for protection against
infections, but excessive production of NO may exert pathologic effects[9-11].
iNOS is mainly activated through the activator protein-1 (AP-1) assembly; and
activation of the extracellular signal-regulated kinase (ERK), leading to the
phosphorylation and activation of IкB- of IкB-kinase-β (IKK-β) and cytosolic
phospholipase A2, and upregulation of arachidonic acid (AA) release. An upsurge of
NF-кB nuclear translocation, activates cyclooxygenase-2 (COX-2) by S-nitrosylation.
COX-2 inevitably triggers the excessive production of prostaglandin E2 (PGE 2)[12].
The primary hypothesis of the involvement of NO in the pathogenesis of IBD was
based on the presence of NO and its metabolites in the intestinal lumen and biological
fluids (i.e., plasma and urine) in patients with IBD, more predominantly observed in
their remission phase and in severe disease[11,13-15]. Rather than inflammation, many
features of IBD are correlated with excessive NO; which can directly act on the
endothelium and smooth muscle cells or may affect the epithelium, resulting in
edema, vasodilatation, and increased mucosal permeability[16]. Overproduction of NO
also stimulates chloride secretion in the colon, leading to diarrhea; one of the main
features of IBD[17]. NO may play a pivotal role in the pathogenesis of some types of
IBD such as toxic megacolon, through regulation of intestinal motility and mucosal
blood supply[18].
As mentioned earlier, iNOS is preliminarily activated by pro-inflammatory
cytokines and immunogenic stimuli, acting via the JAK/STAT signaling pathways[9].
Activation of iNOS and irregular production of NO by pro-inflammatory (i.e., TNF-α,
IFN-γ, IL-1b, IL-4, IL-5, IL-6, IL-8, IL-12, IL-13, IL-17, IL-18 or IL-23) and inflammatory
molecules (i.e., lipopolysaccharide (LPS)[9,10,19], results in further propagation of
inflammatory responses by chemotaxis of neutrophils, natural killer (NK) cells and
macrophages. In addition, NO indirectly induces reactive nitric oxygen species
(RNOS) production. Then, it might react with superoxide, thus, generating
peroxynitrite (OONO-). OONO- is an oxidant for several biological molecules, for
example, it can activate the poly (-ADP-ribose) synthetase (PARS) enzyme, leading to
depletion of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide
(NAD) cellular supply, thereby, enhancing the epithelial permeability of the
intestine[15,20,21]. Furthermore, NO can suppress mitochondrial function and DNA
synthesis through OONO- production. It also enhances the intracellular release of
iron, thus, acting as a cytotoxic agent and perpetuating the mucosal injury and
inflammation[15]. Beyond OONO- production, NO induces RNOS species (i.e., NO2 and
NO-) production[22]. It seems that there is a bidirectional interaction between NO
production and inflammation in IBD, each one exacerbating the other[9]. Molecular
pathways involved in IBD progression are shown in Figure 1.
Despite accumulating evidence supporting the role of excessive NO in the
perpetuation of inflammatory responses, various research groups have shown that
NO can exert immunomodulatory effects by inhibiting IL-12 secretion[23].
Additionally, some studies have shown that iNOS-deficient mice are more susceptible
to colitis, as NO can suppress IL-17 secretion[24,25]. In line with previous findings, it has
been shown that induction of iNOS alleviates mucosal injury and improves tissue
repair[25]. In addition, nitrite supplementation and stimulation of NO release alleviated
mucosal damage in a dextran sulfate sodium (DSS) model of colitis[26,27]. The
pathophysiological significance of NO in the GI tract and possible efficacy of either
natural or synthetic agents on NO have been reviewed by many studies, however,
none of them extensively discussed both natural and synthetic interventions. This
might allow opportunities for IBD drug development mediated by the NO
pathway[2,28].
In spite of such controversies, suppression of NO-dependent pathological events by
natural or synthetic agents was shown to attenuate IBD inflammation and symptoms
in animal models (Figure 2). This paper reviews the pharmacological interventions of
natural and synthetic agents that can affect IBD through the NO pathway.
WJG https://www.wjgnet.com
June 28, 2020 Volume 26 Issue 24
Kamalian A et al. Pharmacological interventions for IBD, targeting NO
3367
Figure 1
Figure 1 Main cellular mechanism of interventions in inflammatory bowel disease. COX-2: Cyclooxygenase-2; iNOS: Inducible nitric oxide synthase; TNF-α:
Tumor necrosis factor alpha; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; IκB: Inhibitor of kappa B; IKκ complex: Inhibitor of kappa kinase
complex; MyD88: Myeloid differentiation primary response 88; P38MAPK: P38Mitogen-activated protein kinase; GSH: Glutathione; P13k: Phosphatidylinositol 13-
kinase; STAT: Signal transducer and activator of transcription proteins; IL-6: Interleukin-6; IL-1: Interleukin-1; PPARγ: Peroxisome proliferator-activated receptor
gamma; TLR: Toll-like receptor; MCP-1: Monocyte chemoattractan-t protein-1; AP-1: Activator protein 1; IRAK: Interleukin-1 receptor-associated kinase; NAC: N-
acetyl cysteine; NO: Nitric oxide; SOD: Superoxide dismutase; CAT: Catalase; TGFβR: Transforming growth factor beta receptor I.
SEARCH METHOD
We searched published literatures on studies that investigated the effects of natural
and synthetic agents on IBD through modulation of the NO pathway. We used broad
search terms: “Nitric oxide” or “NO” or “Nitric oxide pathways” and “Inflammatory
bowel disease” or “IBD”. Electronic databases including Google Scholar and PubMed
were searched from 1980 to May 2018, and the abstracts were screened for relevancy.
The publications that investigated diseases other than IBD, or the interventions except
that of the NO pathway, and studies that were not conducted on animal models, or
did not include a synthetic or natural agent, were excluded.
PHARMACOLOGICAL INTERVENTIONS AFFECTING IBD
THROUGH THE NO PATHWAY
Medicinal plants
The impressive roles of medicinal plants and their isolated chemical constituents
(phytochemicals) in IBD management have been confirmed by numerous studies[29].
Therefore, medicinal plants seem to have a promising future in IBD treatment[30].
Following sections contain a number of plant species and their active ingredients that
are able to inhibit NO, and were shown to have beneficial impacts on IBD (Table 1).
Lavandula spica L. or L. angustifolia Mill.: Members of the Lavandula genus,
Lamiaceae, have been associated with a reduction of chronic inflammation in various
settings, including IBD. Interestingly, in vitro studies suggested that more than one
species of Lavandula works through the NO pathway to reduce inflammation in
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Kamalian A et al. Pharmacological interventions for IBD, targeting NO
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Figure 2
Figure 2 Inhibition of nitric oxide synthase suppresses inflammatory bowel disease. IBD: Inflammatory bowel
disease; NOS: Nitric oxide synthase; NO: Nitric oxide.
various cell lines. For instance, the essential oil of L. eliasii subsp. thalictrifolium
specifically reduced iNOS expression in intestinal cell lines, indicating that these
subspecies may be more appropriate for IBD settings. As expected, the anti-
inflammatory effect of Lavandula species was exerted through the NF-κB signaling
pathway[31,32].
Cannabis sativa L.: The marijuana plant C. sativa and its derivatives, Cannabinoids,
are known to be a potential therapy for IBD. Cannabigerol and Cannabidiol were
found to regulate a set of functions in the body and play a key role in curing IBD,
particularly by reducing the production of nitric compounds, with therapeutic effect
in colitis mice[33].
Olea europaea L.: Extracts from olive (Olea europaea) leaves are used in different
traditional medicines as anti-inflammatory agents. The extract could be a great choice
for the treatment of oxidative stress-induced inflammatory conditions, including IBD,
mainly due to its antioxidant phenolic content, i.e., Oleuropeoside. This extract
inhibited IBD progression, most probably by reducing the production of chemokines
and nitrite compounds such as NO[34].
Retama monosperma (L.) Boiss.:Retama spp. is an indigenous component of
traditional medicine of Mediterranean regions, and its anti-inflammatory and
antioxidant effects have been well accepted. The hypoglycemic effects of this plant
have been attributed to the high concentration of Pinitol, a cyclic polyol, present in the
aerial parts of R. monosperma[35]. However, the antioxidant activities of this plant have
been directly correlated with the titrated concentrations of its flavonoid content[36].
Oral administration of an aqueous extract of the aerial parts of R. monosperma led to a
decrease in iNOS expression mediated through the NF-κB and p38 MAPK signaling
pathways[37].
Hibiscus rosa-sinensis L.: Hibiscus rosa-sinensis, also known as rose mallow or China
rose, is a species of flowering plant belonging to the family Malvaceae. H. rosa-sinensis
was shown to have potential therapeutic value in ameliorating experimental colitis in
laboratory animals, by inhibiting pro-inflammatory mediators such as NO and TNF-α.
The hydroalcoholic extract of the leaves of H. rosa-sinensis; containing alkaloids,
flavonoids, steroids, and phenols; significantly reduced severity of acetic acid-induced
colitis symptoms as assessed by the clinical disease activity score[38].
Curcuma longa L.: Curcumin is the main constituent of the rhizome of Curcuma longa.
Inhibition of COX-1, COX-2, TNF-α, iNOS, and NF-κB, and the potent anti-oxidant
and anti-inflammatory effects of curcumin, makes this compound a great
pharmacological candidate for patients with IBD[39].
