Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway

Journal of Inflammation, Dec 2017

Hyperoside (Hyp) is a flavonoid glycoside compound that has been demonstrated to have anti-inflammatory, 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. 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 factor-erythroid 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. 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 apoptosis-related 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. 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.

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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)


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Lei Yang, Lei Shen, Yue Li, Yanxia Li, Shijie Yu, Shanshan Wang. Hyperoside attenuates dextran sulfate sodium-induced colitis in mice possibly via activation of the Nrf2 signalling pathway, Journal of Inflammation, pp. 25,