Evodiamine prevents dextran sulfate sodium-induced murine experimental colitis via the regulation of NF-κB and NLRP3 inflammasome.
Evodiamine (EVO), an extraction from the traditional Chinese medicine Evodia rutaecarpa, has been reported to possess anti-inflammatory, anti-tumor and other pharmacological activities. However, the effectiveness of EVO to relieve dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) has not been evaluated. In this study, the protective effects and mechanisms of EVO on DSS-induced UC mice were investigated. The results indicated that treatment with EVO ameliorated DSS-induced UC mice body weight loss, disease activity index (DAI), colon length shortening, colonic pathological damage, and myeloperoxidase (MPO) activity. The production of TNF-α, IL-1β and IL-6 was also significantly inhibited by EVO. Further mechanistic results showed that EVO restrained the inflammation by regulating NF-κB signal and NLRP3 inflammasome. Furthermore, results also showed that EVO contributed to the tight junction (TJ) architecture integrity by modulating the expression of zonula occludens-1 (ZO-1) and occludin during colitis. Surprisingly, treatment with EVO reduced the concentration of plasmatic lipopolysaccharide (LPS) and re-balanced the levels of Escherichia coli and Lactobacillus. These findings suggested that EVO may have a potential protective effect on DSS-induced colitis and may be useful for the prevention and treatment of UC.
Shen P
，Zhang Z
，Zhu K
，Cao H
，Liu J
，Lu X
，Li Y
，Jing Y
，Yuan X
，Fu Y
，Cao Y
，Zhang N
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Canna x generalis L.H. Bailey rhizome extract ameliorates dextran sulfate sodium-induced colitis via modulating intestinal mucosal dysfunction, oxidative stress, inflammation, and TLR4/ NF-ҡB and NLRP3 inflammasome pathways.
Genus Canna is used in folk medicine as demulcent, diaphoretic, antipyretic, mild laxative and in gastrointestinal upsets therapy. Canna x generalis (CG) L.H. Bailey is traditionally used as anti-inflammatory, analgesic and antipyretic. Besides, CG is used in Ayurvedic medicines' preparations and in the treatment of boils, wounds, and abscess. Nevertheless, its anti-inflammatory effects against ulcerative colitis (UC) are not yet investigated.
This study aimed to investigate the phytoconstituents of CG rhizome ethanol extract (CGE). Additionally, we aimed to comparatively evaluate its therapeutic effects and underlying mechanisms against the reference drug "sulphasalazine (SAS)" in dextran sodium sulfate (DSS)-induced UC in mice.
Metabolic profiling of CG rhizomes was performed via UHPLC/qTOF-HRMS; the total phenolic, flavonoid and steroid contents were determined, and the main phytoconstituents were isolated and identified. Next, DSS-induced (4%) acute UC was established in C57BL/6 mice. DSS-induced mice were administered either CGE (100 and 200 mg/kg) or SAS (200 mg/kg) for 7 days. Body weight, colon length, disease activity index (DAI) and histopathological alterations in colon tissues were examined. Colon levels of oxidative stress (GSH, MDA, SOD and catalase) and pro-inflammatory [Myeloperoxidase (MPO), nitric oxide (NO), IL-1β, IL-12, TNF-α, and INF-γ] markers were colourimetrically determined. Serum levels of lipopolysaccharide (LPS) and relative mRNA expressions of occludin, TLR4 and ASC (Apoptosis-Associated Speck-Like Protein Containing CARD) using RT-PCR were measured. Protein levels of NLRP3 inflammasome and cleaved caspase-1 were determined by Western blot. Furthermore, immunohistochemical examinations of caspase-3, NF-ҡB and claudin-1 were performed.
Major identified constituents of CGE were flavonoids, phenolic acids, phytosterols, beside five isolated phytoconstituents (β-sitosterol, triacontanol fatty alcohol, β-sitosterol-3-O-β-glucoside, rosmarinic acid, 6-O-p-coumaroyl-β-D-fructofuranosyl α-D-glucopyranoside). The percentage of the phenolic, flavonoid and steroid contents in CGE were 20.55, 6.74 and 98.09 μg of gallic acid, quercetin and β-sitosterol equivalents/mg extract, respectively. In DSS-induced mice, CGE treatment ameliorated DAI, body weight loss and colon shortening. CGE attenuated the DSS-induced colonic histopathological alternations, inflammatory cell infiltration and histological scores. CGE elevated GSH, SOD and catalase levels, and suppressed MDA, pro-inflammatory mediators (MPO and NO) as well as cytokines levels in colonic tissues. Moreover, CGE downregulated LPS/TLR4 signaling, caspase-3 and NF-ҡB expressions. CGE treatment inhibited NLRP3 signaling pathway as indicated by the suppression of the protein expression of NLRP3 and cleaved caspase-1, and the ASC mRNA expression in colonic tissues. Additionally, CGE restored tight junction proteins' (occludin and claudin-1) expressions.
