Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway

Wang, Kai; Lv, Qi; Miao, Yumeng; Qiao, Simiao; Dai, Yue; Wei, Zhifeng

doi:10.1016/j.bcp.2018.07.039

Cited by 125 publications

(77 citation statements)

References 56 publications

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“…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].…”

Section: Discussionsupporting

confidence: 87%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Shastri

Shinde

Sohal

et al. 2020

IJMS

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Oxidative stress is a key player of the inflammatory cascade responsible for the initiation of ulcerative colitis (UC). Although the short chain quinone idebenone is considered a potent antioxidant and a mitochondrial electron donor, emerging evidence suggests that idebenone also displays anti-inflammatory activity. This study evaluated the impact of idebenone in the widely used dextran sodium sulphate (DSS)-induced mouse model of acute colitis. Acute colitis was induced in C57BL/6J mice via continuous exposure to 2.5% DSS over 7 days. Idebenone was co-administered orally at a dose of 200 mg/kg body weight. Idebenone significantly prevented body weight loss and improved the disease activity index (DAI), colon length, and histopathological score. Consistent with its reported antioxidant function, idebenone significantly reduced the colonic levels of malondialdehyde (MDA) and nitric oxide (NO), and increased the expression of the redox factor NAD(P)H (nicotinamide adenine dinucleotide phosphate) dehydrogenase quinone-1 (NQO-1) in DSS-exposed mice. Immunohistochemistry revealed a significantly increased expression of tight junction proteins, which protect and maintain paracellular intestinal permeability. In support of an anti-inflammatory activity, idebenone significantly attenuated the elevated levels of pro-inflammatory cytokines in colon tissue. These results suggest that idebenone could represent a promising therapeutic strategy to interfere with disease pathology in UC by simultaneously inducing antioxidative and anti-inflammatory pathways.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

Shastri

Shinde

Sohal

et al. 2020

IJMS

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“…Nrf2 inducers are under development for a variety of inflammatory, metabolic, degenerative, and neoplastic diseases 65 . The induction of Nrf2 signaling by cardamonin that we observe is consistent with prior reports in the literature [66][67][68] . In this regard, NRF2 levels and target gene expression are elevated in skin fibroblasts derived from long-lived Snell dwarf mice, likely contributing to the multiplex stress resistance observed in these cells 37 .…”

Section: Discussionsupporting

confidence: 93%

High throughput small molecule screening reveals NRF2-dependent and - independent pathways of cellular stress resistance

Lombard

Köhler

Guo

et al. 2019

Preprint

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Biological aging is the dominant risk factor for most chronic diseases. Development of anti-aging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in C. elegans. Transcriptomic analysis implicated Nrf2 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482.Molecules that conferred stress resistance also induced cellular inflammatory pathways, and other core pathways such as AMPK signaling. Small molecules identified in this work may represent attractive candidates to evaluate for their potential pro-health and pro-longevity effects in mammals.

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“…DSS-induced colitis was performed as previously described. 18 Female C57BL/6 mice were fed with 2.5% DSS (dissolved in sterile distilled water) for 7 days, and followed by sterile distilled water alone for another 3 days. The mice were randomly divided into the following groups: Normal group, DSS group, arctigenin (25, 50 mg/kg) group, and NaB (200 mg/kg) group.…”

Section: Induction Of Dss-and Tnbs-induced Colitis In Mice and Drugmentioning

confidence: 99%

“…TNBS-induced colitis was performed as previously described. 18 Female BALB/c mice were deprived of food for 8-12 hours, given with free access to 5% glucose, and anesthetized with avertin (290 mg/kg, i.p.). Then, a flexible catheter was carefully inserted into the colons of mice, and TNBS (1.5 mg dissolved in 100 µL of 40% ethanol) was slowly administered.…”

Section: Induction Of Dss-and Tnbs-induced Colitis In Mice and Drugmentioning

confidence: 99%

Pharmacological activation of ERβ by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases

Yue

et al. 2019

FASEB j.

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are contributed equally to this work.Abbreviations: AAV, adeno-associated virus; BSA, bovine serum albumin; CD, Crohn's disease; DAI, disease activity index; DMEM, Dulbecco's modified eagle medium; DSS, dextran sulfate sodium; ERβ, estrogen receptor β; E2, 17β-estradiol; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; HSP90, heat shock protein 90; HBSS, Hank's balanced salt solution; IBD, inflammatory bowel diseases; IL-1β, interleukin-1β; IFN-γ, Interferon-γ; IL-6, interleukin-6; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; MPO, myeloperoxidase; MLCK, myosin light chain Abstract Intestinal epithelial barrier dysfunction is deeply involved in the pathogenesis of inflammatory bowel diseases (IBD). Arctigenin, the main active constituent in Fructus Arctii (a traditional Chinese medicine), has previously been found to attenuate colitis induced by dextran sulfate sodium (DSS) in mice. The present study investigated whether and how arctigenin protects against the disruption of the intestinal epithelial barrier in IBD. Arctigenin maintained the intestinal epithelial barrier function of mice with DSS-and TNBS-induced colitis. In Caco-2 and HT-29 cells, arctigenin lowered the monolayer permeability, increased TEER, reversed the abnormal expression of tight junction proteins, and restored the altered localization of F-actin induced by TNF-α and IL-1β. The specific antagonist PHTPP or shRNA of ERβ largely weakened the protective effect of arctigenin on the epithelial barrier function of Caco-2 and HT-29 cells. Molecular docking demonstrated that arctigenin had high affinity for ERβ mainly through hydrogen bonds as well as hydrophobic effects, and the protective effect of arctigenin on the intestinal barrier function was largely diminished in ERβ-mutated (ARG346 and/or GLU305) Caco-2 cells. Moreover, arctigenin-blocked TNF-α induced increase of the monolayer permeability in Caco-2 and HT-29 cells and the activation of myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway in an ERβ-dependent manner. ERβ deletion in colons of mice with DSS-induced colitis resulted in a significant attenuation of the protective effect of arctigenin on the barrier integrity and colon inflammation. Arctigenin maintained the integrity of the intestinal epithelial barrier under IBD by upregulating the expression of tight junction proteins through the ERβ-MLCK/MLC pathway. 3070 |

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Cardamonin, a natural flavone, alleviates inflammatory bowel disease by the inhibition of NLRP3 inflammasome activation via an AhR/Nrf2/NQO1 pathway

Cited by 125 publications

References 56 publications

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

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

High throughput small molecule screening reveals NRF2-dependent and - independent pathways of cellular stress resistance

Pharmacological activation of ERβ by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases

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