Vaccinium corymbosum L.: An aqueous extract of highbush blueberry fruit (Vaccinium
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Table 1 Medicinal plants affecting inflammatory bowel disease via modulating nitric oxide pathways
Ref.Plant Plant part/
ingredients
Type of
animal/cells Model of IBD
Route of
administra-
tion
Duration of
treatment
Numbers of
animals in
intervention
group and
control group
Outcomes
[199]Terminalia
catappa
Stem bark Rat 2,4,6-
trinitrobenzene
sulfonic acid
(TNBS)
Oral Two days
before colitis
induction
n = 6 Disease activity
index (DAI) ↓,
myeloperoxida-
se (MPO) ↓,
glutathione
content ↑,
tumor necrosis
factor (TNF)-α
↓, interleukin
(IL)-6 ↓, IL-23 ↓,
cytokine-
induced
neutrophil
chemoattractan
-t 1 ↓, mucin
(MUC)-2 ↑,
MUC-3 ↑, villin
↑
[200]Veronica polita Whole plant Mice Dextran sulfate
sodium (DSS)
Oral 7 d n = 10 DAI ↓,
malondialdehy-
de (MDA) ↓,
nitric acid (NO)
↓, TNF-α ↓, IL-
1β ↓, IL-6 ↓,
inducible nitric
oxide synthase
(iNOS) ↓,
cyclooxygenase
(COX-2) ↓,
nuclear factor
(NF)-κB ↓,
phosphoryla-
tion of Junas
kinase/signal
transducer and
activator of
transcription
(JAK2/STAT-3)
↓
[32]Lavandula
stoechas/
Lavandula
dentate
Aerial parts Rat TNBS Intrarectal 7 d n =10 DAI ↓, MPO ↓,
reduced
glutathione
(GSH) content
↓, iNOS ↓, IL-1β
↓, IL-6 ↓,
monocyte
chemoattrac-
tant protein 1
(MCP-1) ↓,
intercellular
adhesion
molecule 1
(ICAM1) ↓, IL-
17 ↓, MUC-3 ↑,
trefoil factor 3
gene (TFF)-3 ↑
[201]Ziziphora
clinopoides
Aerial parts Mice DSS Oral 7 d before
colitis
induction
n = 6 Colon lipid
peroxidation
(LPO) ↓, total
thiol molecules
(TTM) ↑, total
antioxidant
capacity (TAC)
↑, NO ↑, TNF-α
↓, superoxide
dismutase
(SOD) ↑,
catalase (CAT)
↑
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[202]Lavandula
intermedia
(cultivar
Okanagan)
Essential oil Mice Citrobacter
rodentium
Oral 5-10 d - Mortality and
morbidity ↓,
cecal damage ↓,
damage of
distal colon↔,
iNOS ↓, IFN-γ
↓, IL-22 ↓,
macrophage
inflammatory
protein (MIP)-
2α ↓
[203]Pisum sativum
(Green Pea)
Powdered fruit Mice DSS Oral 9 wk n = 7 DAI ↓, MCP-1
↓, COX-2 ↓, IL-6
↓, IFN-γ ↓, IL-17
↓, iNOS ↓,
MUC-2
secretion ↑,
TFF-3 ↑,
kruppel-like
factor 4 ↑, sam-
pointed domain
Ets
transcription
factor-1 ↑,
activating
transcription
factor 6 (ATF)-6
↓
[33]Cannabis sativa Cannabidiol Mice Dinitrobenzene
sulfonic acid
(DNBS)
Intracolonic 6 d - DAI ↓, iNOS ↓,
nitrite
production ↓,
IL-1β↓, IL-10 ↑,
anandamide &
2-
arachydonylgly
-cerol ↓,
reactive oxygen
species (ROS)
formation ↓
[204]Cannabis sativa Cannabigerol Mice DNBS Intracolonic Preventive
protocol: 6 d/
curative
protocol: 2 d
- Pre-
treatment→DA
I ↓, Fluorescein
isothiocyanate
(FITC)-
conjugated
dextran in the
serum ↓, nitrite
↓ treatment→
MPO ↓, SOD ↑,
iNOS ↓, IL-1β ↓,
interferon
(INF)-γ ↓, IL-10
↑
[34]Olea europaea
(olive)
Leaves Rat Acetic acid
(AA)
Oral 3 d n = 6 DAI ↓, TNF-α ↓,
NO ↓, IL-1β ↓,
IL-6 ↓, iNOS ↓,
IL-2 ↓
[83]Crude canola
(rapeseed) oil
Phenolic
compound 4-
vinyl-2,6-
dimethoxyphen
-ol (canolol)
Mice DSS Oral 7 d - DAI ↓, COX-2
↓, free 8-
hydroxy-2'
deoxyguanosin-
e (OHdG) in
the plasma ↓,
IL-12 ↓, TNF-α
↓, NO ↓
[37]Retama
monosperma
Aerial parts/
flavonoids
Rat TNBS Oral 48, 24 and 1 h
prior to the
induction of
colitis & 24 h
later
n = 10-11 DAI ↓, COX-2
↓, iNOS ↓, p38
mitogen-
activated
protein kinase
(MAPK) ↓
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[38]Hibiscus rosa
sinensis
Leaves/
alkaloid,
flavonoids,
steroid and
phenols
Mice and rat AA Oral 7 d before
colitis
induction
n = 6 DAI ↓, spleen
enlargement ↓,
white blood cell
(WBC) count ↑,
red blood cell
(RBC) count ↑,
hemoglobin
(Hb) ↑,
hematocrit ↑,
platelet count ↑,
SOD ↑, GSH ↑,
LPO ↓, MPO ↓,
nitrite/nitrate
levels ↓, TNF-α
↓
[205]Changtai
granule
Traditional
Chinese
empirical
formula
comprised of
Phellodendro
Chinense,
Sanguisorba
officinalis ,
Euphorbia
humifusa and
polygonum
hydropiper
Rat TNBS Oral 7 d - DAI ↓, MPO ↓,
COX-2 ↓, iNOS
↓, Th1 cytokine
response ↓,
translocation of
NF-κB in
lamina propria
mononuclear
cells ↓
[206]Syringa vulgaris Verbascoside/
phenylpropano
-id glycosides
Rat DNBS Oral 3 d n = 10 DAI ↓, TNF-α ↓,
IL-1β ↓, iNOS ↓,
NO ↓,
poly(ADP
ribose) ↓, IκB-α
levels in colon
↑, pro-matrix
metalloproteina
-se (MMP)-2 ↑,
MMP-9 ↑
[39]Curcuma longa Curcumin Rat TNBS Oral 3 d before
induction of
IBD & was
continued for 5
d after
n = 8 DAI ↓, TNF-α ↓,
MPO ↓, NO ↓,
colonic
hydroxyproline
&
ceruloplasmin
levels ↓,
expression of
MMP-1, MMP-
3 and tissue
inhibitors of
metalloproteina
-ses 1 (TIMP)-1
↓
[39]Ginkgo biloba Root Rat TNBS Oral 3 d before
induction of
IBD & was
continued for 5
d after
n = 8 DAI ↓, TNF-α ↓,
MPO ↓, NO ↓,
colonic
hydroxyproline
and
ceruloplasmin
levels ↓,
expression of
MMP-1, MMP-
3 and TIMP-1 ↓
[207]Cordyceps
militaris Grown
on Germinated
Soybeans (GSC)
Mycelia Mice DSS Oral 2 or 9 d before
colitis
induction
n ≥ 15 DAI ↓, MMP-3
↓, MMP-9 ↓,
TNF-α ↓, iNOS
↓, p53 ↓
[208]Ficus bengalensis Stem bark Rat TNBS Oral 21 d n = 6 DAI ↓, colon
mucosal
damage index
↓, MPO ↓, MDA
↓, NO ↓, SOD ↑
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[46]Vaccinium
corymbosum
(blueberry)
Fruits/phenolic
acids and
flavonoids
Mice DSS Oral 14 d n = 6 DAI ↓, COX-2
↓, IL-1β ↓, p65
NF-κB ↓, IFN-γ
↓, iNOS ↓,
MDA ↓, CAT ↑,
SOD ↑,
prostaglandin
E2 (PGE2) ↑
[209]Hericium
erinaceus (Lion's
Mane
Medicinal
Mushroom)
Mycelia Mice DSS Oral 7 d - DAI ↓, MPO ↓,
TNF-α ↓, IL-1β
↓, IL-6 ↓, NO ↓,
MDA ↓, SOD ↓
in serum
[40]Panax
notoginseng
Root/saponin Mice AOM and DSS Oral 15 d n = 3 DAI ↓, COX-2
↓, iNOS ↓
[75]Citrus nobiletin Nobiletin Rat TNBS Intragastric 7 d (1 d after
colitis
induction)
- MPO ↓, iNOS ↓,
COX-2 ↓,
myosin light-
chain kinase
(MLCK) ↓, NF-
kB ↓, protein
kinase B (Akt)
phosphoryla-
tion ↓, trans
epithelial
electrical
resistance ↓,
inhibition of the
Akt–NF
κB–MLCK
pathway
[66]Vaccinium
corymbosum
(Portuguese
blueberries)
Anthocyanin-
rich fraction
Rat TNBS Intragastric 8 d n = 8 DAI ↓, iNOS ↓,
COX-2 ↓
[41]Malus sylvestris
(apple)
Fruit Rat AA Oral 6 d n = 5-6 iNOS
expression ↓,
COX-2
expression ↓,
Copper Zinc
(CuZn) SOD
expression ↑
protein
expression of
iNOS ↓ in
ulcerated area,
COX-2↔ & 8-
OHdG ↔
[210]Scutellariae
baicalensis
Oroxyloside Mice DSS Intragastrically 10 d n = 8 DAI ↓, MPO ↓,
iNOS ↓, pro-
inflammatory,
cytokines in
serum & colon
↓, peroxisome
proliferator-
activated
receptor
(PPAR)c ↑
→NF-κB ↓
[211]Rheum
tanguticum
Polysaccharide Rat TNBS Intrarectal 5 d n = 12 DAI ↓, NF-κB
p65 ↓, TNF-α ↓,
COX-1↔, COX-
2 ↓, PGE2 ↑,
iNOS ↓
[212]Hypericum
perforatum (St.
John's Wort)
Hypericum
perforatum
extract
Rat TNBS Intraperitoneal 3 and 7 d
treatments
- DAI ↓, CAT ↓,
GSH ↑, tissue
NO ↓, MPO,
glutathione
reductase (GR),
MDA, GSH-Px
↔
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Kamalian A et al. Pharmacological interventions for IBD, targeting NO
3373
[42]Allium sativum
(garlic)
Diallyl sulfide
(DAS) and
diallyl disulfide
(DADS)
Mice DNBS + DAS
DADS
Oral 2 d after first
day of
treatment
n = 10 In vivo→ DAI ↓
In vitro→
DADS→ IL-6 ↓,
hydrogen
sulfide ↑ DAS→
nitrite ↓, STAT-
1 ↓, hydrogen
sulfide ↑
[213]Avena sativa
(oat)
β-glucan Mice DSS Intragastric 14 d n = 20 DAI, TNF-α, IL-
1β, IL-6, iNOS,
NO, MDA,
MPO ↓
[31]Eryngium
duriaei subsp.
