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indomethacin-induced peptic ulcer in rats
presumably via increase in gastric mucosal
SOD, as well as inhibition of histamine release. These findings indicate that marshmallow preparations are a proper choice for
treatment of irritated mucosal tissue, and
thus A. officinalis could be a candidate for future investigations on IBD.
Matricaria chamomilla L.
Oral administration of the ethanolic extract
of chamomile flower at a dose of 500 mg/kg
daily (from 48 h prior to induction of colitis)
reduced serum electrolytes (sodium (Na)
and potassium (K)), and enhanced total
leukocyte count, lymphocyte count, erythrocyte count, blood hemoglobin percentage,
and packed cell volume percentage in glacial
acetic acid–ethanol-induced UC in rabbits
(Al-Hussaini etal., 2012). In a rat model of
acetic acid-induced colitis, aqueous extract
of chamomile flowers (20 and 30 mg/kg)
significantly reduced severe macroscopic
and histopathologic colon injury indices,
which was implicated in reduction of MPO
activity and MDA content of inflamed colon
(Masoumi-Ardakani etal., 2014).
Boswellia serrata Roxb. ex Colebr.
Oleo-gum-resin of Boswellia spp., known as
frankincense or olibanum, contains boswellic acids as the major constituents with potent anti-inflammatory properties. In vitro
and in vivo studies have shown that boswellic acids inhibit the leukotriene biosynthesis
in neutrophilic granulocytes via inhibition
of 5-lipoxygenase. Since the inflammatory
process in IBD is associated with increased
function of leukotrienes, it is thought that
Boswellia serrata has a favorable impact on
inflammatory diseases such as IBD.
In acetic acid-induced colitis in rats, oral
gavage of B. serrata extract (34.2 mg/kg daily)
for 2 days before and after the induction of
colitis led to a significant increase in anal
sphincter pressure, and improved the intestinal mucosal injury and histologic aspects of
the colon. The protective effect of B. serrata
was due to increases in SOD, GPx, and GSH
activities, as well as reduction of LPO (Hartmann et al., 2012). In another study using
acetic acid-induced acute colitis, pretreatment and treatment with B. serrata extract
(oral gavage, 34.2 mg/kg daily) for 2 days suppressed LPO and the expression level of NO
and iNOS, while improving colonic tissue injury and anal sphincter pressure (Hartmann
et al., 2014). Intraperitoneal injection of a
semisynthetic form of acetyl-11-keto-β
boswellic acid (sAKBA) (5 mg/kg/day, for 5
days), the most potent anti-inflammatory
component of frankincense, decreased leukocyte and platelet infiltration into the inflamed colonic site, improving macroscopic
and microscopic colitis symptoms and DAI.
In addition, sAKBA reduced DSS-induced
P-selectin-mediated recruitment of inflammatory cells and upregulation in mice with
colitis (Anthoni etal., 2006). Microarray analyses of hepatic gene expression (i.e., a large
group of lipid metabolism-related genes, and
detoxifying enzymes) pointed out the potential hepatotoxic effects of Boswellia (at high
dosage) with evidence of steatosis, as confirmed in vitro in HepG2 cells, which should be
considered in clinical use (Kiela etal., 2005).
Given the positive outcomes of experimental studies on therapeutic benefits of
B. serrata extracts or its bioactive phytochemicals on IBD, several clinical trials were performed. In 1997, Gupta et al. conducted a
clinical trial in patients with UC in grade II
and III using B. serrata gum resin preparation
(350 mg, 3 times daily for 6 weeks). The gum
resin improved stool properties, histopathologic and microscopic manifestations of
rectal biopsies, as well as blood biochemicals
(i.e., hemoglobin, serum iron (Fe), calcium
(Ca), phosphorus (P), proteins, total leukocytes, eosinophils). While 82% of patients
receiving B. serrata experienced remission,
the remission rate in the sulfasalazine group
was 75% (Gupta etal., 1997). Gupta and colleagues developed another human trial in
2001. Administration of the same preparation at a daily dose of 900 mg for 6 weeks to
patients with chronic colitis resulted in the
same outcomes as their previous study on UC
patients, although, in the B. serrata-treated
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group, the remission rate was higher than
that of sulfasalazine-treated patients (Gupta
etal., 2001). Results of another double-blind,
randomized, placebo-controlled trial revealed
that oral consumption of B. serrata extract
(400 mg, 3 times daily for 6 weeks) was promising for treatment of collagenous colitis.
B. serrata enhanced the number of patients in
clinical remission compared to the placebo
group (per protocol: 63.6%, 95% confidence
interval (CI) 30.8–89.1% versus 26.7%, 95%
CI 7.7–55.1%, P = 0.04; intention-to-treat:
43.8% versus 26.7%, P = 0.25); whereas there
was no effect on histology and quality of life
(Madisch etal., 2007).
Lepidium sativum L.
Garden cress seed oil is a rich source of unsaturated fatty acids such as n-3 fatty acids.
In DSS-induced colitis in rats, addition of
garden cress seed oil to the animals’ diet
reduced the intestinal levels of MPO, leukotriene B4, MDA, NO, TNF-α, and IL-1β.
