Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response

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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Thioredoxin-interacting protein links oxidative stress to inflammasome activation

Nature Immunology ◽

10.1038/ni.1831 ◽

2009 ◽

Vol 11 (2) ◽

pp. 136-140 ◽

Cited By ~ 1336

Author(s):

Rongbin Zhou ◽

Aubry Tardivel ◽

Bernard Thorens ◽

Inpyo Choi ◽

Jürg Tschopp

Keyword(s):

Oxidative Stress ◽

Inflammasome Activation ◽

Interacting Protein ◽

Thioredoxin Interacting Protein

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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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Nitrosative/Oxidative Stress Conditions Regulate Thioredoxin-Interacting Protein (TXNIP) Expression and Thioredoxin-1 (TRX-1) Nuclear Localization

PLoS ONE ◽

10.1371/journal.pone.0084588 ◽

2013 ◽

Vol 8 (12) ◽

pp. e84588 ◽

Cited By ~ 20

Author(s):

Fernando Toshio Ogata ◽

Wagner Luiz Batista ◽

Adriano Sartori ◽

Tarsis Ferreira Gesteira ◽

Hiroshi Masutani ◽

...

Keyword(s):

Oxidative Stress ◽

Nuclear Localization ◽

Stress Conditions ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Thioredoxin 1

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Neuroprotective Activity of Coptisine fromCoptis chinensis(Franch)

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/827308 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Thomas Friedemann ◽

Udo Schumacher ◽

Yi Tao ◽

Alexander Kai-Man Leung ◽

Sven Schröder

Keyword(s):

Oxidative Stress ◽

Neuroprotective Effect ◽

Neuroprotective Activity ◽

Important Ingredient ◽

Promising Candidate ◽

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Chinese Herbal ◽

Tert Butylhydroperoxide ◽

Study Results

Coptis chinensisrhizomes (CR) are one important ingredient of traditional Chinese herbal formulas such as San-Huang-Xie-Xin-Tang which is used for treatment of cardiovascular and neurodegenerative diseases. Recent studies suggest that the extract of CR might be a potential therapeutic agent for amelioration of neurological disorders associated with oxidative stress. In the present study we aimed at revealing the main active compound(s) of the CR extract and at investigating the mechanism of action. Four main alkaloids of the CR extract (berberine, coptisine, jatrorrhizine, and palmatine) were selected for this study. Results showed that out of those alkaloids only pretreatment with coptisine significantly attenuated tert-butylhydroperoxide induced reduction of cell viability, increased rate of apoptosis, and declined mitochondrial membrane potential. Elisa assay and quantitative real-time PCR analyses revealed that thioredoxin-interacting protein (TXNIP) gene expression was downregulated by coptisine, which could explain the neuroprotective effect, hypothetically, by strengthening the thioredoxin defense system against oxidative stress and attenuation of apoptosis signal-regulating kinase (Ask1) mediated apoptotic signaling. A comparison between coptisine and CR extract identified coptisine as the main single component responsible for the neuroprotective effect. Based on the results the CR extract and coptisine are promising candidate agents for prevention or improvement of diabetic neuropathy and neurodegenerative disorders.

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