bims-noxint 2021-05-16 papers

Issue of 2021‒05‒16
five papers selected by
Laia Caja Puigsubira
Uppsala University

Exp Ther Med. 2021 Jul;22(1): 688

Acute glucose fluctuation promotes in vitro intestinal epithelial cell apoptosis and inflammation via the NOX4/ROS/JAK/STAT3 signaling pathway.

Bingyu Chen, Yuanyuan Jia, Dongxue Lu, Zhiguang Sun.

High blood glucose commonly occurs in patients with diabetes mellitus, but little is known of its effects on intestinal epithelial cells, or its associated mechanisms of action therein. In the present study, intestinal epithelial cells were assigned to five groups: i) The normal glucose (NG) group, incubated in 5.0 mmol/l glucose; ii) the constant high glucose (CHG) group, treated with 25.0 mmol/l glucose; iii) the intermittent high glucose (IHG) group, treated with alternating doses of 5.0 and 25.0 mmol/l glucose every 8 h; iv) the mannose group, cultured in 25.0 mmol/l mannose (the osmotic control); and v) the IHG glucose + GKT137831 group, pretreated with 100 nmol/l NADPH oxidase 4 (NOX4) inhibitor, GKT137831, and then exposed to IHG. TNF-α, IL-1 and IL-6 levels were quantified using ELISA kits. Intestinal epithelial cell apoptosis was assessed by flow cytometry and oxidative stress was evaluated by reactive oxygen species (ROS) and malondialdehyde (MDA) detection. The expression levels of proteins associated with apoptosis and involved in the signal transduction of Janus kinase (JAK)/STAT3 pathway were assessed using western blot analysis. The results indicated that NOX4 expression was significantly higher in the CHG group than in the NG group (P<0.01), but lower than in the IHG group (P<0.001). The IHG group exhibited apoptosis and oxidative stress accompanied by the most significant increase in MDA, ROS and inflammatory cytokine levels (P<0.001), which was followed by that of the CHG group. Additionally, the IHG group exhibited reduced Bcl-2, as well as enhanced Bax and cleaved caspase-3 levels compared with the CHG group (P<0.001). Furthermore, the level of phosphorylated (p-)JAK/p-STAT3 was increased to a greater extent in the IHG group than in the CHG group (P<0.001). In conclusion, the findings of the present study indicated that CHG may trigger intestinal epithelial cell apoptosis and inflammation through the NOX4/ROS/JAK/STAT3 pathway, which may be aggravated by acute glucose fluctuation.

Keywords: Janus kinase/STAT3 pathway; NADPH oxidase 4; acute blood glucose fluctuation; inflammation; intestinal epithelial cells; reactive oxygen species

DOI: https://doi.org/10.3892/etm.2021.10120

Front Oncol. 2021 ;11 629974

DDX19A Promotes Metastasis of Cervical Squamous Cell Carcinoma by Inducing NOX1-Mediated ROS Production.

Yanhui Jiang, Baibin Wang, Yongliang Li, Jiahui Shen, Yutao Wei, Hanjie Li, Shangqiu Chen, Hua Yang, Famin Zeng, Changqing Liu, Feng Wang, Huanhuan He, Yong Chen, Jihong Liu.

The major obstacle to treat cervical squamous cell carcinoma (CSCC) is the high prevalence of metastasis, which severely affects 5-year survival rate and quality of life for cancer patients. The DEAD-box helicase family has been reported to be a critical mediator in the development and metastasis of various cancers. DEAD-box helicase 19A (DDX19A) is a member of the DEAD-box helicase family; however, its functional role in CSCC is unclear. In this study, bioinformatics analysis of clinical samples from public databases demonstrated that the expression of DDX19A was elevated in CSCC tissues and that high expression of DDX19A was positively correlated with metastasis and poor clinical outcome. Functionally, we found that DDX19A promoted CSCC cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, overexpression of DDX19A increased NADPH oxidase 1 (NOX1) expression, enhanced reactive oxygen species (ROS) production, and induced the migration and invasion of CSCC cells. Rescue experiments revealed that DDX19A-induced CSCC functional alterations were dependent on NOX1 and that DDX19A-promoted CSCC metastasis was abrogated upon the inhibition of ROS. Our results demonstrated that DDX19A could promote CSCC metastasis by inducing NOX1-mediated ROS production and that blockage of the NOX1/ROS axis might serve as a potential therapeutic target for patients with DDX19A-overexpressed CSCC.