Moreover, DAI scores, colon length, macroscopic scores and morphologic damage, and
the GSH content were improved in colitis
subjects after receiving L. sativum seed oil
(Reddy etal., 2014). The mucilage extracted
from garden cress seeds (100 mg/kg b.w.)
was fed to rats with indomethacin (6 mg/kg
daily)-induced colitis for 2 weeks before and
7 days after induction of colitis. Herbal
treatment ameliorated IBD through mediating the erythrocyte sedimentation rate,
plasma lactate dehydrogenase (LDH) activity, and reduction of intestinal TNF-α, NO,
and MDA levels. Pretreatment with the
mucilage increased GSH level in rats in comparison to untreated animals (Akl et al.,
2021). As mentioned earlier, Magliasa is a
favorable herbal preparation for the treatment of colitis. It is noteworthy that the
formulation of Magliasa contains 50% w/w
of the intact unmilled seeds of L. sativum
(Rahimi et al., 2010). Overall, garden cress
seed extracts alleviate oxidative stress, suppress inflammatory mediators, and reduce
colonic damage in experimentally induced
colitis models.
Anethum graveolens L.
Irritable bowel syndrome (IBS) is a
long-term chronic GI condition. The effectiveness of Anethum graveolens (dill) in 32
patients with IBS was examined in a clinical
trial against the standard control, mebeverine (135 mg, 3 times daily), for 2 weeks.
In dill-treated group (1 capsule with 500 mg
dill powder, three times a day), there was
improvement in all IBS symptoms including
pain severity, pain frequency, stool frequency,
stool consistency, abdominal distension,
incomplete evacuation, urgency, and passing of mucus, in both individual symptom
scores and total improvement scores (Mohammad, 2012).
Malva sylvestris L.
Pretreatment with the aqueous fraction (obtained from aerial parts) and an isolated
polysaccharide compound of M. sylvestris at
a dose of 200 mg/kg daily for 5 days consecutively alleviated the inflammatory
symptoms of experimental IBD in acetic acidinduced colitis in rats. The efficacy of ethanolic and n-hexane fractions was lower in
preventing inflammation. The aqueous fraction was found more protective against UC
compared to the isolated polysaccharide,
suggesting that synergism of other phytochemicals in the aqueous fraction might
contribute in its healing effect. The aqueous
fraction of M. sylvestris is reported to have a
high content of polyphenols and mucilaginous polysaccharides (Hamedi etal., 2016).
Commiphora mukul
(Hook. ex Stocks) Engl.
The gum resin of Commiphora mukul is known
as “guggul” and has been mentioned in TPM
textbooks to have anti-inflammatory function. In a mouse model of T-cell-induced colitis, it was shown that a plant sterol isolated
from the gum resin of C. mukul tree called guggulsterone (GS) exerts immunomodulatory
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activities. GS (30 mg/kg, for 5 days) attenuated colon inflammation by reducing the mediators of adaptive immunity, DAI, as well as
macroscopic and microscopic damage scores
in both TNBS- and oxazolone-induced colitis
in mice. Cis-GS (E-GS) was found more effective than trans-GS (Z-GS) in amelioration of
IBD in vivo. Co-culture of GS and lamina propria-derived T cells obtained from mice treated with TNBS or oxazolone led to reduction of
IL-2, IL-4, and interferon-γ (IFN-γ) production, as well as T-cell proliferation (Mencarelli
etal., 2009). Chemical analyses revealed that
Z-GS is mainly responsible for the anti-inflam-
matory activity of this plant (Sosa e tal., 1993).
Cheon and colleagues reported that GS suppressed IL-1β- or LPS-induced intercellular
adhesion molecule-1 (ICAM-1) expression,
NF-κB transcription activity, and IκB kinase
phosphorylation in human Caco-2 cells and
rat non-transformed IEC-18 cells (Cheon
etal., 2006). GS treatment significantly suppressed the mRNA expression of pro-inflammatory cytokines, including IL-1β, TNF-α,
and iNOS, and inhibited the NF-κB activity in
LPS-stimulated macrophages, a representative of its anti-inflammatory activity (Zhang
etal., 2016). In a recent study, following cerebral ischemic injury, administration of Z-GS
ameliorated astrocyte-mediated neuroinflammation through downregulation of the TLR4
pathway (Liu et al., 2018). Activated TLR4/
NF-κB signaling pathways are involved in the
pathophysiology of many chronic and inflammatory impairments such as IBD (Momtaz
etal., 2021).
administration of R. × damascena extract at
all doses examined (250, 500, and 1000 mg/kg
b.w, for 4 days), and the lowest doses of
volatile oil given orally (100 μl/kg b.w.) or
intraperitoneally (125 μl/kg b.w.), alleviated
histologic and macroscopic indices of colitis,
as well as MPO activity (Latifi etal., 2015).
