Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis

Liu, Qi; Du, Pengcheng; Zhu, Yue; Zhang, Xintong; Cai, Jingzeng; Zhang, Ziwei

doi:10.1007/s00018-022-04155-y

Cited by 47 publications

(16 citation statements)

References 38 publications

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“…Furthermore, the activated inflammasome complex triggers caspases, thereby contributing GSDMD cleavage and macrophage pyroptosis (Evavold et al, 2018;Russo et al, 2021). Pyroptosis is an inflammatory cell death process and has become a novel target for UC treatment (Corcoran, Halai, & Cooper, 2021;Liu et al, 2022). Recent studies have confirmed that it is effective to alleviate colonic inflammation via suppressing caspase-1/GSDMD-mediated macrophage pyroptosis (Wang et al, 2022;Zhang et al, 2022).…”

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confidence: 99%

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Liu

Zhou

Luo

et al. 2022

Phytotherapy Research

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis‐derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis‐related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP‐induced bone marrow‐derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL‐1β release as well as the protein level of NLRP3, caspase‐1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS‐induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside‐treated foecal bacterium into flora‐depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders.

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confidence: 99%

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Liu

Zhou

Luo

et al. 2022

Phytotherapy Research

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“…Gpx family has prominent antioxidant effects, and its reduced activity resulted in a weakened ROS-scavenging capacity of cells, thus affecting the entire growth phase of cells ( 56 ). Txnrd family exerted an irreplaceable antioxidant role, in addition, bound to many proteins and involved in regulating cell growth such as inhibiting apoptosis and autophagy ( 57 , 58 ). Sels, a widely expressed transmembrane protein located in the ER, is critical for ER stress by eliminating misfolding proteins and regulating oxidative stress, apoptosis, and autophagy ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

Schisandrin B Induced ROS-Mediated Autophagy and Th1/Th2 Imbalance via Selenoproteins in Hepa1-6 Cells

et al. 2022

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Schisandrin B (Sch B) is well-known for its antitumor effect; however, its underlying mechanism remains confusing. Our study aimed to investigate the role of selenoproteins in Sch B-induced autophagy and Th1/Th2 imbalance in Hepa1-6 cells. Hepa1-6 cells were chosen to explore the antitumor mechanism and were treated with 0, 25, 50, and 100 μM of Sch B for 24 h, respectively. We detected the inhibition rate of proliferation, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, reactive oxygen species (ROS) level and oxidative stress-related indicators, autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein mRNA expression. Moreover, the heat map, principal component analysis (PCA), and correlation analysis were used for further bioinformatics analysis. The results revealed that Sch B exhibited well-inhibited effects on Hepa1-6 cells. Subsequently, under Sch B treatment, typical autophagy characteristics were increasingly apparent, and the level of punctate MDC staining enhanced and regulated the autophagy-related genes. Overall, Sch B induced autophagy in Hepa1-6 cells. In addition, Sch B-promoted ROS accumulation eventually triggered autophagy initiation. Results of Th1 and Th2 cytokine mRNA expression indicated that Th1/Th2 immune imbalance was observed by Sch B treatment in Hepa1-6 cells. Intriguingly, Sch B downregulated the majority of selenoprotein expression. Also, the heat map results observed significant variation of autophagy-related genes, related Th1/Th2 cytokines, and selenoprotein expression in response to Sch B treatment. PCA outcome suggested the key role of Txnrd1, Txnrd3, Selp, GPX2, Dio3, and Selr with its potential interactions in ROS-mediated autophagy and Th1/Th2 imbalance of Hepa1-6 cells. In conclusion, Sch B induced ROS-mediated autophagy and Th1/Th2 imbalance in Hepa1-6 cells. More importantly, the majority of selenoproteins were intimately involved in the process of autophagy and Th1/Th2 imbalance, Txnrd3, Selp, GPX2, Dio3, and Selr had considerable impacts on the process.

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“…The role of TXNRD3 in cancer development is less known than the role of TXNRD2. It has been shown that knockout of TXNRD3 in mice resulted in increased severe ulcerative colitis and lesions than in corresponding wild-type mice, conditions that are known to be a risk factor for the development of colorectal cancer [ 114 ]. Furthermore, overexpression of TXNRD3 in a murine colon cancer cell line (CT26) increased oxidative stress and necrosis in these cells [ 114 ].…”

Section: Impact Of Selenoproteins On Cancermentioning

confidence: 99%

“…It has been shown that knockout of TXNRD3 in mice resulted in increased severe ulcerative colitis and lesions than in corresponding wild-type mice, conditions that are known to be a risk factor for the development of colorectal cancer [ 114 ]. Furthermore, overexpression of TXNRD3 in a murine colon cancer cell line (CT26) increased oxidative stress and necrosis in these cells [ 114 ]. Despite limited evidence, these findings intimate that TXNRD2 and TXNRD3 also inhibit oxidative stress via the thioredoxin system in cancers as TXNRD1, thereby promoting cancer cell resistance to cell death.…”

Section: Impact Of Selenoproteins On Cancermentioning

confidence: 99%

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

et al. 2022

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A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.

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Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis

Cited by 47 publications

References 38 publications

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Schisandrin B Induced ROS-Mediated Autophagy and Th1/Th2 Imbalance via Selenoproteins in Hepa1-6 Cells

Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers

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