Our findings provided evidence for the therapeutic potential of CGE against UC. CGE restored intestinal mucosal barrier's integrity, mitigated oxidative stress, inflammatory cascade, as well as NF-ҡB/TLR4 and NLRP3 pathways activation in colonic tissues. Notably, CGE in a dose of 200 mg/kg was more effective in ameliorating DSS-induced UC as compared to SAS at the same dose.
Mahmoud TN
，El-Maadawy WH
，Kandil ZA
，Khalil H
，El-Fiky NM
，El Alfy TSMA
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Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB and NLRP3 inflammasome activation.
Previous studies have demonstrated that wogonoside, the glucuronide metabolite of wogonin, has anti-inflammatory, anti-angiogenic and anticancer effects. However, the anti-inflammatory mechanism of wogonoside has not been fully elucidated. Recently, NLRP3 inflammasome has been reported to be correlated with inflammatory bowel disease for its ability to induce IL-1β release. Nevertheless, there are few drug candidates targeting NLRP3 inflammasome for this disease. In this study, we investigated the anti-inflammatory effect of wogonoside in dextran sulfate sodium (DSS)-induced murine colitis and further revealed the underlying mechanisms by targeting NF-κB and NLRP3 inflammasome. Wogonoside treatment dose-dependently attenuated DSS-induced body weight loss and colon length shortening. Moreover, wogonoside prevented DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and significantly decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. The production of pro-inflammatory mediators in serum and colon was also significantly reduced by wogonoside. The underlying mechanisms for the protective effect of wogonoside in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in colons. Furthermore, wogonoside markedly decreased production of IL-1β, TNF-α and IL-6 and suppressed mRNA expression of pro-IL-1β and NLRP3 in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells via inhibiting the activation of NF-κB and NLRP3 inflammasome. In conclusion, our study demonstrated that wogonoside may exert its anti-inflammatory effect via dual inhibition of NF-κB and NLRP3 inflammasome, suggesting that wogonoside might be a potential effective drug for inflammatory bowel diseases.
Sun Y
，Zhao Y
，Yao J
，Zhao L
，Wu Z
，Wang Y
，Pan D
，Miao H
，Guo Q
，Lu N
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Schisandra chinensis (Turcz.) Baill. Protects against DSS-induced colitis in mice: Involvement of TLR4/NF-κB/NLRP3 inflammasome pathway and gut microbiota.
the fruit of Schisandra chinensis (Turcz.) Baill. (SC) is an important traditional Chinese herbal medicine, which has been widely used in traditional Chinese medicine (TCM) for treating intestinal diseases. It is also traditionally used as health product and medicine in Russia and other countries. However, the effect of SC ethanol extract on anti-ulcerative colitis (UC) has not been systematically studied yet.
We investigated the protective effects and underlying action mechanisms of SC extract (SCE) for UC treatment.
An animal model of UC induced by dextran sulfate sodium (DSS) was established. After oral administration of SCE, the Disease Activity Index (DAI) was calculated, the length of colon measured, levels of proinflammatory factors determined, and histopathology carried out to assess the therapeutic efficacy of SCE on UC. The effects of SCE on the toll-like receptor 4/nuclear factor-kappa B/nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 inflammasome (TLR4/NF-κB/NLRP3 inflammasome) signaling pathway were evaluated by western blotting. High-throughput sequencing was done to reveal the effect of SCE on the change of the gut microbiota (GM) in mice with DSS-induced colitis.
SCE significantly reduced the DAI score, restored colon-length shortening, and ameliorated colonic histopathologic injury in mice with DSS-induced colitis. SCE inhibited the inflammatory response by regulating the TLR4/NF-κB/NLRP3 inflammasome pathway in mice with UC. SCE also maintained gut barrier function by increasing the levels of zonula occludens (ZO)-1 and occludin. 16S rRNA sequencing showed that SCE could reverse the GM imbalance caused by UC.
SCE can ameliorate DSS-induced colitis, and that its effects might be associated with suppression of the TLR4/NF-κB/NLRP3 inflammasome pathway and GM regulation, which may provide significant supports for the development of potential candidates for UC treatment.
Bian Z
，Qin Y
，Li L
，Su L
，Fei C
，Li Y
，Hu M
，Chen X
，Zhang W
，Mao C
，Yuan X
，Lu T
，Ji D
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