In a randomized, double-blind clinical trial
on 20 patients with moderate-to-severe UC,
consumption of two rose oil soft capsules
(1000 mg) 3 times daily for 2 months caused
numerical (but not statistical) reduction of
Mayo Clinic (DAI) scores in both placebo
and intervention groups. Inflammatory
Bowel Disease Questionnaire (IBDQ)-9
score was also elevated in both interven
tions before and after the treatment; however, the difference was not significant. In
TPM, there are some topical remedies that
are generally applied on the stomach, lower
abdomen, lower back, and liver to relieve digestive discomforts such as dyspepsia, gastritis, IBD, digestive ulcers, intestinal
worms, and infections. R. × damascena is one
of the most common medicinal herbs that
are used to formulate topical medications
for GI diseases. It was proposed that suppression of oxidative stress, inflammatory
cytokines, and signaling pathways of inflammatory responses, or improvement of
analgesic factors are main mechanisms of
the therapeutic effects of this plant (Tafti
etal., 2017).
Myrtus communis L.
Rosa × damascena Herrm.
Therapeutic values of Rosa × damascena are
mainly attributed to its high content of
polyphenolic components. Several animal
and human studies confirmed that R. × dam-
ascena extracts or its volatile oil interfere in
various cellular and molecular pathways and
repress oxidative- or inflammation-induced
damage of the body cells, tissues, or organs
(Nayebi et al., 2017). A hydroalcoholic ex-
tract of the plant and its volatile oil were
tested in acetic acid-induced UC in rats. Oral
Phytochemical characterization exhibited
that phenolic acids, tannins, flavonoids,
glycosides, and terpenes are the key components of Myrtus communis; whereas monoterpene and sesquiterpene derivatives are
the main ingredients of the essential oil of
this plant (Sisay and Gashaw, 2017). In acetic
acid-induced UC in rats, treatment with
M. communis ethanolic extract (50 and 100
mg/kg, oral gavage for 3 days) reduced colonic
MDA level, MPO activity, and luminol, lucigenin, NO, and peroxynitrite chemiluminescence values. Macroscopic and microscopic
signs of colitis severity were alleviated, along
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with a significant increase in tissue GSH
level (Tafti etal., 2017). In the same animal
model, M. communis hydroalcoholic extract
and its essential oil were given orally to rats,
2 h before induction of colitis and for a further 4 days. The plant extract (50, 100, and
200 mg/kg) and the essential oil (62.5 and
125 μl/kg b.w.) were statistically effective in
improvement of colonic inflammation and
tissue edema, ulcer index, total colitis index,
and MPO activity (Khosropour etal., 2019).
Jabri e tal. (2015) reported that myrtle seeds
are rich in anti-inflammatory compounds
such as malvidin-O-glucoside and delphini
din-3-O-glucoside. The aqueous extract of
myrtle berry seeds significantly reduced
all histologic alterations caused by acetic
acid-induced UC in rats. The extract also
inhibited ROS production by neutrophils,
colonic H2O2, and free Fe and Ca levels during the inflammatory reaction and improved
the enzymatic activity of SOD, CAT, and
GPx. The extract improved the nonenzymatic antioxidants such as GSH and sulfhydryl
group (–SH) in the injured colon mucosa. Inflammation retrieval and protective effect
of this extract was implicated in its ROS
scavenging potential or to inhibition of
intracellular Ca deregulation (Jabri et al.,
2015). The essential oil and crude extract of
the leaves of M. communis showed antiulcerogenic effect in an animal model of gastric
ulcer, which was confirmed by its antioxidant activity in vivo and in vitro. Recovery of
mucosal damage, suppression of the oxidative status associated with inflammation,
and downregulation of pro-inflammatory
cytokines such as IL-1β and TNF-α, as well
as iNOS, ICAM-1, and cervical intraepithelial lesions 1 (CIN 1), were thought to be the
main mechanisms involved in gastroprotective effect of M. communis leaves’ essential
oil and extract (Benchikh, 2018).
Solanum nigrum L.
A growing body of evidence indicates that
Solanum nigrum (black nightshade) fruits
have various valuable pharmacologic activities like antiulcer, antioxidant, and antiinflammatory properties. In a recent study
three S. nigrum genotypes (S. scabrum, S. sa-
charroides, and S. villosum) exhibited antiul-
cerogenic effects through improving both
gastric mucosal texture and microscopic
damage in a rat model of gastric ulcer (Mureithi, 2020). Another mechanistic study
demonstrated that 14 days’ supplementation with S. nigrum extract attenuated
pyloric-ligation/indomethacin-induced gastric ulceration in rats through antioxidant
action and suppression of pro-inflammatory
cytokine formation like TNF-α and IL-1β, as
well as promotion of mucin content (Zaghlool
etal., 2019).
It was shown that an isolated glycoprotein from S. nigrum fruits prevented NO production, LDH release, and MDA formation.
This glycoprotein downregulated the activities of NF-κB (p50) and AP-1 (c-Jun) and
regulated the expression of iNOS and COX-2
due to its antioxidative properties in DSSinduced UC in mice (Joo etal., 2009). In another animal study in acetic acid-induced
UC, S. nigrum at concentrations of 125, 250,
and 500 mg/kg was found effective as either
a prophylactic or protective administration;
however, its activity was not as potent as
dexamethasone at 0.1 mg/kg (El-Meligy
etal., 2015). Together, the potential action
of different parts of this plant, especially the
fruits, in both animal and clinical IBD
models as well as the probable mechanisms
involved remain to be elucidated.
