Thioredoxin Reductase 1 Expression in Colon Cancer: Discrepancy between In Vitro and In Vivo Findings

Background. Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice. Hypothesis. The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice in vivo and lung epithelia in vitro. Methods. Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. In vitro, murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO). Results. In vivo, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. In vitro, AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels. Conclusions. Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between in vivo and in vitro results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.

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Selenide Chitosan Sulfate Improved The Hepatocyte Activity, Growth Performance, and Anti-Oxidation Ability by Activating The Thioredoxin Reductase of Chickens In Vitro and In Vivo

10.21203/rs.3.rs-76175/v1 ◽

2020 ◽

Author(s):

Lele Hou ◽

Huiling Qiu ◽

Lianqin Zhu ◽

Yufeng Huang ◽

Shansong Gao ◽

...

Keyword(s):

Growth Performance ◽

Culture Medium ◽

Thioredoxin Reductase ◽

Dietary Supplementation ◽

Control Group ◽

Treatment Groups ◽

Thioredoxin Reductase 1 ◽

Specific Pathogen

Abstract Background: There are very few studies on the synergy effects of biological antioxidant activity on selenium (Se) and sulfate. This study evaluated the effect of selenide chitosan sulfate (LS-COS-Se) on the hepatocytes activity, growth performance, and anti-oxidation ability by activating the thioredoxin reductase (TrxR) system of specific pathogen free (SPF) chickens in vitro and in vivo. Methods: The hepatocytes were obtained in vitro and a total of 240 SPF White Leghorns chickens (7 days of age and body weight of 45.0 ± 2.0 g) were collected in vivo. The hepatocytes and chickens were randomly allocated into six treatment groups: control group; chitosan (COS) group; sodium selenite (Na2SeO3) group; selenide chitosan (COS-Se) group; chitosan sulfate (LS-COS) group; LS-COS-Se group. After 24 h, the culture medium and hepatocytes were collected and preserved respectively for analyzing the metabolic activity of hepatocytes. Gowth performance was evaluated and chickens were euthanized to obtain plasma and liver tissue to measure antioxidant associated parameter on days 14 and 28. Results: The experiment in vitro showed that the activities of TrxR, superoxide dismutase (SOD), catalase (CAT) in culture medium and the levels of thioredoxin reductase 1 (TrxR-1) and thioredoxin reductase 3 (TrxR-3) mRNA in hepatocytes in LS-COS-Se group were significantly higher (P < 0.05), but the content of malondialdehyde (MDA) and the activity of lactate dehydrogenase (LDH) significantly decreased (P < 0.05) than those in control, COS and LS-COS groups. Compared with Na2SeO3 and COS-Se groups, the levels of TrxR-1 and TrxR-3 mRNA in hepatocytes and the activity of SOD in culture medium significantly increased in LS-COS-Se group (P < 0.05). The experiment in vivo showed that the baby weight on 14d and 28d, the activities of TrxR, SOD and anti-superoxide anion radical (AntiO2-) in plasma and the levels of TrxR-1 and TrxR-3 mRNA in liver of dietary supplementation with LS-COS-Se were significantly higher than those in control, COS and LS-COS groups (P < 0.05). The activities of TrxR and SOD in plasma of dietary supplementation with LS-COS-Se were significantly higher than those of Na2SeO3 group and COS-Se group (P < 0.05). Conclusion: LS-COS-Se as potential antioxidant improved the hepatocytes activity, growth performance, and anti-oxidation ability by activating the TrxR system of SPF chickens in vitro and in vivo. The better biological activity of LS-COS-Se was mainly due to the synergistic effect of Se and sulfate on TrxR system.

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Thioredoxin Reductase 3 Suppression Promotes Colitis and Carcinogenesis via Activating Pyroptosis and Necrosis

10.21203/rs.3.rs-885051/v1 ◽

2021 ◽

Author(s):

Qi Liu ◽

Pengyue Du ◽

Yue Zhu ◽

Xintong Zhang ◽

Jingzeng Cai ◽

...

