Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 inflammasome Activity and Activating Nrf2 Signaling

Yu, Yan; Wu, Dongming; Li, Jing; Deng, Shi‐Hua; Li, Teng; Zhang, Ting; He, Miao; Zhao, Yangyang; Xu, Ying

doi:10.21203/rs.3.rs-24795/v1

Cited by 7 publications

(4 citation statements)

References 41 publications

(53 reference statements)

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“…The bixin dosage in vivo was determined based on prior data reported on bixin administration and toxicity studies in mice. 52,[70][71][72] The mice were divided randomly into five groups. Group1 was the negative control (NC) and unexposed to UV and bixin treatment.…”

Section: Molecular Docking and Simulation Studiesmentioning

confidence: 99%

Multispectroscopic, virtual and in vivo insights into the photoaging defense mediated by the natural food colorant bixin

Kapoor

Kumar

et al. 2023

Food Funct.

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Section: Molecular Docking and Simulation Studiesmentioning

confidence: 99%

Multispectroscopic, virtual and in vivo insights into the photoaging defense mediated by the natural food colorant bixin

Kapoor

Kumar

et al. 2023

Food Funct.

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“…IHC, IF, and western blotting assays were performed to measure the expressions of 4-HNE, GPX4, Nrf2, HO-1, ZO-1, occludin and claudin-5. H&E staining was performed to measure the pathological change in intestinal tissue using our previously described method [21].…”

Section: Immunohistochemical Analysis (Ihc) Immunofluorescence (If) W...mentioning

confidence: 99%

TBHQ attenuates ferroptosis against 5-fluorouracil-induced intestinal epithelial cell injury and intestinal mucositis via activation of Nrf2

Deng

et al. 2021

Cell Mol Biol Lett

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Background Intestinal mucositis is a common side effect of chemotherapy and radiotherapy. Very few drugs can efficiently ameliorate it. Tertiary butylhydroquinone (TBHQ) is a widely used food preservative with known immunomodulatory activity. Whether it has an effect on intestinal mucositis remains unknown. In this study, we investigated the role and mechanism of action of TBHQ on 5-fluorouracil-induced (5-FU-induced) human intestinal epithelial cell (HIEC) injury and intestinal mucositis in mice. Methods We established a cell model of HIEC injury and a mouse model of intestinal mucositis via treatment with 5-FU. Cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release were assessed for the HIECs. Diarrhea, body weight, intestinal length, mucosal damage, and the levels of IL-6, TNF-α, IL-1β, glutathione, reactive oxygen species, and malondialdehyde were determined for the mice. Additionally, we performed immunohistochemical analysis, immunofluorescence, western blotting, quantitative real-time PCR, and ELISA to examine the effects of TBHQ. Finally, HIECs were transfected with an Nrf2 gene silencer to verify its role in ferroptosis. All data were analyzed using one-way analysis of variance or paired t-tests. Results TBHQ markedly decreased LDH release and cell death and improved the proliferative ability of 5-FU-treated HIECs. The TBHQ-treated mice showed reduced weight loss, a lower diarrhea score, and longer colons than the 5-FU-treated mice. The in vivo expressions of IL-1β, IL-6, and TNF-α were suppressed by TBHQ treatment. Ferroptosis was shown to be involved in 5-FU-induced intestinal mucositis, and TBHQ markedly hampered its activation. Mechanistically, TBHQ activated Nrf2 effectively and selective Nrf2 knockdown significantly reduced the anti-ferroptotic functions of TBHQ in 5-FU-treated HIECs. Conclusions TBHQ attenuates ferroptosis in 5-FU-induced intestinal mucositis, making it a potential novel protective agent against intestinal mucositis.

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“…after ROS-mediated interaction of TXNIP to NLRP3 in endoplasmic reticulum (ER) under stressed conditions [15]. The TXNIP-NLRP3 inflammasome is a macromolecular multi-protein compound consisting of TXNIP, NLRP3, adaptor protein ASC, and the effector protein caspase-1 [16]. TXNIP deficiency impairs the activation of the NLRP3 inflammasome and subsequent secretion of inflammatory cytokines, such as interleukin (IL)-1β [17,18].…”

Section: Introductionmentioning

confidence: 99%

Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs

Liu

Zhang

Shi

et al. 2022

BMC Mol and Cell Biol

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Background Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism. Methods HUVECs were exposed to various concentrations of C8-Cer for 12 h, 24 h, 48 h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry. Results The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1β, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs. Conclusion The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.

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Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 inflammasome Activity and Activating Nrf2 Signaling

Cited by 7 publications

References 41 publications

Multispectroscopic, virtual and in vivo insights into the photoaging defense mediated by the natural food colorant bixin

Multispectroscopic, virtual and in vivo insights into the photoaging defense mediated by the natural food colorant bixin

TBHQ attenuates ferroptosis against 5-fluorouracil-induced intestinal epithelial cell injury and intestinal mucositis via activation of Nrf2

Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs

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