Coriandrum sativum L.
The widespread presence of coriander in food
and pharmaceutical preparations, besides its
carminative, antispasmodic, anti-inflammatory, and antioxidant assets, makes Coriandrum
sativum a proper choice for IBD management.
Coriander has strong anti-inflammatory
properties that are mainly correlated with
suppression of pro-inflammatory cytokines
and their downstream pathways such as NO,
iNOS, IL-1β, IL-6, TNF-α, tumor necrosis
factor receptor 1 (TNFR1), ROS, COX-2, NFκB, and MAPK (Wu et al., 2010; Al-Snafi,
2016; Prachayasittikul eta l., 2018; Sari etal.,
2021).
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Heidari etal. (2016) provided evidence
that oral intake of the essential oil and hydroalcoholic extract of the fruits of C. sa-
tivum possessed protective and therapeutic
effects on the acetic acid-induced model of
colitis. Following coriander treatment (extract at 500 and 1000 mg/kg b.w., and essential oil at 0.5 ml/kg b.w.), colon biopsies
showed improved macroscopic and histopathologic scores, alleviation of total colitis
index, and decreased MPO activity (Heidari
etal., 2016). Pretreatment with a polyherbal
ayurvedic formulation containing four dif
-
ferent plant species including Aegle marmel-
os Corrêa, C. sativum, Cyperus rotundus, and
Vetiveria zizanioides was found to be benefi-
cial in acetic acid-induced colitis in mice and
indomethacin-induced enterocolitis in rats,
which are representative of UC and CD,
respectively (Jagtap etal., 2004).
Viola odorata L.
In recent studies anti-inflammatory, analgesic, antioxidant, diuretic, antihypertensive,
and antibacterial activities of sweet violet
were reported (Feyzabadi et al., 2017).
Hepatoprotective activity of Viola odorata is
the most studied property of this herb. In animal studies, V. odorata demonstrated protect-
ive effects against oxidative damage through
suppression of ROS, LPO, and protein carbonyl, as well as increase in GSH content.
Administration of V. odorata also regulated
serum hepatic markers such as blood alanine
aminotransferase (ALP), aspartate aminotransferase (AST), alkaline phosphatase
(ALT), total antioxidant capacity, and total
bilirubin (Qadir et al., 2014; Al-Snafi, 2016;
Habibi et al., 2019). Anti-inflammatory and
antioxidant capabilities of V. odorata have
been documented by many other experimental models. Alipanah etal. (2018) investigated
the cytotoxic, antioxidant, and antimetastatic
properties of the hydroalcoholic extract of V. o d -
orata in a breast cancer-implanted mice model.
It was shown that levels of LDH, γ-glutamyl
transferase (GGT), ALP, carcinoembryonic
antigen, and cancer antigen 15-3 in serum,
and the activities of CAT and SOD in tumor
tissue, were reduced (Alipanah etal., 2018).
Based on our knowledge, there is no
up-to-date information about apparent curative applications of V. odorata preparations on
digestive system disorders.
Quercus infectoria G. Olivier
Most of the studies about the pharmacological application of Quercus infectoria galls
have focused on the anti-inflammatory and
antibacterial properties of this species,
which is implicated by the presence of tannins and, in particular, gallic acid (Kahkeshani etal., 2019; Elham etal., 2020). Oral
administration of the alcohol extract of
Q. infectoria significantly inhibited carrageenan,
histamine, serotonin, and PGE
paw edema, while topical application inhibited phorbol-12-myristate-13-acetate (PMA)induced superoxide (O
ear inflammation. In vitro exposure of rat
•−
) production in
2
-induced
2
peritoneal macrophages to gall extract
ameliorated LPS-stimulated PGE2 and NO
production. The extract also inhibited the
iNOS and formyl-Met-Leu-Phe (FMLP)stimulated degranulation in the neutrophils.
Overall, oral or topical administration of
Q. infectoria gall extract prevented the production of some inflammatory mediators
(Kaur etal., 2004).
In N-ethylmaleimide-induced experimental colitis in rats, oral intake of Q. infec-
toria at doses of 300 and 450 mg/kg for 18
days could significantly prevent physical and
oxidative stress parameters in colon tissue
through improvement of the course of
experimental colitis, histological scoring
like colon mucosal damage index, and
DAI. Downregulation of NF-κB, NO, and
improvement of SOD were described to contribute to the protective effect of Q. infecto-
ria (Solanki et al., 2011). Khanavi et al.
(2014) conducted an investigation on biochemical and pathological parameters of colitis in rats treated with galls of Q. brantii.