Juresianum;
Laserpitium
eliasii subsp.
Thalictrifolium;
Lavandula
luisieri, Thapsia
villosa
Essential oils
(EO)
Primary human
chondrocyte &
C2BBe1
IL-1β or a
cytokine
mixture (IFN-γ,
IL-1β TNF-α)
- EO added 30
min before
cytokine
stimulation
- EO of L.
luisieri→ iNOS
↓, p-IκB-α ↓ in
both cell
models EO of E.
duriaei subsp.
juresianum→
iNOS ↓, p-IκB-α
↓ in human
chondrocytes
EO of L. eliasii
subsp.
thalictrifolium &
O. maritimus →
iNOS ↓ in
C2BBe1 cells
EO of T. villosa
→ inactive in
both cell types
[214]Rhizophora
apiculate
Whole plant Mice AA Intraperitoneal 7 d n = 6 SOD ↑, GSH ↑,
LPO ↓, NO ↓,
MPO ↓, lactate
dehydrogenase
(LDH) ↓, iNOS
↓, COX-2 ↓,
translocation of
NF-κBp65 &
p50 subunits ↓
[215]Polygonum
multiflorum
2,3,5,4'-
tetrahydroxystil
bene-2-O-beta-
d-glucoside
(THSG)
Mice AA+
mitomycin C
Oral 7 d and 24 d n = 12 THSG (60
mg/kg) →DAI
↓, MPO ↓, MDA
↓, NO level ↓,
iNOS ↓, SOD ↑
THSG (120
mg/kg) & 24th
day of
mitomycin C→
> positive
control, 5-
aminosalicylic
acid (5-ASA)
[94]Oryza sativa L.
(black rice )
Anthocyanin
and rosmarinic
acid
Mice DSS Oral 8 d n = 8 Macroscopic
damage ↓,
microscopic
damage ↓, body
weight loss ↓,
iNOS ↓- COX-2
↓, IL-6 ↓, IL-1β
↓, TNF-α ↓
[67]Dioscorea alata Anthocyanidin-
es
Mice TNBS Rectal 7 d n = 10 Macroscopic
damage ↓,
microscopic
damage↓, body
weight loss ↓,
tight junction
proteins ↑,
MPO ↓, iNOS ↓,
TNF-α ↓, IFN-γ
↓
[216]Patrinia
scabiosaefolia
Root Mice DSS Oral 7 d n = 8 Macroscopic
damage ↓,
microscopic
damage↓, IL-6
↓, IL-1β ↓, TNF-
α ↓, iNOS ↓
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Kamalian A et al. Pharmacological interventions for IBD, targeting NO
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[217]Morinda
citrifolia (noni)
Fruit juice/
flavonoids
Mice DSS Oral 9 d n = 8 Microscopic
damage ↓, IL-6
↓, INF-γ ↓, NO
↓, MPO ↓
[201]Ziziphora
clinopoides
(kahlioti)
Aerial parts Mice DSS Oral 7 d n = 6 TNF-α ↓, TAC
↑, TTM ↑, LPO
↓, NO ↓
[44][43]Camellia sinensis
(Black tea)
Theaflavin-
3,30-digallate
Mice TNBS Oral 18 d - Macroscopic
damage ↓,
microscopic
damage ↓,
iNOS ↓, MPO ↓,
TNF-α↓, IFN-γ
↓, IL-12 p40 ↓,
NFκB ↓
Thearubigin Mice TNBS Oral 18 d - Macroscopic
damage ↓,
microscopic
damage ↓,
iNOS ↓, O2- ↓,
MPO ↓, IFN-γ
↓, IL-12 ↓, IL-4
↓, NFκB ↓
[218]Picrasma
quassiodes
Dried
branches/
alkaloids
Mice TNBS Gastric lavage 7 d n = 10 Macroscopic
damage,
microscopic
damage, body
weight loss,
MPO, TNF-α,
IL-8, COX-2,
iNOS↓
[95]Aronia berries Berry extract/
polyphenols
Mice DSS Oral 10 d - Macroscopic
damage,
microscopic
damage, body
weight loss,
TNF-α, IL-6,
PGE2, NO,
MAPK ↓
[199]Terminalia
catappa
Stem/phenolic
compound
Rat TNBS Oral 9 d - Macroscopic
damage ↓,
microscopic
damage ↓, NO
↓, IL-1β ↓,
MUC2 ↑, MUC3
↑
[45]Glycyrrhiza
glabra
(liquorice)
Glabridin Mice DSS Oral 7 d - Macroscopic
damage,
microscopic
damage, body
weight loss,
iNOS, MPO,
COX-2, TNF-α,
IL-6↓
[219]Punica granatum
(pomegranate)
Extract/
phenolic
compounds
Rat DSS Oral 30 d n = 8 Macroscopic
damage ↓,
Bifidobacteria
and Lactobacilli
↑, lipid
peroxidation ↓,
iNOS ↓- COX-2
↓, P53 ↑, cluster
of
differentiation
molecule (CD)
40 ↓, IL-1β ↓,
IL-4 ↓
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[220]Physalis
peruviana
Calyx/flavonoi
-ds, terpenoids
& glycosides
Rat TNBS Intraperitoneal 3 d in
protective
protocol and 15
d in therapeutic
protocol
- Macroscopic
damage ↓,
microscopic
damage ↓,
COX-2 ↓, iNOS
↓, MPO ↓,
NOD-, LRR-
and pyrin
domain-
containing
protein 3
(NLRP3) ↓, IL-
1β ↓, IL-6 ↓, IL-
10 ↓, MUC2 ↑
[221]Perilla frutecens Whole plant Mice DSS Oral 14 d (starting
from 7 d before
induction of
colitis)
n = 6 NF-кB ↓, COX-2
↓, iNOS ↓,
cyclin D1 ↓,
STAT-3
activation ↓,
nuclear factor
erythroid
2–related factor
(Nrf)2 ↑, heme
oxygenase-1
(HO-1) ↑,
interferon
regulatory
factor 3 (IRF3) ↓
PE (10 mg/mL)
in CCD841CoN
human normal
colon epithelial
cells→ TNF-α ↓,
iNOS ↓, P-IкB α
↓, P-STAT-3 ↓,
C-X-C Motif
Chemokine
Receptor 2
(CXCR)2 ↓
IBD: Inflammatory bowel disease.
corymbosum), rich in phenolic acids especially flavonoids, was shown to inhibit iNOS
overexpression through the NF-κB signaling pathway.
Panax notoginseng (Burkill) F.H.Chen: Panax notoginseng (P. notoginseng) is a well-
known Chinese herbal medicine. An interesting character of P. notoginseng is its
potential therapeutic effects on chronic diseases. The root extract of P. notoginseng,
containing saponin, was found to exert inhibitory effects on iNOS and inflammatory
cytokines[40].
Malus pumila Mill.: Apples (Malus spp., Rosaceae) and their products, rich in
polyphenols, have shown diverse biological activities and may contribute to a variety
of beneficial health events such as protecting the intestine against inflammation
initiated by IBD. The preventive effect of polyphenolic concentrated apple extract was
illustrated in an acetic acid-induced IBD rat model, resulting in inhibition of iNOS
overexpression through the NF-κB pathway[41].
Allium sativum L.: Plants of the genus Allium are known for their production of
organosulfur compounds, which have marked biological and pharmacological
properties. Garlic (Allium sativum) is one of the most widely used species, displaying a
broad spectrum of beneficial anti-inflammatory effects. Diallyl sulfide and Diallyl
disulfide are the main organosulfur compounds, with proved inhibitory effects on
nitrite derivatives and pro-inflammatory elements involved in IBD pathogenesis[42].
Camellia sinensis (L.) Kuntze: Camellia sinensis (C. sinensis) leaves are rich in vitamins
(B and C), minerals, polyphenols, caffeic acid, fertaric acid, tannins, and volatiles. In
vivo studies showed that the polyphenol components of C. sinensis, theaflavin, and
thearubigins, downregulated iNOS overexpression through the NF-κB pathway in
oxidative-induced inflammatory complications such as IBD[43,44].
Glycyrrhiza glabra L.: Licorice, derived from the root of Glycyrrhiza glabra, is
extensively used in traditional medicines for a variety of complications and ailments.
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3376
Licorice possesses immune-modulatory and adaptogenic properties, required for the
pathogenesis of IBD. The ethanolic extract of this plant, rich in glabridin, was found to
be effective in IBD as it attenuated pro-inflammatory elements and iNOS
production[45].
Phytochemicals
Table 2 depicts plant-derived compounds that affect IBD by modulating the NO
pathway. Polyphenols are the most investigated plant-derived constituents with well-
documented positive effects for IBD treatment via the NO pathway[46]. According to
their chemical structures and phenolic content, polyphenols are classified into several
subgroups. This section mostly focused on the effects of these subgroups on the NO
pathways.
Flavonoids: Flavonoids are natural products present in a wide range of vascular plant
species. They function in several categories including protection against UV-light and
phytopathogens (i.e., phytoalexins in legumes), attraction of pollinators (i.e.,
anthocyanins in berries), and reduction of reactive oxygen species (ROS) in conditions
of oxidative stress (i.e., quercetin and other flavonols)[47]. Previous studies rigorously
support the effect of flavonoids on suppressing various elements involved in innate
immunity in a variety of hypersensitivity and inflammatory conditions including
osteoarthritis, nephrotoxicity, photodamaged skin, diabetes mellitus, and IBD[48-53]. As
mentioned, iNOS is an inflammatory marker, creating a situation of oxidative stress
by producing high amounts of NO, resulting in a slippery slope of ONOO− formation,
oxidative damage, nitration, and S-nitrosylation of certain biomolecules such as
proteins, lipids, and DNA[54].
During inflammation, flavonoids regulate/reduce NO production and iNOS
expression via 2 main pathways; the NF-κB and JAK/STAT signaling pathways[55-57].
