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Endoplasmic reticulum stress may activate NLRP3 inflammasomes via txnip in preeclampsia

CELL AND TISSUE RESEARCH 2020年第3期379卷 589-599页

作者： Yang, Yong Li, Jianxin Han, Ting-Li Zhou, Xiaobo Qi, Hongbo Baker, Philip N. Zhou, Wei Zhang, Hua Chngqing Hlth Ctr Women & Children Dept Obstet 120 Longshan Rd Chongqing 400021 Peoples R China Chongqing Med Univ Affiliated Hosp 1 Dept Obstet & Gynecol 1 Youyi Rd Chongqing 400016 Peoples R China Chongqing Med Univ Canada China New Zealand Joint Lab Maternal & Fet 1 Yixueyuan Rd Chongqing 400016 Peoples R China Univ Leicester Coll Med Biol Sci & Psychol POB 138 Leicester LE1 9HN Leics England

Preeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been elucidated. It has been reported that thioredoxin-interacting protein (txnip), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, is a key point in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1 beta (IL-1 beta) production in the placenta of patients with PE. The objective of the current study was to explore if txnip plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesized that ER stress would induce txnip production, which would bind with NLRP3 inflammasomes to activate IL-1 beta production. These cells showed a higher protein level of NLRP3 and IL-1 beta, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with txnip siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. Outgrowth of the explant with txnip lentivirus in H/R or tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that txnip could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.

关键词： Preeclampsia (PE) Inflammation Endoplasmic reticulum (ER) stress NLRP3 txnip

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Histone deacetylase 10 exerts antitumor effects on cervical cancer via a novel microRNA-223/txnip/Wnt/β-catenin pathway

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IUBMB LIFE 2021年第4期73卷 690-704页

作者： Zhu, Jinming Han, Shichao Dalian Univ Affiliated Zhongshan Hosp Dept Oncol Dalian Peoples R China Dalian Med Univ Affiliated Hosp 2 Dept Gynecol 467 Zhong Shan Rd Dalian 116021 Liaoning Peoples R China

Dysfunction of histone deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened-out miRNA target. Microarray analysis and RT-qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR-223, upregulated in CC, was regulated by HDAC10 through histone acetylation, while miR-223 inhibited the effects of HDAC10 overexpression in CC. miR-223 targeted the 3 '-UTR of thioredoxin interacting protein (txnip) and suppressed its expression, leading to increased CC development in vitro and in vivo. txnip overexpression impaired Wnt/beta-catenin pathway activity in CC cells.

关键词： cervical cancer HDAC10 microRNA-223 txnip Wnt/beta-catenin pathway

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The pivotal role of extracellular signal-regulated kinase in gap junction mediated regulation of txnip

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CELLULAR SIGNALLING 2017年 38卷 116-126页

作者： Gao, Shan Zhang, Xiling Gao, Kun Zhang, Zhen Huang, Yanru Yoda, Ryuichi Yao, Jian China Med Univ Shengjing Hosp Dept Obstet & Gynecol Shenyang 110004 Liaoning Peoples R China Univ Yamanashi Interdisciplinary Grad Sch Med & Engn Div Mol Signaling Dept Adv Biomed Res Chuo Yamanashi 4093898 Japan Nanjing Univ Chinese Med Affiliated Hosp Dept Nephrol Nanjing Jiangsu Peoples R China

Gap junctions (GJs) play a major role in the control of cell structure, function, and metabolism. However, the molecular mechanisms involved are still poorly understood. Given that thioredoxin-interacting protein (txnip) regulates a broad range of cellular processes, we tested the possible involvement of txnip. Disruption of GJs with several chemical GJ inhibitors or connexin43 (Cx43) siRNA potently suppressed txnip, which was preceded by an activation of extracellular signal-regulated kinase (ERK). Inhibition of ERK or its upstream kinase with chemical inhibitors prevented the reduction of txnip. On the contrary, activation of ERK with mitogens or phosphatase inhibitors reproduced the suppressive effects of GJs. Further analysis revealed that dysfunction of GJs promoted txnip phosphorylation, ubiquitination, and degradation, whereas inhibition of ERK exerted the opposite effects. Moreover, inhibition of GJs elevated Glutl and enhanced cell resistance to ER stress in a similar way to txnip downregulation. Collectively, our study thus characterizes ERK-mediated suppression of txnip as a presently unreported mechanism by which GJs regulate cell behaviors.