Both gall powder and gall hydroalcoholic extract (gavaged for 10 days at dose of 500
mg/kg) decreased TNF-α, IL-1β, LPO, and MPO
activities in TNBS-induced inflammation
in colon tissue (Khanavi et al., 2014). During
the last decade, it was shown that gallic acid
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and its derivatives enhance the gut microbiome activities and modulate immune responses, thereby maintaining intestinal
health. Gene sequencing on mice fecal combined with metabolome analysis exhibited
that gallic acid treatment could modulate
the gut microbiota composition by alterations in metabolic and bacterial profiles
(Yang etal., 2020). Administration of gallic
acid increased carbohydrate and bile acid
metabolism and decreased the amino acid
metabolism in DSS-induced colitis, signifying that gallic acid significantly attenuated
UC by influencing the composition of the
mouse gut microbiome and metabolites.
Upon gallic acid treatment, the mRNA expressions of IL-21 and IL-23, DAI, and the
histopathologic evidence of colon injury
were reduced. The compound also significantly upregulated the expression of Nrf2
and its downstream targets, including UDP-
GT and NQO1, demonstrating that the protective effect of gallic acid on experimental
colitis might be due to the antioxidant activity of this compound (Pandurangan et al.,
2015). The compound suppressed LPSinduced inflammation in transgenic mice
through downregulating the NF-κB pathway
and modulating the immune system responses (Hsiang et al., 2013). In a TNBSinduced UC model, gallic acid increased the
expressions of IL-4 and IL-10, while it downregulated IL-1, IL-6, IL-12, IL-17, IL-23,
TGF-β, and TNF-α expressions. This indi-
cates that gallic acid plays an anti-inflammatory role in UC via inhibiting the NF-κB
pathway (Zhu etal., 2019). Likewise, gallic
acid treatment improved DAI, the histopathologic signs of epithelium injury and
inflammatory cell infiltration score, and the
markers of oxidative stress (i.e., LPO);
whereas it decreased the inflammatory
MPO activity of inflamed colon homogenate
in TNBS-induced UC in rats (Khodayar etal.,
2018; Marinov etal., 2019).
anthocyanins) are putative bioactive
pharmacologic constituents in alfalfa. Suppression of the expression of genes encoding pro-inflammatory cytokines such as
TNF-α, IL-6, and IL-1β, and downregulation of inflammation-related signaling
pathways (i.e., extracellular signal-regulated kinase (ERK)/NF-kB) are supposed to be
involved in anti-inflammatory action of
this herb (Choi et al., 2013; Chen et al.,
2015a,b). A recent study demonstrated
that the hydroalcoholic extract of Medicago
sativa exerted positive pathologic and be
havioral impacts on brain injury caused by
nicotine in vivo. Upon alfalfa treatment,
the serum levels of antioxidant parameters
including GPx and SOD increased, so the
MDA concentration was reduced. Furthermore, inflammatory responses were abrogated in alfalfa-treated animals (Raeeszadeh etal., 2021). In another animal model,
supplementation with alfalfa sprout ethyl
acetate extract lowered the serum TNF-α,
IL-6, and IL-1β levels in LPS-induced inflammation in mice. The same extract significantly reduced IL-6 and IL-1β production
and the NF-κB transactivation of mitogenstimulated RAW264.7 cells (Hong et al.,
2009). Xie etal. reported that oral administration of alfalfa polysaccharides improved
the function of the mouse immune system,
significantly enhanced the leukocyte and
lymphocyte counts, and led to improvements in spleen and thymus indices. They
also reported that alfalfa polysaccharides
improved the intestinal morphology in the
immunological system in mice (Xie et al.,
2019). Thus, the plant has presented antioxidant and anti-inflammatory properties,
although in vivo anticolitis activity still
needs to be investigated.
Bunium persicum (Boiss.) B. Fedtsch.,
Cuminum cyminum L.
Medicago sativa L.
Phytoestrogenic (i.e., isoflavones) and antioxidant compounds (e.g., carotenoids and
Despite the presence of solid data on the efficiency of herbal preparations of Bunium
persicum, and Cuminum cyminum in TPM
textbooks, the lack of information in this
field in modern medicine is significant.
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In acetic acid-induced colitis in rats, oral
intake of B. persicum essential oil (200 and
400 mg/kg) for 5 days decreased macroscopic
and microscopic indices of colitis (Rashidian
et al., 2021). In a double-blind, placebocontrolled study on patients with IBS, consumption of B. persicum powder for 5 weeks
showed no significant effect on symptoms
and inflammatory markers compared to the
placebo group (Abbasi etal., 2018).
C. cyminum contains various alkaloids
and polyphenols (Rai etal., 2012), as well as
high levels of oxygenated monoterpenes, especially γ-terpinene, cuminaldehyde, benzenemethanol, p-cymene, and limonene in
the essential oil (Sanei-Dehkordi et al.,
2016). According to the results of an animal
study on rats with IBS, administration of the
aqueous extract of C. cyminum seeds reduced
movements of the GI tract and IBS, which
was assumed to be associated with the presence of antioxidant substances in this plant
(Teimouri et al., 2019). In vivo, C. cyminum
and its bioactive compounds presented
strong analgesic and acute and chronic antiinflammatory activities (Bhat et al., 2014;
Golabi etal., 2020). In vitro, cumin essential
oil inhibited the mRNA expressions of lipoxygenase (LOX), while blocking the transcriptional activation of NF-κB and inhibiting
the phosphorylation of ERK and c-Jun
N-terminal kinase (JNK) (Wei etal., 2015).