These pathways are stimulated during the inflammatory process, then macrophages
are infiltrated to affected tissues. Thereafter, TLR-4 and INF-γ receptors are activated
and induce the mentioned molecular cascades. Consequently, expression of iNOS is
up-regulated. Flavonoids also downregulate the NO pathway, due to their ability to
suppress elements of the above-mentioned pathways[47].
The peroxisome proliferator-activated receptor γ (PPARγ) was found to be a key
participant in downregulation of iNOS[58]. PPARγ is a major transcription factor of
lipid oxidation and metabolism genes in macrophages, and has anti-inflammatory
activities. Apigenin, chrysin, and kaempferol were found to especially reduce iNOS
expression via PPARγ activation in vitro[59]. Park et al[60] suggested that beyond NF-κB
inhibition, the anti-oxidant activities of flavonoids must be mediated by other
mechanisms. It is reported that trimeric flavonoids exhibit stronger anti-inflammatory
and anti-oxidant properties than monomeric flavonoids. Trimeric flavonoids activate
the NF-κB pathway, while monomeric flavonoids were shown to have a suppressive
effect.
Several protein docking simulation analyses have proposed that flavonoids such as
silibinin and deguelin, can directly bind iNOS and are able to suppress iNOS activity.
Therefore, a number of flavonoids might directly bind iNOS and inhibit its functions,
in a way other than modulating its expression at gene level[61,62]. Overall, flavonoids
significantly diminish pathologic lesions in colonic tissue, attributed to their anti-
inflammatory and antioxidant effects, resulting in NO reduction.
Anthocyanins: Anthocyanins are an important subcategory of flavonoids, available in
many fruits and vegetables with a prominent red, blue, or purple hue. Anthocyanins
were shown to effectively suppress inflammation and tumorigenesis processes in
different cell lines[63-65]. A significant decrease was reported in the expression levels of
TNF-α and iNOS, when anthocyanin-rich fractions (ARF) of purple yam (Dioscorea
alata L.) and Portuguese blueberries (Vaccinium corymbosum L.) were orally
administered to animals. The ARF prepared from the latter fruit reduced iNOS
expression as effectively as 5-aminosalicylic acid (5-ASA) at a molar anthocyanin
concentration approximately 30 times lower than that of 5-ASA[66,67].
Cardamonin: Oral administration of Cardamonin, a chalcanoid produced in members
of the Alpinia genus, reversed the upregulation of TLR-4 and cytokine receptors along
with the cascade of proteins downstream to these receptors (i.e., myeloid
differentiation factor 88, IL-1 receptor-associated kinase-1, inhibitor κBα, and inhibitor
κB kinase-α/β, as well as MAPK and c-Jun NH2-terminal kinase), resulting in
inhibition of the nuclear localization of NF-κB p65 and inactivation of the MAPK
pathway. Cardamonin also suppressed the expression of their target genes, i.e.,
iNOS[68].
Luteolin: Luteolin, a yellow, naturally occurring flavone, interferes with iNOS
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Table 2 Plant-derived compounds affecting inflammatory bowel disease by modulating nitric oxide pathways
Ref.Phytochemical type of animal Model of IBD Route of
administration
Duration of
treatment
Numbers of
animals in
intervention
group and
control group
Outcomes
[71]Naringenin (25,
50, 100 mg/kg
per day)
Rat Acetic acid (AA) Transrectal 7 d before colitis
induction
n = 6 Disease activity
index (DAI) ↓,
total glutathione
sulphadryls (T-
GSH) ↑, non-
protein
sulphadryls ↑,
DNA, RNA and
total protein
content ↑, nitrit
oxide (NO) ↓,
catalase (CAT) ↑,
superoxide
dismutase (SOD)
↑, tumor necrosis
factor (TNF)-α ↓,
interleukin (IL)-
1β ↓, IL-6 ↓
[82]Eupatilin (ethanol
extract of aerial
parts of Artemisiae
herba, EIE) and
quercetin-3-β-D-
glucuronopyrano
side from Rumex
aquaticus (EIQ)
(EIE, 100 mg/kg
& EIQ, 30 mg/kg)
Rat 2,4,6-
trinitrobenzene
sulfonic acid
(TNBS)
Oral 48, 24 and 1 h
prior to the TNBS
instillation and
again 24 h later
n = 6 DAI ↓,
myeloperoxidase
(MPO) ↓, NO ↓,
TNF-α ↓, total
glutathione
sulphadryls
(GSH) ↑,
malondialdehyde
(MDA) ↓
[74]Naringin (20, 40,
or 80 mg/kg)
Rat AA Oral 12 d (8 d before
colitis induction
and 4 d after)
n = 6 DAI ↓, spleen
weight ↓, white
blood cell (WBC)
↑, red blood cell
(RBC) ↑,
hemoglobin (Hb)
↑ & platelet ↑,
lactate
dehydrogenase
(LDH) ↓, alkaline
phosphatase
(ALP) ↓, SOD ↑,
GSH ↑, Colon
lipid peroxidation
(LPO) ↓, NO ↓,
MPO ↓, xanthine
oxidase activity ↓,
protein carbonyl
content ↓, the
number of
unwinded double
strand DNA ↓
[222]Oligonol (0.5 and
5 mg/kg/d)
Mice Dextran sulfate
sodium (DSS)
Oral 7 d before colitis
induction
n = 5 DAI ↓, IkBα
phosphorylation
& degradation ↓,
p65
phosphorylation
& nuclear
translocation ↓,
cyclooxygenase
(COX-2) ↓, iNOS
↓, expression of
antioxidant
enzymes ↑, colon
carcinogenesis ↓,
the incidence and
the multiplicity of
colonic adenoma
↓
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[223]Algal
meroterpene11hy
droxy11Omethyla
mentadione (1, 10
& 20 mg/ kg)
Mice DSS Oral 7 d after colitis
induction
DAI ↓, MPO ↓,
TNF-α ↓, IL-1β ↓,
IL-10 ↓, COX-2 ↓,
iNOS ↓
[224]Fraxinellone Mice DSS and
lipopolysacchari-
de (LPS)
intraperitoneal 9 d n = 10 DAI ↓, MPO ↓,
alkaline
phosphatase
(ALP) ↓,
glutathione ↑, IL-
1β ↓, IL-6 ↓, IL-18
↓, TNF-α ↓,
inhibition of
cluster of
differentiation
molecule 11B
(CD11B).+
macrophage
infiltration,
ICAM1 ↓,
vascular cell
adhesion
molecule 1 ↓,
iNOS ↓, COX-2 ↓,
NO ↓, NF-κB
signaling ↓ &
NOD-, LRR- and
pyrin domain-
containing
protein 3
(NLRP3)
inflammasome ↑
[79]Isoquercitrin (1
and 10 mg/kg/d)
Rat DSS Oral 14 d (DSS
induced the
second half)
n = 8 Colon shortening
↓, COX-2 ↓, iNOS
↓, tissue healing
did not
encompass
rectum
[225]Oridonin (5.0 and
7.5 mg/kg)
Mice TNBS ntraperitoneal 7 d n = 3-9 DAI ↓, TNF-α ↓,
interferon (INF) ↓,
IL-17A ↓, iNOS ↓,
COX-2 ↓, in vitro
lymphocyte
proliferation ↓,
NF-κB p65
expression &
activity ↓
[68]Cardamonin (20,
50, and 100
mg/kg)
Mice DSS Oral 2 d before DSS
treatment & 7 d
after
n = 10 NO ↓, TNF-α ↓,
IL-6 ↓, toll like
receptor (TLR)-4
↓, myeloid
differentiation
factor (MDF) 88 ↓,
IL-1 receptor-
associated kinase-
1 ↓, IκBα ↓, IκBK-
α/β ↓, mitogen-
activated protein
kinase (MAPK) ↓,
c-Jun NH2-
terminal kinase ↓,
nuclear
translocation of
NF-κB p65 ↓
IBD: Inflammatory bowel disease.
expression in IBD models by inhibiting elements of the NF-κB cascade as mentioned
above[69]. Luteolin significantly inhibited IL-8 production, COX-2 and iNOS
expression, and cytokines-induced NO overproduction; indicating that luteolin
negatively modulates the key inflammatory signaling cascades underlying intestinal
inflammation. Mechanistically, inhibition of the JAK/STAT pathway was identified as
a critical mechanism by which luteolin exerts its intestinal anti-inflammatory action[70].
Naringenin and naringin: Naringenin and naringin, the glycosidic form of
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naringenin, belong to the flavanones and are frequently found in grapefruit. These
compounds were shown to decrease the colonic level of NO and inflammatory
cytokines[71,72]. Moreover, naringin reduces colonic xanthine oxidase level, which
catalyzes the conversion of nitrite, both the physiological storage pool of NO and its
metabolites[73]. Concerning NO reduction, pre-treatment with 50 mg/kg/d of
naringenin showed efficiency comparable to Mesalazine (300 mg/kg/d)[71].
Nobiletin: Nobiletin is a widely distributed O-methylated flavone found in citrus
peels, which has recently attracted attentions due to its anti-insulin resistance, anti-
inflammatory, and anti-cancer characteristics[74]. In addition to decreasing the nuclear
localization of NF-κB, nobiletin regulated the tissue production of NO through an
Akt-dependent manner. Oral treatment of nobiletin (40 mg/kg) was shown to be as
potent as 100 mg/kg of Sulfasalazine, a first-line drug in IBD treatment[75].
Quercetin and isoquercetin: Quercetin, the most widely distributed flavonoid, has
been shown to suppress LPS-induced IKK, NF-κB and AP-1 activation; and the IFN-γ-
induced NF-κB, STAT1, and interferon regulatory factor-1 (IRF-1) activation in vitro,
almost all of which are upstream of the NF-κB and JAK/STAT signaling pathways.
Quercetin also induces heme oxygenase-1 (HO-1) expression via activation of tyrosine
kinase and MAPK. Quercetin was shown to partly downregulate iNOS expression
through this pathway[76]. Suppression of PI3K/AKT might reduce the nuclear
translocation of NF-κB and the subsequent increase in iNOS expression[77,78].
Isoquercetin, the 3-O-glucoside of quercetin is present in fruits such as mango, and
has been shown to repress iNOS expression in IBD models, in a dose-dependent
manner[79]. However, isoquercetin displayed little to no effect on histological damage
and the iNOS level in lower segments of the colon, where the damage was
considerably severe, suggesting that the isoquercetin effect might be correlated with
severity and histology of target tissues[79].
