Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway
Yang et al. Journal of Inflammation
Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway
Lei Yang 0
Lei Shen 0
Yue Li 0
Yanxia Li 0
Shijie Yu 0
Shanshan Wang 0
0 Department of Gastroenterology, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University , Wuhan 430060 , China
Background: Hyperoside (Hyp) is a flavonoid glycoside compound that has been demonstrated to have antiinflammatory, anti-apoptotic and antioxidant effects. However, the impact of Hyp on inflammatory bowel disease (IBD) has not been previously explored. Thus, we evaluated the role of Hyp in dextran sodium sulfate (DSS)-induced acute colitis in mice. Methods: We established a mouse model of experimental acute colitis by treating mice with drinking water supplemented with 3.0% DSS for 7 days. The disease activity index (DAI), colon length, histological features and colonic malondialdehyde (MDA) levels were examined using appropriate methods, and COX-2 expression was examined by immunohistochemistry. TNF-α, IL-4, IL-6, IL-10, NF-κB p65, Bcl-2, Bax, Caspase-3, nuclear factorerythroid 2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1) and superoxide dismutase (SOD) levels in colorectal tissues were detected by RT-PCR and western blotting. Results: Hyp significantly attenuated DSS-induced changes in the DAI as well as DSS-induced colonic shortening and histological changes. Hyp also inhibited inflammation, a change reflected by decreases in TNF-α, IL-6, COX-2 and NF-κB p65 expression and increases in IL-10 expression. Hyp suppressed increases in the levels of apoptosisrelated proteins, such as Caspase-3 and Bax, but upregulated the level of the anti-apoptotic protein Bcl2. In addition, Hyp also exerted antioxidant effects. The MDA content was decreased, and the expression of Nrf2 and its downstream targets HO-1 and SOD were increased by Hyp. Conclusions: Based on these findings, Hyp possesses the ability to attenuate colitis, possibly by mitigating colonic inflammation and apoptosis via activation of the Nrf2 signaling pathway.
Hyperoside; DSS-induced colitis; Colonic inflammation; Apoptosis; Nrf2
Background
Ulcerative colitis (UC), one of the subtypes of
inflammatory bowel disease (IBD), is a chronic relapsing and
nonspecific inflammatory disorder of the gastrointestinal
tract. The prevalence of UC is increasing, and UC has
serious effects on the health and quality of life of
affected patients. Despite improvements in our
understanding of UC in recent years, the etiology and
pathogenesis of the disease remain unclear and may be
associated with several factors. UC is thought to be
associated with factors such as genetic susceptibility,
imbalances between gastrointestinal probiotics and
pathogenic bacteria, intestinal mucosa damage, immune
dysfunction and other phenomena. Immune
dysregulation likely underlies the basic pathogenesis of IBD [
1
].
The activation of the NF-κB pathway as well as the
release of related inflammatory cytokines and
proinflammatory mediators, plays an important role in the
pathogenesis of UC [
2, 3
], and increases in the frequency
of apoptosis, a process that results in the loss of
intestinal epithelial cells, also participate in IBD progression
[4]. Furthermore, the roles of oxidative stress and the
oxidant/antioxidant balance in UC development have
recently received increasing attention [
5
].
Nuclear factor-erythroid 2-related factor 2 (Nrf2), a
redox-sensitive transcription factor, is one of the
members of the Cap-N-Collar family of transcription factors.
Nfr2 features a leucine zipper structure [
6
] and plays a
key role in the antioxidant response. When cells are
exposed to oxidative stress, Nrf2 is released from
Kelchlike ECH-associated protein 1 (Keap1), which sequesters
Nrf2 in the cytoplasm, and then binds to Maf or Jun to
form a heterodimer in the nucleus. The heterodimer
combines with the antioxidant response element (ARE)
to promote the expression of genes encoding many
phase II detoxification and antioxidant enzymes,
including hemeoxygenase-1 (HO-1), superoxide dismutase
(SOD), and NOQ1, thereby improving the ability of the
cell to remove electrophilic and reactive oxygen species
(ROS) [
7
]. A Nrf2 deficiency has been shown to
exacerbate colonic injury in a mouse model of experimental
colitis [
8–10
], whereas pharmacological activation of
Nrf2 produced protective effects on the colon [
10, 11
].
The Nrf2 pathway not only upregulates the expression
of various antioxidant enzymes but also downregulates a
series of inflammatory mediators and attenuates
apoptosis [
12, 13
]. These Nrf2-mediated processes are vital to
the ability of the body to resist different types of injury.
Hyperoside (Hyp, a quercetin-3-O-β-D-pyran galactose
glucoside) belongs to the flavonol glycoside family and is
extracted from Hypericum, Ericaceae, Celastraceae and
other species. Hyp exerts a wide vari (...truncated)