Recent research reported that watersoluble polysaccharides of C. cyminum stimu-
lated the production of pro-inflammatory
cytokines in vitro in macrophages and natural
killer cells (Tabarsa etal., 2020). Also, in ethanol-induced hepatic damage, C. cyminum
could successfully reduce the increased activity of AST, ALT, and GGT, and inhibit LPO
(Aruna etal., 2005).
Allium ampeloprasum L., Allium
schoenoprasum L.
Organosulfur and polyphenolic compounds, especially ferulic acid, are major active ingredients
of Allium species (Putnik et al., 2019). In
TNBS-induced colitis in rats, ferulic acid (20 and
40 mg/kg, orally) ameliorated inflammation via
inhibition of oxido-nitrosative stress, apoptosis, pro-inflammatory cytokine production,
and downregulation of COX-2 synthesis (Sadar
etal., 2016). Administration of sodium ferulate
in the rat model of acetic acid-induced colitis improved the colon mucosa damage index and the
histopathologic score, probably due to the antioxidant activity, inhibition of arachidonic acid
metabolism, and NF-κB expression (Dong etal.,
2003). Upon treatment with ferulic acid and its
glycosides, particularly ferulic acid rutinoside,
there was a significant increase in transforming
growth factor-β1 (TGF-β1) levels in THP-1
derived DCs. Oral administration of ferulic acid
rutinoside attenuated DSS-induced colitis in
mice and induced the differentiation of regulatory T cells, indicating the immunomodulatory
effect of this compound on intestinal inflammation (Katayama etal., 2017). The seeds of A.
ampeloprasum are a part of Magliasa herbal formulation with a positive impact on IBD (Rahimi
et al., 2013). In a recent study, daily treatment of
onion bulb extract (Allium cepa) at 100–200 mg/kg
reduced colonic expression and activity of
pro-inflammatory chemokines and apoptotic
signaling pathways and mediators in DSSinduced colitis rats (Khajah etal., 2019).
Cydonia oblonga Mill.
Cydonia oblonga fruits contain various antioxidants such as caffeoylquinic acids and rutin,
whereas the seeds mostly contain mucilage and
organic acids (Silva et al., 2005; Al-Khazraji,
2013). It was shown that intraperitoneal injection of quince juice (800 mg/kg) and quince hydroalcoholic extract (500 mg/kg) for 5 days effectively mitigated UC lesions, extravasation,
and inflammation in damaged colon tissue
similarly to that of the standard, dexamethasone, in a TNBS-model of UC in rats (Minaiyan
et al., 2012). A plethora of studies have confirmed the anti-inflammatory properties of
quince pulp, peel, seed, and leaves. Furthermore, it was shown that quince presents
anti-inflammatory effects through suppression
of NO, LPO, IL-6, and TNF-α levels (Ahmed and
Bastawy, 2014). Essafi-Benkhadir and colleagues showed that quince polyphenols extract inhibited LPS-mediated activation of
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three major cellular pro-inflammatory effectors: NF-κB, p38MAPK, and protein kinase B (Akt) (Essafi-Benkhadir etal., 2012).
Literature data indicate that quercetin
and its derivatives, as one of the constituents
of quince fruit, possess remarkable protective
effects against colon injury in IBD through
induction of intense anti-inflammatory responses or inhibitory effects on oxidative
stress pathways or mediators. They also
restore the proper intestinal host–microbe
relationship and immunologic hemostasis in
animal models of intestinal inflammation,
thereby regulating colitis-stimulated intes
tinal microbiota dysbiosis (Hong and Piao,
2018; Ju etal., 2018; Lin etal., 2019). Rutin
(quercetin 3-rutinoside) was found to ameliorate inflammation in injured colon by suppressing the induction of pro-inflammatory
cytokines and improving colitis histologic
scores (Kwon etal., 2005). In another study,
rutin presented intestinal anti-inflammatory activity in chronic T-lymphocytedependent colitis upon quercetin release
and involvement of mucosal and lymph
node T cells. Rutin treatment reduced the
colonic expression of pro-inflammatory
genes such as interferon (IFN) and decreased
colitis severity by modulating the colonic
microenvironment, resulting in reduced colonic inflammation, promotion of colonic
mucosal injury repair, and attenuation of
colitis-associated microbial dysbiosis (Mascaraque etal., 2014).
Plantago ovata Forssk., Plantago
psyllium L.