Wogonoside: Wogonoside is a bioactive flavonoid derived from the root of Scutellaria
baicalensis Georgi. This glucuronide metabolite of wogonin has been shown to possess
anti-inflammatory and anticancer effects. Recent studies revealed that NOD-, LRR-
and pyrin domain-containing protein 3 (NLRP3) inflammasome are implicated in
IBD, mainly by inducing IL-1β production. To date, only limited agents have been
nominated to target both NF-κB and NLRP3 inflammasome in IBD[80]. In DSS-induced
colitis mice, wogonoside alleviated body weight loss, colon length shortening, colonic
pathological damage, inflammatory cells infiltration, myeloperoxidase (MPO) and
pro-inflammatory mediators levels, and iNOS activity. Furthermore, this compound
reduced IL-1β, TNF-α, and IL-6 production, and downregulated the mRNA
expression of pro-IL-1β and NLRP3 in phorbol myristate acetate (PMA)-differentiated
monocytic THP-1 cells, through suppression of NF-κB and NLRP3 inflammasomes.
Wogonoside also repressed iNOS expression, twice more potent than 5-ASA, by
suppressing both NF-κB and NLRP-3 inflammasomes, which were not targeted by 5-
ASA[81].
Other flavonoids: A number of flavonoids have also been reported to reduce iNOS
expression and inflammatory cytokines in IBD models such as (1) Rutin (the glycoside
combining the flavonol quercetin and the disaccharide rutinose found in citrus fruits
but not quercetin itself)[81]; (2) Glabridin (an isoflavone of the root extract of licorice)[45];
(3) Eupatilin (an O-methylated flavone from the aerial parts of Artemisiae herba); and
(4) Quercetin-3-β-D-glucuronopyranoside (isolated from Rumex aquaticus)[82].
Other polyphenols: In this section, we discuss other polyphenolic compounds rather
than flavonoids.
Canolol
A major component of crude canola oil called canolol, has been put in the spotlight
due to its anti-mutagenesis roles. Canolol was shown to affect IBD and NO
production in the manner discussed above[83]. It was reported that following canolol
treatment, IL-12, TNF-α, COX-2, iNOS, and the oxidative responding molecules (i.e.,
HO-1) were suppressed[83].
Curcumin
Hydroxycinnamic acids are a subcategory of polyphenols. Among these compounds,
curcumin a bright yellow curcumoid found in turmeric, is the main spice in curry, and
is considered as an antioxidant, anti-inflammatory, and anti-tumorigenesis substance.
In addition to suppressing NO production and iNOS expression during reducing
inflammation in IBD models[39], curcumin plays an anti-epileptic role in the central
nervous system by downregulating neuronal NOS, improving endothelial
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dysfunction and vascular remodeling through upregulation of eNOS[84-86]. It has also
been reported that the anti-inflammatory effect of curcumin has been implicated in
suppression of the protein components of the NF-κB and JAK/STAT pathways[51,86,87].
Gallic acid, thea-3,3'-bigallate, and thearubigin
Among the polyphenols, hydrobenzoic acids have received considerable attentions.
Gallic acid itself and its derivatives such as thea-3,3'-bigallate and thearubigin (a
polymer of epigallocatechin and epigallocatechin gallate found in black tea), were
shown to modulate iNOS expression and NF-κB suppression[45,46,88]. In addition, gallic
acid acts through the IL-6/STAT-3 signaling pathway, not via iNOS expression[88,89].
Oligonol
Oligonol is a lychee-fruit-derived low molecular weight polyphenol containing
catechin-type monomers and oligomers with beneficial effects on memory in amyloid
β-induced Alzheimer's disease models, and reduces tissue injury in various organs by
inhibiting the expression of NF-κB p65, COX-2, and iNOS[90,91]. It was shown that
oligonol improved inflammation through downregulation of iNOS expression and
NO production, although the compound enhanced cardiac health by increasing NO
production and vasodilation, which was mediated by eNOS upregulation[91,92].
Oligonol can mediate IBD symptoms mainly via iNOS suppression[93].
Rosmarinic acid
Rosmarinic acid is abundantly present in phenolic acid-rich species such as black rice
and Aronia berry. Oral administration of rosmarinic acid ameliorated colonic
inflammation and downregulated iNOS expression[94,95]. Moreover, rosmarinic acid
reduced IL-6, IL-1β, and IL-22 expression, and suppressed the protein levels of COX-2
and iNOS in IBD by inhibiting the NF-κB and STAT-3 signaling pathways[96].
Dairy products
Therapeutic dietary products have long been of interest in mitigating inflammation.
For instance, goat cheese whey; a by-product of the cheese-making process, is rich in
amino acids threonine and cysteine, and oligosaccharides such as sialic acid; which
can act as an antioxidant with considerable immunomodulatory function[97,98]. In
addition to increasing mucin synthesis by threonine and cysteine[99,100], it can modulate
the colonic flora in a murine model of colitis[100]. In acetic acid-induced colitis rats, the
anti-oxidative and anti-inflammatory properties of goat cheese whey have been
shown to reduce iNOS expression, comparable to Sulfasalazine[101]. Whether specific
component/s of goat cheese whey is responsible for such effects requires
clarification[101].
It has been demonstrated that glycomacropeptide, a product of the enzymatic
hydrolysis of casein, can have immunomodulatory effects by altering the colonic
bacterial population, i.e., accommodating host-friendly microorganisms and
confronting pathogens[102-104]. Pre-treatment of colitis rats with glycomacropeptide,
inhibited pro-inflammatory cytokines production, iNOS expression, and improved
anorexia[105].
Probiotics and prebiotics
Although various data suggest that intestinal microorganisms trigger inflammation,
and the efficacy of antibiotics is being clarified in IBD subjects; it seems the aberrant
immune response to intestinal antigens plays a major role in the pathogenesis of IBD.
In this regard, extensive research on commensal flora has revealed noticeable
variations in the composition of gut microbiota in IBD patients compared with
healthy controls[106-108], active phases of IBD compared with inactive phases, and
between the parts of the intestine affected by IBD[109-111]. During past decades, ingestion
of live microorganisms available as probiotics[112] or non-digestible substrates for
selective microorganisms known as prebiotics[113], has been introduced as a method of
altering the intestinal microbiome and to potentially prevent or reduce inflammation
in IBD[114]. Herein, we review evidence on the efficiency of pro- and pre-biotics in IBD
treatment, specifically through modulation of NO production. Overall, it seems that
pro- and pre-biotics attenuate NO production by suppression of the IκB/NF-κB
pathway[115], i.e., via IκB-α degradation and ubiquitination in epithelial cells[116,117]. The
anti-inflammatory properties of probiotics may be related to the suppression of
proteasome function and inhibition of the transmission of complexes shaped by NF-
κB and PPAR-γ from the nucleus[118]. In addition, IL-10 secretion and the suppression
of dendritic cells-induced IL-12 secretion attenuated the immunomodulatory effects
and iNOS activity[118].
Lactobacillus farciminis: L. farciminis has been shown to release NO in vitro. In 2004,
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Lamine et al[119] showed that oral administration of L. farciminis in a 2,4,6-
trinitrobenzene sulfonic acid (TNBS) model of rat colitis, similar to sodium
nitroprusside, led to intraluminal NO release, alleviated the macroscopic evidence of
colitis, and attenuated iNOS and MPO activities. In 2006, Peran et al[120] designed a
study to investigate the potency of L. fermentum in the TNBS model of rat colitis.
Treatment with L. fermentum promoted Lactobacillus species growth and short-chain
fatty acids (SCFAs) production, reduced microscopic colitis, extenuated oxidative
stress, and ameliorated TNF-α secretion and iNOS expression. They subsequently
performed a comparative analysis of the effectiveness of probiotics in the same model,
in which treatment with Bifidobacterium lactis, also known as L. acidophilus, reduced
iNOS expression, and prevented intestinal inflammation and diarrhea[121]. However, L.
casei seemed to have no significant effect on iNOS expression[121].
B. lactis was shown to transiently activate NF-κB expression and p38 MAPK, the
bacterium also inhibited the expression of iNOS and COX-2, and TNF-α production.
This was achieved by facilitating a cross-talk between the intestine epithelial cells and
immune cells[122], indicating the anti-inflammatory effect of B. lactis. On the other
hand, L. acidophilus and L. fermentum, secondary to a decrease in inflammatory
cytokines release and neutrophil activation, reduced iNOS expression and oxidative
stress[120]. In contrast, L. farciminis, seems to exert its anti-inflammatory effect mainly
by generating NO in the intestine, and partly through reducing the release of pro-
inflammatory cytokines, and by enhancing the barrier integrity and modification of
intestinal flora[123].
In DSS-induced colitis mice, administration of L. plantarum AN1 strain cells, which
were derived from the fermented fish aji-narezushi, enhanced endogenous
Lactobacillus growth, especially L. reuteri, and protected against colitis with a
significant effect on mucosal damage[124]. On the other hand, in vitro administration of
both live and heated L. plantarum AN1 strains to murine macrophage RAW264.7 cells,
improved the anti-inflammatory effect by reducing NO secretion[124], supporting the
outcomes of previous studies.
In addition to the beneficial effects of Lactobacillus in reducing NO production in
animal models of colitis, the protective effects of L. rhamnosus GG on normal human
colon epithelial cells and murine macrophages, by increasing iNOS expression, has
been reported[125]. Thus, it appears that Lactobacillus may be beneficial in alleviating
colitis by modulating iNOS expression. In the DSS model of colitis[126], oral
administration of Rhodobacter sphaeroides extract (LycogenTM), reduced pro-
inflammatory cytokines and NO production, decreased colonic bacteria, and
prevented weight loss and colon shortening, while improving survival[126].