Keywords: DDX19A; Nox1; cervical squamous cell carcinoma; metastasis; reactive oxygen species

DOI: https://doi.org/10.3389/fonc.2021.629974

Sci Rep. 2021 May 14. 11(1): 10350

trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway.

Yusuke Hirata, Miki Takahashi, Yuto Yamada, Ryosuke Matsui, Aya Inoue, Ryo Ashida, Takuya Noguchi, Atsushi Matsuzawa.

trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

DOI: https://doi.org/10.1038/s41598-021-89506-8

Free Radic Biol Med. 2021 May 06. pii: S0891-5849(21)00285-9. [Epub ahead of print]

Extracellular miRNAs in redox signaling: health, disease and potential therapies.

Gabriel Palermo Ruiz, Henrique Camara, Narayana P B Fazolini, Marcelo A Mori.

Extracellular microRNAs (miRNAs) have emerged as important mediators of cell-to-cell communication and intertissue crosstalk. MiRNAs are produced by virtually all types of eukaryotic cells and can be selectively packaged and released to the extracellular medium, where they may reach distal cells to regulate gene expression cell non-autonomously. By doing so, miRNAs participate in integrative physiology. Oxidative stress affects miRNA expression, while miRNAs control redox signaling. Disruption in miRNA expression, processing or release to the extracellular compartment are associated with aging and a number of chronic diseases, such as obesity, type 2 diabetes, neurodegenerative diseases and cancer, all of them being conditions related to oxidative stress. Here we discuss the interplay between redox balance and miRNA function and secretion as a determinant of health and disease states, reviewing the findings that support this notion and highlighting novel and yet understudied venues of research in the field.

Keywords: Aging; Cancer; Cardiovascular Disease; Exosomes; Extracellular vesicles; Metabolic syndrome; Neurodegenerative diseases; Oxidative stress; RNA therapeutics; Redox biology; miRNA

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.05.004

Oncol Lett. 2021 Jul;22(1): 503

HMGB1 knockdown increases the radiosensitivity of esophageal squamous cell carcinoma by regulating the expression of molecules involved in DNA repair.

Guohu Han, Rui Ling, Changchun Sun, Xuefeng Wang, Yuepeng Zhou, Lijiang Yu, Shenzha Liu.

Radiotherapy is an effective therapeutic strategy in esophageal squamous cell carcinoma (ESCC). However, acquired radioresistance of cancer cells leads to radiotherapy failure. The present study aimed to investigate the mechanisms of the effect of high mobility group box 1 (HMGB1) on the radiation sensitivity of ESCC. Small interfering RNA (si) transfection was used to generate three groups of TE-1 cells (TE-1, negative control and TE-1+siHMGB1), and the protein expression levels of HMGB1 in TE-1 cells were detected by western blotting. These groups of TE-1 cells were irradiated with different doses (0, 2, 4, 6 and 8 Gy) of X-rays after transfection. Subsequently, the viability of TE-1 cells was detected using an MTT assay, and the survival fraction of TE-1 cells was observed using a colony formation assay. The apoptotic rate, reactive oxygen species (ROS) content and levels of phosphorylated (p)-histone H2AX at S139 (p-γH2AX) of the cells were detected by flow cytometry. The alterations in mRNA expression levels of nicotinamide adenine nucleotide phosphate oxidase (NOX)1 and NOX5 were detected by reverse transcription-quantitative PCR, while the changes in protein levels of caspase-3, poly(ADP-ribose) polymerase, p-p38, p-ERK1/2 and p-JNK were detected by western blotting. The results revealed that HMGB1 knockdown significantly decreased cell viability, and the apoptosis rate of TE-1 cells transfected with siHMGB1 combined with radiation treatment was increased compared with that in cells with either siHMGB1 transfection or radiation treatment alone. HMGB1 knockdown increased nicotinamide adenine nucleotide phosphate oxidase-mediated ROS production and induced DNA damage via the MAPK signaling pathway, which may promote apoptosis and radiosensitivity after radiation in TE-1 cells. In conclusion, targeting HMGB1 may represent a promising strategy to increase the efficacy of radiation therapy for ESCC.

Keywords: esophageal carcinoma; high mobility group box 1; histone H2AX; radiosensitivity; reactive oxygen species

DOI: https://doi.org/10.3892/ol.2021.12764