Plantago ovata is a well-known plant for GI
problems, i.e., constipation, diarrhea, IBS,
IBD, and colon cancer (Madgulkar et al.,
2015). The plant seeds mainly contain
hydrocolloids, acidic and neutral polysaccharides (Sarfraz etal ., 2017). A soluble fiber
(psyllium) obtained from the husk of P. ov a ta
seeds has clinical benefits in patients with
IBD by remission maintenance and protection of the intestinal mucosa through reducing ulceration. This was attributed to a high
content of short-chain fatty acids in the
dietary fiber and consequently increased luminal production of short-chain fatty acids,
which were shown to induce immunomodulatory responses, accelerate healing and
regeneration processes of the intestinal epithelium, and regulate the gut microflora
(Pituch-Zdanowska etal., 2015). In a TNBS
model of rat colitis, administration of a fiber-supplemented diet (5% w/w P. ov a t a
seeds) for 2 weeks prior to colitis induction,
and for 1 week after, significantly reduced
the intestinal inflammation that was associ
-
ated with decreased TNF-α level and NOS
activity in the large intestine. A higher concentration of the short-chain fatty acid esters (mainly butyrate and propionate) was
recorded in the intestinal contents in fiber-supplemented rats (Rodríguez-Cabezas
etal., 2002). In a transgenic rat model of intestinal inflammation, supplementation with
a high-fiber diet containing 5% w/w psyllium seeds for 13 weeks improved the intestinal cytoarchitecture via downregulation of
pro-inflammatory markers like NO, leukotriene B4, and TNF-α. A significantly higher
production of short-chain fatty acid esters,
butyrate, and propionate was also observed
in psyllium-treated animals. Upon butyrate
and propionate exposure, TNF-α production
reduced in vitro (Rodrı guez-Cabezas et al.,
2003). A clinical trial was conducted on 105
patients with UC, based on the theory that
colonic fermentation of P. o va t a seeds results
in butyrate formation, which is thought to
be effective in UC treatment. Oral treatment
with P. ova ta seeds (10 g, twice daily) was almost as effective as mesalamine to maintain
remission in patients with UC. Thus, psyllium seems to be a promising candidate for
future clinical studies in patients with IBD.
Punica granatum L.
A growing body of evidence indicates the
potential therapeutic and preventive properties of dietary supplements made from pomegranate for serious chronic complications
such as cancer and inflammatory diseases. Flavonoids, anthocyanins, punicic acid, and ellagitannins are the main bioactive compounds
present in pomegranate. Upon intestinal
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metabolism, ellagitannins are hydrolyzed to
ellagic acid, which is the main active compound of pomegranate (Marín etal., 2013).
In acute DSS-induced UC in mice, dietary
supplementation with ellagic acid (2% w/w)
for 7 days ameliorated the disease severity
marginally by modulating inflammatory
mediators. However, in a chronic UC model,
consumption of ellagic acid (0.5% w/w) significantly inhibited the progression of the
disease, attenuated intestinal inflammation,
and decreased histologic scores. Moreover,
enzymes such as COX-2 and iNOS were
downregulated and the signaling pathways
were blocked, proposing that ellagic acid may
be favorable for UC treatment in chronic UC
patients (Marín etal., 2013). In 2010, Larrosa
etal. compared the effect of pomegranate intake (250 mg/kg) and its main microbiotaderived metabolite, urolithin-A (UROA, 15
mg/kg), on colon inflammation in DSSinduced colitis in rats for 5 days. Both
pomegranate and UROA decreased inflammation markers and modulated the gut
microbiota. Pomegranate, but not UROA, decreased oxidative stress in plasma and colon
mucosa. The authors concluded that UROA
might be the most active anti-inflammatory
compound derived from pomegranate ingestion in healthy subjects; whereas in colon inflammation, anti-inflammatory effects could
be due to the nonmetabolized ellagitanninrelated fraction (Larrosa etal., 2010).
Treatment with P. granatum extract and
its ellagic acid-rich fraction (100 and 200
mg/kg, orally) for 7 days significantly attenuated DSS-induced colonic inflammation along with reduction of histamine,
MPO, and oxidative stress (Singh et al.,
2009). Similarly, pomegranate fruit extract
improved UC severity and symptoms in dini
trobenzene sulfonic acid (DNBS)-induced colitis in rats, and attenuated oxidative stress
parameters levels, while it increased SOD activity (Darji et al., 2010). Pre-treatment and
post-treatment of rats with pomegranate in a
TNBS model of colitis decreased the serum
MPO, GSH, ALP, fibrinogen, and CRP levels
(Riaz etal., 2017). Kamat and Singh reported
that combination of Aegle marmelos and P.
granatum effectively improved DAI and colitis
macroscopy indices in a murine model of
DSS-induced acute colitis (Kamat and Singh,
2019). Peritoneal injection of P. granatum
juice and purified punicalagin in DNBS-induced colitis in animals significantly lowered
the disease extent and severity, and repressed
the gene expression of TNF-α, IL-18, and IL1β through decrease of the NF-κB mRNA
level. The results of the study suggested that
P. granatum juice has a higher potency than
purified punicalagin (Shah et al., 2016).