More recently, combination therapy with probiotics has been examined in animal
models of colitis. A combination of four live bacterial strains (L. acidophilus, L.
plantarum, B. lactis and B. breve) form a probiotic cocktail named "Ultrabletique". It was
shown that oral administration of Ultrabiotique in DSS-induced colitis, attenuated
microscopic evidence of inflammation, reduced NO production, as measured in the
supernatants of peritoneal macrophages (PMQ) cultures[127]. Later, a study by Toumi et
al[128] demonstrated that Ultrabletique treatment ameliorated plasma NO and IFN-γ
production in association with reduced expression of colonic TLR-4, iNOS and NF-κB
in DSS-induced colitis. LPS-induced TLR-4 stimulation, activated the NF-κB pathway,
thereby, inducing iNOS expression. On the other hand, LPS-induced production of
IFN-γ leads to the activation of IRF-1 and NF-κB. In vivo, co-localization and
interaction of IRF-1 and NF-κB in the macrophage nucleus, physically bends the iNOS
promoter DNA and leads to NO production[129]. In this study, Ultrabiotique
significantly reversed these mechanisms.
Kefir, a natural beverage consisting of a fermented dairy product obtained by
exposing milk to yeast and bacteria; composed of Lactobacillus, Acetobacteria,
Streptococcus and yeasts; attenuated colitis in DSS mouse model by extenuating pro-
inflammatory cytokines and NO production[128]. In a study by Soufli et al[130] the
laminated layer of Echinococcus granulosus cyst increased IL-10 expression, and
decreased the expression of TNF-α, IFN-γ, NF-κB, and iNOS, thus, improving colitis.
Helminth antigens from organisms such as Trichuris suis have previously been used in
IBD subjects; however, the underlying mechanisms are undetermined[131-133],
investigations into their potential to relieve inflammation in IBD are warranted.
In addition to direct anti-inflammatory effects of bacterial antigens, probiotic
products may have such effects. Fermentation of water-soluble fibers by anaerobic
bacteria leads to SCFA production. For instance, hydrolyzation and fermentation of
inulin, a natural beta-fructan extracted from many types of plants, by microbiota and
Lactobacilli in the intestinal lumen results in SCFAs formation (i.e., butyric acid). It was
shown that inulin suppressed inflammation in DSS-induced colitis rats, at least partly
mediated by reducing NO production[127]. Previous studies have shown that SCFAs
significantly suppressed pro-inflammatory cytokines expression in intestinal cells via
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downregulation of NF-κB[134,135]. Arribas et al[136] developed a caramel with a high
content of difructose dianhydrides and their glycosylated derivatives, cyclic fructans
that were shown to provide an appropriate environment for Lactobacillus and
Bifidobacterium species. In addition, the intestinal microbiota is able to produce SCFAs
by fermentation of DFAs, and can further promote their anti-inflammatory effects by
reducing iNOS expression.
Animal oils
The advantage of polyunsaturated fatty acids (PUFAs) intake in IBD was elucidated
by epidemiologic studies in Eskimos[137] and by lower levels of PUFAs in patients'
sera[138]. Although, data are conflicting, most of the studies support the efficiency of
PUFAs in IBD[137]. PUFAs are able to attenuate inflammation, as in IBD, by altering the
production of eicosanoids and COX-2, and by modulating PPAR-γ and NF-κB[139-143].
The inefficacy of omega-3 PUFAs has been reported in a study on protection against
IBD, which was in contrast to conjugated linoleic acid (CLA)[143].
Omega-6 PUFAs such as (17S)-hydroxy-docosapentaenoic acid, but not (10, 17S)-
dihydroxy-docosapentaenoic acid, exhibited inhibitory effects on iNOS expression in
a DSS model of colitis, as well as predominating M2 macrophages with anti-
inflammatory properties in vitro[144]. Additionally, (5E,7Z,10Z,13Z,16Z,19Z)-4-
Hydroxy-5,7,10,13,16,19-docosahexaenoic acid, a potential agonist of PPAR-γ with
antidiabetic property[145], has been shown to modulate colitis through suppression of
iNOS. Although, these effects are independent of PPAR-γ inhibition[146].
Amino acids
Glutamine: Glutamine at concentrations above 0.5 mmol/L reduced NF-κB nuclear
transportation, iNOS expression, and attenuated colitis severity[147]. Indeed, the
intrarectal administration of glutamine has been associated with less intestinal
damage and reduced the expression of STAT-1, STAT-5, and NF-κB, decreased pro-
inflammatory cytokines (i.e., IL-8 and IL-6) production, and enhanced IL-10 in an IBD
model[148].
L-Arg: Administration of L-Arg enhanced the survival time of colitis animals, while
reducing the expression of iNOS and NF-κB. However, different studies have
reported various results on the beneficial effect of L-Arg on the colon[149,150].
Synthetic molecules
Previous studies showed that NF-κB inhibitors directly suppresse the expression of
NF-κB dependent pro-inflammatory mediators, including iNOS. Therefore, blockade
of the NF-κB signal transduction pathway may be one of the major mechanisms
underlying several synthetic molecules in management of IBD. Hence, the following
sections will discuss studies in which NF-κB/NO signaling helped to improve IBD
complications (Table 3).
NF-κB-NO dependent synthetic molecules
To date, numerous “NF-κB and NO inhibitors” have been introduced with potentially
beneficial effects in colitis treatment[151,152]. Notably, the NF-κB inhibitory effects of
these molecules are mostly due to the blockade of NF-κB translocation to the nucleus,
either by inhibiting P65 or IκB degradation.
COG112: It is known that Apolipoprotein E has immunomodulatory effects and
synthetically derived Apolipoprotein E-mimetic peptides were found to be useful in
models of sepsis and neuroinflammation. For example, one of these peptides,
COG112, was shown to cause a significant reduction of iNOS expression in a colitis
model[153]. COG112 also improved the clinical parameters of survival, body weight,
colon weight, and histologic injury in these animals. Moreover, COG112 inhibited
colon tissue iNOS, keratinocytes, TNF-α, IFN-γ, and IL-17 mRNA expression, and
reduced the nuclear translocation of NF-κB. The IKK activity was also reduced, a
necessary factor for activation of the canonical NF-κB pathway[153].
Dexamethasone: Dexamethasone is a corticosteroid, and exhibited a predictable
positive effect on colitis-induced colon damage, which was correlated with reduced
iNOS expression and NF-κB activity. This effect was even stronger when
dexamethasone was administered in particle or microsphere form[151,152].
Pioglitazone: Pioglitazone is a PPARγ ligand, approved for diabetes treatment.
Pioglitazone was also found to be an NF-κB-DNA binding inhibitor, allowing a
reduction in iNOS expression and inflammation. Moreover, PPARγ itself can bind
NF-κB and block its normal function, hence, reducing iNOS expression and other
inflammatory end products of the NF-κB pathway[154,155].
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Table 3 Synthetic compounds affecting inflammatory bowel disease by modulation of nitric oxide pathways
Ref.Type of animal Model of IBD Intervention Duration of
treatment
Numbers of
animals in
intervention group
and control group
Outcomes
[226]Rat Dextran sulfate
sodium (DSS)
Dinitrate-barbiturate
(rectally twice daily)
5 d n = 12 Matrix
metalloproteinase
(MMP)-9 activity ↓,
disease activity ↓,
colonic injury ↓
[227]Rats Lipopolysaccharide
(LPS)
Ursodeoxycholate
(gavage)
4 d n = 4 Circulating
nitrite/nitrate ↓,
intestinal epithelial
inducible nitric
oxide synthase
(iNOS) activity ↓,
colonic injury ↓
[177]Rat Acetic acid (AA) N-Acetylcysteine
(NAC) (100 mg/kg
for 7 d, 20 mg/kg for
2 d) (intraperitoneal,
intracolonic)
2 d, 7 d - 100 mg/kg NAC →
tissue
myeloperoxidase ↓,
glutathione ↓, NO ↓,
colonic injury ↓ 20
mg/kg NAC→ no
protective effects
[229]Rat 2,4,6-trinitrobenzene
sulfonic acid
(TNBS), AA
NG-nitro-L arginine
methyl ester (L-
NAME)
accompanied by
TNBS or 7 d before
AA
n = 55 TNBS-treated rats→
tissue injury ↓, lesion
area ↓, colonic
weight ↓,
myeloperoxidase
activity ↓, nitric
oxide synthase
(NOS) activity ↓ 24
hours after AA+
capsaicin pretreated
rats→ tissue injury
↓, lesion area ↓,
colonic weight ↓,
NOS activity ↓ TNBS
+ L-NAME treated
rats→ mean arterial
blood pressure was
higher than in TNB
treated rats
[228]Mice Dinitrobenzene
sulfonic acid (DNBS)
Trichinella spiralis
antigens (helminth
ags), (rectal
submucosal)
5 d before DNBS
induction
n = 6-8 Macroscopically and
histologically colitis
↓, mortality rate↓,
MPO activity↓, IL-1β
production↓,
inducible nitric
oxide synthase
(iNOS) expression ↓,
IL-13 ↑,
transforming growth
factor beta (TGF)-β
↑, TH2 dominancy
[170]Human mixed
mono- nuclear cells
(MMCs) co-cultured
with HT-29 cells
from UC patients
IFN-γ and LPS Budesonide or
prednisolone
(corticosteroids)
Incubation or Pre-
treatment
- Nitrite content ↓,
iNOS expression ↓
[191]Rat TNBS Arginine-Glycine-
Aspartic acid (RGD)-
functionalized silk
fibroin nanoparticles
(SFN) (intrarectal, 1
mg/rat)
7 d n = 10 Adhesion of
integrins of the cell
surface to the extra-
cellular matrix of
connective tissue ↓→
leukocyte
recruitment to the
inflamed intestinal
tissue ↓→ iNOS
expression ↓
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[179]Mice DSS Pravastatin, an 3-
hydroxy-3-
methylglutaryl
(HMG)-CoA
reductase inhibitor,
(intraperitoneal, 1
mg/kg)
10 d n = 4-9 Cachexia ↓,
hematochezia ↓,
intestinal epithelial
permeability ↓ with
no effect on serum
cholesterol, colonic
injury ↓, expression
of mucosal vascular
addressin cell
adhesion molecule 1
(MAdCAM-1) ↓,