关键词： Gap junctions txnip Extracellular signal-regulated kinase (ERK) Glutl Cell death

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Extracellular Matrix Remodeling Regulates Glucose Metabolism through txnip Destabilization

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CELL 2018年第1期175卷 117-+页

作者： Sullivan, William J. Mullen, Peter J. Schmid, Ernst W. Flores, Aimee Momcilovic, Milica Sharpley, Mark S. Jelinek, David Whiteley, Andrew E. Maxwell, Matthew B. Wilde, Blake R. Banerjee, Utpal Coller, Hilary A. Shackelford, David B. Braas, Daniel Ayer, Donald E. Vallim, Thomas Q. de Aguiar Lowry, William E. Christofk, Heather R. Univ Calif Los Angeles David Geffen Sch Med Dept Biol Chem Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Mol & Med Pharmacol Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Mol Cell & Dev Biol Los Angeles CA 90095 USA Univ Calif Los Angeles Mol Biol Inst Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Pulm & Crit Care Med Los Angeles CA 90095 USA Univ Utah Huntsman Canc Inst Dept Oncol Sci Salt Lake City UT 84112 USA Univ Calif Los Angeles Eli & Edythe Broad Ctr Regenerat Med & Stem Cell Los Angeles CA 90095 USA Univ Calif Los Angeles Metabol Ctr Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Med Los Angeles CA 90095 USA Univ Calif Los Angeles Jonsson Comprehens Canc Ctr Los Angeles CA 90095 USA

The metabolic state of a cell is influenced by cellextrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinasemediated induction of the mRNA decay factor ZFP36, which targets txnip transcripts for degradation. Because txnip promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasmamembrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

关键词： extracellular matrix glucose metabolism hyaluronidase receptor tyrosine kinase signaling ZFP36 mRNA degradation txnip GLUT1 trafficking cell migration cell biology

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BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting txnip in cutaneous melanoma

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APOPTOSIS 2020年第3-4期25卷 179-191页

作者： Li, Kezhu Tang, Mingrui Tong, Shuang Wang, Chenchao Sun, Qiang Lv, Mengzhu Sun, Xu Wang, Ting Jin, Shifeng China Med Univ Affiliated Hosp 1 Dept Plast Surg 155 Nanjing North St Shenyang 110001 Liaoning Peoples R China

Treatment of advanced BRAF(V600)-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted txnip which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAF(V600)-mutant melanoma patients.

关键词： miR-152-5p Melanoma Metastasis BRAFi txnip

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A potential mechanism of metformin-mediated regulation of glucose homeostasis: Inhibition of Thioredoxin-interacting protein (txnip) gene expression

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CELLULAR SIGNALLING 2012年第8期24卷 1700-1705页

作者： Chai, Tin Fan Hong, Shin Yee He, Hongpeng Zheng, Liling Hagen, Thilo Luo, Yan Yu, Fa-Xing Zhejiang Univ Sch Basic Med Sci Hangzhou 310058 Zhejiang Peoples R China Natl Univ Singapore Dept Biochem Singapore 117597 Singapore Univ Calif San Diego Dept Pharmacol La Jolla CA 92093 USA Univ Calif San Diego Moores Canc Ctr La Jolla CA 92093 USA

Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the txnip gene promoter is reduced, suggesting that the transcription of the txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes. (C) 2012 Elsevier Inc. All rights reserved.

关键词： Metformin txnip Glycolysis Diabetes OXPHOS

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TLR4/NF-κB axis induces fludarabine resistance by suppressing txnip expression in acute myeloid leukemia cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2018年第1期506卷 33-40页

作者： Huy, Hangsak Kim, Tae-Don Kim, Won Sam Kim, Dong Oh Byun, Jae-Eun Kim, Mi Jeong Park, Young-Jun Yoon, Suk Ran Noh, Ji-Yoon Lee, Jungwoon Lee, Kyoo-Hyung Choi, Inpyo Jung, Haiyoung KRIBB Immunotherapy Convergence Res Ctr Daejeon 34141 South Korea Univ Sci & Technol Dept Funct Genom Daejeon 34113 South Korea Chungbuk Natl Univ Sch Life Sci Dept Biochem Cheongju 28644 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept Internal MedHematol Sect Seoul 05505 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept Internal MedOncol Sect Seoul 05505 South Korea