Keyword(s):

Oxidative Stress ◽

Ulcerative Colitis ◽

Colon Cancer ◽

Intracellular Calcium ◽

Cancer Cells ◽

Thioredoxin Reductase ◽

Intestinal Secretion ◽

Colon Cancer Cells

Abstract Background Txnrd3 as selenoprotein play key roles in antioxidant process and sperm maturation. Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease are becoming significantly increasing disease worldwide in recent years which are proved relative to diet especially selenium intake. Methods In the present study, 8-week-old C57BL/6N male Txnrd3-/-, Txnrd3-/+, Txnrd3+/+ mice weight 25-30g were randomly chosen and each group 30 mice. Feed 3.5% DSS drinking water and normal water continuously for 7 days. Mouse colon cancer cells (CT26) were cultured in vitro to establish Txnrd3 overexpressed/knocked-down model by cell transfection technology. Morphology and ultrastructure, calcium levels, ROS level, cell death were observed and detected in vivo and vitro. Results Ulcerative colitis was more severe, morphological and ultrastructural lesions were extremely significant in Txnrd3-/- mice based on the fact that expression of NLRP3, Caspase1, RIPK3, MLKL related to pyroptosis and necrosis pathway was significantly increased. Overexpression of Txnrd3 could lead to increased oxidative stress through intracellular calcium outflow induced oxidative stress increase. Followed by necrosis and pyroptosis pathway activation and further inhibit the growth and proliferation of colon cancer cells. Conclusion Txnrd3 overexpression leads to intracellular calcium outflow, endoplasmic reticulum stress, and increased ROS, which eventually leads to necrosis and focal death of colon cancer cells, while Txnrd3-/- mice depth of the crypt deeper, weakened intestinal secretion and immune function. And aggravate the occurrence of ulcerative colitis. The present study lays a foundation for the prevention and treatment of ulcerative colitis and colon carcinoma in clinic treatment.

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Large volume spark discharge and plasma jet-technology for generating plasma-oxidized saline targeting colon cancer in vitro and in vivo

Journal of Applied Physics ◽

10.1063/5.0033406 ◽

2021 ◽

Vol 129 (5) ◽

pp. 053301

Author(s):

Eric Freund ◽

Lea Miebach ◽

Ramona Clemen ◽

Michael Schmidt ◽

Amanda Heidecke ◽

...

Keyword(s):

Colon Cancer ◽

Large Volume ◽

Plasma Jet ◽

Spark Discharge

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Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

Scientific Reports ◽

10.1038/s41598-020-80911-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kazim Husain ◽

Domenico Coppola ◽

Chung S. Yang ◽

Mokenge P. Malafa

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Metastasis ◽

Annexin V ◽

Cancer Cell Growth ◽

Ki 67 ◽

Sox2 Expression ◽

Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

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Sophocarpine can enhance the inhibiting effect of oxaliplatin on colon cancer liver metastasis—in vitro and in vivo

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-020-02032-8 ◽

2021 ◽

Author(s):

Yu-Shen Yang ◽

Dan Wen ◽

Xue-Feng Zhao

Keyword(s):

Colon Cancer ◽

Liver Metastasis ◽

Inhibiting Effect ◽

Colon Cancer Liver Metastasis

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Targeting a Lipid Desaturation Enzyme, SCD1, Selectively Eliminates Colon Cancer Stem Cells through the Suppression of Wnt and NOTCH Signaling

Cells ◽

10.3390/cells10010106 ◽

2021 ◽

Vol 10 (1) ◽

pp. 106

Author(s):

Yeongji Yu ◽

Hyejin Kim ◽

SeokGyeong Choi ◽

JinSuh Yu ◽

Joo Yeon Lee ◽

...

Keyword(s):

Colon Cancer ◽

Notch Signaling ◽

Cultured Cells ◽

Pcr Analysis ◽

Marker Genes ◽

Dependent Manner ◽

Lipid Desaturation ◽

Novel Target

The elimination of the cancer stem cell (CSC) population may be required to achieve better outcomes of cancer therapy. We evaluated stearoyl-CoA desaturase 1 (SCD1) as a novel target for CSC-selective elimination in colon cancer. CSCs expressed more SCD1 than bulk cultured cells (BCCs), and blocking SCD1 expression or function revealed an essential role for SCD1 in the survival of CSCs, but not BCCs. The CSC potential selectively decreased after treatment with the SCD1 inhibitor in vitro and in vivo. The CSC-selective suppression was mediated through the induction of apoptosis. The mechanism leading to selective CSC death was investigated by performing a quantitative RT-PCR analysis of 14 CSC-specific signaling and marker genes after 24 and 48 h of treatment with two concentrations of an inhibitor. The decrease in the expression of Notch1 and AXIN2 preceded changes in the expression of all other genes, at 24 h of treatment in a dose-dependent manner, followed by the downregulation of most Wnt- and NOTCH-signaling genes. Collectively, we showed that not only Wnt but also NOTCH signaling is a primary target of suppression by SCD1 inhibition in CSCs, suggesting the possibility of targeting SCD1 against colon cancer in clinical settings.

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