mucosal endothelial
nitric-oxide synthase
(eNOS) mRNA
degradation ↓, eNOS
expression ↑,
protective effects of
pravastatin in DSS-
induced colitis were
not found in eNOS-
deficient mice
[153]Mice Pathogen Citrobacter
rodentium as an
infection model and
DSS as an injury
model
Antennapedia-
linked
Apolipoprotein E-
mimetic peptide
COG112,
(intraperitoneal)
Concurrent with
induction of colitis,
during induction
plus recovery, or
only during the
recovery phase of
disease
n = 4 C. rodentium treated
mice→ improving
the clinical
parameters of
survival, body
weight loss, colon
weight, histologic
injury, expression of
iNOS & the CXC
chemokine
keratinocytes (KC) &
macrophage
inflammatory
protein (MIP)-2,
more effective in
iNOS-deficient mice,
DSS treated mice→
body weight loss ↓,
colon length ↓,
histologic injury ↓,
iNOS ↓, KC ↓, TNF-α
↓, IFN-γ ↓, IL-17
mRNA expression↓,
nuclear translocation
of NF-κB ↓, IKB
kinase (IKK) activity
↓
[192]Mice DSS 3,3-
Diindolylmethane
(oral)
7 d, commencing at
the same time DSS
exposure began
n = 5 Number of iNOS- &
COX-2-producing
cells ↓
[147]Rat DSS Glutamine (oral) 7 d with DSS n = 13 Cytokine-induced
iNOS expression↓,
nuclear translocation
of NF-κB p65
subunit ↓, cellular
heat shock proteins
(HSP)25 & HSP70 in
a dose-dependent
manner ↑
[180]Rat TNBS Lactulose (oral) 2 wk before TNBS
adminstration
n = 10 MPO activity ↓,
colonic TNF-α ↓,
leukotriene B4↓,
iNOS expression ↓,
levels of Lactobacilli
and Bifidobacteria
species in colonic
contents ↑
[229]Rat Iodoacetamide NG-nitro - L-NAME
(oral)
21 d n = 9-16 lesion area ↓, NOS
activity ↓
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[200]Mice DSS GL-V9, a
synthesized
flavonoid derivative
(intragastric)
From day 1 to day
10
- Inflammatory cells
infiltration↓,
myeloperoxida-se
(MPO) activity ↓,
iNOS activity ↓, ROS
& MDA generation
↓, SOD ↓, GSH
reservoir ↑, pro-
inflammatory
cytokines
production in serum
& colon ↓; pro-
inflammatory
cytokines ↓, ROS
production ↓,
antioxidant defenses
↑ in mouse
macrophage
RAW264.7 cells by
promoting
thioredoxin-1
expression
[159]Mice DSS Glucosamine
oligomers
(Chitooligosaccharid
-es) (oral)
5 d n = 8 Number of positive
areas of iNOS &
nuclear factor (NF)-
κB staining in the
colonic epithelium ↓
[27]Mice DSS Nitrite (1 mmol/L)
or nitrate (10
mmol/L) (oral)
7 d n = 27-29 Nitrite (1 mM) →
DAI score↓, colon
length ↑, iNOS
expression ↓,
histopathology ↓,
DSS-induced
decrease in colonic
mucus thickness↓,
goblet cell
abundance ↑. Nitrate
(10 mM)→ DAI-
score ↓
[176]Rats, mice TNBS and DSS Doxycycline (oral) 5 d after the first
DSS colitis induction
n = 10-21 Macrophages → IL-8
production ↓ by
intestinal epithelial
cells & NO
production ↓. TNBS-
colitic rats (5, 10 and
25 mg/kg) → DAI
score ↓, colonic
tissue damage ↓,
mRNA expression of
IL-6, TNF, IL-17,
intercellular
adhesion molecule 1
(ICAM1), iNOS &
MCP-1 ↓, partial
restoration of the
mRNA levels of
markers of intestinal
barrier function
(ZO-1, occludin &
mucin (MUC)-3
[173]Ulcerative Colitis
(UC) and Crohn's
Disease (CD)
patients
- Corticosteroids
(Sulfasalazine and
Azathioprine)
(intravenous)
- (1) UC treated with
high dose
corticosteroids (6
patients, 10 blocks);
(2) UC patients who
had never received
corticosteroids (10
patients, 16 blocks);
(3) CD treated with
high dose
corticosteroids (12
patients, 24 blocks);
(4) Non-
inflammatory, non-
neoplastic controls
(4 patients, 6 blocks)
Immunostaining
with an antibody
raised against the C
terminal end of
iNOS for NOS→
diffuse in UC &
patchy in CD in
epithelial cells &
was most intense
near areas of
inflammation, Non-
inflamed epithelium
showed no
immunoreactivity,
treatment with
corticosteroids made
no difference to the
amount of NOS
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[162]Rat TNBS Telmisartan
(angiotensin II
receptor antagonist)
(oral, 10 mg/kg)
10 d before TNBS
and until day 4 of
TNBS
n = 8 DAI score ↓, colon
weight/length ratio
↓, macroscopic
damage ↓,
histopathological
findings ↓.
Inflammation ↓,
leukocyte migration
↓, TNF-α ↓,
prostaglandin E2
(PGE2) ↓, MPO
activity ↓,
restoration of IL-10
mRNA and protein
expression of NF-κB
p65↓, mRNA
expression of COX-2
and iNOS ↓,
peroxisome
proliferator-
activated receptor
(PPAR)-γ ↑,
oxidative stress ↓
[lipid peroxidation
(LPO) ↓, NO ↓, GSH
↑, TAC ↑, SOD ↑,
glutathione
peroxidase
activity↑], apoptosis
↓ (mRNA, protein
expression and
activity of caspase-3
↓, cytochrome C and
Bax mRNA ↓, Bcl-2
↓)
IBD: Inflammatory bowel disease.
Tropisetron: Tropisetron is a serotonin 5-hydroxytryptamine 3 receptor antagonist
and is mainly used as an antiemetic agent. Tropisetron was shown to have an anti-
inflammatory effect via PPARγ upregulation, resulting in NF-κB blockade and
diminishing NO production[156]. This drug reduced the expression of β-catenin and
COX-2 in a colitis-associated cancer experimental group, while the levels of IL-1β,
TNF-α, TLR-4, and Myd88 were significantly decreased with tropisetron treatment[157].
Cyclopentenone prostaglandin 15-deoxy-Δ 12,14-PGJ 2: Treatment of experimental
colitis model rats with 15-deoxy-Δ 12,14-PGJ 2 (15d-PGJ2) resulted in significant
attenuation of severity of colon damage, which was attributed to reduced iNOS and
suppressed NF-κB-DNA binding in 15d-PGJ2 treated group[158].
Glucosamine oligomers: Colitis animals treated with glucosamine oligomers have
shown a significant reduction in the expression of iNOS and NF-κB, and prolongation
of survival time[159]. Oral administration of glucosamine oligomers inhibited
inflammation in colonic mucosa by suppressing MPO activity in inflammatory cells,
and by reducing NF-κB, COX-2, iNOS, and the serum levels of TNF-α and IL-6[159].
8-hydroxydeoxy guanosine: 8-hydroxydeoxy guanosine (8-OHdG) is a product of
ROS attacking guanine bases in DNA, which can bind thymidine rather than cytosine.
Therefore, 8-OHdG is a biomarker of mutagenesis consequent to oxidative stress. It
was shown that the administration of exogenous 8-OHdG can repress NF-κB
signaling, pro-inflammatory cytokines, COX-2 and iNOS expression in stress-induced
and inflammation-based GI tract conditions. Such outcomes might show a potential
beneficial therapeutic effect[160].
Macrophage migration inhibitory factor inhibitor: In RAW 264.7 cells, migration
inhibitory factor (MIF) inhibitor significantly reduced inflammation by inhibiting
MIF-induced NF-κB nuclear translocation and NO production, proposing a new
strategy for colitis management[161].
Telmisartan: Telmisartan administration diminished NF-κB p65 protein expression,
and reduced the expression of iNOS and COX-2 in a colitis rat model[162].
Amitriptyline: Amitriptyline is an antidepressant that is used to control the
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psychosomatic symptoms of GI disorders. It was reported that amitriptyline inhibited
the degradation of IκB, and the production of NO and TNF-α[163], suggesting a possible
role for amitriptyline in colitis treatment.
Recombinant human IL-11: In vitro treatment of macrophages with recombinant
human IL-11 (rhIL-11) caused a meaningful decrease in NF-κB-DNA binding and the
production of pro-inflammatory cytokines and NO. Co-administration of normal
intestinal cells with rhIL-11 reduced cellular proliferation, representative of a possible
function of rhIL-11 in treating colitis patients with IL-11[164].
Non-NF-κB dependent synthetic molecules
Herein, we address studies that evaluated the effect of synthetic compounds on NO
production and colitis severity, regardless of the NF-κB pathway.
NO intervention: Although the whole context of this review has been concentrated on
the detrimental effect of the overproduction of NO in colitis progression, some studies
indicated that a basal amount of NO, mainly produced by eNOS, is necessary for
normal colon physiology. In animal models of colitis, the administration of nitrite or
nitrate results in attenuation of colitis activity and damage, covering both preventive
and therapeutic approaches[28]. Considering the key role of NO in colon damage
induced by colitis, one would think it is reasonable to develop a set of direct iNOS
inhibitors to manage the condition. Despite such a straightforward idea, the iNOS
inhibitors raised a contentious scientific arguement, as a number of investigations
reported no improvement, while some others have found promising results[165,166]. For
instance, Methylene blue which is a well-known NOS inhibitor was shown to reduce
mucosal inflammation damage and decrease the expression of iNOS and MPO in
colitis experimental models[167]. The difference in eNOS antagonism affinity of
antagonists used in each study was assumed to be the underlying reason for this
inconsistency.
Nicotine: The positive effect of nicotine on UC, but not CD, has been known for quite
a long time. However, data are not congruent regarding the correlation between NO
and nicotine; some have noted a significant decrease in iNOS expression and NO
production, while in some cases these effects were not observed. However, it has been
accepted that nicotine is able to reduce the severity of colon inflammation in some
settings[168,169].
Anti-inflammatory drugs: As noted above, dexamethasone had positive effects on
colitis mainly by reducing NF-κB activity. Budesonide and Prednisolone, which are
corticosteroids, attenuated inflammation and iNOS expression in UC cases[170].
Celecoxib, Rofecoxib, and Nimesulide, which are non-steroidal COX-2 inhibitor anti-
inflammatory drugs, have also significantly repressed iNOS activity and
inflammatory damage in the colon[171,172]. Sulfasalazine and Azathioprine did not affect
NO production in colitis[173].