Overcoming drug resistance is one of key issues in treating refractory acute myeloid leukemia (AML). The Toll-like receptor 4 (TLR4) signaling pathway is involved in many aspects of biological functions of AML cells, including the regulation of pro-inflammatory cytokine products, myeloid differentiation, and survival of AML cells. Thus, targeting TLR4 of AML patients for therapeutic purposes should be carefully addressed. In this regard, we investigated the possible role of TLR4 as a regulatory factor against fludarabine (FA) cytotoxicity activity. Here, we identified the differential expression of TLR4 and CD14 receptors in AML cell lines and examined their relationship to FA sensitivity. We found that the stimulation of TLR4 with lipopolysaccharide (LPS) in a TLR4-expressing cell line, THP-1, increased cell viability under FA treatment condition and showed that TLR4 stimulation overcame FA sensitivity through the activation of NF-kappa B, which subsequently upregulated several anti-apoptotic genes. The inhibition of TLR4/NF-kappa B signaling could partially or completely reverse LPS-induced cell survival under FA treatment conditions. Interestingly, we found that the expression of thioredoxin-interacting protein (txnip), a well-known tumor suppressor, was induced by FA treatment;however, it was suppressed by LPS treatment. Furthermore, the expression level of txnip was critical for FA-induced cytotoxicity or LPS-induced FA resistance of THP-1 cells. Our data suggest that txnip plays an important role in FA-induced cytotoxicity and TLR4/NF-kappa B-mediated FA resistance of AML cells. Therefore, txnip may be a potential therapeutic target for AML treatment. (C) 2018 Elsevier Inc. All rights reserved.

关键词： Fludarabine TLR4 NF-kappa B txnip AML

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MiRNA-338-5p reduced inflammation through txnip/NLRP3 inflammasome axis by CXCR4 in DSS-induced colitis

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MOLECULAR & CELLULAR TOXICOLOGY 2020年第2期16卷 149-158页

作者： Huang, Xunru Lin, Yijuan Zheng, Xueyan Wang, Chengdang Fujian Med Univ Affiliated Hosp 1 Dept Gastroenterol 20 Cha Zhong Rd Fuzhou 350004 Fujian Peoples R China Fujian Med Univ Digest Dis Lab Fuzhou 350004 Fujian Peoples R China

Backgrounds miRNAs, about 20-25 bases in length, are short-chain non-coding RNAs existing in the body, which are widely involved in the biological regulation of the organism. miRNAs inhibit the expression of target genes by specifically binding to target genes, thereby exerting biological effects. Methods We investigated the function of miRNA-338-5p on inflammation and its possible mechanisms in colitis Results In DSS-induced colitis model, we found that miRNA-338-5p expression was reduced. Therefore, down-regulation of miRNA-338-5p increased inflammation and induced CXCR4, txnip, and NLRP3 protein expression in in vitro model. Meanwhile, over-expression of miRNA-338-5p reduced inflammation and suppressed CXCR4, txnip, and NLRP3 protein expression in in vitro model. Therefore, miRNA-338-5p may possess anti-inflammatory effects in colitis. However, si-CXCR4 reduced the anti-inflammatory effects of miRNA-338-5p in invitro model. Then, si-NLRP3 also reduced the anti-inflammatory effects of miRNA-338-5p in in vitro model. These results showed that miRNA-338-5p reduced inflammation in colitis through the txnip/NLRP3 inflammasome axis by CXCR4. Conclusion MiRNA-338-5p may potentially serve as novel therapeutic avenues for colitis.

