Sinomenine alleviates dextran sulfate sodium‑induced colitis via the Nrf2/NQO‑1 signaling pathway

Abstract

Sinomenine (SIN), a pure alkaloid isolated from Sinomenium acutum, has been widely used in arthritis for its anti-inflammatory effect, but little is known about the effect of SIN on human ulcerative colitis (UC). In the present study, the effect and mechanism of SIN was examined in a dextran sulfate sodium (DSS)-induced murine colitis model, which mimics human UC. Oral administration of SIN significantly suppressed the elevated disease activity index and ameliorated colonic histological damage in a DSS-induced colitis model. Tumor necrosis factor-α, interleukin-6 and inducible nitric oxide synthase levels were also reduced as detected by reverse transcription-quantitative polymerase chain reaction. In addition, SIN reversed the decreased colon length and colonic superoxide dismutase activity. Furthermore, western blot analysis revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream genes, heme oxygenase-1 and NADP(H) quinone oxidoreductase 1 (NQO-1), were markedly activated by SIN. The current results indicated that SIN alleviated DSS-induced colitis in mice, which may be due to its antioxidant properties and was at least in part dependent on the Nrf2/NQO-1 signaling pathway. Therefore, SIN may have potential applications as a protective drug for patients with UC.

Idebenone Protects against Acute Murine Colitis via Antioxidant and Anti-Inflammatory Mechanisms

“…Instead, idebenone significantly improved the body weight, DAI and histopathology. Our results support the previously reported involvement of oxidative stress in the pathogenesis of disease [15] and justify the use of antioxidants to alleviate structural tissue damage [19,27,46,47].…”

“…The antioxidants SOD and NQO-1 directly eliminate free superoxide radicals to protect against lipid peroxidation [50,51]. Previous reports of acute gut inflammation in the DSS model observed a significant increase in lipid peroxidation and reduced levels of antioxidant enzymes (NQO-1 and SOD) [18,19,[52][53][54][55][56], which were replicated in the present study. We also observed a significant reduction in MDA levels after treatment with idebenone, which is consistent with a previous report where idebenone effectively suppressed lipid peroxidation in brain mitochondria [57].…”

“…This adaptive response is cytoprotective and enhances desensitisation against cytotoxicity and oxidative damage. There is some evidence that activation of the Nrf-2/NQO-1 redox pathway via pharmacological pre-conditioning can ameliorate DSS-induced inflammation in mice [17][18][19]. Current treatment of ulcerative colitis with non-steroidal anti-inflammatory drugs (NSAIDS), allopurinol, corticosteroids, immunosuppressant and biological agents show potential adverse effects, such as steroid dependency and infections [20][21][22][23].…”

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

“…This beneficial effect was also observed on DSS-induced murine colitis, and a molecular mechanism study further revealed that sinomenine (100 mg/kg of body weight in mice, p.o.) could markedly increase the expression of Nrf2 and its downstream genes, heme oxygenase-1 and NADP(H) quinone oxidoreductase 1 (NQO-1) (Zhou et al, 2018). It was indicated that sinomenine could attenuate colonic mucosal injury by improving the colonic oxidative status via the Nrf2/NQO-1 signaling pathway (Figure 2).…”

Anatabine ameliorates intestinal inflammation and reduces the production of pro-inflammatory factors in a dextran sulfate sodium mouse model of colitis

“…Plant-derived alkaloids evodiamine and rutaecarpine inhibit corticosterone production by decreasing the activity of cAMP-related pathways in rat zona fasciculata–reticularis cells [ 63 ]. Sinomenine, an isoquinoline alkaloid which ameliorates colitis and inflammatory gene expression in several mouse models of IBD [ 64 , 65 ], also reduces the levels of cAMP, intracellular Ca 2+ , and phosphorylated CREB in morphine-treated SH-SY5Y cells [ 66 ]. Strikingly, our findings suggested that factors contributing to anatabine-associated reduction of GPCR cascades included a wide range of cyclic nucleotide phosphodiesterases (PDEs) —including several subtypes of PDE1, PDE3, PDE4, PDE7, PDE8, and PDE10—which modulate the intracellular concentrations of cAMP and cyclic guanosine monophosphate (cGMP) by regulating their rates of degradation [ 67 ].…”