Consumption of pomegranate beverage re
duced inflammation and ulceration in intestinal
colitis through modulation of the miR-145/
p70S6K1/HIF1α axis and downregulation of
the expression of TNF-α, IL-1β, COX-2, and
iNOS (at mRNA and protein levels) in DSSinduced colitis in rats and in LPS-treated
CCD-18Co colon myofibroblastic cells. Moreover,
the rats treated with pomegranate showed a
significant regulation in their intestinal microbiome and an increase in butyrate-producing
bacteria (Kim etal., 2017). A dry whole pomegranate decoction (obtained from mesocarp)
and its main components, polysaccharides and
ellagitannins, significantly prevented the development of abdominal pain induced in rats
by DNBS, although ellagitannins were found
more potent than polysaccharides (Parisio
etal., 2020).
Administration of pomegranate beverage in rats with UC exhibited that pomegranate polyphenols downregulated the
mammalian target of rapamycin (mTOR)
downstream pathway through reduction of
ERK1/2. In silico modeling indicated a high
binding of docked gallic acid to the catalytic
domain of insulin-like growth factor 1 receptor (IGF-1R), which may suppress the
activity of the enzyme. Ellagic acid docked
effectively into the catalytic domains of
both IGF-1R and epidermal growth factor
receptor (EGFR) (Kim etal., 2016). In accordance with previous study, pomegranate juice
caused reduction of colon inflammation in
chronic model of colitis through reduction
of p70S6K by upregulating miR-145 and
downregulating the MAPK/ERK1/2 pathway (Kim etal., 2014).
In a randomized, placebo-controlled
clinical trial, patients with UC were randomized to receive an aqueous extract of pomegranate peel for 4 weeks as an adjuvant to
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standard medications. The Lichtiger Colitis
Activity Index (LCAI) was measured at baseline, week 4, and week 10. The LCAI score
was similarly reduced in both the pomegranate and placebo groups; however, the clinical
response was higher with pomegranate compared to placebo at week 4, but not at week
10 (Kim et al., 2016). In another human
study including 78 individuals, the difference between therapeutic responses of hot
and cold temperament patients (based on
TPM) with UC to pomegranate peel extract
was monitored for 4 weeks based on the
LCAI scoring system. Here, therapeutic re
sponse was significantly higher in patients
with hot temperament compared to patients
with cold temperament in the pomegranate-treated group, indicating the significance
of considering syndrome differentiation and
temperaments in interpreting the effect of
herbal medicine on UC (Kamali etal., 2017).
Conclusively, it seems that synergism between the antioxidant and anti-inflammatory actions of the bioactive constituents of
pomegranate makes it beneficial as an IBD
treatment (Nascimento and Araruna, 2016).
Rhus coriaria L.
In vitro and in vivo models provided strong
scientific evidence on the anti-inflammatory and antioxidant effects of sumac, associated with inhibition of ROS production,
NO release, and pro-inflammatory cytokines
(Khalilpour etal., 2018; Momeni etal., 2019).
Although therapeutic effects of sumac on
bowel complaints have been extensively
mentioned in folk medicine of various countries, only limited studies are available in
this context.
A recent study reported that oral sumac
improved clinical aspects of the intestinal injury in newborn rats with necrotizing enterocolitis. Treatment with sumac reduced protein
degradation products in the intestinal tissues
and also decreased the intestinal epithelial
cell apoptosis, which was associated with suppression of caspase-3, caspase-8, and caspase-9
immunoreactivity. In ethanol-induced gastric
ulcer in rats, the hydroalcoholic extract of
Rhus coriaria at doses of 145 and 248 mg/kg
(orally) significantly inhibited gastric lesions, which was confirmed by ulcer index,
ulcer score, and histopathologic evaluations
(Ahmad etal., 2013). A later study resulted
in similar outcomes in indomethacin- and
water immersion-induced restraint gastric
ulcer in an animal model, further confirming
the antiulcer properties of this plant (Ahmad
etal., 2015).
Plantago major L.,
Plantago lanceolata L.
Plantago major has previously presented significant anti-inflammatory effects (Hussan
etal., 2015; Zubair etal., 2019) and is widely
used to treat various GI diseases such as
diarrhea, constipation, and gastric ulcers. In
a randomized, double-blind clinical trial including 61 subjects with UC, after 8 weeks of
intervention with P. m a j o r (roasted seeds,
3600 mg/day), abdominal tenderness, gastroesophageal reflux, and gastric pain were
significantly less severe in the treated group
compared to the control group. Visible blood
in stool, distension, and anal pain were decreased in the P. m a j o r group, although the
differences were not statistically significant
between the two groups (Baghizadeh etal.,
2021). In a case report study involving a
35-year-old man with chronic pancolitis
who received P. m a j o r decoction twice daily,
the patient’s symptoms improved within a
few days after commencing treatment (Tafazoli etal., 2022). Oral administration of the
methanol extracts of P. m a j o r leaves at the
dose of 400 mg/kg significantly decreased
the average ulcer index and total protein in
gastric juice in aspirin-induced gastric ulcer
(Atta et al., 2005). The polyholozidic fraction of P. ma jo r leaves and seeds also showed
gastroprotective effects in experimental
models (Hriscu etal., 1990).
Malus species
Various species of apple represent a valuable
source of quercetin glycosides, catechin,
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