Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Background: Alterations in the thioredoxin (TRX) antioxidant system have been implicated in the pathogenesis of cardiac injury, particularly in the diabetic setting. While constitutively present, TRX activity is reduced by the presence of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We hypothesized that by increasing TxnIP, diabetes may reduce TRX activity and contribute to oxidative stress. Methods: Cell culture studies were performed using the H9C2 rat cardiomyoblast cell line and neonatal cardiomyocytes isolated from 1 day old Sprague Dawley rat neonates. In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as a measure of oxidative stress. Results: In- vitro, high glucose (25mmol/l) resulted in increased TxnIP mRNA expression in both neonatal cardiomyocytes as well as H92C cells (2.21 ± 0.6 v 1.00 ± 0.19, p<0.05 compared to normoglycaemic conditions) with a 45% reduction in TRX activity (0.11 ± 0.01 v 0.061± 0.003, p<0.01). In-vivo, diabetes led to a 250% rise in TxnIP mRNA expression compared to control (2.54 ± 0.5 v 1.00 ± 0.11, p<0.001) that was accompanied by a three fold rise in urinary 8-OHdG (680 ± 280 v 1395 ± 391 ng/ml, p<0.001). Conclusion: In both the in vitro and in vivo settings, high glucose leads to TxnIP over-expression associated with reduced TRX activity thereby increasing oxidative stress and implicating this system in the pathogenesis of the cardiac dysfunction that characterizes the diabetic state. Pharmacological manipulation of the TRX-TxnIP system may represent a novel target to reduce diabetic complications.

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A Pan-cancer Analysis of Thioredoxin-interacting Protein as an Immunological and Prognostic Biomarker

10.21203/rs.3.rs-1243997/v1 ◽

2022 ◽

Author(s):

Xuxue Guo ◽

Mei Huang ◽

Haonan Zhang ◽

Qianhui Chen ◽

Ying Hu ◽

...

Keyword(s):

Immune Cell ◽

Prognostic Biomarker ◽

Redox Homeostasis ◽

Critical Role ◽

The Cancer Genome Atlas ◽

Inflammasome Activation ◽

Post Translational Modification ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Pan Cancer

Abstract BackgroundThe critical role of thioredoxin-interacting protein (TXNIP) in cellular sulfhydryl redox homeostasis and inflammasome activation is already widely known, however, no pan-cancer analysis is currently available. MethodsWe thus first explored the potential roles of TXNIP across thirty-three tumors mainly based on The Cancer Genome Atlas and Gene Expression Omnibus datasets. ResultsTXNIP is lowly expressed in most cancers, and distinct associations exist between TXNIP expression and the prognosis of tumor patients. TXNIP expression was associated with tumor mutational burden, microsatellite instability, mismatch repair genes, tumor infiltrating immune cell abundance as well as cancer-associated fibroblasts. Moreover, ubiquitin mediated proteolysis, protein post-translational modification and other related pathways were involved in the functional mechanisms of TXNIP. ConclusionsOur first pan-cancer study offers a relatively comprehensive understanding of the carcinostatic roles of TXNIP across different tumors. And this molecule may be considered as a potential immunological and prognostic biomarker.

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Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer’s Disease Brain

Journal of Alzheimer s Disease ◽

10.3233/jad-180814 ◽

2019 ◽

Vol 68 (1) ◽

pp. 255-265 ◽

Cited By ~ 16

Author(s):

Lexiao Li ◽

Saifudeen Ismael ◽

Sanaz Nasoohi ◽

Kazuko Sakata ◽

Francesca-Fang Liao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Nlrp3 Inflammasome Activation

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NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia

Journal of Diabetes Research ◽

10.1155/2015/504761 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Pan Gao ◽

Fang-Fang He ◽

Hui Tang ◽

Chun-Tao Lei ◽

Shan Chen ◽

...

Keyword(s):

Nadph Oxidase ◽

Antioxidant Defense System ◽

Inflammasome Activation ◽

Podocyte Injury ◽

Interacting Protein ◽

Nalp3 Inflammasome ◽

Thioredoxin Interacting Protein ◽

A Subunit ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression ofgp91phox, a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1βproduction and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG-exposed podocytes genetic deletion of TXNIP by shRNA reversedgp91phoxoverexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN.Erratum to “NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia”

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Diabetes impairs exercise training-associated thioredoxin response and glutathione status in rat brain

Journal of Applied Physiology ◽

10.1152/japplphysiol.91252.2008 ◽

2009 ◽

Vol 106 (2) ◽

pp. 461-467 ◽

Cited By ~ 40

Author(s):

Zekine Lappalainen ◽

Jani Lappalainen ◽

Niku K. J. Oksala ◽

David E. Laaksonen ◽

Savita Khanna ◽

...

Keyword(s):

Oxidative Stress ◽

Exercise Training ◽

Redox Status ◽

Antioxidant Defenses ◽

Sod Activity ◽

Interacting Protein ◽

Glutathione Peroxidase 1 ◽

Thioredoxin Interacting Protein ◽

Streptozotocin Induced Diabetes ◽

Diabetic Brain

Regular exercise plays an important preventive and therapeutic role in oxidative stress-associated diseases such as diabetes and its complications. Thiol antioxidants including thioredoxin (TRX) and glutathione (GSH) have a crucial role in controlling cellular redox status. In this study, the effects of 8 wk of exercise training on brain TRX and GSH systems, and antioxidant enzymes were tested in rats with or without streptozotocin-induced diabetes. We found that in untrained animals, the levels of TRX-1 (TRX1) protein and activity, and thioredoxin-interacting protein (TXNip) were similar in diabetic and nondiabetic animals. Exercise training, however, increased TRX1 protein in nondiabetic animals without affecting TXNip levels, whereas diabetes inhibited the effect of training on TRX1 protein and also increased TXNip mRNA. In addition, the proportion of oxidized glutathione (GSSG) to total GSH was increased in animals with diabetes, indicating altered redox status and possibly increased oxidative stress. Glutathione peroxidase-1 (GPX1) levels were not affected by diabetes or exercise training, although diabetes increased total GPX activity. Both diabetes and exercise training decreased glutathione reductase (GRD) activity and cytosolic superoxide dismutase (Cu,Zn-SOD) levels. Nevertheless, diabetes or training had no effect on Cu,Zn-SOD mRNA, Mn-SOD protein, total SOD activity, or catalase mRNA, protein, or activity. Our findings suggest that exercise training increases TRX1 levels in brain without a concomitant rise in TXNip, and that experimental diabetes is associated with an incomplete TRX response to training. Increased oxidative stress may be both a cause and a consequence of perturbed antioxidant defenses in the diabetic brain.

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The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

International Journal of Molecular Sciences ◽

10.3390/ijms22041693 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1693

Author(s):

Alison Domingues ◽

Julia Jolibois ◽

Perrine Marquet de Rougé ◽

Valérie Nivet-Antoine

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

Therapeutic Target ◽

Redox Status ◽

Interacting Protein ◽

Cellular Redox ◽

Thioredoxin Interacting Protein ◽

Potential Biomarker ◽

Ischemic Diseases

Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.

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