Drugs with collateral anti-inflammatory effects: A broad list of chemical compounds
and drugs has been investigated as NO inhibitors. Of note, Trimetazidine,
Minocycline, N-Acetylcysteine, Pravastatin, Glutamine, Lactulose, Carvedilol, and
Melatonin are all among the approved drugs for other medical conditions rather than
inflammation, nonetheless, they have also been shown to possess anti-inflammatory
and iNOS inhibitory effects, at least to some extent.
Trimetazidine: Trimetazidine is mainly used for angina pectoris and is considered to
be a favorable drug for colitis treatment that reduces colon damage severity and NO
production. The effect of Trimetazidine was correlated with the antioxidant properties
of this drug[174].
Minocycline: Apart from Minocycline's antibiotic properties, it has also been shown
to regulate inflammation in some medical conditions. In colitis, Minocycline inhibited
iNOS expression and reduced colon inflammation, damage and mortality[175].
Although activation of the NF-κB pathway by Minocycline is greatly supported by the
literature, enhancement of NF-κB in colonic tissue is still in doubt[175].
Doxycycline: Another antibiotic, Doxycycline, has shown promising immuno-
modulatory properties. Doxycycline can ameliorate colitis and colon damage by
decreasing the pro-inflammatory cytokine, IL-8 and NO generation, an effect which is
even enhanced when it is concurrently administered with Saccharomyces boulardii[176].
N-acetylcysteine: N-acetylcysteine (NAC) is a known antioxidant agent and has been
shown to substantially reduce colon damage and NO production, particularly in
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Kamalian A et al. Pharmacological interventions for IBD, targeting NO
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relatively higher doses[177]. In a DSS-induced colitis model, NAC attenuated
macroscopic and histopathologic colonic damage similar to 5-ASA treated mice. In
addition, NAC reduced colonic MPO activity, ROS, TNF-α, and IL-1β levels, while
elevating paraoxonase/arylesterase 1 (PON1) activity, and GSH concentration.
Overexpression of PON1 and scavenging of oxygen-derived free radicals might be the
mechanisms underlying the protective effect of NAC in colitis treatment[178].
Pravastatin: Pravastatin is a β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase
inhibitor, able to ameliorate colitis severity and reduce colitis symptoms. Colitis
model mice lacking eNOS have not shown this effect, suggesting that Pravastatin
exerts its anti-inflammatory effects by upregulating eNOS expression rather than
inhibiting iNOS[179].
Lactulose: Lactulose is a well-known osmotic anti-constipation agent, but also reduces
TNF-α and leukotriene B4 production, as well as iNOS inhibition, mostly due to its
probiotic properties, leading to Lactobacilli and Bifidobacteria overgrowth in the
colon[180].
Carvedilol: Carvedilol, a nonselective β-adrenoceptor antagonist with α1-
adrenoceptor antagonist activity, is also an antioxidant and anti-inflammatory agent.
Carvedilol attenuated colon histopathological damage and iNOS expression, and
reduced TNF-α, IL-1 β, IL-6 and PGE2 levels[181].
Melatonin: Melatonin administration in colitis models improved the disease
symptoms, and decreased the expression of iNOS, COX-2 and MPO[182,183]. There have
been some efforts to develop colon-specific sodium alginate gels containing
melatonin, to confirm melatonin associated anti-inflammatory effects[182]. The fact that
melatonin is a sleep-related neurohormone might propose a relationship between
sleep patterns and colitis pathogenesis, which can be a topic of future studies.
Miscellaneous compounds
Soluble guanylate cyclase inhibitors: Colitis is associated with a reduced soluble
guanylate cyclase (SGc) sensitivity, hence, a reduced colonic response to nitrergic
stimuli. This finding puts forward the idea that inhibition of SGc might enhance colon
protection in colitis. In contrast, several studies claimed that the pharmacological
inhibition of SGc does not exert any protective effects in colitis[184].
Calpain inhibitor I: Calpain is a family of calcium-dependent proteases, and although
their physiologic functions are poorly understood, they are thought to be of
importance in cellular functions such as cell mobility and apoptosis[185]. Calpain
inhibition has been found to cause a significant reduction in iNOS expression in colitis
animals[186].
IL-4: Transfection of colon with IL-4-gene-carrying adenovirus vectors has
successfully increased IL-4 concentration, and significantly reduced the expression of
INF-γ, MPO and iNOS[187].
TNF-α Convertase (TACE/ADAM17) inhibition: BB1101, a TACE/ADAM17
inhibitor has shown a promising suppressive effect on iNOS expression and TNF-α
release in the colon of IBD animals, leading to a significant anti-inflammatory
effect[188].
α-Melanocyte-stimulating hormone: In colitis settings, administration of α-
Melanocyte-stimulating hormone, a melanogenesis stimulator, can significantly affect
NO production, modulating inflammation and providing protective benefits in the
colon[189].
Ursodeoxycholate: Ursodeoxycholate, a bile acid, has successfully protected the colon
against LPS-induced colitis in rats, mainly by hampering iNOS activity[190].
(Arginine-glycine-aspartic acid) RGD motif: It has been proposed that integrins have
great importance in colitis pathogenesis and their dysfunction can cause an inflamed
colon due to leukocyte recruitment. As an integrin motif, administration of RGD to
the colon, using silk functionalized particles, resulted in a significant decrease in iNOS
expression[191].
3,3′-diindolylmethane: 3,3’-diindolylmethane, a cruciferous family of vegetables
derived molecule has been shown to inhibit iNOS and COX-2 expression[192]. The
underlying mechanism is not fully understood.
GL-V9: This compound is a synthetic flavonoid, capable of inhibiting inflammatory
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cells infiltration and decreasing MPO and iNOS activities[193]. Furthermore, GL-V9
decreased pro-inflammatory cytokines and ROS production, increased antioxidant
defenses in mouse macrophage RAW264.7 cells; mainly by promoting Trx-1
expression. It has been demonstrated that GL-V9 decreased oxidative stress by up-
regulating Trx-1 via activation of the AMPK/FOXO3a pathway, suggesting that GL-
V9 might be a potential choice for IBD[193].
Propionyl-L-carnitine: Propionyl-L-carnitine, an antioxidant molecule, inhibited
oxidative stress-induced CAM expression, thus, reducing leukocyte infiltration in the
colon, which then led to a significant reduction in iNOS expression[194].
Tetrahydrobiopterin: The enzyme cofactor tetrahydrobiopterin is a fundamental part
of biogenic amine synthesis, lipid metabolism and redox coupling of NOS. An oral
suspension of tetrahydrobiopterin was shown to reduce iNOS activity and increase
regulatory T cells in the colon environment, leading to reduced colon inflammation,
shrinkage and swelling[195].
CONCLUSION
It has been shown that NO has a significant role in the pathogenesis and treatment of
IBD. In this paper, pharmacological interventions that affect IBD, especially those
modulating the NO pathways, were reviewed in two distinct categories: natural
agents and synthetic agents. The outcomes of this study demonstrated that herbal
agents i.e., flavonoids can decrease NO production and iNOS expression, leading to
therapeutic effects comparable with Mesalazine in IBD. NF-κB and JAK/STAT are the
major pathways involved in this process. Activation of PPARγ, inhibition of iNOS,
and suppression of TLR-4 upregulation; in addition to the secretion of inflammatory
cytokines are considered to be the main therapeutic mechanisms of flavonoids in this
regard. This review indicates that other polyphenol compounds could also be
beneficial, mainly due to iNOS modulation and NF-κB suppression. Interestingly, a
number of these compounds could even upregulate eNOS, which is necessary for
normal colon physiology. Probiotics and prebiotics can also alter the intestinal
microbiome and have the ability to prevent or reduce inflammation in IBD. Previous
studies indicated that pro- and pre-biotics reduce NO production and suppress iNOS
activity through different mechanisms such as suppressing the IκB/NF-κB pathway,
IL-10 secretion, dendritic cells-induced IL-12 secretion, and modulating the expression
of iNOS and TLR 4. It has been suggested that dairy products have similar properties,
seemingly by alterating the colonic bacterial population. Fatty acids such as PUFAs
can also improve IBD by modulating the production of eicosanoids, COX-2, PPAR-γ,
and NF-κB, and exhibiting inhibitory effects on iNOS.
Sulfasalazine and Azathioprine are fundamental anti-inflammatory and
immunomodulatory drugs for IBD treatment, but have no effect on NO production in
colitis. Synthetic compounds could also be effective treatments for IBD, of which some
(i.e., Dexamethasone, Pioglitazone, Tropisetron) can act through the NO and NF-κB
signaling pathways. Other therapeutic compounds could regulate NO, independent
of NF-κB. For instance, nicotine; anti-inflammatory agents (i.e., Prednisolone and
Celecoxib); β-adrenoceptor antagonist with α1-adrenoceptor antagonist activity (i.e.,
Carvedilol); antioxidants (i.e., N-Acetylcysteine); and specific iNOS inhibitors (i.e.,
Methylene blue) are able to attenuate iNOS expression and NO production, directly or
by mechanisms other than the NF-κB signaling pathway.
It is important to mention that the IBD inhibitory effects of phytochemicals or their
combination with conventional therapeutics are principally implicated due to their
ability to modulate the main pathophysiological factors of IBD development;
inflammatory cytokines (i.e., IL-6, IL-12) production. Although, such treatments are
affordable, they can alleviate the pain and inhibit inflammation in IBD patients,
however, the major drawback of natural compounds is their mode of action, and their
limited bioavailability at the site of inflammation. In comparison, the antibody based
treatments such as anti-TNF biologics (i.e., Infliximab, Adalimumab or Etanercept)
have more specificity, can lower cytokine production, inhibit inflammatory cell
recruitment, and induce cell death of inflammatory cells, while representing less
efficacy, as a significant percentage of patients do not respond to anti-TNF treatment.
Furthermore, such therapeutics are expensive and showed some adverse effects such
as increased risk of infection and malignancy or may cause de novo autoimmune
diseases[196-198]. Overall, this review highlights the importance of NO in the
pathogenesis and treatment of IBD. It seems the (co)administration of natural or
chemical NO-regulating compounds might be favorable for patients suffering from
IBD. Further investigations and well-designed trials are worth consideration.
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