关键词： miRNA-338-5p txnip NLRP3 CXCR4 Colitis

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MicroRNA-20a negatively regulates expression of NLRP3-inflammasome by targeting txnip in adjuvant-induced arthritis fibroblast-like synoviocytes

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JOINT BONE SPINE 2016年第6期83卷 695-700页

作者： Li, Xiao-Feng Shen, Wen-Wen Sun, Ying-Yin Li, Wan-Xia Sun, Zheng-Hao Liu, Yan-Hui Zhang, Lei Huang, Cheng Meng, Xiao-Ming Li, Jun Anhui Med Univ Anhui Key Lab Bioact Nat Prod Sch Pharm Meishan Rd 81 Hefei 230032 Peoples R China Anhui Med Univ Inst Liver Dis Meishan Rd 81 Hefei 230032 Peoples R China Anhui Inst Innovat Drugs Meishan Rd 81 Hefei 230032 Peoples R China

Objectives: Rheumatoid arthritis (RA) is a heterogenic and systemic autoimmune disease characterized by synovitis and joint structural damage. However, the pathogenesis of RA is still obscure. It has been reported microRNA-20a (miRNA-20a) was significantly associated with the regulation of pro inflammatory cytokines release in RA FLS. The purpose of this study was to explore the function and underlying mechanisms of miRNA-20a on NLRP3-inflammasome in adjuvant-induced arthritis (AA) fibroblast-like synoviocytes (FLSs) in vitro. Methods: In this study, using a combination of Western blotting, Q-PCR, and ELISA analysis, we investigated the influence and function of miRNA-20a on NLRP3-inflammasome by targeting txnip in AA FLSs. Results: In the present study, the expression of NLRP3-inflammasome was significant up-regulated in AA model in vitro. Our study indicated that silence of NLRP3 down-regulated the expression of NLRP3-inflammasome and the secretion of IL-1 beta and MMP-1. Moreover, over-expression of miR-20a decreased formation of NLRP3-inflammasome, including NLRP3, ASC and caspase-1, and suppressed the secretion of IL-1 beta and MMP-1, along with down-regulated the expressions of txnip in primary FLSs isolated from AA. With the combined use of prediction programs and luciferase assay, the rat txnip mRNA 3'UTR predicted to be targeted by miR-20a. Similarly, inhibitor txnip expression by txnip-siRNA markedly repressed formation of NLRP3-inflammasome and the secretion of IL-1 beta and MMP-1. Conclusion: Taken together, these results indicate that miR-20a may play a pivotal role in the NLRP3-inflammasome by targeted inhibit txnip expression in AA FLSs. (C) 2016 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

关键词： MicroRNA-20a txnip NLRP3-inflammasome RA

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mROS-txnip axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI

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INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 2018年 98卷 43-53页

作者： Wen, Yi Liu, Yi-Ran Tang, Tao-Tao Pan, Ming-Ming Xu, Sheng-Chun Ma, Kun-Ling Lv, Lin-Li Liu, Hong Liu, Bi-Cheng Southeast Univ Zhongda Hosp Inst Nephrol Sch Med Nanjing Jiangsu Peoples R China

Ischemia/reperfusion (I/R) is a critical risk factor for acute kidney injury (AKI). Recent studies provided evidence that tubular epithelial cells (TEC)-associated inflammation aggravates kidney injury and impairs tissue repair after I/R injury. Here we demonstrated that the Nod-like receptor protein 3 (NLRP3) inflammasome is activated by mitochondrial reactive oxygen species (mROS) during I/R injury via direct interactions between the inflammasome and thioredoxin-interacting protein (txnip). Firstly, we found that NLRP3 inflammasome activation was induced by I/R injury, peaking at day 3 after reperfusion. Consistent with this observation, NLRP3 deletion significantly attenuated I/R-induced kidney damage and markers of inflammasome activation. Then, we observed mitochondrial dysfunction, characterized by ultrastructural changes and cytochrome C (Cyt c) redistribution. Mitochondria-targeted antioxidant MitoTEMPO prevented mROS overproduction and the decline in mitochondrial membrane potential (MMP) in vitro. MitoTEMPO treatment also inhibited NLRP3 inflammasome activation and co-localization of NLRP3 and txnip after simulated ischemia/reperfusion (SI/R) injury. Finally, we transfected HK-2 cells with txnip siRNA to explore the role of txnip in mROS-induced NLRP3 inflammasome activation. We found that txnip siRNA significantly inhibited NLRP3 inflammasome activation. These results demonstrate that NLRP3 inflammasome is activated through the mROS-txnip-NLRP3 pathway and provide a potential therapeutic target in ischemic AKI.

关键词： Ischemic AKI NLRP3 inflammasome Mitochondrial dysfunction txnip

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